U.S. patent application number 11/418353 was filed with the patent office on 2006-09-14 for n-substituted piperidine derivatives as serotonin receptor agents.
Invention is credited to Carl-Magnus Andersson, Alma Fejzic, Eva Louise Hansen, Jan Pawlas, Nathalie Schlienger.
Application Number | 20060205722 11/418353 |
Document ID | / |
Family ID | 30000684 |
Filed Date | 2006-09-14 |
United States Patent
Application |
20060205722 |
Kind Code |
A1 |
Andersson; Carl-Magnus ; et
al. |
September 14, 2006 |
N-substituted piperidine derivatives as serotonin receptor
agents
Abstract
Disclosed herein are compounds of Formula I, ##STR1## or a
pharmaceutically acceptable salt, amide, ester, or prodrug thereof.
Also disclosed are methods of inhibiting an activity of a monoamine
receptor comprising contacting the monoamine receptor or a system
containing the monoamine receptor with an effective amount of one
or more of the compounds of Formula I. Disclosed are also methods
of inhibiting an activation of a monoamine receptor comprising
contacting the monoamine receptor or a system containing the
monoamine receptor with an effective amount of one or more of the
compounds of Formula I. Furthermore, methods of treating psychotic
disease using a compound of Formula I are disclosed.
Inventors: |
Andersson; Carl-Magnus;
(Hjarup, SE) ; Schlienger; Nathalie;
(Frederiksberg, DK) ; Fejzic; Alma;
(Frederiksberg, DK) ; Hansen; Eva Louise; (Hojby,
DK) ; Pawlas; Jan; (Frederiksberg, DK) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
30000684 |
Appl. No.: |
11/418353 |
Filed: |
May 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11299566 |
Dec 12, 2005 |
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11418353 |
May 3, 2006 |
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10601070 |
Jun 20, 2003 |
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11299566 |
Dec 12, 2005 |
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60391269 |
Jun 24, 2002 |
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Current U.S.
Class: |
514/235.2 ;
514/270; 514/326; 544/128; 544/310; 546/207; 546/208; 546/209;
546/210 |
Current CPC
Class: |
A61P 9/12 20180101; C07D
249/08 20130101; A61P 25/16 20180101; A61P 43/00 20180101; A61P
25/32 20180101; A61P 25/36 20180101; A61P 25/18 20180101; A61P
25/22 20180101; C07D 405/04 20130101; A61P 9/10 20180101; C07D
405/06 20130101; C07D 405/14 20130101; A61P 15/10 20180101; A61P
25/20 20180101; A61P 25/00 20180101; A61P 25/24 20180101; A61P
25/34 20180101; C07D 413/06 20130101; C07D 231/12 20130101; C07D
211/58 20130101; C07D 401/06 20130101; A61P 9/00 20180101; A61P
7/02 20180101; A61P 25/14 20180101; A61P 15/08 20180101; A61P 25/28
20180101; C07D 411/06 20130101; A61P 25/02 20180101; C07D 211/62
20130101; C07D 233/56 20130101 |
Class at
Publication: |
514/235.2 ;
514/270; 514/326; 544/128; 544/310; 546/207; 546/208; 546/209;
546/210 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/454 20060101 A61K031/454; C07D 413/02
20060101 C07D413/02; C07D 409/02 20060101 C07D409/02; C07D 405/02
20060101 C07D405/02; C07D 403/02 20060101 C07D403/02; C07D 401/02
20060101 C07D401/02 |
Claims
1. A compound of Formula I ##STR19## or a pharmaceutically
acceptable salt, amide, ester, or prodrug thereof, wherein R.sup.1
is selected from the group consisting of optionally substituted
heterocyclyl, and optionally substituted
(heterocyclyl)C.sub.1-6-alkyl; R.sup.2 and R.sup.3 are
independently selected from the group consisting of hydrogen,
C.sub.1-6-alkyl and halogen or such that R.sup.2 together with
R.sup.3 forms a ring; m is selected from the group consisting of 0,
1, and 2; n is selected from the group consisting of 1, 2, and 3;
Ar.sup.1 is an optionally substituted aryl or heteroaryl; W is
selected from the group consisting of oxygen and sulfur; X is
selected from the group consisting of optionally substituted
methylene, optionally substituted ethylene, optionally substituted
propylene, optionally substituted vinylene, and CH.sub.2N(R.sup.N),
wherein R.sup.N is selected from hydrogen and C.sub.1-6-alkyl; and
Ar.sup.2 is an optionally substituted aryl or heteroaryl.
2. The compound of claim 1, wherein said heterocyclyl or said
(heterocycly)C.sub.1-6-alkyl is optionally substituted with one or
more groups selected from the group consisting of hydrogen,
halogen, hydroxy, alkoxy, alkyl, and amino.
3. The compound of claim 1, wherein said heterocyclyl is selected
from the group conssiting of tetrahydrothiopyran, 4H-pyran,
tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin,
1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin,
1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,
succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
hydantoin, dihydrouracil, morpholine, trioxane,
hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,
pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,
pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole,
1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline,
isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,
thiazolidine, and 1,3-oxathiolane.
4. The compound of claim 1, wherein R.sup.1 is selected from the
group consisting of an optionally substituted (heterocyclyl)methyl,
an optionally substituted (heterocyclyl)ethyl, or an optionally
substituted (heterocyclyl)propyl.
5. The compound of claim 1, wherein R.sup.2 and R.sup.3 are
hydrogen, m is 1, n is 1, and W is oxygen.
6. The compound of claim 1, wherein Ar.sup.1 is an optionally
substituted aryl, selected from the group consisting of
alkyl-substituted phenyl, alkoxy-substituted phenyl,
halogen-substituted phenyl, hydroxy-substituted phenyl and
amino-substituted phenyl, wherein said alkyl is selected from the
group consisting of methyl, ethyl, propyl, n-butyl, sec-butyl and
tert-butyl, and said alkoxy is selected from the group consisting
of methoxy, ethoxy, propxy, n-butoxy, sec-butoxy, and
tert-butoxy.
7. The compound of claim 1, wherein Ar.sup.1 is 4-substituted
aryl.
8. The compound of claim 7, wherein Ar.sup.1 is halogen-substituted
phenyl.
9. The compound of claim 1, wherein X is selected from the group
consisting of optionally substituted methylene, optionally
substituted ethylene, and CH.sub.2N(R.sup.N).
10. The compound of claim 9, wherein X is CH.sub.2N(R.sup.N).
11. The compound of claim 1, wherein Ar.sup.2 is an aryl optionally
substituted with a substituent selected from the group consisting
of alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, heteroaryl,
and heterocyclyl.
12. The compound of claim 1, wherein Ar.sup.2 is 4-substituted
aryl.
13. The compound of claim 11, wherein said substituent on Ar.sup.2
is selected from the group consisting of chloro, fluoro, hydroxy,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,
tert-butoxy, trifluoromethoxy, N-morpholinyl, N-pyrrolidinyl,
N-pyrazolyl, N-triazolyl and 2-oxopyrrolidinyl.
14. The compound of claim 1, wherein said compound is selected from
the group consisting of:
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4-
-isobutoxybenzyl)carbamide, hydrochloride;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-
-hydroxy-2-methylpropoxy)phenyl]acetamide, tartrate;
N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluoroben-
zyl)-2-(4-isobutoxyphenyl)acetamide, dihydrochloride;
1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino}piperidin-1--
yl)propyl]piperidine-4-carboxylic acid methyl ester,
dihydrochloride;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolidin-2-yl-
)ethyl]piperidin-4-yl}acetamide, dioxalate;
N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl}-N-(4-fluoroben-
zyl)-2-(4-isobutoxyphenyl)acetamide, dioxalate;
N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperidin-4-yl-
}-2-(4-isobutoxyphenyl)acetamide, dioxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-{1-[3-(2-methylpiperidin-1-yl)p-
ropyl]piperidin-4-yl}acetamide, dioxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-[1-(3-pyrrolidin-1-yl-propyl)pi-
peridin-4-yl]acetamide, dioxalate;
N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobe-
nzyl)-2-(4-isobutoxyphenyl)acetamide, dioxalate;
N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]piperidi-
n-4-yl}-2-(4-isobutoxyphenyl)acetamide, dioxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-o-
xazolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate;
N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)N-{1-[3-(4-(S)-isopropyl-
-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate;
N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-y-
l)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide, oxalate;
N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]-
piperidin-4-yl}-2-(4-propoxyphenyl)acetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl-
]-2-(4-isobutoxyphenyl)acetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl-
]-2-(4-propoxyphenyl)acetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pr-
opoxyphenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4-i-
sobutoxybenzyl)carbamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fl-
uorophenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-p-tol-
ylacetamide, tartrate;
2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-flu-
orobenzyl)acetamide, tartrate;
2-(2,3-Dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-
-yl}-N-(4-fluorobenzyl)acetamide, tartrate;
N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluoro-
benzyl)-2-(4-isobutoxyphenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tr-
ifluoromethylphenyl)acetamide, tartrate;
2-(4-Cyanophenyl)-N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-flu-
orobenzyl)acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl-
)ethyl]piperidin-4-yl}acetamide, hydrochloride;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)e-
thyl]piperidin-4-yl}acetamide, hydrochloride;
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[2-(2-oxo-imidazolidin-1-y-
l)ethyl]piperidin-4-yl}acetamide, hydrochloride;
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dih-
ydro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;
hydrochloride;
N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-2-
-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide, hydrochloride;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(2-oxo-2,3-dihydrobenzoimi-
dazol-1-yl)propyl]piperidin-4-yl}-acetamide, hydrochloride;
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[4-(2-oxo-2,3-dihydrobenzo-
imidazol-1-yl)butyl]piperidin-4-yl}acetamide, hydrochloride;
N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-N-
-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide, hydrochloride;
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4-
-isopropoxy-benzyl)carbamide, oxalate;
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxyphenyl}N-(4--
methylbenzyl)acetamide, hydrochloride;
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4--
isobutoxyphenyl)acetamide, hydrochloride;
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyphenyl)-N-
-(4-methylbenzyl)acetamide, hydrochloride;
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4--
propoxyphenyl)acetamide, tartrate;
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1,3-diox-
olane-2-yl)ethyl]piperidin-4-yl}carbamide, oxalate;
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl-propyl)-
piperidin-4-yl]carbamide, oxalate;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl)piperi-
din-4-yl]acetamide, dihydrochloride;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholin-4-ylpropyl)piper-
idin-4-yl]acetamide, dihydrochloride;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-morpholin-4-ylpropyl)pip-
eridin-4-yl]acetamide, dihydrochloride;
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-[1-(3-morpholin-4-yl-propyl)p-
iperidin-4-yl]acetamide, dihydrochloride;
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl-propyl)-
piperidin-4-yl]carbamide, oxalate;
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropyl-2-oxa-
zolidinon-1-yl-propyl)piperidin-4-yl]carbamide, tartrate;
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{1-[2-(2,5,5-trimethyl-1,3-d-
ioxan-2-yl)ethyl]}piperidin-4-yl]carbamide, oxalate;
N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(-
4-isopropoxybenzyl)carbamide, oxalate;
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-N'--
(4-isopropoxybenzyl)carbamide, oxalate;
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{[2-(1-methyl
pyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide, oxalate;
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(-
4-isobutoxyphenyl)acetamide, oxalate;
N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyp-
henyl)acetamide, tartrate;
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(-
4-fluorophenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fl-
uorophenyl)acetamide, tartrate:
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tr-
ifluoromethoxyphenyl)acetamide, tartrate:
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pr-
opoxyphenyl)acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-yl)piper-
idin-4-yl]acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-ylmethyl-
)piperidin-4-yl]acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-4-yl)et-
hyl]piperidin-4-yl]acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)piperidi-
n-4-yl]acetamide, tartrate;
N-[1-((S)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide, tartrate;
N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)--
2-(4-isobutoxyphenyl)acetamide, tartrate;
2-(4-Benzyloxyphenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-
-fluorobenzyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-hy-
droxyphenylacetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-me-
thoxyphenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
opropylphenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tr-
ifluoromethoxy-phenyl)acetamide, tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-et-
hoxyphenyl)-acetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
opropoxyphenyl)-acetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-pheny-
lacetamide, oxalate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-
-fluoroethoxy)-phenyl]acetamide, oxalate;
N-{1-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluoroben-
zyl)-2-(4-isobutoxyphenyl)acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-
-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxol-
an-2-yl)ethyl]piperidin-4-yl}acetamide, oxalate;
N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobe-
nzyl)-2-(4-isobutoxyphenyl)acetamide, oxalate;
N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidi-
n-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isopropylphenyl}N-{1-[2-((S)-4-methyl-1,3-dioxola-
n-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]
piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dio-
xan-2-yl)ethyl] piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dioxolan-2-
-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-yl)propy-
l]piperidin-4-yl}acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-propyl)pi-
peridin-4-yl}-acetamide, dihydrochloride;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-2-yloxy-
)ethyl]-piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-piperidin-1-yl)pr-
opyl]piperidin-4-yl}acetamide;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-1-yl)p-
ropyl]piperidin-4-yl}acetamide, hydrochloride;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl-2-oxo-o-
xazolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-3-yl)p-
ropyl]piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-oxo-oxaz-
olidin-3-yl)propyl]piperidin-4-yl}acetamide, tartrate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-ethyl-2-oxo-oxazo-
lidin-3-yl)-propyl]piperidin-4-yl}acetamide, oxalate;
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-yl)eth-
yl]piperidin-4-yl}acetamide, L-tartrate;
2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-flu-
orobenzyl)-acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutylamino-phenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pr-
opylamino-phenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(1-
-nitropropyl)-phenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-
-oxopyrrolidin-1-yl)phenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutylsulfanyl-phenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-io-
dophenyl)-acetamide, L-tartrate;
2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-flu-
orobenzyl)-acetamide, L-tartrate;
2-[4-(1-Hydroxyiminoethyl)phenyl]-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidi-
n-4-yl}-N-(4-fluorobenzyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-mo-
rpholin-4-yl-phenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-py-
razol-1-ylphenyl)acetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-2-(4-isobutoxyphenylacetamide, L-tartrate;
N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-py-
razol-1-ylphenyl)acetamide, L-tartrate;
N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)--
2-(4-isobutoxyphenyl)acetamide, tartrate; and
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(1-
,2,4-triazol-4-yl)phenyl]acetamide, L-tartrate.
15. A pharmaceutical composition comprising at least one compound
of claim 1 and a pharmaceutically acceptable carrier, eluent, or
excipient.
16. A method of inhibiting an activity of a monoamine receptor
comprising contacting the monoamine receptor or a system containing
the monoamine receptor with an amount of one or more of the
compounds of claim 1 that is effective in inhibiting the activity
of the monoamine receptor.
17. The method of claim 16, wherein the monoamine receptor is a
serotonin receptor.
18. The method of claim 17, wherein the serotonin receptor is the
5-HT2A subclass.
19. The method of claim 17, wherein the serotonin receptor is in
the central nervous system.
20. The method of claim 17, wherein the serotonin receptor is in
the peripheral nervous system.
21. The method of claim 17, wherein the serotonin receptor is in
blood cells or platelets.
22. The method of claim 17, wherein the serotonin receptor is
mutated or modified.
23. The method of claim 16, wherein the activity is signaling
activity.
24. The method of claim 16, wherein the activity is
constitutive.
25. The method of claim 16, wherein the activity is associated with
serotonin receptor activation.
26. A method of inhibiting an activation of a monoamine receptor
comprising contacting the monoamine receptor or a system containing
the monoamine receptor with an amount of a compound of one or more
of the compounds of claim 1 that is effective in inhibiting the
activation of the monoamine receptor.
27. The method of claim 26, wherein the activation is by an
agonistic agent.
28. The method of claim 27, wherein the agonistic agent is
exogenous.
29. The method of claim 27, wherein the agonistic agent is
endogenous.
30. The method of claim 26, wherein the activation is
constitutive.
31. The method of claim 26, wherein the monoamine receptor is a
serotonin receptor.
32. The method of claim 31, wherein the serotonin receptor is the
5-HT2A subclass.
33. The method of claim 31, wherein the serotonin receptor is in
the central nervous system.
34. The method of claim 31, wherein the serotonin receptor is in
the peripheral nervous system.
35. The method of claim 31, wherein the serotonin receptor is in
blood cells or platelets.
36. The method of claim 31, wherein the serotonin receptor is
mutated or modified.
37. A method of alleviating at least one symptom of a disease
condition associated with a monoamine receptor comprising
administering to a subject in need of such treatment a
therapeutically effective amount of one or more of the compounds of
claim 1.
38. The method of claim 37, wherein the disease condition is
selected from the group consisting of schizophrenia,
schizoaffective disorders, psychosis, drug induced psychosis, and
side effects observed with the treatment of chronic
neurodegenerative disorders with a selective serotonin reuptake
inhibitor (SSRI).
39. The method of claim 38, wherein said neurodegenerative disorder
is selected from Alzheimer's disease, Parkinson's disease, Lewy
Body Dementia, Frontotemporal Dementia, Spinocerebellar Atrophy,
and Huntington's disease.
40. The method of claim 37, wherein the disease condition is
selected from the group consisting of Reynaud's Phenomena,
migraine, hypertension, thrombosis, vasospasm, ischemia,
depression, anxiety, motor tics, Tourette's syndrome, dyskinesias,
on/off phenomena, tremor, rigidity, bradykinesia, psychomotor
slowing, addiction, including alcohol addiction, opioid addiction,
and nicotine addiction, sleep disorders, appetite disorders, and
decreases in libido and ejaculatory problems.
41. The method of claim 37, wherein the disease condition is
associated with dysfunction of a monoamine receptor.
42. The method of claim 37, wherein the disease condition is
associated with activation of a monoamine receptor.
43. The method of claim 37, wherein the disease condition is
associated with increased activity of monoamine receptor.
44. The method of claim 37, wherein the monoamine receptor is a
serotonin receptor
45. The method of claim 44, wherein the serotonin receptor is the
5-HT2A subclass.
46. The method of claim 44, wherein the serotonin receptor is in
the central nervous system.
47. The method of claim 44, wherein the serotonin receptor is in
the peripheral nervous system.
48. The method of claim 44, wherein the serotonin receptor is in
blood cells or platelets.
49. The method of claim 44 wherein the serotonin receptor is
mutated or modified.
50. A method of treating schizophrenia comprising administering to
a subject in need of such treatment a therapeutically effective
amount of a compound of one or more of the compounds of claim
1.
51. A method of treating migraine comprising administering to a
subject in need of such treatment a therapeutically effective
amount of a compound of one or more of the compounds of claim
1.
52. A method of treating psychosis comprising administering to a
subject in need of such treatment a therapeutically effective
amount of a compound of one or more of the compounds of claim
1.
53. A method for identifying a genetic polymorphism predisposing a
subject to being responsive to one or more of the compounds of
claim 1, comprising: administering to a subject a therapeutically
effective amount of the compound; measuring the response of said
subject to said compound, thereby identifying a responsive subject
having an ameliorated disease condition associated with a monoamine
receptor; and identifying a genetic polymorphism in the responsive
subject, wherein the genetic polymorphism predisposes a subject to
being responsive to the compound.
54. The method of claim 53 wherein the ameliorated disease
condition is associated with the 5-HT class or 5-HT2A subclass of
monoaminergic receptors.
55. A method for identifying a subject suitable for treatment with
one or more of the compounds of claim 1, comprising detecting the
presence of a polymorphism in a subject wherein the polymorphism
predisposes the subject to being responsive to the compound, and
wherein the presence of the polymorphism indicates that the subject
is suitable for treatment with one or more of the compounds of
claim 1.
56. A method of alleviating a condition associated with
non-selective antipsychotic compounds comprising administering a
therapeutically effective amount of one or more of the compounds of
claim 1 to a subject suffering from said condition.
57. The method according to claim 56, wherein the compound of claim
1 is a selective antagonist or inverse agonist of a 5-HT2A
receptor.
58. The method of according to claim 56, wherein the compound of
claim 1 has little to no activity on other monamine receptors.
59. The method according to claim 58, wherein one of the other
monamine receptors is a dopamine D2 receptor.
60. A method of alleviating a condition which is a side effect
which can arise in an individual who takes an antipsychotic
compound which possess broad activity at multiple monamine
receptors subtypes, comprising administering a therapeutically
effective amount of one or more of the compounds of claim 1 to
subject suffering from said condition.
61. The method according to claim 60, wherein the compound of claim
1 is a selective antagonist or inverse agonist of a 5-HT2A
receptor.
62. The method of according to claim 60, wherein the compound of
claim 1 has little to no activity on other monamine receptors.
63. The method according to claim 62, wherein one of the other
monamine receptors is a dopamine D2 receptor.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 11/299,566, filed Dec. 12, 2005, by Andersson
et al., and entitled "N-SUBSTITUTED PIPERIDINE DERIVATIVES AS
SEROTONIN RECEPTOR AGENTS," which claims priority to U.S.
application Ser. No. 10/601,070, filed Jun. 20, 2003, by Andersson
et al., and entitled "N-SUBSTITUTED PIPERIDINE DERIVATIVES AS
SEROTONIN RECEPTOR AGENTS," which in turn claims priority to U.S.
Provisional Application Ser. No. 60/391,269, filed Jun. 24, 2002,
by Andersson, and entitled "N-(HETEROCYCLYLALKYL)PIPERIDINE
DERIVATIVES AS SEROTONIN RECEPTOR AGENTS," all of which are hereby
incorporated by reference herein in their entirety, including any
drawings.
FIELD OF THE INVENTION
[0002] The present invention relates to azacyclic compounds with
pharmacokinetic properties for the treatment of symptoms, diseases
and disorders associated with monoamine receptors, including
serotonin receptors.
BACKGROUND OF THE INVENTION
[0003] Serotonin or 5-hydroxytryptamine (5-HT) plays a significant
role in the functioning of the mammalian body. In the central
nervous system, 5-HT is an important neurotransmitter and
neuromodulator that is implicated in such diverse behaviors and
responses as sleeping, eating, locomotion, perceiving pain,
learning and memory, sexual behavior, and controlling body
temperature and blood pressure. In the spinal column, serotonin
plays an important role in the control systems of the afferent
peripheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)).
Peripheral functions in the cardiovascular, hematological, and
gastrointestinal systems have also been ascribed to 5-HT. 5-HT has
been found to mediate a variety of contractile, secretory, and
electrophysiologic effects including vascular and nonvascular
smooth muscle contraction, and platelet aggregation. (Fuller,
Biology of Serotonergic Transmission, 1982; Boullin, Serotonin In
Mental Abnormalities 1:316 (1978); Barchas, et al., Serotonin and
Behavior, (1973)). The 5-HT2A receptor subtype (also referred to as
subclass) is widely yet discretely expressed in the human brain,
including many cortical, limbic, and forebrain regions postulated
to be involved in the modulation of higher cognitive and affective
functions. This receptor subtype is also expressed on mature
platelets where it mediates, in part, platelet aggregation, one of
the initial steps in the process of vascular thrombosis.
[0004] Given the broad distribution of serotonin within the body,
it is understandable that tremendous interest in drugs that affect
serotonergic systems exists (Gershon, et al., The Peripheral
Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et al., J.
Cardiovascular Pharmacol. 15: Supp. 7 (1990)). Serotonin receptors
are members of a large human gene family of membrane-spanning
proteins that function as transducers of intercellular
communication. They exist on the surface of various cell types,
including neurons and platelets, where, upon their activation by
either their endogenous ligand serotonin or exogenously
administered drugs, they change their conformational structure and
subsequently interact with downstream mediators of cellular
signaling. Many of these receptors, including the 5-HT2A subclass,
are G-protein coupled receptors (GPCRs) that signal by activating
guanine nucleotide binding proteins (G-proteins), resulting in the
generation, or inhibition of, second messenger molecules such as
cyclic AMP, inositol phosphates, and diacylglycerol. These second
messengers then modulate the function of a variety of intracellular
enzymes, including kinases and ion channels, which ultimately
affect cellular excitability and function.
[0005] At least 15 genetically distinct 5-HT receptor subtypes have
been identified and assigned to one of seven families (5-HT1-7).
Each subtype displays a unique distribution, preference for various
ligands, and functional correlate(s).
[0006] Serotonin may be an important component in various types of
pathological conditions such as certain psychiatric disorders
(depression, aggressiveness, panic attacks, obsessive compulsive
disorders, psychosis, schizophrenia, suicidal tendency), certain
neurodegenerative disorders (Alzheimer-type dementia, Parkinsonism,
Huntington's chorea), anorexia, bulimia, disorders associated with
alcoholism, cerebral vascular accidents, and migraine (Meltzer,
Neuropsychopharmacology, 21:106S-115S (1999); Barnes & Sharp,
Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci.
Biobehavioral Rev., 14:35 (1990)). Recent evidence strongly
implicates the 5-HT2 receptor subtype in the etiology of such
medical conditions as hypertension, thrombosis, migraine,
vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia,
sleep disorders and appetite disorders.
[0007] Schizophrenia is a particularly devastating neuropsychiatric
disorder that affects approximately 1% of the human population. It
has been estimated that the total financial cost for the diagnosis,
treatment, and lost societal productivity of individuals affected
by this disease exceeds 2% of the gross national product (GNP) of
the United States. Current treatment primarily involves
pharmacotherapy with a class of drugs known as antipsychotics.
Antipsychotics are effective in ameliorating positive symptoms
(e.g., hallucinations and delusions), yet they frequently do not
improve negative symptoms (e.g., social and emotional withdrawal,
apathy, and poverty of speech).
[0008] Currently, nine major classes of antipsychotics are
prescribed to treat psychotic symptoms. Use of these compounds is
limited, however, by their side effect profiles. Nearly all of the
"typical" or older generation compounds have significant adverse
effects on human motor function. These "extrapyramidal" side
effects, so termed due to their effects on modulatory human motor
systems, can be both acute (e.g., dystonic reactions, a potentially
life threatening but rare neuroleptic malignant syndrome) and
chronic (e.g., akathisias, tremors, and tardive dyskinesia). Drug
development efforts have, therefore, focused on newer "atypical"
agents free of these adverse effects.
[0009] Antipsychotic drugs have been shown to interact with a large
number of central monoaminergic neurotransmitter receptors,
including dopaminergic, serotonergic, adrenergic, muscarinic, and
histaminergic receptors. It is likely that the therapeutic and
adverse effects of these drugs are mediated by distinct receptor
subtypes. The high degree of genetic and pharmacological homology
between these receptor subtypes has hampered the development of
subtype-selective compounds, as well as the determination of the
normal physiologic or pathophysiologic role of any particular
receptor subtype. Thus there is a need to develop drugs that are
selective for individual receptor classes and subclasses amongst
monoaminergic neurotransmitter receptors.
[0010] The prevailing theory for the mechanism of action of
antipsychotic drugs involves antagonism of dopamine D2 receptors.
Unfortunately, it is likely that antagonism of dopamine D2
receptors also mediates the extrapyramidal side effects. Antagonism
of 5-HT2A is an alternate molecular mechanism for drugs with
antipsychotic efficacy, possibly through antagonism of heightened
or exaggerated signal transduction through serotonergic systems.
5-HT2A antagonists are therefore good candidates for treating
psychosis without extrapyramidal side effects.
[0011] Traditionally, these receptors have been assumed to exist in
a quiescent state unless activated by the binding of an agonist (a
drug that activates a receptor). It is now appreciated that many,
if not most, of the GPCR monoamine receptors, including serotonin
receptors, can exist in a partially activated state in the absence
of their endogenous agonists. This increased basal activity
(constitutive activity) can be inhibited by compounds called
inverse agonists. Both agonists and inverse agonists possess
intrinsic activity at a receptor, in that they alone can activate
or inactivate these molecules, respectively. In contrast, classic
or neutral antagonists compete against agonists and inverse
agonists for access to the receptor, but do not possess the
intrinsic ability to inhibit elevated basal or constitutive
receptor responses.
[0012] The present investigators have recently elucidated an
important aspect of 5-HT2A receptor function by applying the
Receptor Selection and Amplification Technology (U.S. Pat. No.
5,707,798, 1998; Chem Abstr. 128:111548 (1998) and citations
therein), to the study of the 5-HT2 subclass of serotonin
receptors. R-SAT is a phenotypic assay of receptor function that
involves the heterologous expression of receptors in mammalian
fibroblasts. Using this technology we were able to demonstrate that
native 5-HT2A receptors possess significant constitutive, or
agonist-independent, receptor activity (U.S. Pat. No. 6,358,698;
Weiner et. al. J. Pharmacol. Exp. Ther. 2001, 299 (1), 268-276,
both of which are hereby incorporated by reference herein in their
entirety, including any drawings). Furthermore, by directly testing
a large number of centrally acting medicinal compounds with known
clinical activity in neuropsychiatric disease, we determined that
compounds with antipsychotic efficacy all shared a common molecular
property. Nearly all of these compounds, which are used by
psychiatrists to treat psychosis, were found to be potent 5-HT2A
inverse agonists. This unique clinico-pharmacologic correlation at
a single receptor subtype is compelling evidence that 5-HT2A
receptor inverse agonism is a molecular mechanism of antipsychotic
efficacy in humans.
[0013] Detailed pharmacological characterization of a large number
of antipsychotic compounds revealed that they possess broad
activity at multiple related receptor subtypes. Most of these
compounds display agonist, competitive antagonist, or inverse
agonist activity at multiple monoaminergic receptor subtypes,
including serotoninergic, dopaminergic, adrenergic, muscarinic and
histaminergic receptors. This broad activity is likely responsible
for the sedating, hypotensive, and motor side effects of these
compounds. It would therefore be of great advantage to develop
compounds that are selective inverse agonists of the 5-HT2A
receptor, but which have little or no activity on other monamine
receptors subtypes, especially dopamine D2 receptors. Such
compounds may be useful in the treatment of human disease (e.g., as
anti-psychotics), and may avoid the adverse side effects associated
with non-selective receptor interactions.
[0014] U.S. Pat. No. 4,853,394 discloses
N-(Hydroxyethylpiperid-4-yl) esters and amides which with gastic
motility enhancing, anti-emetic activity and 5-HT antagonist
activity.
[0015] EP 0 260 070 discloses the acetic acid ester of
4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butan-
one for the alleviation, palliation, mitigation, or inhibition of
the manifestations of psychic abnormalities.
SUMMARY OF THE INVENTION
[0016] Disclosed herein are compounds of Formula I, ##STR2## or a
pharmaceutically acceptable salt, amide, ester, or prodrug thereof,
wherein
[0017] R.sup.1 is selected from the group consisting of optionally
substituted heterocyclyl, and optionally substituted
(heterocyclyl)C.sub.1-6-alkyl;
[0018] R.sup.2and R.sup.3 are independently selected from the group
consisting of hydrogen, C.sub.1-6-alkyl and halogen or such that
R.sup.2 together with R.sup.3 forms a ring;
[0019] m is selected from the group consisting of 0, 1, and 2;
[0020] n is selected from the group consisting of 1, 2, and 3;
[0021] Ar.sup.1 is an optionally substituted aryl or
heteroaryl;
[0022] W is selected from the group consisting of O and S;
[0023] X is selected from the group consisting of optionally
substituted methylene, optionally substituted ethylene, optionally
substituted propylene, optionally substituted vinylene, and
CH.sub.2N(R.sup.N), wherein R.sup.N is selected from hydrogen and
C.sub.1-6-alkyl; and
[0024] Ar.sup.2 is an optionally substituted aryl or
heteroaryl.
[0025] Also disclosed are methods of inhibiting an activity of a
monoamine receptor comprising contacting the monoamine receptor or
a system containing the monoamine receptor with an effective amount
of one or more of the compounds of Formula I. Disclosed are also
methods of inhibiting an activation of a monoamine receptor
comprising contacting the monoamine receptor or a system containing
the monoamine receptor with an effective amount of one or more of
the compounds of Formula I. Furthermore, methods of treating
psychotic disease using a compound of Formula I are disclosed.
DETAILED DESCRIPTION OF THE INVENTION
[0026] For the purpose of the current disclosure, the following
definitions shall in their entireties be used to define technical
terms, and shall also, in their entireties, be used to define the
scope of the composition of matter for which protection is sought
in the claims. The term "Constitutive activity" is defined as the
basal activity of a receptor which is independent of the presence
of an agonist. Constitutive activity of a receptor may be measured
using a number of different methods, including cellular (e.g.,
membrane) preparations (see, e.g., Barr &. Manning, J. Biol.
Chem. 272:32979-87 (1997)), purified reconstituted receptors with
or without the associated G-protein in phospholipid vesicles
(Cerione et al., Biochemistry 23:4519-25 (1984)), and functional
cellular assays (U.S. Pat. No. 6,358,698).
[0027] The term "agonist" is defined as a compound that increases
the activity of a receptor when it contacts the receptor.
[0028] The term "antagonist" is defined as a compound that competes
with an agonist or inverse agonist for binding to a receptor,
thereby blocking the action of an agonist or inverse agonist on the
receptor. However, an antagonist (also known as a "neutral"
antagonist) has no effect on constitutive receptor activity.
[0029] The term "inverse agonist" is defined as a compound that
decreases the basal activity of a receptor (i.e., signaling
mediated by the receptor). Such compounds are also known as
negative antagonists. An inverse agonist is a ligand for a receptor
that causes the receptor to adopt an inactive state relative to a
basal state occurring in the absence of any ligand. Thus, while an
antagonist can inhibit the activity of an agonist, an inverse
agonist is a ligand that can alter the conformation of the receptor
in the absence of an agonist. The concept of an inverse agonist has
been explored by Bond et al. in Nature 374:272 (1995). More
specifically, Bond et al. have proposed that unliganded
.beta..sub.2-adrenoceptor exists in an equilibrium between an
inactive conformation and a spontaneously active conformation.
Agonists are proposed to stabilize the receptor in an active
conformation. Conversely, inverse agonists are believed to
stabilize an inactive receptor conformation. Thus, while an
antagonist manifests its activity by virtue of inhibiting an
agonist, an inverse agonist can additionally manifest its activity
in the absence of an agonist by inhibiting the spontaneous
conversion of an unliganded receptor to an active conformation.
[0030] The term "5-HT2A receptor" is defined as a receptor, having
an activity corresponding to the activity of the human serotonin
receptor subtype, which was characterized through molecular cloning
and pharmacology as detailed in Saltzman et al., Biochem. Biophys.
Res. Comm. 181:1469-78; and Julius et al., Proc. Natl. Acad. Sci.
USA 87:928-932.
[0031] The term "subject" refers to an animal, preferably a mammal,
most preferably a human, who is the object of treatment,
observation or experiment.
[0032] The term "selective" is defined as a property of a compound
whereby an amount of the compound sufficient to effect a desired
response from a particular receptor type, subtype, class or
subclass causes a substantially smaller or no effect upon the
activity other receptor types.
[0033] The terms "selectivity" or "selective," in relation to an
inverse agonist, are understood as a property of a compound of the
invention whereby an amount of compound that effectively inversely
agonizes the 5-HT2A receptor, and thereby decreases its activity,
causes little or no inverse agonistic or antagonistic activity at
other, related or unrelated, receptors. In particular, certain
compounds of the invention have been found not to interact strongly
with other serotonin receptors (5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C,
4A, 6, and 7) at concentrations where the signaling of the 5-HT2A
receptor is strongly or completely inhibited. Preferably, the
compounds of the invention are also selective with respect to other
monoamine-binding receptors, such as the dopaminergic,
histaminergic, adrenergic and muscarinic receptors. Compounds that
are highly selective for 5-HT2A receptors may have a beneficial
effect in the treatment of psychosis, schizophrenia or similar
neuropsychiatric disorders, while avoiding adverse effects
associated with drugs hitherto suggested for this purpose.
[0034] The EC.sub.50 for an agonist is intended to denote the
concentration of a compound needed to achieve 50% of a maximal
response seen in R-SAT. For inverse agonists, EC.sub.50 is intended
to denote the concentration of a compound needed to achieve 50%
inhibition of an R-SAT response from basal, no compound,
levels.
[0035] As used herein, the term "coadministration" of
pharmacologically active compounds refers to the delivery of two or
more separate chemical entities, whether in vitro or in vivo.
Coadministration refers to the simultaneous delivery of separate
agents; to the simultaneous delivery of a mixture of agents; as
well as to the delivery of one agent followed by delivery of a
second agent or additional agents. In all cases, agents that are
coadministered are intended to work in conjunction with each
other.
[0036] In the present context the term "aryl" is intended to mean a
carbocyclic aromatic ring or ring system. Moreover, the term "aryl"
includes fused ring systems wherein at least two aryl rings, or at
least one aryl and at least one C.sub.3-8-cycloalkyl share at least
one chemical bond. Some examples of "aryl" rings include optionally
substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl,
tetralinyl, fluorenyl, indenyl, and indanyl. The term "aryl"
relates to aromatic, preferably benzenoid groups, connected via one
of the ring-forming carbon atoms, and optionally carrying one or
more substituents selected from heterocyclyl, heteroaryl, halo,
hydroxy, amino, cyano, nitro, alkylamido, acyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl,
C.sub.1-6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl,
sulfamoyl, or trifluoromethyl. The aryl group may be substituted at
the para and/or meta positions. Representative examples of aryl
groups include, but are not limited to, phenyl, 3-halophenyl,
4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl,
4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 4-trifluoromethoxyphenyl 3-cyanophenyl,
4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl,
hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl,
4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl,
4-triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl.
[0037] In the present context, the term "heteroaryl" is intended to
mean a heterocyclic aromatic group where one or more carbon atoms
in an aromatic ring have been replaced with one or more heteroatoms
selected from the group comprising nitrogen, sulfur, phosphorous,
and oxygen.
[0038] Furthermore, in the present context, the term "heteroaryl"
comprises fused ring systems wherein at least one aryl ring and at
least one heteroaryl ring, at least two heteroaryl rings, at least
one heteroaryl ring and at least one heterocyclyl ring, or at least
one heteroaryl ring and at least one C.sub.3-8-cycloalkyl ring
share at least one chemical bond.
[0039] The term "heteroaryl" is understood to relate to aromatic,
C.sub.3-8 cyclic groups further containing one oxygen or sulfur
atom or up to four nitrogen atoms, or a combination of one oxygen
or sulfur atom with up to two nitrogen atoms, and their substituted
as well as benzo- and pyrido-fused derivatives, preferably
connected via one of the ring-forming carbon atoms. Heteroaryl
groups may carry one or more substituents, selected from halo,
hydroxy, amino, cyano, nitro, alkylamido, acyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-aminoalkyl,
C.sub.1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl,
sulfamoyl, or trifluoromethyl. In some embodiments, heteroaryl
groups may be five- and six-membered aromatic heterocyclic systems
carrying 0, 1, or 2 substituents, which may be the same as or
different from one another, selected from the list above.
Representative examples of heteroaryl groups include, but are not
limited to, unsubstituted and mono- or di-substituted derivatives
of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,
indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole,
benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole,
indazole, tetrazole, quionoline, isoquinoline, pyridazine,
pyrimidine, purine and pyrazine, which are all preferred, as well
as furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,
triazole, benzotriazole, pteridine, phenoxazole, oxadiazole,
benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline,
and quinoxaline. In some embodiments, the substituents are halo,
hydroxy, cyano, O--C.sub.1-6-alkyl, C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl, amino-C.sub.1-6-alkyl.
[0040] In the present context, the term "alkyl" and
"C.sub.1-6-alkyl" are intended to mean a linear or branched
saturated hydrocarbon chain wherein the longest chain has from one
to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, and hexyl. An alkyl chain may be optionally
substituted.
[0041] The term "heterocyclyl" is intended to mean three-, four-,
five-, six-, seven-, and eight-membered rings wherein carbon atoms
together with from 1 to 3 heteroatoms constitute said ring. A
heterocyclyl may optionally contain one or more unsaturated bonds
situated in such a way, however, that an aromatic i-electron system
does not arise. The heteroatoms are independently selected from
oxygen, sulfur, and nitrogen.
[0042] A heterocyclyl may further contain one or more carbonyl or
thiocarbonyl functionalities, so as to make the definition include
oxo-systems and thio-systems such as lactams, lactones, cyclic
imides, cyclic thioimides, cyclic carbamates, and the like.
[0043] Heterocyclyl rings may optionally also be fused to aryl
rings, such that the definition includes bicyclic structures.
Preferred such fused heterocyclyl groups share one bond with an
optionally substituted benzene ring. Examples of benzo-fused
heterocyclyl groups include, but are not limited to,
benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene
ring structures.
[0044] Some examples of "heterocyclyls" include, but are not
limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,
piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,
piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,
imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole,
1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.
Binding to the heterocycle may be at the position of a heteroatom
or via a carbon atom of the heterocycle, or, for benzo-fused
derivatives, via a carbon of the benzenoid ring.
[0045] The term "(heterocyclyl)C.sub.1-6-alkyl" is understood as
heterocyclyl groups connected, as substituents, via an alkyl, each
as defined herein. The heterocyclyl groups of
(heterocyclyl)C.sub.1-6-alkyl groups may be substituted or
unsubstituted. The term "(heterocyclyl)C.sub.1-6-alkyl" is intended
to mean an alkyl chain substituted at least once with a
heterocyclyl group, typically at the terminal position of the alkyl
chain.
[0046] In the present context, the term "C.sub.2-8-alkenyl" is
intended to mean a linear or branched hydrocarbon group having from
two to eight carbon atoms and containing one or more double bonds.
Some examples of C.sub.2-8-alkenyl groups include allyl,
homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and
octenyl. Some examples of C.sub.2-8-alkenyl groups with more than
one double bond include butadienyl, pentadienyl, hexadienyl,
heptadienyl, heptatrienyl and octatrienyl groups as well as
branched forms of these. The position of the unsaturation (the
double bond) may be at any position along the carbon chain.
[0047] In the present context the term "C.sub.2-8-alkynyl" is
intended to mean a linear or branched hydrocarbon group containing
from two to eight carbon atoms and containing one or more triple
bonds. Some examples of C.sub.2-8-alkynyl groups include ethynyl,
propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups
as well as branched forms of these. The position of unsaturation
(the triple bond) may be at any position along the carbon chain.
More than one bond may be unsaturated such that the
"C.sub.2-8-alkynyl" is a di-yne or enedi-yne as is known to the
person skilled in the art.
[0048] In the present context, the term "C.sub.3-8-cycloalkyl" is
intended to cover three-, four-, five-, six-, seven-, and
eight-membered rings comprising carbon atoms only. A
C.sub.3-8-cycloalkyl may optionally contain one or more unsaturated
bonds situated in such a way, however, that an aromatic
.pi.-electron system does not arise.
[0049] Some examples of preferred "C.sub.3-8-cycloalkyl" are the
carbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentene,
cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene,
1,4-cyclohexadiene, cycloheptane, cycloheptene.
[0050] The terms "(aryl)C.sub.1-6-alkyl" is intended to mean an
aryl group connected, as a substituent, via a C.sub.1-6-alkyl, each
as defined herein. The aryl groups of (aryl)C.sub.1-6-alkyl may be
substituted or unsubstituted. Examples include benzyl, substituted
benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl.
[0051] The terms "(cycloalkyl)C.sub.1-6-alkyl" is intended to mean
a cycloalkyl groups connected, as substituents, via an alkyl, each
as defined herein.
[0052] When used herein, the term "O--C.sub.1-6-alkyl" is intended
to mean C.sub.1-6-alkyloxy, or alkoxy, such as methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy and hexyloxy
[0053] The term "halogen" includes fluorine, chlorine, bromine and
iodine.
[0054] In the present context, i.e. in connection with the terms
"C.sub.1-6-alkyl", "aryl", "heteroaryl", "heterocyclyl",
"C.sub.3-8-cycloalkyl", "heterocyclyl(C.sub.1-6-alkyl)",
"(cycloalkyl)alkyl", "O--C.sub.1-6-alkyl", "C.sub.2-8-alkenyl", and
"C.sub.2-8-alkynyl", the term "optionally substituted" is intended
to mean that the group in question may be substituted one or
several times, such as 1 to 5 times, or 1 to 3. times, or 1 to 2
times, with one or more groups selected from C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, oxo (which may be represented in the tautomeric
enol form), carboxyl, amino, hydroxy (which when present in an enol
system may be represented in the tautomeric keto form), nitro,
alkylsulfonyl, alkylsulfenyl,
alkylsulfinyl,C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
formyl, amino, mono- and di(C.sub.1-6-alkyl)amino; carbamoyl, mono-
and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylhydroxyimino, cyano,
guanidino, carbamido, C.sub.1-6-alkanoyloxy,
C.sub.1-6-alkylsulphonyloxy, dihaloger-C.sub.1-6-alkyl,
trihalogen-C.sub.1-6-alkyl, heterocyclyl, heteroaryl, and halo. In
general, the above substituents may be susceptible to further
optional substitution.
[0055] The term "salts" is intended to mean pharmaceutically
acceptable acid addition salts obtainable by treating the base form
of a functional group, such as an amine, with appropriate acids
such as inorganic acids, for example hydrohalic acids; typically
hydrochloric, hydrobromic, hydrofluoric, or hydroiodic acid;
sulfuric acid; nitric acid; phosphoric acid and the like; or
organic acids, for example acetic, propionic, hydroacetic,
2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic,
propanedioic, butanedioic, (Z)-2-butenedioic, (E)-butenedioic,
2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,
2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,
ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic acid,
cyclohexanesulfamic, 2-hydoxybenzoic, 4-amino-2-hydroxybenzoic, and
other acids known to the skilled practitioner.
[0056] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs are
inactive derivatives of the compounds of this invention that are
readily convertible in vivo into the required compound.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985). Metabolites of
these compounds include active species that are produced upon
introduction of compounds of this invention into the biological
milieu.
[0057] Where the compounds according to the invention have at least
one chiral center, they may exist as a racemate or as enantiomers.
It should be noted that all such isomers and mixtures thereof are
included in the scope of the present invention. Furthermore, some
of the crystalline forms for compounds of the present invention may
exist as polymorphs and as such are intended to be included in the
present invention. In addition, some of the compounds of the
present invention may form solvates with water (i.e., hydrates) or
common organic solvents. Such solvates are also included in the
scope of this invention.
[0058] Where the processes for the preparation of the compounds
according to the invention give rise to mixtures of stereoisomers,
such isomers may be separated by conventional techniques such as
preparative chiral chromatography. The compounds may be prepared in
racemic form or individual enantiomers may be prepared by
stereoselective synthesis or by resolution. The compounds may be
resolved into their component enantiomers by standard techniques,
such as the formation of diastereomeric pairs by salt formation
with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric
acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by
fractional crystallization and regeneration of the free base. The
compounds may also be resolved using a chiral auxiliary by
formation of diastereomeric derivatives such as esters, amides or
ketals followed by chromatographic separation and removal of the
chiral auxiliary.
[0059] The compounds of the present invention are effective upon
administration orally. In vivo experiments performed in rodents
have indicated that a lower dose of the compounds of the present
invention results in equal or improved behavioral responses in
animal models of psychosis. These results are indicative of a
higher bioavailability of the compounds of the present invention,
compared to the compounds disclosed in the prior art. An improved
bioavailability is corroborated by the observation that the new
compounds presented herein are not significantly more potent when
assayed for their effects on serotonin receptors in vitro, and yet
represent a substantial improvement when orally administered. The
highly improved efficacy observed after oral dosing is probably a
result of increased metabolic stability, improved physicochemical
properties, such as solubility or chemical stability, or different
pharmacokinetic characteristics, such as distribution,
permeability, or the like. Without being bound to a particular
theory, it is reasonable to ascribe such differences to the
presence of a heterocyclic substituent at the nitrogen of the
piperidine ring of these compounds. The presence of such a
heterocyclic substituent could affect the behavior of these
derivatives in terms of solubility and/or metabolic lability. The
presence of heteroatoms in substituents close to the nitrogen would
also be suspected to influence the basicity of the nitrogen, which,
in turn, might affect properties such as distribution (Log D) or
metabolism.
[0060] Generally, a high degree of bioavailability of any
pharmaceutical is considered highly beneficial. This relates
primarily to the ability to be able to administer an efficacious
yet safe dose of the drug to all subjects irrespective of their
potential predisposition to polymorphism-dependent drug metabolism.
Examples of many such polymorphisms are well known in the art.
Thus, a drug which undergoes substantial metabolism, either during
its first pass through the liver or in the gastrointestinal tract,
will display a relatively low, and sometimes dose-dependent,
bioavailability measured as the plasma concentration achieved after
peroral distribution. Inter-individual differences in drug exposure
are generally more severe when a drug is heavily metabolized, and,
as a consequence, displays low oral bioavailability. Subjects with
polymorphisms resulting in changes in the activity of
drug-metabolizing enzymes are likely to become exposed to very
different (normally much higher) plasma levels than those
displaying a normal metabolic activity. Hence, aspects of the
present invention relate to novel compounds which display
characteristics suggestive of superior drug properties when
compared to those previously known in the art.
[0061] In general, compounds of Formula I are active at monoamine
receptors, specifically serotonin receptors. Several compounds of
the invention share the common property of acting as inverse
agonists at the 5-HT2A receptor. Thus, experiments performed on
cells transiently expressing the human phenotype of said receptor
have shown that the compounds of general Formula I attenuate the
signaling of such receptors in the absence of additional ligands
acting upon the receptor. The compounds have thus been found to
possess intrinsic activity at this receptor and are able to
attenuate the basal, non-agonist-stimulated, constitutive signaling
responses that the 5-HT2A receptor displays. The observation that
the compounds of general Formula I are inverse agonists also
indicates that these compounds have the ability to antagonize the
activation of 5-HT2A receptors that is mediated by endogenous
agonists or exogenous synthetic agonist ligands.
[0062] In certain embodiments, the present invention provides
compounds that show a relatively high degree of selectivity towards
the 5-HT2A subtype of serotonin receptors relative to other
subtypes of the serotonin (5-HT) family of receptors as well as to
other receptors, most particularly the monoaminergic G-protein
coupled receptors, such as dopamine receptors. In other
embodiments, the compounds of the present invention act as inverse
agonists at the 5-HT2A subtype of serotonin receptors.
[0063] The compounds of general Formula I may therefore be useful
for treating or alleviating symptoms of disease conditions
associated with impaired function, in particular elevated levels of
activity, of especially 5-HT2A receptors, whether this impaired
function is associated with improper levels of receptor stimulation
or phenotypical aberrations.
[0064] Others have previously hypothesized that certain
neuropsychological diseases might be caused by altered levels of
constitutive activity of monoamine receptors. Such constitutive
activity might be modified via contacting the relevant receptor
with a synthetic inverse agonist. By directly testing a large
number of centrally acting medicinal compounds with known clinical
activity in neuropsychiatric disease, we determined that compounds
with antipsychotic efficacy all shared a common molecular property.
Nearly all of these compounds that are used by psychiatrists to
treat psychosis were found to be potent 5-HT2A inverse agonists.
This correlation is compelling evidence that 5-HT2A receptor
inverse agonism is a molecular mechanism of antipsychotic efficacy
in humans.
[0065] Detailed pharmacological characterization of a large number
of antipsychotic compounds in our laboratory revealed that they
possess broad activity at multiple related receptor subtypes. Most
of these compounds display either agonist, competitive antagonist,
or inverse agonist activity at multiple monoaminergic receptor
subtypes including serotoninergic, dopaminergic, adrenergic,
muscarinic and histaminergic receptors. This broad activity is
likely responsible for the sedating, hypotensive, and motor side
effects of these compounds. It follows that the compounds disclosed
herein will possess efficacy as, for example, novel antipsychotics,
but will have fewer or less severe side effects than existing
compounds.
[0066] Thus, in the first aspect, the present invention relates to
a compound of Formula I, ##STR3## or a pharmaceutically acceptable
salt, amide, ester, or prodrug thereof, wherein
[0067] R.sup.1 is selected from the group consisting of optionally
substituted heterocyclyl, and optionally substituted
(heterocyclyl)C.sub.1-6-alkyl;
[0068] R.sup.2 and R.sup.3 are independently selected from the
group consisting of hydrogen, C.sub.1-6-alkyl and halogen or such
that R.sup.2 together with R.sup.3 forms a ring;
[0069] m is selected from the group consisting of 0, 1, and 2;
[0070] n is selected from the group consisting of 1, 2, and 3;
[0071] Ar.sup.1 is an optionally substituted aryl or
heteroaryl;
[0072] W is selected from the group consisting of O and S;
[0073] X is selected from the group consisting of optionally
substituted methylene, optionally substituted ethylene, optionally
substituted propylene, optionally substituted vinylene, and
CH.sub.2N(R.sup.N), wherein R.sup.N is selected from hydrogen and
C.sub.1-6-alkyl; and
[0074] Ar.sup.2 is an optionally substituted aryl or
heteroaryl.
[0075] As discussed, the presence of a heterocyclic substituent at
the nitrogen of the piperidine ring of these compounds is
considered to improve the bioavailability of the compounds, in
comparison to related compounds known to the person skilled in the
art.
[0076] In some embodiments, the heterocyclyl or
(heterocyclyl)C.sub.1-6-alkyl of R.sup.1 may be optionally
substituted. The substituent may be selected from halogen, hydroxy,
alkyl, alkoxy, and amino. In some embodiments, the substituent may
be on the alkyl chain or the ring system. In further embodiments
the substituent is on the ring system.
[0077] In certain embodiments, the heterocyclyl ring in R.sup.1 may
be selected from the group consisting of tetrahydrothiopyran,
4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane,
1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin,
1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,
succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
hydantoin, dihydrouracil, morpholine, trioxane,
hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,
pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,
pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole,
1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline,
isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,
thiazolidine, and 1,3-oxathiolane. In some embodiments, the
heterocyclyl ring is selected from 1,3-dioxane, 1,3-dioxolane, and
tetrahydropyran.
[0078] The azacyclic ring may be a 5, 6, or 7-membered ring as
reflected in that m may be selected from 0, 1 and 2. In certain
embodiments, however, the azacyclic ring is a 6-membered ring,
wherein m is 1.
[0079] The azacyclic ring, further to being substituted at the
nitrogen position, may be substituted with R.sup.2 and R.sup.3.
R.sup.2 and R.sup.3 may be independently selected from the group
consisting of hydrogen, C.sub.1-6-alkyl, and halogen, or such that
R.sup.2 together with R.sup.3 forms a ring. That is to say that
R.sup.2 and R.sup.3 may be biradicals which combine to form a 3-,
4-, 5-, 6-, or 7-membered ring system with the atoms of the
azacyclic ring.
[0080] In some embodiments, the azacyclic ring system is selected
from ##STR4## wherein R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen, halogen, hydroxyl,
and C.sub.1-6 alkyl. In certain embodiments R.sup.7 and R.sup.8 are
hydrogen.
[0081] In other embodiments, R.sup.2 and R.sup.3 are hydrogen.
[0082] In some embodiments, R.sup.1 is an optionally substituted
(heterocyclyl)C.sub.1-6-alkyl. In certain of these embodiments,
R.sup.1 is an optionally substituted (heterocyclyl)methyl, an
optionally substituted (heterocyclyl)ethyl, or an optionally
substituted (heterocyclyl)propyl. In other embodiments, R.sup.1 is
an optionally substituted (heterocyclyl)ethyl.
[0083] Ar.sup.1 is linked to a central nitrogen atom via a short
aliphatic chain 1, 2, or 3 carbon atoms in length. In certain
embodiments, n is 1, resulting in a methylene spacer between the
central nitrogen atom and Ar.sup.1. Ar.sup.1 may be an optionally
substituted aryl or heteroaryl. In some embodiments, Ar.sup.1 is an
optionally substituted aryl. In some embodiments, the central
nitrogen atom is linked to an optionally substituted benzyl
group.
[0084] In certain embodiments Ar.sup.1 is an optionally substituted
aryl, which may be a 4-substituted aryl. The 4-substituent of the
4-substituted aryl may be any substituent known to the person
skilled in the art, such as a C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
carboxyl, amino, hydroxy, thiol, nitro, cyano, guanidino, carbamido
and halogen. In some embodiments, the halogen is fluoro, while in
other embodiments, the halogeni s chloro.
[0085] In other embodiments, Ar.sup.1 is selected from the group
consisting of alkyl-substituted phenyl, alkoxy-substituted phenyl,
halogen-substituted phenyl, hydroxy-substituted phenyl and
amino-substituted phenyl. In some embodiments, the substituent may
be present 0 to 5 times, or 0 to 4 times, or 0 to 3 times, such as
0, 1, 2, or 3 times. In certain embodiments, the substituent is
present 1 to 2 times. In some embodiments, Ar.sup.1 is a
4-substituted aryl selected from the group consisting of
4-halophenyl and 4-alkylphenyl. In some embodiments, the phenyl
group is 4-fluorophenyl.
[0086] In other embodiments, Ar.sup.1 is an optionally substituted
heteroaryl. The heteroaryl may be substituted with substituents
known to the person skilled in the art, such as a C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano,
guanidino, carbamido and halogen.
[0087] Further to being linked to both the azacyclic ring and to
Ar.sup.1 via a short aliphatic chain, the central nitrogen is
linked to Ar.sup.2 via a 2 to 4 carbon spacer unit. This spacer
unit comprises a carbonyl or thiocarbonyl function wherein W is
selected from the group consisting of oxygen and sulfur. In some
embodiments W is oxygen.
[0088] In certain embodiments, X may be selected from the group
consisting of optionally substituted methylene, optionally
substituted ethylene, optionally substituted propylene, optionally
substituted vinylene, and CH.sub.2N(R.sup.N). Thus X may extend the
spacer unit by 1 to 3 atoms between the central nitrogen and
Ar.sup.2 and render the central nitrogen part of an amide or
carbamide. In some embodiments, X is selected from the group
consisting of optionally substituted methylene, optionally
substituted ethylene, and CH.sub.2N(R.sup.N). In some embodiments,
X is an optionally substituted methylene, or CH.sub.2N(R.sup.N),
wherein R.sup.N may be hydrogen.
[0089] In certain embodiments, Ar.sup.2 may be an optionally
substituted aryl or heteroaryl. In certain embodiments, Ar.sup.2 is
an optionally substituted aryl. In some embodiments, Ar.sup.2 is a
4-substituted aryl.
[0090] In a further embodiment, Ar.sup.2 may be selected from the
group consisting of alkoxy-substituted phenyl, halogen-substituted
phenyl, hydroxy-substituted phenyl, amino-substituted phenyl, and
heterocyclyl-substituted phenyl.
[0091] In certain embodiments, Ar.sup.2 is a 4-substituted aryl
wherein the substituent is selected from the group consisting of
alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, heterocyclyl,
and heteroaryl. In some embodiments, the substituent on Ar.sup.2 is
selected from chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, trifluoromethoxy,
N-morpholinyl, N-pyrrolidinyl, N-pyrazolyl, N-triazolyl and
2-oxopyrrolidinyl.
[0092] In another aspect, the present invention relates to a
compound selected from the group consisting of
[0093]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-N'-(4-isobutoxybenzyl)carbamide, hydrochloride;
[0094]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-[4-(2-hydroxy-2-methylpropoxy)phenyl]acetamide, tartrate;
[0095]
N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl}-N-(4-fl-
uorobenzyl)-2-(4-isobutoxyphenyl)acetamide, dihydrochloride;
[0096]
1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino}piper-
idin-1-yl)propyl]piperidine-4-carboxylic acid methyl ester,
dihydrochloride;
[0097]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolid-
in-2-yl)ethyl]piperidin-4-yl}acetamide, dioxalate;
[0098]
N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl}-N-(4-fl-
uorobenzyl)-2-(4-isobutoxyphenyl)acetamide, dioxalate;
[0099]
N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperid-
in-4-yl}-2-(4-isobutoxyphenyl)acetamide, dioxalate;
[0100]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[3-(2-methylpiperidin-
-1-yl)propyl]piperidin-4-yl}acetamide, dioxalate;
[0101]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-[1-(3-pyrrolidin-1-yl-pr-
opyl)piperidin-4-yl]acetamide, dioxalate;
[0102]
N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-f-
luorobenzyl)-2-(4-isobutoxyphenyl)acetamide, dioxalate;
[0103]
N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]p-
iperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide, dioxalate;
[0104]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[3-(4-(S)-isopropyl-2-
-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate;
[0105]
N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl}N-{1-[3-(4-(S)-is-
opropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,
oxalate;
[0106]
N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazoli-
din-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,
oxalate;
[0107]
N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)-
propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide, oxalate;
[0108]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-isobutoxyphenyl)acetamide, oxalate;
[0109]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluoropheny-
l)ethyl]-2-(4-isobutoxyphenyl)acetamide, oxalate;
[0110]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluoropheny-
l)ethyl]-2-(4-propoxyphenyl)acetamide, oxalate;
[0111]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-propoxyphenyl)acetamide, tartrate;
[0112]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
N'-(4-isobutoxybenzyl)carbamide, tartrate;
[0113]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-fluorophenyl)acetamide, tartrate;
[0114]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-p-tolylacetamide, tartrate;
[0115]
2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-
-(4-fluorobenzyl)acetamide, tartrate;
[0116]
2-(2,3-Dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]pipe-
ridin-4-yl}-N-(4-fluorobenzyl)acetamide, tartrate;
[0117]
N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-
-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide, tartrate;
[0118]
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-isobutoxyphenyl)acetamide, tartrate;
[0119]
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-trifluoromethylphenyl)acetamide, tartrate;
[0120]
2-(4-Cyanophenyl}N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N--
(4-fluorobenzyl)acetamide, tartrate;
[0121]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[2-(2-oxo-imidazolidi-
n-1-yl)ethyl]piperidin-4-yl}acetamide, hydrochloride;
[0122]
2-(4-Methoxyphenyl}N-(4-methylbenzyl}N-{1-[2-(2-oxo-imidazolidin-1-
-yl)ethyl]piperidin-4-yl}acetamide, hydrochloride;
[0123]
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[2-(2-oxo-imidazolid-
in-1-yl)ethyl]piperidin-4-yl}acetamide, hydrochloride;
[0124]
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[3-(3-methyl-2-oxo-2-
,3-dihydro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;
hydrochloride;
[0125]
N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin--
4-yl}-2-(4-methoxyphenyl}N-(4-methylbenzyl)acetamide,
hydrochloride;
[0126]
2-(4-Methoxyphenyl}N-(4-methylbenzyl}N-{1-[3-(2-oxo-2,3-dihydroben-
zoimidazol-1-yl)propyl]piperidin-4-yl}-acetamide,
hydrochloride;
[0127]
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[4-(2-oxo-2,3-dihydr-
obenzoimidazol-1-yl)butyl]piperidin-4-yl}acetamide,
hydrochloride;
[0128]
N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin--
4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide,
hydrochloride;
[0129]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-N'-(4-isopropoxy-benzyl)carbamide, oxalate;
[0130]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxypheny-
l}N-(4-methylbenzyl)acetamide, hydrochloride;
[0131]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-2-(4-isobutoxyphenyl)acetamide, hydrochloride;
[0132]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyph-
enyl}N-(4-methylbenzyl)acetamide, hydrochloride;
[0133]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-2-(4-propoxyphenyl)acetamide, tartrate;
[0134]
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1-
,3-dioxolane-2-yl)ethyl]piperidin-4-yl}carbamide, oxalate;
[0135]
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl--
propyl)piperidin-4-yl]carbamide, oxalate;
[0136]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl-
)piperidin-4-yl]acetamide, dihydrochloride;
[0137]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)N-[1-(3-morpholin-4-ylpropyl-
)piperidin-4-yl]acetamide, dihydrochloride;
[0138]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-morpholin-4-ylpro-
pyl)piperidin-4-yl]acetamide, dihydrochloride;
[0139]
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-[1-(3-morpholin-4-yl-pr-
opyl)piperidin-4-yl]acetamide, dihydrochloride;
[0140]
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl--
propyl)piperidin-4-yl]carbamide, oxalate;
[0141]
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropy-
l-2-oxazolidinon-1-yl-propyl)piperidin-4-yl]carbamide,
tartrate;
[0142]
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{1-[2-(2,5,5-trimethy-
l-1,3-dioxan-2-yl)ethyl]}piperidin-4-yl]carbamide, oxalate;
[0143] N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl
}-N-(4-fluorobenzyl)-N'-(4-isopropoxybenzyl)carbamide, oxalate;
[0144]
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenz-
yl)-N'-(4-isopropoxybenzyl)carbamide, oxalate;
[0145] N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{[2-(1-methyl
pyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide, oxalate;
[0146]
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenz-
yl)-2-(4-isobutoxyphenyl)acetamide, oxalate;
[0147]
N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-iso-
butoxyphenyl)acetamide, tartrate;
[0148]
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenz-
yl)-2-(4-fluorophenyl)acetamide, tartrate;
[0149]
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-fluorophenyl)acetamide, tartrate:
[0150]
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-trifluoromethoxyphenyl)acetamide, tartrate:
[0151]
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-propoxyphenyl)acetamide, tartrate;
[0152]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-[1-(tetrahydropyran-4-yl-
)piperidin-4-yl]acetamide, tartrate;
[0153]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-[1-(tetrahydropyran-4-yl-
methyl)piperidin-4-yl]acetamide, tartrate;
[0154]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran--
4-yl)ethyl]piperidin-4-yl]acetamide, tartrate;
[0155]
N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)p-
iperidin-4-yl]acetamide, tartrate;
[0156]
N-[1-((S)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)--
2-(4-isobutoxyphenyl)acetamide, tartrate;
[0157]
N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorob-
enzyl)-2-(4-isobutoxyphenyl)acetamide, tartrate;
[0158]
2-(4-Benzyloxyphenyl}N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl-
}-N-(4-fluorobenzyl)acetamide, tartrate;
[0159]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-hydroxyphenylacetamide, tartrate;
[0160]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-methoxyphenylacetamide, tartrate;
[0161]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-isopropylphenyl)acetamide, tartrate;
[0162]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-trifluoromethoxy-phenyl)acetamide, tartrate;
[0163]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-ethoxyphenyl)-acetamide, oxalate;
[0164]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-isopropoxyphenyl)acetamide, oxalate;
[0165]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-phenylacetamide, oxalate;
[0166]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-[4-(2-fluoroethoxy)-phenyl]acetamide, oxalate;
[0167]
N-{1-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fl-
uorobenzyl)-2-(4-isobutoxyphenyl)acetamide, oxalate;
[0168]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-
-dioxan-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;
[0169]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[2-((S)-4-methyl-1,3--
dioxolan-2-yl)ethyl]-piperidin-4-yl }acetamide, oxalate;
[0170]
N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-f-
luorobenzyl)-2-(4-isobutoxyphenyl)acetamide, oxalate;
[0171]
N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]
piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;
[0172]
N-(4-Fluorobenzyl)-2-(4-isopropylphenyl)-{1-[2-((S)-4-methyl-1,3-d-
ioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;
[0173]
N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]
piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;
[0174]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[2-(2,5,5-trimethyl-1-
,3-dioxan-2-yl)ethyl] piperidin-4-yl}acetamide, oxalate;
[0175]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dio-
xolan-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;
[0176]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-y-
l)propyl]piperidin-4-yl}acetamide, tartrate;
[0177]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-pr-
opyl)piperidin-4-yl}-acetamide, dihydrochloride;
[0178]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran--
2-yloxy)ethyl]-piperidin-4-yl}acetamide, oxalate;
[0179]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-piperidin--
1-yl)propyl]piperidin-4-yl}acetamide;
[0180]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-
-1-yl)propyl]piperidin-4-yl}acetamide, hydrochloride;
[0181]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl--
2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate;
[0182]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-
-3-yl)propyl]piperidin-4-yl}acetamide, oxalate;
[0183]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-o-
xo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide, tartrate;
[0184]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[3-((S)-4-ethyl-2-oxo-
-oxazolidin-3-yl)-propyl]piperidin-4-yl}acetamide, oxalate;
[0185]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-
-yl)ethyl]piperidin-4-yl}acetamide, L-tartrate;
[0186]
2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-
-(4-fluorobenzyl)-acetamide, L-tartrate;
[0187]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-isobutylamino-phenyl)acetamide, L-tartrate;
[0188]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-propylamino-phenyl)acetamide, L-tartrate;
[0189]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-(1-nitropropyl)-phenyl)acetamide, L-tartrate;
[0190]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-[4-(2-oxopyrrolidin-1-yl)phenyl)acetamide, L-tartrate;
[0191]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-isobutylsulfanyl-phenyl)acetamide, L-tartrate;
[0192]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-iodophenyl)-acetamide, L-tartrate;
[0193]
2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-
-(4-fluorobenzyl)-acetamide, L-tartrate;
[0194]
2-[4-(1-Hydroxyiminoethyl)phenyl}N-{1-[2-(1,3-dioxan-2-yl)ethyl)pi-
peridin-4-yl}-N-(4-fluorobenzyl)acetamide, L-tartrate;
[0195]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-morpholin-4-yl-phenyl)acetamide, L-tartrate;
[0196]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-pyrazol-1-yl-phenyl)acetamide, L-tartrate;
[0197]
N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluor-
obenzyl)-2-(4-iso-butoxyphenyl)acetamide, L-tartrate;
[0198]
N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)--
2-(4-pyrazol-1-yl-phenyl)acetamide, L-tartrate;
[0199]
N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorob-
enzyl)-2-(4-isobutoxyphenyl)acetamide, tartrate; and
[0200]
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)--
2-[4-(1,2,4-triazol-4-yl)phenyl]acetamide, L-tartrate.
[0201] As stated, the present inventors have found that compounds
of Formula I are effective modulators of the 5-HT2A subtype of
human serotonin receptors. The invention thus further relates to a
method of inhibiting an activity of a monoamine receptor comprising
contacting the monoamine receptor or a system containing the
monoamine receptor with an effective amount of one or more of the
compounds as defined herein. The monoamine receptor may be a
serotonin receptor, typically of the 5HT2A subclass.
[0202] The serotonin receptor may alternatively be in the central
nervous system or in the peripheral nervous system. Typically, the
serotonin receptor may be in blood cells or platelets. In certain
embodiments, the serotonin receptor may be mutated or modified.
[0203] The activity of a monoamine receptor that is modulated may
typically be signaling activity. Moreover, the activity may
typically be constitutive. The activity associated with serotonin
receptor may typically be activation.
[0204] In another aspect, the present invention relates to a method
of inhibiting an activation of a monoamine receptor comprising
contacting the monoamine receptor or a system containing the
monoamine receptor with an effective amount of one or more of the
compounds as defined herein. The activation, which may be inhibited
by the method of the invention, may typically be an activation
resulting from an agonistic agent. The agonistic agent may be
exogenous or the agonistic agent may be endogenous. Moreover, the
activation may be constitutive.
[0205] Another aspect of the present invention relates to the
treatment of disease conditions associated with dysfunction of a
monoamine receptor and to the use of a compound of Formula I for
the preparation of a medicament for the treatment of a disease
condition associated with a monoamine receptor. The disease
condition may be associated with activation of a monoamine
receptor, such as associated with increased activity of monoamine
receptor.
[0206] In yet another aspect, the present invention relates to a
method of treating schizophrenia comprising administering to a
subject in need of such treatment a therapeutically effective
amount of a compound of Formula I, as defined herein. Alternatively
stated, the invention relates, in part, to the use of a compound of
Formula I for the preparation of a medicament for the treatment of
schizophrenia. A further aspect relates to a method of treating
migraine comprising administering to a subject in need of such
treatment a therapeutically effective amount of a compound of
Formula I. Alternatively stated, the invention relates, in part, to
the use of a compound of Formula I for the preparation of a
medicament for the treatment of migraine. A further aspect of the
invention relates to a method of treating psychosis comprising
administering to a subject in need of such treatment a
therapeutically effective amount of a compound of Formula I.
Alternatively stated, the invention relates, in part, to the use of
a compound of Formula I for the preparation of a medicament for the
treatment of psychosis. A still further aspect of the invention
relates to a method of treating psychotic symptoms, such as
hallucinations, consequent of administration of dopamine agonists,
such as L-dopa, to individuals in need of treatment, such as people
suffering from Parkinson's comprising administering a compound of
Formula I. Alternatively stated, the invention relates, at least in
part, to the use of a compound of Formula I for the preparation of
a medicament for the treatment of psychotic symptoms, such as
hallucinations, consequent of administration of dopamine agonists,
such as L-dopa, to individuals in need of treatment, such as people
suffering from Parkinson's disease.
[0207] Another aspect of the present invention relates to a method
of treating a disease condition associated with a monoamine
receptor comprising administering to a subject in need of such
treatment a therapeutically effective amount of one or more of the
compound of Formula I, as defined herein. The disease condition may
be selected from the group consisting of schizophrenia,
schizoaffective disorders; psychosis and related behavioral
abnormalities observed with neurodegenerative disorders including
Parkinson's, Alzheimer's disease, Lewy Body Dementia,
Frontotemporal Dementia, Huntington's disease, and Spinocerebellar
Atrophy; drug induced psychosis including side effects observed
with selective serotonin reuptake inhibitor (SSRI) treatment of
chronic neurodegenerative disorders such as Alzheimer's,
Parkinson's and Huntington's disease; Reynaud's Phenomena;
migraine; hypertension; thrombosis; vasospasm; ischemia;
depression; anxiety; "motor tics"; Tourette's syndrome;
dyskinesias, on/off phenomena, tremor, rigidity, bradykinesia,
psychomotor slowing, addiction, including alcohol addiction, opioid
addiction, and nicotine addiction; sleep disorders; appetite
disorders; decreases in libido and ejaculatory problems. Thus, the
invention thus relates to the use of a compound of Formula I, as
defined herein, for the preparation of a medicament for the for the
treatment of diseases and conditions selected from the group
consisting of schizophrenia, schizoaffective disorders; psychosis
and related behavioural abnormalities observed with
neurodegenerative disorders including Parkinson's, Alzheimer's
disease, Lewy Body Dementia, Frontotemporal Dementia, Huntington's
disease, and Spinocerebellar Atrophy; drug induced psychosis
including side effects observed with SSRI treatment of chronic
neurodegenerative disorders such as Alzheimer's, Parkinson's and
Huntington's disease; Reynaud's Phenomena; migraine; hypertension;
thrombosis; vasospasm; ischemia; depression; anxiety; "motor tics";
Tourette's syndrome; dyskinesias, on/off phenomena, tremor,
rigidity, bradykinesia, psychomotor slowing, addiction, including
alcohol addiction, opioid addiction, and nicotine addiction; sleep
disorders; appetite disorders; decreases in libido and ejaculatory
problems.
[0208] Another aspect of the present invention relates to the
treatment of drug induced psychosis and the treatment of side
effects observed with SSRI treatment behavioural aspects of chronic
neurodegenerative disorders, typically to the treatment of
psychotic symptoms, such as hallucinations, consequent of
administration of dopamine agonists, such as L-dopa, to individuals
in need of treatment, such as people suffering from
Parkinson's.
[0209] Similarly, aspects of the invention relate to a method for
the treatment of diseases and conditions as described herein
comprising administering an adjunctive or therapeutic amount of one
or more of the compound of Formula I. The invention thus relates to
the use of a compound of Formula I for the preparation of a
medicament for the treatment of diseases and conditions as
described herein wherein the compound of Formula I is the sole
active agent in the medicament or is an adjunctive wherein the
medicament further comprises an agent known to the person skilled
in the art for the treatment of said diseases and conditions.
[0210] Other aspects of the invention relate to pharmaceutical
compositions comprising an effective amount of a compound of
general Formula I. Compounds of the present invention may be
administered in any of the foregoing compositions and according to
dosage regimens established in the art whenever specific
pharmacological modification of the activity of monoamine receptors
is required.
[0211] Aspects of the present invention also provide pharmaceutical
compositions comprising one or more compounds of the invention
together with a pharmaceutically acceptable diluent or excipient.
Preferably such compositions are in unit dosage forms such as
tablets, pills, capsules (including sustained-release or
delayed-release formulations), powders, granules, elixirs,
tinctures, syrups and emulsions, sterile parenteral solutions or
suspensions, aerosol or liquid sprays, drops, ampoules,
auto-injector devices or suppositories; for oral, parenteral (e.g.,
intravenous, intramuscular or subcutaneous), intranasal, sublingual
or rectal administration, or for administration by inhalation or
insufflation, and may be formulated in an appropriate manner and in
accordance with accepted practices such as those disclosed in
Remington's Pharmaceutical Sciences, (Gennaro, ed., Mack Publishing
Co., Easton Pa., 1990, herein incorporated by reference).
Alternatively, the compositions may be in sustained-release form
suitable for once-weekly or once-monthly administration; for
example, an insoluble salt of the active compound, such as the
decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. The present invention also contemplates
providing suitable topical formulations for administration to,
e.g., eye or skin or mucosa.
[0212] A further aspect of the invention relates to a method for
identifying a genetic polymorphism predisposing a subject to being
responsive to one or more of the compounds of Formula I, as defined
herein, comprising:
[0213] administering to a subject a therapeutically effective
amount of the compound;
[0214] measuring the response of said subject to said compound,
thereby identifying a responsive subject having an ameliorated
disease condition associated with a monoamine receptor; and
identifying a genetic polymorphism in the responsive subject,
wherein the genetic polymorphism predisposes a subject to being
responsive to the compound. The ameliorated disease condition is
typically associated with the 5-HT class or 5-HT2A subclass of
monoaminergic receptors.
[0215] A further aspect of the invention relates to a method for
identifying a subject suitable for treatment with one or more of
the compounds of Formula I, comprising detecting the presence of a
polymorphism in a subject wherein the polymorphism predisposes the
subject to being responsive to the compound, and wherein the
presence of the polymorphism indicates that the subject is suitable
for treatment with one or more of the compounds of Formula I.
Methods of Preparation
[0216] The compounds in accordance with the present invention may
be synthesized by methods described below, or by modification of
these methods. Ways of modifying the methodology include, among
others, temperature, solvent, reagents etc, and will be obvious to
those skilled in the art.
[0217] For instance, compounds of the formula C may be synthesized
from the corresponding ketone A by reductive amination utilizing
any primary amine. The reaction is conveniently carried out by
stirring the reactants in an inert solvent such as methanol or
ethanol containing acetic acid. As reducing agent NaBH.sub.4,
NaCNBH.sub.3, BH.sub.3.pyridine or any related reagent may be used
including solid-supported reagents. The reaction is typically
carried out at room temperature. The ketone A, as exemplified by
the piperidone, may be chosen from a list of compounds
corresponding to the Z-group listed in formula (I). The ketones can
either be obtained commercially or synthesized by methodology
disclosed in Lowe et al. J Med. Chem. 37: 2831-40 (1994); Carroll
et al. J. Med. Chem. 35:2184-91 (1992); or Rubiralta et al.
Piperidine--Structure, Perparation, Reactivity and Synthetic
Applications of Piperidine and its Derivatives. (Studies in Organic
Chemistry 43, Elsevier, Amsterdam, 1991). The protecting group P
includes groups such as those described in T. W. Greene and P. G.
M. Wuts, Protective Groups in Organic Chemistry, 3. Ed. John Wiley
& Sons, 1999, and they should be chosen in such a way, that
they are stable to the reaction conditions applied and readily
removed at a convenient stage using methodology known from the art.
Typical protecting groups are N-Boc, N-Cbz, N-Bn.
[0218] Alternatively, the amine C can be synthesized from the
primary amine B by reductive amination with any aldehyde. The
reaction is conveniently carried out by stirring the reactants in
an inert solvent such as methanol or ethanol containing acetic
acid. As reducing agent NaBH.sub.4, NaCNBH.sub.3, BH.sub.3-pyridine
or any related reagent may be used including solid-supported
reagents. The reaction is typically carried out at room
temperature. The primary amine B, as exemplified by the
4-aminopiperidine, may be chosen from a list of compounds
corresponding to the Z-groups listed in formula (I). The amines can
either be obtained commercially or synthesized from the
corresponding ketones. The protecting group P may be chosen as
stated above.
[0219] Alternatively, the amine C can be synthesized from the
primary amine B by alkylation with any alkylating agent
(R-L.sub.1). The leaving group L.sub.1 is suitably a halogen atom,
e.g., bromine or iodine, or a sulfonate, e.g. tosylate or mesylate,
or another leaving group favoring the reaction. The reaction is
conveniently carried out by stirring the reagents under basic
conditions in an inert solvent, e.g., diisopropylethylamine in
acetonitrile, or K.sub.2CO.sub.3 in N,N-dimethylformamide. The
reaction is typically carried out at temperatures between room
temperature and 80.degree. C. The primary amine B, as exemplified
by the 4-aminopiperidine, may be chosen from a list of compounds
corresponding to the Z-groups listed in formula (I). The amines can
either be obtained commercially or synthesized from the
corresponding ketones. The protecting group P may be chosen as
stated above. ##STR5##
[0220] Wherein R and R* are defined in agreement with Formula I,
and P represents a suitable protecting group, and L.sub.1
represents a suitable leaving group.
[0221] The secondary amine C may be acylated using any isocyanate
or isothiocyanate (Q.sub.1-N.dbd.C.dbd.W) to give the corresponding
ureas or thioureas D. The reaction is typically carried out by
stirring the reactants, using an excess of isocyanate or
isothiocyanate in an inert solvent, e.g., dichloromethane at a
temperature between 0.degree. C. and room temperature and under dry
conditions. The amine C may also be acylated using any carboxylic
acid halide (Q.sub.2COX), e.g., chloride, or carboxylic anhydride
((Q.sub.2C.dbd.O).sub.2O) to give amides of the general structure
E. The reaction is typically carried out using an excess of the
acylating agent and a suitable base, e.g., triethylamine or
diisopropylethylamine in an inert solvent, e.g., dichloromethane,
at a temperature between 0.degree. C. and room temperature and
under dry conditions. As an alternative to the carboxylic acid
halides and carboxylic acid anhydrides, the amine C may be acylated
using a carboxylic acid (Q.sub.2COOH) and a suitable coupling
reagent e.g. PyBroP, DCC or EDCI. The reaction is typically carried
out using an excess of the acylating agent and the coupling reagent
in an inert solvent, e.g., dichloromethane at a temperature between
0.degree. C. and room temperature and under dry conditions. The
compounds of the general structure (E) may be converted into the
corresponding thioamides using methodology disclosed in Varma et
al., Org. Lett. 1: 697-700 (1999); Cherkasov et al. Tetrahedron
41:2567 (1985); or Scheibye et al, Bull. Soc. Chim. Belg. 87:229
(1978). ##STR6##
[0222] Wherein R, Q.sub.1, Q.sub.2, and W are defined in agreement
with formula (I), P represents a suitable protecting group, and X
represents a halide.
[0223] The substituent T on the ring nitrogen in compounds F or G
can be introduced by a two step procedure. First, the protecting
group on the urea D or the amide E is removed using well-known
methods. For example, the N-Boc group is removed by treating the
protected compound with 4 M HCl in dioxane or trifluoroacetic acid
in dichloromethane. Second, the secondary amines obtained from D
and E can be alkylated by reductive amination using any aldehyde
(T*-CHO) or ketone (T=O). The reaction is conveniently carried out
by stirring the reactants in an inert solvent such as methanol or
ethanol. As a reducing agent, solid-supported borohydride,
NaBH.sub.4, NaCNBH.sub.3, BH.sub.3-pyridine, H.sub.2/Pd--C or any
related reagent may be used, including solid-supported reagents.
The reaction is typically carried out at room temperature.
[0224] Alternatively, the compounds F and G can be synthesized from
the secondary amine obtained from D or E as described above by
alkylation with any alkylating agent (T-L.sub.1). The leaving group
L.sub.1 is suitably a halogen atom, e.g., bromine or iodine, or a
sulfonate, e.g., tosylate or mesylate, or another leaving group
favoring the reaction. The reaction is conveniently carried out by
stirring the reagents under basic conditions in an inert solvent,
for example diisopropylethylamine in acetonitrile, or
K.sub.2CO.sub.3 in N,N-dimethylformamide. The reaction is typically
carried out at temperatures between room temperature and 80.degree.
C.
[0225] Alternatively, the T-group can be introduced in the first
step of the synthetic sequence leading to the compounds in
accordance with the present invention by N-alkylation of compound H
with any alkylating agent (T-L.sub.1). The leaving group L.sub.1 is
suitably a halogen atom, e.g., bromine or iodine, or a sulfonate,
e.g., tosylate or mesylate, or another leaving group favoring the
reaction. The reaction is conveniently carried out by stirring the
reagent under basic conditions in an inert solvent, e.g.,
diisopropylethylamine in acetonitrile, or K.sub.2CO.sub.3 in
N,N-dimethylformamide. The reaction is typically carried out at
temperatures between room temperature and 80.degree. C.
Alternatively the T-group can be introduced in the first step by
reductive amination using any aldehyde (T*-CHO) or ketone (T=O) and
a suitably protected compound H', exemplified by 4-piperidone
ethylene ketal. The reaction is conveniently carried out by
stirring the reactants in an inert solvent such as methanol or
ethanol. As a reducing agent, solid-supported borohydride,
NaBH.sub.4, NaCNBH.sub.3, BH.sub.3-pyridine, H.sub.2/Pd--C or any
related reagent may be used, including solid-supported reagents.
The reaction is typically carried out at room temperature, but less
reactive carbonyl compounds may require higher temperatures and/or
the pre-formation of the corresponding imine under water removal
before addition of the reducing agent. Removal of the protecting
group gives the desired compound J. The secondary amine H and H',
as exemplified by 4-piperidone and its protected derivative, may be
chosen from a list of compounds corresponding to the Z-groups
listed in formula (I). The amines can either be obtained
commercially or synthesized from methodology disclosed in Lowe et
al., J. Med. Chem. 37:2831-40 (1994); and Carroll et al., J. Med.
Chem. 35:2184-91 (1992).
[0226] Alternatively, compounds of the general structure J may be
synthesized starting from K using the method disclosed in: Kuehne
et al., J. Org. Chem. 56:2701 (1991); and Kuehne et al., J. Org.
Chem. (1991), 56:513. ##STR7##
[0227] Wherein R, Q.sub.1, Q.sub.2, W, and T are defined in
agreement with formula (I), and L.sub.1 is a suitable leaving
group.
[0228] Heterocyclylalkyl alkylating agents such as T-L.sub.1 may be
commercially available or are typically obtained by alkylation of a
heterocycle with a bifunctional alkyl- linker, as shown below. The
leaving groups L.sub.1 and L.sub.2 are suitably a halogen atom,
e.g., chlorine, bromine or iodine, or a sulfonate, e.g., tosylate
or mesylate, or another leaving group favoring the reaction. The
reaction is conveniently carried out by stirring the reagent under
basic conditions in an inert solvent, e.g., diisopropylethylamine
in acetonitrile, or K.sub.2CO.sub.3 in N,N-dimethylformamide. The
reaction is typically carried out at temperatures between room
temperature and 80.degree. C. The alkylating agent hence obtained
can be either reacted in situ in the next step with the secondare
amine (i.e. deprotected D/E, or H) or isolated from the reaction
mixture before its further use. Heterocyclylalkyl alcohols such as
T*-CH.sub.2OH or T-OH may also be converted into suitable
alkylating agents T-L, by transforming the hydroxyl into a leaving
group, e.g. by tosylation, mesylation or halogenation.
Alternatively, T*-CH.sub.2OH or T-OH may be oxidized to the
corresponding aldehydes or ketones T*-CHO or T=O with, for example,
pyridinium chlorochromate, CrO.sub.3-H.sub.2SO.sub.4, or via the
Swern or Dess-Martin procedures, to be used in a reductive
amination step with the secondary amines as described above.
##STR8##
[0229] Wherein Y, p and T are defined in agreement with formula
(I), and L.sub.1 and L.sub.2 are suitable leaving groups.
[0230] The building blocks incorporating the aromatic groups
Ar.sub.1 and Ar.sub.2 may either be obtained commercially or
synthesized from methodology disclosed in the literature. The
introduction of substituents on Ar.sub.1 and Ar.sub.2 may be
performed from a suitable precursor at any appropriate stage of the
preparation of the compounds.
[0231] For instance, compounds containing an alkoxy substituents
may be typically prepared by Williamson ether synthesis from the
corresponding hydroxyaryl derivatives.
[0232] Structures bearing an amine substituent on Ar.sub.1 or
Ar.sub.2 may be obtained from a suitable halo- or pseudohalo
precursor (e.g. Br, I--, Cl--, triflate-, nonaflate-,
tosylate-substituted aryl derivatives) by metall-catalyzed
amination chemistries, such as Pd-- or Ni-- (Hartwig, Angew. Chem.
Int. Ed., 1998, 37, 2046-2067; Yang & Buchwald, J.
Organometallic Chem., 1999, 576, 125-146; Hartwig in Modern
Amination Methods; Ricci, Ed.; Wiley-VCH: Weinheim, Germany, 2000)
or Cu-catalyzed (Buchwald et al, Org. Lett., 2002, 4, 581-584;
Kwong & Buchwald, Org. Lett., 2003, 5, 793-796). Alternatively,
these compounds can be obtained from aniline-based precursors
either by alkylation (Hickinbottom, J. Chem. Soc. 1930, 992), or by
reductive amination (Emerson & Walters, J. Am. Chem. Soc.,
1938, 60, 2023; Milovic et al, Synthesis, 1991, 11, 1043-1045), or
by dehydrative alkylation (Rice & Kohn, J. Am. Chem. Soc.,
1955, 77, 4052; Brown & Reid, J. Am. Chem. Soc., 1924, 46,
1838). Additionally, compounds of this type may also be synthesized
from corresponding boronic acids by Cu-catalyzed coupling (Antilla
& Buchwald, Org. Lett., 2001, 3, 2077-2079).
[0233] The structures bearing an amide substituent on Ar.sub.1 or
Ar.sub.2 may be obtained from a suitable halo- or pseudohalo
precursor either by Pd catalyzed (Yin & Buchwald, J. Am. Chem.
Soc., 2002, 124, 6043-6048) or by Cu catalyzed (Buchwald et al, J
Am. Chem. Soc., 2002, 124, 7421-7428) amidation chemistries.
Alternatively, these compounds may also be obtained from the
corresponding aniline precursors either by acylation (Wolf, Liebigs
Ann. Chem., 1952, 576, 35; Yasukara et al, J. Chem. Soc. Perkin
Trans. 1, 2000, 17, 2901-2902; Nigam & Weedon, J. Chem. Soc.,
1957, 2000) or by formylation (Hirst & Cohen, J. Chem. Soc.,
1895, 67, 830; Olah & Kuhn, Chem. Ber. 1956, 89, 2211; Guthrie
et al, Can. J Chem., 1993, 71, 2109-2122).
[0234] Compounds that carry an alkylsulfanyl substituent on
Ar.sup.1 or Ar.sub.2 be obtained from a suitable halo- or
pseudohalo precursor by Pd catalyzed (Li, J. Org. Chem., 2002, 67,
3643-3650), or Cu catalyzed (Kwong & Buchwald, Org. Lett.,
2002, 4, 3517-3520) thioetherification chemistry. Alternatively,
these compounds may be prepared by alkylation of corresponding
benzenethiol precursors (Vogel, J. Chem. Soc., 1948, 1809; Landini
& Rocca, Synthesis, 1974, 565-566; Bun-Hoi et al, J. Org Chem.,
1951, 16, 988). Alternatively, alkylarylsulfanyls may be obtained
by irradiation of benzenethiols and alkenes (Screttas &
Micha-Screttas, J. Org. Chem., 1978, 43, 1064-1071).
[0235] Compounds of the invention bearing an acyl group on Ar.sub.1
or Ar.sub.2 may be prepared from corresponding aryl iodides by Pd
catalyzed (Cacchi et al, Org. Lett, 2003, 5, 289-293) acylation
chemistry. Alternatively, they may be obtained from the
corresponding benzenes by Friedel-Crafts chemistry (Read, J. Am.
Chem. Soc., 1922, 44, 1746-1755), or by addition of aryl-Grignard
reagents to nitrites (Whitmore et al, J. Am. Chem. Soc., 1947, 69,
235-237) or to acyl chlorides (Whitmore & Lester, J. Am. Chem.
Soc., 1942, 64, 1247), or by either Pd-catalyzed (Goo.beta.en &
Ghosh, Angew. Chem. Int. Ed. Engl., 2001, 40, 3458-3460) or
Rh-catalyzed acylation of arylboronic acids.
[0236] Compounds of the invention that bear an N-containing
aromatic heterocycle on Ar.sub.1 or Ar.sub.2 can be obtained either
by metall-catalyzed cross-couplings (Buchwald et al, Org. Lett.,
2002, 2, 1403-1406; Buchwald et al, J. Am. Chem. Soc., 2001, 123,
7727-7729; Buchwald et al, J. Am. Chem. Soc., 2002, 124,
11684-11688). Alternatively, they may be accessed from suitable
precursors such as aryl hydrazines, aryl amines or aryl nitrites
according to literature procedures (e.g. Alvisi, Gazz. Chem. Ital.,
1892, 22, 159; Finar, Godfrey, J. Chem. Soc., 1954, 2293; Muri et
al, Synth. Commun., 1998, 28, 1299-1321; Artico et al, Europ. J.
Med. Chem. Chim. Ther., 1992, 27, 219-228; Biagi et al., Farmaco
Ed. Sci. 1988, 43, 597-612; Stefancich et al, Farmaco Ed. Sci.,
1984, 39, 752-764).
[0237] In general, during any of the processes for preparation of
the compounds of the present invention, it may be necessary and/or
desirable to protect sensitive or reactive groups on any of the
molecules concerned. This may be achieved by means of conventional
protecting groups, such as those described in Protective Groups in
Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and
Greene & Wuts, Protective Groups in Organic Synthesis, John
Wiley & Sons, 1991. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
EXAMPLES
[0238] The examples below are non-limiting and are only
illustrative of some of the embodiments of the present
invention.
Chemical Synthesis
[0239] General procedures. .sup.1H NMR spectra were recorded at 400
MHz on a Varian Mercury-VX400 MHz spectrometer and chemical shifts
are given in 6-values [ppm] referenced to the residual solvent peak
chloroform (CDCl.sub.3) at 7.26 and methanol (CD.sub.3OD) at 3.31
ppm. Coupling constants, J, are reported in Hertz. Unless otherwise
stated, the NMR spectra of the compounds are described for their
free amine form. Due to the presence of rotamers, two sets of
signals are generally observed and rotamer ratios are reported.
Where the corresponding signals for each of the two rotamers could
unmistakably be identified, they are reported together [e.g.
4.66-4.58 and 3.76-3.68 (2m, 1H)]. Acidic ion-exchange solid phase
extraction (SPE) cartridges were MEGA BE-SCX from Varian.
[0240] Materials and solvents were of the highest grade available
from commercial sources and were used without further
purification.
[0241] HPLC/LCMS Method. The analysis was performed on a combined
prep/analytical Waters/Micromass system consisting of a ZMD single
quadropole mass spectrometer equipped with electrospray ionization
interface. The HPLC system consisted of a Waters 600 gradient pump
with on-line degassing, a 2700 sample manager and a 996 PDA
detector. Separation was performed on an X-Terra MS C18, 5 .mu.m
4.6.times.50 mm column. Buffer A: 10 mM ammoniumacetate in water,
buffer B: 10 mM ammoniuacetate in acetonitrile/water 95/5. A
gradient was run from 30% B to 100% B in 7 min, hold at 100% B for
1 min and re-equilibrated for 5.5 min. The system was operated at 1
ml/min.
[0242] Preparation of hydrochloride salts. Typically, the tertiary
amines were dissolved in dichloromethane, treated with an excess of
1M HCl in diethylether and precipitated from n-heptane. The
solvents were removed in vacuo and after drying, the hydrochloride
salts were obtained as colourless solids.
[0243] Preparation of oxalate or tartrate salts. Typically, the
tertiary amines were dissolved in methanol, treated with 1 eq. of
the appropriate acid, the solvent removed and the salt redissolved
in dichloromethane and precipitated from n-heptane. The solvents
were removed in vacuo affording the salts as colourless solids.
Preparation of Phenylacetyl Chloride Derivatives
[0244] The phenylacetic acid derivative (15 mmol) was dissolved in
dichloromethane (100 mL), and oxalylchloride (45 mmol) was added
slowly. The reaction mixture was stirred for 4 hours and then
evaporated to dryness. The product was obtained as a colourless oil
and used immediately after preparation in the acylation step.
4-Isobutoxyphenylacetic acid (128NLS28)
[0245] Methyl 4-hydroxyphenyl acetate (14.6 g, 0.0885 mol) was
dissolved in DMF (200 mL), potassium carbonate (31.0 g, 0.224 mmol)
added and the mixture was stirred for 1 h at rt.
1-Bromo-2-methylpropane (19.2 mL, 0.177 mol) was added and the
mixture was heated at 80.degree. C. for 3 days under vigorous
stirring. The mixture was cooled to rt, filtered, the solvent
removed and the residue partitioned between 1.5M NaOH and ethyl
acetate. The organic layer was evaporated, the residue dissolved in
methanol (100 mL) and water (100 mL), KOH (10 g, 0.178 mol) added
and the mixture stirred overnight at rt. The methanol was removed
by evaporation, the mixture extracted with dichloromethane. The
organic layer was discarded, the aqueous layer acidified with 4M
HCl to pH2-3 and extracted twice with dichloromethane. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
evaporated to give the title compound (16.9 g, 92%) as a colourless
solid.
4-Propoxyphenylacetic acid (98AF77-66)
[0246] Prepared as described for 128NLS28 using propylbromide as
the alkylating agent.
4-Isopropoxyphenylacetic acid (130AF24-163)
[0247] Prepared as described for 128NLS28 using isopropylbromide as
the alkylating agent.
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4--
isobutoxybenzyl)carbamide hydrochloride (80MBT86-2C)
[0248] 4-Piperidone hydrochloride monohydrate (4.0 g, 26.0 mmol)
was dissolved in dichloromethane (130 mL). After addition of
triethylamine (8.66 g, 85.8 mmol), the mixture was stirred for 10
min and then cooled to 0.degree. C. Trifluoroacetic anhydride (12.0
g, 57.2 mmol) was added dropwise under stirring. After 2 h at room
temperature, the reaction was stopped by addition of water (100
mL), and the aqueous phase was extracted with dichloromethane
(2.times.100 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
1-(trifluoroacetyl)-4-piperidone (5.07 g, 100%).
[0249] 4-Fluorobenzylamine (3.14 g, 25.9 mmol) was dissolved in
methanol (150 mL). 1-(trifluoroacetyl)-4-piperidone (5.07 g, 25.9
mmol) was added, and the pH was adjusted to .about.5 with acetic
acid. The reaction mixture was stirred for 5 min and NaBH.sub.3CN
(2.46 g, 38.9 mmol) was added slowly under stirring. After 20 h at
room temperature the reaction was concentrated. 2 M NaOH (100 mL)
was added and the aqueous phase was extracted with dichloromethane
(2.times.100 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
N-(4-fluorobenzyl)-1-(trifluoroacetyl)piperidin-4-amine (50ELH85,
2.91 g, 37%).
[0250] 4-isobutoxyphenylacetic acid (7.6 g, 36.5 mmol) was
dissolved in THF (50 mL). Proton Sponge.TM. (8.2 g, 38 mmol) was
added, and the mixture was stirred for 15 min. Diphenylphosphoryl
azide (10.6 g, 38 mmol) was added dropwise and the mixture was
heated to reflux for 4 h. The mixture was cooled to room
temperature and placed in the freezer at -18.degree. C. for 20 h.
The resulting white precipitate was vigorously stirred with diethyl
ether (250 mL) for 15 min and filtered. The filtrate was evaporated
to give crude 4-isobutoxybenzyl isocyanate (1.97 g, 9.6 mmol),
which was dissolved in dichloromethane (50 mL) and added to a
solution of 50ELH85 (2.91 g, 9.6 mmol) in dichloromethane (50 mL).
The reaction mixture was stirred for 20 h and concentrated. The
crude product was purified by flash chromatography (0-5% methanol
in dichloromethane) to give
N-(4-fluorobenzyl)-N-[1-(trifluoroacetyl)piperidin-4-yl]-N'-(4-is-
obutyloxybenzyl)carbamide (76ELH17, 3.90 g, 91%).
[0251] The compound 76ELH17 (3.90 g, 8.7 mmol) was dissolved in
methanol (12 ml) and added to a 2 M solution of potassium carbonate
in methanol (100 mL) under stirring. After 4 h the methanol was
evaporated, and the aqueous phase was extracted with
dichloromethane (2.times.100 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and concentrated to give a
semi-pure solid (2.95 g), which was purified by flash
chromatography (10% methanol in dichloromethane with 1%
triethylamine) to give
N-(4-fluorobenzyl)-N-(piperidin-4-yl)-N'-(4-isobutyloxybenzyl)carbamide
(76ELH 18, 1.40 g, 39%) as a colourless solid. LCMS m/z 414
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3): .delta. 7.21-6.75 (m, 8H),
4.47-4.42 (m, 1H), 4.39 (t, J=5 Hz, 1H), 4.35 (s, 2H), 4.27 (d, J=5
Hz, 2H), 3.68 (d, J=6 Hz, 2H), 3.13-3.06 (m, 2H), 2.74-2.66 (m,
2H), 2.11-1.99 (m, 1H), 1.78-1.71 (m, 3H), 1.58-1.46 (m, 2H), 1.00
(d, J=6 Hz, 6H).
[0252] The compound 76ELH18 (200 mg, 0.484 mmol) was dissolved in
acetonitrile (20 mL). Potassium carbonate (74 mg, 0.553 mmol) and
sodium iodide (80 mg, 0.553 mmol) was added followed by
2-(2-bromoethyl)-1,3-dioxolane (100 mg, 0.553 mmol). The reaction
mixture was heated to reflux for 20 h. The mixture was
concentrated, water (50 mL) was added, and the aqueous phase was
extracted with dichloromethane (2.times.50 mL). The combined
organic phases were dried over Na.sub.2SO.sub.4, filtered and
evaporated. The resulting oil was purified twice by flash
chromatography (5% methanol in dichloromethane) to give a
colourless oil (50 mg, 20%). R.sub.f=0.70 (MeOH/CH.sub.2Cl.sub.2
1:9). LCMS m/z 514 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3): .delta.
7.21-6.75 (m, 8H), 4.94 (t, J=4.5 Hz, 1H), 4.73-4.62 (m, 1H), 4.58
(t, J=5.5 Hz, 1H), 4.41 (s, 2H), 4.26 (d, J=5.5 Hz, 2H), 4.00-3.80
(m, 4H), 3.68 (d, J=6.0 Hz, 2H), 3.43-3.35 (m, 2H), 2.94-2.87 (m,
2H), 2.68-2.57 (m, 2H), 2.45-2.32 (m, 2H), 2.20-2.13 (m, 2H),
2.10-2.00 (m, 1H), 1.88-1.81 (m, 2H), 1.00 (d, J=6.0 Hz, 6H). HPLC
t.sub.R=8.1 min.
[0253] The collected compound was converted into its hydrochloride
salt, which was obtained as a colourless solid (80MBT86-2C).
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2--
hydroxy-2-methylpropoxy)phenyl]acetamide, tartrate (106MBT54D)
[0254] Methyl (4-hydroxyphenyl)acetate (500 mg, 3.0 mmol) was
dissolved in DMF (3 mL). K.sub.2CO.sub.3 (829 mg, 6.0 mmol) was
added followed by isobutylene oxide (800 .mu.L, 9.0 mmol). The
mixture was heated to 150.degree. C. by microwave irradiation for
30 min and concentrated. The residue was dissolved in a 1:1 mixture
of methanol and water (20 mL). NaOH (1 g) was added and the mixture
was stirred for 30 min. Methanol was removed by rotary evaporation.
The aqueous phase was acidified by 4 M HCl and extracted with
dichloromethane (2.times.50 mL). The combined organic phases were
extracted with 2 M NaOH (2.times.50 mL). The combined aqueous
phases were subsequently acidified by 4 M HCl and extracted with
dichloromethane (2.times.50 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated to afford
[4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid (106MBT52-D, 470
mg, 70%) as a colourless solid. .sup.1H-NMR (CDCl.sub.3): .delta.
7.19 (m, 2H), 6.88 (m, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 1.34 (s.
6H).
[0255] The acid 106MBT52-D (150 mg, 0.67 mmol) was dissolved in
dichloromethane (10 mL).
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine
(118AF52-95, 180 mg, 0.56 mmol) was added followed by triethylamine
(235 .mu.L, 0.84 mmol). Bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate (PyBroP, 392 mg, 0.84 mmol) was added, and the
mixture was stirred at room temperature for 2 h. The mixture was
concentrated and passed onto a prewashed (methanol) ion exchange
column (0.88 mmol/g, 1 g). The column was washed with methanol
(8.times.4 mL) and the remaining product was eluted off the column
with 10% NH.sub.4OH in methanol (2.times.4 mL) and evaporated. The
resulting oil was dissolved in dichloromethane (20 mL) and washed
with saturated aqueous NaHCO.sub.3 (5.times.20 mL). The organic
phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. The
resulting oil was purified by flash chromatography (0-5% methanol
in dichloromethane) to give a colourless oil (110 mg, 31%).
R.sub.f=0.64 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 529 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, rotamers 0.4:0.6): .delta. 7.25-6.82 (m,
8H), 4.64-4,48 (m, 2.4H), 4.44 (s, 1.2H), 4.10-4.03 (m, 2H),
3.79-3.67 (m, 5.2H), 3.50 (s, 1.2H), 2.90-2.81 (m, 2H), 2.42-3.95
(m, 2H), 2.12-1.98 (m, 2.2H), 1.87-1.79 (m, 0.8H), 1.76-1.48 (m,
5.2H), 1.36-1.27 (m, 7.8H). HPLC t.sub.R=6.1 min.
[0256] The collected compound was converted into its tartrate salt,
which was obtained as a colourless solid (106MBT54-D).
N-(4-Fluorobenyzl)-N-(piperidin-4-yl)-2-(4-isobutoxyphenyl-acetamide
(103NLS56)
[0257] To a solution of the amine 118AF93-51 (10.37 g, 30.3 mmol)
and triethylamine (9.36 mL, 60.6 mmol) in dichloromethane (200 mL)
a solution of 4-isobutoxyphenylacetyl chloride 128NLS28 (8.93 g,
39.4 mmol) in dichloromethane (100 mL) is added dropwise at
0.degree. C. The solution is stirred at rt for 3 h, then water is
added and the mixture washed with sat. aq. NaHCO3. The organic
layer was washed with 5% HCl, water and brine, dried over sodium
sulfate, filtered and evaporated in vacuo. The residue was purified
by silica gel column chromatography eluting with a stepwise
gradient of 0-50% ethyl acetate in n-heptane, affording
N-(4-Fluorobenyzl)-N-[1-(benzyloxycarbonyl)piperidin-4-yl]-2-(4-isobutoxy-
phenyl)acetamide as a colourless oil.
[0258] This compound was dissolved in abs. ethanol (200 mL) and
hydrogenated overnight at rt using Pd/C (10%, 1 g) as a catalyst.
The mixture was filtered over Celite, the solvent removed and the
residue dried in vacuo to give a colourless oil (7.02 g, 58% over
both steps). This compound was used without further purification.
LCMS m/z 399 [M+H].sup.+.
[0259] HPLC t.sub.R=8.8 min.
N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenz-
yl)-2-(4-isobutoxyphenyl)acetamide dihydrochloride (103NLS45-B)
[0260] To 3,5-dimethylpiperidine (43 .mu.L, 0.33 mmol) in DMF (1
mL) was added potassium carbonate (132 mg, 1.0 mmol), followed by
1-chloro-3-iodopropane (32 .mu.mol, 0.30 mmol) and the mixture
stirred at 50.degree. C. for 2 h. After cooling to rt, a solution
of 103NLS56 (100 mg, 0.25 mmol) in DMF (0.5 mL) was added, followed
by sodium iodide (45 mg, 0.30 mmol). The mixture was shaken for 20
h at 60.degree. C., filtered, evaporated to dryness and purified by
silica gel column chromatography, eluting with a stepwise gradient
of 0-10% methanol in dichloromethane. The residue was further
purified by passage over a reversed phase C.sub.18 SPE cartridge,
giving the desired compound (35 mg, 25%), which was converted into
its dihydrochloride salt.
[0261] R.sub.f=0.61 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 552
[M+H].sup.+. HPLC t.sub.R=8.7 min.
1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino}piperidin-1-y-
l)propyl]piperidine-4-carboxylic acid methyl ester, dihydrochloride
(103NLS45E)
[0262] Prepared following the same method as described for
103NLS45-B, using piperidine-4-carboxylic acid methyl ester (44
.mu.L, 0.33 mmol). Yield: 7 mg, 5%.
[0263] LCMS m/z 582 [M+H].sup.+. HPLC t.sub.R=7.8 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolidin-2-yl)-
ethyl]piperidin-4-yl}acetamide, dioxalate (103NLS63-G).
[0264] To a solution of the amine 103NLS56 (15 mg, 0.038 mmol) in
DMF (0.3 mL) was added a solution of
2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (8.4 mg, 0.045
mmol) in DMF (0.1 mL), followed by caesium carbonate (50 mg, 0.15
mmol) and sodium iodide (6.8 mg, 0.045 mmol). The mixture was
stirred overnight at 60.degree. C., partitioned between
dichloromethane and sat. aq. NaHCO.sub.3 solution. The organic
layer was dried over sodium sulfate, filtered and evaporated. The
residue was purified by preparative reversed phase (C.sub.18) HPLC
and the obtained compound (10.5 mg, 54%) converted into its
dioxalate salt.
[0265] LCMS m/z 510 [M+H].sup.+. HPLC t.sub.R=8.1 min.
N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl}-N-(4-fluorobenz-
yl)-2-(4-isobutoxyphenyl)acetamide, dioxalate (103NLS69-A)
[0266] To a solution of 2,6-dimethylmorpholine (6.1 .mu.L, 49
.mu.mol) in DMF (0.3 mL) 1-chloro-3-iodopropane (4.9 .mu.L, 45
.mu.mol) in DMF (0.05 mL) was added, followed by caesium carbonate
(50 mg, 0.15 mmol). The mixture was shaken at 50.degree. C. for 3
h. After cooling to rt, the piperidine derivative 103NLS56 (15 mg,
38 .mu.mol) in DMF (0.1 mL) and sodium iodide (6.8 mg, 45 .mu.mol)
were added and stirring maintained overnight at 60.degree. C. The
mixture was partitioned between dichloromethane and sat. aq.
NaHCO.sub.3 solution. The organic layer was dried over sodium
sulfate, filtered and evaporated. The residue was purified by
preparative reversed phase (C.sub.18) HPLC and the obtained
compound (6.3 mg, 30%) converted into its dioxolate salt.
[0267] LCMS m/z 554 [M+H].sup.+. HPLC t.sub.R=8.7 min.
N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperidin-4-yl}-
-2-(4-isobutoxyphenyl)acetamide, dioxalate (103NLS69-B)
[0268] Prepared following the same method as described for
103NLS69-A, using 3-hydroxypiperidine hydrochloride (6.8 mg, 49
.mu.mol). Yield: 7.9 mg, 30%. LCMS m/z 540 [M+H].sup.+. HPLC
t.sub.R=8.1 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-methylpiperidin-1-yl)p-
ropyl]piperidin-4-yl}acetamide, dioxalate (103NLS69-C)
[0269] Prepared following the same method as described for
103NLS69-A, using 2-methylpiperidine (5.8 .mu.L, 49 .mu.mol).
Yield: 5.2 mg, 26%. LCMS m/z 538 [M+H].sup.+. HPLC t.sub.R=8.7
min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-pyrrolidin-1-yl-propyl)pi-
peridin-4-yl]acetamide dioxalate (103NLS69-D
[0270] Prepared following the same method as described for
103NLS69-A, using pyrrolidine (5.0 .mu.L, 49 .mu.mol). Yield: 4.6
mg, 24%. LCMS m/z 510 [M+H].sup.+. HPLC t.sub.R=8.4 min.
N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluoroben-
zyl)-2-(4-isobutoxyphenyl)acetamide, dioxalate (103NLS69-E)
[0271] Prepared following the same method as described for
103NLS69-A, using 2,5-dimethylpyrrolidine (6.0 .mu.L, 49 .mu.mol).
Yield: 3.4 mg, 17%. LCMS m/z 538 [M+H].sup.+. HPLC t.sub.R=8.7
min.
N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]piperidin-
-4-yl}-2-(4-isobutoxyphenyl)acetamide, dioxalate (103NLS69-F)
[0272] Prepared following the same method as described for
103NLS69-A, using 3-hydroxymethylpiperidine (5.5 .mu.L, 49
.mu.mol). Yield: 5.5 mg, 26%. LCMS m/z 554 [M+H].sup.+. HPLC
t.sub.R=8.0 min.
(4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one
(103NLS94)
[0273] Sodium hydride (60% suspension in oil, 288 mg, 7.2 mmol) was
added to a solution of (S)-4-isopropyl-2-oxazolidinone (775 mg, 6.0
mmol) in dry tetrahydrofuran (50 mL) under argon atmosphere. The
suspension was stirred for 15 min at rt, then
1-bromo-3-chloropropane (1.18 mL, 12.0 mmol) was added dropwise
over 30 min. The mixture was refluxed overnight, filtered and the
filtrate evaporated in vacuo. Purification of the residue by silica
gel column chromatography, eluting with a stepwise gradient of 0-4%
methanol in dichloromethane afforded
(4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (824 mg, 67
%) as a colourless oil.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-ox-
azolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate (11
7NLS01)
[0274] To a solution of 103NLS56 (207 mg, 0.52 mmol) potassium
carbonate (215 mg, 1.56 mmol) was added, followed by the alkylating
agent 103NLS94 (127 mg, 0.62 mmol) and sodium iodide (93 mg, 0.62
mmol). The mixture was stirred at 65.degree. C. overnight, the
solvent removed and the residue partitioned between ethyl acetate
and water. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue was purified by silica gel
column chromatography, eluting with a stepwise gradient of 0-4%
methanol in dichloromethane. Further purification of the compound
was performed by passage over an acidic ion exchange SPE cartridge,
affording the desired compound (209 mg, 71%) as a colourless oil,
which was converted into its oxalate salt.
[0275] R.sub.f=0.35 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 568
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.21-6.80 (m, 8H, Ar--H), 4.60-4.53 (m, 0.6H, pip-H), 4.49 and 4.43
(2s, 2H, benzyl-H), 4.19-4.14 (m, 1H, oxa-CH.sub.2), 4.06-4.01 (m,
1H, oxa-CH.sub.2), 3.77-3.67 (m, 4.2H, pip-H, oxa-NCH,
CH.sub.2OiBu, benzyl-H), 3.53-3.46 (m, 2.2H, benzyl-H,
OCONCH.sub.2), 2.98-2.85 (m, 3H, pip-H, OCONCH.sub.2), 2.39-2.25
(m, 2H, NCH.sub.2), 2.10-2.00 (m, 3.2H, CH(CH.sub.3).sub.2, pip-H,
CH.sub.OiBu), 1.85-1.50 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.29 (m,
0.8H, pip-H), 1.01-0.99 (m, 6H, CH.sub.3OiBu), 0.89-0.83 (m, 6H,
CH(CH.sub.3).sub.2). HPLC t.sub.R=8.9 min.
N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-
-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate
(117NLS03-A)
[0276] Prepared following the same method as described for 117NLSO1
using
N-[2-(4-fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)-N-(piperidin-4-yl)aceta-
mide (111 mg, 0.27 mmol, prepared by the procedure described for
103NLS56). Yield: 90 mg, 57%.
[0277] R.sub.f=0.30 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 582
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.18-6.80 (m, 8H, Ar--H), 4.40-4.35 (m, 0.4H, pip-H), 4.20-4.15 (m,
1H, oxa-CH.sub.2), 4.05-4.01 (m, 1H, oxa-CH.sub.2), 3.75-3.46 (m,
6.6H, pip-H, oxa-NCH, CH.sub.2OiBu, benzyl-H, OCONCH.sub.2), 3.36
(m, 2H, ArCH.sub.2CH.sub.2N), 3.02-2.84 (m, 3H, pip-H,
OCONCH.sub.2), 2.81-2.75 (m, 2H, ArCH.sub.2), 2.37-2.25 (m, 2H,
NCH.sub.2), 2.09-1.98 (m, 2.8H, CH(CH.sub.3).sub.2, pip-H,
CH.sub.OiBu), 1.85-1.62 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.31 (m,
1.2H, pip-H), 1.00-0.97 (m, 6H, CH.sub.3OiBu), 0.89-0.84 (m, 6H,
CH(CH.sub.3).sub.2). HPLC t.sub.R=9.1 min.
N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl-
)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide, oxalate
(117NLS03-B)
[0278] Prepared following the same method as described for 117NLS01
using
N-[2-(4-fluorophenyl)ethyl]-N-(piperidin-4-yl)-2-(4-propoxyphenyl)acetami-
de (108 mg, 0.27 mmol, prepared by the procedure described for
103NLS56). Yield: 76 mg, 50%.
[0279] R.sub.f=0.33 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 568
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.17-6.81 (m, 8H, Ar--H), 4.40-4.35 (m, 0.4H, pip-H), 4.20-4.15 (m,
1H, oxa-CH.sub.2), 4.05-4.01 (m, 1H, oxa-CH.sub.2), 3.90-3.85 (m,
2H, OCH.sub.2OPr), 3.72-3.48 (m, 4.6H, pip-H, oxa-NCH, benzyl-H,
OCONCH.sub.2), 3.36-3.30 (m, 2H, ArCH.sub.2CH.sub.2N), 2.99-2.86
(m, 3H, pip-H, OCONCH.sub.2), 2.80-2.74 (m, 2H, ArCH.sub.2),
2.38-2.26 (m, 2H, NCH.sub.2), 2.11-2.03 (m, 1.8H,
CH(CH.sub.3).sub.2, pip-H), 1.87-1.64 (m, 8H, pip-H, CH.sub.2OPr,
NCH.sub.2CH.sub.2), 1.31 (m, 1.2H, pip-H), 1.03-0.98 (m, 3H,
CH.sub.3OPr), 0.88-0.83 (m, 6H, CH(CH.sub.3).sub.2). HPLC
t.sub.R=8.5 min.
N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]p-
iperidin-4-yl}-2-(4-propoxyphenyl)acetamide, oxalate
(117NLS03-C)
[0280] Prepared following the same method as described for 117NLSO1
using
N-(4-fluorobenzyl)-N-(piperidin-4-yl)-2-(4-propoxyphenyl)acetamide
(104 mg, 0.27 mmol, prepared by the procedure described for
103NLS56). Yield: 120 mg, 80%.
[0281] R.sub.f=0.36 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 554
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.19-6.78 (m, 8H, Ar--H), 4.57-4.48 (m, 0.6H, pip-H), 4.48 and 4.42
(2s, 2H, benzyl-H), 4.18-4.12 (m, 1H, oxa-CH.sub.2), 4.04-4.00 (m,
1H, oxa-CH.sub.2), 3.91-3.85 (m, 2H, OCH.sub.2OPr), 3.75-3.66 (m,
2.2H, pip-H, oxa-NCH, benzyl-H), 3.49-3.43 (m, 2.2H, benzyl-H,
OCONCH.sub.2), 2.98-2.80 (m, 3H, pip-H, OCONCH.sub.2), 2.33-2.25
(m, 2H, NCH.sub.2), 2.05-1.50 (m, 10.2H, CH(CH.sub.3).sub.2,
NCH.sub.2CH.sub.2, pip-H, CH.sub.2OPr), 1.27 (m, 0.8H, pip-H),
1.18-0.98 (m, 3H, CH.sub.3OPr), 0.87-0.81 (m, 6H,
CH(CH.sub.3).sub.2). HPLC t.sub.R=8.3 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-(4-iso-
butoxyphenyl)acetamide, oxalate (103NLS63-F)
[0282] Prepared following the same method as described for 117NLS01
using and 103NLS56 (262 mg, 0.657 mmol) and
2-(2-bromoethyl)-1,3-dioxane as the alkylating agent. No sodium
iodide was required. Yield: 152 mg, 45%.
[0283] R.sub.f=0.35 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 513
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.26-6.80 (m, 8H, Ar--H), 4.63-4.39 (m, 3.6H, pip-H, dioxane-H,
benzyl-H), 4.09-4.01 (m, 2H, dioxane-H), 3.78-3.64 (m, 5.2H, pip-H,
dioxane-H, CH.sub.2OiBu, benzyl-H), 3.50 (s, 1.2H, benzyl-H),
2.92-2.79 (m, 2H, pip-H), 2.43-2.34 (m, 2H, NCH.sub.2), 2.10-1.96
(m, 3.2H, dioxane-H, pip-H, CH.sub.OiBu), 1.88-1.48 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.35-1.24 (m, 1.8H, dioxane-H, pip-H), 1.01 (m,
6H, CH.sub.3OiBu). HPLC t.sub.R=8.8 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-
-2-(4-isobutoxyphenyl)acetamide, oxalate (117NLS03-D)
[0284] Prepared following the same method as described for
117NLS03-A using 2-(2-bromoethyl)-1,3-dioxane as the alkylating
agent. No sodium iodide was required. Yield: 99 mg, 70%.
[0285] R.sub.f=0.35 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 527
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.7:0.3) .delta.
7.18-6.80 (m, 8H, Ar--H), 4.58-4.54 (m, 1H, dioxane-H), 4.48-4.41
(m, 0.3H, pip-H), 4.10-4.06 (m, 2H, dioxane-H), 3.77-3.66 (m, 5.4H,
dioxane-H, benzyl-H, CH.sub.2OiBu), 3.64-3.52 (m, 1.3H, benzyl-H,
pip-H), 3.37-3.32 (m, 2H, CH.sub.2NCO), 2.99 and 2.89 (2m, 2H,
pip-H), 2.82-2.76 (m, 2H, ArCH.sub.2), 2.49-2.39 (m, 2H,
NCH.sub.2), 2.12-2.00 (m, 2.6H, dioxane-H, pip-H, CH.sub.OiBu),
1.88-1.67 (m, 6H, pip-H, CH.sub.2OiBu, NCH.sub.2CH.sub.2),
1.35-1.31 (m, 2.4H, dioxane-H, pip-H), 1.00 (t, 6H, J=6.6,
CH.sub.3OiBu). HPLC t.sub.R=8.8 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-
-2-(4-propoxyphenyl)acetamide, oxalate (117NLS03-E)
[0286] Prepared following the same method as described for
117NLS03-B using 2-(2-bromoethyl)-1,3-dioxane as the alkylating
agent. No sodium iodide was required. Yield: 90 mg, 65%.
[0287] R.sub.f=0.23 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 513
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.7:0.3) .delta.
7.21-6.81 (m, 8H, Ar--H), 4.58-4.54 (m, 1H, dioxane-H), 4.48-4.42
(m 0.3H, pip-H), 4.10-4.06 (m, 2H, dioxane-H), 3.91-3.86 (m, 2H,
CH.sub.2OPr), 3.77-3.69 (m, 3.4H, dioxane-H, benzyl-H), 3.63-3.56
(m, 1.3H, benzyl-H, pip-H), 3.38-3.31 (m, 2H, CH.sub.2NCO), 2.99
and 2.89 (2m, 2H, pip-H), 2.82-2.76 (m, 2H, ArCH.sub.2), 2.49-2.39
(m, 2H, NCH.sub.2), 2.12-2.00 (m, 1.6H, dioxane-H, pip-H),
1.87-1.65 (m, 8H, pip-H, CH.sub.2OPr, NCH.sub.2CH.sub.2), 1.35-1.31
(m, 2.4H, dioxane-H, pip-H), 1.05-1.00 (m, 3H, CH.sub.3OPr). HPLC
t.sub.R=8.0 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pro-
poxyphenyl)acetamide, tartrate (117NLS03-F)
[0288] Prepared following the same method as described for
117NLS03-C using 2-(2-bromoethyl)-1,3-dioxane as the alkylating
agent. No sodium iodide was required. Yield: 107 mg, 79%.
[0289] R.sub.f=0.41 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 499
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.20-6.80 (m, 8H, Ar--H), 4.62-4.56 (m, 0.6H, pip-H), 4.54-4.51 (m,
1H, dioxane-H), 4.49 and 4.43 (2s, 2H, benzyl-H), 4.08-4.04 (m, 2H,
dioxane-H), 3.92-3.87 (m, 2H, OCH.sub.2OPr), 3.76-3.68 (m, 3.2H,
pip-H, dioxane-H, benzyl-H), 3.50 (s, 1.2H, benzyl-H), 2.90-2.83
(m, 2H, pip-H), 2.43-2.36 (m, 2H, NCH.sub.2), 2.10-1.98 (m, 2.2H,
dioxane-H, pip-H,), 1.86-1.51 (m, 8H, pip-H, CH.sub.2OPr,
NCH.sub.2CH.sub.2), 1.32-1.27 (m, 1.8H, dioxane-H, pip-H),
1.05-0.99 (m, 3H, CH.sub.3). HPLC t.sub.R=7.6 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4-is-
obutoxybenzyl)carbamide, tartrate (117NLS25)
[0290] Prepared following the same method as described for 117NLSO1
using 2-(2-bromoethyl)-1,3-dioxane (24 .mu.L, 0.18 mmol) as the
alkylating agent and
N-(4-fluorobenzyl)-N'-(4-isobutoxybenzyl)-N-(piperidin-4-yl)car-
bamide (76ELH18, 50 mg, 0.12 mmol). No sodium iodide was required.
Yield: 38 mg, 60%.
[0291] R.sub.f=0.32 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 528
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 7.18-6.74 (m, 8H,
Ar--H), 4.53 (t, 1H, J=5.1, dioxane-H), 4.46 (t, 1H, J=5.3, NH),
4.33-4.25 (m, 5H, pip-H, benzyl-H), 4.08-4.04 (m, 2H, dioxane-H),
3.75-3.68 (m, 2H, dioxane-H), 3.66 (d, 2H, J=6.6, CH.sub.2OiBu),
2.93-2.88 (m, 2H, pip-H), 2.43-2.39 (m, 2H, NCH.sub.2), 2.09-1.98
(m, 4H, CH.sub.OiBu, dioxane-H, pip-H), 1.77-1.56 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.32-1.28 (m, 1H, dioxane-H), 0.99 (d, 6H,
J=6.6, CH.sub.3OiBu). HPLC t.sub.R=8.7 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-flu-
orophenyl)acetamide, tartrate (117NLS87-A)
[0292] To a solution of 118AF52-95 (300 mg, 0.93 mmol) and
triethylamine (0.52 mL, 3.72 mmol) in dry THF (10 mL) at 0.degree.
C. a solution of 4-fluorophenylacetyl chloride (0.19 mL, 1.39 mmol)
in THF (5 mL) was added dropwise and stirring was continued at rt
for 3 h. The reaction mixture was filtered and the filtrate
evaporated to dryness. The residue was partitioned between ethyl
acetate and 1M NaOH, the organic layer washed with brine, dried
over Na.sub.2SO.sub.4, filtered and evaporated. Purification by
silica gel column chromatography, eluting with a stepwise gradient
of 0-8% methanol in dichloromethane, followed by purification of
the compound by passage over an acidic ion exchange SPE cartridge,
afforded the desired compound (131 mg, 31%), which was converted to
its tartrate form as described above.
[0293] R.sub.f=0.39 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 459
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.25-6.88 (m, 8H, Ar--H), 4.58-4.52 (m, 0.6H, pip-H), 4.50 (t, 1H,
J=5.1, dioxane-H), 4.48 and 4.44 (2s, 2H, benzyl-H), 4.06-4.02 (m,
2H, dioxane-H), 3.78 and 3.50 (2s, 2H, benzyl-H), 3.72-3.64 (m,
2.4H, pip-H, dioxane-H), 2.84 (m, 2H, pip-H), 2.40-2.35 (m, 2H,
NCH.sub.2), 2.07-1.99 (m, 2.2H, dioxane-H, pip-H), 1.85-1.50 (m,
6H, pip-H, NCH.sub.2CH.sub.2), 1.30-1.25 (m, 1.8H, dioxane-H,
pip-H). HPLC t.sub.R=6.9 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-p-toly-
lacetamide, tartrate (117NLS87-B)
[0294] Prepared following the same method as described for
117NLS87-A using 4-methylphenylacetyl chloride and 118AF52-95 (300
mg, 0.93 mmol). Yield: 119 mg, 28%.
[0295] R.sub.f=0.43 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 455
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
7.17-6.87 (m, 8H, Ar--H), 4.60-4.53 (m, 0.5H, pip-H), 4.50 (t, 1H,
J=5.1, dioxane-H), 4.48 and 4.41 (2s, 2H, benzyl-H), 4.05-4.01 (m,
2H, dioxane-H), 3.77-3.66 (m, 3.5H, pip-H, benzyl-H, dioxane-H),
3.50 (s, 1H, benzyl-H), 2.87-2.80 (m, 2H, pip-H), 2.40-2.34 (m, 2H,
NCH.sub.2), 2.30 and 2.28 (2s, 3H, CH.sub.3), 2.07-1.95 (m, 2H,
dioxane-H, pip-H), 1.83-1.50 (m, 6H, pip-H, NCH.sub.2CH.sub.2),
1.29-1.25 (m, 2H, dioxane-H, pip-H). HPLC t.sub.R=7.7 min.
2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluo-
robenzyl)acetamide, tartrate (128NLS22-A)
[0296] Benzofuran-5-yl-acetic acid was prepared adapting a
procedure by Dunn et al. (J. Med. Chem., 1986, 29, 2326) and
converted into the corresponding acetyl chloride by treatment with
oxalylchloride. The title compound was prepared from 118AF52-95 (58
mg, 0.18 mmol) following the same method as described for
117NLS87-A. Yield: 27 mg, 43%.
[0297] R.sub.f=0.52 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 481
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.64-6.68 (m, 9H, Ar--H), 4.62-4.54 (m, 0.6H, pip-H) 4.53-4.44 (m,
3H, dioxane-H, benzyl-H), 4.07-4.03 (m, 2H, dioxane-H), 3.82-3.61
(m, 3.2H, pip-H, benzyl-H, dioxane-H), 3.45 (s, 1.2H, benzyl-H),
2.91-2.80 (m, 2H, pip-H), 2.44-2.35 (m, 2H, NCH.sub.2), 2.08-1.98
(m, 2.2H, dioxane-H, pip-H), 1.85-1.56 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.32-1.27 (m, 1.8H, dioxane-H, pip-H). HPLC
t.sub.R=6.6 min.
2-(2,3-Dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4--
yl}-N-(4-fluorobenzyl)acetamide, tartrate (128NLS22-B)
[0298] The compound (2,3-Dihydrobenzofuran-5-yl)acetic acid was
prepared adapting a procedure by Dunn et al. (J. Med. Chem., 1986,
29, 2326) and converted into the corresponding acetyl chloride by
treatment with oxalylchloride. The title compound was prepared from
118AF52-95 (58 mg, 0.18 mmol) following the same method as
described for 117NLS87-A. Yield: 27 mg, 31%.
[0299] R.sub.f=0.50 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 483
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.10-6.60 (m, 7H, Ar--H), 4.55-4.40 (m, 5.6H, pip-H, dioxane-H.
benzyl-H, ArOCH.sub.2), 4.01-3.97 (m, 2H, dioxane-H), 3.72-3.62 (m,
3.2H, pip-H, benzyl-H, dioxane-H), 3.41 (s, 1.2H, benzyl-H),
3.14-3.06 (m, 2H, OCH.sub.2CH.sub.2), 2.80 (m, 2H, pip-H),
2.35-2.30 (m, 2H, NCH.sub.2), 1.99-1.93 (m, 2.2H, dioxane-H,
pip-H), 1.80-1.44 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.27-1.22 (m,
1.8H, dioxane-H, pip-H). HPLC t.sub.R=6.9 min.
N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorob-
enzal)-2-(4-isobutoxyphenyl)acetamide, tartrate (11 7NLS37)
[0300] 1-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)ethanol was prepared
according to literature procedures (Carman R. M et al., Aust. J.
Chem., 1998, 51, 955) and oxidized to the aldehyde by treatment
with pyridinium chlorochromate. The crude aldehyde (80 mg, 0.55
mmol) was added to a solution of 103NLS56 (184 mg, 0.46 mmol) in
methanol (5 mL). Acetic acid (0.05 mL) was added, followed by
sodium cyanoborohydride (58 mg, 0.92 mmol) and the mixture stirred
overnight at rt. The solvent was removed and the residue
partitioned between dichloromethane and 1M NaOH. The organic layer
was washed with sat. NH.sub.4Cl, dried over Na.sub.2SO.sub.4,
filtered and evaporated. Purification by silica gel column
chromatography eluting with 0-5% methanol in dichloromethane
afforded the desired compound (50 mg, 21%), which was converted
into its tartrate salt.
[0301] R.sub.f=0.39 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 527
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) 6 7.22-6.79
(m, 8H, Ar--H), 4.62-4.54 (m, 0.6H, pip-H), 4.49 and 4.42 (2s, 2H,
benzyl-H), 4.06-3.98 (m, 1H, dioxolane-H), 3.75-3.66 (m,4.4H,
pip-H, CH.sub.2OiBu, benzyl-H), 3.48 (m, 2H, dioxolane-H),
2.89-2.83 (m, 2H, pip-H), 2.45-2.25 (m, 2H, NCH.sub.2), 2.07-1.99
(m, 2.2H, pip-H, CH.sub.OiBu), 1.85-1.51 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.36-1.28 (m, 6.8H, C(CH.sub.3).sub.2, pip-H),
1.02-0.99 (m, 6H, CH.sub.3OiBu). HPLC t.sub.R=9.3 min.
4-[2-(Tosyloxy)ethyl]-1,3-dioxane (128NLS46-B)
[0302] A suspension of 1,3,5-pentanetriol (1.01 g, 8.33 mmol),
paraformaldehyde (0.46 g) and methanesulfonic acid (0.33 mL) in DMF
(3 mL) is heated for 10 min at 130.degree. C. under microwave
irradiation. The mixture was partitioned between ethyl acetate and
water, the organic layer dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was dissolved in methanol (3 mL), conc. HCl
(0.09 mL) added, and the mixture heated at 80.degree. C. for 10 min
under microwave irradiation. Ethyl acetate and 2M NaOH were added,
the aqueous layer extracted twice with ethyl acetate and the
combined organic layers washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The crude product was
treated with p-tosylchloride and DMAP following literature
procedures (Moune et al., J. Org. Chem., 1997, 62, 3332). The title
compound (1.18 g, 49% overall crude yield) was obtained as a
yellowish oil, which was used without purification.
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine
(128NLS52)
[0303] To a suspension of 4-piperidone monohydrate hydrochloride
(1.26 g, 8.23 mmol) in acetonitrile (100 mL), potassium carbonate
(3.4 g, 24.6 mmol) was added, followed by the tosylate 128NLS46-B
(3.54 g, 12.36 mmol) and sodium iodide (1.85 g, 12.35 mmol) and
stirring was continued overnight at 60.degree. C. The mixture was
filtered, the filtrate evaporated in vacuo and the residue
partitioned between 1M NaOH and ethyl acetate. The organic layer
was separated, the aqueous layer extracted twice with ethyl acetate
and the combined organic layers dried over sodium sulphate,
filtered and evaporated to dryness. Purification of the residue by
silica gel column chromatography, eluting with a stepwise gradient
of 0-4% methanol in dichloromethane, afforded
1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-one (128NLS50, 1.73 g,
98%).
[0304] To a solution of 128NLS50 (1.73 g, 8.13 mmol) in methanol
(100 mL) was added dropwise 4-fluorobenzylamine (0.93 mL, 8.13
mmol) and acetic acid. Sodium cyanoborohydride (2.15 g, 40 mmol)
was added slowly to the mixture at 0.degree. C. and stirring was
continued at rt overnight. The reaction mixture was concentrated in
vacuo and the residue partitioned between dichloromethane and 1M
NaOH, the aqueous layer extracted twice with dichloromethane and
the combined organic layers dried over Na.sub.2SO.sub.4, filtered
and evaporated to dryness. Purification of the residue by a short
silica gel column chromatography eluting with 0-30% methanol in
dichloromethane gave the title compound (1.51 g, 58%) as a
colourless solid.
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-
butoxyphenyl)acetamide, tartrate (128NLS62)
[0305] Prepared following the same method as described for
117NLS87-A using 4-isobutoxyphenylacetyl chloride and 128NLS52 (480
mg, 1.49 mmol). Yield: 458 mg, 60%.
[0306] R.sub.f=0.36 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 513
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.21-6.80 (m, 8H, Ar--H), 5.01 (d, 1H, J=6.1, dioxane-H), 4.66-4.56
(m, 1.6H, pip-H, dioxane-H) 4.51 and 4.44 (2s, 2H, benzyl-H),
4.09-4.05 (m, 1H, dioxane-H), 3.77 and 3.51 (2s, 2H, benzyl-H),
3.70-3.57 (m, 4.4H, pip-H, dioxane-H, CH.sub.2OiBu), 2.91-2.83 (m,
2H, pip-H), 2.45-2.34 (m, 2H, NCH.sub.2), 2.10-2.00 (m, 2.2H,
pip-H, CH.sub.OiBu), 1.85-1.26 (m, 8.8H, pip-H, dioxane-H,
NCH.sub.2CH.sub.2), 1.03-1.00 (m, 6H, CH.sub.3OiBu). HPLC
t.sub.R=8.8 min.
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tri-
fluoromethylphenyl)acetamide, tartrate (128NLS54-A)
[0307] Prepared following the same method as described for
117NLS87-A using 4-trifluorophenylacetyl chloride and 128NLS52 (116
mg, 0.32 mmol). Yield: 52 mg, 32%.
[0308] R.sub.f=0.42 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 509
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.60-6.90 (m, 8H, Ar--H), 4.99 (d, 1H, J=6.1, dioxane-H), 4.65-4.54
(m, 1.6H, pip-H, dioxane-H), 4.52 and 4.47 (2s, 2H, benzyl-H),
4.07-4.04 (m, 1H, dioxane-H), 3.88 (s, 0.8H, benzyl-H), 3.69-3.56
(m, 3.6H, benzyl-H, pip-H, dioxane-H), 2.89 (m, 2H, pip-H),
2.49-2.31 (m, 2H, NCH.sub.2), 2.07-1.99 (m, 1.2H, pip-H), 1.89-1.36
(m, 8.8H, pip-H, dioxane-H, NCH.sub.2CH.sub.2). HPLC t.sub.R=7.3
min.
2-(4-Cyanophenyl)-N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluo-
robenzyl)acetamide, tartrate (128NLS54-C)
[0309] 4-Cyanophenylacetic acid was synthesized according a method
by Jaeger et al. (J. Chem. Soc., 1941, 744-747) and converted to
the corresponding acetyl chloride by treatment with oxalylchloride.
The title compound was prepared following the same method as
described for 117NLS87-A using 4-cyanophenylacetyl chloride and
128NLS52 (116 mg, 0.32 mmol). Yield: 60 mg, 40%.
[0310] R.sub.f=0.40 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 466
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.7:0.3) .delta.
7.62-6.89 (m, 8H, Ar--H), 4.97 (d, 1H, J=6.1, dioxane-H), 4.63 (m,
1H, dioxane-H), 4.59-4.47 (m, 2.7H, pip-H, benzyl-H), 4.06-4.02 (m,
1H, dioxane-H), 3.86 (s, 0.6H, benzyl-H), 3.69-3.55 (m, 3.7H,
benzyl-H, pip-H, dioxane-H), 2.91-2.86 (m, 2H, pip-H), 2.47-2.30
(m, 2H, NCH.sub.2), 2.05-1.39 (m, 10H, pip-H, dioxane-H,
NCH.sub.2CH.sub.2). HPLC t.sub.R=4.3 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-{1-[2-(2-oxo-imidazolidin-1-yl)e-
thyl]piperidin-4-yl}acetamide, hydrochloride (69NLS97)
[0311] Prepared following the same method as described for 117NLS01
using 103NLS56 (240 mg, 0.60 mmol) and
1-(2-tosyloxyethyl)-2-imidazolidinone as the alkylating agent.
Yield: 95 mg, 31%.
[0312] LCMS m/z 511 [M+H].sup.+..sup.1H-NMR (CD.sub.3OD, rotamers
0.6:0.4) .delta. 7.24-6.81 (m, 8H, Ar--H), 4.56 and 4.52 (2s, 2H,
benzyl-H), 4.41-4.37 and 3.93-3.88 (m, 1H, pip-H), 3.84 and 3.56
(2s, 2H, benzyl-H), 3.73-3.69 (m, 2H, CH.sub.2OiBu), 3.46-3.20 (m,
6H, imid-CH.sub.2, NCH.sub.2CH.sub.2), 2.99-2.85 (m, 2H, pip-H),
2.44 (m, 2H, NCH.sub.2), 2.10-1.96 (m, 3.2H, pip-H, CH.sub.OiBu),
1.67-1.62 (m, 3H, pip-H), 1.30 (m, 0.8H, pip-H), 1.03-0.99 (m, 6H,
J=6.6, CH.sub.3OiBu).HPLC t.sub.R=9.5 min.
[0313] Choosing the appropriate secondary amines (prepared in
analogy to the method described for 103NLS56), following compounds
were prepared using a similar procedure:
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)et-
hyl]piperidin-4-yl}acetamide, hydrochloride (63ELH39-B)
[0314] LCMS m/z 465 [M+H].sup.+..sup.1H-NMR (CDCl.sub.3, rotamers
0.6:0.4) .delta. 7.30-6.80 (m, 8H), 4.60-4.53 (m, 0.6H), 4.50 and
4.43 (2s, 2H), 3.78 (m, 4.2H), 3.51 (s, 1.2H), 3.46-3.24 (m, 6H),
2.92-2.79 (m, 2H), 2.46-2.40 (m, 2H), 2.35 and 2.29 (2s, 3H),
2.11-2.05 (m, 1.2H), 1.92-1.86 (m, 0.8H), 1.65-1.50 (m, 3.2H,
partly covered by HDO signal), 1.31 (m, 0.8H).
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dihy-
dro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;
hydrochloride (103NLS39)
[0315] Prepared following the same method as described for 117NLS01
using
N-(4-fluorobenzyl)-N-(piperidin-4-yl)-2-(4-isoproxyphenyl)acetamide
(229 mg, 0.59 mmol) and
1-(3-chloropropyl)-3-methyl-1,3-dihydrobenzimidazol-2-one as the
alkylating agent.
[0316] Yield: 205 mg, 61%. R.sub.f=0.29 (MeOH/CH.sub.2Cl.sub.2
5:95). LCMS m/z 573 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers
0.5:0.5) .delta. 7.18-6.78 (m, 12H, Ar--H), 4.59-4.43 (m, 3.5H,
pip-H, OCH, benzyl-H), 3.88 (t, 2H, J=6.8, NCONCH.sub.2), 3.74 (m,
1.5H, pip-H, benzyl-H), 3.49 (s, 1H, benzyl-H), 3.38 and 3.37 (2s,
3H, NCH.sub.3), 2.93-2.79 (m, 2H, pip-H), 2.36-2.29 (m, 2H,
NCH.sub.2), 2.02-1.95 (m, 1H, pip-H), 1.90-1.46 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.31-1.25 (m, 7H, pip-H, CH(CH.sub.3).sub.2).
HPLC t.sub.R=8.0 min.
[0317] Choosing the appropriate secondary amines (prepared in
analogy to the method described for 103NLS56) and alkylating
agents, following compounds were prepared using a similar
procedure:
[0318]
N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin--
4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide,
hydrochloride (63ELH29A).
[0319]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(2-oxo-2,3-dihydrob-
enzoimidazol-1-yl)propyl]piperidin-4-yl}-acetamide, hydrochloride
(50ELH89).
[0320]
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[4-(2-:oxo-2,3-dihyd-
robenzoimidazol-1-yl)butyl]piperidin-4-yl}acetamide, hydrochloride
(63ELH91).
[0321]
N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin--
4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide,
hydrochloride (63ELH89).
4-(4-Fluorobenzylamino)-piperidine-1-carboxylic acid benzyl ester
(118AF93-51)
[0322] A solution of 4-fluorobenzylamine (5.48 g, 43.8 mmol) in a
mixture of methanol and acetic acid (5:1, 60 mL) was added dropwise
to a solution of benzyl 4-oxo-1-piperidine carboxylate (10.2 g,
43.8 mmol) in methanol (150 mL) at rt. To this mixture sodium
cyanoborohydride (5.50 g, 87.5 mmol) was slowly added. After 20
hours stirring at rt the reaction mixture was neutralized and the
solvent was removed by evaporation under reduced pressure. The
residue was partitioned between dichloromethane and water. The
organic layer was dried over sodium sulphate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with 7% methanol in dichloromethane,
afforded the desired compound (9.0 g, 60 %).
[0323] R.sub.f=0.56 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 343
[M+H].sup.+. HPLC t.sub.R=6.2 min.
N-(1-Benzyloxycarbonylpiperidin-4-yl)-N-(4-fluorobenzyl)-N'-(4-isopropoxyb-
enzyl)carbamide (118AF97-120)
[0324] 1,8-Bis(dimethylamino)-naphtalene (3.19 g, 14.9 mmol) was
added to a solution of 4-(isopropoxy)phenyl acetic acid (2.89 g,
14.9 mmol) in dry tetrahydrofuran (18 mL) at rt under argon
atmosphere. After 25 minutes stirring at rt diphenylphosphoryl
azide (4.10 g, 14.9 mmol) was added dropwise and the mixture
refluxed for 6 hours. It was allowed to cool to rt and then stored
at -20.degree. C. overnight to precipitate out the ammonium
phosphate salt. A mixture of diethyl ether and ethyl acetate (1:1
v/v, 25 mL) was added to the cold reaction mixture. The precipitate
was filtered from the reaction mixture and washed with diethyl
ether: ethyl acetate (1:1 v/v, 20 mL). The filtrate was evaporated
to dryness giving 1-isocyanatomethyl-4-isopropoxybenzene as an oil
(3.2 g), which was used in the next step without further
purification.
[0325] Sodium carbonate (3.5 g, 25.3 mmol) was added to the
solution of 4-(4-fluorobenzyl amino)-piperidine-1-carboxylic acid
benzyl ester 118AF93-51 (5.7g, 16.7 mmol) in dry tetrahydrofuran
(20 mL). To this suspension a solution of
1-isocyanatomethyl-4-isopropoxybenzene (3.2 g, 16.7 mmol) in dry
tetrahydrofuran (10 mL) was added under argon atmosphere. The
reaction mixture was stirred overnight at rt. Afterwards the
mixture was partitioned between dichloromethane and water. The
organic layer was dried over sodium sulphate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with 8% methanol in dichloromethane
afforded the desired compound (2.0 g, 22%).
[0326] R.sub.f=0.36 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 534
[M+H].sup.+. HPLC t.sub.R=10.2 min.
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-piperidin-4-yl-carbamide
, oxalate (118AF99-121)
[0327] The desired compound was obtained by hydrogenation of
118AF97-120 (2.0 g, 3.75 mmol) in absolute ethanol (100 mL) using
palladium on carbon as a catalyst. The product was purified by
column chromatography on silica gel eluting with stepwise gradient
of 5-10% methanol in dichloromethane. Yield: 1.16 g, 77%.
[0328] R.sub.f=0.10 (MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 400
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 7.19 (m, 2H, Ar--H),
7.01-6.69 (m, 4H, Ar--H), 6.76 (m, 2H, Ar--H), 4.51-4.40 (m, 3H,
pip-H, OCH(CH.sub.3), NH), 4.35 (s, 2H, benzyl-H), 4.28 (s, 1H,
benzyl-H), 4.27 (s, 1H, benzyl-H), 3.14-3.07 (m, 2H, pip-H),
2.74-2.68 (m, 2H, pip-H), 2.10 (broad s, 1H, NH), 1.78-1.70 (m, 2H,
pip-H), 1.58-1.48 (m, 2H, pip-H), 1.31 (d, 6H, J=6.0,
OCH(CH.sub.3)). HPLC t.sub.R=5.9 min.
N-{1-[2-(1
,-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4--
isopropoxy-benzyl)carbamide, oxalate (130AF10-147)
[0329] Potassium carbonate (0.21 g, 1.50 mmol) was added to a
solution of 118AF99-121 (0.3 g, 0.75 mmol) in dry
N,N-dimethylformamide (2 mL). The suspension was shaken for 30
minutes at 58.degree. C. A solution of
2-(2-bromoethyl)-1,3-dioxolane (0.163 g, 0.90 mmol) in dry
N,N-dimethylformamide (0.4 mL) was added dropwise to the warm
suspension and the heating was continued overnight. The mixture was
allowed to cool to rt, then filtered and partitioned between water
and dichloromethane. The organic layer was washed with a aqueous
solution of 4% magnesium sulphate and evaporated to dryness.
Purification of the residue by silica gel column chromatography,
eluting with 4% methanol in dichloromethane, afforded the desired
compound (197 mg, 53%). The product was converted to its oxalate
form as described above.
[0330] R.sub.f=0.39 (MeOH/CH.sub.2Cl.sub.2 4:94). LCMS m/z 500
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 7.17 (m, 2H, Ar--H),
7.00-6.95 (m, 4H, Ar--H), 6.76 (m, 2H, Ar--H), 4.88 (t, 1H, J=4.8,
dioxolane-H), 4.51-4.44 (m, 2H, NH, CH(CH.sub.3).sub.2), 4.36-4.26
(m, 5H, benzyl-H, pip-H), 3.95-3.80 (m, 4H, dioxolane-H), 2.98-2.91
(m, 2H, pip-H), 2.48-2.43 (m, 2H, NCH.sub.2), 2.10-2.01 (m, 2H,
pip-H), 1.85-1.79 (m, 2H, NCH.sub.2CH.sub.2), 1.76-1.58 (m, 4H,
pip-H), 1.30 (d, 6H, J=6.0, CH(CH.sub.3).sub.2). HPLC t.sub.R=6.9
min.
[0331] Choosing the appropriate secondary amines (prepared in
analogy to the method described for 103NLS56), following compounds
were prepared using the same procedure:
[0332]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxypheny-
l)-N-(4-methylbenzyl)acetamide, hydrochloride (63ELH29B).
[0333]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-2-(4-isobutoxyphenyl)acetamide, hydrochloride (74AKU06-2).
[0334]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyph-
enyl1N-(4-methylbenzyl)acetamide, hydrochloride (76ELH07).
[0335]
N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl-
)-2-(4-propoxyphenyl)acetamide, tartrate (38PH50).
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxo-
lane-2-yl)ethyl]piperidin-4-yl}carbamide, oxalate (130AF12-148)
[0336] 4 M HCl (0.5 mL) and water (0.5 mL) were added to a solution
of 130AF10-147 (50 mg, 0.10 mmol) in 1.4-dioxane (1 mL). The
mixture was stirred in a sealed flask for 10 minutes under
microwave irradiation at 120.degree. C. Afterwards the mixture was
partitioned between dichloromethane and water. The organic layer
was dried over sodium sulphate, filtered and evaporated to dryness.
The residue was dissolved in 1.4-dioxane (1 mL) and a solution of
(S)-(+)-propylene glycol (39 mg, 0.51 mmol) in 1.4-dioxane (0.5 mL)
was added. After addition of HCl (4M in dioxane, 0.5 mL) the
mixture was stirred in a sealed flask for 20 minutes under
microwave irradiation at 120.degree. C. The mixture was partitioned
between saturated sodium bicarbonate solution and dichloromethane.
The organic layer was evaporated to dryness. Purification of the
residue by silica gel column chromatography, eluting with a
stepwise gradient of 4-8% methanol in dichloromethane afforded the
desired compound (2.1 mg, 4%). The product was converted to its
oxalate form as described above.
[0337] R.sub.f=0.36 (MeOH/CH.sub.2Cl.sub.2 4:94). LCMS m/z 514
[M+H].sup.+. HPLC t.sub.R=7.2 min.
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl-propyl)p-
iperidin-4-yl]carbamide oxalate (130AF09-145)
[0338] A solution of 1-chloro-3-bromopropane in dry tetrahydrofuran
(2 mL) was added to a cold suspension of morpholine (200 mg, 2.29
mmol) and sodium carbonate (0.63 g, 4.56 mmol) in dry
tetrahydrofuran (8 mL) at 0.degree. C. The mixture was stirred at
45.degree. C. overnight. The mixture was allowed to cool to rt,
filtered and evaporated to dryness. Purification of the residue by
silica gel column chromatography, eluting with a mixture of ethyl
acetate and n-heptane (70:30), afforded
3-chloro-1-morpholin-4-yl-propane (156 mg, 42 %).
[0339] A solution of 3-chloro-1-morpholin-4-yl-propane (7.6 mg,
0.046 mmol) in dry N,N-dimethylformamide (0.10 mL) was added to a
solution of 118AF99-121 (15 mg, 0.037 mmol) and caesium carbonate
(40 mg, 0.123 mmol) in a mixture of dry N,N-dimethylformamide and
acetonitrile (1:2, 0.30 mL). After addition of sodium iodide (7.0
mg, 0.047 mmol) the mixture was shaken overnight at 60.degree. C.
The mixture was allowed to cool to rt. Acetonitrile was removed by
evaporation under reduced pressure and the residue was partitioned
between dichloromethane (2 mL) and water (1 mL). The organic layer
was evaporated to dryness. Purification of the residue by
preparative reversed phase HPLC (C.sub.18) afforded the desired
compound (6.1 mg, 32%).
[0340] LCMS m/z 527 [M+H].sup.+. HPLC t.sub.R=6.2 min.
[0341] Choosing the appropriate secondary amines (prepared in
analogy to the method described for 103NLS56), following compounds
were prepared using a simkilar procedure:
[0342]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl-
)piperidin-4-yl]acetamide, dihydrochloride (63ELH40-2).
[0343]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholin-4-ylpropy-
l)piperidin-4-yl]acetamide, dihydrochloride (63ELH41-2).
[0344]
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-[1-(3-morpholin-4-ylprop-
yl)piperidin-4-yl]acetamide, dihydrochloride (74AKU07-2).
[0345]
N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl>N-[1-(3-morpholin-4-yl-
-propyl)piperidin-4-yl]acetamide, dihydrochloride (76ELH14-A).
N-(4-Fluorobenzal)-N'-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl-propyl)p-
iperidin-4-yl]carbamide, oxalate (13 OAF09-146)
[0346] The desired compound was synthesized from piperidine,
1-chloro-3-bromopropane and 118AF99-121 (15 mg, 0.037 mmol) using
the same method as for preparation of 130AF09-145. Yield: 5.8 mg,
30%.
[0347] LCMS m/z 525 [M+H].sup.+. HPLC t.sub.R=6.8 min.
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropyl-2-oxaz-
olidinon-1-yl-propyl)piperidin-4-yl]carbamide, tartrate (130AF
14-152)
[0348] The desired compound was synthesized from
(4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one 103NLS94 (7.4
mg, 0.045 mmol) and 118AF99-121 (15 mg, 0.037 mmol) using the same
method as for preparation of 130AF09-145. Yield: 3.3 mg, 16%.
[0349] LCMS m/z 569 [M+H].sup.+. HPLC t.sub.R=8.2 min.
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{1-[2-(2,5.5-trimethyl-1,3-di-
oxan-2-yl)ethyl]}piperidin-4-yl]carbamide, oxalate
(130AF07-143)
[0350] The desired compound was synthesized from
2-bromo-1-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethane (10.7 mg, 0.045
mmol) and 118AF99-121 (15 mg, 0.037 mmol) using the same method as
for preparation of 130AF09-145. Yield: 8.3 mg, 15%.
[0351] LCMS m/z 556 [M+H].sup.+. HPLC t.sub.R=9.6 min.
N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N'-(4-
-isopropoxybenzyl)carbamide, oxalate (13 OAF07-131)
[0352] The desired compound was synthesized from
3-chloro-1-(1,3-dioxolan-2-yl)-propane (6.79 mg, 0.045 mmol) and
118AF99-121 (15 mg, 0.037 mmol) using the same method as for
preparation of 130AF09-145. Yield: 5.6 mg, 11%.
[0353] LCMS m/z 514 [M+H].sup.+. HPLC t.sub.R=8.3 min.
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-N'-(-
4-isopropoxybenzyl)carbamide, oxalate (13 OAF05-129)
[0354] A solution of 2,2-dimethyl-1,3-dioxan-5-one (9.75 mg, 0.075
mmol) in methanol (0.10 mL) was added to a solution of 118AF99-121
(15 mg, 0.037 mmol) in methanol (0.10 mL). The reaction mixture was
stirred at rt after addition of acetic acid (60 .mu.L of 1 M
solution in methanol). After 2 h stirring a solution of sodium
cyanoborohydride (5 mg, 0.079 mmol) in methanol (0.10 mL) was added
and stirring was continued overnight at rt. The solvent was removed
by evaporation under reduced pressure and the residue partitioned
between 2 M aq. sodium hydroxide and dichloromethane. The layers
were separated by filtration over PTFE filter. The organic layer
was evaporated to dryness. Purification of the residue by
preparative reversed phase HPLC (C.sub.18) afforded the desired
compound (2.3 mg, 12%).
[0355] LCMS m/z 514 [M+H].sup.+. HPLC t.sub.R=9.0 min.
N-(4-Fluorobenzyl)-N'-(4-isopropoxybenzyl)-N-{[2-(1-methyl
pyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide, oxalate
(130AF07-135)
[0356] The desired compound was synthesized from
2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (7.7 mg, 0.041
mmol) and 118AF99-121 (15 mg, 0.037 mmol) using the same method as
for the preparation of 130AF09-145. Yield: 4.4 mg, 23%.
[0357] LCMS m/z 511 [M+H].sup.+. HPLC t.sub.R=7.0 min.
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzal)-2-(4-
-isobutoxyphenyl)acetamide, oxalate (130AF22-105)
[0358] A solution of 2,2-dimethyl-1,3-dioxan-5-one (81 mg, 0.62
mmol) in methanol (10 mL) was added dropwise to a solution of
103NLS56 (179 mg, 0.45 mmol) in methanol (10 mL). The reaction
mixture was stirred at rt after addition of acetic acid (200
.mu.L). After 2 hours sodium cyanoborohydride (56 mg, 0.90 mmol)
was slowly added and stirring was continued overnight at rt. The
mixture was neutralized with few drops of 2 M aq sodium hydroxide.
The solvent was removed by evaporation under reduced pressure and
the residue partitioned between water and dichloromethane. The
organic layer was dried over sodium sulphate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with 6% methanol in dichloromethane,
afforded the desired compound (98 mg, 43%).
[0359] R.sub.f=0.32 (MeOH/CH.sub.2Cl.sub.2, 6:94). LCMS m/z 513
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.26-6.79 (m, 8H, Ar--H), 4.63-4.54 (m, 0.6H, pip-H), 4.50 &
4.43 (2s, 2H, benzyl-H), 3.91 & 3.88 (2d, 1H, J=5.6,
dioxane-H), 3.79-3.67 (m, 6.2 H, dioxane-H, benzyl-H, pip-H,
CH.sub.2OiBu), 3.51 (s, l.2H, benzyl-H), 2.98-2.88 (m, 2H, pip-H),
2.64-2.52 (m, 1H, dioxane-H), 2.38-2.28 (m, 1.2H, pip-H), 2.17-2.00
(m, 1.8H, CH(CH.sub.3).sub.2, pip-H), 1.72-1.47 (m, 3.2H, pip-H),
1.43 (m, 0.8H, pip-H), 1.38-1.22 (m, 6H, dioxane-CH.sub.3), 1.01
(m, 6H, CH(CH.sub.3).sub.2). HPLC t.sub.R=10.0 min.
N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyph-
enyl-acetamide, tartrate (130AF26-164)
[0360] 3 M aq HCl (1 mL) and water (1 mL) were added to a solution
of 130AF22-105 (98.2 mg, 0.19 mmol) in 1.4-dioxane (2 mL) and the
mixture stirred in a sealed flask under microwave irradiation for
10 minutes at 120.degree. C. The mixture was partitioned between
water and dichloromethane and the organic layer dried over sodium
sulphate, filtered and evaporated to dryness. The residue was
dissolved in 1.4-dioxane (2 mL). To this solution a solution of
formaldehyde (37% water solution, 101 mg, 1.16 mmol) in 1.4-dioxane
(0.5 mL) was added. The reaction mixture was stirred in a sealed
flask for 30 minutes under microwave irradiation at 120.degree. C.
Molecular sieves (4 .ANG.) were added to the reaction mixture at rt
and removed after 24 hours. The mixture was heated for an
additional 20 minutes at 120.degree. C. under microwave irradiation
and partitioned between dichloromethane and sodium bicarbonate. The
organic layer was dried over sodium sulphate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with 6% methanol in dichloromethane,
afforded the desired compound (17 mg, 18%). The product was
converted to its tartrate form as described above.
[0361] R.sub.f=0.30 (MeOH/CH.sub.2Cl.sub.2, 6:94). LCMS m/z 485
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.80 (m, 8H, Ar--H), 4.88 (m, 1H, dioxane-H), 4.61-4.56 (m,
1.6H, dioxane-H, pip-H), 4.50 & 4.43 (2s, 2H, benzyl-H),
4.12-4.06 (m, 2H, dioxane-H) 3.85-3.60 (m, 5.2 H, dioxane-H,
benzyl-H, pip-H, CH.sub.2OiBu), 3.51 (s, 1.2H, benzyl-H), 2.94-2.86
(m, 2H, pip-H), 2.59-2.48 (m, 1H, dioxane-H), 2.37-2.28 (m, 1.2H,
pip-H), 2.17-2.01 (m, 1.8H, CH(CH.sub.3).sub.2, pip-H), 1.68-1.46
(m, 3.2H, pip-H), 1.46-1.30 (m, 0.8H, pip-H), 1.02 (m, 6H,
CH(CH.sub.3).sub.2). HPLC t.sub.R=9.5 min.
N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-
-fluorophenyl)acetamide, tartrate (130AF35-168)
[0362] The desired compound was synthesized from
2,2-dimethyl-1,3-dioxan-5-one (59 mg, 0.45 mmol) and
N-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide
(83 mg, 0.24 mmol) using the same method as for preparation of
130AF22-105. The starting material
N-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide
was prepared in the same way as 103NLS56.
[0363] R.sub.f=0.26 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 459
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.28-6.91 (m, 8H, Ar--H), 4.63-4.52 (m, 0.6H, pip-H), 4.51 &
4.46 (2s, 2H, benzyl-H), 3.92-3.88 (m, 2H, dioxane-H), 3.82-3.69
(m, 3.2 H, dioxane-H, benzyl-H, pip-H), 3.54 (s, 1.2H, benzyl-H),
2.99-2.90 (m, 2H, pip-H), 2.62-2.51 (m, 1H, dioxane-H), 2.39-2.28
(m, 1.2H, pip-H), 2.18-2.10 (m, 0.8H, pip-H), 1.72-1.50 (m, 3.2H,
pip-H), 1.42-1.31 (m, 6.8H, pip-H, dioxane-CH.sub.3). HPLC
t.sub.R=7.9 min.
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-flu-
orophenyl)acetamide, tartrate (130AF41-171)
[0364] The starting material
N-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide
was prepared in the same way as 103NLS56.
[0365] Potassium carbonate (64 mg, 0.46 mmol) was added to a
solution of
N-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide
(79.4 mg, 0.23 mmol) in dry N,N-dimethylformamide (3 mL). To this
suspension a solution of 4-[2-(tosyloxy)ethyl]-1,3-dioxane
128NLS46B (99 mg, 0.35 mmol) in dry N,N-dimethylformamide (1 mL)
was added dropwise at rt. The reaction mixture was stirred
overnight at 60.degree. C. and it was partitioned between
dichloromethane and water. The organic layer was dried over sodium
sulphate, filtered and evaporated to dryness. Purification of the
residue by silica gel column chromatography, eluting with stepwise
gradient of 2-5% methanol in dichloromethane, afforded the desired
product (71 mg, 67%). The product was converted to its tartrate
form as described above.
[0366] R.sub.f=0.41 (MeOH/CH.sub.2Cl.sub.2, 6:96). LCMS m/z 459
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.28-6.90 (m, 8H, Ar--H), 4.99 (m, 1H, dioxane-H), 4.77-4.64 (m,
1.6H, pip-H, dioxane-H), 4.52 (s, 2H, benzyl-H), 3.80-3.56 (m,
4.4H, dioxane-H, benzyl-H, pip-H), 3.21-3.08 (m, 1.2H, pip-H),
2.96-2.88 (m, 0.8H, pip-H), 2.75-2.56 (m, 1.2H, NCH.sub.2),
2.52-2.24 (m, 2H, pip-H, NCH.sub.2), 2.04-1.30 (m, 9.8H, pip-H,
NCH.sub.2CH.sub.2, dioxane-H). HPLC t.sub.R=6.4 min.
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tri-
fluoromethoxyphenyl)acetamide, tartrate (130AF80-186)
[0367] Triethylamine (125 .mu.L, 0.89 mmol) was added to a solution
of
N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine
128NLS52 (96 mg, 0.30 mmol) in dry dichloromethane (5 mL) at rt.
The solution was cooled to -10.degree. C. and a solution of
(4-trifluoromethoxyphenyl)acetyl chloride (71 mg, 0.30 mmol) in dry
dichloromethane (1 mL) was added dropwise. The reaction mixture was
stirred overnight at rt. The solvent was removed by evaporation
under reduced pressure. The residue was suspended in
tetrahydrofuran and filtered. The filtrate was evaporated to
dryness and the residue was purified by silica gel column
chromatography, eluting with 4% methanol in dichloromethane, to
give the desired compound (46 mg, 30%). The compound was converted
to its tartrate form as described above.
[0368] R.sub.f=0.33 (MeOH/CH.sub.2Cl.sub.2, 6:94). LCMS m/z 459
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.34-6.91 (m, 8H, Ar--H), 5.01 (d, 1H, J=6.0, dioxane-H), 4.66-4.54
(m, 1.6H, pip-H, dioxane-H), 4.52 & 4.49 (2s, 2H, benzyl-H),
4.09-4.05 (m, 1H, dioxane-H), 3.83 (s, 0.8H, benzyl-H), 3.72-3.56
(m, 3.6 H, dioxane-H, benzyl-H, pip-H), 2.94-2.86 (m, 2H, pip-H),
2.50-2.32 (m, 2H, NCH.sub.2), 2.11-2.00 (m, 1.2H, pip-H), 1.90-1.52
(m, 8.8H, pip-H, NCH.sub.2CH.sub.2, dioxane-H). HPLC t.sub.R=7.6
min.
N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-(4-pro-
poxyphenyl)acetamide, tartrate (130AF71-184)
[0369] Triethylamine (163 .mu.L, 1.17 mmol) was added to a solution
of
N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine
128NLS52 (126 mg, 0.39 mmol) in dry dichloromethane (5 mL) at rt.
The solution was cooled to -15.degree. C. and a solution of
(4-propoxyphenyl)acetyl chloride (92 mg, 0.43 mmol) in dry
dichloromethane (2 mL) was added dropwise. The reaction mixture was
stirred for 2 hours at rt. The solvent was removed by evaporation
under reduced pressure. The residue was suspended in
tetrahydrofuran and filtered. The filtrate was evaporated to
dryness and the residue was purified by silica gel column
chromatography, eluting with a stepwise gradient of 0-4% methanol
in dichloromethane, to give the desired compound (66 mg, 34%). The
product was converted to its tartrate form as described above.
[0370] R.sub.f=0.16 (MeOH/CH.sub.2Cl.sub.2, 4:96). LCMS m/z 499
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.78 (m, 8H, Ar--H), 5.00 (m, 1H, dioxane-H), 4.66-4.54 (m,
1.6H, pip-H, dioxane-H), 4.50 & 4.44 (2s, 2H, benzyl-H),
4.10-4.03 (m, 1H, dioxane-H), 3.92-3.87 (m, 2H, OCH.sub.2OPr),
3.78-3.50 (m, 4.4 H, dioxane-H, benzyl-H, pip-H), 2.92-2.82 (m, 2H,
pip-H), 2.50-2.29 (m, 2H, NCH.sub.2), 2.09-1.98 (m, 1.2H, pip-H),
1.88-1.27 (m, 10.8H, pip-H, NCH.sub.2CH.sub.2, dioxane-H,
CH.sub.2OPr), 1.05-099 (m, 3H, CH.sub.3OPr). HPLC t.sub.R=7.6
min.
N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-yl)piperi-
din-4-yl]acetamide, tartrate (130AF33-166)
[0371] A solution of tetrahydro-4H-pyran-4-one (43 mg, 0.42 mmol)
in methanol (1 mL) was added to a solution of 103NLS56 (57 mg, 0.14
mmol) in methanol (2 mL). After addition of acetic acid (100 .mu.L)
the reaction mixture was stirred for 15 minutes in a sealed flask
under microwave irradiation at 100.degree. C. Afterwards sodium
cyanoborohydride (26 mg, 0.42 mmol) was added to the mixture and
stirring was continued for additional 60 min under microwave
irradiation at 80.degree. C. The mixture was passed over an acidic
ion-exchange SPE cartridge. Further purification of the product by
silica gel column chromatography, eluting with a stepwise gradient
of 2-5% methanol in dichloromethane, afforded the desired compound
(19.2 mg, 28%). The compound was converted to its tartrate form as
described above.
[0372] R.sub.f=0.18 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 483
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.80 (m, 8H, Ar--H), 4.64-4.56 (m, 0.6H, pip-H), 4.51&
4.45 (2s, 2H, benzyl-H), 4.02-3.96 (m, 2H, THP--H), 3.77-3.68 (m,
3.2H, benzyl-H, CH.sub.2OiBu, pip-H), 3.51 (s, 1.2H, benzyl-H),
3.30 (t, 2H, J=12.0, THP--H), 2.98-2.88 (m, 2H, pip-H), 2.46-2.34
(m, 1H, THP--H), 2.28-2.19 (m, 1.2H, pip-H), 2.10-1.99 (m, 1.8H,
CH.sub.OiBu, pip-H), 1.73-1.47 (m, 7.2H, pip-H, THP--H), 1.39-1.33
(m, 0.8H, pip-H), 1.01 (m, 6H, CH.sub.3OiBu). HPLC t.sub.R=8.0
min.
N-(4-Fluorobenzyl)-2-(4-isobutoxylphenyl)-N-[1-(tetrahydropyran-4-ylmethyl-
)piperidin-4-yl]acetamide, tartrate (130AF82-187)
[0373] The title compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS-
56 (110 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-yl carbaldehyde
(63 mg, 0.55 mmol) using the same method as for preparation of
130AF33-166. Yield: 18 mg, 13%.
[0374] R.sub.f=0.30 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 497
[M+H].sup.+. HPLC t.sub.R=8.4 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-{1-[2-(tetrahydropyran-4-yl)ethy-
l]piperidin-4-yl]acetamide, tartrate (130AF83-188)
[0375] The title compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS-
56 (110 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-yl acetalaldehyde
(70.5 mg, 0.55 mmol) using the same method as for preparation of
130AF33-166. Yield: 40 mg, 29%.
[0376] R.sub.f=0.30 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 511
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.80 (m, 8H, Ar--H), 4.65-4.55 (m, 0.6H, pip-H), 4.51&
4.44 (2s, 2H, benzyl-H), 3.95-3.89 (m, 2H, THP--H), 3.78-3.66 (m,
3.2H, benzyl-H, CH.sub.2OiBu, pip-H), 3.51 (s, 1.2H, benzyl-H),
3.34 (t, 2H, J=12.0, THP--H), 2.92-2.82 (m, 2H, pip-H), 2.34-2.26
(m, 2H, NCH.sub.2CH.sub.2), 2.11-1.96 (m, 2.2H, pip-H,
CH.sub.OiBu), 1.84-1.20 (m, 11.8H, pip-H, THP--H,
CH.sub.2CH.sub.2N), 1.02 (m, 6H, CH.sub.3OiBu). HPLC t.sub.R=8.2
min.
N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-
-4-yl]acetamide, tartrate (130AF37-169)
[0377] The desired compound was synthesized from
tetrahydro-4H-pyran-4-one and
N-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide
using the same method as for preparation of 130AF33-166. The
starting material
N-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide
was prepared in the same way as 103NLS56.
[0378] R.sub.f=0.29 (MeOH7CH.sub.2Cl.sub.2, 5:95). LCMS m/z 429
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.29-6.91 (m, 8H, Ar--H), 4.64-4.55 (m, 0.6H, pip-H), 4.52 &
4.48 (2s, 2H, benzyl-H), 4.02-3.95 (m, 2H, THP--H), 3.80 (s, 0.8H,
benzyl-H), 3.75-3.64 (m, 0.4H, pip-H), 3.54 (s, 1.2H, benzyl-H),
3.34 (t, 2H, J=12.0, THP--H), 2.99-2.90 (m, 2H, pip-H), 2.48-2.36
(m, 1H, THP--H), 2.26-2.20 (m, 1.2H, pip-H), 2.08-2.00 (m, 0.8H,
pip-H), 1.76-1.47 (m, 7.2H, pip-H, THP--H), 1.41-1.34 (m, 0.8H,
pip-H). HPLC t.sub.R=5.6 min.
N-[1-((S)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-iso-
butoxyphenyl)acetamide, tartrate (130AF65-182)
[0379] The compound
(R)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol was
synthesized according to Moune et al (J. Org. Chem., 1997, 62,
3332-3339). Potassium carbonate (83 mg, 0.60 mmol) was added to a
solution of 103NLS56 (94 mg, 0.24 mmol) in dry
N,N-dimethylformamide (3 mL). To this suspension a solution of
(R)-5-[(4-methyl-benzenesulfonyl)oxy]pentane-1,3-diol (82 mg, 0.28
mmol) in dry N,N-dimethylformamide (1 mL) was added, followed by
addition of sodium iodide (43 mg, 0.29 mmol). The reaction mixture
was stirred overnight at 60.degree. C. It was allowed to cool to
rt, filtered and evaporated to dryness. The residue was partitioned
between dichloromethane and 2M aq sodium hydroxide. The organic
layer was dried over sodium sulphate, filtered and evaporated to
dryness. Purification of the residue by silica gel column
chromatography, eluting with a stepwise gradient of 6-10% methanol
in dichloromethane, afforded the desired compound (35 mg, 29%),
which was converted to its tartrate form as described above.
[0380] R.sub.f=0.48 (MeOH/CH.sub.2Cl.sub.2, 10:90). LCMS m/z 501
[M+H].sup.+. HPLC t.sub.R=7.4 min.
N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-
-(4-isobutoxyphenyl)acetamide, tartrate (130AF67-183)
[0381] Paraformaldehyde (9 mg, 0.28 mmol) and hydrochloric acid (4M
in 1.4-dioxane, 0.5 mL) were added to a solution of tartaric acid
salt of 130AF65-182 (37 mg, 0.056 mmol) in 1.4-dioxane. The
reaction mixture was stirred for 2 hours in a sealed flask under
microwave irradiation at 120.degree. C. and partitioned between
dichloromethane and sodium bicarbonate. The organic layer was
washed with brine, dried over sodium sulphate, filtered and
evaporated to dryness. Purification of the residue by acidic
ion-exchange SPE cartridge afforded the desired compound (9.0 mg,
31%), which was converted to its tartrate form as described above.
The enantiomeric excess (ee) was determined to be 94% using chiral
HPLC analysis (Chiralpak AD column, 4.6.times.250 mm;
heptane/I-PrOH 50:50, 0.3% DEA; 0.5 mL/min; t.sub.R 20.5 min).
[0382] R.sub.f=0.41 (MeOH/CH.sub.2Cl.sub.2, 8:92). LCMS m/z 513
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.80 (m, 8H, Ar--H), 5.00 (m, 1H, dioxane-H), 4.68-4.54 (m,
1.6H, pip-H, dioxane-H), 4.51 & 4.45 (2s, 2H, benzyl-H), 4.06
(m, 1H, dioxane-H), 3.77-3.48 (m, 6.4H, dioxane-H, benzyl-H,
CH.sub.2OiBu, pip-H), 2.98-2.79 (m, 2H, pip-H), 2.50-2.58 (m, 2H,
NCH.sub.2), 2.14-1.99 (m, 2.2H, CH.sub.OiBu, pip-H), 1.90-1.25 (m,
8.8H, pip-H, NCH.sub.2CH.sub.2, dioxane-H), 1.02 (m, 6H,
CH.sub.3OiBu). HPLC t.sub.R=8.7 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine
(118AF52-95)
[0383] Sodium carbonate (17.4 g, 125.9 mmol) was added to a
solution of 4-piperidone monohydrate hydrochloride (6.45 g, 42.0
mmol) in acetonitrile (200 mL). After 30 minutes stirring at rt a
solution of 2-(2-bromoethyl)-1,3-dioxane (8.45 g, 43.3 mmol) in
acetonitrile (50 mL) was added dropwise to the reaction mixture and
stirring was continued overnight at rt and at reflux for an
additional 2 hours. The solvent was removed by evaporation under
reduced pressure and the residue was partitioned between water and
dichloromethane. The organic layer was dried over sodium sulphate,
filtered and evaporated to dryness. Purification of the residue by
silica gel column chromatography, eluting with 7% methanol in
dichloromethane, afforded
1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-one (6.19 g, 69%).
[0384] A solution of 1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-one
(6.19 g, 29 mmol) in methanol (80 mL) was added dropwise to a
solution of 4-fluorobenzylamine (3.9 mL, 34 mmol) in methanol (100
mL) under argon atmosphere at rt. After 30 minutes stirring at rt
the reaction mixture was acidified (pH=5) with acetic acid and
cooled to 0.degree. C. Sodium cyanoborohydride (2.15 g, 40 mmol)
was added slowly to the cold mixture and stirring was continued at
rt overnight. The reaction mixture was basified with 2M NaOH and
concentrated in vacuo. The residue was partitioned between ethyl
acetate and water. The organic layer was dried over sodium
sulphate, filtered and evaporated to dryness. The residue was
dissolved in abs. ethanol (57 mL). A solution of maleic acid (3.31
g, 28.5 mmol) in abs. ethanol (60 mL) was added to this solution
resulting in precipitate formation. The precipitate was collected
by filtration and converted to the free base by a basic extraction.
Yield: 8.5 g, 91%.
[0385] R.sub.f=0.29 (MeOH/CH.sub.2Cl.sub.2, 7:93). LCMS m/z 323
[M+H].sup.+..sup.1H NMR (CDCl.sub.3) .delta. 7.25 (m, 2H, Ar--H),
6.95 (m, 2H, Ar--H), 4.54 (t, 1H, J=5.6, dioxane-H), 4.07-4.02 (m,
2H, dioxane-H), 3.73-3.67 (m, 4H, dioxane-H, benzyl-H), 2.85-2.79
(m, 2H, pip-H), 2.49-2.37 (m, 3H, NCH.sub.2, pip-H), 2.05-1.72 (m,
7H, pip-H, NCH.sub.2CH.sub.2, dioxane-H), 1.44-1.25 (m, 4H,
dioxane-H, pip-H, NH). HPLC t.sub.R=1.4 min.
2-(4-Benzyloxyphenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4--
fluorobenzyl)acetamide tartrate (118AF66-102)
[0386] A solution of triethylamine (0.89 mL, 6.38 mmol) and
118AF52-95 (0.80 g, 2.48 mmol) in dry THF (10 mL) was cooled to
0.degree. C. A solution of 4-benzyloxyphenylacetyl chloride (0.72
g, 2.76 mmol) was added dropwise to the cold reaction mixture and
stirring was continued at rt for 2 h. The reaction mixture was
filtered and the filtrate evaporated to dryness. Purification of
the residue by silica gel column chromatography, eluting with a
stepwise gradient of 0-6% methanol in dichloromethane afforded the
desired compound (0.53 g, 39%), which was converted to its tartrate
form as described above.
[0387] R.sub.f=0.27 (MeOH/CH.sub.2Cl.sub.2, 7:93). LCMS m/z 547
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.46-6.86 (m, 13H, Ar--H), 5.08-5-02 (m, 2H, PhCH.sub.2O),
4.64-4.42 (m, 3.6H, pip-H, benzyl-H, dioxane-H), 4.11-4.02 (m, 2H,
dioxane-H), 3.79-3.67 (m, 3.2H, dioxane-H, benzyl-H, pip-H), 3.50
(s, 1.2H, benzyl-H), 2.94-2.80 (m, 2H, pip-H), 2.46-2.34 (m, 2H,
NCH.sub.2), 2.12-1.98 (m, 2.2H, dioxane-H, pip-H), 1.87-1.50 (m,
6H, pip-H, NCH.sub.2CH.sub.2), 1.36-1.24 (m, 1.8H, pip-H,
dioxane-H). HPLC t.sub.R=8.9 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-hyd-
roxyphenyl)-acetamide, tartrate (118AF67-103)
[0388] The desired compound was afforded by hydrogenation of
118AF66-102 (0.50 g, 0.92 mmol) in absolute ethanol (200 mL) using
palladium on carbon as a catalyst. The product was purified by
column chromatography on silica gel eluting with a stepwise
gradient of 3-6% methanol in dichloromethane. The desired compound
(0.22 g, 53%) was converted to its tartrate form as described
above.
[0389] R.sub.f=0.30 (MeOH/CH.sub.2Cl.sub.2, 6:94). LCMS m/z 457
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.13-6.86 (m, 6H, Ar--H), 6.72-6.64 (m, 2H, Ar--H), 4.66-4.57 (m,
0.6H, pip-H), 4.54 (m, 1H, dioxane-H), 4.48 & 4.37 (2s, 2H,
benzyl-H), 4.08-4.01 (m, 2H, dioxane-H), 3.80-3.66 (m, 3.2H,
dioxane-H, benzyl-H, pip-H), 3.47 (m, 1.2H, benzyl-H), 2.94-2.82
(m, 2H, pip-H), 2.47-2.39 (m, 2H, NCH.sub.2), 2.10-1.97 (m, 2.2H,
dioxane-H, pip-H), 1.88-1.53 (m, 6H, pip-H, NCH.sub.2CH.sub.2),
1.34-1.25 (m, 1.8H, pip-H, dioxane-H). HPLC t.sub.R=3.0 min.
I.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-met-
hoxyphenyl)-acetamide, tartrate (118AF60-96)
[0390] A solution of triethylamine (0.57 mL, 4.09 mmol) and
118AF52-95 (328 mg, 1.02 mmol) in dry THF (5 mL) was cooled to
0.degree. C. A solution of 4-methoxyphenylacetyl chloride (376 mg,
2.04 mmol) was added dropwise to the cold reaction mixture and
stirring was continued for 20 h at rt. The reaction mixture was
partitioned between 2M NaOH and water. The organic layer was dried
over sodium sulphate, filtered and evaporated to dryness. The
residue was purified by silica gel column chromatography, eluting
with a stepwise gradient of 0-6% methanol in dichloromethane. Final
purification of the product by acidic ion-exchange SPE cartridge
afforded the desired compound (153 mg, 33%), which was converted to
its tartrate form as described above.
[0391] R.sub.f=0.40 (MeOH/CH.sub.2Cl.sub.2, 4:96). LCMS m/z 471
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3,rotamers 0.4:0.6) .delta.
7.24-6.79 (m, 8H, Ar--H), 4.63-4.54 (m, 0.6H, pip-H), 4.52 (t, 1H,
J=5.2, dioxane-H), 4.49 & 4.44 (2s, 2H, benzyl-H), 4.09-4.01
(m, 2H, dioxane-H), 3.79-3.68 (m, 6.2H, dioxane-H, benzyl-H, pip-H,
OCH.sub.3), 3.50 (m, 1.2H, benzyl-H), 2.91-2.80 (m, 2H, pip-H),
2.43-2.36 (m, 2H, NCH.sub.2), 2.10-1.98 (m, 2.2H, dioxane-H,
pip-H), 1.86-1.51 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.34-1.26 (m,
1.8H, pip-H, dioxane-H). HPLC t.sub.R=7.0 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-
propylphenyl)-acetamide. tartrate (118AF63-100)
[0392] The desired compound was synthesized from 118AF52-95 (400
mg, 1.24 mmol) and 4-isopropylphenylacetyl chloride (340 mg, 1.73
mmol) using the same method as for preparation of 118AF66-102.
Further purification by acidic ion-exchange SPE cartridge was
performed. Yield: 273 mg, 46%.
[0393] R.sub.f=0.34 (MeOH/CH.sub.2Cl.sub.2, 7:93). LCMS m/z 483
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.22-6.89 (m, 8H, Ar--H), 4.64-4.43 (m, 3.6H, pip-H, dioxane-H,
benzyl-H), 4.09-4.02 (m, 2H, dioxane-H), 3.79 (s, 0.8H, benzyl-H),
3.76-3.66 (m, 2.4H, dioxane-H, pip-H), 3.54 (m, 1.2H, benzyl-H),
2.92-2.79 (m, 3H, pip-H, CH(CH.sub.3).sub.2), 2.41-2.35 (m, 2H,
NCH.sub.2), 2.12-1.98 (m, 2.2H, dioxane-H, pip-H), 1.85-1.49 (m,
6H, pip-H, NCH.sub.2CH.sub.2), 1.34-1.19 (m, 7.8H, pip-H,
dioxane-H, CH(CH.sub.3).sub.2). HPLC t.sub.R=8.6 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tri-
fluoromethoxy-phenyl)acetamide, tartrate (118AF58-98)
[0394] The desired compound was synthesized from 118AF52-95 (328
mg, 1.02 mmol) and 4-trifluoromethoxyphenylacetyl chloride (345 mg,
1.44 mmol) using the same method as for preparation of 118AF66-102.
Yield: 267 mg, 49%.
[0395] R.sub.f=0.31 (MeOH/CH.sub.2Cl.sub.2, 4:96). LCMS m/z 525
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.30-6.90 (m, 8H, Ar--H), 4.63-4.48 (m, 3.6H, pip-H, dioxane-H,
benzyl-H), 4.05 (m, 2H, dioxane-H), 3.82 (s, 0.8H, benzyl-H),
3.76-3.62 (m, 2.4H, dioxane-H, pip-H), 3.55 (m, 1.2H, benzyl-H),
2.92-2.84 (m, 2H, pip-H), 2.43-2.36 (m, 2H, NCH.sub.2), 2.10-1.96
(m, 2.2H, dioxane-H, pip-H), 1.88-1.79 (m, 0.8H, pip-H), 1.76-1.52
(m, 5.2H, pip-H, NCH.sub.2CH.sub.2), 1.38-1.26 (m, 1.8H, pip-H,
dioxane-H). HPLC t.sub.R=8.4 min.
II.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-eth-
oxyphenyl)-acetamide, oxalate (118AF68-104)
[0396] The desired compound was synthesized from 118AF52-95 (400
mg, 1.24 mmol) and 4-ethoxyphenylacetyl chloride (300 mg, 1.51
mmol) using the same method as for preparation of 118AF66-102.
Further purification by acidic ion-exchange SPE cartridge was
performed. Yield: 0.15 g, 25%.
[0397] R.sub.f=0.26 (MeOH/CH.sub.2Cl.sub.2, 6:94). LCMS m/z 485
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3,rotamers 0.4:0.6) .delta.
7.20-6.79 (m, 8H, Ar--H), 4.64-4.54 (m, 0.6H, pip-H), 4.52 (t, 1H,
J=5.2, dioxane-H), 4.49 & 4.43 (2s, 2H, benzyl-H), 4.07-3.97
(m, 4H, dioxane-H, OCH.sub.2), 3.76-3.66 (m, 3.2H, dioxane-H,
pip-H, benzyl-H), 3.49 (s, 1.2H, benzyl-H), 2.91-2.80 (m, 2H,
pip-H), 2.42-2.32 (m, 2H, NCH.sub.2), 2.10-1.97 (m, 2.2H,
dioxane-H, pip-H), 1.86-1.48 (m, 6H, pip-H, NCH.sub.2CH.sub.2),
1.42-1.36 (m, 3H, CH.sub.3), 1.34-1.24 (m, 1.8H, pip-H, dioxane-H).
HPLC t.sub.R=7.6 min.
III.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-
propoxyphenyl)-acetamide, oxalate (118AF73-107)
[0398] The desired compound was synthesized from 118AF52-95 (400
mg, 1.24 mmol) and 4-isopropoxyphenylacetyl chloride (340 mg, 1.60
mmol) using the same method as for preparation of 118AF66-102.
Further purification by acidic ion-exchange SPE cartridge was
performed. Yield: 91 mg, 15%.
[0399] R.sub.f=0.58 (MeOH/CH.sub.2Cl.sub.2, 8:92). LCMS m/z 499
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.19-6.78 (m, 8H, Ar--H), 4.64-4.42 (m, 4.6H, pip-H, dioxane-H,
benzyl-H, CH.sub.OiPr), 4.07 (m, 2H, dioxane-H), 3.76-3.68 (m,
3.2H, dioxane-H, pip-H, benzyl-H), 3.49 (s, 1.2H, benzyl-H),
2.91-2.80 (m, 2H, pip-H), 2.42-2.35 (m, 2H, NCH.sub.2), 2.10-1.99
(m, 2.2H, dioxane-H, pip-H), 1.85-1.51 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.31 (m, 7.8H, OCH(CH.sub.3).sub.2, pip-H,
dioxane-H). HPLC t.sub.R=8.1 min.
IV.
N-{1-[2-(1.3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-phenyl-
acetamide, oxalate (118AF77-109)
[0400] The desired compound was synthesized from 118AF52-95 (300
mg, 0.93 mmol) and phenylacetyl chloride (197 mg, 1.27 mmol) using
the same method as for preparation of 118AF66-102. Further
purification by acidic ion-exchange SPE cartridge was performed.
Yield: 68 mg, 17%.
[0401] R.sub.f=0.28 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 441
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.33-6.89 (m, 9H, Ar--H), 4.65-4.44 (m, 3.6H, pip-H, dioxane-H,
benzyl-H), 4.09-4.03 (m, 2H, dioxane-H), 3.84 (s, 0.8H, benzyl-H),
3.76-3.67 (m, 2.4H, dioxane-H, pip-H), 3.57 (s, 1.2H, benzyl-H),
2.92-2.79 (m, 2H, pip-H), 2.44-2.34 (m, 2H, NCH.sub.2), 2.10-1.98
(m, 2.2H, dioxane-H, pip-H), 1.86-1.51 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.34-1.23 (m, 1.8H, pip-H, dioxane-H). HPLC
t.sub.R=6.1 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2--
fluoroethoxy)-phenyl]acetamide, oxalate (118AF85-113)
[0402] The desired compound was synthesized from 118AF52-95 (360
mg, 1.11 mmol) and 4-(2-fluoroethoxy)phenylacetyl chloride (282 mg,
1.30 mmol) using the same method as for preparation of 118AF66-102.
Further purification by acidic ion-exchange SPE cartridge was
performed. Yield: 84 mg, 15%.
[0403] R.sub.f=0.36 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 503
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.27-6.84 (m, 8H, Ar--H), 4.80 (m, 1H, OCH.sub.2CH.sub.2F), 4.68
(m, 1H, OCH.sub.2CH.sub.2F), 4.65-4.45 (m, 3.6H, pip-H, dioxane-H,
benzyl-H), 4.22 (m, 1H, OCH.sub.2CH.sub.2F), 4.16 (m, 1H,
OCH.sub.2CH.sub.2F), 4.10-4.03 (m, 2H, dioxane-H), 3.79-3.68 (m,
3.2H, dioxane-H, pip-H, benzyl-H), 3.51 (s, 1.2H, benzyl-H),
2.92-2.82 (m, 2H, pip-H), 2.44-2.36 (m, 2H, NCH.sub.2), 2.12-1.99
(m, 2.2H, dioxane-H, pip-H), 1.88-1.51 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.35-1.26 (m, 1.8H, pip-H, dioxane-H). HPLC
t.sub.R=7.0 min.
N-{1-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenz-
yl)-2-(4-isobutoxyphenyl)acetamide, oxalate (118AF27-83)
[0404] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide 103NLS63F (22 mg, 0.042 mmol) and
2,2-dimethyl-1,3-propandiol (33 mg, 0.38 mmol) using the same
method as for preparation of 130AF12-148. Purification of the
product by reversed phase HPLC (C.sub.18) afforded the title
compound (2.8 mg, 12%). LCMS m/z 541 [M+H].sup.+. HPLC t.sub.R=9.9
min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan--
2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate (118AF29-84)
[0405] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide 103NLS63F (38 mg, 0.074 mmol) and
(R)-(-)-1,3-butandiol (33 mg, 0.38 mmol) using the same method as
for preparation of 130AF12-148. Purification of the product by
reversed phase HPLC (C.sub.18) afforded the title compound (11.6
mg, 28%). LCMS m/z 527 [M+H].sup.+. HPLC t.sub.R=8.7 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxola-
n-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate (118AF31-85)
[0406] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide 103NLS63F (40 mg, 0.078 mmol) and
(S)-(+)-propylene glycol (30 mg, 0.39 mmol) using the same method
as for preparation of 130AF12-148. Purification of the product by
reversed phase HPLC (C.sub.18) afforded the title compound (21 mg,
53%). LCMS m/z 513 [M+H].sup.+. HPLC t.sub.R=9.9 min.
N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluoroben-
zyl)-2-(4-isobutoxyphenyl)acetamide, oxalate (118AF37-88)
[0407] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
obutoxyphenyl)acetamide 103NLS63F (40 mg, 0.078 mmol) and
2,4-pentandiol (41 mg, 0.39 mmol) using the same method as for
preparation of 130AF12-148. Purification of the product by reversed
phase HPLC (C.sub.18) afforded the title compound (9 mg, 21%). LCMS
m/z 541 [M+H].sup.+. HPLC t.sub.R=10.5 min.
N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-
-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide oxalate
(118AF87-114)
[0408] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tr-
ifluoromethoxyphenyl)acetamide 118AF58-98 (70 mg, 0.13 mmol) and
(S)-(+)-propylene glycol (53 mg, 0.69 mmol) using the same method
as for preparation of 130AF12-148. Purification of the product by
silica gel column chromatography, eluting with a stepwise gradient
of 0-4% methanol in dichloromethane, afforded the title compound
(31 mg, 46%). R.sub.f=0.17 (MeOH/CH.sub.2Cl.sub.2 4:96). LCMS m/z
525 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.34-6.91 (m, 8H, Ar--H), 5.03 & 4.92 (2t, 1H, J=4.8,
dioxolane-H), 4.66-4.56 (m, 0.6H, pip-H), 4.52 & 4.49 (2s, 2H,
benzyl-H), 4.22-4.07 (m, 1.4H, dioxolane-H), 3.95-3.89 (m, 0.6H,
dioxolane-H), 3.84 (s, 0.8H, benzyl-H), 3.74-3.64 (m, 0.4H, pip-H),
3.57 (s, 1.2H, benzyl-H), 3.40-3.33 (m, 1H, dioxolane-H), 2.78-2.86
(m, 2H, pip-H), 2.49-2.38 (m, 2H, NCH.sub.2), 2.10-2.01 (m, 1.2H,
pip-H), 1.70-1.53 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.40-1.22 (m,
3.8H, pip-H, CH.sub.3). HPLC t.sub.R=8.7 mm.
N-(4-Fluorobenzyl)-2-(4-isopropylphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxola-
n-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate (118AF91-117)
[0409] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-is-
opropylphenyl)acetamide 118AF63-100 (150 mg, 0.31 mmol) and
(S)-(+)-propylene glycol (95 mg, 1.24 mmol) using the same method
as for preparation of 130AF12-148. Purification by silica gel
column chromatography, eluting with a stepwise gradient of 0-4%
methanol in dichloromethane, afforded the title compound (51.2 mg,
34%).
[0410] R.sub.f=0.19 (MeOH/CH.sub.2Cl.sub.2, 4:96). LCMS m/z 483
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.24-6.90 (m, 8H, Ar--H), 5.03 & 4.92 (2t, 1H, J=4.8,
dioxolane-H), 4.67-4.55 (m, 0.6H, pip-H), 4.51 & 4.47 (2s, 2H,
benzyl-H), 4.21-4.07 (m, 1.4H, dioxolane-H), 3.94-3.89 (m, 0.6H,
dioxolane-H), 4.81-3.50 (m, 1.2H, benzyl-H, pip-H), 3.55 (s, 1.2H,
benzyl-H), 3.40-3.33 (m, 1H, dioxolane-H), 2.94-2.83 (m, 3H, pip-H,
CH(CH.sub.3).sub.2), 2.47-2.38 (m, 2H, NCH.sub.2), 2.09-2.01 (m,
1.2, pip-H), 1.86-1.52 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.31-1.19
(m, 9.8H, pip-H, CH.sub.3, CH(CH.sub.3).sub.2). HPLC t.sub.R=8.6
min.
N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]piperidin-4-
-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate
(118AF75-108)
[0411] The desired compound was synthesized from
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-tr-
ifluoromethoxyphenyl)acetamide 118AF58-98 (70 mg, 0.13 mmol) and
(R)-(-)-1,3-butandiol (60 mg, 0.66 mmol) using the same method as
for preparation of 130AF12-148. Purification of the product by
silica gel column chromatography, eluting with a stepwise gradient
of 0-4% methanol in dichloromethane, afforded the title compound
(28 mg, 40%).
[0412] R.sub.f=0.24 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 539
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.33-6.91 (m, 8H, Ar--H), 4.64-4.48 (m, 3.6H, benzyl-H, dioxane-H,
pip-H), 4.04 (m, 1H, dioxane-H), 3.83 (s, 0.8H, benzyl-H),
3.75-3.63 (m, 2.4H, dioxane-H, pip-H), 3.56 (s, 1.2H, benzyl-H),
2.92-2.83 (m, 2H, pip-H), 2.44-2.38 (m, 2H, NCH.sub.2), 2.09-2.01
(m, 1.2 pip-H), 1.89-1.53 (m, 7H, dioxane-H, pip-H,
NCH.sub.2CH.sub.2), 1.44-1.31 (m, 1.8H, dioxane-H, pip-H), 1.19 (m,
3H, CH.sub.3). HPLC t.sub.R=9.0 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-diox-
an-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate (118AF33-86)
[0413] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS-
56 (145 mg, 0.36 mmol) and
2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane (104.5 mg, 0.44 mmol)
using the same method as for synthesis of 130AF65-182. Purification
of the product by silica gel column chromatography, eluting with 5%
methanol in dichloromethane, afforded the title compound (119 mg,
58%).
[0414] R.sub.f=0.15 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 555
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.20-6.79 (m, 8H, Ar--H), 4.66-4.56 (m, 0.6H, pip-H), 4.49 &
4.43 (2s, 2H, benzyl-H), 3.76-3.68 (m, 3.2H, pip-H, benzyl-H,
CH.sub.2OiBu), 3.52-3.47 (m, 4H, dioxane-H), 3.41 (m, 1.2H,
benzyl-H), 2.93-2.84 (m, 2H, pip-H), 2.48-2.40 (m, 2H, NCH.sub.2),
2.11-2.00 (m, 2.2H, CH.sub.OiBu, pip-H), 1.87-1.80 (m, 2.8H, pip-H,
NCH.sub.2CH.sub.2), 1.72-1.50 (m, 3.2H, pip-H), 1.33 (s, 3.8H,
CH.sub.3, pip-H), 1.02-0.87 (m, 12H, CH.sub.3). HPLC t.sub.R=9.8
min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dioxolan-2--
yl)ethyl]-piperidin-4-yl}acetamide, oxalate (118AF35-87)
[0415] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (311 mg, 0.78 mmol) and
2-(2-bromoethyl)-2-methyl-1,3-dioxolane (188 mg, 0.96 mmol) using
the same method as for synthesis of 130AF65-182. Purification by
silica gel column chromatography, eluting with 5% methanol in
dichloromethane, afforded the title compound (61 mg, 15%).
[0416] R.sub.f=0.20 (MeOH/CH.sub.2Cl.sub.2, 5:95). LCMS m/z 513
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.17-6.76 (m, 8H, Ar--H), 4.64-4.52 (m, 0.6H, pip-H), 4.47 &
4.41 (2s, 2H, benzyl-H), 3.93-3.82 (m, 4H, dioxolane-H), 3.76-3.63
(m, 3.2H, benzyl-H, CH.sub.2OiBu, pip-H), 3.47 (s, 1.2H, benzyl-H),
2.94-2.83 (m, 2H, pip-H), 2.43-2.32 (m, 2H, NCH.sub.2), 2.12-1.97
(m, 2.2H, CH.sub.OiBu, pip-H), 1.84-1.72 (m, 2.8H, pip-H,
NCH.sub.2CH.sub.2), 1.70-1.50 (m, 3.2H, pip-H), 1.27 (s, 3.8H,
CH.sub.3, pip-H), 0.98 (m, 6H, CH.sub.3OiBu). HPLC t.sub.R=8.8
min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-yl)propyl-
]piperidin-4-yl}acetamide, tartrate (118AF79-39)
[0417] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (156 mg, 0.39 mmol) and 2-(3-chloropropyl)-1,3-dioxolane
(62 .mu.L, 0.47 mmol) using the same method as for synthesis of
130AF65-182. Purification by silica gel column chromatography,
eluting with a stepwise gradient of 0-4% methanol in
dichloromethane, afforded the title compound (49 mg, 25%).
[0418] R.sub.f=0.45 (MeOH/CH.sub.2Cl.sub.2, 7:93). LCMS m/z 513
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.79 (m, 8H, Ar--H), 4.84 (t, 1H, J=4.4, dioxolane-H),
4.66-4.56 (m, 0.6H, pip-H), 4.50 & 4.44 (2s, 2H, benzyl-H),
3.95-3.90 (m, 2H, dioxolane-H), 3.84-3.67 (m, 5.2H, benzyl-H,
CH.sub.2OiBu, pip-H, dioxolane-H), 3.50 (s, 1.2H, benzyl-H),
2.94-2.84 (m, 2H, pip-H), 2.34-2.27 (m, 2H, NCH.sub.2), 2.10-1.98
(m, 2.2H, CH.sub.OiBu, pip-H), 1.84-1.78 (m, 0.8H, pip-H),
1.71-1.50 (m, 7.2H, pip-H, NCH.sub.2CH.sub.2), 1.34-1.25 (m, 0.8H,
pip-H), 1.01 (m, 6H, CH.sub.3OiBu). HPLC t.sub.R=8.0 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-propyl)pip-
eridin-4-yl}-acetamide, dihydrochloride (98AF36-43)
[0419] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS-
56 (189 mg, 0.47 mmol), 1-piperidine (61 .mu.L, 0.61 mmol) and
1-chloro-3-iodopropane (61 .mu.L, 0.57 mmol) using the same method
as for synthesis of 130AF09-145. Purification of the product by
silica gel column chromatography, eluting with 10% methanol in
dichloromethane, afforded the title compound (75.6 mg, 31%).
[0420] R.sub.f=0.13 (MeOH/CH.sub.2Cl.sub.2, 1:4). LCMS m/z 524
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.81 (m, 8H, Ar--H), 4.66-4.54 (m, 0.6H, pip-H), 4.51 &
4.45 (2s, 2H, benzyl-H), 3.78-3.68 (m, 3.2H, benzyl-H,
CH.sub.2OiBu, pip-H), 3.52 (s, 1.2H, benzyl-H), 2.93-2.83 (m, 2H,
pip-H), 2.40-2.23 (m, 8H, NCH.sub.2), 2.15-1.26 (m, 15H, pip-H,
CH(CH.sub.3).sub.2, CH.sub.2), 1.02 (m, 6H, CH(CH.sub.3).sub.2).
HPLC t.sub.R=8.0 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-2-yloxy)-
ethyl]-piperidin-4-yl}acetamide, oxalate (98AF41-44)
[0421] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (185 mg, 0.46 mmol) and
2-(2-chloroethoxy)-tetrahydro-2H-pyran (75 .mu.L, 0.51 mmol) using
the same method as for synthesis of 130AF09-145. Purification of
the product by silica gel column chromatography, eluting with 4.5%
methanol in dichloromethane, afforded the title compound (96 mg,
40%).
[0422] R.sub.f=0.18 (MeOH/CH.sub.2Cl.sub.2, 4:96). LCMS m/z 527
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.21-6.78 (m, 8H, Ar--H), 4.67-4.56 (m, 0.6H, pip-H), 4.54 (m, 1H,
THP), 4.49 & 4.44 (2s, 2H, benzyl-H), 3.86-3.66 (m, 5.2H,
benzyl-H, CH.sub.2OiBu, pip-H, CHO), 3.58-3.43 (m, 3.2H, benzyl-H,
CHO), 3.01-2.89 (m, 2H, pip-H), 2.62 & 2.55 (2t, 2H, J=6.0,
NCH.sub.2CH.sub.2O), 2.26-2.17 (m, 1.2H, pip-H), 2.12-1.96 (m,
1.8H, CH.sub.OiBu, pip-H), 1.82-1.44 (m, 9.2H, pip-H, THP),
1.33-1.26 (m, 0.8H, pip-H), 1.01 (m, 6H, CH(CH.sub.3).sub.2). HPLC
t.sub.R=7.2 min.
N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo--piperidin-1-yl)pr-
opyl]piperidin-4-yl}acetamide (98AF73-64)
[0423] Sodium hydride (60% suspension in oil, 26 mg, 0.65 mmol) was
added to a solution of 2-piperidone (54 mg, 0.54 mmol) in dry THF
(2 mL) under argon atmosphere. After 15 minutes stirring at rt the
reaction mixture was cooled to 0.degree. C. over 15 minutes. A
solution of 1-bromo-3-chloropropane (160 .mu.L, 1.62 mmol) was
added dropwise to the cold mixture and stirring was continued
overnight at rt. The mixture was partitioned between water and
ethyl acetate, the organic layer dried over sodium sulphate,
filtered and evaporated to dryness. Purification of the residue on
silica gel column chromatography, eluting with a stepwise gradient
of 60-80% ethyl acetate in n-heptane, afforded
1-(3-chloropropyl)-piperidin-2-one (33 mg, 35%).
[0424] R.sub.f=0.22 (ethyl acetate/n-heptane 8:2). LCMS m/z 176
[M+H].sup.+. HPLC t.sub.R=1.8 min.
[0425] A solution of 1-(3-chloropropyl)-piperidin-2-one (32 mg,
0.18 mmol) in dry DMF (2 mL) was added to a suspension of potassium
carbonate (52 mg, 0.38 mmol) and
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (62 mg, 0.15 mmol) in dry DMF (2 mL). After addition of
sodium iodide (25 mg, 0.17 mmol) the mixture was stirred overnight
at 48.degree. C. Afterwards it was partitioned between water and
dichloromethane. The organic layer were dried over sodium sulphate,
filtered and evaporated to dryness. Purification of the residue by
reversed phase HPLC (C.sub.18) afforded the desired compound (2.6
mg, 3%).
[0426] R.sub.f=0.11 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 538
[M+H].sup.+. HPLC t.sub.R=8.2 min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-1-yl)pr-
opyl]piperidin-4-yl}acetamide, hydrochloride (98AF76-65)
[0427] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (107 mg, 0.27 mmol), 2-pyrrolidone and
1-bromo-3-chloropropane using the same method as for synthesis of
98AF73-64. Purification of the product by silica gel column
chromatography, eluting with a stepwise gradient of 4-8% methanol
in dichloromethane, afforded the title compound (15 mg, 11%).
[0428] R.sub.f=0.39 (MeOH/CH.sub.2Cl.sub.2 1:9). LCMS m/z 524
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.20-6.80 (m, 8H), 4.65-4.53 (m, 0.6H), 4.50 & 4.44 (2s, 2H),
3.76-3.67 (m, 3.2H), 3.51 (m, 1.2H), 3.34 (t, 2H, J=7.2), 3.26 (t,
2H, J=7.2), 2.95-2.82 (m, 2H), 2.38-2.25 (m, 4H), 2.12-1.96 (m,
4.2H), 1.86-1.56 (m, 6H), 1.29 (m, 0.8H), 1.01 (m, 6H). HPLC
t.sub.R=7.6 min.
N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl-2-oxo-ox-
azolidin-3-yl)propyl]piperidin-4-yl}acetamide, oxalate (98AF
100-73)
[0429] Sodium hydride (55% suspension in oil, 144 mg, 3.31 mmol)
was added to a solution of (R)-4-isopropyl-2-oxazolidinone (356 mg,
2.75 mmol) in dry tetrahydrofuran (17 mL) under argon atmosphere.
The suspension was stirred for 1 hour at rt, then cooled to
0.degree. C. and a solution of 1-bromo-3-chloropropane in dry
tetrahydrofuran (3 mL) was added dropwise. After 48 h stirring at
58.degree. C. the mixture was quenched with water. The solvent was
removed by evaporation under reduced pressure and the residue
partitioned between water and dichloromethane. The organic layer
was evaporated to dryness. Purification of the residue by silica
gel column chromatography, eluting with a mixture of ethyl acetate
and n-Heptane (70:30), afforded
(4R)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (401 mg,
71%).
[0430] A solution of
(4R)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (160 mg, 0.78
mmol) in dry DMF (2 mL) was added to a suspension of potassium
carbonate (217 mg, 1.57 mmol) and
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)N-piperidin-4-yl-acetamide
103NLS56 (250 mg, 0.63 mmol) in dry DMF (6 mL). After addition of
sodium iodide (113 mg, 0.75 mmol) the mixture was stirred overnight
at 62.degree. C. and partitioned between water and dichloromethane.
The organic layer were dried over sodium sulphate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with 5% methanol in dichloromethane,
afforded the desired compound (143 mg, 40%).
[0431] R.sub.f=0.28 (MeOH/CH.sub.2Cl.sub.2 6:96). LCMS m/z 568
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.20-6.78 (m, 8H, Ar--H), 4.61-4.51 (m, 0.6H, pip-H), 4.48 &
4.42 (2s, 2H, benzyl-H), 4.15 (t, 1H, J=8.8, oxa-H), 4.01 (m, 1H,
oxa-H), 3.78-3.64 (m, 4.2H, pip-H, benzyl-H, oxa-H, CH.sub.2OiBu),
3.48 (m, 2.2H, benzyl-H, CONCHCH.sub.2), 2.92-2.79 (m, 3H, pip-H,
CONCHCH.sub.2), 2.34-2.22 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2),
2.10-1.96 (m, 3.2H, pip-H, CH.sub.iPr, CH.sub.OiBu), 1.76-1.50 (m,
6H, pip-H, NCH.sub.2CH.sub.2), 1.32-1.26 (m, 0.8H, pip-H), 0.99 (m,
6H, CH.sub.3OiBu), 0.81-0.87 (m, 6H, CH.sub.3iPr). HPLC t.sub.R=9.1
min.
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-3-yl)pr-
opyl]piperidin-4-yl}acetamide, oxalate (98AF94-71)
[0432] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (298 mg, 0.75 mmol), 2-oxazolidoneand
1-bromo-3-chloropropane using the same method as for synthesis of
98AF100-73. Purification of the product by silica gel column
chromatography, eluting with 5% methanol in dichloromethane,
afforded the title compound (157 mg, 40%).
[0433] R.sub.f=0.23 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 526
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.20-6.78 (m, 8H, Ar--H), 4.61-4.50 (m, 0.6H, pip-H), 4.48 &
4.42 (2s, 2H, benzyl-H), 4.29-4-24 (m, 2H, oxa-OCH.sub.2),
3.78-3.65 (m, 3.2H, pip-H, benzyl-H, CH.sub.2OiBu), 3.52-3.48 (m,
3.2H, benzyl-H, oxa-NCH.sub.2), 3.25 (t, 2H, J=7.2,
CONCH.sub.2CH.sub.2CH.sub.2N), 2.89-2.80 (m, 2H, pip-H), 2.33-2.26
(m, 2H, NCH.sub.2CH.sub.2CH.sub.2NCO), 2.09-1.76 (m, 3H, pip-H,
CH.sub.OiBu), 1.71-1.49 (m, 5.2H, pip-H,
NCH.sub.2CH.sub.2CH.sub.2), 1.33-1.27 (m, 0.8H, pip-H), 1.00 (m,
6H, CH.sub.3OiBu). HPLC t.sub.R=7.8 min.
(S)-4-Methyl-oxazolidin-2-one (118AF10-77)
[0434] Triethylamine (0.94 mL, 6.65 mmol) was added dropwise to a
solution of L-alaninol (500 mg, 6.65 mmol) and
1,1-carbonyldiimidazole (1.29 g, 7.98 mmol) in dry THF (10 mL) at
rt, under argon atmosphere. The reaction mixture was stirred
overnight at 60.degree. C. The solvent was removed by evaporation
under reduced pressure. Purification of the residue by silica gel
column chromatography, eluting with 6% methanol in dichloromethane,
afforded the desired compound (450 mg, 67%).
[0435] R.sub.f=0.39 (MeOH/CH.sub.2Cl.sub.2 6:94). .sup.1H NMR
(CDCl.sub.3) .delta. 6.74 (m, 1H), 4.45-4.34 (m, 1H), 4.98-4.77 (m,
2H), 1.17 (m, 3H).
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-oxo-oxazo-
lidin-3-yl)propyl]piperidin-4-yl}acetamide, tartrate
(118AFI18-81)
[0436] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (205 mg, 0.52 mmol), (S)-4-methyl-oxazolidin-2-one
(118AF10-77) and 1-bromo-3-chloropropane using the same method as
for synthesis of 98AF100-73. Further purification by acidic
ion-exchange SPE cartridge was performed. Yield: 106 mg, 38%.
[0437] R.sub.f=0.22 (MeOH/CH.sub.2Cl.sub.2 6:94). LCMS m/z 540
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.20-6.78 (m, 8H, Ar--H), 4.61-4.50 (m, 0.6H, pip-H), 4.48 &
4.42 (2s, 2H, benzyl-H), 4.34 (m, 1H, oxa-H), 3.84-3.66 (m, 5.2H,
pip-H, benzyl-H, oxa-H, CH.sub.2OiBu), 3.49 (s, 1.2H, benzyl-H),
3.42-3.34 (m, 1H, CONCH.sub.2), 3.09-3.00 (m, 1H, CONCH.sub.2),
2.92-2.79 (m, 2H, pip-H), 2.33-2.26 (m, 2H, NCH.sub.2), 2.10-1.98
(m, 2.2H, pip-H, CH.sub.OiBu), 1.86-1.76 (m, 0.8H, pip-H),
1.72-1.48 (m, 5.2H, pip-H, NCH.sub.2CH.sub.2), 1.29 (m, 0.8H,
pip-H), 1.22 (m, 3H, oxa-CH.sub.3), 0.99 (m, 6H, CH.sub.3OiBu).
HPLC t.sub.R=8.4 min.
V.
(S)-4-Ethyl-oxazolidin-2-one (118AF08-76)
[0438] Triethylamine (0.80 mL, 5.74 mmol) was added dropwise to a
solution of (S)-(+)-2-amino-1-butanol (515 mg, 5.77 mmol) and
1,1-carbonyldiimidazole (1.10 g, 6.78 mmol) in dry THF (10 mL) at
rt under argon atmosphere. The reaction mixture was stirred
overnight at rt. The solvent was removed by evaporation under
reduced pressure. Purification of the residue by silica gel column
chromatography, eluting with 6% methanol in dichloromethane,
afforded the desired compound (485 mg, 73%). R.sub.f=0.42
(MeOH/CH.sub.2Cl.sub.2 6:94).
N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-ethyl-2-oxo-oxazol-
idin-3-yl)-propyl]piperidin-4-yl}acetamide, oxalate
(118AF16-80)
[0439] The desired compound was synthesized from
N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide
103NLS56 (202 mg, 0.51 mmol), (S)-4-ethyl-oxazolidin-2-one
(118AF08-76) and 1-bromo-3-chloropropane using the same method as
for synthesis of 98AF100-73. Purification of the product by acidic
ion-exchange SPE cartridge afforded the title compound (126 mg,
44%).
[0440] R.sub.f=0.28 (MeOH/CH.sub.2Cl.sub.2 6:94). LCMS m/z 554
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3, rotamers 0.4:0.6) .delta.
7.20-6.78 (m, 8H, Ar--H), 4.61-4.52 (m, 0.6H, pip-H), 4.48 &
4.42 (2s, 2H, benzyl-H), 4.32-4.26 (m, 1H, oxa-H), 3.94-3.88 (m,
1H, oxa-H), 3.76-3.66 (m, 4.2H, pip-H, benzyl-H, oxa-H,
CH.sub.2OiBu), 3.49 (s, 1.2H, benzyl-H), 3.46-3.37 (m, 1H,
CONCH.sub.2), 3.04-2.96 (m, 1H, CONCH.sub.2), 2.90-2.78 (m, 2H,
pip-H), 2.33-2.24 (m, 2H, NCH.sub.2), 2.11-1.96 (m, 2.2H, pip-H,
CH.sub.OiBu), 1.82-1.75 (m, 0.8H, pip-H), 1.74-1.42 (m, 7.2H,
pip-H, NCH.sub.2CH.sub.2, CH.sub.2CH.sub.3), 1.29 (m, 0.8H, pip-H),
1.00 (m, 6H, CH.sub.3OiBu), 0.85 (m, 3H, CH.sub.2CH.sub.3). HPLC
t.sub.R=8.7 min.
2-(2-Bromoethyl)-1,3-oxothiolane (121JP11)
[0441] Adapting a procedure by Yamada et al (Tetrahedron Lett.,
1998, 39, 7709-7712), boron trifluoride ether complex (5 mL, 40
mmol) was added dropwise to a mixture of
2-(2-bromoethyl)-1,3-dioxolane (1.45 g, 8.0 mmol) and
2-mercaptoethanol (2.81 mL, 40 mmol) in dichloromethane (15 mL) at
rt under Ar atmosphere and stirred at rt overnight. Sat. aq.
NaHCO.sub.3 (100 mL) was added to the crude mixture, followed by
extraction using Et.sub.2O (3.times.100 mL), drying
(Na.sub.2SO.sub.4) and evaporation in vacuo. Purification by
Kugelrohr distillation (90.degree. C., 1.0 mmHg) afforded 1.08 g of
the title compound as a yellow oil. The purity of this material
after distillation was 71% (determined by GC analysis) and it was
used as such in the alkylation step (121JP12).
N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-yl)ethy-
l]piperidin-4-yl}acetamide, L-tartrate (121JP12)
[0442] The title compound was prepared by the general procedure
described above for 103NLS63-F using 103NLS56 (130 mg, 0.33 mmol)
and 121JP11 (85 mg, 0.43 mmol) as the alkylating agent. Workup as
in 121JP11 followed by vacuum filtration chromatography over silica
gel (VFC, ethyl acetate/n-heptane 0:1.fwdarw.ethyl
acetate/n-heptane 1:0.fwdarw.ethyl acetate/MeOH 4:1) gave 85 mg
(51%) of 121JP12 as colourless thick oil. The L-tartrate salt was
prepared as described above.
[0443] R.sub.f=0.57 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 515
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
7.20-6.76 (m, 8H), 5.10-5.00 (m, 1H, oxothiolane-H), 4.66-4.54 (m,
0.5H, pip-H), 4.48 and 4.42 (2s, 2H, benzyl-H), 4.30-4.22 (m, 1H,
oxothiolane-H), 3.78-3.64 (m, 4.5H, pip-H, benzyl-H, oxothiolane-H,
OCH.sub.2OiBu), 3.48 (s, 1H, benzyl-H), 3.01-2.82 (m, 4H, pip-H,
oxothiolane-H), 2.60-2.34 (m, 2H, NCH.sub.2), 2.21-1.56 (m, 8H,
pip-H, NCH.sub.2CH.sub.2, CH.sub.OiBu), 1.32-1.22 (m, 1H, pip-H),
1.04-0.96 (m, 6H, CH.sub.3OiBu. HPLC t.sub.R=10.1 mm.
2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluo-
robenzyl)-acetamide, L-tartrate (121JP13)
[0444] The title compound was prepared by the procedure described
above for 117NLS87-A using 118AF52-95 (200 mg, 0.62 mmol) and
4-bromophenylacetic acid (500 mg, 2.32 mmol). Sat. aq. NaHCO.sub.3
(100 mL) was added to the crude mixture, followed by extraction
using CH.sub.2Cl.sub.2 (3.times.100 mL), drying (Na.sub.2SO.sub.4)
and evaporation in vacuo. VFC over silica gel (ethyl
acetate/n-heptane 1:1.fwdarw.ethyl acetate/n-heptane
1:0.fwdarw.ethyl acetate/MeOH 2:1) gave 250 mg (78 %) of 121JP12 as
a thick oil. The L-tartrate salt was prepared as described
above.
[0445] R.sub.f=0.49 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 521
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.50-6.88 (m, 8H), 4.62-4.57 (m, 0.4H, pip-H), 4.50 (t, 1H, J=4.9,
dioxane-H) 4.48 and 4.42 (2s, 2H, benzyl-H), 4.06-4.00 (m, 2H,
dioxane-H), 3.76 and 3.50 (2s, 2H, benzyl-H), 3.75-3.60 (m, 2.6H,
pip-H, dioxane-H), 3.01 and 2.90 (2d, 2H, J=10.5, pip-H), 2.52 and
2.41 (2t, 2H, J=8.0, NCH.sub.2), 2.10-1.98 (m, 2.2 H, dioxane-H,
pip-H), 1.97-1.58 (m, 6H, pip-H, NCH.sub.2CH.sub.2), 1.38-1.20 (m,
1.8H, dioxane-H, pip-H). HPLC t.sub.R=8.3 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-
butylamino-phenyl)acetamide, L-tartrate (121 JP27)
[0446] Adapting a protocol by Buchwald et al (J. Am. Chem. Soc.,
1996, 118, 7215-7216), 121JP13 (100 mg, 192 .mu.mol), isobutylamine
(17 mg, 230 .mu.mol), Pd.sub.2dba.sub.3 (11.6 mg, 19.2 .mu.mol),
BINAP (12.0 mg, 38.4 .mu.mol) and NaOtBu (25.8 mg, 269 .mu.mol)
were weighed into a flask, toluene (2 mL) was added and the
resulting mixture was stirred at 80.degree. C. for 18 h. Workup as
in 121JP13 followed by preparative reversed-phase (C.sub.18) HPLC
afforded 25.7 mg (27.0%) of 121JP27 as a thick colourless oil. The
L-tartrate salt was prepared as described above.
[0447] R.sub.f=0.30 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 512
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
7.10-6.81 (m, 6H), 6.59-6.49 (m, 2H), 4.65-4.55 (m, 0.5H, pip-H),
4.55-4.50 (m, 1H, dioxane-H), 4.50 and 4.43 (2s, 2H, benzyl-H),
4.10-4.02 (m, 2H, dioxane-H), 3.80-3.67 (m, 3.5H, pip-H, benzyl-H,
dioxane-H) 3.45 (s, 1H, benzyl-H), 2.95-2.85 (m, 4H, pip-H,
NHCH.sub.2CH(CH.sub.3).sub.2)), 2.45-2.35 (m, 2H, NCH.sub.2),
2.09-1.99 (m, 2H, dioxane-H, pip-H), 1.91-1.50 (m, 7H,
NCH.sub.2CH.sub.2, pip-H, NHCH.sub.2CH(CH.sub.3).sub.2), 1.38-1.25
(m, 2H, dioxane-H, pip-H), 0.98 (m, 6H,
NHCH.sub.2CH(CH.sub.3).sub.2). HPLC t.sub.R=8.2 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pro-
pylamino-phenyl)acetamide, L-tartrate (121 JP28)
[0448] Prepared identically as described in the protocol for the
synthesis of 121JP27, using propylamine (16 mg, 230 .mu.mol)
instead of isobutylamine to afford 24 mg (25%) of 121JP28 as a
thick oil. The L-tartrate salt was prepared as described above.
[0449] R.sub.f=0.33 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 498
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
7.11-6.82 (m, 6H), 6.53-6.43 (m, 2H), 4.58-4.49 (m, 0.5H, pip-H),
4.48-4.45 (m, 1H, dioxane-H), 4.42 and 4.35 (2s, 2H, benzyl-H),
4.05-3.95 (m, 2H, dioxane-H), 3.70-3.60 (m, 3.5H, pip-H, benzyl-H,
dioxane-H), 3.40 (s, 1H, benzyl-H), 3.05-2.95 (m, 2H, pip-H),
2.85-2.70 (m, 2H, NHCH.sub.2CH.sub.2CH.sub.3), 2.48-2.38 (m, 2H,
NCH.sub.2), 2.05-1.90 (m, 2H, dioxane-H, pip-H), 1.92-1.40 (m, 8H,
NCH.sub.2CH.sub.2, pip-H, NHCH.sub.2CH.sub.2CH.sub.3), 1.40-1.28
(m, 2H, dioxane-H, pip-H), 0.98 (m, 3H,
NHCH.sub.2CH.sub.2CH.sub.3). HPLC t.sub.R=7.3 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(1--
nitropropyl)-phenyl)acetamide, L-tartrate (121JP34)
[0450] Adapting a protocol by Vogl & Buchwald (J. Org. Chem.,
2002, 67, 106-111), 121JP13 (135 mg, 0.26 mmol), 1-nitropropane (47
mg, 0.52 mmol), Cs.sub.2CO.sub.3 (95 mg, 0.29 mmol),
2-di-tert-butylphosphinobiphenyl (15.5 mg, 52 .mu.mol) and
Pd.sub.2dba.sub.3 (11.9 mg, 13 .mu.mol) were weighed into a flask,
DME (2 mL) was added and the reaction was stirred at 60.degree. C.
for 20 h. Workup as in 121JP13 followed by preparative TLC
(CH.sub.2Cl.sub.2/MeOH, 15:1, 10.times. eluted) afforded 22 mg
(16%) of 121JP34 as a thick colourless oil. The L-tartrate salt of
the title compound was prepared as described above.
[0451] R.sub.f=0.58 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 528
[M+H].sup.+. HPLC t.sub.R=8.1 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2--
oxopyrrolidin-1-yl)phenyl)acetamide L-tartrate (121JP31)
[0452] Adapting a protocol by Yin & Buchwald (J. Am. Chem.
Soc., 2002, 124, 6043-6048), 121JP13 (124 mg, 0.24 mmol),
pyrrolidone (24.7 mg, 0.29 mmol), Cs.sub.2CO.sub.3 (111 mg, 0.34
mmol), Xantphos (20.8 mg, 0.036 mmol) and Pd.sub.2dba.sub.3 (11.0
mg, 0.012 mmol) were weighed into a flask, dioxane (2 mL) was added
and the reaction was stirred at 90.degree. C. for 70 h. Workup as
in 121JP13 and purification as in 121JP27 afforded 8 mg (7%) of
121JP31 as a thick colourless oil. The L-tartrate salt was prepared
as described above.
[0453] R.sub.f=0.31 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 524
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.60-6.80 (m, 8H), 4.60-4.50 (m, 0.4H, pip-H), 4.47 (t, 1H, J=5.1,
dioxane-H) 4.42 and 4.38 (2s, 2H, benzyl-H), 4.04-3.97 (m, 2H,
dioxane-H), 3.82-3.60 (m, 5.4H, pip-H, dioxane-H, benzyl-H,
pyrrol-H), 3.25 (s, 1.2H, benzyl-H), 2.90-2.72 (m, 2H, pip-H),
2.60-2.50 (m, 2H, pyrrol-H), 2.39-2.32 (m, 2H, NCH.sub.2) 2.18-1.90
(m, 4.2 H, dioxane-H, pip-H, pyrrol-H), 1.81-1.40 (m, 6H, pip-H,
NCH.sub.2CH.sub.2), 1.32-1.18 (m, 1.8H, dioxane-H, pip-H). HPLC
t.sub.R=4.9 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-
butylsulfanyl-phenyl)acetamide L-tartrate (121JP33)
[0454] Adapting a protocol by Li (J. Org. Chem., 2002, 67,
3643-3650), 121JP13 (120 mg, 0.231 mmol), 2-methyl-1-propanethiol
(25 mg, 0.28 mmol), [(t-Bu).sub.2P(OH)].sub.2PdCl.sub.2 (11.6 mg,
0.0231 mmol) and NaOtBu (44 mg, 0.46 mmol) were weighed into a
flask, toluene (2 mL) was added and the reaction was stirred at
110.degree. C. for 16 h. Workup as in 121JP13 and purification as
in 121JP27 afforded 1.7 mg (1.4%) of 121JP33 as a thick colourless
oil. The L-tartrate salt of the title compound was prepared as
described above.
[0455] R.sub.f=0.46 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 529
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.24-6.82 (m, 8H), 4.57-4.48 (m, 0.4H, pip-H), 4.47 (t, 1H, J=5.1,
dioxane-H), 4.45 and 4.38 (2s, 2H, benzyl-H), 4.05-3.95 (m, 2H,
dioxane-H), 3.72 (s, 0.8 H, benzyl-H), 3.70-3.60 (m, 2.6H, pip-H,
dioxane-H) 3.44 (s, 1.2H, benzyl-H), 2.87-2.75 (m, 2H, pip-H), 2.72
(t, 2H, J=6.5, SCH.sub.2CH(CH.sub.3).sub.2)), 2.38-2.28 (m, 2H,
NCH.sub.2), 2.05-1.88 (m, 2.2H, dioxane-H, pip-H), 1.81-1.48 (m,
7H, NCH.sub.2CH.sub.2, pip-H, SCH.sub.2CH(CH.sub.3).sub.2),
1.30-1.20 (m, 1.8H, dioxane-H, pip-H), 0.98 (t, 6H, J=6.7,
SCH.sub.2CH(CH.sub.3).sub.2). HPLC t.sub.R=8.8 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iod-
ophenyl)-acetamide, L-tartrate (121JP40)
[0456] The title compound was prepared by the procedure described
above 117NLS87-A using 118AF52-95 (400 mg, 1.24 mmol) and
4-iodophenylacetic acid (1.22 g, 4.64 mmol). Workup as in 121JP13
and purification as in 121JP34 gave 320 mg (46%) of 121JP40 as a
colourless thick oil. The L-tartrate salt was prepared as described
above.
[0457] R.sub.f=0.52 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 567
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.65-7.55 (m, 2H), 7.16-6.85 (m, 6H), 4.59-4.50 (m, 0.6H, pip-H),
4.51 (t, 1H, J=5.0, dioxane-H), 4.50 and 4.42 (2s, 2H, benzyl-H),
4.09-4.00 (m, 2H, dioxane-H), 3.75 and 3.49 (2s, 2H, benzyl-H),
3.74-3.54 (m, 2.4 H, pip-H, dioxane-H), 2.85 (d, 2H, J=10.6,
pip-H), 2.41-2.35 (m, 2H, NCH.sub.2), 2.08-1.95 (m, 2.2H,
dioxane-H, pip-H), 1.88-1.50 (m, 6H, pip-H, NCH.sub.2CH.sub.2),
1.39-1.27 (m, 1.8H, dioxane-H, pip-H). HPLC t.sub.R=8.6 min.
2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluo-
robenzyl)-acetamide, L-tartrate (121JP44).
[0458] Adapting a protocol by Cacchi et al (Org. Lett, 2003, 5,
289-293), 121JP40 (68 mg, 0.12 mmol), acetic anhydride (61 mg, 0.6
mmol), Pd.sub.2dba.sub.3 (1.4 mg, 1.5 .mu.mol), lithium chloride
(26 mg, 0.6 mmol) and EtNiPr.sub.2 (31 mg, 0.24 mmol) were weighed
into a flask, DMF (0.9 mL) was added and the resulting mixture was
stirred at 100.degree. C. for 18 h. Workup as in 121JP13 and
purification as in 121JP34 afforded 19 mg (33%) of 121JP44 as a
thick colourless oil. The L-tartrate salt was prepared as described
above.
[0459] R.sub.f=0.50 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 483
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) 7.88-7.78
(m, 2H), 7.36-6.84 (m, 6H), 4.58-4.49 (m, 0.4H, pip-H), 4.48-4.46
(m, 1H, dioxane-H), 4.45 and 4.38 (2s, 2H, benzyl-H), 4.05-3.95 (m,
2H, dioxane-H), 3.81 and 3.55 (2s, 2H, benzyl-H), 3.70-3.60 (m,
2.6H, pip-H, dioxane-H) 2.85-2.75 (m, 2H, pip-H), 2.54 and 2.52
(2s, 3H, CH.sub.3), 2.38-2.27 (m, 2H, NCH.sub.2), 2.05-1.92 (m,
2.2H, dioxane-H, pip-H), 1.81-1.45 (m, 6H, NCH.sub.2CH.sub.2,
pip-H), 1.32-1.22 (m, 1.8H, dioxane-H, pip-H). HPLC t.sub.R=5.5
min.
2-[4-(1-Hydroxyiminoethyl)phenyl]-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-
-4-yl}-N-(4-fluorobenzyl)acetamide, L-tartrate (121JP48)
[0460] 121JP44 (14 mg, 29 .mu.mol), pyridine (4.6 mg, 58 .mu.mol)
and ethanol (5 mL) were placed in a flask, to which hydroxylamine
hydrochloride (4.1 mg, 58 .mu.mol) was added and the resulting
mixture was stirred at rt for 5 h. Workup as in 121JP13 and
purification as in 121JP34 afforded 7 mg (49%) of 121JP48 as a
thick colourless oil. The L-tartrate salt was prepared as described
above.
[0461] R.sub.f=0.40 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 498
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) 7.63-7.51
(m, 2H), 7.33-6.88 (m, 6H), 4.66-4.58 (m, 0.4H, pip-H), 4.56-4.53
(m, 1H, dioxane-H), 4.51 and 4.40 (2s, 2H, benzyl-H), 4.10-4.04 (m,
2H, dioxane-H), 3.85 and 3.58 (2s, 2H, benzyl-H), 3.78-3.67 (m,
2.6H, pip-H, dioxane-H) 2.97-2.83 (m, 2H, pip-H), 2.47-2.37 (m, 2H,
NCH.sub.2), 2.26 and 2.24 (2s, 3H, CH.sub.3), 2.12-1.98 (m, 2.2H,
dioxane-H, pip-H), 1.88-1.58 (m, 6H, NCH.sub.2CH.sub.2, pip-H),
1.37-1.29 (m, 1.8H, dioxane-H, pip-H). HPLC t.sub.R=4.0 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-mor-
pholin-4-yl-phenyl)acetamide, L-tartrate (121JP49)
[0462] Adapting a protocol by Buchwald et al (Org Lett., 2002, 4,
581-584), 121JP40 (50 mg, 88 .mu.mol), morpholine (9.2 mg, 106
.mu.mol), CuI (1.7 mg, 8.8 .mu.mol) and K.sub.3PO.sub.4 (37.6 mg,
177 .mu.mol) were weighed into a flask in air atmosphere, ethylene
glycol (2 mL) was added and the resulting mixture was stirred at
80.degree. C. for 16 h under air atmosphere. Workup as in 121JP13
and purification as in 121JP34 afforded 4.7 mg (10%) of 121JP49 as
a thick colourless oil. The L-tartrate salt was prepared as
described above.
[0463] R.sub.f=0.33 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 526
[M+H].sup.+..sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.18-6.72 (m, 8H), 4.62 and 4.37 (2s, 2H, benzyl-H), 4.57-4.50 (m,
0.4H, pip-H), 4.50-4.42 (m, 1H, dioxane-H), 4.05-3.95 (m, 2H,
dioxane-H), 3.82-3.75 (m, 4H, morph-H), 3.69 and 3.43 (2s, 2H,
benzyl-H), 3.68-3.61 (m, 2.6H, pip-H, dioxane-H), 3.12-3.03 (m, 4H,
morph-H), 2.85-2.75 (m, 2H, pip-H), 2.38-2.27 (m, 2H, NCH.sub.2),
2.07-1.90 (m, 2.2H, dioxane-H, pip-H), 1.82-1.45 (m, 6H,
NCH.sub.2CH.sub.2, pip-H), 1.30-1.22 (m, 1.8H, dioxane-H, pip-H).
HPLC t.sub.R=6.2 min.
N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyr-
azol-1-yl-phenyl)acetamide, L-tartrate (121JP56)
[0464] Adapting a protocol by Buchwald et al (J. Am. Chem. Soc.,
2001, 123, 7727-7729), 121JP40 (48 mg, 85 .mu.mol), pyrazole (7 mg,
102 .mu.mol), CuI (0.4 mg, 1.7 .mu.mol), racemic
trans-1,2-cyclohexanediamine (1.0 mg, 8.5 .mu.mol), and
K.sub.2CO.sub.3 (25 mg, 181 .mu.mol) were weighed into a flask,
dioxane (1.5 mL) was added and the resulting mixture was stirred at
110.degree. C. for 60 h. Workup as in 121JP13 and purification as
in 121JP34 afforded 3.9 mg (9%) of 121JP56 as a thick colourless
oil. The L-tartrate salt was prepared as described above.
[0465] R.sub.f=0.27 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 507
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.6:0.4) .delta.
7.86 and 7.82 (2d, 1H, J=2.2, pyraz-H), 7.64 (d, 1H, J=4.4,
pyraz-H), 7.62-6.83 (m, 8H), 6.42-6.36 (m, 1H, pyraz-H), 4.60-4.49
(m, 0.6H, pip-H), 4.48 (t, 1H, J=5.1, dioxane-H), 4.45 and 4.38
(2s, 2H, benzyl-H), 4.05-3.95 (m, 2H, dioxane-H), 3.80 and 3.54
(2s, 2H, benzyl-H), 3.70-3.61 (m, 2.4H, pip-H, dioxane-H) 2.85-2.75
(m, 2H, pip-H), 2.38-2.28 (m, 2H, NCH.sub.2), 2.07-1.90 (m, 2.2H,
dioxane-H, pip-H), 1.82-1.45 (m, 6H, NCH.sub.2CH.sub.2, pip-H),
1.35-1.22 (m, 1.8H, dioxane-H, pip-H). HPLC t.sub.R=6.4 min.
2-(2-Bromopropyl)-1,3-dioxane (121 JP80)
[0466] Adapting a procedure of Buchi and Wuest (J. Org. Chem, 1969,
34, 1122-1123), crotonaldehyde (3 g, 43 mmol) was added dropwise to
conc. aq. HBr (5.2 g, 64 mmol) over 5 min at 5.degree. C. under air
atmosphere. After 15 min of stirring at 5.degree. C., during which
time the mixture changed from colourless to brownish,
1,3-propanediol (8.1 g, 107 mmol) was added and the reaction was
stirred at 5.degree. C. for further 0.5 h before allowing it warm
to rt, and finally stirring it at rt for 2 h. The crude reaction
mixture was then n-heptane extracted (2.times.200 mL), the combined
n-heptane extracts were Na.sub.2SO.sub.4 dried, evaporated in vacuo
and 121JP80 was isolated by Kugelrohr distillation (75.degree. C.,
0.18 mmHg) to obtain 124 mg (1.4%) of the title compound as a
colourless liquid.
[0467] Characterization Data: .sup.1H-NMR (CDCl.sub.3) .delta. 4.73
(dd, 1H, J=7.2, 3.4), 4.26-4.18 (m, 1H), 4.15-4.06 (m, 2H),
3.83-3.75 (m, 2H), 2.15-1.97 (m, 3H), 1.71 (d, 3H, J=6.6),
1.38-1.32 (m, 1H).
N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-
-2-(4-iso-butoxyphenyl-acetamide, L-tartrate (121JP84)
[0468] The title compound was prepared by the procedure described
above 103NLS63-F using 103NLS56 (202 mg, 0.51 mmol) and 121JP80
(124 mg, 0.59 mmol) as the alkylating agent. Workup as in 121JP13
and purification as in 121JP34 gave 1.9 mg (0.7%) of 121JP84 as a
thick oil. The L-tartrate salt was prepared as described above.
[0469] R.sub.f=0.43 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 527
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
7.19-6.80 (m, 8H), 4.50-4.33 (m, 3.5H, dioxane-H, benzyl-H, pip-H),
4.04-3.93 (m, 2H, dioxane-H), 3.72-3.55 (m, 5.5H, dioxane-H,
benzyl-H, pip-H, OCH.sub.2OiBu), 3.42 (s, 1H, benzyl-H), 2.78-2.59
(m, 2H, pip-H), 2.34-2.16 (m, 1H, NCH), 2.08-1.89 (m, 2H, pip-H,
CH.sub.OiBu), 1.79-0.77 (m, 17H, CH.sub.3.sub.OiBu, NCHCH.sub.3,
NCHCH.sub.2, pip-H, dioxane-H). HPLC t.sub.R=8.5 min.
4-Iodophenylacetic acid ethyl ester (121JP58) .
[0470] 4-Iodophenylacetic acid (3 g), ethanol (20 mL) and conc.
H.sub.2SO.sub.4 (5 mL) were refluxed overnight. Ca. 15 mL ethanol
was then evaporated, the residue was extracted with dichloromethane
(3.times.100 mL), the combined organic extracts were washed with
sat. aq. NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and evaporated in
vacuo to afford 2.97 g (90%) of 121JP58 as a yellow oil.
[0471] Characterization Data: .sup.1H-NMR (CDCl.sub.3) .delta. 7.62
(d, 2H, J=8.4), 7.02 (d, 2H, J=8.4), 4.07 (q, 2 H, J=7.0), 3.59 (s,
2H), 1.12 (t, 3H, J=7.0).
4-Pyrazol-1-ylphenylacetic acid ethyl ester (121JP64)
[0472] 121JP58 (290 mg, 1.0 mmol) was treated identically as
121JP40 for the synthesis of 121JP56. After heating the reaction to
110.degree. C. for 72 h and workup as in 121JP13, the crude mixture
was purified by VFC (CH.sub.2Cl.sub.2/MeOH 1:0-20:1) to furnish 180
mg (78 %) of 121JP64 as a yellow oil.
[0473] Characterization Data: .sup.1H-NMR (CDCl.sub.3) .delta. 7.92
(dd, 1H, J=2.3, 1.0), 7.72 (d, 1H, J=1.3), 7.62 (d, 2H, J=8.7),
7.39 (d, 2H, J=8.7), 6.42 (dd, 1H, J=2.5, 1.9), 4.18 (q, 2 H,
J=7.0), 3.61 (s, 2H), 1.22 (t, 3H,J=7.1).
4-Pyrazol-1-ylphenylacetic acid (121JP68, 87)
[0474] 121JP64 (180 mg, 0.78 mmol), lithium hydroxide monohydrate
(164 mg, 3.9 mmol), H.sub.2O (10 mL) and THF (10 mL) were stirred
overnight at rt. The crude mixture was then extracted with
dichloromethane (3.times.150 mL), the pH of the aqueous phase was
adjusted to ca. pH 3 using 4M HCl and extracted with
dichloromethane (3.times.150 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to
provide 128 mg (81%) of 121JP68 as a yellow solid.
[0475] Characterization Data: .sup.1H-NMR (CDCl.sub.3) .delta. 7.90
(m, 1H), 7.75 (m, 1H), 7.63 (d, 2H, J=8.6), 7.38 (d, 2H, J=8.6),
6.45 (m, 1H), 3.68 (s, 2H).
N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyr-
azol-1-yl-phenyl)acetamide L-tartrate (121JP91)
[0476] The title compound was prepared by the general procedure
described above 117NLS87-A using 128NLS52 (87 mg, 0.27 mmol) and
121JP87 (60 mg, 0.27 mmol). Workup as in 121JP13 and purification
as in 121JP34 gave 25 mg (18%) of 121JP91 as a colourless oil. The
L-tartrate salt was prepared as described above.
[0477] R.sub.f=0.34 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z 507
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
7.92 and 7.88 (2d, 1H, J=2.2, pyraz-H), 7.71 (d, 1H, J=4.7,
pyraz-H), 7.69-6.90 (m, 8H), 6.48-6.42 (m, 1H, pyraz-H), 5.00 (d,
1H, J=6.3, dioxane-H), 4.65 (d, 1H, J=6.4, dioxane-H), 4.63-4.55
(m, 0.5H, pip-H), 4.52 and 4.46 (2s, 2H, benzyl-H), 4.10-4.02 (m,
1H, dioxane-H), 3.86 and 3.57 (2s, 2H, benzyl-H), 3.78-3.55 (m,
2.5H, pip-H, dioxane-H) 2.93-2.82 (m, 2H, pip-H), 2.49-2.30 (m, 2H,
NCH.sub.2), 2.10-1.98 (m, 1H, pip-H), 1.90-1.33 (m, 9H,
NCH.sub.2CH.sub.2, pip-H, dioxane-H). HPLC t.sub.R=5.2 min.
N-[1-((R)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-iso-
butoxyphenyl)acetamide, tartrate (130AF93-189)
[0478] The desired compound was synthesized from
(S)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol (Moune et al,
J. Org. Chem., 1997, 62, 3332-3339) and 103NLS56 using the same
method as described for the preparation of 130AF65-182.
[0479] R.sub.f=0.48 (MeOH/CH.sub.2Cl.sub.2, 10:90). LCMS m/z 501
[M+H].sup.+. HPLC t.sub.R=7.4 min.
N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-
-(4-isobutoxyphenyl)acetamide, tartrate (130AF95-190)
[0480] The desired compound (7.9 mg, 55%) was synthesized from
130AF93-189 (18.6 mg, 0.028 mmol) using the same method as for the
synthesis of 130AF67-183. The enantiomeric excess was determined to
be 99% using chiral HPLC analysis (Chiralpak AD column,
4.6.times.250 mm; heptane/I--PrOH 50:50, 0.3% DEA; 0.5 mL/min;
t.sub.R 22.7 min). The .sup.1H NMR and LCMS data were identical
with 130AF67-183.
1-(1,2,4-Triazol-4-yl)phenylacetic acid (141JP01)
[0481] Adapting a protocol by Catarzi et al (J. Med Chem., 2001,
44, 3157-3165), diformylhydrazine (352 mg, 4.0 mmol) and then
dropwise trimethylsilyl chloride (2.53 mL, 20 mmol) and Et.sub.3N
(1.30 mL, 9.3 mmol) were added to a suspension of
4-aminophenylacetic acid (201 mg, 1.33 mmol) in anhydrous pyridine.
The mixture was heated at 100.degree. C. overnight, volatiles were
removed at reduced pressure and the resulting solid was treated
with water (6 mL), collected, washed with H.sub.2O and dried in
vacuo to provide 251 mg (93%) of 141JP01 as a light brown solid.
LCMS m/z 204[M+H].sup.+. .sup.1H-NMR (DMSO-d.sub.6) .delta. 9.05
(s, 2H), 7.62 (d, 1H, J=8.6), 7.40 (d, 1H, J=8.2), 3.61 (s,
2H).
N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4(1,2-
,4-triazol-4-yl)phenyl]acetamide, L-tartrate (141JP13)
[0482] The acid 141JP01 (35 mg, 0.17 mmol),
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine
(118AF52-95, 55 mg, 0.17 mmol) and diisopropylethylamine (52 mg,
0.51 mmol) were dissolved in DMF (5 mL).
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP, 119
mg, 0.25 mmol) was added, and the mixture was stirred at rt for 2
h. The mixture was concentrated and passed onto an acidic ion
exchange SPE cartridge. The cartridge was washed with methanol
(8.times.4 mL) and the remaining product was eluted off the column
with 10% NH.sub.4OH in methanol (2.times.4 mL) and evaporated. The
resulting oil was purified as in 121JP34 to give 47 mg (54%) of
141JP13 as a colourless oil. The L-tartrate salt was prepared as
described above.
[0483] R.sub.f=0.26 (MeOH/CH.sub.2Cl.sub.2 1:10). LCMS m/z
508[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, rotamers 0.5:0.5) .delta.
8.47 and 8.41 (2s, 1H, --H), 7.48-6.89 (m, 8H, Ar--H), 4.62-4.56
(m, 0.6H, pip-H), 4.56-4.49 (m, 3H, dioxane-H, benzyl-H), 4.10-4.01
(m, 2H, dioxane-H), 3.79 and 3.61 (2s, 2H, benzyl-H), 3.77-3.67 (m,
2.4H, pip-H, dioxane-H), 2.94-2.84 (m, 2H, pip-H), 2.45-2.35 (m,
2H, NCH.sub.2), 2.10-1.43 (m, 9H, dioxane-H, NCH.sub.2CH.sub.2,
pip-H), 1.37-1.27 (m, 1 H, dioxane-H).
In Vitro Determination of Receptor Activity
[0484] Receptor Selection and Amplification (R-SAT) Assays. The
functional receptor assay, Receptor Selection and Amplification
Technology (R-SAT.TM.), was used (with minor modifications from the
procedure described previously (Brann, M. R. U.S. Pat. No.
5,707,798, 1998; Chem. Abstr. 1998, 128, 111548) to screen
compounds for efficacy at the 5-HT.sub.2A receptor. Briefly, NIH3T3
cells were grown in 96 well tissue culture plates to 70-80%
confluence. Cells were transfected for 12-16 h with plasmid DNAs
using superfect (Qiagen Inc.) as per manufacturer's protocols.
R-SAT's were generally performed with 50 ng/well of receptor and 20
ng/well of .beta.-galactosidase plasmid DNA. All receptor and
G-protein constructs used were in the pSI mammalian expression
vector (Promega Inc) as described previously. The 5-HT.sub.2A
receptor gene was amplified by nested PCR from brain cDNA using the
oligodeoxynucleotides based on the published sequence (Saltzman et.
al, Biochem. Biophys. Res. Comm. 1991, 181, 1469). For large-scale
transfections, cells were transfected for 12-16 h, then trypsinized
and frozen in DMSO. Frozen cells were later thawed, plated at
10,000-40,000 cells per well of a 96 well plate that contained
drug. With both methods, cells were then grown in a humidified
atmosphere with 5% ambient CO.sub.2 for five days. Media was then
removed from the plates and marker gene activity was measured by
the addition of the .beta.-galactosidase substrate o-nitrophenyl
.beta.-D-galactopyranoside (ONPG, in PBS with 5% NP-40). The
resulting colorimetric reaction was measured in a
spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data
were analyzed using the computer program XLFit (IDBSm). Efficacy is
the percent maximal repression compared to repression by a control
compound (ritanserin in the case of 5-HT.sub.2A). pIC.sub.50 is the
negative of the log(IC.sub.50), where IC.sub.50 is the calculated
concentration in Molar that produces 50% maximal repression.
In Vivo Determination of Behavioral Effects
[0485] Animals and Apparatus. Male NSA mice (Harlan; San Deigo,
Calif.) were used as subjects. Mice weighed 20-30 g. Animals were
housed 8/cage in the One Cage system (One Cage; Lab Products, Inc.,
Seaford, Del.) with bedding (1/8 inch Bed "O" Cob; Harlan Teklad,
Madison, Wis.) in a room with controlled temperature
22.+-.3.degree. C. and a 12 hour light:dark cycle (lights on 6 am).
Water and standard rodent chow (Harlan Teklad) were continuously
available in the home cage. For testing, plastic locomotor activity
cages (20.times.20.times.30 cm; AccuScan Instruments, Columbus,
Ohio) were equipped with photocell beams for monitoring horizontal
activity. Data were collected using Versamax computer software
(AccuScan Instruments).
Procedure.
[0486] For determination of spontaneous activity, test compounds
were administered alone (s.c. 10 min or p.o. 30 min before the
session). For hyperactivity experiments, mice were injected with
0.3 mg/kg MK-801 i.p. 15 min presession (the peak dose for
producing hyperactivity in an inverted-U dose-effect curve as
determined in pilot experiments) in combination with vehicle or
test compound. Motor activity data were collected during a 15 min
session in a lit room. Mice had no prior exposure to the motor
cages. Each dose or dose combination was tested in a separate group
of mice (n=8).
Data Analysis.
[0487] Distance traveled (cm) was calculated and averaged across
animals in a group. An analysis of variance (ANOVA) and post-hoc
Dunnett's t-test comparions to vehicle control were conducted for
each dose-response function. The lowest dose found to be
significantly different from vehicle control was defined as the
minimum effective dose (MED).
[0488] Compound Activity TABLE-US-00001 TABLE 1 MED 5HT2A %INH
5HT2A pIC50 in vivo po (mg/kg) 103NLS45-B ##STR9## 84 7.6 117NLS01
##STR10## 104 9.7 1 103NLS63-F ##STR11## 101 9.5 103NLS69-A
##STR12## 96 8.7 117NLS03-B ##STR13## 85 8.4 117NLS25 ##STR14## 94
8.9 128NLS22-A ##STR15## 98 8.5 118AF37-88 ##STR16## 105 9.2
098AF76-65 ##STR17## 100 9.1 118AF16-80 ##STR18## 103 9.1
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