U.S. patent application number 10/802970 was filed with the patent office on 2005-01-20 for azacyclic compounds.
Invention is credited to Andersson, Carl-Magnus A., Croston, Glenn, Hansen, E.L., Uldam, Allan Kjaersgaard.
Application Number | 20050014757 10/802970 |
Document ID | / |
Family ID | 22688370 |
Filed Date | 2005-01-20 |
United States Patent
Application |
20050014757 |
Kind Code |
A1 |
Andersson, Carl-Magnus A. ;
et al. |
January 20, 2005 |
Azacyclic compounds
Abstract
Compounds and methods are provided for the treatment of disease
conditions in which modification of serotonergic receptor activity
has a beneficial effect. In the method, an effective amount of a
compound is adminstered to a patient in need of such treatment.
Inventors: |
Andersson, Carl-Magnus A.;
(Glostrup, DK) ; Croston, Glenn; (San Diego,
CA) ; Hansen, E.L.; (Glostrup, DK) ; Uldam,
Allan Kjaersgaard; (Glostrup, DK) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
22688370 |
Appl. No.: |
10/802970 |
Filed: |
March 16, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10802970 |
Mar 16, 2004 |
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10409782 |
Apr 7, 2003 |
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6756393 |
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10409782 |
Apr 7, 2003 |
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09800096 |
Mar 6, 2001 |
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6815458 |
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60187289 |
Mar 6, 2000 |
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Current U.S.
Class: |
514/248 ;
514/249 |
Current CPC
Class: |
C07D 407/06 20130101;
A61P 9/00 20180101; C07D 207/14 20130101; A61K 31/55 20130101; C07D
417/12 20130101; A61P 3/04 20180101; C07D 451/02 20130101; A61P
43/00 20180101; A61P 25/02 20180101; A61P 25/24 20180101; A61P
25/22 20180101; A61P 7/02 20180101; C07D 451/06 20130101; A61P 9/12
20180101; A61P 25/18 20180101; C07D 487/08 20130101; C07D 401/06
20130101; A61K 31/445 20130101; A61P 9/10 20180101; A61P 25/00
20180101; A61K 31/40 20130101; C07D 401/12 20130101; C07D 409/06
20130101; C07D 407/12 20130101; C07D 409/12 20130101; A61P 25/20
20180101; C07D 211/58 20130101; A61P 9/08 20180101; C07D 211/26
20130101; A61P 25/06 20180101 |
Class at
Publication: |
514/248 ;
514/249 |
International
Class: |
A61K 031/50 |
Claims
We claim:
1. A compound of formula (I) 10wherein Z is 11in which R is a
hydrogen, a cyclic or straight-chained or branched acyclic organyl
group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an
aralkyl or heteroaralkyl group; n is 0, 1, or 2; X.sub.1 is
methylene, vinylene, or an NH or N(lower alkyl) group; and X.sub.2
is methylene, or, when X.sub.1 is methylene or vinylene, X.sub.2 is
methylene or a bond; or when X.sub.1 is methylene, X.sub.2 is O, S,
NH, or N(lower alkyl) or a bond; Y.sub.1 is methylene and Y.sub.2
is methylene, vinylene, ethylene, propylene, or a bond; or Y.sub.1
is a bond and Y.sub.2 is vinylene; or Y.sub.1 is ethylene and
Y.sub.2 is O, S, NH, or N(lower alkyl); Ar.sub.1 and Ar.sub.2
independently are unsubstituted or substituted aryl or heteroaryl
groups, provided that Ar.sub.1 and Ar.sub.2 are not simultaneously
phenyl; and W is oxygen or sulfur.
2. A compound according to claim 1, wherein Y.sub.1 is methylene
and Y.sub.2 is a bond, methylene, ethylene, or vinylene; or Y.sub.1
is ethylene and Y.sub.2 is O or S; and X.sub.1 is methylene and
X.sub.2 is a bond, methylene, O, or S; or X.sub.1 is NH or N(lower
alkyl) and X.sub.2 is methylene.
3. A compound according to claim 2, wherein Z is 12and W is
oxygen.
4. A compound according to claim 3, wherein Ar.sub.1 and Ar.sub.2
independently are mono- or disubstituted phenyl groups.
5. A compound according to claim 4, wherein R is a hydrogen, a
lower alkyl group, a cyclic organyl group, or a substituted or
unsubstituted aralkyl or heteroaralkyl group; n is 1; Y.sub.1 is
methylene, Y.sub.2 is a bond, methylene, ethylene, or vinylene;
X.sub.1 is methylene and X.sub.2 is a bond, or. X.sub.1 is NH or
N(lower alkyl) and X.sub.2 is methylene; and Ar.sub.1 and Ar.sub.2
are phenyl groups, independently p-substituted with groups selected
from lower alkyl, lower alkoxy and halogen.
6. A compound according to claim 1, having a formula (II) 13wherein
R.sup.N is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;
Ar.sup.L is selected from lower alkyl, lower alkoxy and halogen
Ar.sup.R is selected from lower alkyl, lower alkoxy and halogen; k
is 1 or 2 and A.sup.- is a suitable anion.
7. The compound according to claim 1, wherein the compound is
selected from the group consisting of:
N-(1-(1-methylethyl)piperidin-4-yl)-N-((4-m-
ethylphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-(2,2-dimethylethyl)pipe-
ridin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacet-
amide;
N-(1-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny-
lacetamide;
N-(1-cyclohexylpiperidin-4-yl)-N-(4-methylphenyl)methyl)-4-met-
hoxyphenylacetamide;
N-(1-cyclopentylpiperidin-4-yl)-N-((4-methylphenyl)me-
thyl)-4-methoxyphenylacetamide;
N-(1-cyclobutylpiperidin-4-yl)-N-((4-methy-
lphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-cyclopropylpiperidin-4-yl)--
N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-meth-
oxyphenylacetamide;
N-(1-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphe-
nyl)methyl)-4-methoxyphenylacetamide;
N-(1-(cyclopropylmethyl)piperidin-4--
yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy-
phenylacetamide;
N-(1-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)-
methyl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(piperidin--
4-yl)-N]-phenylmethylcarbamide;
N-((4-methylphenyl)methyl)-N-(1-(2-methylp-
ropyl)piperidin-4-yl)-N'-phenylmethylcarbamide;
N-(1-((2-bromophenyl)methy-
l)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N-phenylmethylcarbamide;
N-(1-((4-hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4-methylpheny-
l)methyl)-N'-phenylmethylcarbamide;
N-(1-((5-ethylthien-2-yl)methyl)piperi-
din-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide;
N-(1-(imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-p-
henylmethylcarbamide;
N-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylp-
henyl)methyl)-N'-phenylmethylcarbamide;
N-(1-((4-fluorophenyl)methyl)piper-
idin-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide;
N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-4-methoxyphenylacet-
amide;
N-(1-ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny-
lacetamide;
N-((4-methylphenyl)methyl)-N-(1-propylpiperidin-4-yl)-4-methox-
yphenylacetamide; N-(1
butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-m-
ethoxyphenylacetamide;
N-(1-(3,3-dimethylbutyl)piperidin-4-yl)-N-((4-methy-
lphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-(cyclohexylmethyl)piperidin-
-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-4-methoxy-
phenylacetamide;
N-((4-methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)p-
iperidin-4-yl)-4-methoxyphenylacetamide;
N-(1-((4-hydroxyphenyl)methyl)pip-
eridin-4-yl)-N-(4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(1-((2-hydroxyphenyl)methyl)piperidin-4-yl)-N-(4-methylphenyl)methyl)-4-
-methoxyphenylacetamide;
N-(3-phenylpropyl)-N-(piperidin-4-yl)-4-methoxyph- enylacetamide;
N-(2-phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetami- de;
N-((2-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamid-
e;
N-((2-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((3,4-di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetam-
ide;
N-((4-fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamid-
e;
N-((2,4-di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylaceta-
mide;
N-((3-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetami-
de;
N-((3-bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-(1-(phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyph-
enylacetamide;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenylaceta- mide;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-phenylpropionamide-
;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-(phenylthio)acetamide;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenoxyacetamide;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)acetamid-
e;
N-(4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacetamide-
;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylacetamide;
N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-2,5-di-methoxyphenylaceta-
mide;
N-((4-methylphenyl)methyl)-N-1-piperidin-4-yl)-4chlorophenylacetamid-
e;
N-((4-methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N'-pheny-
lmethylcarbamide;
N-((4-methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-
-3-yl)-4-methoxyphenylacetamide;
2-(4-methoxyphenyl)-N-4-methylbenzyl)-N-(-
piperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-meth- ylpiperidin-4-yl)
acetamide; 2-(4-methoxyphenyl)-N-4-methylbenzyl)-N-(1-et-
hylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-e-
thylpiperidin-4-yl)acetamide.
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-i-
sopropylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-N-4-chlorobenzyl)-N-
-(piperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-4-chlorbenzyl)-N-(1-cycl-
opentylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N--
(1-isopropylpiperidin-4-yl) acetamide;
2-(phenyl)-N-(4-trifluoromethylbenz-
yl)-N-(1-methylpiperidin-4-yl)acetamide;
2-(4-fluorophenyl)-N-(4trifluorom-
ethylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;
2-(4-Methoxyphenyl)-N-(-
4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;
2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperi-
dinyl)acetamide;
2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidi-
n-4-yl)acetamide;
2-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperi- din-4-yl)
acetamide; 2-(phenyl)-N-(4-fluorobenzyl)-N-((1-methylpiperidin-4-
-yl)acetamide;
2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylp-
iperidin-4-yl) acetamide;
2-(4-trifluoromethylphenyl)-N-[4methoxycarbonyl)-
benzyl]-N-(1-methylpiperidin-4-yl)acetamide;
2-Phenyl-N-[4-(methoxycarbony- l)benzyl]-N-(1-methylpiperidin-4-yl)
acetamide; 2-(4-Chlorophenyl)-N-[4-(m-
ethoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;
2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4--
yl)acetamide;
2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N--
(1-methylpiperidin-4-yl)acetamide;
2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-- N-(1-methylpiperidin-4-yl)
acetamide, 2-(4Chlorophenyl)-N-[4-(methoxycarbo-
nyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;
2-(4-Methoxyphenyl)-N-[4--
(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;
2-(4methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(4-chloromethyl-2-thiazolylmet-
hyl)piperidin-4-yl]acetamide; 2-(4
methoxyphenyl)-N-(4-methylbenzyl)-N-{1-- [3-(1,3
dihydro-2H-benzimidazol-2-on-1-yl)propyl]piperidin-4-yl}acetamide;
2-(4-methoxyphenyl)-N-(2-4-(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl-
) acetamide;
2-(4-methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-met-
hylpiperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)-
ethyl]-N-(1-methylpiperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-[2-(3-ch-
lorophenyl)ethyl]-N-(1-methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-y-
l)acetamide;
2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpi-
peridin-4-yl) acetamide;
2-(4-ethoxyphenyl)-N-[2-(4-fluorophenethyl]-N-(1--
methylpiperidin-4-yl) acetamide;
2-(4-ethoxyphenyl)-N-(4-fluorobenzyl)-N-(-
1-methylpiperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N- -{1
[22-hydroxyethoxy)ethyl]piperidin-4-yl}acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-((2-chloro-5-thienyl)methyl)
piperidin-4-yl]acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2--
(imidazolidinon-1-yl)ethyl)piperidin-4-yl]acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2,4-(1H,3H)quinazolinedio-
n-3-yl)ethyl]piperidin-4-yl}acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenz-
yl)-N-{1-[2-(1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(3-indolyl)ethyl]piperidin-
-4-yl}acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-[3-(1,2,4-tri-
azol-1-yl)propyl]piperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-(4-methyl-
benzyl)-N-[1-(5-benzofurazanylmethyl)piperidin-4-yl]acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-chlorobenzo[b]thien-3-ylme-
thyl)piperidin-4-yl]acetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-
-(5-phenyl-1,2,4-oxadiazol-3-ylmethyl)piperidin-4-yl]acetamide;
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)acetam-
ide;
2-(4-Chlorophenyl)-N-4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)-acetam-
ide;
2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide,2-(4-
-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;
2-(4-Chlorophenyl)-N-4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)aceta-
mide; 2-(4-Fluorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin
4-yl)acetamide;
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethy-
l)-piperidin-4-yl)-acetamide;
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-c-
yclobutylpiperidin-4-yl)acetamide;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)--
N-(1-cyclobutylpiperidin-4-yl)acetamide,2-(4-Methoxyphenyl)-N-(4-methylben-
zyl)-N-(tropin-4-yl)-acetamide;
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4--
yl)-N'-benzyl-carbamide;
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'--
phenyl-carbamide;
N-Phenethyl-N-(1-methylpiperidin-4-yl)-N'-benzyl-carbami- de;
2-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;
2-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl-
)-acetamide;
2-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-
-yl)acetamide;
2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidi-
n-4-yl)acetamide;
2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperid-
in-4-yl)acetamide;
2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiper-
idin-4-yl)acetamide;
N-Phenethyl-N-(1-methylpiperidin-4-yl)-N'-phenyl-carb- amide;
N-(3-Phenylpropyl)-N-1-methylpiperidin-4-yl)-N'-benzyl-carbamide;
N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-phenyl-carbamide;
2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin--
4-yl)acetamide;
2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperi-
din-4-yl) acetamide;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(3-tropen-4--
yl)acetamide;
2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-y-
l)acetamide;
N-Phenethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-ami- ne;
2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetamide;
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-methoxybenzyl)carbami-
de;
2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
2-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpip-
eridin-4-yl)acetamide;
2-(4-Methoxyphenyl)-N-4-methylbenzyl)-N-(1-t-butylp-
iperidin-4-yl)acetamide;
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'--
phenethyl-carbamide;
N-Phenethyl-N-(1-methylpiperidin-4-yl)-N'-phenethyl-c- arbamide;
N-(4-Methylbenzyl)-N 1-t-butylpiperidin-4-yl)-N'-(4-methoxybenzy-
l)carbamide;
2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-- yl)
acetamide;
2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-- 4-yl)
acetamide;
2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiper-
idin-4-yl) acetamide;
2-(4-t-Butoxyphenyl)-N-4-methylbenzyl)-N-(1-methylpi- peridin-4-yl)
acetamide; 2-(4-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methyl-
piperidin-4-yl) acetamide;
2-(4-Propoxyphenyl)-N-(4-flourobenzyl)-N-(1-met- hylpiperidin-4-yl)
acetamide; 2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(-
1-methylpiperidin-4-yl) acetamide; and
2-(4-t-Butoxyphenyl)-N-(4-fluoroben-
zyl)-N-(1-methylpiperidin-4-yl) acetamide.
8. A compound of formula (I) 14wherein Z is 15in which R is a
hydrogen, a cyclic or straight-chained or branched acyclic organyl
group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an
aralkyl or heteroaralkyl group; and n is 0, 1, or 2; X.sub.1 is
methylene, vinylene, or an NH or N(lower alkyl) group; and X.sub.2
is methylene, or, when X.sub.1 is methylene or vinylene, X.sub.2 is
methylene or a bond; or when X.sub.1 is methylene, X.sub.2 is O, S,
NH, or N(lower alkyl) or a bond; Y.sub.1 is methylene and Y.sub.2
is methylene, vinylene, ethylene, propylene, or a bond; or Y.sub.1
is a bond and Y.sub.2 is vinylene; or Y.sub.1 is ethylene and
Y.sub.2 is O, S, NH, or N(lower alkyl); Ar.sub.1 and Ar.sub.2 are
different unsubstituted or substituted aryl or heteroaryl groups;
and W is oxygen or sulfur.
9. A compound according to claim 8, wherein Y.sub.1 is methylene
and Y.sub.2 is a bond, methylene, ethylene, or vinylene; or Y.sub.1
is ethylene and Y.sub.2 is O or S; and X.sub.1 is methylene and
X.sub.2 is a bond, methylene, O, or S; or X.sub.1 is NH or N(lower
alkyl) and X.sub.2 is a methylene.
10. A compound according to claim 9, wherein Z is 16and W is
oxygen.
11. A compound according to claim 10, wherein Ar.sub.1 and Ar.sub.2
independently are mono- or disubstituted phenyl groups.
12. A compound according to claim 11, wherein R is a hydrogen, a
lower alkyl group, a cyclic organyl group, or an, optionally
substituted, alalkyl or heteroaralkyl group; n is 1; Y.sub.1 is
methylene, Y.sub.2 is a bond, methylene, ethylene, or vinylene;
X.sub.1 is methylene and X.sub.2 is a bond, or X.sub.1 is NH or
N(lower alkyl) and X.sub.2 is methylene; and Ar.sub.1 and Ar.sub.2
are phenyl groups, independently p-substituted with groups selected
from alkyl, lower alkoxy and halogen.
13. A compound according to claim 7, having a formula (II):
17wherein R.sup.N is hydrogen, lower allyl, aralkyl, or
heteroaralkyl; Ar.sup.L is selected from lower alkyl, lower alkoxy
and halogen Ar.sup.R is selected from lower alkyl, lower alkoxy and
halogen; k is 1 or 2 and A.sup.- is a suitable anion.
14. A pharmaceutical composition comprising an effective amount of
a compound of formula (I): 18wherein Z is 19in which R is a
hydrogen, a cyclic or straight-chained or branched acyclic organyl
group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an
aralkyl or heteroaralkyl group; and n is 0, 1, or 2; X.sub.1 is
methylene, vinylene, or an NH or N(lower alkyl) group; and X.sub.2
is methylene, or, when X.sub.1 is methylene or vinylene, X.sub.2 is
methylene or a bond; or when X.sub.1 is methylene, X.sub.2 is O, S,
NH, or N(lower alkyl) or a bond; Y.sub.1 is methylene and Y.sub.2
is methylene, vinylene, ethylene, propylene, or a bond; or Y.sub.1
is a bond and Y.sub.2 is vinylene; or Y.sub.1 is ethylene and
Y.sub.2 is O, S, NH, or N(lower alkyl); Ar.sub.1 and Ar.sub.2
independently are unsubstituted or substituted aryl or heteroaryl
groups, provided that Ar.sub.1 and Ar.sub.2 are not simultaneously
phenyl; and W is oxygen or sulfur; or a pharmaceutically acceptable
salt, ester or prodrug thereof, and a pharmaceutically acceptable
diluent or excipient.
15. 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.
16. The method of claim 15 wherein the monoamine receptor is a
serotonin receptor.
17. The method of claim 16 wherein the serotonin receptor is the
5-HT2A subclass.
18. The method of claim 16 wherein the serotonin receptor is in the
central nervous system.
19. The method of claim 16 wherein the serotonin receptor is in the
peripheral nervous system.
20. The method of claim 16 wherein the serotonin receptor is in
blood cells or platelets.
21. The method of claim 16 wherein the serotonin receptor is
mutated or modified.
22. The method of claim 15 wherein the activity is signaling
activity.
23. The method of claim 1S wherein the activity is
constitutive.
24. The method of claim 15 wherein the activity is associated with
serotonin receptor activation.
25. 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.
26. The method of claim 25 wherein the activation is by an
agonistic agent.
27. The method of claim 26 wherein the agonistic agent is
exogenous.
28. The method of claim 26 wherein the agonistic agent is
endogenous.
29. The method of claim 25 wherein the activation is
constitutive.
30. The method of claim 25 wherein the monoamine receptor is a
serotonin receptor.
31. The method of claim 30 wherein the serotonin receptor is the
5-HT2A subclass.
32. The method of claim 30 wherein the serotonin receptor is in the
central nervous system.
33. The method of claim 30 wherein the serotonin receptor is in the
peripheral nervous system.
34. The method of claim 30 wherein the serotonin receptor is in
blood cells or platelets.
35. The method of claim 30 wherein the serotonin receptor is
mutated or modified.
36. 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 compounds of claim 1.
37. The method of claim 36 wherein the disease condition is
selected from the group consisting of schizophrenia, psychosis,
migraine, hypertension, thrombosis, vasospasm, ischemia,
depression, anxiety, sleep disorders and appetite disorders.
38. The method of claim 36 wherein the disease condition is
associated with dysfunction of a monoamine receptor.
39. The method of claim 36 wherein the disease condition is
associated with activation of a monoamine receptor.
40. The method of claim 36 wherein the disease condition is
associated with increased activity of monoamine receptor.
41. The method of claim 36 wherein the monoamine receptor is a
serotonin receptor
42. The method of claim 41 wherein the serotonin receptor is the
5-HT2A subclass.
43. The method of claim 41 wherein the serotonin receptor is in the
central nervous system.
44. The method of claim 41 wherein the serotonin receptor is in the
peripheral nervous system.
45. The method of claim 41 wherein the serotonin receptor is in
blood cells or platelets.
46. The method of claim 41 wherein the serotonin receptor is
mutated or modified.
47. 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.
48. 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.
49. 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.
50. 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.
51. The method of claim 50 wherein the ameliorated disease
condition is associated with the 5-HT class or 5-HT2A subclass of
monoaminergic receptors.
52. 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.
Description
[0001] This application claims the benefit of priority from
copending U.S. Provisional Application Ser. No. 60/187,289 filed
Mar. 6, 2000
FIELD OF THE INVENTION
[0002] The present invention relates to novel compounds that affect
monoamine receptors, including serotonin receptors. The invention
specifically provides compounds that are active as inverse
agonists, and therefore also as antagonists, at the 5-HT2A subtype
of human serotonin receptors. The invention also provides methods,
utilizing the compounds of the invention for modulating 5-HT2A
receptor-mediated events, that are useful for treating or
alleviating disease conditions in which modification of the
activity of these receptors is beneficial.
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, 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 referered 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,
Neuropharlmacology, 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
monoarminergic 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] We 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. Patent Application Ser. No. 60/103,317, herein
incorportated by reference). 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.
SUMMARY OF THE INVENTION
[0014] The present invention provides compounds of the general
formula (I) that affect monoamine receptors, especially serotonin
receptors, and share as a common property inverse agonist activity
at the 5-HT2A subtype of human serotonin receptors: 1
[0015] wherein
[0016] Z is a group selected from 2
[0017] R is hydrogen, a cyclic or straight-chained or branched
acyclic organyl group, a lower hydroxyalkyl group, a lower
aminoalkyl group, or an aralkyl or heteroaralkyl group;
[0018] n is 0, 1, or 2;
[0019] X.sub.1 is methylene, vinylene, or an NH or N(lower alkyl)
group; and
[0020] X.sub.2 is methylene, or, when X.sub.1 is methylene or
vinylene, X.sub.2 is methylene or a bond; or when X.sub.1 is
methylene, X.sub.2 is O, S. NH, or N(lower alkyl) or a bond;
[0021] Y.sub.1 is methylene and Y.sub.2 is methylene, vinylene,
ethylene, propylene, or a bond; or
[0022] Y.sub.1 is a bond and Y.sub.2 is vinylene; or
[0023] Y.sub.1 is ethylene and Y.sub.2 is O, S, NH, or N(lower
alkyl);
[0024] Ar.sub.1 and Ar.sub.2 independently are unsubstituted or
substituted aryl or heteroaryl groups;
[0025] W is oxygen or sulfur; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
[0026] The present invention also provides pharmaceutical
compositions comprising an effective amount of a compound of
formula (I) or pharmaceutically acceptable salts, esters, or
prodrugs thereof.
[0027] Also provided 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 a compound of formula (I), as well as kits for performing the
same. Preferably, the receptor is a serotonin receptor of the
5-HT2A subclass. The receptor may be located in either the central
or peripheral nervous system, blood cells or platelets, and may be
mutated or modified. In a preferred embodiment, the receptor is
constitutively active.
[0028] Furthermore, 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 compound of formula
(I), as well as kits for performing the same. In a preferred
embodiment, the compound is selective for the 5-HT2A serotonin
receptor. In another preferred embodiment, the compound has little
or substantially no anti-dopaminergic activity. The receptor may be
constitutively active or may be activated by an endogenous or
exogenous agonistic agent.
[0029] Another aspect of the present invention relates to a method
of treating a disease condition associated with a monoamine
receptor comprising administering to a mammal in need of such
treatment an effective amount of a compound of formula (I), and
kits for performing the same. Examples of disease conditions for
which such treatment using the compounds of the invention, or
pharmaceutical compositions comprising them, is useful include, but
are not limited to, neuropsychiatric diseases such as schizophrenia
and related idiopathic psychoses, depression, anxiety, sleep
disorders, appetite disorders, affective disorders such as major
depression, bipolar disorder, and depression with psychotic
features, and Tourette's Syndrome. Said compounds may also be
beneficial for the treatment of drug-induced psychoses as well as
psychoses secondary to neurodegenerative disorders such as
Alzheimer's or Huntington's Disease. The compounds of the invention
may also be useful in treating hypertension, migraine, vasospasm,
ischemia and the primary treatment and secondary prevention of
various thrombotic conditions including myocardial infarction,
thrombotic or ischemic stroke, idiopathic and thrombotic
thrombocytopenic purpura, and peripheral vascular disease.
[0030] Further provided is a method for identifying a genetic
polymorphism predisposing a subject to being responsive to a
compound of formula (I), comprising administering to a subject an
effective amount of the compound; 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. Also provided are kits for
performing the same.
[0031] A method for identifying a subject suitable for treatment
with the compound of formula (I) and kits for identifying the same,
is also provided. According to the method, the presence of a
polymorphism that predisposes the subject to being responsive to
the compound is detected, wherein the presence of the polymorphism
indicates that the subject is suitable for treatment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is a graph showing data obtained from a dose response
analysis of 26HCH17 and ritanserin as 5-HT2A receptor inverse
agonists.
[0033] FIG. 2 is a graphic representation of in vivo pharmacology
data obtained in mice with
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylp-
iperidin-4-yl)acetamide hydrochloride. FIG. 2A shows the effects of
this novel antipsychotic agent compound in a head twitch behavioral
model; FIG. 2B shows the results of locomotor experiments; and in
FIG. 2C pre-pulse inhibition study results are shown.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Definitions
[0035] 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.
[0036] "Constitutive activity" is defined as the elevated 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. Patent Application Ser. No. 60/103,317).
[0037] "Agonist" is defined as a compound that increases the
activity of a receptor when it contacts the receptor.
[0038] An "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.
[0039] An "inverse agonist" is defined as a compound that decreases
the basal activity of a receptor (i.e., signalling 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.
[0040] The "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.
[0041] The term "subject" refers to an animal, preferably a mammal,
most preferably a human, who is the object of treatment,
observation or experiment.
[0042] "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 with
substantially little or no effect upon the activity other receptor
types. "Selectivity" or "selective," as an inverse agonist is
understood as a property of a compound of the invention whereby an
amount of compound that effectively inversely agonises 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, the compounds of the invention
have surprisingly 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 signalling 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.
[0043] EC50 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, EC50 is intended to denote the
concentration of a compound needed to achieve 50% inhibition of an
R-SAT response from basal, no compound, levels.
[0044] As used herein, "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.
[0045] "Cyclic organyl groups" are aliphatic, alicyclic groups in
which carbon atoms form a ring. In preferred embodiments containing
four, five, six or seven carbon atoms, the ring, as a substituent,
is connected either directly via one of the ring atoms or via one
or more appended carbon atoms. Particular examples of such groups
include cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl,
cyclohexylmethyl, cyclohexylethyl groups, and the like.
[0046] "Straight-chained acyclic organyl groups" are substituent
groups consisting of a linear arrangement of carbon atoms, where
accordingly each carbon atom binds a maximum of two other carbon
atoms, connected through single, double, or triple bonds. The
straight-chained organyl groups may contain none, one, or several
multiple bonds, and are, for example, commonly referred to as
alkyl, alkenyl or alkynyl, or alkadienyl groups, respectively.
Examples of straight-chained organyl groups include methyl, ethyl,
propyl, butyl, pentyl, hexyl, propenyl, butenyl, pentadienyl,
propargyl, butynyl.
[0047] "Branched acyclic organyl groups" are substituent groups
consisting of a branched arrangement of carbon atoms, where
accordingly one or more carbon atoms may bind more than two other
carbon atoms, connected through single, double, or triple bonds.
The branched organyl groups may contain none, one, or several
multiple bonds. Examples of branched organyl groups include
iso-propyl, iso-butyl, tert-butyl, methylbutyl, methylbutenyl,
methylbutynyl.
[0048] "Lower alkoxy groups" are C.sub.1-6 cyclic or acyclic
organyl groups connected, as substituents, via an oxygen atom.
Examples of lower alkoxy groups include methoxy, ethoxy,
iso-propoxy, butoxy, tert-butoxy.
[0049] "Lower alkyl groups" are C.sub.1-6 cyclic, straight-chained
or branched aliphatic substituent groups connected via a carbon
atom. Examples include methyl, ethyl, propyl, butyl, methylbutyl,
cyclopropyl, cyclohexyl, iso-propyl, tert-butyl.
[0050] "Lower alkylamino groups" are understood as lower alkyl
groups connected, as substituents, via a nitrogen atom, which may
carry one or two lower alkyl groups. Particular examples include
methylamino, dimethylamino, iso-propylamino. Optionally, lower
aminoalkyl groups may consist of 4-6 membered nitrogen-containing
rings, such as pyrrolidino.
[0051] "Lower aminoalkyl groups" are lower alkyl groups carrying,
as a substituent, an additional amino group. Examples include
aminomethyl and aminoethyl.
[0052] "Lower hydroxyalkyl groups" are understood as lower alkyl
groups carrying, as a substituent, an additional hydroxy group.
Examples include hydroxymethyl, hydroxyethyl, 2-hydroxy-2-propyl,
hydroxypentyl.
[0053] "Acyl groups" are hydrogen or lower alkyl groups connected,
as substituents, via a carbonyl group. Examples include formyl,
acetyl, propanoyl.
[0054] "Halo groups" are understood to be fluoro, chloro, bromo, or
iodo substituents, with fluoro and chloro being generally
preferred.
[0055] "Lower alkylene groups" are straight-chained tethering
groups, forming bonds to connect molecular fragments via their
terminal carbon atoms. Examples include methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), propylene
(--CH.sub.2CH.sub.2CH.sub.2--) or butylene (--(CH.sub.2).sub.4--)
groups.
[0056] "Vinylene groups" are ethene-1,2-diyl groups (--CHCH--)
having (E) or (Z) configuration.
[0057] "Aralkyl groups" are aryl groups connected, as substituents,
via a lower alkylene group. The aryl groups of aralkyl groups may
be substituted or unsubstituted. Examples include benzyl,
substituted benzyl, 2-phenylethyl, 3-phenylpropyl,
naphthylalkyl.
[0058] `Heteroaralkyl groups` are understood as heteroaryl groups
connected, as substituents, via a lower alkylene group. The
heteroaryl groups of heteroaralkyl groups may be substituted or
unsubstituted. Examples include 2-thienylmethyl, 3-thienylmethyl,
furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl,
isoxazolylalkyl, imidazolylalkyl, and their substituted as well as
benzo-fused analogs.
[0059] "Aryl groups" are aromatic, preferably benzenoid or
naphthoid, groups connected via one of the ring-forming carbon
atoms, and optionally carrying one or more substituents selected
from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, lower
alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower
alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl,
or trifluoromethyl. Preferred aryl groups are phenyl, and, most
suitably, substituted phenyl groups, carrying one or two, same or
different, of the substituents listed above. The preferred pattern
of substitution is para and/or meta. 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, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl,
naphthyl, hydroxynaphthyl, hydroxymethylphenyl,
trifluoromethylphenyl.
[0060] "Heteroaryl groups" are understood as aromatic, C.sub.2-6
cyclic groups containing one O or S atom or up to four N atoms, or
a combination of one O or S atom with up to two N 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, lower alkoxy,
lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower
alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl,
or trifluoromethyl. Preferred heteroaryl groups are 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 disubstituted derivatives of furan, benzofuran,
thiophene, benzothiophene, pyrrole, indole, oxazole, benzoxazole,
isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole,
imidazole, benzimidazole, pyrazole, indazole, and tetrazole, which
are all preferred, as well as furazan, 1,2,3-oxadiazole,
1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole,
pyridine, quionoline, isoquinoline, pyridazine, pyrimidine, purine,
pyrazine, pteridine, and triazine. The most preferred substituents
are halo, hydroxy, cyano, lower alkoxy, lower alkyl, lower
hydroxyalkyl, lower alkylamino, and lower aminoalkyl.
[0061] The present invention provides compounds preferably showing
a realtively high selectivity toward serotonin receptors,
particularly, 5-HT2A receptors, which may have a beneficial effect
in the treatment of neuropsychiatric disorders.
[0062] According to one embodiment, the present invention provides
compounds of the general formula (I): 3
[0063] wherein
[0064] Z is 4
[0065] in which
[0066] R is a hydrogen, a cyclic or straight-chained or branched
acyclic organyl group, a lower hydroxyalkyl group, a lower
aminoalkyl group, or an aralkyl or heteroaralkyl group;
[0067] n is 0, 1, or 2;
[0068] X.sub.1 is methylene, vinylene, or an NH or N (lower alkyl)
group; and
[0069] X.sub.2 is methylene, or, when X.sub.1 is methylene or
vinylene, X.sub.2 is methylene or a bond; or when X.sub.1 is
methylene, X.sub.2 is O, S, NH, or N(lower alkyl) or a bond;
[0070] X
[0071] Y.sub.1 is methylene and Y.sub.2 is methylene, vinylene,
ethylene, propylene, or a bond; or
[0072] Y.sub.1 is a bond and Y.sub.2 is vinylene; or
[0073] Y.sub.1 is ethylene and Y.sub.2 is O, S, NH, or N(lower
alkyl);
[0074] Ar.sub.1 and Ar.sub.2 independently are unsubstituted or
substituted aryl or heteroaryl groups; and
[0075] W is oxygen or sulfur;
[0076] or a pharmacologically acceptable salt, ester, or prodrug
thereof.
[0077] In general, compounds of formula (I) are active at monoamine
receptors, specifically serotonin receptors. Preferred compounds
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 signalling 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 signalling responses that the
5-HT2A receptor displays. The observation that the compunds 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.
[0078] In a preferred embodiment, the present invention provides
compounds that preferably 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 another preferred embodiment, the compounds of the
present invention act as inverse agonists at the 5-HT2A subtype of
serotonin receptors.
[0079] 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.
[0080] Others have previously hypothesised 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.
[0081] 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.
[0082] The present invention also provides pharmaceutical
compositions comprising an effective amount of a compound of
general formula (I).
[0083] In a preferred embodiment of the compounds of formula (I),
Y.sub.1 is methylene and Y.sub.2 is a bond, methylene, ethylene, or
vinylene, or Y.sub.1 is ethylene and Y.sub.2 is O or S, and X.sub.1
is methylene and X.sub.2 is a bond, methylene, O, or S, or X.sub.1
is NH or N(lower alkyl).
[0084] In a further preferred embodiment of the compounds of
formula (I), Z is 5
[0085] and W is oxygen.
[0086] In a more preferred embodiment of the compounds of formula
(I), n is 1, Y.sub.1 is methylene, Y.sub.2 is a bond, methylene,
ethylene, or vinylene, X.sub.1 is methylene and X.sub.2 is a bond,
or X.sub.1 is NH or N(lower alkyl) and X.sub.2 is methylene. In a
further preferred embodiment of the compounds of formula (I), W is
oxygen and Ar.sub.1 and Ar.sub.2 are different aryl or heteroaryl
groups, with different mono-substituted phenyl groups being
particularly preferred. Preferably, Ar.sub.1 and Ar.sub.2 are not
simultaneously phenyl.
[0087] Also preferred compounds of formula (I) are those where Z is
1-(organyl or aralkyl)-4-piperidinyl.
[0088] In another embodiment, the invention provides preferred
compounds ot the formula (II): 6
[0089] in which R.sup.N is hydrogen, lower alkyl, aralkyl, or
heteroaralkyl;
[0090] Ar.sup.L is selected from lower alkyl, lower alkoxy and
halogen
[0091] Ar.sup.R is selected from lower alkyl, lower alkoxy and
halogen;
[0092] k is 1 or 2
[0093] and A.sup.- is a suitable anion.
[0094] According to the invention, a suitable anion may be any
anion capable of forming a pharmaceutically acceptable salt of the
compound, as described in further detail below.
[0095] The present invention also provides a method of inhibiting
an activity of a monoamine receptor. This method comprises
contacting a monoamine receptor or a system containg the monamine
receptor, with an effective amount of a compound of formula (I).
Accoding to one embodiment, the monamine receptor is a serotonin
receptor. In a preferred embodiment, the compound is selective for
the 5-HT2A receptor subclass. In another preferred embodiment, the
compound has little or substantially no activity to other types of
receptors, including other serotonergic receptors and most
particularly, monoaminergic G-protein coupled receptors, such as
dopaminergic receptors.
[0096] The system containing the monoamine receptor may, for
example, be a subject such as a mammal, non-human primate or a
human. The receptor may be located in the central or peripheral
nervous system, blood cells or platelets.
[0097] The system may also be an in vivo or in vitro experimental
model, such as a cell culture model system that expresses a
monamine receptor, a cell-free extract thereof that contains a
monoamine receptor, or a purified receptor. Non-limiting examples
of such systems are tissue culture cells expressing the receptor or
extracts or lysates thereof. Cells that may be used in the present
method include any cells capable of mediating signal transduction
via monoamine receptors, expecially the 5-HT2A receptor, either via
endogenous expression of this receptor (e.g., certain types of
neuronal cells lines, for example, natively express the 5-HT2A
receptor), or following transfection of cells with plasmids
containing the receptor gene. Such cells are typically mammalian
cells (or other eukaryotic cells, such as insect cells or Xenopus
oocytes), because cells of lower organisms generally lack the
appropriate signal transduction pathways for the present purpose.
Examples of suitable cells include: the mouse fibroblast cell line
NIH 3T3 (ATCC CRL 1658), which responds to transfected 5-HT2A
receptors by stimulating growth; RAT 1 cells (Pace et al., Proc.
Natl. Acad. Sci. USA 88:7031-35 (1991)); and pituitary cells
(Vallar et al., Nature 330:556-58 (1987)). Other useful mammalian
cells for the present method include HEK 293 cells, CHO cells and
COS cells.
[0098] The invention specifically provides methods of inhibiting an
activity of a native, mutated or modified monoamine receptor. Also
provided are kits for performing the same. In a preferred
embodiment, the activity of the receptor is a signalling activity.
In another preferred embodiment, the activitiy of the receptor is
the constitutive basal activity of the receptor. Preferrably, the
compound is an inverse agonist selective for the 5-HT2A receptor.
Most preferably, the compound has little or substantially no
activity toward other serotonergic or other monoaminergic
receptors, such as dopaminergic receptors.
[0099] In one embodiment, the activity of the receptor is a
response, such as a signalling response, to an endogenous agonist,
such as 5-HT, or an exogenous agonistic agent, such as a drug or
other synthetic ligand. The compound of formula (I) preferably acts
by inversely agonising or antagonising the receptor.
[0100] Furthermore, 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 one or more compounds of the invention.
The activation of the receptor may be due to an exogenous or
endogenous agonist agent, or may be the constitutive activation
associated with a native, mutated or modified receptor. The
receptor may purified or present in an in vitro or in vivo system.
The receptor may also be present in the central or peripheral
nervous system, blood cells or platelets of a nonhuman or human
subject. Also provided are kits for performing the same.
[0101] In a preferred embodiment, the compound is selective for
5-HT class serotonin receptors, more preferably, the 5-HT2A sublass
of serotonin receptors. In another preferred embodiment, the
compound has little or substantially no anti-dopaminergic
activity.
[0102] The present invention provides methods of treating a disease
condition associated with a monoamine receptor comprising
administering to a mammal in need of such treatment an effective
amount of a compound of formula (I). The invention specifically
provides methods for treating or alleviating disease conditions
associated with improper function or stimulation of native, as well
as mutated or otherwise modified, forms of central serotonin
receptors, particularly the 5-HT class of such receptors,
comprising administration of an effective amount of a selective
inverse agonist of the general formula (I) to a host in need of
such treatment. Also provided are kits for performing the same.
[0103] In a preferred embodiment, the receptor is the 5-HT2A
subclass. In one embodiment, the disease condition is associated
with dysfunction of the serotonin receptor. In another embodiment,
the disease condition is associated with activation of the
serotonin receptor, preferably inappropriately elevated or
constitutive activation, elevated serotonergic tone, as well as
disease conditions associated with secondary cellular functions
imparied by such pathologies.
[0104] Examples of diseases for which such treatment using the
compounds of the invention, or pharmaceutical compositions
comprising such compounds, is useful include, but are not limited
to, neuropsychiatric diseases such schizophrenia and related
idiopathic psychoses, anxiety, sleep disorders, appetite disorders,
affective disorders such as major depression, bipolar disorder, and
depression with psychotic features, and Tourette's Syndrome,
drug-induced psychoses, psychoses secondary to neurodegenerative
disorders such as Alzheimer's or Huntington's Disease. It is
anticipated that the compounds of this invention, particularly
selective inverse agonists of 5-HT2A that show little or no
activity on dopaminergic receptors, may be especially useful for
treating schizophrenia. Treament using the compounds of the
invention may also be useful in treating migraine, vasospasm,
hypertension, various thrombotic conditions including myocardial
infarction, thrombotic or ischemic stroke, idiopathic and
thrombotic thrombocytopenic purpura, and peripheral vascular
disease.
[0105] In a further embodiment the present invention provides
methods for treating or alleviating a disease condition associated
with improper function, dysfunction, or stimulation of native, as
well as mutated or otherwise modified, forms of central or
peripheral monoamine receptors, such methods comprising
administration of an effective amount of a compound of the general
formula (I) to a host in need of such treatment. Preferably the
monamine receptor is serotonin receptor in the peripheral nervous
system, blood or platelets; more preferably a 5-HT2A subclass
receptor. In additional embodiments, the disease condition is
associated with increased activity or activation of a serotonin
receptor. Also provided are kits for performing the same.
[0106] The present invention also pertains to the field of
predictive medicine in which pharmacogenomics is used for
prognostic (predictive) purposes. Pharmacogenomics deals with
clinically significant hereditary variations in the response to
drugs due to altered drug disposition and abnormal action in
affected persons. See e.g., Eichelbaum, Clin Exp Pharmacol.
Physiol., 23:983-985 (1996), and Linder, Clin. Chem. 43:254-66
(1997). In general, two types of pharmacogenetic conditions can be
differentiated: genetic conditions transmitted as a single factor
altering the way drugs act on the body (altered drug action), and
genetic conditions transmitted as single factors altering the way
the body acts on drugs (altered drug metabolism). These
pharmacogenetic conditions can occur as naturally occurring
polymorphisms.
[0107] One pharmacogenomics approach to identifying genes that
predict drug response, known as "a genome-wide association," relies
primarily on a high-resolution map of the human genome consisting
of already known gene-related markers (e.g., a "bi-allelic" gene
marker map that consists of 60,000-100,000 polymorphic or variable
sites on the human genome, each of which has two variants). Such a
high-resolution genetic map can be compared to a map of the genome
of each of a statistically significant number of patients taking
part in a Phase II/III drug trial to identify markers associated
with a particular observed drug response or side effect.
Alternatively, such a high-resolution map can be generated from a
combination of some ten-million known single nucleotide
polymorphisms (SNPs) in the human genome. As used herein, a "SNP"
is a common alteration that occurs in a single nucleotide base in a
stretch of DNA. For example, a SNP may occur once per every 1,000
bases of DNA. A SNP may be involved in a disease process; however,
the vast majority may not be disease-associated. Given a genetic
map based on the occurrence of such SNPs, individuals can be
grouped into genetic categories depending on a particular pattern
of SNPs in their individual genome. In such a manner, treatment
regimens can be tailored to groups of genetically similar
individuals, taking into account traits that may be common among
such genetically similar individuals.
[0108] Alternatively, a method termed the "candidate gene approach"
can be utilized to identify genes that predict drug response.
According to this method, if a gene that encodes a drug's target is
known (e.g., a protein or a receptor of the present invention), all
common variants of that gene can be fairly easily identified in the
population and it can be determined if having one version of the
gene versus another is associated with a particular drug
response.
[0109] Alternatively, a method termed the "gene expression
profiling", can be utilized to identify genes that predict drug
response. For example, the gene expression of an animal dosed with
a drug (e.g., a molecule or modulator of the present invention) can
give an indication whether gene pathways related to toxicity have
been turned on.
[0110] Information generated from more than one of the above
pharmacogenomics approaches can be used to determine appropriate
dosage and treatment regimens for prophylactic or therapeutic
treatment of an individual. This knowledge, when applied to dosing
or drug selection, can avoid adverse reactions or therapeutic
failure and thus enhance therapeutic or prophylactic efficiency
when treating a subject with a molecule or modulator of the
invention, such as a modulator identified by one of the exemplary
screening assays described herein. As we have described previously,
this approach can also be used to identify novel candidate receptor
or other genes suitable for further pharmacological
characterization in vitro and in vivo.
[0111] Accordingly, the present invention also provides methods and
kits for identifying a genetic polymorphism predisposing a subject
to being responsive to a compound described herein. The method
comprises administering to a subject an effective amount of a
compound; identifying a responsive subject having an ameliorated
disease condition associated with a monamine receptor; and
identifying a genetic polymorphism in the responsive subject,
wherein the genetic polymorphism predisposes a subject to being
responsive to the compound. It is anticipated that this method may
be useful both for predicting which individuals are responsive to
therapeutic effects of a compound and also for predicting those
likely to experience adverse side effect responses. This approach
may be useful for identifying, for example, polymorphisms in a
serotonin receptor that lead to constitutive activation and are
thus amenable to inverse agonist therapy. In addition, this method
may be useful for identifying polymorphisms that lead to altered
drug metabolism whereby toxic byproducts are generated in the body.
Such a mechanism has been implicated in the rare, but potentially
life threatening side effects of the atypical antipsychotic,
clozapine.
[0112] In a related embodiment, a method for identifying a subject
suitable for treatment with a compound of the present invention is
provided. According to the method, the presence of a polymorphism
that predisposes the subject to being responsive to the compound is
detected, the presence of the polymorphism indicating that the
subject is suitable for treatment. Also provided are kits for
performing the same.
[0113] The compounds of this invention preferably show selective
inverse agonist activity towards the 5-HT2A receptor. Such activity
is defined by an ability of the ligand to attenuate or abolish the
constitutive signaling activity of this receptor. Selectivity in
the present context is understood as a property of a compound of
the invention whereby an amount of compound that effectively
inversely agonizes the 5HT2A receptor and thereby decreases its
activity causes little or no inverse agonistic or antagonistic
activity at other, related or unrelated, receptors. In particular,
the compounds of the invention have surprisingly 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 muscaruuic
receptors.
[0114] A particularly preferred embodiment of this invention
includes:
[0115]
N-(1-(1-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-me-
thoxyphenylacetamide;
[0116]
N-(1-(2,2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)--
4-methoxyphenylacetamide;
[0117]
N-(1-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphen-
ylacetamide;
[0118]
N-(1-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny-
lacetamide;
[0119]
N-(1-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy-
phenylacetamide;
[0120]
N-(1-cyclopentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methox-
yphenylacetamide;
[0121]
N-(1-cyclobutylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy-
phenylacetamide;
[0122]
N-(1-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methox-
yphenylacetamide;
[0123]
N-(1-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)--
4-methoxyphenylacetamide;
[0124]
N-(1-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
-methoxyphenylacetamide;
[0125]
N-(1-(cyclopropylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)--
4-methoxyphenylacetamide;
[0126]
N-(1-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-m-
ethoxyphenylacetamide;
[0127]
N-(1-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4--
methoxyphenylacetamide;
[0128]
N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-N'-phenylmethylcarbam-
ide;
[0129]
N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N'--
phenylmethylcarbamide;
[0130]
N-(1-((2-Bromophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)meth-
yl)-N'-phenylmethylcarbamide;
[0131]
N-(1-((4-Hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4
methylphenyl)methyl)-N'-phenylmethylcarbamide;
[0132]
N-(1-((5-Ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-methylphenyl)-
methyl)-N'-phenylmethylcarbamide;
[0133]
N-(1-(Imidazol-2-ylmethyl)piperidin-4-yl)-N-(4-methylphenyl)methyl)-
-N'-phenylmethylcarbamide;
[0134]
N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N-
'-phenylmethylcarbamide;
[0135]
N-(1-((4-Fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)met-
hyl)-N'-phenylmethylcarbamide;
[0136]
N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetam-
ide;
[0137]
N-((4-Methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-4-methoxyphen-
ylacetamide;
[0138]
N-(1-Ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny-
lacetamide;
[0139]
N-((4-Methylphenyl)methyl)-N-(1-propylpiperidin-4-yl)-4-methoxyphen-
ylacetamide;
[0140]
N-(1-Butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny-
lacetamide;
[0141]
N-(1-(3,3-Dimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)--
4-methoxyphenylacetamide;
[0142]
N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
-methoxyphenylacetamide;
[0143]
N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-4-m-
ethoxyphenylacetamide;
[0144]
N-((4-Methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)piperidin-4-
-yl)-4-methoxyphenylacetamide;
[0145]
N-(1-(((4-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)m-
ethyl)-4-methoxyphenylacetamide;
[0146]
N-(1-((2-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)me-
thyl)-4-methoxyphenylacetamide;
[0147]
N-(3-Phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
[0148]
N-(2-Phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
[0149]
N-((2-Methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylaceta-
mide;
[0150]
N-((2-Chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetam-
ide;
[0151]
N-((3,4-Di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenyl-
acetamide;
[0152]
N-(4-Fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetami-
de;
[0153]
N-((2,4-Di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenyla-
cetamide;
[0154]
N-((3-Methylphenyl)methyl)-N-(piperidin-4-yl)methoxyphenylacetamide-
;
[0155]
N-((3-Bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetami-
de;
[0156]
N-(1-(Phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-met-
hoxyphenylacetamide;
[0157]
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenylacetamide;
[0158]
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-phenylpropionamid-
e;
[0159]
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(phenylthio)acetami-
de;
[0160] N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenoxy
acetamide;
[0161]
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)ac-
etamide;
[0162]
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacet-
amide;
[0163]
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylaceta-
mide;
[0164]
N-((4-Methylphenyl)methyl)-N-piperidin-4-yl)-2,5-di-methoxyphenylac-
etamide;
[0165]
N-(4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-chlorophenylacetam-
ide;
[0166]
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N'-p-
henylmethylcarbamide;
[0167]
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-me-
thoxyphenylacetamide;
[0168]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide;
[0169]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0170]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)
acetamide;
[0171]
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-ethylpiperidin-4-yl)acet-
amide;
[0172]
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)
acetamide;
[0173]
2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide;
[0174]
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentylpiperidin-4-y-
l) acetamide;
[0175]
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)
acetamide;
[0176]
2-(phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0177]
2-(4-fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-
-4-yl) acetamide;
[0178]
2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidi-
n-4-yl) acetamide;
[0179]
2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methyl-
piperidin-4-yl)acetamide;
[0180]
2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)ace-
tamide;
[0181]
2-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0182]
2-(phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;
[0183]
2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-
-4-yl) acetamide;
[0184]
2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-meth-
ylpiperidin-4-yl)acetamide;
[0185]
2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)
acetamide;
[0186]
2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperid-
in-4-yl)acetamide;
[0187]
2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperi-
din-4-yl)acetamide;
[0188]
2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-meth-
ylpiperidin-4-yl)acetamide;
[0189]
2-Phenyl-N-[4-methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)
acetamide;
[0190]
2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperid-
in-4-yl)acetamide;
[0191]
2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperi-
din-4-yl)acetamide;
[0192]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(4-chloromethyl-2-thiaz-
olylmethyl)piperidin-4-yl]acetamide;
[0193] 2-(4 methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3(1,3
dihydro-2H-benzimidazol-2-on-1-yl)propyl]piperidin-4-yl}acetamide;
[0194]
2-(4-methoxyphenyl)-N-(2-4-(fluorophenyl)ethyl)-N-(1-methylpiperidi-
n-4-yl) acetamide;
[0195]
2-(4-methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-methylpip-
eridin-4-yl)acetamide;
[0196]
2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpipe-
ridin-4-yl)acetamide;
[0197]
24-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin--
4-yl)acetamide;
[0198]
2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperid-
in-4-yl)acetamide;
[0199]
2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidi-
n-4-yl) acetamide;
[0200]
2-(4-ethoxyphenyl)-N-[2-(4-fluorophenethyl]-N-(1-methylpiperidin-4--
yl) acetamide;
[0201]
2-(4-ethoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)ace-
tamide;
[0202]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-hydroxyethoxy)eth-
yl]piperidin-4-yl}acetamide;
[0203]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-((2-chloro-5-thienyl)me-
thyl) piperidin-4-yl]acetamide;
[0204]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-(imidazolidinon-1-yl-
)ethyl)piperidin-4-yl]acetamide;
[0205]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2,4(1H,3H)quinazoli-
nedion-3-yl)ethyl]piperidin-4-yl}acetamide;
[0206]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(1,3-dioxolan-2-yl)e-
thyl]piperidin-4-yl}acetamide;
[0207]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(3-indolyl)ethyl]pip-
eridin-4-yl}acetamide;
[0208]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,2,4-triazol-1-yl)-
propyl]piperidin-4-yl}acetamide;
[0209]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-benzofurazanylmethyl-
)piperidin-4-yl]acetamide;
[0210]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-chlorobenzo[b]thien--
3-ylmethyl)piperidin-4-yl]acetamide;
[0211]
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-phenyl-1,2,4-oxadiaz-
ol-3-ylmethyl)piperidin-4-yl]acetamide;
[0212]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)-
acetamide;
[0213]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)-ace-
tamide;
[0214]
2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide,2--
(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;
[0215]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-y-
l)-acetamide;
[0216]
2-(4-Fluorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-ac-
etamide;
[0217]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperid-
in-4-yl)-acetamide;
[0218]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl-
)acetamide;
[0219]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-y-
l)-acetamide;
[0220]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(tropin-4-yl)-acetamide;
[0221]
N-(4-Methylbenzyl)-N-(methylpiperidin-4-yl)-N'-benzyl-carbamide;
[0222]
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-phenyl-carbamide;
[0223]
N-Phenethyl-N-(1-methylpiperidin-4-yl)-N'-benzyl-carbamide;
[0224]
2-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;
[0225]
2-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidi-
n-4-yl)-acetamide;
[0226]
2-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-a-
cetamide;
[0227]
2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)--
acetamide;
[0228]
2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-methylpiperidin-4-yl)-aceta-
mide;
[0229]
2-(4-Hydroxyphenyl)-N-4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-ac-
etamide;
[0230]
N-Phenethyl-N-(1-methylpiperidin-4-yl)-N'-phenyl-carbamide;
[0231]
N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-benzyl-carbamide;
[0232]
N-(3-Phenylpropyl)-N-methylpiperidin-4-yl)-N'-phenyl-carbamide;
[0233]
2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpipe-
ridin-4-yl)acetamide;
[0234]
2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl)
acetamide;
[0235]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(3-tropen-4-yl)acetamide;
[0236]
2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)aceta-
mide;
[0237]
N-Phenethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-amine;
[0238]
2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetami-
de;
[0239]
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-methoxybenzyl)c-
arbamide;
[0240]
2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-y-
l) acetamide;
[0241]
2-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidi-
n-4-yl)acetamide;
[0242]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)a-
cetamide;
[0243]
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-phenethyl-carbamid-
e;
[0244]
N-Phenethyl-N-(1-methylpiperidin-4-yl)-N'-phenethyl-carbamide;
[0245]
N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N'-(4-methoxybenzyl)-
carbamide;
[0246]
2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0247]
2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0248]
2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0249]
2-(4-t-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0250]
2-(4-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0251]
2-(4-Propoxyphenyl)-N-(4-flourobenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0252]
2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)
acetamide;
[0253] and,
2-(4-t-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-
-yl) acetamide.
[0254] Suitable pharmaceutically acceptable salts of the compounds
of this invention include acid addition salts that may, for
example, be formed by mixing a solution of the compound according
to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, sulphuric acid, fumaric acid,
maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid,
citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of the invention carry an acidic
moiety, suitable pharmaceutically acceptable salts thereof may
include alkali metal salts, e.g., sodium or potassium salts;
alkaline earth metal salts, e.g., calcium or magnesium salts; and
salts formed with suitable organic ligands, e.g., quaternary
ammonium salts. Examples of pharmaceutically acceptable salts
include the acetate, benzenesulfonate, benzoate, bicarbonate,
bisulfate, bitartrate, borate, bromide, calcium, carbonate,
chloride, clavulanate, citrate, dihydrochloride, fumarate,
gluconate, glutamate, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, nitrate, N-methylglucamine ammonium
salt, oleate, oxalate, phosphate/diphosphate, salicylate, stearate,
sulfate, succinate, tannate, tartrate, tosylate, triethiodide and
valerate salt.
[0255] 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.
[0256] 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.
[0257] 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-1-tartar- ic acid, followed by
fractional crystallization and regeneration of the free base. The
compounds may also be resolved by formation of diastereomeric
esters or amides followed by chromatographic separation and removal
of the chiral auxiliary.
[0258] 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.
[0259] The present invention also provides 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 incorportated 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.
[0260] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders, lubricants, disintegrating agents,
flavoring agents and coloring agents can also be incorporated into
the mixture. Suitable binders include, without limitation, starch,
gelatin, natural sugars such as glucose or beta-lactose, natural
and synthetic gums such as acacia, tragacanth or sodium alginate,
carboxymethylcellulose polyethylene glycol waxes and the like.
Lubricants used in these dosage forms include, without limitation,
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like.
[0261] For preparing solid compositions such as tablets, the active
ingredient is mixed with a suitable pharmaceutical excipient such
as the ones described above and other pharmaceutical diluents,
e.g., water, to form a solid preformulation composition containing
a homogeneous mixture of a compound of the present invention or a
pharmaceutically acceptable salt thereof. By the term "homogeneous"
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules. The solid preformulation composition may then be
subdivided into unit dosage forms of the type described above
containing from 0.1 to about 50 mg of the active ingredient of the
present invention. The tablets or pills of the present composition
may be coated or otherwise compounded to provide a dosage form
affording the advantage of prolonged action. For example, the
tablet or pill can comprise an inner core containing the active
compound and an outer layer as a coating surrounding the core. The
outer coating may be an enteric layer that serves to resist
disintegration in the stomach and permits the inner core to pass
intact into the duodenum or to be delayed in release. A variety of
materials can be used for such enteric layers or coatings including
a number of polymeric acids and mixtures of polymeric acids with
conventional materials such as shellac, cetyl alcohol and cellulose
acetate.
[0262] The liquid forms in which the present compositions may be
incorporated for administration orally or by injection include
aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils such as
cottonseed oil, sesame oil, coconut oil or peanut oil, as well as
elixirs and similar pharmaceutical carriers. Suitable dispersing or
suspending agents for aqueous suspensions include synthetic and
natural gums such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose, gelatin, methylcellulose or
polyvinylpyrrolidone. Other dispersing agents that may be employed
include glycerin and the like. For parenteral administration,
sterile suspensions and solutions are desired. Isotonic
preparations that generally contain suitable preservatives are
employed when intravenous administration is desired. The
compositions can also be formulated as an ophthalmic solution or
suspension formation, i.e., eye drops, for ocular
administration
[0263] Consequently, the present invention also relates to a method
of alleviating or treating a disease condition in which
modification of monoamine receptor activity, in particular 5-HT2A
serotonergic receptor activity, has a beneficial effect by
administering a therapeutically effective amount of a compound of
the present invention to a subject in need of such treatment. Such
diseases or conditions may, for instance arise from inappropriate
stimulation or activation of serotonergic receptors. It is
anticipated that by using compounds that are selective for a
particular serotonin receptor subtype, in particular 5-HT2A, the
problems with adverse side effects observed with the known
antipsychotic drugs, such as extrapyramidal effects, may be avoided
substantially.
[0264] The term "therapeutically effective amount" as used herein
means an amount of an active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease being treated.
[0265] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses, for example, two, three or four
times daily. Furthermore, compounds of the present invention may be
administered in intranasal form via topical use of suitable
intranasal vehicles, via transdermal routes, using those forms of
transdermal skin patches well known to persons skilled in the art,
by implantable pumps; or by any other suitable means of
administration. To be administered in the form of a transdermal
delivery system, for example, the dosage administration will, of
course, be continuous rather than intermittent throughout the
dosage regimen.
[0266] The dosage regimen utilizing the compounds of the present
invention is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of
the patient; the severity of the condition to be treated; the route
of administration; the renal and hepatic function of the patient;
and the particular compound employed. A physician or veterinarian
of ordinary skill can readily determine and prescribe the effective
amount of the drug required to prevent, counter or arrest the
progress of the disease or disorder that is being treated.
[0267] The daily dosage of the products may be varied over a wide
range from about 0.01 mg to about 100 mg per adult human per day.
For oral administration, the compositions are preferably provided
in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5,
5.0, 10.0, 15.0, 25.0 or 50.0 mg of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
A unit dose typically contains from about 0.001 mg to about 50 mg
of the active ingredient, preferably from about 1 mg to about 10 mg
of active ingredient. An effective amount of the drug is ordinarily
supplied at a dosage level of from about 0.0001 mg/kg to about 25
mg/kg of body weight per day. Preferably, the range is from about
0.001 to 10 mg/kg of body weight per day, and especially from about
0.001 mg/kg to 1 mg/kg of body weight per day.
[0268] Compounds according to the present invention may be used
alone at appropriate dosages defined by routine testing in order to
obtain optimal pharmacological effect on a monoaminergic receptor,
in particular the 5-HT2A serotonergic receptor subtype, while
minimizing any potential toxic or otherwise unwanted effects. In
addition, co-administration or sequential administration of other
agents that improve the effect of the compound may, in some cases,
be desirable.
[0269] The pharmacological properties and the selectivity of the
compounds of this invention for specific serotonergic receptor
subtypes may be demonstrated by a number of different assay methods
using recombinant receptor subtypes, preferably of the human
receptors if these are available, e.g. conventional second
messenger or binding assays. A particularly convenient functional
assay system is the receptor selection and amplification assay
disclosed in U.S. Pat. No. 5,707,798, which describes a method of
screening for bioactive compounds by utilizing the ability of cells
transfected with receptor DNA, e.g., coding for the different
serotonergic subtypes, to amplify in the presence of a ligand of
the receptor. Cell amplification is detected as increased levels of
a marker also expressed by the cells.
[0270] Methods of Preparation
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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. 7
[0275] 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.
[0276] 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. 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). 8
[0277] 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.
[0278] The substituent G on the ring nitrogen 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). 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 or any related reagent may be used, including
solid-supported reagents. The reaction is typically carried out at
room temperature.
[0279] 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.
[0280] 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. The
secondary amine H, as exemplified by 4-piperidone, 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. 37:283140 (1994); and Carroll et al., J. Med. Chem.
35:2184-91 (1992).
[0281] 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. 9
[0282] 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.
[0283] 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
[0284] The invention is disclosed in further detail in the
following examples that are not in any way intended to limit the
scope of the invention as claimed.
[0285] General LC-MS procedure for Examples 1-41: All spectra were
obtained using an HP1100 LC/MSD-instrument. A setup with a binary
pump, autosampler, column oven, diode array detecter, and
electrospray ionization interface was used. A reversed phase column
(C18 Luna 3 mm particle size, 7.5 cm.times.4.6 mm ID) with a guard
cartridge system was used. The column was maintained at a
temperature of 30.degree. C. The mobile phase was acetonitrile/8 mM
aqueous ammonium acetate. A 15 minute gradient program was used,
starting at 70% acetonitrile, over 12 minutes to 95% acetonitrile,
over 1 minute back to 70% acetonitrile, where it stayed for 2
minutes. The flow rate was 0.6 ml/min. The t.sub.r values reported
in the specific examples below were obtained using this
procedure.
Example 1
N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-N'-phenylmethylcarbamide
(26HCH65)
[0286] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine, carboxylate (800 mg,
2.63 mmol) in dry dichloromethane (20 ml) was added
benzylisocyanate (0.65 ml, 5.26 mmol). The solution was stirred at
room temperature. After 48 h, an excess of
2-dimethylaminoethylamine was added. The mixture was stirred for
another 24 h, before it was concentrated. The resulting solid was
redissolved in dichloromethane (20 ml), sequentially washed with
HCl (0.2 N, 3.times.30 ml), and water (20 ml), dried
(Na.sub.2SO.sub.4), filtered and concentrated. Flash chromatography
in dichloromethane:methanol 10:1 gave
N-((4-methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-N'-
-phenylmethylcarbamide (760 mg, 66%), which was dissolved in
diethyl ether (5 ml). HCl (4 M) in dioxane (3 ml) was added, and
the solution was stirred at room temperature for 60 min, then
concentrated. The resulting oil was redissolved in a mixture of
dichloromethane and diethyl ether (4:1). The organic layer was
extracted with HCl (0.2 M, 3.times.20 ml). The combined aqueous
layers were treated with NaOH (0.2 M) until basic (pH>8), then
extracted with dichloromethane (3.times.20 ml). The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give the title compound. Yield: 406 mg, 70%;
.sup.13C-NMR (CDCl.sub.3): .delta. 21.3, 31.6, 45.0, 45.9, 46.4,
53.0, 126.3, 127.2, 127.4, 128.6, 129.8, 135.3, 137.4, 139.7,
158.5.
Example 2
N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N'-phenylm-
ethylcarbamide (26HCH66-02)
[0287] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 2-Methylpropionaldehyde (0.08 ml,
0.6 mmol) was added followed by solid-supported borohydride (150
mg, 2.5 mmol/g resin; Aldrich 32, 864-2). The mixture was shaken at
room temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 ml, 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. IR: 1640,
1185, 1110 cm.sup.-1; LC-MS: (M+H).sup.+394.2, t.sub.r 5.60
min.
Example 3
N-(1-((2-Bromophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'--
phenylmethylcarbamide (26HCH66-03)
[0288] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 2-Bromobenzaldehyde (0.07 ml, 0.6
mmol) was added followed by solid-supported borohydride (150 mg,
2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room
temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 ml, 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. IR: 1635,
1180, 1110 cm.sup.-1; LC-MS: (M+H).sup.+506.1, t.sub.r 8.37
min.
Example 4
N-(1-((4-Hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl-
)methyl)-N'-phenylmethylcarbamide (26HCH66-04)
[0289] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 4-Hydroxy-3-methoxybenzaldehyde
(91 mg, 0.6 mmol) was added followed by solid-supported borohydride
(150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was
shaken at room temperature. After 48 h, the resin was filtered off
and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic
solution. After 24 h, the mixture was concentrated and redissolved
in methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound.
.sup.13C-NMR (CD.sub.3OD, selected): .delta. 19.9, 55.4, 126.5,
127.0, 128.1, 129.0, 140.3, 148.0, 148.1, 158.8.
Example 5
N-(1-((5-Ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-
-N'-phenylmethylcarbamide (26HCH66-05)
[0290] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 5-Ethyl-2-thiophencarboxaldehyde
(84 mg, 0.6 mmol) was added followed by solid-supported borohydride
(150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was
shaken at room temperature. After 48 h, the resin was filtered off
and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic
solution. After 24 h, the mixture was concentrated and redissolved
in methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. IR: 1640,
1185, 1110, 805, 700, 620 cm.sup.-1; LC-MS: (M+H).sup.+462.3,
t.sub.r 7.52 min.
Example 6
N-(1-(Imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-ph-
enylmethylcarbamide (26HCH66-06)
[0291] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). Imidazole-2-carboxaldehyde (58
mg, 0.6 mmol) was added followed by solid-supported borohydride
(150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was
shaken at room temperature. After 48 h, the resin was filtered off
and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic
solution. After 24 h, the mixture was concentrated and redissolved
in methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. IR: 1620,
1190, 1100, 805, 700, 620 cm.sup.-1; LC-MS: (M+H).sup.+418.2,
t.sub.r 2.05 min.
Example 7
N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-pheny-
lmethylcarbamide (26HCH66-09)
[0292] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (67 mg,
0.6 mmol) was added followed by solid-supported borohydride (150
mg, 2.5 mmol/g resin; Aldrich 32,8642). The mixture was shaken at
room temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 ml, 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. IR: 1635,
1175, 1100, 805, 695, 620 cm.sup.-1; LC-MS: (M+H).sup.+434.4,
t.sub.r 7.44 min.
Example 8
N-(1-((4-Fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-
-phenylmethylcarbamide (26HCH66-10)
[0293] The product from example 1 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 4-Fluorobenzaldehyde (0.08 ml,
0.6 mmol) was added followed by solid-supported borohydride (150
mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at
room temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 ml, 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. IR: 1640,
1175, 1110, 805, 700, 620 cm.sup.-1; LC-MS: (M+H).sup.+446.3,
t.sub.r 5.62 min.
Example 9
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-N'-phenylmet-
hylcarbamide hydrochloride (26HCH16D)
[0294] To a solution of 1-benzyl-4-piperidone (1.74 g, 9.2 mmol)
and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was
added sodium borohydride (525 mg) in small portions over 30 min.
The reaction mixture was stirred at room temperature. After 16 h,
the mixture was concentrated. Water (30 ml) was added, and the
mixture was extracted with dichloromethane (2.times.20 ml). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give
4-((4-methylphenyl)methyl)amino-1-phenylmethylpiperidine. The crude
product was used without further purification.
[0295] 4-((4-Methylphenyl)methyl)amino-1-phenylmethylpiperidine
(800 mg, 2.7 mmol) was dissolved in dry dichloromethane (30 ml).
Benzylisocyanate (543 mg, 4.1 mmol) was added. The reaction mixture
was stirred at room temperature. After 16 h, water (10 ml) was
added followed by NaOH (6 N, 2 ml). After additional 30 minutes of
stirring the white crystals were filtered off. The organic layer
was isolated and dried (Na.sub.2SO.sub.4), filtered, and
concentrated. Flash chromatography in dichloromethane/methanol 10/1
left N-((4-Methylphenyl)methyl)-N-(1-(pheny-
lmethyl)piperidin-4-yl)-N'-phenylmethylcarbamide Yield: 820 mg,
71%; A sample was concentrated with HCl (4 M in dioxane) followed
by recrystallization from dichloromethane/diethyl ether leaving the
title compound. .sup.1H-NMR (CDCl.sub.3): .delta. 1.87 (br d, 2H),
2.30 (s, 3H), 2.59 (dq, 2H), 2.76 (br q, 2H), 3.44 (br d, 2H), 4.09
(d, 2H), 4.30 (d, 2H), 4.40 (s, 2H), 4.64-4.76 (m, 2H), 6.98-7.64
(Aromatic protons, 14H); .sup.13C-NMR (CDCl.sub.3): .delta. 21.2,
26.7, 45.0, 46.0, 49.7, 52.2, 61.0, 126.2, 127.26, 126.31, 128.2,
128.6, 129.6, 129.9, 130.4, 131.6, 134.4, 137.6, 139.3, 158.5;
.sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.8, 26.4, 27.8,
40.3, 44.3, 51.6, 51.9, 54.5, 60.5, 110.0, 112.1, 114.0, 114.2,
117.5, 125.9, 126.2, 126.7, 126.8, 128.9, 129.1, 129.2, 129.4,
129.7, 130.1, 131.2, 134.5, 137.4, 159.1, 173.8, 175.0; Mp.
109-112.degree. C.; Elemental analysis: Found C, 70.06; H, 7.62; N,
8.60; calcd for monohydrate: C, 69.76; H, 7.53; N, 8.72.
Example 10
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-N'-phenylmet-
hylcarbamide oxalate (34JJ59oxal)
[0296]
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-N'-ph-
enylmethylcarbamide was prepared as described in example 9 above. A
sample was precipitated as the oxalate and recrystallized from
ethyl acetate to give the title compound. .sup.13C-NMR
(CDCl.sub.3): .delta. 21.2, 27.0, 45.0, 45.9, 49.9, 52.1, 60.6,
126.1, 127.3, 127.4, 128.5, 128.7, 129.6, 130.0, 130.4, 131.2,
134.3, 137.7, 139.3, 158.4, 163.4; Mp. 180-182.degree. C.;
Elemental analysis: Found C, 69.54; H, 6.73; N, 7.96; calcd for
monooxalate: C, 69.61; H, 6.82; N, 8.12.
Example 11
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphe-
nylacetamide hydrochloride (26HCH17)
[0297] To a solution of 1-benzyl-4-piperidone (1.74 g, 9.2 mmol)
and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was
added sodium borohydride (525 mg) in small portions over 30 min.
The reaction mixture was stirred at room temperature. After 16 h,
the mixture was concentrated. Water (30 ml) was added, and the
mixture was extracted with dichloromethane (2.times.20 ml). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give
4-((4-methylphenyl)methyl)amino-1-phenylmethylpiperidine. The crude
product was used without further purification.
[0298] To a solution of
4-((4-Methylphenyl)methyl)amino-1-phenylmethylpipe- ridine (800 mg,
2.7 mmol) in dry dichloromethane (30 ml) was added
diisopropylethylamine (1.5 ml) followed by 4-methoxyphenylacetyl
chloride (997 mg, 5.4 mmol). The reaction mixture was stirred at
room temperature. After 16 h, the reaction mixture was
concentrated, redissolved in diethyl ether, and extracted with HCl
(0.6 N). The aqueous layer was isolated, treated with NaOH (1 N)
until basic, and extracted with dichloromethane (20 ml). The
organic layer was isolated and dried (Na.sub.2SO.sub.4), filtered,
and concentrated, and redissolved in diethyl ether. The
hydrochloride was formed by addition of HCl (4 M in dioxane), and
recrystallized from diethyl ether to give the title compound.
Yield: 600 mg, 50%; .sup.1H-NMR (CDCl.sub.3): .delta. 1.75 (d, 2H),
2.32 (s, 3H, 2.50 (q, 2H), 2.70 (q, 2H), 3.38 (d, 2H), 3.54 (s,
2H), 3.78 (s, 3H), 4.06 (d, 2H), 4.54 (s, 2H), 4.82 (m, 1H),
6.78-7.60 (aromatic protons, 13 HE); .sup.13C-NMR (CDCl.sub.3):
.delta. 21.0, 26.0, 40.3, 46.3, 49.0, 51.8, 55.3, 60.8, 114.2,
125.6, 126.6, 127.9, 129.4, 129.60, 129.62, 130.3, 131.4, 134.8,
137.1, 158.7, 172.9; Mp. 197-200.degree. C.; Elemental analysis:
Found C, 71.29; H, 7.25; N, 5.73; calcd for hydrate: C, 71.37; H,
7.43; N, 5.74.
Example 12
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphe-
inylacetamide oxalate (34JJ61oxal)
[0299]
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-met-
hoxyphenylacetamide was prepared as described in example 11 above.
A sample was precipitated as the oxalate and recrystallized from
tetrahydrofuran to give the title compound. .sup.13C-NMR
(CDCl.sub.3): .delta. 21.2, 26.4, 40.6, 52.0, 55.5, 114.4, 125.9,
126.7, 128.4, 129.6, 129.8, 129.9, 130.4, 131.2, 134.6, 137.6,
158.9, 163.3, 172.9; Mp. 171-173.degree. C.; Elemental analysis:
Found C, 69.56; H, 6.74; N, 5.16; calcd for monooxalate: C, 69.48;
H, 6.61; N, 5.40.
Example 13
N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide
(26HCH71B)
[0300] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (862 mg,
2.83 mmol) in dry dichloromethane (10 ml) was added
diisopropylethylamine (1.1 ml, 6.5 mmol) followed by
4-methoxyphenylacetyl chloride (0.66 ml, 4.3 mmol). The reaction
mixture was stirred at room temperature. After 48 h, water (5 ml)
was added, and the mixture was stirred for additional 2 h before
extracted with NaOH (0.2 N, 2.times.15 ml), HCl (0.2 N. 2.times.15
ml), and water (15 ml). The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated to give
N-((4-methylphenyl)methyl)-N
1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-m-
ethoxyphenylacetamide. The crude product was used without any
further purification. N-((4-Methylphenyl)methyl)-N-(1
tert-butyloxycarbonyl)piper- idin-4-yl)-4-methoxyphenylacetamide
was dissolved in ether (2 ml) and HCl (3 ml, 4 M in dioxane) was
added. The reaction mixture was stirred at room temperature. After
2 h, water (5 ml) was added, and the mixture was extracted with HCl
(0.1 N, 3.times.30 ml). The combined aqueous layers were treated
with NaOH (0.2 N) until basic (pH>8). The aqueous layer was
extracted with diethyl ether (2.times.20 ml). The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated, before
dissolved in methanol (2 ml). The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated. Additional flash
chromatography in dichloromethane/methanol 1/1.fwdarw.methanol
containing 2% NH.sub.3 gave the title compound. Yield: 466 mg, 47%;
.sup.3C-NMR (CD.sub.3OD, rotamers): .delta. 19.9, 27.8, 29.7, 40.2,
40.3, 44.4, 44.45, 44.50, 52.4, 54.5, 55.5, 114.0, 114.1, 126.0,
126.7, 126.9, 127.3, 128.7, 129.3, 129.6, 129.7, 135.1, 136.1,
136.2, 137.1, 159.0, 159.1, 173.1, 173.7.
Example 14
N-(1-(3,3-Dimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-metho-
xyphenylacetamide (26HCH79-5)
[0301] The product from example 13 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 3,3-Dimethylbutyraldehyde (0.143
ml, 1.1 mmol) was added followed by solid-supported borohydride
(150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was
shaken at room temperature. After 48 h, the resin was filtered off
and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic
solution. After 24 h, the mixture was concentrated and redissolved
in methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 26
mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9, 27.4, 28.4,
28.8, 29.2, 29.3, 38.3, 38.4, 40.2, 40.3, 44.3, 52.0, 52.3, 52.4,
53.9, 54.6, 54.9, 114.0, 114.1, 126.0, 126.8, 127.0, 127.3, 128.8,
129.4, 129.8, 129.9, 135.0, 136.1, 136.3, 137.1, 158.96, 159.05,
173.2, 173.8.
Example 15
N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methox-
yphenylacetamide (26HCH79-6)
[0302] The product from example 13 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (0.138
ml, 1.1 mmol) was added followed by solid-supported borohydride
(150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was
shaken at room temperature. After 48 h, the resin was filtered off
and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic
solution. After 24 h, the mixture was concentrated and redissolved
in methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 17
mg; HRMS (FAB.sup.+, NBA) (M+H).sup.+449.3163,
C.sub.29H.sub.41N.sub.2O.sub.2 requires 449.3168; LC-MS:
(M+H).sup.+449.2, t.sub.r 7.92 min.
Example 16
N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)+methoxyphe-
nylacetamide (26HCH79-7)
[0303] The product from example 13 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml).). 2-Methylpropionaldehyde (0.104
ml, 1.1 mmol) was added followed by solid-supported borohydride
(150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was
shaken at room temperature. After 48 h, the resin was filtered off
and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic
solution. After 24 h, the mixture was concentrated and redissolved
in methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 19
mg; HRMS (FAB.sup.+, NBA) (M+H).sup.+409.2858,
C.sub.26H.sub.37N.sub.2O.sub.2 requires 409.2855; LC-MS:
(M+H).sup.+409.2, t.sub.r 5.97 min.
Example 17
N-((4-Methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)piperidin-4-yl)-4--
methoxyphenylacetamide (26HCH79-8)
[0304] The product from example 13 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 4-Methylbenzaldehyde (0.134 ml,
1.1 mmol) was added followed by solid-supported borohydride (150
mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at
room temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 mL 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 22
mg; HRMS (FAB.sup.+, NBA) (M+H).sup.+457.2853,
C.sub.30H.sub.37N.sub.2O.sub.2 requires 457.2855; LC-MS:
(M+H).sup.+457.2, t.sub.r 6.97 min.
Example 18
N-(1-((4-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
-methoxyphenylacetamide (26HCH79-9)
[0305] The product from example 13 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg,
1.1 mmol) was added followed by solid-supported borohydride (150
mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at
room temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 ml, 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 19
mg; HRMS (FAB.sup.+, NBA) (M+H).sup.+459.2655,
C.sub.29H.sub.35N.sub.2O.sub.3 requires 459.2648; LC-MS:
(M+H).sup.+4590.1, t.sub.r 2.84 min.
Example 19
N-(1-((2-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
-methoxyphenylacetamide (26HCH79-10)
[0306] The product from example 13 above (20 mg, 0.06 mmol) was
dissolved in abs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml,
10.1 mmol) was added followed by solid-supported borohydride (150
mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at
room temperature. After 48 h, the resin was filtered off and acetic
anhydride (0.02 ml, 0.2 mmol) was added to the organic solution.
After 24 h, the mixture was concentrated and redissolved in
methanol (2 ml). The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 16
mg; HRMS (FAB.sup.+, NBA) (M+H).sup.+459.2633,
C.sub.29H.sub.35N.sub.2O.sub.3 requires 459.2648; LC-MS:
(M+H).sup.+459.2, t.sub.r 5.81 min.
Example 20
N-(3-Phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide
(26HCH80-1)
[0307] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 3-phenylpropylamine (0.143 ml, 1 mmol) in methanol (1 ml) was
added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-(3-phenylpropyl)amino-pip-
eridine carboxylate. Yield: 110 mg. To a solution of tert-butyl
4-(3-phenylpropyl)amino-piperidine carboxylate (50 mg, 0.16 mmol)
in dichloromethane (6 ml) was added diisopropylethylamine (0.070
ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml,
0.35 mmol). The reaction mixture was stirred at room temperature.
After 18 h, water (2 ml) was added. The mixture was stirred for
another 2 h. The mixture was sequentially washed with HCl (0.2 N,
2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and water (10 ml),
dried (Na.sub.2SO.sub.4), filtered and concentrated to give
N-(3-phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piper-
idin-4-yl)-4-methoxyphenylacetamide. The crude product was used
without any further purification.
N-(3-Phenylpropyl)-N-(1-(tert-butyloxycarbonyl)-
piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl
ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction
mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6
N) was added followed by dichloromethane (10 ml). The mixture was
extracted with water (2.times.15 ml), dried (Na.sub.2SO.sub.4),
filtered to give a clear solution. The solution was added on to a
column carrying strongly acidic cation exchange resin (0.3 mmol/g
resin), which was washed with methanol (3.times.6 ml), and eluted
with 10% NH.sub.3 in methanol, and concentrated to give the title
compound. Yield: 61 mg; .sup.13C-NMR (CD.sub.3OD, rotamers):
.delta. 27.8, 29.4, 30.8, 32.3, 32.7, 33.3, 40.2, 40.5, 42.0, 44.5,
44.6, 44.9, 52.7, 54.56, 54.57, 54.9, 114.0, 114.1, 125.7, 126.1,
127.0, 127.4, 128.2, 128.3, 128.5, 129.47, 129.55, 141.2, 141.8,
158.9, 159.0, 172.5, 172.7.
Example 21
N-(2-Phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylmethylacetamide
(26HCH80-2)
[0308] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 2-phenylethylamine (0.143 ml, 1 mmol) in methanol (1 ml) was
added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl
4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a
solution of tert-butyl 4-(2-phenylethyl)amino-piperidine
carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.1 5 ml), NaOH (0.2 N.
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperi-
din-4-yl)-4-methoxyphenylacetamide. The crude product was used
without any further purification.
N-(2-Phenylethyl)-N-(1-(tert-butyloxycarbonyl)piper-
idin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether
(2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction
mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6
N) was added followed by dichloromethane (10 ml). The mixture was
extracted with water (2.times.15 ml), dried (Na.sub.2SO.sub.4),
filtered to give a clear solution. The solution was added on to a
column carrying strongly acidic cation exchange resin (0.3 mmol/g
resin), which was washed with methanol (3.times.6 ml), and eluted
with 10% NH.sub.3 in methanol, and concentrated to give the title
compound. Yield: 52 mg; .sup.13C-NMR (CD.sub.3OD, rotamers):
.delta. 27.1, 28.5, 34.9, 36.6, 40.2, 40.4, 44.1, 44.2, 44.4, 53.3,
54.2, 54.6, 114.0, 114.1, 126.2, 126.6, 127.2, 127.4, 128.3, 128.6,
128.79, 128.82, 129.7, 138.5, 139.5, 158.96, 159.0, 172.7,
173.1
Example 22
N-(2-Methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylmethylacetami-
de (26HCH80-4)
[0309] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 2-methoxybenzylamine (0.130 ml, 1 mmol) in methanol (1 ml) was
added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-((2-methoxyphenyl)methyl)-
amino-piperidine carboxylate. Yield: 211 mg. To a solution of
tert-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate
(50 mg, 0.16 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-((2-methoxyphenyl)methyl)-N-(1-(tert--
butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The
crude product was used without any further purification.
N-((2-Methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-
-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and
HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was
stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was
added followed by dichloromethane (10 ml). The mixture was
extracted with water (2.times.15 ml), dried (Na.sub.2SO.sub.4),
filtered to give a clear solution. The solution was added on to a
column carrying strongly acidic cation exchange resin (0.3 mmol/g
resin), which was washed with methanol (3.times.6 ml), and eluted
with 10% NH.sub.3 in methanol, and concentrated to give the title
compound. Yield: 40 mg; .sup.13C-NMR (CD.sub.3OD, rotamers):
.delta. 26.1, 27.4, 40.0, 40.1, 43.5, 43.9, 51.5, 53.4, 54.5,
54.58, 54.63, 54.78, 54.83, 110.1, 110.5, 113.76, 113.78, 113.84,
114.0, 114.1, 120.1, 120.5, 125.4, 126.0, 126.5, 126.7, 127.1,
127.3, 127.7, 128.8, 129.8, 130.0, 130.08, 130.14, 156.5, 157.0,
159.0, 159.1, 173.2, 173.8.
Example 23
N-((2-Chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide
(26HCH805)
[0310] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 2-chlorobenzylamine (0.121 ml, 1 mmol) in methanol (1 ml) was
added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-((2-chlorophenyl)methyl)a-
mino-piperidine carboxylate. Yield: 137 mg. To a solution of
tert-butyl 4-((2-chlorophenyl)methyl)amino-piperidine carboxylate
(50 mg, 0.15 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-((2-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbon-
yl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was
used without any further purification.
N-((2-Chlorophenyl)methyl)-N-(1-(tert-b-
utyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was
dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane)
was added. The reaction mixture was stirred at room temperature.
After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane
(10 ml). The mixture was extracted with water (2.times.15 ml),
dried (Na.sub.2SO.sub.4), filtered to give a clear solution. The
solution was added on to a column carrying strongly acidic cation
exchange resin (0.3 mmol/g resin), which was washed with methanol
(3.times.6 ml), and eluted with 10% NH.sub.3 in methanol, and
concentrated to give the title compound. Yield: 45 mg; .sup.13C-NMR
(CD.sub.3OD, rotamers): .delta. 25.8, 26.9, 40.0, 40.1, 42.9, 43.4,
43.7, 46.0, 51.1, 53.0, 54.6, 113.77, 113.84, 114.0, 114.1, 126.6,
126.8, 127.08, 127.13, 127.3, 127.4, 128.1, 129.0, 129.2, 129.8,
130.0, 130.2, 131.9, 132.2, 135.0, 135.3, 159.1, 173.4, 173.8.
Example 24
N-(3,4-Di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamid-
e (26HCH80-6)
[0311] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 3,4-di-methoxybenzylamine (0.151 ml, 1 mmol) in methanol (1 ml)
was added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was added
and the mixture was stirred for 1 h, before it was concentrated.
The resulting oil was redissolved in diethyl ether (20 ml),
extracted with HCl (0.1 N, 1.times.15 ml). The aqueous layer was
washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until
basic (pH>8), before extracted with dichloromethane (20 ml). The
organic layer was dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give tert-butyl 4-((3,4-di-methoxyphenyl)me-
thyl)amino-piperidine carboxylate. Yield: 162 mg. To a solution of
tert-butyl 4-((3,4-dimethoxyphenyl)methyl)amino-piperidine
carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 nil), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-(3,4-di-methoxyphenyl)methyl)-N-(1-(tert-butyl-
oxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude
product was used without any further purification.
N-((3,4-Di-methoxyphenyl)methy-
l)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide
was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in
dioxane) was added. The reaction mixture was stirred at room
temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by
dichloromethane (10 ml). The mixture was extracted with water
(2.times.15 ml), dried (Na.sub.2SO.sub.4), filtered to give a clear
solution. The solution was added on to a column carrying strongly
acidic cation exchange resin (0.3 mmol/g resin), which was washed
with methanol (3.times.6 ml), and eluted with 10% NH.sub.3 in
methanol, and concentrated to give the title compound. Yield: 54
mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 25.9, 27.3, 40.0,
40.1, 43.5, 43.8, 44.1, 51.4, 53.5, 54.6, 55.4, 110.2, 111.0,
111.9, 112.2, 114.0, 114.2, 118.6, 119.4, 127.1, 127.4, 129.9,
130.0, 130.5, 132.1, 148.2, 148.7, 149.2, 149.7, 158.98, 159.05,
173.3, 173.6.
Example 25
N-((4-Fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide
(26HCH80-7)
[0312] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 4-fluorobenzylamine (0.114 ml, 1 mmol) in methanol (1 ml) was
added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-((4-fluorophenyl)methyl)a-
mino-piperidine carboxylate. Yield: 130 mg. To a solution of
tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate
(50 mg, 0.16 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-((4-fluorophenyl)methyl)-N-(1-(tert-butyloxycarbon-
yl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was
used without any further purification.
N-((4-Fluorophenyl)methyl)-N-(1-(tert-b-
utyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was
dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane)
was added. The reaction mixture was stirred at room temperature.
After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane
(10 ml). The mixture was extracted with water (2.times.15 ml),
dried (Na.sub.2SO.sub.4), filtered to give a clear solution. The
solution was added on to a column carrying strongly acidic cation
exchange resin (0.3 mmol/g resin), which was washed with methanol
(3.times.6 ml), and eluted with 10% NH.sub.3 in methanol, and
concentrated to give the title compound. Yield: 45 mg; .sup.13C-NMR
(CD.sub.3OD, rotamers): .delta. 26.1, 27.5, 40.1, 43.6, 43.8, 44.0,
51.6, 53.6, 54.6, 113.77, 113.84, 114.0, 114.1, 114.7, 114.9,
115.3, 115.6, 126.8, 127.2, 128.1, 128.6, 128.7, 129.8, 130.0,
130.1, 130.6, 131.0, 133.8, 159.1, 173.3, 173.6.
Example 26
N-((2,4-Di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamid-
e (26HCH88)
[0313] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 2,4-di-chlorobenzylamine (0.135 ml, 1 mmol) in methanol (1 ml)
was added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-((2,4-di-chlorophenyl)met-
hyl)amino-piperidine carboxylate. Yield: 97 mg. To a solution of
tert-butyl 4-((2,4-dichlorophenyl)methyl)amino-piperidine
carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-(2,4-di-chlorophenyl)methyl)-N-(1-(te-
rt-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The
crude product was used without any further purification.
N-((2,4-Di-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-y-
l)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml)
and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was
stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was
added followed by dichloromethane (10 ml). The mixture was
extracted with water (2.times.15 ml), dried (Na.sub.2SO.sub.4),
filtered to give a clear solution. The solution was added on to a
column carrying strongly acidic cation exchange resin (0.3 mmol/g
resin), which was washed with methanol (3.times.6 ml), and eluted
with 10% NH.sub.3 in methanol, and concentrated to give the title
compound. Yield: 39 mg; .sup.13C-NMR (CD.sub.3OD, rotamers):
.delta. 25.7, 26.8, 40.0, 42.6, 43.3, 43.7, 51.2, 53.0, 54.5, 54.6,
113.8, 113.8, 114.0, 114.1, 127.0, 128.4, 128.8, 129.8, 130.0,
130.1, 131.0, 132.7, 132.9, 134.5, 159.1, 173.4, 173.6.
Example 27
N-((3-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide
(26HCH809)
[0314] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 3-methylbenzylamine (0.125 ml, 1 mmol) in methanol (1 ml) was
added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-((3-methylphenyl)methyl)a-
mino-piperidine carboxylate. Yield: 136 mg. To a solution of
tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate
(50 mg, 0.16 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-((3-methylphenyl)methyl)-N-(1-(tert-butyloxycarbon-
yl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was
used without any further purification.
N-(3-Methylphenyl)methyl)-N-(1-(tert-bu-
tyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was
dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane)
was added. The reaction mixture was stirred at room temperature.
After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane
(10 ml). The mixture was extracted with water (2.times.15 ml),
dried (Na.sub.2SO.sub.4), filtered to give a clear solution. The
solution was added on to a column carrying strongly acidic cation
exchange resin (0.3 mmol/g resin), which was washed with methanol
(3.times.6 ml), and eluted with 10% NH.sub.3 in methanol, and
concentrated to give the title compound Yield: 48 mg; .sup.13C-NMR
(CD.sub.3OD, rotamers): .delta. 20.4, 26.8, 28.3, 40.2, 43.9, 44.1,
44.5, 51.8, 54.2, 54.57, 54.61, 114.0, 114.1, 123.2, 123.7, 126.7,
127.0, 127.1, 127.3, 128.0, 128.1, 128.7, 129.8, 129.9, 137.9,
138.6, 138.9, 159.0, 159.1, 173.1, 173.7.
Example 28
N-((3-Bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide
(26HCH80-10)
[0315] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml)
and 3-bromobenzylamine hydrobromide (222 mg, 1 mmol) in methanol (1
ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 4.4 ml). The resulting solution
was stirred at room temperature. After 24 h, water (2 ml) was
added, and the mixture was stirred for 1 h, before it was
concentrated. The resulting oil was redissolved in diethyl ether
(20 ml), extracted with HCl (0.1 N, 1.times.15 ml). The aqueous
layer was washed with diethyl ether (10 ml) and treated with 0.2 N
NaOH until basic (pH>8), before extracted with dichloromethane
(20 ml). The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give tert-butyl 4-((3-bromophenyl)methyl)am-
ino-piperidine carboxylate. Yield: 142 mg. To a solution of
tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate
(50 mg, 0.14 mmol) in dichloromethane (6 ml) was added
diisopropylethylamine (0.070 ml, 0.4 mmol) followed by
4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction
mixture was stirred at room temperature. After 18 h, water (2 ml)
was added. The mixture was stirred for another 2 h. The mixture was
sequentially washed with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N,
2.times.15 ml), and water (10 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated to give
N-((3-bromophenyl)methyl)-N-(1-(tert-butyloxycarbony-
l)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was
used without any further purification.
N-((3-Bromophenyl)methyl)-N-(1-(tert-bu-
tyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was
dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane)
was added. The reaction mixture was stirred at room temperature.
After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane
(10 ml). The mixture was extracted with water (2.times.15 ml),
dried (Na.sub.2SO.sub.4), filtered to give a clear solution. The
solution was added on to a column carrying strongly acidic cation
exchange resin (0.3 mmol/g resin), which was washed with methanol
(3.times.6 ml), and eluted with 10% NH.sub.3 in methanol, and
concentrated to give the title compound. Yield: 49 mg; .sup.13C-NMR
(CD.sub.3OD, rotamers): .delta. 26.6, 28.2, 40.2, 43.9, 44.0, 51.8,
54.1, 54.6, 113.76, 113.84, 114.1, 114.2, 122.2, 125.0, 125.5,
126.7, 127.1, 129.2, 129.5, 129.7, 129.8, 129.9, 130.0, 130.5,
130.6, 140.8, 141.8, 159.1, 173.3, 173.7.
Example 29
N-(1-(Phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphe-
nylacetamide (26HCH76B)
[0316] To a solution of 4-amino-N-benzylpiperidine (200 mg, 1.05
mmol) in methanol (2 ml) was added trans-cinnamaldehyde (211 mg,
1.6 mmol), followed by Acetic acid in methanol (1 M, 1.4 ml) and
sodium cyanoborohydride in methanol (0.3 M, 4.4 ml). The reaction
mixture was stirred at room temperature. After 48 h, water (2 ml)
was added. The mixture was stirred for another 2 h before
concentrated and redissolved in diethyl ether (20 ml). The organic
layer was extracted with HCl (0.1 N, 2.times.10 ml). The combined
aqueous layers were treated with NaOH (0.2 N) until basic
(pH>8). The mixture was extracted with dichloromethane
(2.times.10 ml). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The crude product, which was
used without any further purification, was dissolved in
dichloromethane (5 ml). Diisopropylethylamine (284 mg, 2.1 eq.) was
added, followed by 4-methoxyphenylacetyl chloride (387 mg, 2.0 eq).
The reaction mixture was stirred at room temperature. After 18 h,
water (2 ml) was added. After additional 2 h dichloromethane (10
ml) was added. The mixture was extracted with NaOH (0.2 N,
3.times.15 ml), and water. (5 ml). The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was
redissolved in methanol (2 ml) and added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound.
.sup.13C-NMR (CDCl.sub.3): .delta. 28.5, 38.1, 46.6, 47.4, 50.9,
54.7, 62.9, 113.7, 125.5, 126.4, 126.6, 127.4, 127.9, 128.5, 128.6,
129.6, 130.0, 135.2, 135.3, 138.0, 158.2, 173.2.
Example 30
N-((4-Methylphenyl)methyl)-N-piperidin-4-yl)phenylacetamide
(26HCH78-1)
[0317] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by phenylacetyl
chloride (81 mg, 0.53 mmol). The reaction mixture was stirred at
room temperature. After 20 h, water (1 ml) was added. The mixture
was stirred for another 2 h, before diethyl ether (20 ml) was
added. The mixture was sequentially extracted with HCl (0.2 N,
2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and H.sub.2O (10 ml),
dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
material was dissolved in diethyl ether (2 ml) and HCl (4 M in
dioxane, 1 ml). The reaction mixture was stirred at room
temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by
dichloromethane (10 ml). The mixture was extracted with water
(2.times.10 ml), dried (Na.sub.2SO.sub.4), and filtered to give a
clear solution. The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 38
mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9, 26.9, 28.4,
41.0, 41.1, 44.0, 44.1, 44.4, 51.9, 54.4, 126.1, 126.7, 126.8,
126.9, 128.5, 128.7, 128.78, 128.81, 128.9, 129.4, 129.5, 134.9,
135.2, 135.6, 136.0, 136.3, 137.2, 172.8, 173.3.
Example 31
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl).sub.3-phenylpropionamide
(26HCH78-2)
[0318] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
44-methylphenyl)methyl)amino-pipe- ridine carboxylate (80 mg, 0.26
mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine
(0.11 ml, 2.4 eq.) followed by 3-phenylpropionyl chloride (0.078
ml, 0.53 mmol). The reaction mixture was stirred at room
temperature. After 20 h, water (1 ml) was added. The mixture was
stirred for another 2 h, before diethyl ether (20 ml) was added.
The mixture was sequentially extracted with HCl (0.2 N, 2.times.15
ml), NaOH (0.2 N, 2.times.15 ml), and H.sub.2O (10 ml), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude material
was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1
ml). The reaction mixture was stirred at room temperature. After 2
h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml).
The mixture was extracted with water (2.times.10 ml), dried
(Na.sub.2SO.sub.4), and filtered to give a clear solution. The
solution was added on to a column carrying strongly acidic cation
exchange resin (0.3 mmol/g resin), which was washed with methanol
(3.times.6 ml), and eluted with 10% NH.sub.3 in methanol, and
concentrated to give the title compound. Yield: 43 mg; .sup.13C-NMR
(CD.sub.3OD, rotamers): .delta. 19.9, 27.4, 29.0, 31.4, 31.7, 34.7,
35.7, 44.2, 44.3, 51.6, 54.2, 125.9, 126.07, 126.15, 126.8, 128.3,
128.4, 128.7, 128.8, 129.3, 135.1, 136.1, 136.2, 137.0, 141.1,
141.2, 173.9, 174.4.
Example 32
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)(phenylthio)acetamide
(26HCH78-3)
[0319] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by
(phenylthio)acetyl chloride (0.078 ml, 0.53 mmol). The reaction
mixture was stirred at room temperature. After 20 h, water (1 ml)
was added. The mixture was stirred for another 2 h, before diethyl
ether (20 ml) was added. The mixture was sequentially extracted
with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and
H.sub.2O (10 ml), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2
ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was
stirred at room temperature. After 2 h, NaOH (6 N. 1 ml) was added
followed by dichloromethane (10 ml). The mixture was extracted with
water (2.times.10 ml), dried (Na.sub.2SO.sub.4), and filtered to
give a clear solution. The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated to give the title compound.
Yield: 18 mg; HRMS (FAB.sup.+, NBA) (M+H).sup.+355.1841,
C.sub.21H.sub.21N.sub.2OS requires 355.1844; LC-MS:
(M+H).sup.+3550.1, t.sub.r 2.62 min.
Example 33
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)phenoxyacetamide
(26HCH784)
[0320] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by phenoxyacetyl
chloride (0.073 ml, 0.53 mmol). The reaction mixture was stirred at
room temperature. After 20 h, water (1 ml) was added. The mixture
was stirred for another 2 h, before diethyl ether (20 ml) was
added. The mixture was sequentially extracted with HCl (0.2 N,
2.times.15 ml), NaOH (0.2. N, 2.times.15 ml), and H.sub.2O (10 ml),
dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
material was dissolved in diethyl ether (2 ml) and HCl (4 M in
dioxane, 1 ml). The reaction mixture was stirred at room
temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by
dichloromethane (10 ml). The mixture was extracted with water
(2.times.10 ml), dried (Na.sub.2SO.sub.4), and filtered to give a
clear solution. The solution was added on to a column carrying
strongly acidic cation exchange resin (0.3 mmol/g resin), which was
washed with methanol (3.times.6 ml), and eluted with 10% NH.sub.3
in methanol, and concentrated to give the title compound. Yield: 24
mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9, 25.8, 27.4,
43.5, 43.7, 44.4, 51.9, 52.3, 66.9, 114.7, 114.8, 116.7, 117.0,
121.4, 123.6, 126.3, 126.8, 128.4, 128.9, 129.3, 129.5, 129.6,
131.0, 134.4, 136.1, 137.4, 158.3, 169.8, 170.1.
Example 34
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)acetamide
(26HCH78-5)
[0321] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by
4-chlorophenoxyacetyl chloride (0.082 ml, 0.53 mmol). The reaction
mixture was stirred at room temperature. After 20 h, water (1 ml)
was added. The mixture was stirred for another 2 h, before diethyl
ether (20 ml) was added. The mixture was sequentially extracted
with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and
H.sub.2O (10 ml), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2
ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was
stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added
followed by dichloromethane (10 ml). The mixture was extracted with
water (2.times.10 ml), dried (Na.sub.2SO.sub.4), and: filtered to
give a clear solution. The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated to give the title compound.
Yield: 21 mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9,
26.2, 27.8, 43.6, 43.9, 44.4, 52.2, 52.5, 67.0, 116.2, 116.4,
126.2, 126.3, 126.8, 128.6, 128.9, 129.1, 129.3, 129.5, 131.0,
134.4, 135.6, 136.4, 137.5, 157.1, 169.4, 169.7.
Example 35
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacetamide
(26HCH78-6)
[0322] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by
3-methoxyphenylacetyl chloride (97 mg, 0.53 mmol). The reaction
mixture was stirred at room temperature. After 20 h, water (1 ml)
was added. The mixture was stirred for another 2 h, before diethyl
ether (20 ml) was added. The mixture was sequentially extracted
with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and
H.sub.2O (10 ml), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2
ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was
stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added
followed by dichloromethane (10 ml). The mixture was extracted with
water (2.times.10 ml), dried, (Na.sub.2SO.sub.4), and filtered to
give a clear solution. The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated to give the title compound.
Yield: 26 mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9,
26.3, 27.7, 41.0, 43.7, 43.9, 44.4, 51.5, 53.8, 54.5, 54.6, 112.2,
112.6, 114.3, 114.5, 121.0, 121.2, 126.1, 126.8, 128.8, 129.4,
129.5, 129.8, 134.8, 136.0, 136.3, 136.5, 136.9, 137.2, 160.2,
160.3, 172.8, 173.2.
Example 36
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylacetamide
(26HCH78-7)
[0323] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by
4-fluorophenylacetyl chloride (0.072 ml, 0.53 mmol). The reaction
mixture was stirred at room temperature. After 20 h, water (1 ml)
was added. The mixture was stirred for another 2 h, before diethyl
ether (20 ml) was added. The mixture was sequentially extracted
with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and
H.sub.2O (10 ml), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2
ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was
stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added
followed by dichloromethane (10 ml). The mixture was extracted with
water (2.times.10 ml), dried (Na.sub.2SO.sub.4), and filtered to
give a clear solution. The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated to give the title compound.
Yield: 26 mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9,
26.1, 27.4, 39.7, 39.9, 43.5, 43.8, 44.4, 51.3, 53.4, 114.9, 115.1,
115.3, 126.1, 126.7, 128.5, 128.8, 129.4, 130.7, 130.8, 130.9,
131.0, 131.2, 131.6, 134.8, 136.0, 136.3, 137.2, 160.9, 163.3,
172.7, 173.2.
Example 37
N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-2,5-di-methoxyphenylacetam-
ide (26HCH78-8)
[0324] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by
2,5-di-methoxyphenylacetyl chloride (0.092 ml, 0.53 mmol). The
reaction mixture was stirred at room temperature. After 20 h, water
(1 ml) was added. The mixture was stirred for another 2 h, before
diethyl ether (20 ml) was added. The mixture was sequentially
extracted with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N. 2.times.15
ml), and H.sub.2O (10 ml), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2
ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was
stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added
followed by dichloromethane (10 ml). The mixture was extracted with
water (2.times.10 ml), dried (Na.sub.2SO.sub.4), and filtered to
give a clear solution. The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated to give the title compound.
36 mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 20.0, 26.5,
28.2, 35.1, 35.7, 44.0, 44.4, 51.6, 53.8, 54.99, 55.03, 55.2, 55.5,
111.4, 111.7, 112.4, 112.9, 116.6, 116.9, 124.98, 125.02, 126.1,
126.7, 128.8, 129.3, 135.0, 136.1, 136.3, 137.0, 151.3, 151.7,
153.9, 154.0, 173.1, 173.5.
Example 38
N-(4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-chlorophenylacetamide
(26HCH78-9)
[0325] To a solution of commercially available tert-butyl
4-oxo-1-piperidine carboxylate (1.75 g, 8.8 mmol) and
4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added
acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH.sub.3 in
methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture
was stirred for 1 h, before it was concentrated. Flash
chromatography in dichloromethane:methanol 10:1 gave tert-butyl
4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4
g, 98%. To a solution of tert-butyl
4-(4-methylphenyl)methyl)amino-pi- peridine carboxylate (80 mg,
0.26 mmol) in dichloromethane (1.8 ml) was added
diisopropylethylamine (0.11 ml, 2.4 eq.) followed by
4-chlorophenylacetyl chloride (99 mg, 0.53 mmol). The reaction
mixture was stirred at room temperature. After 20 h, water (1 ml)
was added. The mixture was stirred for another 2 h, before diethyl
ether (20 ml) was added. The mixture was sequentially extracted
with HCl (0.2 N, 2.times.15 ml), NaOH (0.2 N, 2.times.15 ml), and
H.sub.2O (10 ml), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2
ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was
stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added
followed by dichloromethane (10 ml). The mixture was extracted with
water (2.times.10 ml), dried (Na.sub.2SO.sub.4), and filtered to
give a clear solution. The solution was added on to a column
carrying strongly acidic cation exchange resin (0.3 mmol/g resin),
which was washed with methanol (3.times.6 ml), and eluted with 10%
NH.sub.3 in methanol, and concentrated to give the title compound.
Yield: 22 mg; .sup.13C-NMR (CD.sub.3OD, rotamers): .delta. 19.9,
26.3, 27.7, 39.9, 40.0, 43.6, 43.9, 44.4, 51.5, 53.6, 126.1, 126.7,
128.2, 128.4, 128.6, 128.9, 129.4, 129.6, 130.7, 130.9, 131.2,
131.6, 132.5, 132.7, 133.9, 134.1, 134.4, 134.8, 135.9, 136.3,
137.2, 172.4, 172.9.
Example 39
N-(4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N'-phenylmet-
hylcarbamide (26HCH50)
[0326] To a solution of 3-amino-1-phenylmethylpyrrolidine (353 mg,
2 mmol) and 4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20
ml) was added acetic acid in methanol (2 M, 6.7 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 3 ml). The mixture was stirred at
room temperature. After 24 h, water (5 ml) was added. The mixture
was stirred for another hour before concentrated. Flash
chromatography in dichloromethane/methano- l 10/1 gave
N-((4-methylphenyl)methyl)amino-1-phenylmethylpyrrolidine.
[0327] N-((4-Methylphenyl)methyl)amino-1-phenylmethylpyrrolidine
(35 mg, 0.125 mmol) was dissolved in dichloromethane (1.5 ml), and
benzylisocyanate (0.09 ml, 0.3 mmol) was added. The reaction
mixture was stirred at room temperature. After 48 h, the crude
reaction mixture was added on to a column carrying strongly acidic
cation exchange resin, which was washed with methanol (3.times.6
ml), and eluted with 10% NH.sub.3 in methanol, and concentrated to
give the title compound. Yield: 48 mg, 92%; .sup.13C-NMR
(CD.sub.3OD): .delta. 20.0, 29.7, 44.2, 51.3, 53.4, 56.4, 57.8,
58.7, 126.8, 127.1, 127.3, 127.6, 128.3, 128.4, 128.9, 129.1,
135.9, 136.8, 140.3, 158.5.
Example 40
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyph-
enylacetamide (26HCH52)
[0328] To a solution of 3-amino-1-phenylmethylpyrrolidine (353 mg,
2 mmol) and 4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20
ml) was added acetic acid in methanol (2 M, 6.7 ml) followed by
NaCNBH.sub.3 in methanol (0.3 M, 3 ml). The mixture was stirred at
room temperature. After 24 h, water (5 ml) was added. The mixture
was stirred for another hour before concentrated. Flash
chromatography in dichloromethane/methano- l 10/1 gave
N-((4-methylphenyl)methyl)amino-1-phenylmethylpyrrolidine.
[0329] To a solution of
N-((4-Methylphenyl)methyl)amino-1-phenylmethylpyrr- olidine (35 mg,
0.125 mmol), diisopropylethylamine (0.14 ml) in dichloromethane
(1.5 ml) was added 4-methoxyphenylacetyl chloride (0.1 ml, 0.5
mmol). The reaction mixture was stirred at room temperature. After
48 h, the crude reaction mixture was concentrated and redissolved
in methanol. The solution was added on to a column carrying
strongly acidic cation exchange resin, which was washed with
methanol (3.times.6 ml), and eluted with 10% NH.sub.3 in methanol,
and concentrated. Flash chromatography in dichloromethane/methanol
10/1 gave the title compound. Yield: 20 mg, 38%; .sup.13C-NMR
(CD.sub.3OD): .delta. 21.3, 30.2, 40.8, 47.8, 53.6, 53.9, 55.5,
57.5, 60.2, 114.4, 125.7, 127.0, 127.1, 127.3, 127.4, 128.4, 128.5,
128.7, 128.9, 129.2, 129.8, 130.0, 135.9, 137.0, 158.6.
Example 41
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphe-
nylthioacetamide (RO)
[0330] A mixture of
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidi-
n-4-yl)-(4-methoxyphenylmethyl)acetamide (20 mg, 0.045 mmol) and
Lawesson's reagent (25 mg, 0.062 mmol), was taken in a glass vial
and mixed thoroughly with magnetic stirbars. The glass vial was
then irradiated in a microwave oven (900 W, Whirlpool M401) for 8
min. Upon completion of the reaction, the yellow-colored material
was transferred to an ion-exchange column with the aid of methanol
(2 ml). The ion-exchange column was subsequently washed with
CH.sub.2Cl.sub.2 (2 ml) and methanol (2 ml) and the product was
thereafter eluted from the ion-exchange column (10% NH.sub.3 in
methanol, 2 ml) to give
N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyph-
enylmethyl thioacetamide (20 mg, 97%) as a white solid; LC-MS:
(M+H).sup.+459, t.sub.r 9.60 min; TLC (CH.sub.2Cl.sub.2/methanol
20:1) R.sub.f=0.38.
Example 42
Receptor Selection and Amplification (R-SAT) Assays
[0331] The functional receptor assay, Receptor Selection and
Amplification Technology (R-SAT), was used (with minor
modifications from that previously described U.S. Pat. No.
5,707,798) to screen compounds for efficacy at the 5-HT2A receptor.
Briefly, NIH3T3 cells were grown in 96 well tissue culture plates
to 70-80% confluence. Cells were transfected for 12-16 hours with
plasmid DNAs using superfect (Qiagen Inc.) as per manufacture'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 in U.S. Pat. No.
5,707,798. The 5HT2A receptor gene was amplified by nested PCR from
brain cDNA using the oligodeoxynucleotides based on the published
sequence (see Saltzman et. al. Biochem. Biophys. Res. Comm.
181:1469-78 (1991)). Large-scale transfections, cells were
transfected for 12-16 hours, 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
CO2 for five days. Media was then removed from the plates and
marker gene activity was measured by the addition of the
beta-galactosidase substrate 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 5HT2A). pIC50 is the negative
of the log(IC50), where IC50 is the calculated concentration in
Molar that produces 50% maximal repression. The results obtained
for six compounds of the invention are presented in the following
table.
1TABLE 1 Efficacy of Compounds at the 5-HT2A Receptor Efficacy
pIC50 Compound (average) Efficacy(stdev) (average) pIC50 (stdev)
26HCH52 98 5.0 7.31 0.16 26HCH66-03 76 13.3 7.42 0.01 26HCH66-05
109 3.0 7.55 0.15 26HCH80-2 89 4.6 7.78 0.17 26HCH80-7 87 3.7 7.70
0.26 26HCH80-10 91 4.9 7.21 0.05
Example 43
In Vitro Efficacy of 26HCH17 as an Inverse Agonist at the 5HT2A
Receptor
[0332] The graph shown in FIG. 1 represents the data obtained from
a dose response analysis of 26HCH17 and ritanserin as 5-HT2A
receptor inverse agonists. Briefly, the 5-HT2A receptor, and the
alpha subunit of the guanine nucleotide binding protein Gq were
transiently transfected into NIH3T3 cells and assayed using the
functional receptor assay, Receptor Selection and Amplification
Technology (R-SAT) essentially as disclosed in U.S. Pat. No.
5,707,798. Each compound was screened at seven serially diluted
concentrations in triplicate. Data were analyzed using least
squares fit analysis with GraphPad Prism (San Diego, Calif.), and
are reported normalized to percent response.
Example 44
Selectivity Profile of Inverse Agonist 26HCH16D
[0333] R-SAT assays (as described in Example 42) were carried out
with cells transfected with receptors (listed below) to determine
the receptor selectivity profile for compound 26HCH16D. 5HT2A
inverse agonist data (IC50 nM; % efficacy) were derived from
detailed dose response curves (7 points in triplicate). All other
data (initial concentration at which at least 30% efficacy
observed; actual efficacy figure) derived from the 4 dose profiling
protocol in which compounds were tested at 4 doses in duplicate.
nr=activity less than 30% at all doses tested (3, 30, 300, 3000
nM), therefore EC50/IC50 greater than 3000 nM). The results are
presented in the following table.
2TABLE 2 Profile of 5-HT2A Inverse Agonist 26HCH16D Receptor
Efficacy 5HT2A (human) Agonist nr Inverse Agonist 0.9 nM; 79% 5HT2B
(human) Agonist nr Antagonist 3000 nM; 60% 5HT2C (human) Agonist nr
Inverse Agonist 3000 nM; 79% 5HT1A (human) Agonist nr Antagonist nr
5HT1A (rat) Antagonist nr 5HT1E (human) Agonist nr D2 (human)
Agonist nr Antagonist 3000 nM; 73% H1 (human) Agonist nr Antagonist
3000 nM; 30% alpha1a/D (rat) Agonist nr Antagonist nr alpha1b/B
(hamster) Agonist nr Antagonist nr alpha1c/A (human) Agonist nr
Antagonist 3000 nM; 46% alpha2A (human) Agonist nr Antagonist nr
alpha2B (human) Agonist nr Antagonist nr alpha2C (human) Agonist nr
Antagonist nr m1 (human) Agonist nr Antagonist nr
[0334] As indicated above, 26HCH16D is a highly selective 5-HT2A
inverse agonist
[0335] General LC-MS Procedure for Working Examples ELH01-46,
MBT01-14 and AKU01-38.
[0336] In the following examples, HPLC/MS analyses were performed
using either of two general methods (Method A or Method B). The
t.sub.r values reported below were obtained using, one of these
procedures, as indicated in the specific examples.
[0337] The methods were as follows:
[0338] Method A: Agilent HP1100 HPLC/MSD.
[0339] G1312A Binary pump, G1313A Autosampler, G1316A Column
compartment, G1315A Diode array detector (190-450 mm), 1946A MSD,
electrospray ionization.
[0340] Chromatography:
[0341] 8 mM Ammoniumacetate in Water/Acetonitrile.
[0342] Gradient start at 70% org. up to 100% org. over 12 min, down
to 70% org. over 0.5 min. held for 3.5 min. Total runtime 16 mL
Flowrate 1 ml/min
[0343] Column, Phenomenex Luna C18(2) 3 um 75.times.4.6 mm.
[0344] MS Parameters:
[0345] Drying gas, 10 l/min. Nebulizer pressure, 40 psig. Gas temp,
350 C. VCap, 4000.
[0346] Method B: Waters/Micromass HPLC/MS
[0347] 600 LC-pump, 2700 Sample manager, 2487 Dual absorbance
detector (channel A--205 nm, channel B--235 nm), Micromass
ZMD-mass-spectrometer, electrospray ionization.
[0348] Chromatography:
[0349] 0.15% TFA in Water/Acetonitrile.
[0350] Gradient start at 30% org. up to 100% org. over 10 min, held
for 3 min. down to 30% org. over 0.5 min, held for 4.5 min. Total
run time 18 min. Flowrate, 1 ml/min.
[0351] Column, Symmetry C18, 5 .mu.m, 4.6.times.50 mm. or
[0352] 10 mM ammoniumacetate in water/acetonitrile.
[0353] Gradient start at 30% org. for 2.5 min, up to 100% org. over
10 min, held for 9 min, down to 30% org. over 0.5 min, held for 5
min. Total run time 27 min. Flowrate, 1 ml/mini.
[0354] Column: Phenomenex Synergi C12, 4 .mu.m, 4.6.times.50
mm.
[0355] MS Parameters:
[0356] Desolvation gas, 404 l/H. Capillary, 5.3 kV. Cone, 36V.
Extractor, 3V. Source block temp, 130 C. Desolvation temp, 250
C.
Example 45
2-(4-methoxyphenyl)-N-(piperdin-4-yl) acetamide (50ELH87)
[0357] Reaction Step 1: N-trifluoroacetyl-4-piperidone
(50ELH84)
[0358] 4-Piperidone hydrochloride monohydrate (4.0 g, 26 mmol, 1.0
eq) was dissolved in 130 ml of dichloromethane. After addition of
triethylamine (8.66 g, 3.3 eq) the reaction mixture was stirred for
10 min. The mixture was cooled on an ice-bath (0.degree. C.).
Trifluoroacetic anhydride (12.0 g, 2.2 eq) was added dropwise under
stirring. After 2 hours the reaction was quenched by addition of
distilled water. The aqueous phase was extracted twice with
dichloromethane. The combined organic layers were collected and
dried with sodium sulfate. Concentration afforded
N-trifluoroacetyl-4-piperidone.
[0359] Reaction Step 2:
4-(4-Methylbenzylamino)-1-(trifluoroacetyl)piperid- in
(50ELH85)
[0360] Methanol (150 ml) was added to an Erlenmeyer flask and
acetic acid was added under stirring until pH 5.
4-Methylbenzylamine (3.14 g, 25.9 mmol) and
N-trifluoroacetyl-4-piperidone (from reaction step 1) (5.065 g,
25.9 mmol) were added to a 250 ml round-bottomed flask and
dissolved in the methanol/acetic acid (150 ml) solution previously
made. The reaction mixture was stirred for 5 min and NaCNBH.sub.3
(2.46 g, 38.9 mmol) was added slowly under stirring. After 20 hours
the reaction was concentrated and transferred to a separatory
funnel containing dichloromethane and distilled water. The aqueous
phase was made basic by addition of Na.sub.2CO.sub.3. The aqueous
phase was extracted twice with dichloromethane. The combined
organic layers were collected and dried with Na.sub.2SO.sub.4.
Concentration afforded, 4-(4-methylbenzylamine)-1--
(trifluoroacetyl)piperidine. UV/MS 60/53 (M.sup.+301), t.sub.r (A,
MS) 3.267.
[0361] Reaction Step 3:
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-triflu-
oroacetylpiperidin-4-yl)acetamide (50ELH86)
[0362] The product from reaction step 2 (7.8 g, 25.9 mmol) was
dissolved in 100 ml of dichloromethane and stirred while
4-methoxyphenylacetyl chloride (4.8 g, 25.9 mmol) was added. After
4 hours, heptane was added whereupon the product precipitated as
the hydrochloride salt. The solvent was removed by evaporation. The
crude material was purified by flash chromatography EtOAc/Heptane
(1:2) Yield (overall: Reaction steps 1+2+3) 3.912 g (34%), UV/MS
91/58 (M+449), t.sub.r (A, MS) 4.319. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 6.80-7.15 (Ar, 4H), 4.64 (brt, 1H), 4.4 (s,
2H), 3.95 (d, 2H), 3.72 (s, 3H), 3.50 (s, 2H), 3.09 (t, 2H), 2.7
(t, 2H), 2.32 (s, 3H), 1.75 (brt, 2H). .sup.13C-NMR 172.5; 158.8;
137.4; 134.9; 129.9; 129.9; 129.8; 127.1; 125.8; 114.3; 55.4; 52.2;
47.3; 45.3; 43.4.40.6; 30.1; 29.2; 21.2.
[0363] Reaction Step 4:
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidi- n-4-yl)
acetamide (50ELH87)
[0364] The product from reaction step 3 (3.9 g, 8.7 mmol) was
dissolved in methanol (12 ml). In a 250 ml round bottom flask a
saturated solution of potassium carbonate in methanol was prepared.
To this solution, the
2-(4-methoxyphenyl)-K-(4-methylbenzyl)-N-(N-trifluoroacetpiperidin-4-yl)a-
cetamide solution was added under stirring. After 4 hours, the
solution was concentrated and the remaining solid taken upin base
and dichloromethane. The combined organic layers were dried with
sodium sulfate and concentrated. UV/MS 91/72 (M.sup.+353), t, (A,
MS) 2.210.
[0365] The corresponding hydrochloride salt was also prepared, by
dissolving the free base in dichloromethane (1 ml) and HCl (1 eq. 2
M HCl in ether) was added with stirring. The salt was precipitated
by addition of the dichloromethane solution into heptane.
Concentration on the rotary evaporator returned the product is
white crystals.
Example 46
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(50ELH27)
[0366] Reaction Step 1: 4-(4-Methylbenzylamino)-1-methylpiperidine
(50ELH25)
[0367] Methanol (50 ml) was added to an Erlenmeyer flask and acetic
acid was added under stirring until pH 5. Methylbenzylamine (1.0 g,
8.8 mmol) and 1-Methyl-4-piperidone (1.1 g, 8.8 mmol) were added to
a 100 ml round-bottomed flask and dissolved in the methanol/acetic
acid (40 ml) solution previously made. The reaction mixture was
stirred for 5 min and NaCNBH.sub.3 (0.83 g, 13.2 mmol) was added
slowly under stirring. After 20 hours the reaction was concentrated
and transferred to a separatory funnel containing dichloromethane
and distilled water. The aqueous phase was made basic by addition
of Na.sub.2CO.sub.3. The aqueous phase was extracted twice with
dichloromethane. The combined organic layers were collected and
dried with Na.sub.2SO.sub.4. Concentration afforded the title
compound. Yield (crude): 98%. UV/MS 89/88 (M.sup.+353), t.sub.r (A,
MS) 3.982.
[0368] Reaction Step 2:
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methyl- piperidin-4-yl)
acetamide (50ELH27)
[0369] The product from reaction step 1 (1.9 g, 8.7 mmol) was
dissolved in 40 ml of dichloromethane and stirred while
4-methoxyphenylacetylchloride (1.606 g, 8.7 mmol) was added. After
4 hours, heptane was added whereupon the product precipitated as
the hydrochloride salt. The solvent was removed by evaporation. The
crude material was purified by flash chromatography first eluting
with 10% MeOH in CH.sub.2Cl.sub.2 and thereafter eluting with 0-20%
MeOH in CH.sub.2Cl.sub.2 and 5%0 NEt.sub.3. Yield (overall:
Reaction steps 1+2): 77%. UV/MS: 100/100 (M+367), t, (A, MS) 4.359,
R.sub.f 0.15 (2% MeOH in CH.sub.2Cl.sub.2). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 12.6 (s, 1H), 7.16 (d, J=7.0 Hz, 2H), 7.10 (d,
J=7.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 4.87
(tt, J=11.0, 4.0 Hz, 1H), 4.53 ppm (s, 2H), 3.78 (s, 3H), 3.55 (s,
2H), 3.42 (brd, J=11.0 Hz, 2H), 2.80 (brq, J=1.0 Hz, 2H), 2.7 (d,
J<0.0 Hz, 3H), 2.42 (dq, J=13.0, 3.0 Hz, 2H), 2.34 (s, 3H), 1.78
(brd, J=13.0 Hz, 2H). .sup.13C-NMR 173.1; 158.9; 137.4; 134.8;
129.9; 126.7; 125.8; 114.4; 76.9; 55.5; 54.6; 48.8; 43.7; 40.5;
26.4; 21.2
Example 47
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclohexylmethylpiperidin-4-yl-
)acetamide (42ELH45)
[0370] 50ELH87 (the hydrochloride salt) (0.5 g, 1.29 mmol, 1.0 eq)
was dissolved in ethanol (100 ml). Cyclohexanecarboxaldehyde (2.5
g, 20 eq.) was added followed by addition of sodium borohydride
(0.084 g, 2.0 eq.). The reaction was stirred for 36 h and acetic
acid (3 ml) was added. The reaction was stirred for additionally 2
h and extracted with sodium hydrogen carbonate (3 times) and
dichloromethane. The organic layers were dried with sodium sulfate
and concentrated. The product was purified by flash chromatography
(1-10% MeOH in CH.sub.2Cl.sub.2). The resulting product was
dissolved in ether (20 ml) and MeOH (added dropwise until
dissolved) and HCl (1 eq. 2 M HCl in ether) was added under
stirring. The hydrochloride salt of
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclohe-
xylmethylpiperidin-4-yl) acetamide precipitated and the white
crystals were filtered. Yield 80 mg (16%), UV/MS 100/100
(M.sup.+449), r.sub.t (A, MS) 7.105, mp 133-135.degree. C., R.sub.f
0.25 (2% MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 11.9 (brs, 1H), 7.12 (q, 4H), 7.02 (d, 2H), 6.80 (d, 2H),
4.87 (m, 1H), 4.58 (s, 2H), 3.77 (s, 3H), 3.55 (s, 2H), 3.48 (m,
2H), 2.70 (m, 4H), 2.31 (s, 3H), 1.91 (d, 2H), 1.75 (m, 3H), 1.64
(d, 1H), 1.22 (d, 2H), 1.13 (tt, 2H), 1.02 (brq, 2H). .sup.13C-NMR
173.1; 158.8; 137.2; 135.1; 129.9; 129.8; 126.8; 125.8; 114.4;
64.1; 55.5; 53.4; 49.2; 46.5; 40.4; 33.9; 25.9; 25.8; 25.7;
21.2.
Example 48
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide
(42ELH80)
[0371] 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq) was dissolved in
acetonitrile (15 ml) and ethyl bromide (0.232 g, 3.0 eq.) was added
under stirring. After 2 min Hunkgs base (0.084 g, 10.0 eq.) was
added. After 36 hours, the solution was extracted with sodium
hydrogen carbonate solution and dichloromethane (3 times). The
organic layers were dried with sodium sulfate and concentrated
yielding a yellow oil. The product was purified by flash
chromatography (2% MeOH in CH.sub.2Cl.sub.2). The resulting product
was dissolved in dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in
ether) was added under stirring. The salt was precipitated by
addition of the dichloromethane solution into heptane.
Concentrationon the rotary evaporator gave the product as white
crystals. Yield 170 mg (63%), UV/MS 98/95 (M+381), mp
153-155.degree. C., r.sub.t (A, MS) 3.033, R.sub.f 0.35 (3%
MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
12.2 (s, 1H), 7.15 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.82 (d,
2H), 4.89 (m, 11H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (s, 2H), 3.50
(d, 2H), 2.90 (m, 1H), 2.7 (brq, 2H), 2.45 (m, 2H), 2.34 (s, 3H),
1.80 (d, 21), 1.44 (t, 3H). .sup.3C-NMR 173.1; 158.9; 137.3; 134.9;
129.9; 125.8; 114.4; 55.5; 52.3; 52.0; 49.2; 46.5; 40.5; 26.2;
21.2; 9.5.
Example 49
2-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide
(42ELH85).
[0372] This compound was prepared similarly to 50ELH27
[0373] Reaction-Step 1: (42ELH84)
[0374] Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol,
1.0 eq.), 4-chlorobenzylamine (0.626 g, 1.0 eq.), sodium
cyanoborohydride (0.279 g, 1.5 eq.).
[0375] Reaction-Step 2: (42ELH85)
[0376] Starting materials: 42ELH84, 4-methoxyphenylacetylchloride
(0.774 g, 1.0 eq.).
[0377] The procedure was analogous to 50ELH27, but the product was
purified by ion-exchange chromatography followed by HPLC. The
hydrochloride salt was made by dissolving the free base in
dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether) was added
under stirring. The salt was precipitated by addition of the
dichloromethane solution into heptane followed by concentration on
the rotary evaporator.
[0378] Product: White crystals. UV/MS 98/97 (M.sup.+387), r.sub.t
(A, MS) 2.953. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.6 (s,
1H), 7.35 (d, 2H), 7.18 (d, 2H), 7.05 (d, 2H), 6.82 (d, 211), 4.89
(m, 1H), 4.55 (s, 2H), 3.80 (s, 3H), 3.55 (s, 2H), 3.45 (brs, 2H),
2.80 (brs, 2H), 2.72 (s, 3H), 2.25 (brs, 3H), 1.80 (brs, 2H).
.sup.3C-NMR 173.0; 158.9; 136.5; 133.6; 129.8; 129.4; 127.3; 126.3;
114.5; 55.5; 54.6; 48.7; 46.3; 43.7; 40.5; 26.3.
[0379]
50-244-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(t-isopropylpiperidin-4-y-
l) acetamide (42ELH79).
[0380] Procedure as 42ELH80
[0381] Starting materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq.),
isopropylbromide (0.262 g, 3.0 eq.).
[0382] Product: Yield 130 mg (46%), UV/MS 100/100 (M.sup.+395),
r.sub.t (A, MS) 3.360. .sup.1H-NMR (400 MHz, CDCl.sub.3) & 12.0
(s, 1H), 7.15 (d, 2H), 7.10 (d, 2H), 7.05 (d, 2H), 6.82 (d, 2H),
4.87 (m, 1H), 4.60 (s, 2H), 3.79 (s, 3H), 3.57 (s, 2H), 3.38 (brd,
3H), 2.79 (q, 2H), 2.63 (q, 2H), 2.34 (s, 3H), 1.80 (d, 2H), 1.39
(d, 6H). .sup.13C-NMR 173.1; 158.9; 137.3; 135.1; 129.8; 126.8;
125.8; 114.4; 57.9; 49.4; 48.2; 46.5; 40.5; 25.9; 21.2; 16.9.
Example 51
2-(4-Methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl) acetamide
(42ELH89) (As Starting Material in Other Reactions, Used
Unpurified)
[0383] Procedure as 50ELH27.
[0384] Reaction Step 1: N-Trifluoroacetyl-4-piperidone
(42ELH86)
[0385] Starting materials: 4-Piperidone hydrochloride monohydrate
(2.0 g, 13 mmol, 1.0 eq), trifluoroacetic anhydride (6.0, 2.2 eq.).
TLC showed full conversion.
[0386] Product: R.sub.f 0.9 (10% MeOH/CH.sub.2Cl.sub.2).
[0387] Reaction step 2:
4-(4-Chlorobenzylamino)-1-(trifluoroacetyl)piperid- in
(42ELH87)
[0388] Starting materials: 42ELH86 (2.5 g, 12.8 mmol, 1.0 eq.),
4-Chlorobenzylamine (1.8 g, 1.0 eq.)
[0389] Reaction Step 3: 2-(4-Methoxyphenyl)-N-(4-chlorobenzyl)-N-(1
trifluoroacetylpiperidin-4-yl)acetamide (42ELH88)
[0390] Starting materials: 42ELH87 (4.0 g, 12.5 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (2.31 g, 1.0 eq.)
[0391] Reaction Step 4:
2-(4-Methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidi- n-4-yl)
acetamide (42ELH89)
[0392] Product: Yield: 2 g (57%), UV/MS 80/82 (M+373), R.sub.f 0.2
(50% EtOAc/Heptane).
Example 52
2-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-1-cyclopentylpiperidin-4-yl)acetam-
ide (42ELH91).
[0393] Procedure as 42ELH80, but the product was purified by HPLC.
The acidic eluent was made basic with sodium carbonate and
extracted with dichloromethane (3 times). The combined organic
layers were collected and dried with sodium sulfate and
concentrated. The remaining product was dissolved in 1 ml of
dichloromethane and HCl (1 eq. 2 M HCl in ether) was added under
stirring. This solution was added drop-wise to a large excess of
n-heptane to make the hydrochloride precipitate. The solvent was
evaporated off to form white crystals of
24-methoxyphenyl)-N-(4-chlorbenz-
yl)-N-(1-cyclopentylpiperidin-4-yl)acetamide, hydrochloride.
[0394] Starting materials: 42ELH89 (0.25 g, 0.67 mmol, 1.0 eq.),
cyclopentylbromide (0.3, 3.0 eq.)
[0395] Product: Yield: 211.2 mg (76%). Purification by
ion-exchange: UV/MS 90/98. Purification by HPLC UV/MS 100/100
(M.sup.+ 441), R.sub.f 0.2 (3% MeOH/CH.sub.2Cl.sub.2), r.sub.t (A,
MS) 4.067. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.2 (brs,
1H), 7.32 (d, 2H), 7.17 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.90
(brt, 1H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (brd, 2H), 3.54 (s,
2H), 3.14 (brq, 2H), 2.58 (brq, 2H), 2.04 (m, 4H), 1.89 (m, 41),
1.75 (brd, 2H). 13 C-NMR 173.0; 158.9; 133.5; 129.8; 129.3; 127.3;
126.4; 114.5; 68.4; 55.5; 51.9; 49.1; 46.2; 40.5; 28.5; 26.0;
23.8.
Example 53
2-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetami-
de (42ELH90).
[0396] 42ELH89 (0.25 g, 0.67 mmol, 1.0 eq) was transferred to a 4
ml vial and dissolved in acetonitrile (2 ml). Isopropyl bromide
(0.25 g, 3.0 eq.) was added along with Hunigs base (0.87 g, 10.0
eq.). The vial was sealed and shaken for 4 days at 60.degree. C.
The reaction mixture was transferred to a separatory funnel with
distilled water and CH.sub.2Cl.sub.2. The aqueous phase was made
basic with sodium hydrogen carbonate and extracted with
dichloromethane (3 times). The organic layers were collected and
dried with sodium sulfate and concentrated, this resulted in a
yellow oil. The product was purified by flash chromatography (3%
MeOH in CH.sub.2Cl.sub.2). The resulting product was dissolved in
dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether) was added
under stirring. The salt precipitated by addition of the
dichloromethane solution into heptane. Concentration on the rotary
evaporator returned the product as white crystals. Yield 101.2 mg
(63%), UV/MS 94/96 (M+415), R.sub.f 0.25 (3%
MeOH/CH.sub.2Cl.sub.2)
[0397] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.05 (brs, 1H),
7.36 (d, 2H), 7.18 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.88 (m,
1H), 4.60 (s, 2H), 3.79 (s, 3H), 3.55 (d, 2H), 3.36 (d, 3H), 2.80
(brq, 2H), 2.65 (brq, 2H), 1.76 (brd, 2H), 1.39 (d, 6H).
.sup.13C-NMR 173.0; 159.0; 137.0; 136.0; 129.7; 129.3; 127.4;
126.4; 114.5; 57.9; 55.5; 49.2; 48.2; 46.2; 40.5; 25.8; 16.9.
Example 54
2-(Phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(50ELH14b)
[0398] Procedure as for 50ELH27. Purification was done by HPLC. The
hydrochloride salt was made by dissolving the free-base in
dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether) was added
under stirring. The salt was precipitated by addition of the
dichloromethane solution into heptane followed by
concentration.
[0399] Reaction-Step 1:
4-(4-Triflouromethylbenzylamino)-1-methylpiperidin (50ELH2).
[0400] Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0
mmol, 1.0 eq.), 4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.).
[0401] Product: UV/MS 80/92 (M.sup.+273).
[0402] Reaction-Step 2:
2-(Phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methyl-
piperidin-4-yl)acetamide (50ELH14b).
[0403] Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.),
phenylacetylchloride (0.068 g, 1.0 eq.).
[0404] Product: UV/MS 100/97 (M.sup.+ 390), r.sub.t (A, MS) 3.797,
R.sub.f 0.3 (50% MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR (400 MHz,
CDCl.sub.3, rotamers 54/46) .delta. 7.52 (d, 2H), 7.42 (d, 2H),
7.12-7.30 (m, 4H), 4.63 and 3.74 (2m, 1H), 4.38 (brs, 2H), 3.80 and
3.50 (2s, 3H), 3.31 and 2.78 (2d, 2H), 2.33 and 2.18 (2s, 2H), 2.24
and 1.65-1.90 (t and m, 4H), 1.60 and 1.22 (2d, 2H), 1.
.sup.13C-NMR 172.3; 171.8; 143.9; 135.1; 134.8; 129.1; 129.0;
128.9; 128.7; 127.4; 127.3; 127.2; 126.3; 126.1; 126.0; 56.0; 55.2;
54.9; 50.9; 46.8; 45.2; 44.9; 42.2; 41.7; 30.6; 28.4.
Example 55
2-(4-Fluorophenyl)-N-4-trifluoromethylbenzyl)-N-(1-methylpiperidinyl)aceta-
mide (50ELH14c)
[0405] Procedure as 50ELH14B.
[0406] Reaction-Step 2:
2-(4-Fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(-
1-methylpipendin-4-yl)acetamide (50ELH14c).
[0407] Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.),
4-fluorophenylacetylchloride (0.076 g, 1.0 eq.).
[0408] Product: Yield 69.7 mg (36%), UV/MS 100/98 (M+409), r.sub.t
(A, MS) 3.839, R.sub.f 0.3 (5% MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR
(400 MHz, DMSO, rotamers 65/35) .delta. 10.80 and 10.60 (2s, 1H),
7.71 and 7.62 (2d, 2H), 7.47 and 7.38 (2d, 2H), 7.00-7.36 (t and m,
411), 4.70 and 4.50 (2s, 2H), 4.30 (m, 10), 3.93 and 3.56 (2s, 2H),
3.34 (s, 2H), 3.00 (brq, 2H), 2.64 (s, 3H), 2.08 (m, 2H), 1.68 and
1.58 (2d, 2H). .sup.13C-NMR 176.8; 176.4; 167.6; 165.3; 150.0;
149.0; 136.6; 132.5; 131.0; 130.5; 120.6; 120.5; 120.5; 120.4;
58.1; 58.0; 57.0; 54.5; 52.0; 49.3; 47.6; 45.0; 32.4; 31.4.
Example 56
2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)-
acetamide (50ELH14d)
[0409] Procedure as 50ELH14B.
[0410] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl-N-(-
1-methylpiperidin-4-yl acetamide (50ELH14d).
[0411] Starting materials: 50ELH2 (0.15 g, 0.55 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.1 g, 1.0 eq.).
[0412] Product: Yield 57.5 mg (29%), UV/MS 99/100 (M.sup.+ 421),
r.sub.t (B, MS) 6.30, R.sub.f 0.25 (3% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.4 (brs, 1H), 7.55 (d,
2H), 7.28 (d, 2H), 6.96 (d, 2H), 4.84 (brt, 1H), 4.59 (s, 2H), 3.72
(s, 3H), 3.46 (s, 2H), 3.38 (d, 2H), 2.78 (q, 2H), 2.64 (s, 3H),
2.38 (q, 2H), 1.70 (d, 2H). .sup.13C-NMR 173.0; 159.0; 142.3;
130.0; 129.8; 126.3; 126.2; 114.7; 114.5; 55.5; 54.4; 48.7; 46.5;
43.6; 40.6; 26.3.
Example 57
2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperid-
in-4-yl)acetamide (50ELH14a)
[0413] Procedure as 50ELH14B.
[0414] Reaction-Step 2:
2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbe-
nzyl)-N-(1-methylpiperidin-4-yl)acetamide (SOELH14a).
[0415] Starting materials: SOELH2 (0.12 g, 0.44 mmol, 1.0 eq.),
4-trifluoromethylphenylacetylchloride (0.1 g, 1.0 eq.).
[0416] Product: Yield 92.6 mg (42%), UV/MS 89/93 (M.sup.+ 458),
r.sub.t (A, MS) 4.211, R.sub.f 0.3 (5% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.7 (brs, 1H), 7.56 (d,
2H), 7.48 (d, 2H), 7.17 (d, 2H), 4.86 (m, 1H), 4.63 (s, 2H), 3.58
(s, 3H), 3.40 (d, 2H), 2.75 (q, 2H), 2.65 (d, 3H), 2.46 (dq, 2H),
1.73 (brs, 2H). .sup.13C-NMR 171.8; 141.9; 138.4; 129.4; 127.9;
126.3; 126.3; 126.2; 125.9; 125.8; 54.4; 48.8; 46.6; 43.6; 40.9;
26.2.
Example 58
2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(50ELH6) Procedure as 50ELH14B.
[0417] Reaction-Step 1: 4-(4-Fluorobenzylamino)-1-methylpiperidine
(50ELH4).
[0418] Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0
mmol, 1.0 eq.), 4-fluorobenzylamine (1.25 g, 1.0 eq.).
[0419] Product: Yield 2.154 g (97%), UV/MS 79/89 (M.sup.+ 223).
[0420] Reaction-Step 2:
2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylp-
iperidin-4-yl)acetamide (50ELH14a).
[0421] Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.),
4-fluorophenylacetylchloride (0.096 g, 1.0 eq.).
[0422] Product: Yield 57 mg (29%), UV/MS 100/100 (M.sup.+ 359),
r.sub.t (A, MS) 3.763, R.sub.f 0.25 (3% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.6 (brs, 1H), 7.2 (dd,
2H), 7.06 (m, 4H), 6.98 (t, 2H), 4.88 (tt, 1H), 4.58 (s, 41H), 3.45
(d, 2H), 2.81 (q, 2H), 2.72 (d, 3H), 2.48 (brq, 2H), 1.78 (brs,
2H). .sup.13C-NMR 172.5; 163.4; 160.8; 133.4; 130.6; 130.2; 127.5;
127.4; 116.3; 116.1; 115.9; 115.7; 54.5; 48.8; 46.2; 43.6; 40.3;
26.3.
Example 59
2-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(50ELH8).
[0423] Procedure as 50ELH14B
[0424] Reaction-Step 2:
[0425] Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.1 g, 1.0 eq.).
[0426] Product: Yield 54 g (26%), UV/MS 100/100 (M.sup.+ 371),
r.sub.t (A, MS) 3.257, R.sub.f 0.25 (3% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.2 (brs, 1H), 7.12 (m,
2H), 6.97 (m, 4H), 6.75 (d, 2H), 4.80 (brt, 1H), 4.49 (s, 2H), 3.71
(s, 3H), 3.47 (s, 2H), 3.37 (d, 2H), 2.8 (q, 2H), 2.64 (s, 3H),
2.35 (q, 2H), 1.69 (d, 2H). .sup.13C-NMR 173.0; 163.5; 161.1;
158.9; 133.7; 133.6; 129.8; 127.6; 127.5; 126.5; 116.2; 116.0;
114.6; 114.5; 55.5; 54.4; 48.8; 46.2; 43.6; 40.5; 26.4.
Example 60
2-(Phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide
(50ELH10)
[0427] Procedure as 50ELH14B.
[0428] Reaction-Step 2:
2-(Phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin- -4-yl)
acetamide (50ELH10).
[0429] Starting materials: 50ELH4 (0.13 g, 0.59 mmol, 1.0 eq.),
phenylacetylchloride (0.091 g, 1.0 eq.).
[0430] Product: UV/MS 100/94 (M.sup.+ 341), r.sub.t (A, MS) 3.127,
R.sub.f 0.25 (3% MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR (400 MHz,
DMSO, rotamers 54/56) .delta. 12.38 (brs, 1H), 7.35-7.00 (m, 9H),
4.55 and 4.40 (2s, 2H), 4.50 and 4.25 (brt, 1H), 3.91 and 3.56 (2s,
2H), 3.30 (Hidden under water signal)(2H), 2.98 (d, 2H), 2.64 (s,
3H), 2.09 (brt, 2H), 1.66 and 1.45 (2brd, 2H). .sup.13C-NMR 171.9;
171.6; 162.8; 160.4; 136.5; 136.2; 135.4; 129.9; 129.7; 129.5;
129.2; 129.0; 128.9; 128.7; 127.2; 127.1; 116.2; 116.0; 115.6;
53.2; 52.5; 49.8; 46.9; 44.0; 42.8; 40.9; 40.6; 40.4; 40.2; 40.0;
39.8; 39.6; 27.7; 26.6.
Example 61
2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)a-
cetamide (50ELH12.sup.2)
[0431] Procedure as 50ELH14B.
[0432] Reaction Step 0: 4-Trifluoromethylphenylacetyl chloride
(50ELH12.sup.1)
[0433] 4-Trifluorophenylacetic acid (1.0 g) and thionyl chloride
(15 ml) were refluxed for 1 h. The excess thionyl chloride was
evaporated off. NMR showed complete conversion.
[0434] Reaction-Step 2:
2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(-
1-methylpiperidin-4-yl)acetamide (50ELH122).
[0435] Starting materials: 50ELH4 (0.12 g, 0.55 mmol, 1.0 eq.),
4-trifluoromethylphenylacetylchloride (SOELH12')(0.11 g, 0.5 mmol,
1.0 eq.).
[0436] Product: Yield-47.1 mg (24%), UV/MS 96/96 (M.sup.+ 409),
r.sub.t (A, MS) 4.566, R.sub.f 0.25 (3% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.52 (d, 2H), 7.22 (d,
2H), 7.17 (dd, 2H), 7.04 (t, 2H), 4.86 (brt, 1H), 4.58 (s, 2H),
3.64 (s, 2H), 3.45 (brd, 2H), 2.84 (brq, 2H), 2.71 (d, 3H), 2.45
(brq, 2H), 1.77 (brd, 2H). .sup.13C-NMR 171.8; 163.6; 161.2; 138.7;
133.3; 129.8; 129.5; 127.5; 127.4; 125.8; 125.7; 116.4; 116.2;
54.4; 48.9; 46.3; 43.6; 40.8; 26.3.
Example 62
4-(4-Methoxybenzylamino)-1-methylpiperidine (50ELH18)
[0437] Procedure as 50ELH27.
[0438] Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0
mmol, 1.0 eq.), 4-methoxybenzylamine (1.37 g, 1.0 eq.).
[0439] Product: UV/MS 95/95 (M+235), r.sub.t (A, MS) 3.509.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.3-6.8 (in, 4H), 3.77
(s, 3H), 3.73 (s, 2H), 2.86 (m, 2H), 2.55 (m, 1H), 2.30 (s, 3H),
2.1 (t, 2H), 1.96 (dd, 2H), 1.50 (m, 2H).
Example 63
2-(4-Trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiper-
idin-4-yl)acetamide (50ELH20A)
[0440] Procedure as 50ELH14B.
[0441] Reaction-step 1: Methyl
4-(N-[1-methylpiperidine-4-yl]aminomethyl benzoate (50ELH19).
[0442] Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0
mmol, 1.0 eq.), methyl 4-(aminomethyl)benzoate hydrochloride (2.0
g, 1.0 eq.).
[0443] Product: UV/MS 81/88 (M.sup.+ 263), r.sub.t (A, MS) 3.060.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (d, 2H), 7.20 (d,
2H), 3.90 (s, 3H), 3.85 (s, 2H), 2.96 (dt, 2H), 2.7 (brs, 1H), 2.62
(m, 1H), 2.40 (s, 3H), 2.28 (t, 2H), 1.96 (m, 2H), 1.56 (m,
2H).
[0444] Reaction-Step 2:
2-(4-Trifluoromethylphenyl)-N-[4-(methoxycarbonyl)-
benzyl]-N-(1-methylpiperidin-4-yl)acetamide (50ELH20A).
[0445] Starting materials: 50ELH19 (0.20 g, 0.76 mmol, 1.0 eq.),
50ELH12.sup.1 (0.169 g, 1.0 eq.).
[0446] Product: Yield 108.9 mg (32%), UV/MS 100/100 (M.sup.+ 448),
r.sub.t (A, MS) 3.327, R.sub.f 0.3 (5% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, DMSO, rotamers 56/44) .delta. 10.7 and 10.4
(2brs, 1H), 7.96-7.28 (m, 8H), 4.70 and 4.51 (2s, 2H), 4.30 (brt,
1H), 4.06 and 3.69 (2s, 2H), 3.83 and 3.81 (2s, 3H), 3.00 (m, 2H),
2.63 (m, 3H), 2.05 (brt, J=12 Hz, 2H), 1.69 (brt, J=12 Hz, 2H).
.sup.13C-NMR (CDCl.sub.3) 171.9; 166.7; 142.9; 138.5; 130.7; 130.1;
129.7; 126.2; 125.9; 55.2; 52.5; 49.2; 47.4; 41.2; 32.1; 26.6;
22.9; 14.3.
Example 64
2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide
(50 ELH20B)
[0447] Procedure as 50ELH14B
[0448] Reaction-step 2:
2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methyl-
piperidin-4-yl)acetamide (50ELH20B)
[0449] Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.),
phenylacetylchloride (0.117 g, 1.0 eq.).
[0450] Product: Yield 82.5 g (29%), UV/MS 100/100 (M.sup.+381),
r.sub.t (A, MS). 2.652, R.sub.f 0.25 (3% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 12.2 (brs, 1H), 8.00 (d,
J=7.4, 2H), 7.4-7.2 (m, 4H), 7.08 (d, J=7.4, 2H), 4.89 (brt, 1H),
4.62 (s, 2H), 3.90 (s, 3H), 3.56 (s, 2H), 3.42 (d, J=11.0, 2H),
2.84 (q, J=1.0, 2H), 2.68 (d, J=3.6, 3H), 2.40 (q, J=11.0, 2H),
1.77 (brd, J=11.0, 2H). .sup.13C-NMR 173.0; 168.0; 143.3; 136.7;
130.6; 129.0; 127.4; 125.9; 54.5; 52.4; 48.8; 43.6; 41.4; 26.3.
Example 65
2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl-
)acetamide (50ELH20C).
[0451] Procedure as 50ELH14B.
[0452] Reaction-Step 2:
2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-
-(1-methylpiperidinyl)acetamide (50ELH20C).
[0453] Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.),
4-chlorophenylacetylchloride (0.131 g, 1.0 eq.).
[0454] Product: Yield 79.2 g (26%), UV/MS 100/96 (M+399), r.sub.t
(A, MS) 2.333. .sup.1H-NMR (400 MHz, DMSO, rotamers 62/38) .delta.
10.8 and 10.60 (2brs, 1H), 7.95 and 7.85 (2d, J=8.6, 2H), 7.4 and
7.28 (2d, 2H), 7.35 and 7.14 (2m, 4H), 4.67 and 4.50 (2s, 2H), 4.29
(m, 1H), 3.93 and 3.84 (2s, 2H), 3.81 (s, 3H), 3.21 (d, J=1.9, 2H),
3.00 (*, J=11.9, 2H), 2.63 (s, 3H), 2.06 (m, 2H), 1.68 and 1.56 (d,
J=11.9, 2H). .sup.13C-NMR (CDCl.sub.3) 172.6; 166.7; 163.4; 161.0;
143.0; 130.7; 130.6; 130.5; 126.0; 115.9; 115.7; 54.7; 52.4; 48.9;
46.9; 44.0; 40.4; 26.4.
Example 66
2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidinyl)a-
cetamide (50ELH20D).
[0455] Procedure as 50ELH14B.
[0456] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]--
N-(1-methylpiperidin-4-yl)acetamide (50ELH20D).
[0457] Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.140 g, 1.0 eq.).
[0458] Product: Yield 108.6 g (26%), WV/MS 100/99 (M.sup.+ 410),
r.sub.t (A, MS) 2.280. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
12.38 (brs, 1H), 8.00 (d, J=7.2, 2H), 7.28 (d, J=7.2, 2H), 7.00 (d,
J=7.2, 2H), 6.79 (d, J=7.2, 2H), 4.88 (brt, 1H), 4.61 (s, 2H), 3.90
(s, 3H), 3.75 (s, 3H), 3.42 (brd, J=10.7, 2H), 2.84 (q, J=10.7,
2H), 2.68 (d, J=3.6, 3H), 2.40 (brq, J=10.7, 2H), 1.75 (d, J=10.7,
2H). .sup.3C-NMR 173.0; 166.8; 159.0; 143.3; 130.5; 129.9; 129.8;
126.3; 125.9; 114.5; 55.5; 54.7; 52.4; 48.7; 46.7; 43.6; 40.6;
32.1; 26.3; 22.9; 14.3.
Example 67
2-(4-TMethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-y-
l)acetamide (50ELH23)
[0459] Procedure as 50ELH14B.
[0460] Reaction-Step 2:
I-Phenyl-N-[2-(4-methylphenyl)ethyl]-N-(1-methylpi-
peridin-4-yl)amide (50ELH23).
[0461] Starting materials:
4-(2-Phenylethyl)amino-1-methylpiperidine (0.20 g, 0.86 mmol, 1.0
eq.), benzoylchloride (0.158 g, 1.0 eq.).
[0462] Product: Yield 159 mg (50%), UV/MS 100/100 (M.sup.+337),
r.sub.t (A, MS) 3.289, R.sub.f 0.55 (10% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (400 MHz, DMSO (80.degree. C.)) .delta. 10.9 (brs, 1H),
7.44 (s, 2H), 7.34 (d, J=3.0 Hz, 2H), 7.04 (d, J=7.0 Hz, 2H), 6.95
(brs, 2H), 4.00 (brs, 1H), 3.40 (d, J=4.2 Hz, 2H), 3.35 (d, J=4.2
Hz, 2H), 2.95 (brs, 2H), 2.77 (t, J=3.2 Hz, 2H), 2.40 (q, J=6.4 Hz,
2H), 2.24 (s, 3H) 1.83 (d, J=6.4 Hz, 2H). .sup.13C-NMR (CDCl.sub.3)
171.6; 138.1; 136.3; 136.0; 129.8; 129.6; 129.1; 129.1; 126.7;
53.6; 52.4; 46.1; 42.9; 35.9; 27.3; 21.1.
Example 68
2-(4-Methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-methylpiperidin-4-yl)acetam-
ide (50ELH65)
[0463] Procedure as 50ELH14B.
[0464] Reaction-Step 1: 4-(3-Phenylaminopropyl)piperidine
(50ELH59)
[0465] Starting materials: 1-Methyl-4-piperidone (1.1 ml, 7.4 mmol,
1.0 eq.), 3-phenylpropylamine (1.35 g, 1.0 eq.).
[0466] Product. UV/MS 100/94 (M.sup.+ 233), r.sub.t (A, MS)
3.534.). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.28-7.12 (m,
5H), 3.40 (brs, 1H), 2.84 (dt, J=12.3 and 3.5 Hz, 2H), 2.64 (q,
J=7.0 Hz, 4H), 2.51 (m, 1H), 2.27 (s, 3H), 2.05 (brt, J=12.3 Hz,
2H), 1.82 (m, 2H), 1.44 (m, 2H).
[0467] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-met-
hylpiperidin-4-yl)acetamide (50ELH65)
[0468] Starting materials: 50ELH59 (0.50 g, 2.2 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.398 g, 1.0 eq.).
[0469] Product: Yield 153 mg (43%), UV/MS 100/100 (M.sup.+ 381),
r.sub.t (A, MS) 2.938. .sup.1H-NMR (400 MHz, DMSO, rotamers 55/45)
.delta. 11.0 and 10.90 (2brs, 1H), 7.30-7.10 (m, J=7.9 Hz, 6H),
6.97 (d, J=7.9 Hz, 1H), 4.22 and 4.06 (2dt, dH), 3.70 (s, 3H),
3.35. (t, J=10.4 Hz, 2H), 3.15 (m, 2H), 3.00 (q, J=10.4 Hz, 2H),
2.66 (d, 3H), 2.52 (q, J=7.9 Hz, 2H), 2.17 (brq, J=12 Hz, 2H) 1.73
(m, 2H), 1.70 and 1.52 (2d, J=12 Hz, 2H). .sup.13C-NMR (DMSO)
171.3; 171.0; 158.6; 142.2; 141.7; 130.0; 129.0; 128.0; 128.5;
128.2; 126.6; 114.5; 55.7; 55.7; 53.5; 53.3; 50.1; 44.5; 42.9;
41.9; 33.7; 33.1; 32.9; 31.4; 27.8; 26.8.
Example 69
2-(4-Methoxyphenyl)-N-12-(4-methylphenyl)ethyl)-N-(1-methylpiperidin-4-yl)-
acetamide (50ELH68)
[0470] Procedure as 50ELH14B
[0471] Reaction-Step 1: 4-[2-(4-Methylphenyl)ethylamino]-piperidin
(SOELH58)
[0472] Starting materials: 1-Methyl-4-piperidone (1.1 ml, 7.4 mmol,
1.0 eq.), 2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.).
[0473] Product: UV/MS 100/91 (M.sup.+ 233), r.sub.t (A, MS)
3.933.). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.4 (s, 5H),
3.27 (brs, 1H), 2.84 (d, J=7.0 Hz, 4H), 2.75 (m, 2H), 2.54 (m, 1H),
2.29 (2xs, 6H), 2.10 (brt, J=12.3 Hz, 2H), 1.86 (brd, 2H), 1.45 (m,
2H).
[0474] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(4-methylphenyl)ethyl)-N--
1-methylpiperidin-4-yl)acetamide (50ELH68)
[0475] Starting materials: 50ELH58 (0.30 g, 1.3 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.238 g, 1.0 eq.).
[0476] Product: Yield 125 mg (26%), UV/MS 100/99 (M.sup.+381),
r.sub.t (A, MS) 3.156. .sup.1H-NMR (400 MHz, DMSO, rotamers 50/50)
.delta. 11.0 and 10.90 (2brs, 1H), 7.25-7.04 (m, J=8.7 Hz, 6H),
6.87 and 6.84 (2d, J=8.7 Hz, 2H), 4.30 and 4.09 (2dt, J=11.5 Hz,
dH), 3.73 and 3.58 (2s, 2H), 3.71 and 3.70 (2s, 3H), 3.35 (m,
(Underneath waterpeak) 3H), 3.24 (m, 1H), 3.02 (m J=11.5 Hz, 2H),
2.80-2.62 (m, 5H), 2.32 and 2.20 (2q, 11.5 Hz, 2H), 2.26 and 2.24
(2s, 3H) 1.78 and 1.49 (2d, J=11.5 Hz, 2H). .sup.13C-NMR (DMSO)
171.5; 171.2; 158.6; 136.8; 136.2; 136.0; 135.8; 130.7; 130.5;
129.7; 129.6; 129.4; 129.2; 128.4; 128.3; 114.5; 55.8; 55.7; 53.3;
53.3; 52.2; 50.2; 46.8; 43.9; 42.9; 36.8; 35.2; 27.6; 26.8;
21.3.
Example 70
2-(4-Methoxyphenyl)-N-[2-(2-thionyl)ethyl]-N-(1-methylpiperidin-4-yl)aceta-
mide (50ELH71A)
[0477] Procedure as 50ELH14B
[0478] Reaction-Step 1: 4-[2-(2-Thienyl)ethylamino]piperidin
(50ELH67A)
[0479] Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol,
1.0 eq.), thiophene-2-ethylamine (0.563 g, 1.0 eq.).
[0480] Product: UV/MS 94/93 (M.sup.+ 225).
[0481] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(2-thienylethyl]-N-(1-met-
hylpiperidinyl)acetamide (50ELH71A)
[0482] Starting materials: 50ELH67A (0.243 g, 1.08 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).
[0483] Product: Yield 80.7 mg (33%), UV/MS 100/100 (M.sup.+ 373),
r.sub.t (A, MS) 2.613. .sup.1H-NMR (400 MHz, DMSO, rotamers 50/50)
.delta. 10.8 and 10.6 (2brs, 1H), 7.36 and 7.31 (2d, J=4.7 Hz, 1H),
7.20 and 7.06 (2d, J=8.3 Hz, 2H), 7.00-6.92 (m, J=4.7 and 2.8 Hz,
2H), 6.87 and 6.40 (2d, 8.3 Hz, 2H), 4.22 and 4.08 (2dt, J=12.2 Hz,
1H), 3.71 (s, 3H), 3.70 (s, 2H), 3.46-3.30 (m, 4H), 3.10-2.90 (m,
4H), 2.67 (m, 21H), 2.28 and 2.12 (2q, J=12 Hz, 2H), 1.80 and 1.50
(2d, J=12 Hz, 2H). .sup.13C-NMR (DMSO) 172.5; 158.9; 139.6; 130.0;
129.6; 126.8; 124.5; 114.5; 55.5; 54.7; 49.3; 45.8; 43.8; 41.3;
31.9; 29.9
Example 71
2-(4-Methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(1-methylpiperidin-4-yl)a-
cetamide (50ELH71C)
[0484] Procedure as 50ELH14B
[0485] Reaction-Step 1: 4-[2-(4-nitrophenyl)ethylamino]-piperidin
(50ELH67C)
[0486] Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol,
1.0 eq.), 4-nitrophenyl-2-ethylamine (0.897 g, 1.0 eq.).
[0487] Product: WV/MS 96/89 (M.sup.+ 264), r.sub.t (A, MS)
3.264.
[0488] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(-
1-methylpiperidin-4-yl)acetamide (50ELH71A)
[0489] Starting materials: 50ELH67C (0.285 g, 1.08 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).
[0490] Product: Yield 130.9 mg (30%), UV/MS 100/100 (M.sup.+ 412),
r.sub.t (A, MS) 2.219. .sup.1H-NMR (400 MHz, DMSO, rotamers 50/50)
.delta. 10.8 and 10.6 (2brs, 1H), 8.17 and 8.12 (2d, J=8.6 Hz, 2H),
7.58 and 7.48 (2d, J=8.6 Hz, 2H), 7.2 and 7.1 (2d, J=8.6 Hz, 2H),
6.87 and 6.40 (2d, J=8.6 Hz, 2H), 4.25 and 4.10 (2dt, J=12 Hz, 1H),
3.72 (s, 3H), 3.70 (s, 2H), 3.48-3.30 (m, 4H), 3.10-2.84 (m, 4H),
2.69 and 2.67 (2d, J=4.7 Hz, 3H), 2.34 and 2.15 (2q, J=3.2 Hz, 2H),
1.79 and 1.47 (2d, J=13.2 Hz, 2H).
Example 72
2-(4-Methoxyphenyl)-N-(2-thienylmethyl)-N-(1-methylpiperidin-4-yl)acetamid-
e (50ELH73A)
[0491] Procedure as 50ELH14B.
[0492] Reaction-Step 1:
4-[(2-Thienylmethyl)amino]-1-methylpiperidine (50ELH66A)
[0493] Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol,
1.0 eq.), 2-thienylmethylamine (0.52 g, 1.0 eq.).
[0494] Product: UV/MS 77/86 (M.sup.+ 211), r.sub.t (A, MS)
2.739.
[0495] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-(2-thienylmethyl)-N-(1-methy-
lpiperidin-4-yl)acetamide (50ELH73A)
[0496] Starting materials: 50ELH66A (0.228 g, 1.08 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).
[0497] Product: Yield 178.4 mg (50%), UV/MS 100/98 (M+359), r.sub.t
(A, MS) 3.117. .sup.1H-NMR (400 MHz, DMSO) .delta. 10.9 and 10.6
(2brs, 1H), 7.47 and 7.32 (2d, J=4.5 Hz, 1H), 7.20 and 7.03 (2d,
J=8.4 Hz, 2H), 7.03 and 6.98 (2m, 1H), 6.87 (m, 3H), 4.70 and 4.57
(2s, 2H), 4.42 and 4.16 (2t, J=11.9 Hz, 1H), 3.77 and 3.60 (2s,
2H), 3.51 (s, 3H), 3.15 (m, 2H), 2.98 (m, J=11.9 Hz, 2H), 2.65 (2d,
J=4.5 Hz, 3H), 2.25 and 2.17 (2q, J=11.9 Hz, 2H), 1.69 and 1.44
(2d, J=11.9 Hz, 2H). .sup.13C-NMR (DMSO) 171.4; 158.6; 143.2;
130.7; 128.1; 126.6; 126.3; 125.9; 114.5; 55.7; 53.3; 52.6; 50.0;
42.8; 27.7; 26.8.
Example 73
2-(4-Methoxyphenyl)-N-(furfuryl)-N-(1-methylpiperidin-4
yl)acetamide (50ELH73B).
[0498] Procedure as 50ELH14B.
[0499] Reaction-Step 1: 4-(Furfurylamino)-1-methylpiperidin
(50ELH66B)
[0500] Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol,
1.0 eq.), Furfurylamine (0.43 g, 1.0 eq.).
[0501] Product: UV/MS 77/92 (M+195), r.sub.t (A, MS) 2.812).
[0502] Reaction-Step 2:
2-(4-Methoxyphenyl-N-(furfuryl)-N-(1-methylpiperid-
in-4-yl)acetamide (50ELH73B).
[0503] Starting materials: 50ELH66B (0.21 g, 1.08 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).
[0504] Product: Yield 134 mg (36%), UV/MS 100/99 (M.sup.+ 343),
r.sub.t (A, MS) 2.401. .sup.1H-NMR (400 MHz, DMSO, rotamers 57/43)
.delta. 10.95 and 10.75 (2brs, 1H), 7.63 and 7.48 (s, 1H), 7.18 and
7.06 (2d, J=7.7 Hz, 2H), 6.85 (t, J=7.7 Hz, 2H), 6.44 and 6.33 (2d,
J=7.7 Hz, 1H), 6.37 and 6.11 (2s, 1H) 4.5 and 4.34 (2s, 2H), 4.42
and 4.18 (2dt, J=1 and 2 Hz, 1H), 3.75 and 3.65 (2s, 2H) 3.70 (s,
3H), 3.33 (hidden, 2H), 3.0 (q, 211), 2.64 (d, J=4.7 Hz, 311), 2.15
(dq, J=11 and 2 Hz, 2H), 1.65 and 1.50 (2d, J=11 Hz, 2H).
Example 74
2-(2-thienylmethyl)-N-(4-methylphenylmethyl)-N-(1-methylpiperidin-4-yl)ace-
tamide (50ELH82)
[0505] Procedure as 50ELH14B
[0506] Reaction-Step 2:
2-(2-thienylmethyl)-N-(4-methylphenylmethyl)-N-(1--
methylpiperidin-4-yl)acetamide (50ELH82)
[0507] Starting materials: 50ELH25 (0.30 g, 1.38 mmol, 1.0 eq.),
thiophene-2-acetylchlorid (0.22 g, 1.0 eq.).
[0508] Product: Yield 235 mg (62%), UV/MS 97/93 (M.sup.+ 343),
r.sub.t (A, MS) 2.795. .sup.1H-NMR (400 MHz, DMSO, rotamers 54/46)
.delta. 10.8 and 10.60 (2brs, 1H), 7.4 and 7.35 (2d, 1H), 7.2-6.76
(m, 6H), 4.55 and 4.4 (2s, 2H), 4.49 and 4.26 (2dt, J=11 and 2 Hz,
2H), 4.15 and 3.79 (2s, 2H), 3.32 (d, J=11 Hz, 2H), 2.99 (q, 2H),
2.63 (s, 3H), 2.27 and 2.23 (2s, 3H), 2.09 (q, J=11 Hz, 2H), 1.66
and 1.55 (2d, J=11 Hz, 2H).
Example 75
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acet-
amide (42ELH75)
[0509] Procedure as for 42ELH80, except that the reaction was run
at 60.degree. C. for 3 days.
[0510] Starting materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq.),
Cyclopentylbromide (0.288 g, 3.0 eq.).
[0511] Product: Yield 91.2 mg (34%), UV/MS 88/93 (M.sup.+ 421),
r.sub.t (A, MS) 4.450.
Example 76
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-(3-(1,3-dihydro-2H-benzimidazo-
l-2-one-1-yl)propyl)piperidine-4yl)acetamide (50ELH89).
[0512] 50ELH87 (0.05 g, 0.14 mmol, 1 eq.) was transferred to a 4 ml
vial and dissolved in 1 ml of acetonitrile. Then,
13-chloropropyl)-1,3-dihydro- -2H-benzimidazol-2-one (0.032 g, 1.1
eq.), sodium carbonate (0.022 g, 1.1 eq.) and KI (one crystal) were
added and the vial was sealed and shaken for 20 h at 82.degree. C.
The mixture was extracted with distilled water (pH 10, sodium
carbonate) and dicltloromethane (3 times) the organic layers were
dried with sodium sulfate and concentrated. The title compound was
purified by HPLC and evaporated to dryness, forming a
trifluoroacetic acid salt. Yield 8.8 mg (12%). UV/MS 100/100
(M.sup.+527), r.sub.t (A, MS) 2.851.
Example 77
2-(4-Methoxyphenyl)-N-(4methylbenzyl)-N-[1-(2-methylthiazol-4ylmethyl)pipe-
ridin 4yl]acetamide (63ELH1A).
[0513] 50ELH87 (0.3 g, 0.852 mmol, 1.0 eq) and
4-(chloromethyl)-2-methylth- iazole hydrochloride (0.235 g, 1.5 eq)
were added to a 7 ml vial and dissolved in acetonitrile (3 ml).
Potassium carbonate (141.3 g, 1.2 eq) and a crystal of potassium
iodide were added and the vial was sealed and shaken for 20 h at
82.degree. C. The reaction mixture was extracted with distilled
water (made basic by potassium carbonate, pH 10) and
dichloromethane. The crude product was dried with sodium sulfate
and concentrated. After purification by HPLC the product was
converted into the hydrochloride salt by dissolving the free base
in 1 ml dichloromethane and adding 1 eq. HCl in ether (2M). This
mixture was added drop-wise to an excess of heptane where the
product precipitated. The solvent was removed by evaporation
leaving a white powder as the product yield 83.8 mg (21%), UV/MS
100/90 (M.sup.+ 463), r.sub.t (B, MS) 11.82.
Example 78
2-(4-Methoxyphenyl)-N-(24-(fluorophenyl)ethyl)-N-(1-methylpiperdin-4-yl)ac-
etamide (50ELH93A)
[0514] Procedure as 50ELH14B.
[0515] Reaction-Step 1:
4-[24-(Fluorophenyl)ethylamino]-1-methylpiperidine (50ELH92A)
[0516] Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol,
1.0 eq.), 4-(fluorophenyl)ethylamine (0.369 g, 1.0 eq.).
[0517] Product: UV/MS 60/92 (M.sup.+ 237), r.sub.t (A, MS)
3.422.
[0518] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-(2-4-(fluorophenyl)ethyl)-N--
(1-methylpiperidin-4-yl)acetamide (50ELH93A)
[0519] Starting materials: 50ELH92A (0.625 g, 2.65 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
[0520] Product: Yield 181 mg (18%), UV/MS 87/97 (M.sup.+ 385),
r.sub.t (A, MS) 2.783. R.sub.f 0.8 (10% MeOH/CH.sub.2Cl.sub.2).
.sup.1H-NMR (490 MHz, DMSO, rotamers 50/50) .delta. 10.9 (brs, 1H),
7.56-6.8 (m, 8H), 4.26 and 4.02 (2brt, 2H), 3.70 and 3.95 (2s, 3H),
3.59 and 3.57 (2s, 2H), 3.4-3.15 (m, 5H), 2.96-2.66 (m, 5H), 2.62
and 2.56 (2s, 3H), 2.29 and 2.10 (2q, 2H), 1.73 and 1.41 (2d, 2H).
.sup.13C-NMR (DMSO) 172.5; 171.4; 171.3; 162.9; 162.7; 160.5;
160.3; 158.9; 158.6; 136.1; 136.1; 135.3; 131.4; 131.3; 131.1;
131.0; 131.0; 130.6; 130.5; 128.4; 128.4; 126.9; 115.9; 115.8;
115.7; 115.6; 114.5; 55.7; 53.7; 53.5; 52.7; 52.3; 50.7; 46.7;
43.8; 43.2; 43.0; 36.3; 34.7; 27.9; 26.9.
Example 79
2-(4-Methoxyphenyl)-N-12-(2,5dimethoxyphenyl)ethyl]-N-(1-methylpiperidin-4-
-yl)acetamide (50ELH93C)
[0521] Procedure as 50ELH14B. A small amount was purified by HPLC
and evaporated to dryness, forming the trifluoroacetic acid
salt.
[0522] Reaction-Step 1:
4-[2-(2,5-dimethoxyphenyl)ethylamino]-1-methylpipe- ridine
(50ELH92A)
[0523] Starting materials: Methyl-4-piperidone (0.3 g, 2.65 mmol,
1.0 eq.), 2,5-(dimethoxyphenyl)ethylamine (0.481 g, 1.0 eq.).
[0524] Product: UV/MS 81/90 (M.sup.+ 279), r.sub.t (A, MS)
2.868.
[0525] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethy-
l]-N-(1-methylpiperidin-4-yl)acetamide (50ELH93C)
[0526] Starting materials: 50ELH93C (0.737 g, 2.65 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
[0527] Product: UV/MS 82/100 (M.sup.+ 427), r.sub.t (B, MS) 8.44.
R.sub.f 0.8 (10% MeOH/CH.sub.2Cl.sub.2).
Example 80
2-(4-Methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-
-yl)acetamide (50ELH93D)
[0528] Procedure as 50ELH14B, but purified by HPLC and evaporated
to dryness forming the trifluoroacetic acid salt.
[0529] Reaction-Step 1:
4-[2-(2,4-Dichlorophenyl)ethylamino]-1-methylpiper- idine
(50ELH92D)
[0530] Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol,
1.0 eq.), 2,5-(dichlorophenyl)ethylamine (0.50 g, 1.0 eq.).
[0531] Product: UV/MS 82/92 (M+287), r.sub.t (A, MS) 4.875.
[0532] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl-
]-N-(1-methylpiperidinyl)acetamide (SOELH93D)
[0533] Starting materials: 50ELH93D (0.76 g, 2.65 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
[0534] Product: UV/MS 100/96 (M.sup.+ 435), r.sub.t (A, MS) 4.415.
R.sub.f 0.8 (10% MeOH/CH.sub.2Cl.sub.2).
Example 81
2-(4-Methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)-
acetamide (50ELH93E)
[0535] Procedure as 50ELH14B, but purified on HPLC and evaporated
to dryness forming the trifluoroacetic acid salt.
[0536] Reaction-Step 1:
4-[(3-Chlorophenyl)ethyl)amino]-1-methylpiperidine (50ELH92E)
[0537] Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol,
1.0 eq.), 3-(chlorophenyl)ethylamine (0.413 g, 1.0 eq.).
[0538] Product: UV/MS 86/88. (M+253), r.sub.t (A, MS) 3.175.
[0539] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N--
(1-methylpiperidin-4-yl)acetamide (50ELH93E)
[0540] Starting materials: 50ELH93E (0.67 g, 2.65 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
[0541] Product: UV/MS 100/100 (M.sup.+ 401), r.sub.t (A, MS) 3.464.
R.sub.f 0.8 (10% MeOH/CH.sub.2Cl.sub.2).
Example 82
2-(4-Methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl-
)acetamide (50ELH95B)
[0542] Procedure as 50ELH14B. Purified by HPLC and evaporated to
dryness forming the trifluoroacetic acid salt.
[0543] Reaction-Step 1:
4-[(4-Methoxyphenyl)ethyl)amino]-1-methylpiperidin- e
(50ELH94B)
[0544] Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol,
1.0 eq.), 4-methoxyphenylethylamine (0.40 g, 1.0 eq.).
[0545] Product: UV/MS 74/87 (M.sup.+ 249), r.sub.t (A, MS)
2.935.
[0546] Reaction-Step 2:
2-(4-Methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-
-(1-methylpiperidin-4-yl)acetamide (50ELH95B)
[0547] Starting materials: 50ELH94B (0.657 g, 2.65 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
[0548] Product: UV/MS 100/100 (M.sup.+ 397), r.sub.t (A, MS) 2.389.
R.sub.f 0.8 (10% MeOH/CH.sub.2Cl.sub.2).
Example 83
2-(4-Methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)-
acetamide (50ELH95D)
[0549] Procedure as 50ELH14B. Purified on HPLC and evaporated to
dryness, forming the trifluoroacetic acid salt.
Reaction-Step 1: 4-[2-((3-Fluorophenyl)ethyl
amino]-1-methylpiperidine (50ELH94D)
[0550] Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol,
1.0 eq.), 3-fluorophenylethylamine (0.369 g, 1.0 eq.).
[0551] Product: UV/MS 74/89 (M.sup.+ 237), r.sub.t (A, MS)
2.946.
[0552] Reaction-Step 2:
2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N--
(1-methylpiperidin-4-yl)acetamide (50ELH95D)
[0553] Starting materials: 50ELH94D (0.625 g, 2.65 mmol, 1.0 eq.),
4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
[0554] Product: UV/MS 100/95 (M.sup.+ 385), r.sub.t (A, MS) 2.946.
R.sub.f 0.8 (10% MeOH/CH.sub.2Cl.sub.2)
Example 84
2-(4-ethoxyphenyl)-N-[24-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ace-
tamide (63ELH20)
[0555] Reaction Step 1: 4-Ethoxyphenylacetic acid chloride
(63ELH19) 4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was
transferred to a 7 ml vial and dissolved in thionylchloride (3 ml).
The reaction mixture was shaken at 70.degree. C. for 2Y.sub.2
hours. Thionylchloride was evaporated off and the resulting product
was used unpurified.
[0556] Reaction Step 2:
24-Ethoxyphenyl)-N-[2-(4-fluorophenyl)ethyl]-N-(1--
methylpiperidin-4-yl)acetamide (63ELH20)
[0557] 63ELH17 (0.11 g, 0.47 mmol) was transferred to a 4 ml vial
and dissolved in dichloromethane. 63ELH19 (0.084 mg, 1 eq.) was
added and the vial was sealed and the reaction shaken for 20 h. The
product was extracted in distilled water (made basic with potassium
carbonate, pH 10) and dichloromethane. Dried with sodium sulfate
and concentrated. Purified by HPLC. The extraction, drying and
concentration was repeated and the product re-dissolved in
dichloromethane (1 ml) and HCl (1 eq., 2 M in ether) was added. The
mixture was added drop-wise to an excess of heptane whereupon the
salt precipitated. Yield 33.4 mg (18%), UV/MS: 92/100 (M+399),
t.sub.r (B, MS) 10.38.
Example 85
2-(4-Ethoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(63ELH21)
[0558] 50ELH4 (0.11 g, 0.49 mmol, 1.0 eq.) was transferred to a 4
ml vial and dissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0
eq.) was added and the vial was sealed and the reaction shaken for
20 h. The product was extracted in distilled water (made basic with
potassium carbonate, pH 10) and dichloromethane. Dried with sodium
sulfate and concentrated. Purified by HPLC. The extraction, drying
and concentration was repeated and the product dissolved in
dichloromethane (1 ml) and HCl (1 eq., 2 M in ether) is added. This
mixture was added drop-wise to an excess of heptane whereupon the
salt precipitated. Yield 31.1 mg (16%), UV/MS: 94/100 (M+385),
t.sub.r (A, MS) 2.573.
Example 86
N-((4-methylphenyl)methyl)-N-1-methylpiperidin-4-yl)-2-(3-hydroxy-4-methox-
yphenyl)acetamide (57 MBT12B)
[0559] N-((4-methylphenyl)methyl)-4-amino-1-methylpiperidine
(50ELH25) (105 mg, 0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic
acid (88 mg, 0.48 mmol) were dissolved in DMF (10 ml).
Diisopropylethylamine (DIEA, 250 .mu.L, 1.44 mmol) was added
followed by bromo-tris-pyrrolidino-phosphoniu- m
hexafluorophosphate (PyBrOP, 336 mg, 0.72 mmol), and the mixture
was stirred at r.t for 1 h. Water (50 mL) was added, and the
reaction mixture was extracted with EtOAc (2.times.50 mL). Drying
by Na.sub.2SO.sub.4 and concentration yielded 514 mg crude
material, which was purified by flash chromatography (0-30% MeOH in
CH.sub.2Cl.sub.2). This gave 105 mg (57%) of the title compound as
a white solid. R.sub.f=0.20 (10% MeOH in CH.sub.2Cl.sub.2). HPLC-MS
(method A) showed MH.sup.+=383. UV/MS(%)=100192. .sup.1H-NMR (400
MHz, CD.sub.3OD, Rotamers 52:48): .delta. 7.18-6.58 (m, 7H), 4.53
(s, 2H), 4.31 and 3.97 (2m, 1H), 3.82 and 3.81 (2s, 3H), 3.80 and
3.55 (2s, 2H), 3.04 and 2.85 (2m, 2H), 2.41 and 2.32 (2s, 3H), 2.35
and 2.12 (2m, 2H), 2.29 and 2.27 (2s, 3H), 1.83 and 1.74 (2m, 2H),
1.72 and 1.33 (2m, 2H)
Example 87
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(3,4-dihydroxyphen-
yl)acetamide (57 MBT24B)
[0560]
N-((4-methylphenyl)methyl)-N-(1-methylpiperidine-4-yl)-2-(3-hydroxy-
-4-methoxyphenyl)acetamide (57 MBT12B) (52 mg, 0.136 mmol) was
dissolved in CH.sub.2Cl.sub.2 (1 mL) and cooled to -78.degree. C.
Boron tribromide (1 M in CH.sub.2Cl.sub.2, 204 .mu.l, 0.204 mmol)
was added dropwise and the cooling bath was removed. After stirring
for 2 h, methanol (2 mL) was added and the mixture was evaporated.
The resulting oil was purified by preparative HPLC to give 24 mg
(48%) of the title compound as a white solid. HPLC-MS (method A)
showed MH.sup.+=369. UV/MS(%)=100/97. .sup.1H-NMR (400 MHz,
CD.sub.3OD, Rotamers 33:67): .delta. 7.19-6.47 (m, 7H), 4.54 and
4.53 (2s, 2H), 4.23 (m, 1H), 3.83 and 3.58 (2s, 2H), 3.46 and 3.40
(2br d, J=12 Hz, 2H), 3.02 and 2.95 (2br t, J=12 Hz, 2H), 2.79 (s,
3H), 2.33 and 2.28 (2s, 3H), 2.17 and 1.84 (2dq, J=4, 12 Hz, 2H),
1.87 and 1.48 (2br d, J=12 Hz, 2H)
Example 88
N-((3-hydroxy-4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-metho-
xyphenyl)acetamide (57 MBT54B)
[0561] N-((4-methoxyphenyl)methyl)-4-amino-1-methylpiperidine (1 g,
4.27 mmol) was dissolved in 4% formic acid in methanol (60 in L).
10% Pd/C (1 g) was added under argon and the reaction mixture was
heated to reflux for 24 h. The mixture was filtered through celite
and the filtrate was acidified with conc. HCl to pH 1.
Concentration yielded a yellow oil which was purified by flash
chromatography (MeOH/CH.sub.2Cl.sub.2 3:7+3.5% NH.sub.4OH) to give
249 mg (51%) of 4-amino-1-methylpiperidine (57-MBT36B) as a white
solid. R.sub.f=0.13 (10% MeOH in CH.sub.2Cl.sub.2+3.5% NH.sub.4OH).
HPLC-MS (method B) showed MH.sup.+=15. UV/MS(%)=-/100.
[0562] 4-Amino-1-methylpiperidine (57 MBT36B) (26 mg, 0.231 mmol)
was dissolved in methanol (1 mL) and 3-hydroxy-4-methylbenzaldehyde
(32 mg, 0.231 mmol) and acetic acid (33 .mu.L) were added. The
mixture was cooled to 0.degree. C. NaBH.sub.3CN (29 mg, 0.462 mmol)
was added and the cooling bath was removed. After 3 h the reaction
mixture was evaporated and flash chromatography (0-30% MeOH in
CH.sub.2Cl.sub.2) gave 27 mg (50%) of
N-((3-hydroxy-4-methylphenyl)methyl)-4-amino-1-methylpiperidine (57
MBT44C) as a white solid. R.sub.f=0.27 (11% MeOH in
CH.sub.2Cl.sub.2+3.5% NH.sub.4OH). HPLC-MS (method A) showed
MH.sup.+=235. UV/MS(%)=99/99.
[0563]
N-((3-hydroxy-4methylphenyl)methyl)-4-amino-1-methylpiperidine (57
MBT44C) (27 mg, 0.115 mmol) was dissolved in CH.sub.2Cl.sub.2 (2
mL). 4-Methoxyphenylacetyl chloride (17 .mu.L, 0.115 mmol) was
added dropwise under argon. After 3 h, n-heptane (3 mL) was added
and the mixture was evaporated. Flash chromatography (0-20% MeOH in
CH.sub.2Cl.sub.2) gave 14 mg (32%) of the title compound as a white
solid. R.sub.f=0.32 (10% MeOH in CH.sub.2Cl.sub.2+3.5% NH.sub.4OH).
HPLC-MS (method A) showed MH.sup.+=383. UV/MS(%)=99196. .sup.1H-NMR
(400 MHz, CD.sub.3OD, Rotamers 63:37): .delta. 7.28-6.55 (m, 7H),
4.48 (s, 2H), 4.37 and 3.95 (2m, 1H), 3.78 and 3.77 (2s, 3H), 3.06
and 2.89 (2br d, J=12 Hz, 2H), 2.42 and 2.32 (2s, 3H), 2.40 and
2.12 (2m, 2H), 2.18 and 2.12 (2s, 3H), 1.86 and 1.83 (2m, 2H), 1.75
and 1.35 (2br d, J=12 Hz, 2H)
Example 89
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-bromophenyl)ace-
tamide hydrochloride (57 MBT70-1D)
[0564] 4-Bromophenylacetic acid (54 mg, 0.252 mmol) was dissolved
in CH.sub.2Cl.sub.2 (2 mL), and
N-((4-methylphenyl)methyl)-4-amino-1-methylp- iperidine (292 mg/mL
stock solution in CH.sub.2Cl.sub.2, 171 .mu.L, 0.229 mmol) and
polystyrene supported diisopropylethylamine (PS-DIEA with a loading
of 3.57 mmol/g, 192 mg, 0.687 mmol) was added followed by
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 160
mg/mL stock solution, 1 mL, 0.334 mmol). The reaction mixture was
shaken for 1 h at r.t. and filtered onto a prewashed (methanol) ion
exchange column (0.88 mmol/g, 1 g). The column was washed with
methanol (8*4 mL) and the remaining product was eluted off the
column with 10% NH.sub.4OH in methanol (2*4 mL) and evaporated. The
resulting oil was filtered through silica (H=4 cm, D=1 cm) with
methanol/CH.sub.2Cl.sub.2 1:9 (20 mL), evaporated and subjected to
a second ion exchange column (0.88 mmol/g, 1 g). The column was
washed with methanol (8*4 mL) and the remaining product was eluted
off the column with 10% NH.sub.4OH in methanol (2*4 mL) and
evaporated on rotavap and oil pump. The product was dissolved in
CH.sub.2Cl.sub.2 (0.5 mL) and HCl in diethylether (1.0 M, 0.1 mL,
0.1 mmol) was added. The solution was added to n-heptane (3 mL) and
evaporation afforded 29 mg (25%) of the title compound as a white
solid. R.sub.f=0.31 (10% MeOH in CH.sub.2Cl.sub.2). HPLC-MS (method
B) showed MH.sup.+=416. UV/MS(%)=100/99.
Example 90
N-((4-methylphenyl)methyl)-N-methylpiperidin-4-yl)-2-(4-iodophenyl)acetami-
de hydrochloride (57 MBT70-2D)
[0565] The title compound was prepared according to example MBT04.
Yield: 33 mg (26%). R.sub.f=0.31 (10% MeOH in CH.sub.2Cl.sub.2).
HPLC-MS (method B) showed MH.sup.+=463. UV/MS(%)=100/98.
Example 91
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-(2-propyl)pheny-
l)acetamide hydrochloride (57 MBT703D)
[0566] The title compound was prepared according to example MBT04.
Yield: 36 mg (34%). R.sub.f=0.31 (10% MeOH in CH.sub.2Cl.sub.2).
HPLC-MS (method B) showed MH.sup.+=379. UV/MS(%)=100/97.
Example 92
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-trifluoromethox-
yphenyl)acetamide hydrochloride (57 MBT704D)
[0567] The title compound was prepared according to example MBT04.
Yield: 35 mg (30%). R.sub.f=0.27 (10% MeOH in CH.sub.2Cl.sub.2).
HPLC-MS (method B) showed MH.sup.+=421. UV/MS(%)=100/99.
Example 93
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methylthiopheny-
l)acetamide hydrochloride (57 MBT705D)
[0568] The title compound was prepared according to example MBT04.
Yield: 35 mg (33%). R.sub.f=0.30 (10% MeOH in CH.sub.2Cl.sub.2).
HPLC-MS (method B) showed MH.sup.+=383. UV/MS(%)100/99.
Example 94
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-(N,N-dimethylam-
ino)phenyl)acetamide hydrochloride (57 MBT70-6D)
[0569] The title compound was prepared according to example
MBT04.
[0570] Yield: 16 mg (15%). R.sub.f=0.25 (10% MeOH in
CH.sub.2Cl.sub.2). HPLC-MS (method A) showed MH.sup.+=380.
UV/MS(%)=100/100.
Example 95
N-((4methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-nitrophenyl)acet-
amide hydrochloride (57 MBT707D)
[0571] The title compound was prepared according to example MBT04.
Yield: 28 mg (27%). R.sub.f=0.27 (10% MeOH in CH.sub.2C.sub.2).
HPLC-MS (method B) showed MH.sup.+=382. UV/MS(%)=100/100.
Example 96
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxy-3-methy-
lphenyl)acetamide hydrochloride (57 MBT708D)
[0572] The title compound was prepared according to example MBT04.
Yield: 34 mg (32%). R.sub.f=0.30 (10% MeOH in CH.sub.2Cl.sub.2).
HPLC-MS (method B) showed MH.sup.+=381. UV/MS(%)=100/99.
Example 97
N-((4methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4pyridyl)acetamide
hydrochloride (57MBT70-9F)
[0573] The title compound was prepared according to example MBT04.
Yield: 18 mg (17%). R.sub.f=0.09 (10% MeOH in CH.sub.2Cl.sub.2).
HPLC-MS (method A) showed MH.sup.+=338. UV/MS(%)=100/100.
Example 98
N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methylphenyl)ac-
etamide hydrochloride (57MBT62B)
[0574] The title compound was prepared according to example MBT04.
Yield: 10 mg (35%). R.sub.f=(10% MeOH in CH.sub.2Cl.sub.2). HPLC-MS
(method A) showed MH.sup.+=351. UV/MS(%)=100/100.
Example 99
N-(4-(hydroxymethyl)phenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4methoxyp-
henyl)acetamide hydrochloride (57MBT72D)
[0575] To a stirred suspension of LiAlH.sub.4 (285 mg, 7.52 mmol)
in diethylether (10 mL) at 0.degree. C. was added a solution of
4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL)
over 15 min. The grey reaction mixture was heated to reflux for 3
h. After cooling to r.t., the mixture was treated successively with
water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous
stirring. The resulting white slurry was filtered and washed with
CH.sub.2Cl.sub.2 (20 mL). Extraction with additional
CH.sub.2Cl.sub.2 (20 mL) and n-butanol (20 mL) and evaporation
yielded an oil, which upon flash chromatography (0-15% MeOH in
CH.sub.2Cl.sub.2) gave 152 mg (29%) of 4-(aminomethyl)benzylalcoh-
ol (57 MBT52B) as a white solid. R.sub.f=0.5 1 (30% MeOH in
CH.sub.2Cl.sub.2+3.5% NH.sub.4OH).
[0576] 1-Methyl-4-piperidone (84 .mu.L, 0.73 mmol) was dissolved in
methanol (5 mL) and 4-(aminomethyl)benzylalcohol (57 MBT52B) (100
mg, 0.73 mmol) was added followed by acetic acid (125 EL).
NaBH.sub.3CN (92 mg, 1.46 mmol) was added and the mixture was
stirred for 3 h. The reaction mixture was evaporated and 2M NaOH (5
mL) was added. Extraction with CH.sub.2Cl.sub.2 (4*5 mL), drying
with Na.sub.2SO.sub.4 and evaporation gave 152 mg (87%) of
N-(4-hydroxymethyl)phenyl)methyl)-4-amin- o 1-methylpiperidine (57
MBT56D) as a white solid. HPLC-MS (method B) showed MH.sup.+=235.
UV/MS(%)=100/100.
[0577]
N-(4-(Hydroxymethyl)phenyl)methyl)-4-amino-1-methylpiperidine (57
MBT56D) (20 mg, 0.0853 mmol) was dissolved in CH.sub.2Cl.sub.2 (2
mL) and 4-methoxyphenylacetyl chloride (26 .mu.L, 0.171 mmol) was
added dropwise. The reaction mixture was stirred for 1 h and water
(500 .mu.L) was added followed by evaporation. A solution of sodium
(5 mg, 0.179 mmol) in methanol (2 mL) was added. After stirring for
4 h, the solution was transferred to a prewashed (methanol) ion
exchange column (0.88 mmol/g, 1 g) and washed with methanol (4*4
mL). The remaining product was eluted off the column with 10%
NH.sub.4OH in methanol (2*4 mL) and evaporated. The resulting oil
was filtered through silica (H=4 cm, D=1 cm) with
methanol/CH.sub.2Cl.sub.2 2:8 (20 mL), evaporated and subjected to
a second ion exchange column (0.88 mmol/g, 1g). The column was
washed with methanol (8*4 mL) and the remaining product was eluted
off the column with 10% NH.sub.4OH in methanol (2*4 mL) and
evaporated on rotavap and oilpump. The product was dissolved in
CH.sub.2Cl.sub.2 (0.5 mL) and HCl in diethylether (1.0 M, 0.1 mL,
0.1 mmol) was added. The solution was added to n-heptane (3 mL) and
evaporation afforded 14 mg (39%) of the title compound as a white
solid. R.sub.f=0.16 (10% MeOH in CH.sub.2Cl.sub.2). HPLC-MS (method
B) showed MH.sup.+=383. UV/MS(%)=100/96.
Example 100
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)acetami-
de (47AKU-7)
[0578] 1-Trifluoroacetyl-4-piperidone (47AKU-2)
[0579] 4-Piperidone hydrochloride monohydrate (3.85 g, 25 mmol) and
Triethylamine (10.5 ml, 75 mmol) were partly dissolved in 100 ml of
dichloromethane and stirred for 10 min. Reaction mixture was then
cooled on ice-bath and trifluoroacetic anhydride (7.2 ml, 50 mmol)
was slowly added over 10 min. Ice-bath was removed and mixture was
stirred overnight. Additional trifluoroacetic anhydride (2 ml)was
added and the mixture was stirred for 1 hr. Water (200 ml) was
added. Phases were separated and aq. phase was re-extracted with
dichloromethane. Combined organic phases were washed with brine,
dried over MgSO.sub.4 and concentrated (40.degree. C.) giving 4.97
g (100%) 47AKU-2 as yellow crystals. TLC (5% methanol in
dichloromethane): R.sub.f=0.8. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta.=3.87-3.99 (4H, m); 2.54-2.61 (4H, m). .sup.3C-NMR
(CDCl.sub.3): .delta. 204.7, 118.0, 115.1, 44.2, 42.8, 41.2,
40.5.
[0580] 4-(4-Methylbenzylamino)-1-trifluoroacetyl-piperidine
(47AKU-3)
[0581] 47AKU-2 (4.97 g, 25 mmol) was dissolved in 100 ml methanol
and 4-methylbenzyl-amine (3.2 ml, 25 mmol) was added. Mixture was
stirred and acetic acid (2 ml) was added until pH.about.5.
NaCNBH.sub.3 (3.15 g, 50 mmol) was slowly added. After magnetic
stirring for 20 hrs the methanol was partly removed on the rotary
evaporator (40.degree. C.). Dichloromethane, 2M NaOH and water were
added until pH.about.10. Phases were separated and aq. phase was
then re-extracted twice with dichloromethane. Combined organic
phases were washed with brine and dried over MgSO.sub.4.
Concentration (40.degree. C.) yielded 6.94 g (92%) 47AKU-3. TLC
(10% methanol in dichloromethane): R.sub.f=0.6. HPLC-MS (Method A):
M.sup.+=301.0 (UV/MS(%)=94/100).
[0582]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-trifluoroacetylpiperidin-
-4-yl)acetamide (47AKU4)
[0583] 47AKU-3 (3.01 g, 10 mmol) in 25 ml of dichloromethane was
placed in a 100 ml flask. Triethylamnie (1.4 ml, 10 mmol) was added
and the mixture was cooled on an ice-bath and stirred for 10 min.
4-Chlorophenylacetyl chloride (1.90 g, 10 mmol) was dissolved in 10
ml dichloromethane and added slowly to the ice-cold mixture. After
15 min. the ice-bath was removed and the mixture was left for 1 hr.
Precipitation was observed. The reaction mixture was then
concentrated at aspirator pressure (40.degree. C.). The crude
product was purified by flash chromatography (0-50% ethylacetate in
heptane) yielding 2.38 g (53%) 47AKU-4. TLC (100% dichloromethane):
R.sub.f=0.6. HPLC-MS (Method A): M.sup.+=453.0
(UV/MS(%)=89/84).
[0584]
2-4-Chlorophenyl)-N-(4-methylbenzyl)-N-piperidin-4-yl)acetamide
(47AKU-6)
[0585] 47AKU4 (2.38 g; 5 mmol) was dissolved in 50 ml of methanol.
K.sub.2CO.sub.3 (3.5 g; 25 mmol) was added in one portion. After
magnetic stirring for 20 hrs, additional K.sub.2CO.sub.3 (1 g) was
added. After 4 hrs magnetic stirring methanol was partly removed by
evaporation (40.degree. C.). Ethyl acetate (100 ml) and water (100
ml) were added. The phases were separated and the aq. phase was
then re-extracted with ethylacetate. The combined organic phases
were dried over MgSO.sub.4 and concentrated (40.degree. C.) giving
1.95 g (100%) 47AKU-6. TLC (20% methanol in dichloromethane):
R.sub.f=0.3. HPLC-MS (Method A): M.sup.+=357.1
(UV/MS(%)=84/95).
[0586]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)-
-acetamide (47AKU-7)
[0587] 47AKU-6 (358 mg, 1,0 mmol) was dissolved in 20 ml of
acetonitrile. Triethylamine (1.4 ml, 10 mmol) was added and mixture
was stirred for 10 min. Isopropyl bromide (370 mg, 3.0 mmol) was
dissolved in 5 ml of acetonitrile and added to the reaction mixture
which was stirred at room temp. for 20 hrs and then heated to
60.degree. C. for 4 hrs. After cooling, ethylacetate (25 ml) and
water (25 ml) were added. The phases were separated and the aq.
phase was then re-extracted with ethylacetate. The combined organic
phases were washed with brine, dried over MgSO.sub.4 and
concentrated (40.degree. C.) giving 362 mg of crude product.
Purification by flash chromatography (0-10% methanol in
dichloromethane) and HCl-precipitation from 2M HCl/diethyl ether in
dichloromethane/heptane gave 76 mg (18%) 47AKU-7. TLC (10% methanol
in dichloromethane): R.sub.f=0.4. Mp=223-224.degree. C. HPLC-MS
(Method A): M.sup.+=399.1 (UV/MS(%)=100/99). .sup.1H-NMR (400 MHz,
CDCl.sub.3): S=7.03-7.29 (8H, m); 4.86 (1H, m); 4.61 (2H, m); 3.58
(2H, m); 3.37 (3H, m); 2.82 (2H, m); 2.64 (2H, m); 2.34 (3H, s);
1.80 (2H, m); 1.39 (6H, d). .sup.13C-NMR (CDCl.sub.3): .delta.
172.4, 137.4, 134.8, 133.3, 133.1, 130.4, 129.9, 129.0, 125.8,
58.0, 49.5, 48.2, 46.6, 40.4, 26.0, 21.2, 17.0.
Example 101
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide
(47AKU-12)
[0588] 47AKU-6 (358 mg, 1.0 mmol) was dissolved in 20 ml of
acetonitrile. Triethylamine (1.4 ml, 10 mmol) was added and the
mixture was stirred for 10 min. Ethyl bromide (370 .mu.l, 5.0 mmol)
was added. The mixture was then heated to 50.degree. C. and stirred
overnight. After cooling, water (25 ml) and ethylacetate (25 ml)
were added. The phases were separated and the aq. phase was
re-extracted with ethylacetate. The combined organic phases were
washed with brine and dried over MgSO.sub.4. Evaporation
(40.degree. C.) yielded 406 mg of crude product. Purification by
ion exchange chromatography (washout with 10% aq. NH.sub.4OH (25%)
in methanol) gave 166 mg (43%) 47AKU-12. The HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.5. HPLC-MS (Method A):
M.sup.+=385.1 (UV/MS(%)=100/99). .sup.1H-NMR (400 MHz, CDCl.sub.3,
rotamers): .delta.=7.02-7.34 (8H, m); 4.62 (1H, m); 4.46 and 4.53
(2H, 2s); 3.81 (1H, s); 3.55 (2H, s); 2.92 (2H, m); 2.34 (3H, s);
2.29 (1H, s); 1.98 (2H, m); 1.52-1.84 (4H, 20m); 1.03 (3H, t).
.sup.13C-NMR (CDCl.sub.3): .delta.=171.7, 137.2, 135.4, 133.9,
132.8, 130.4, 129.7, 128.9, 125.8, 52.8, 52.4, 46.5, 40.8, 31.2,
29.8, 21.2, 12.4.
Example 102
2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(47AKU-13)
[0589] 47AKU-5 (218 mg, 1.0 mmol) was dissolved in 2 ml of
dichloromethane in a 50 ml flask. Phenylacetyl chloride (134 .mu.l,
1.0 mmol) was added. After 3 hrs stirring at room temp. mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by ion exchange chromatography (washout with 10% aq.
NH.sub.4OH (25%) in methanol) and flash chromatography (0-10%
methanol in dichloromethane) giving 48 mg (14%) 47AKU-13. HCl-salt
was prepared from 2M HCl/diethylether in dichloromethane/heptane.
TLC (10% methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method
A): M.sup.+=337.1 (UV/MS(%)=98/98). .sup.1H-NMR (400 MHz,
CDCl.sub.3, rotamers): .delta.=7.01-7.40 (9H, m); 4.63 (1H, m);
4.53 and 4.45 (2H, 2s); 3.85 and 3.61 (2H, 2s); 2.86 and 2.77 (2H,
2m); 2.35 and 2.29 (3H, 2s); 2.25 and 2.20 (3H, 2s); 2.09 (2H, m);
1.61-186 (4H, m). .sup.13C-NMR (CDCl.sub.3): .delta.=1072.2, 137.1,
135.5, 129.7, 128.9, 128.8, 127.2, 126.9, 125.8, 55.3, 51.6, 46.6,
46.1, 41.6, 29.5, 21.2.
Example 103
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-((1-methylpiperidin-4-yl)-acetamid-
e (47AKU-8)
[0590] 4-(4-Methylbenzylamino)-1-methyl-piperidine (47AKU-5)
[0591] 1-Methyl-4-piperidone (1.13 g, 10 mmol) was dissolved in 20
ml of methanol and added to a 100 ml flask. 4-Methylbenzylamine
(1.21 g, 10 mmol) in 10 ml of methanol was added. Acetic acid
(.about.1.5 ml) was added until pH.about.5. NaCNBH.sub.3 (1.26 g,
20 mmol) was slowly added. After 20 hrs magnetic stirring methanol
was partly removed on Rotavapor (40.degree. C.). Dichloromethane,
water and 2M NaOH were added until pH.about.10. The phases were
separated and aq. phase was extracted twice with dichloromethane.
The combined organic phases were washed with brine and dried over
MgSO.sub.4. Concentration on Rotavapor (40.degree. C.) yielded 2.06
g crude (93%) 47AKU-5. TLC (20% methanol in dichloromethane):
R.sub.f=0.3. HPLC-MS (Method A): M.sup.+=219.1
(UV/MS(%)=89/98).
[0592]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ace-
tamide
[0593] (47AKU-8)
[0594] 47AKU-5 (437 mg, 2.0 mmol) was dissolved in 10 ml of
dichloromethane in a 50 ml flask. Triethylamine (280 .mu.l, 2.0
mmol) was added and the mixture was cooled to 0.degree. C. on an
ice bath and stirred for 10 min. 4-Chlorophenylacetyl chloride (380
mg, 20.0 mmol) was dissolved in 10 ml of dichloromethane and added
to the cooled mixture. After 2 hrs stirring at room temp.
additional dichloromethane (10 ml) and water (20 ml) were added.
The phases were separated and the aq. phase was re-extracted with
dichloromethane. The combined organic phases were dried over
MgSO.sub.4 and concentrated on the Rotavapor (40.degree. C.) giving
755 mg of crude product. Purification by flash chromatography
(0-10% methanol in dichloromethane) gave 485 mg (65%) product.
Further purification by ion exchange chromatography (washout with
10% aq. NH.sub.4OH (25%) in methanol) gave 239 mg (32%) 47AKU-8.
The HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.4. Mp=217-219.degree. C. HPLC-MS (Method A):
M.sup.+=371.1 (UV/MS(% O)99/99). .sup.1H-NMR (400 MHz, CD.sub.3OD):
.delta. 7.05-7.39 (8H, m); 4.80 (3H, s); 4.62+4.56 (2H, 2s); 4.35
(1H, m); 4.00 (1H, s); 3.71 (1H, s); 3.46 (2H, m); 3.06 (2H, m);
2.80 (3H, s); 2.32+2.27 (3H, 2s); 2.19 (1H, m). .sup.3C-NMR
(CD.sub.3OD): .delta.=173.0, 137.5, 134.5, 133.9, 132.6, 130.6,
129.5, 128.5, 126.2, 54.0, 51.4, 42.6, 40.2, 31.8, 26.6, 19.9.
Example 104
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)aceta-
mide (47AKU-11)
[0595] 47AKU-6 (358 mg, 1,0 mmol) was dissolved in 20 ml of
acetonitrile. Triethylamine (1.4 ml, 10 mmol) was added and mixture
was stirred for 10 min. Cyclopentylbromide (540 .mu.l, 5.0 mmol)
was added and the mixture was stirred at room temp. After 20 hrs
the mixture was heated to 50.degree. C. for an additional 24 hrs.
The reaction mixture was then cooled and water (25 ml) and
ethylacetate (25 ml) were added. The phases were separated and the
aq. phase was re-extracted with ethylacetate. The combined organic
phases were washed with brine and dried over MgSO.sub.4.
Concentration on Rotavapor (45.degree. C.) yielded 426 mg of crude
product. Purification by ion exchange chromatography (washout with
10% aq. NH.sub.4OH (25%) in methanol) and flash chromatography
(0-10% methanol in dichloromethane) gave 76 mg (18%) 47AKU-11. The
HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.5. HPLC-MS (Method A): M.sup.+=425.1 (UV/MS(%)=100/97).
.sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta.=7.01-7.34 (8H,
m); 4.67 (1H, m); 4.49 and 4.52 (2H, 2s); 3.54 (2H, s); 3.15 and
3.02 (2H, 2m); 2.64 (1H, m); 2.27 and 2.34 (3H, 2s); 2.20 (1H, m);
1.85 (4H, m); 1.69 (4H, m); 1.53 (41, m); 1.37 (1H, m).
.sup.13C-NMR (CDCl.sub.3): .delta.=171.9, 137.2, 135.2, 133.8,
132.9, 130.4, 129.7, 128.9, 125.8, 67.7, 52.4, 52.1, 46.5, 40.7,
30.2, 28.8, 24.3, 21.2.
Example 105
2-(4-Flourophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(47AKU-14)
[0596] 47AKU-5 (218 mg, 1.0 mmol) was dissolved in 3 ml of
dichloromethane in a 50 ml flask. 4-Fluorophenylacetyl chloride
(150 .mu.l, 1.1 mmol) was added. After 4 hrs stirring at room temp.
the mixture was concentrated on Rotavapor (40.degree. C.). The
crude product was purified by flash chromatography (0-10% methanol
in dichloromethane) giving 243 mg (68%) 47AKU-14. The HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.5. HPLC-MS (Method A):
M.sup.+=355.1 (UV/MS(%)=100/100). .sup.1H-NMR (400 MHz,
CDCl.sub.3): =6.92-7.33 (8H, m); 4.73 (1H, m); 4.52 (2H, s); 3.56
(2H, 2s); 3.44 (5H, m); 3.25 (2H, m); 2.52-2.67 (4H, m); 2.33 (3H,
s). .sup.3C-NMR (CDCl.sub.3): .delta.=172.5, 163.3, 160.9, 139.5,
134.8, 130.6, 129.8, 125.8, 115.8, 54.6, 50.8, 49.9, 46.7, 40.4,
27.2, 21.2.
Example 106
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperidin-4-yl-
)acetamide (47AKU-18)
[0597] 47AKU-6-2 (358 mg, 1,0 mmol) was dissolved in 10 ml of
acetonitrile in 50 ml flask. Triethylamine (1.4 ml, 10 mmol) was
added and mixture was stirred for 10 min.
[0598] 2-Bromoethanol (215 .mu.l, 3.0 mmol) was added. Reaction
mixture was then heated to 60.degree. C. and stirred overnight.
After cooling ethylacetate (25 ml) and water. (25 ml) were added.
Phases were separated and aq. phase was re-extracted with
ethylacetate. Combined organic phases were washed with brine, dried
over MgSO.sub.4 and concentrated on Rotavapor (40.degree. C.)
giving 406 mg crude product. Purification by flash chromatography
(0-10% methanol in dichloromethane) afforded 253 mg (63%) 47AKU-18.
HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.4. HPLC-MS (Method A): M.sup.+=401.1 (UV/MS(%)=100/100).
.sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta.=7.04-7.34 (8H,
m); 4.60 (1H, m); 4.52 and 4.45 (2H, 2s); 3.55 (4H, m); 3.03 (1H,
bs); 2.92 (2H, m); 2.52 (2H, m); 2.36 and 2.31 (3H, 2s); 2.19 (2H,
m); 1.66 (4H, m).). .sup.13C-NMR (CDCl.sub.3): .delta.=171.7,
137.3, 135.2, 133.8, 132.9, 130.4, 129.8, 128.9, 125.8, 59.4, 58.1,
53.1, 52.3, 46.8, 40.8, 29.7, 21.2.
Example 107
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-aceta-
mide (47AKU-19)
[0599] 1-Cyclobutyl-4-piperidone (47AKU-15).
[0600] Partly dissolved quartenary salt (1.23 g, 3.7 mmol)
(prepared according to the procedure outlined in the synthesis of
47AKU47) was slowly added to a refluxing solution of
Cyclobutylamine (178 mg, 2.5 mmol) and Potassium carbonate (48 mg,
0.34 mmol) in ethanol. The mixture was refluxed for 1.5 hrs. After
cooling to room temp water (10 ml) and dichloromethane (25 ml) were
added. Phases were separated and aq. phase was re-extracted with
dichloromethane. Combined organic phases were dried over MgSO.sub.4
and concentrated on Rotavapor (40.degree. C.) giving 419 mg crude
47AKU-15. TLC (10% methanol in dichloromethane): R.sub.f=0.4.
HPLC-MS (Method A): M.sup.+=154.1 (MS(%)=75).
[0601] 4-(4-Methylbenzylamino)-1-cyclobutyl-piperidine
(47AKU-16)
[0602] 4-Methylbenzylamine (215 mg, 1.8 mmol) was dissolved in 5 ml
methanol and placed in 50 ml flask. 47AKU-15 (270 mg, 1.8 mmol) in
5 ml methanol was added. Acetic acid (0.3 ml) was added until
pH.about.5. NaCNBH.sub.3 (226 mg, 3.6 mmol) was slowly added. Gas
evolution observed. After 24 hrs magnetic stirring dichloromethane,
2M NaOH and water were added until pH.about.0. Phases were
separated and aq. phase was then re-extracted with dichloromethane.
Combined organic phases were dried over MgSO.sub.4 and concentrated
on Rotavapor (40.degree. C.) yielding 419 mg crude 47AKU-16. TLC
(10% methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=259.1 (UV/MS(%)-=44/87).
[0603]
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl-
)acetamide (47AKU-19)
[0604] 47AKU-16 (209 mg, 0.8 mmol) was placed in. 50 ml flask and 5
ml dichloromethane was added. 4-Chlorophenylacetyl chloride (171
mg, 0.9 mmol) in 5 ml dichloromethane was added. After 5 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 101 mg
(31%) product. Further purification by ion exchange chromatography
(washout with 10% aq. NH.sub.4OH (25%) in methanol) gave 55 mg
(17%) 47AKU-19. Oxalate-salt was prepared from Oxalic acid (1.1 eq)
in dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.6. HPLC-MS (Method B): M.sup.+=411.2 (UV/MS(%)=91/86).
.sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta. 7.33-7.01 (8H,
m); 4.62 (1H, m); 4.52 and 4.46 (2H, 2s); 3.80 (1H, s); 3;45 and
3.54 (2H, 2s); 2.86 (2H, m); 2.66 (2H, m); 2.28 and 2.34 (3H, 2s);
1.98 (2H, m); 1.80 (2H, m); 1.70-1.52 (6H, m). .sup.13C-NMR
(CDCl.sub.3): .delta.=171.7, 137.2, 135.4, 133.9, 132.9, 130.4,
129.7, 128.9, 125.7, 60.4, 52.3, 49.4, 46.5, 40.7, 29.4, 27.6,
21.2, 14.2.
Example 108
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)aceta-
mide (47AKU-20)
[0605] 47AKU-16 (209 mg, 0.8 mmol) was placed in 50 ml flask and 5
ml dichloromethane was added. 4-Methoxyphenylacetyl chloride (167
mg, 0.9 mmol) in 5 ml dichloromethane was added. After 5 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 72 mg
(22%) product. Further purification by ion exchange chromatography
(washout with 10% aq. NH.sub.4OH (25%) in methanol) gave 67 mg
(20%) 47AKU-20. Oxalate-salt was prepared from Oxalic acid (1.1 eq)
in dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.6. HPLC-MS (Method B): M.sup.+=407.3 (UV/MS(%)-=3/77).
.sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta.=7.26-6.79 (8H,
m); 4.62 (1H, m); 4.52 and 4.45 (2H, 2s); 3.79 (1H, m); 3.77 (3H,
s); 3.52 and 3.45 (2H, 2s); 2.84 (2H, m); 2.66 (2H, m); 2.34 and
2.28 (3H, 2s); 1.98 (2H, m); 1.81 (2H, m); 1.72-1.51 (6H, m).
.sup.3C-NMR (CDCl.sub.3): .delta.=172.5, 158.7, 137.0, 135.7,
130.4, 129.8, 127.4, 125.8, 114.3, 60.4, 55.5, 52.1, 49.4, 46.4,
40.6, 29.4, 27.6, 21.2, 14.2.
Example 109
(47AKU-21)2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(tropin-4-yl)acetamide
(47AKU-21)
[0606] 4-(4-Methylbenzylamino)-tropane (47AKU-17)
[0607] 4-Methylbenzylamine (607 mg, 5.0 mmol) was dissolved in 10
ml methanol and placed in 100 ml flask. Tropinone (697 mg, 5.0
mmol) in 10 ml methanol was added. Acetic acid (0.75 ml) was added
until pH.about.5. NaCNBH.sub.3 (628 mg, 10 mmol) was slowly added.
Gas evolution observed. After 20 hrs magnetic stirring
dichloromethane, 2M NaOH and water were added until pH.about.10.
Phases were separated and aq. phase was then re-extracted with
dichloromethane. Combined organic phases were dried over
MgSO.sub.4. Concentration on Rotavapor (40.degree. C.) yielded 1.14
g crude 47AKU-17. TLC (10% methanol in dichloromethane):
R.sub.f=0.4. HPLC-MS (Method A): M.sup.+=245.2
(UV/MS(%)=65/96).
[0608]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(tropin-4-yl)-acetamide
(47AKU-21)
[0609] 47AKU-17 (244 mg, 1.0 mmol) was placed in 50 ml flask and 5
ml dichloromethane was added. 4-Methoxyphenylacetyl chloride (203
mg, 1.1 mmol) in 10 ml dichloromethane was added. After 3 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by ion
exchange chromatography (washout with 10% aq. NH.sub.4OH (25%) in
methanol) and flash chromatography (0-10% methanol in
dichloromethane) giving 202 mg (51%) 47AKU-21. Oxalate-salt was
prepared from Oxalic acid (1.1 eq) in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method B):
M.sup.+=393.3 (UV/MS(%)=94/92). .sup.1H-NMR (400 MHz, CDCl.sub.3,
isomers): .delta.=7.02-7.17 (6H, m); 6.78-6.87 (2H, m); 4.74 (1H,
s); 4.44 (1H, s); 3.78 and 3.77 (3H, 2s); 3.68 (1H, m); 3.66 and
3.55 (3H, 2s); 2.65 (2H, m); 2.56 (2H, m); 2.32 (3H, s); 2.12-2.26
(6H, m); 2.05 (2H, m). .sup.13C-NMR (CDCl.sub.3): & 173.2,
171.4, 158.8, 137.1, 129.7, 127.6, 126.9, 126.0, 114.4, 63.4, 60.9,
55.5, 54.6, 47.5, 41.5, 40.4, 32.8, 31.1, 27.5, 24.9, 21.2.
Example 110
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-benzyl-carbamide
(47AKU-22)
[0610] 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml
dichloromethane and placed in 50 ml flask. Benzylisocyanate (160
mg, 1.2 mmol) in 5 ml dichloromethane was added. After 16 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 236 mg
(67%) 47AKU-22. Oxalate-salt was prepared from Oxalic acid (1.1
eq)in dichloromethane/heptane. TLC (10% methanol in
dichloromethane): R.sub.f=0.5. HPLC-MS (Method B): M.sup.+=352.3
(UV/MS(%)=100/100). .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
7.26-7.02 (9H, m); 4.61 (1H, m); 4.41 (1H, m); 4.33 (4H, m); 2.87
(2H, m); 2.32 (3H, s); 2.25 (3H, s); 2.09 (2H, m); 1.79-1.62 (4H,
m). .sup.13C-NMR (CDCl.sub.3): .delta.=158.6, 139.7, 137.3, 135.4,
129.8, 128.6, 127.4, 127.2, 126.2, 55.5, 52.2, 46.2, 45.8, 45.0,
30.2, 21.2.
Example 111
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4yl)-N'-phenyl carbamide
(47AKU-24)
[0611] 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml
dichloromethane and placed in 50 ml flask. Phenylisocyanate (143
mg, 1.2 mmol) in 5 ml dichloromethane was added. After 4 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 181 mg
(54%) 47AKU-24. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.4. HPLC-MS (Method A): M.sup.+=338.3 (UV/MS(%)=100/100).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 7.12-7.24 (8H, m);
6.93-6.98 (1H, m); 6.26 (1H, s); 4.45 (3H, s); 2.90 (2H, d); 2.36
(3H, s); 2.28 (3H, s); 2.12 (2H, m); 1.69-1.85 (4H, m).
.sup.13C-NMR (CDCl.sub.3): .delta.=156.1, 139.3, 137.8, 134.9,
130.1, 128.9, 126.3, 123.1, 119.9, 55.5, 52.3, 46.3, 46.2, 30.3,
21.3.
Example 112
N-Phenethyl-N-(1-methylpiperidin 4-yl)-N'-benzyl-carbamide
(47AKU-25)
[0612] 4-(2-Phenylethyl)amino-1-methylpiperidine (110 mg, 0.5 mmol)
was dissolved in 5 ml dichloromethane and placed in 50 ml flask.
Benzylisocyanate (80 mg, 0.6 mmol) in 5 ml dichloromethane was
added. After 20 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 164 mg (84%) 47AKU-25. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f 0.4. HPLC-MS (Method A):
M.sup.+=352.3 (UV/MS(%)=100/100). .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.=7.34-7.09 (10H, m); 4.52 (1H, m); 4.35 (2H,
d); 4.08 (1H, m); 3.33 (2H, t); 2.92 (2H, m); 2.82 (2H, t); 2.28
(3H, s); 2.07 (2H, m); 1.84-1.66 (4H, m). .sup.13C-NMR
(CDCl.sub.3): .delta.=157.9, 139.8, 139.1, 129.0, 128.9, 128.8,
127.8, 127.4, 126.9, 55.7, 52.8, 46.2, 45.3, 44.8, 37.5, 30.6.
Example 113
2-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(47AKU-26a)
[0613] 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml
dichloromethane in 50 ml flask.
[0614] 4-Fluorophenylacetyl chloride (104 mg, 0.6 mmol) was added.
After 20 hrs stirring at room temp. mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 87 mg
(49%) 47AKU-26a. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane- . HPLC-MS (Method A): M.sup.+=353.1
(UV/MS(%)=96/88).
Example 114
2-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidinyl)-ac-
etamide (47AKU-26b)
[0615] 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml
dichloromethane in 50 ml flask.
[0616] 4-Trifluoromethylphenylacetyl chloride (134 mg, 0.6 mmol)
was added. After 20 hrs stirring at room temp. mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 81 mg (39%) 47AKU-26b. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane.
HPLC-MS (Method A): M.sup.+=421.1 (UV/MS(%)=90/100).
Example 115
2-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamid-
e (47AKU-26c)
[0617] 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml
dichloromethane in 50 ml flask.
[0618] 4-Fluorophenylacetyl chloride (104 mg, 0.6 mmol) was added.
After 20 hrs stirring at room temp. mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 68 mg
(37%) 47AKU-26c. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane- . HPLC-MS (Method A): M.sup.+=371.1
(UV/MS(%)=100/97).
Example 116
2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)acetamid-
e (47AKU-26d)
[0619] 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml
dichloromethane in 50 ml flask.
[0620] 4-Methoxyphenylacetyl chloride (111 mg, 0.6 mmol) was added.
After 20 hrs stirring at room temp. mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 77 mg
(40%) 47AKU-26d. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane- . HPLC-MS (Method A): M.sup.+=383.1
(UV/MS(%)=100/100).
Example 117
2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperidin-4-yl)-acetamide
(47AKU-28)
[0621] 4-(4-Chlorobenzylamino)-1-methyl-piperidine (47AKU-27)
[0622] 1-Methyl-4-piperidone (566 mg, 5.0 mmol) was dissolved in 10
ml methanol and placed in 100 ml flask. 4-Chlorobenzylamine (708
mg, 5.0 mmol) was added.
[0623] Mixture was stirred and Acetic acid (0.75 ml) was added
until pH.about.5. NaCNBH.sub.3 (628 mg, 10 mmol) was slowly added.
Gas evolution observed. After magnetic stirring for 16 hrs methanol
was partly removed on Rotavapor (40.degree. C.). Dichloromethane,
2M NaOH and water were added until pH.about.10. Phases were
separated and aq. phase was then re-extracted with dichloromethane.
Combined organic phases were dried over MgSO.sub.4. Concentration
on Rotavapor (40.degree. C.) yielded 1.14 g crude 47AKU-27. TLC
(10% methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=239.1 (MS(%)=96).
[0624]
2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperidin-4-yl)ace-
tamide
[0625] (47AKU-28)
[0626] p-Tolylacetic acid (1.50 g) was dissolved in 10 ml
thionylchloride and placed in 50 ml flask. Mixture was heated to
reflux for 2 hrs and then concentrated on Rotavapor (40.degree.
C.).
[0627] p-Tolylacetic chloride (202 mg, 1.2 mmol) in 5 ml
dichloromethane was added to 47AKU-27 (239 mg, 1.0 mmol) in 5 ml
dichloromethane. After 4 hrs magnetic stirring the reaction mixture
was concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (6-10% methanol in
dichloromethane) giving 104 mg (28%) 47AKU-28. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane- . TLC
(10% methanol in dichloromethane): R.sub.f=0.5. HPLC-MS (Method A):
M.sup.+=371.1 (UV/MS(%)=100/90). .sup.1H-NMR (400 MHz, CDCl.sub.3,
rotamers): .delta.=7.34-6.99 (8H, m); 4.57 (1H, m); 4.50 and 4.44
(2H, 2s); 3.80 (1H, s); 3.55 (1H, s); 2.96 and 2.82 (2H, 2m); 2.34
(1H, m); 2.32 (3H, s); 2.24 and 2.15 (3H, 2s); 1.91 (1H, m);
1.81-1.59 (4H, m). .sup.13C-NMR(CDCl.sub.3): .delta.=172.5, 138.2,
136.8, 133.4, 131.8, 129.7, 129.2, 128.6, 127.4, 54.9, 51.3, 46.7,
41.3, 30.6, 28.6, 21.2.
Example 118
2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-1-methylpiperidin-4-yl)-acetamide
(47AKU-29)
[0628] 42ELH-77 (41 mg, 0.1 mmol) was dissolved in 1 ml dry
dichloromethane and placed in oven-dried 10 ml flask. Mixture was
cooled to -78.degree. C. on a dry-ice/isopropanol bath.
Borontribromide (1.0 M in dichloromethane, 150 .mu.l, 0.15 mmol)
was slowly added at
[0629] -78.degree. C. Ice-bath was removed and mixture was left at
room temp. for 2 hrs. Water (3 ml) and saturated NaCl (aq.) were
added and aq. phase was extracted with dichloromethane,
ethylacetate and n-butanol. Combined organic phases were dried over
MgSO.sub.4 and concentrated on Rotavapor (40.degree. C.). Crude
product was purified by flash chromatography (0-20% methanol in
dichloromethane) giving 22 mg (63%) 47AKU-29. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=353.2 (UV/MS(%)=100/100). .sup.1H-NMR (400 MHz, CDCl.sub.3,
rotamers): .delta.=7.07-6.60 (8H, m); 4.48 (1H, m); 4.39 (2H, s);
3.76 and 3.66 (4H, 2bs); 3.41 (2H, s); 3.08 (2H, m); 2.49 (1H, m);
2.42 (2H, bs); 2.22 and 2.16 (3H, 2s); 1.96-1.82 (2H, m); 1.66-1.56
(1H, m). .sup.13C-NMR (CDCl.sub.3): .delta.=173.7, 156.0, 137.3,
134.6, 129.7, 129.6, 125.1, 125.4, 115.7, 54.4, 50.4, 46.8, 44.0,
40.5, 27.3, 20.9.
Example 119
N-Phenethy-N-(1-methylpiperidin-4-yl)-N'-phenyl-carbamide
(47AKU-30)
[0630] 4-(2-Phenylethyl)amino-1-methylpiperidine (10 mg, 0.5 mmol)
was dissolved in 5 ml dichloromethane and placed in 50 ml flask.
Phenylisocyanate (71 mg, 0.6 mmol) in 5 ml dichloromethane was
added. After 16 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified twice by flash chromatography (0-10% methanol in
dichloromethane) giving 131 mg (78%) 47AKU-30. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method A):
M.sup.+=338.1 (UV/MS(%)=99/100). .sup.1-NMR (400 MHz, CDCl.sub.3):
.delta.=7.36-6.93 (10H, m); 6.24 (1H, s); 4.31 (1H, m); 3.50 (2H,
t); 3.20 (2H, d); 2.89 (2H, t); 2.57 (2H, m); 2.50 (3H, s); 2.26
(2H, m); 1.79 (2H, m). .sup.13C-NMR (CDCl.sub.3): .delta.=155.8,
139.2, 139.0, 129.4, 129.3, 128.9, 127.3, 123.2, 120.4, 54.9, 51.3,
45.5, 44.3, 37.6, 28.3.
Example 120
N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N-benzyl-carbamide
(47AKU-31)
[0631] 4-(3-Phenylpropyl)amino-1-methylpiperidine (160 mg, 0.7
mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml
flask. Benzylisocyanate (107 mg, 0.8 mmol) in 5 ml dichloromethane
was added. After 2 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified twice by flash chromatography (0-10% methanol in
dichloromethane) giving 156 mg (61%) 47AKU-31. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=366.1 (UV/MS(%)=100/100). .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.=7.34-7.07 (10H, m); 4.33 (3H, m); 4.14 (1H,
m); 3.04 (2H, m); 2.89 (2H, d); 2.57 (2H, t); 2.28 (3H, s); 2.06
(2H, m); 1.87 (2H, m); 1.75-1.62 (4H, m). .sup.13C-NMR
(CDCl.sub.3): .delta.=157.5, 141.0, 140.0, 129.0, 128.6, 128.3,
128.0, 127.6, 126.6, 55.6, 52.1, 46.3, 45.1, 41.6, 33.4, 32.2,
30.6.
Example 121
N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-phenyl-carbamide
(47AKU-32)
[0632] 4-(3-Phenylpropyl)amino-1-methylpiperidine (160 mg, 0.7
mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml
flask. Phenylisocyanate (95 mg, 0.8 mmol) in 5 ml dichloromethane
was added. After 20 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 106 mg (43%) 47AKU-32. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=352.1 (UV/MS(%)=1100/100). .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.=7.35-6.95 (10H, m); 5.99 (1H, s); 4.18 (1H,
m); 3.17 (2H, t); 2.91 (2H, d); 2.65 (2H, t); 2.28 (3H, s); 2.07
(2H, m); 1.97 (2H, m); 1.81-1.66 (4H, m). .sup.13C-NMR
(CDCl.sub.3): .delta.=154.9, 141.0, 139.3, 129.2, 129.0, 129.0,
126.8, 123.1, 120.0, 55.6, 52.2, 46.2, 41.8, 33.4, 32.3, 30.6.
Example 122
2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-
-yl)acetamide (47AKU-33)
[0633] 1-(4-Methoxyphenyl)-1-cyclopropane carboxylic acid (230 mg,
1.2 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml
flask. Mixture was heated to reflux for 2 hrs and then concentrated
on Rotavapor (40.degree. C.). The acid chloride (250 mg, 1.2 mmol)
in 5 ml dichloromethane was added to 47AKU-5 (220 mg, 1.0 mmol) in
5 ml dichloromethane. After 2 hrs magnetic stirring the reaction
mixture was concentrated on Rotavapor (40.degree. C.). Crude
product was purified twice by flash chromatography (0-10% methanol
in dichloromethane) giving 201 mg, (51%) 47AKU-33. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f 0.6. HPLC-MS (Method A):
M.sup.+=393.2 (UV/MS(%)=95/88).
[0634] .sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta.
7.22-6.70 (8H, m); 4.44 (2H, s); 4.26 (1H, m); 3.74 (3H, s); 3.12
and 2.89 (2H, 2m); 2.51 (1H, m); 2.32 (3H, m); 2.26 (3H, s);
2.08-1.52 (4H, m); 1.36 (2H, bs); 1.15-0.95 (3H, m). .sup.13C-NMR
(CDCl.sub.3): .delta.=172.9, 158.6, 136.6, 132.7, 129.2, 128.6,
127.9, 127.4, 114.4, 55.5, 55.1, 54.4, 45.2, 45.0, 29.8, 29.2,
21.2, 13.8.
Example 123
2-(4-Methoxyphenyl)-N-(1-phenylethyl)-N-(1-methylpiperidin-4-yl)acetamide
(47AKU-37) 4-Alpha-methylbenzylamino-1-methyl-piperidine
(47AKU-36)
[0635] DL-Phenylethylamine (606 mg, 5.0 mmol) was dissolved in 10
ml methanol and 1-Methyl-4-piperidone (566 mg, 5.0 mmol) in 10 ml
methanol was added. Mixture was stirred and Acetic acid (0.75 ml)
was added until pH.about.5. NaCNBH.sub.3 (628 g, 10 mmol) was
slowly added. Gas evolution observed. After magnetic stirring for
20 hrs methanol was partly removed on Rotavapor (40.degree. C.).
Ethylacetate, 2M NaOH and water were added until pH.about.10.
Phases were separated and aq. phase was then re-extracted with
ethylacetate and dichloromethane. Combined organic phases were
dried over MgSO.sub.4. Concentration on Rotavapor (40.degree. C.)
yielded 838 mg crude 47AKU-36. TLC (10% methanol in
dichloromethane): R.sub.f=0.3. HPLC-MS (Method A): M.sup.+=219.1
(UV/MS(%)=1100/94).
[0636]
2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl)
acetamide (47AKU-37)
[0637] 47AKU-36 (218 mg, 1.0 mmol) was dissolved in 10 ml
dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl
chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added.
After 16 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 256 mg (70%) 47AKU-37. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.5. HPLC-MS (Method A):
M.sup.+=367.3 (UV/MS(%)=100/99).
[0638] .sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta.
7.34-7.06 (7H, m); 6.84 (2H, d); 5.10 (1H, m); 3.77 (3H, s); 3.67
(2H, m); 3.17 (1H, m); 3.03-2.75 (3H, m); 2.64 (3H, s); 2.38 (2H,
m); 1.77-1.05 (6H, m). .sup.13C-NMR (CDCl.sub.3): .delta. 172.0,
158.9, 139.9, 130.0, 129.0, 128.2, 127.1, 114.5, 55.5, 53.1, 51.4,
42.4, 41.3, 31.1, 29.5, 24.9, 18.1.
Example 124
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(3-tropen-4-yl)acetamide
(47AKU-39)
[0639] 4-Methylbenzylmino-tropane (47AKU-38)
[0640] 4-Methylbenzylamine (1.21 g, 10 mmol) and Tropinone (1.39 g,
10 mmol) were placed in 100 ml flask and dissolved in 50 ml
toluene. Mixture was heated to reflux for 3 hrs and water was
removed using a Dean/Stark water-separator. Crude product was
concentrated on Rotavapor (40.degree. C.) giving 47AKU-38. TLC (10%
methanol in dichloromethane): R.sub.f=0.3. .sup.1H-NMR (400 MHz,
CDCl.sub.3, isomers): 7.20-7.09 (4H, m); 4.47 (1H, m); 3.81 (1H,
s); 3.42 (1H, m); 3.31 (1H, m); 2.77-2.56 (2H, m); 2.47 and 2.41
(3H, 2s); 2.33 and 2.31 (3H, 2s); 2.27-1.97 (4H, m); 1.69-1.54 (2H,
m).
[0641]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(3-tropen-4-yl)acetamide
(47AKU-39)
[0642] 47AKU-38 (242 mg, 1.0 mmol) was dissolved in 5 ml
dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl
chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added.
After 16 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 69 mg (18%) 47AKU-39. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method A):
M.sup.+=391.2 (UV/MS(%)=91/86).
[0643] .sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers):
.delta.=7.22-6.82 (8H, m); 5.41 (1H, bs); 4.71-4.52 (2H, m); 3.78
(3H, s); 3.68 (2H, m); 3.44-3.24 (2H, m); 2.72-2.36 (5H, m); 2.32
(3H, s); 2.25-2.00 (2H, m); 1.80-1.54 (2H, .sup.13C-NMR
(CDCl.sub.3): .delta.=170.8, 158.7, 137.4, 134.9, 130.1, 129.3,
128.9, 126.9, 114.2, 59.0, 58.0, 55.5, 49.5, 46.3, 39.7, 35.9,
33.8, 29.7, 21.3.
Example 125
2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(47AKU40)
[0644] 2-Phenylbutyric acid (197 mg, 1.2 mmol) was dissolved in 2
ml thionylchloride and placed in 50 ml flask. Mixture was heated to
reflux for 2 hrs and then concentrated on Rotavapor (50.degree.
C.). The acid chloride (1.2 mmol) in 5 ml dichloromethane was added
to 47AKU-5 (158 mg, 0.72 mmol) in 5 ml dichloromethane. After 20
hrs magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 196 mg
(74%) 47AKU-40. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.5. HPLC-MS (Method A): M.sup.+=365.4 (UV/MS(%)=99/100).
.sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers): .delta.=7.32-6.98 (8H,
m); 4.77 (1H, bs); 4.50 (1H, d); 4.29 (1H, d); 3.43 and 3.21 (3H,
2m); 2.72 (2H, m); 2.62 (3H, s); 2.43 (1H, m); 2.32 (3H, s); 2.21
(3H, m); 2.04 (2H, m); 1.67 (3H, m); 0.92-0.72 (3H, m). .sup.3C-NMR
(CDCl.sub.3): .delta.=174.7, 139.9, 137.3, 135.2, 129.7, 129.0,
127.8, 127.3, 125.8, 54.5, 51.6, 49.4, 46.0, 43.8, 28.9, 26.7,
26.3, 21.2, 12.7.
Example 126
2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetamide
(47AKU43)
[0645] 4-(1-Indanamino)-1-methyl-piperidine (47AKU42)
[0646] 1-Aminoindane (666 mg, 5.0 mmol) was dissolved in 10 ml
methanol and placed in 100 ml flask. 1-Methyl-4-piperidone (566 mg,
5.0 mmol) in 10 ml methanol was added. Mixture was stirred and
Acetic acid (0.75 ml) was added until pH.about.5. NaCNBH.sub.3 (628
g, 10 mmol) was slowly added. Gas evolution observed. After
magnetic stirring for 16 hrs methanol was partly removed on
Rotavapor (40.degree. C.). Dichloromethane, 2M NaOH and water were
added until pH.about.10. Phases were separated and aq. phase was
then re-extracted with ethylacetate and dichloromethane. Combined
organic phases were dried over MgSO.sub.4. Concentration on
Rotavapor (40.degree. C.) yielded 1.06 g 47AKU42. TLC (10% methanol
in dichloromethane): R.sub.f 0.3. HPLC-MS (Method A): M.sup.+=231.1
(UV/MS(%)=72/91).
[0647] 2-(4-Methoxyphenyl)-N-1-indanyl)-N-(1-methylpiperidin-4-yl)
ac tamide (47AKU43)
[0648] 47AKU42 (230 mg, 1.0 mmol) was dissolved in 10 ml
dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl
chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added.
After 16 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 194 mg (51%) 47AKU43. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.5. HPLC-MS (Method A):
M.sup.+=379.2 (UV/MS(%)=94/90).
Example 127
(47AKU44)-N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-methoxybenzy-
l)carbamide (47AKU-44)
[0649] 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml
dichloromethane and placed in 50 ml flask.
4-Methoxybenzylisocyanate (196 mg, 1.2 mmol) in 10 ml
dichloromethane was added. After 16 hrs magnetic stirring the
reaction mixture was concentrated on Rotavapor (40.degree. C.).
Crude product was purified by flash chromatography (0-10% methanol
in dichloromethane) giving 192 mg (50%) 47AKU-44. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=382.3 (UV/MS(%)=100/94). .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta.=7.10 (4H, m); 6.98 (2H, m); 6.76 (2H, m); 4.58 (1H, t);
4.45 (1H, m); 4.33 (2H, s); 4.25 (2H, d); 3.76 (3H, s); 2.97 (2H,
m); 2.34 (3H, s); 2.32 (3H, s); 2.24 (2H, m); 1.78 (4H, m).
.sup.13C-NMR (CDCl.sub.3): .delta.=158.9, 158.5, 137.3, 135.2,
131.8, 129.8, 128.8, 126.2, 114.1, 55.5, 55.4, 51.7, 45.8, 45.7,
44.5, 29.7, 21.2.
Example 128
2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)aceta-
mide (47AKU45)
[0650] 3,4-Dimethoxyphenylbutyric acid (235 mg, 1.2 mmol) was
dissolved in 2 ml thionylchloride and placed in 50 ml flask.
Mixture was heated to reflux for 2 hrs and then concentrated on
Rotavapor (50.degree. C.). The acid chloride (1.2 mmol) in 5 ml
dichloromethane was added to 47AKU-5 (219 mg, 1.0 mmol) in 10 ml
dichloromethane. After 16 hrs magnetic stirring the reaction
mixture was concentrated on Rotavapor (40.degree. C.). Crude
product was purified by flash chromatography (0-10% methanol in
dichloromethane) giving 129 mg (33%) 47AKU45. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method A):
M.sup.+=397.4 (UV/MS(%)=98/89). .sup.1H-NMR (400 MHz, CDCl.sub.3,
rotamers): .delta.=7.17-6.60 (7H, m); 4.75 (1H, m); 4.51 (2H, s);
3.83 (3H, s); 3.79 (3H, s); 3.53 (2H, s); 3.27 (2H, d); 2.65 (2H,
t); 2.58 (3H, s); 2.32. (3H, s); 2.24 (2H, m); 1.72 (2H, d).
.sup.13C-NMR (CDCl.sub.3): .delta.=172.8, 149.3, 148.3, 137.4,
135.0, 129.8, 127.4, 125.8, 121.0, 112.2, 111.6, 56.2, 56.1, 54.6,
49.6, 46.7, 44.0, 40.9, 27.0, 21.2.
Example 129
2-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-
acetamide (47AKU46)
[0651] 3,4-Methylenedioxyphenylacetic acid (216 mg, 1.2 mmol) was
dissolved in 2 ml thionylchloride and placed in 50 ml flask.
Mixture was heated to reflux for 2 hrs and then concentrated on
Rotavapor (50.degree. C.). The acid chloride (1.2 mmol) in 5 ml
dichloromethane was added to 47AKU-5 (219 mg, 1.0 mmol) in 10 ml
dichloromethane. After 2 hrs magnetic stirring the reaction mixture
was concentrated on Rotavapor (40.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 188 mg (49%) product. Further purification
by ion exchange chromatography (washout with 10% aq. NH.sub.4OH
(25%) in methanol) yielded 149 mg (39%) 47AKU46. HCl-salt was
prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC
(10% methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method A):
M.sup.+=381.2 (UV/MS(%)=96/95). .sup.1H-NMR (400 MHz, CDCl.sub.3,
rotamers): .delta.=7.17-7.02 (4H, m); 6.77-6.51 (3H, m); 5.91 and
5.93 (2H, 2s); 4.70 (1H, m); 4.52 and 4.49 (2H, 2s); 3.51 (2H, s);
3.26 (2H, d); 2.49 (3H, s); 2.33 (3H, s); 2.14-1.66 (6H, m)
.sup.3C-NMR (CDCl.sub.3): .delta.=172.5, 148.1, 146.8, 137.3,
135.1, 129.8, 128.6, 125.8, 121.9, 109.4, 108.5, 101.2, 54.8, 50.2,
46.7, 44.6, 41.1, 27.7, 21.2.
Example 130
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-acetami-
de (47AKU49)
[0652] 1-t-Butyl-4-piperidone (47AKU47)
[0653] 1-Benzyl-4piperidone (1.89 g, 10 mmol) was dissolved in 15
ml acetone. Methyliodide (0.90 ml, 15 mmol) was slowly added over 5
min. After 2 hrs magnetic stirring additional Methyliodide (1.8 ml,
30 mmol) was added. After 1 hr magnetic stirring 20 ml
diethyl-ether was added. Crude product was collected by filtration
and washed with acetone/diethylether. White crystals were dried
under vacuum giving 806 mg quartenary salt. TLC (10% methanol in
dichloromethane): R.sub.f=0.7. Partly dissolved salt in 5 ml water
was added to 50.degree. C. hot mixture of t-Butylamine (120 mg, 1.6
mmol) and Potassium carbonate (32 mg, 0.22 mmol) in 3 ml ethanol.
The resulting mixture was stirred and heated to reflux (80.degree.
C.) for 1 hr. After cooling water (20 ml) and dichloromethane (20
ml) were added. Phases were separated and aq. phase was
re-extracted with dichloromethane and ethylacetate. Combined
organic phases were dried over MgSO.sub.4 and concentrated on
Rotavapor (40.degree. C.) giving 496 mg 47AKU47. TLC (10% methanol
in dichloromethane): R.sub.f=0.3. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.=2.82 (4H, t); 2.41 (4H, t); 1.12 (9H, s).
.sup.13C-NMR (CDCl.sub.3): .delta. 210.2, 54.3, 46.4, 42.4, 26.6.
Crude product contained .about.25% (.sup.1H-NMR) starting material
(1-Benzyl-4-piperidone).
[0654] 4-(4-Methylbenzylamino)-1-t-butyl-piperidine (47AKU48)
[0655] 4Methylbenzylamine (268 mg, 2.2 mmol) was dissolved in 5 ml
methanol and placed in 50 ml flask. 47AKU47 (305 mg, 2.0 mmol) in 5
ml methanol was added. Acetic acid (0.3 ml) was added until
pH.about.5. NaCNBH.sub.3 (250 mg, 4.0 mmol) was slowly added. Gas
evolution observed. After 4 hrs magnetic stirring dichloromethane,
2M NaOH and water were added until pH.about.10. Phases were
separated and aq. phase was then re-extracted with dichloromethane
and ethylacetate. Combined organic phases were dried over
MgSO.sub.4. Concentration on Rotavapor (40.degree. C.) yielded 556
mg crude 47AKU48. TLC (20% methanol in dichloromethane):
R.sub.f=0.4. HPLC-MS (Method A): M.sup.+=261.2 (MS(%)=57).
[0656]
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)a-
cetamide
[0657] (47AKU49)
[0658] 47AKU48 (556 mg, 2.1 mmol) was placed in 50 ml flask and 5
ml dichloromethane was added. 4-Methoxyphenylacetyl chloride (739
mg, 4.0 mmol) in 10 ml dichloromethane was added. After 4 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-10% methanol in dichloromethane) giving 124 mg
(15%) product. Further purification by ion exchange chromatography
(washout with 10% aq. NH.sub.4OH (25%) in methanol) gave 91 mg
(11%) 47AKU49. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f 0.5. HPLC-MS (Method A): M.sup.+=409.4 (UV/MS(%)=100/90).
.sup.1H-NMR (400 MHz, CDCl.sub.3): &=7.11 (4H, m); 7.03 (2H,
d); 6.79 (2H, d); 4.78 (1H, m); 4.56 (2H, s); 3.76 (3H, s); 3.53
(2H, s); 3.43 (2H, m); 2.63 (2H, m); 2.47 (2H, m); 2.31 (3H, s);
1.74 (2H, d); 1.36 (9H, s). .sup.13C-NMR (CDCl.sub.3):
.delta.=173.0, 158.8, 137.1, 135.3, 129.8, 129.7, 127.0, 125.8,
114.3, 55.6, 55.5, 49.8, 46.5, 46.4, 40.5, 26.7, 25.1, 21.2.
Example 131
N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-phenylethyl-carbamide
(58AKU-1)
[0659] 47AKU-5-2 (219 mg, 1.0 mmol) was dissolved in 5 ml
dichloromethane and placed in 50 ml flask. Phenethylisocyanate (177
mg, 1.2 mmol) in 5 ml dichloromethane was added. After 6 hrs
magnetic stirring the reaction mixture was concentrated on
Rotavapor (40.degree. C.). Crude product was purified by flash
chromatography (0-15% methanol in dichloromethane) giving 134 mg
(37%) 58AKU-1. HCl-salt was prepared from 2M HCl/diethylether in
dichloromethane/heptane. TLC (10% methanol in dichloromethane):
R.sub.f=0.5. HPLC-MS (Method A): M.sup.+=366.3 (UV/MS(%)=99/96).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=7.21-6.97 (9H, m); 4.33
(1H, m); 4.26 (1H, m); 4.21 (2H, s); 3.39 (2H, q); 2.85 (2H, m);
2.67 (2H, t); 2.31 (3H, s); 2.24 (3H, s); 2.06 (2H, m); 1.73-1.57
(4H, m). .sup.13C-NMR (CDCl.sub.3): .delta.=158.7, 139.5, 137.0,
135.4, 129.7, 128.8, 128.6, 126.3, 126.1, 55.6, 52.2, 46.2, 45.8,
42.2, 36.4, 30.2, 21.2.
Example 132
N-Phenylethyl-N-(1-methylpiperidin-4-yl)-N'-phenethyl-carbamide
(58AKU-2)
[0660] 4-(2-Phenylethyl)amino-1-methylpiperidine (131 mg, 0.6 mmol)
was dissolved in 5 ml dichloromethane and placed in 50 ml flask.
Phenethylisocyanate (103 mg, 0.7 mmol) in 5 ml dichloromethane was
added. After 4 hrs magnetic stirring the reaction mixture was
concentrated on Rotavapor (45.degree. C.). Crude product was
purified by flash chromatography (0-10% methanol in
dichloromethane) giving 198 mg (90%) 58AKU-1. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=366.3 (UV/MS(%)=100/100). .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.=7.33-7.16 (8H, m); 7.01 (2H, m); 4.23 (1H, t);
4.04 (1H, m); 3.47 (2H, q); 3.17 (2H, t); 2.89 (2H, m); 2.78 (2H,
t); 2.66 (2H, t); 2.28 (3H, s); 2.05 (2H, m); 1.79-1.59 (4H, m).
.sup.13C-NMR (CDCl.sub.3): >157.8, 139.6, 139.0, 129.0, 128.9,
128.8, 126.8, 126.7, 55.7, 52.5, 46.2, 44.6, 42.0, 37.3, 36.4,
30.5.
Example 133
N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N'-(4-methoxybenzyl)
carbamide (58AKU-3)
[0661] 47AKU-5-2 (404 mg, 1.6 mmol) was dissolved in 5 ml
dichloromethane and placed in 50 ml flask.
4-Methoxybenzylisocyanate (326 mg, 2.0 mmol) in 5 ml
dichloromethane was added. After 20 hrs magnetic stirring the
reaction mixture was concentrated on Rotavapor (45.degree. C.).
Crude product was purified three times by flash chromatography
(0-20% methanol in dichloromethane and 0-30% methanol in
ethylacetate) giving 155 mg (23%) 58AKU-3. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.3. HPLC-MS (Method A):
M.sup.+=424.2 (UV/MS(%)=92/83). .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta.=7.10 (4H, m); 6.99 (2H, m); 6.76 (2H, m); 4.53 (1H, m);
4.35 (3H, s); 4.26 (2H, d); 3.77 (3H, s); 3.09 (2H, m); 2.32 (3H,
s); 2.22 (2H, m); 1.81-1.54 (4H, m); 1.06 (9H, s). .sup.13C-NMR
(CDCl.sub.3): .delta. 158.9, 158.6, 137.1, 135.6, 131.9, 129.7,
128.8, 126.2, 114.0, 62.6, 55.5, 53.0, 45.9, 45.7, 44.5, 31.0,
26.3, 21.2.
Example 134
2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(58AKU4)
[0662] 4-Ethoxyphenylacetic acid (270 mg, 1.5 mmol) was dissolved
in 2 ml thionylchloride and placed in 50 ml flask. Mixture was
heated to reflux for 2 hrs and 5' then concentrated on Rotavapor
(45.degree. C.). The acid chloride (1.5 mmol) in 5 ml
dichloromethane was added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml
dichloromethane. After 20 hrs magnetic stirring the reaction
mixture was concentrated on Rotavapor (40.degree. C.). Crude
product was purified by flash chromatography (0-10% methanol in
dichloromethane) giving 272 mg (60%) 58AKU4. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.4. HPLC-MS (Method A):
M.sup.+=381.2 (UV/MS(%)=98/91). .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta.=7.17-6.99 (6H, m); 6.82-6.76 (2H, m); 4.73 (1H, m); 4.48
(2H, s); 3.98 (2H, q); 3.52 (2H, s); 3.22 (2H, d); 2.61 (2H, t);
2.54 (3H, s); 2.32 (3H, s); 2.14 (2H, s); 1.71 (2H, d); 1.38 (3H,
t). .sup.13C-NMR (CDCl.sub.3): .delta. 172.9, 158.2, 137.3, 135.0,
129.9, 129.8, 126.8, 125.8, 114.9, 63.7, 54.6, 49.8, 46.7, 44.1,
40.6, 27.2, 21.2, 15.0.
Example 135
2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide
(58AKU-5)
[0663] 4-Butoxyphenylacetic acid (317 mg, 1.5 mmol) was dissolved
in 2 ml thionylchloride and placed in 50 ml flask. Mixture was
heated to reflux for 2 hrs and +then concentrated on Rotavapor
(45.degree. C.). The acid chloride (1.5 mmol) in 5 ml
dichloromethane was added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml
dichloromethane. After 20 hrs magnetic stirring the reaction
mixture was concentrated on Rotavapor (40.degree. C.). Crude
product was purified by flash chromatography (0-10% methanol in
dichloromethane) giving 230 mg (47%) 58AKU-5. HCl-salt was prepared
from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%
methanol in dichloromethane): R.sub.f=0.5. HPLC-MS (Method A):
M.sup.+=409.2 (UV/MS(%)=98/93). .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 7.15-6.96 (6H, m); 6.78 (2H, m); 4.74 (1H, m); 4.48 (2H,
s); 3.91 (2H, t); 3.52 (2H, s); 3.27 (2H, d); 2.72 (2H, t); 2.58
(3H, s); 2.32 (3H, s); 2.23 (2H, m); 1.72 (4H, d); 1.45 (2H, m);
0.95 (3H, t). .sup.13C-NMR (CDCl.sub.3): .delta.=173.0, 158.4,
137.3, 135.0, 129.8, 126.6, 125.8, 115.0, 67.9, 54.4, 49.5, 46.7,
43.8, 40.6, 31.5, 26.8, 21.2, 19.4, 14.0.
Example 136
2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetami-
de (58AKU6)
[0664] 47AKU-29-2 (245 mg, 0.7 mmol) was dissolved in 10 ml
dimethylformamide and placed in 50 ml flask. KOH (196 mg, 3.5 mmol)
and Isopropylbromide (200 .mu.l, 2.1 mmol) were added. Mixture was
heated to 50.degree. C. and stirred for 24 hrs. After cooling water
and ethylacetate were added. Phases were separated and aq. phase
was then re-extracted with dichloromethane. Combined organic phases
were washed with brine, dried over MgSO.sub.4 and concentrated on
Rotavapor (40.degree. C.) giving 188 mg. Crude product was purified
by flash chromatography (0-10% methanol in dichloromethane)
yielding 136 mg (49%) 58AKU-6. HCl-salt was prepared from 2M
HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in
dichloromethane): R.sub.f 0.3. HPLC-MS (Method B): M.sup.+=395
(UV/MS(%)=95/91). .sup.1H-NMR (400 MHz, CDCl.sub.3, rotamers):
.delta.=7.23-7.01 (6H, m); 6.79 (2H, m); 4.60 (1H, m); 4.51 (1H,
m); 4.44 (1H, s); 3.77 (1H, s); 3.52 (1H, s); 2.83 (2H, m); 2.76
(2H, m); 2.28 and 2.34 (3H, 2s); 2.19 and 2.22 (3H, 2s); 2.05 (1H,
m); 1.86-1.55 (4H, m); 1.32 (6H, d). .sup.13C-NMR (CDCl.sub.3):
.delta.=172.6, 157.0, 137.1, 135.6, 129.8, 129.7, 125.8, 116.2,
70.1, 55.3, 51.6, 46.6, 46.1, 40.8, 29.6, 22.3, 21.2.
Example 137
Receptor Selection and Amplification (R-SAT) Assays
[0665] The functional receptor assay, Receptor Selection and
Amplification Technology (R-SAT), was used (with minor
modifications from that previously described U.S. Pat. No.
5,707,798) to screen compounds for efficacy at the 5-HT2A receptor.
Briefly, NIH3T3 cells were grown in 96 well tissue culture plates
to 70-80% confluence. Cells were transfected for 12-16 hours with
plasmid DNAs using superfect (Qiagen Inc.) as per manufacture'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 in U.S. Pat. No.
5,707,798. The 5HT2A receptor gene was amplified by nested PCR from
brain cDNA using the oligodeoxynucleotides based on the published
sequence (see Saltzman et. al. Biochem. Biophys. Res. Comm.
181:1469-78 (1991)). Large-scale transfections, cells were
transfected for 12-16 hours, 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 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 5HT2A). pIC50 is the negative
of the log(IC50); where IC50 is the calculated concentration in
Molar that produces 50% maximal repression. The results obtained
for several compounds of the invention are presented in Table 4,
below.
3TABLE 4 Efficiency and pIC50 of Compounds at the 5-HT2A Receptor
Compared to Ritanserin Compound Percent Efficacy pIC50 26HCH17 94
8.3 26HCH65 103 8.2 26HCH66-05 126 8.1 26HCH79-5 94 8.2 26HCH79-6
83 8.3 26HCH79-10 102 7.8 26HCH71B 124 7.9 42ELH45 108 9.0 50ELH27
108 8.7 47AKU-7 120 8.1 42ELH80 122 8.5 42ELH79 110 8.5 42ELH91 108
8.0 42ELH85 118 7.8 42ELH75 109 8.3 47AKU-12 112 8.1 47AKU-8 113
8.1 47AKU-22 117 7.9 47AKU-21 117 7.9 47AKU-20 120 8.0 50ELH8 129
7.8 50ELH68 96 8.4 50ELH65 92 7.9 47AKU-44 112 8.5 57MBT12B 75 7.7
58AKU-4 110 9.6 58AKU-3 111 8.1 58AKU-5 99 9.5 58AKU-6 101 9.8
57MBT54B 95 7.9 50ELH95B 119 8.0 50ELH93E 72 8.1 50ELH93D 58 7.8
50ELH93A 106 8.7 63ELH1A 104 8.3 50ELH89 111 9.7 63ELH20 95 9.0
57MBT70-8D 119 7.7 57MBT70-5D 105 8.4 57MBT70-4D 98 8.5 57MBT70-3D
87 8.9 57MBT70-2D 105 8.2 57MBT70-1D 120 7.9 63ELH21 100 8.5
57MBT62B 119 7.9 57MBT70-6E 115 8.0
Example 138
Selectivity Profile for
2-(4Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylp-
iperidin-4-yl)acetamide hydrochloride
[0666] The R-SAT assay (described above in example 137) was used to
investigate the selectivity of
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(-
1-methylpiperidin-4-yl)acetamide hydrochloride. The results from a
broad profiling of this compound at a variety of receptors are
reported in Table 4 below. NR means No Response, i.e. the compound
investigated showed no effect at the receptor studied.
4TABLE 4 Selectivity of 2-(4-Methoxyphenyl)-N-(4-me- thylbenzyl)-
N-(1-methylpiperidin-4-yl)acetamide RECEPTOR ASSAY pEC50/pIC50
5-HT.sub.1A agonist NR antagonist NR 5-HT.sub.1B agonist NR
antagonist NR 5-HT.sub.1D agonist NR antagonist NR 5-HT.sub.1E
agonist NR antagonist NR 5-HT.sub.1F agonist NR antagonist NR
5-HT.sub.2A agonist NR inverse agonist 8.8 5-HT.sub.2B agonist NR
inverse agonist 6.9 5-HT.sub.2C agonist NR inverse agonist 7
5-HT.sub.4 agonist NR inverse agonist NR 5-HT.sub.6 agonist NR Inv.
Agonist 6.8 5-HT7 agonist NR inverse agonist 6.9 m1 agonist NR
antagonist NR m2 agonist NR antagonist NR m3 agonist NR antagonist
NR m4 agonist NR antagonist NR m5 agonist NR antagonist NR D1
agonist NR antagonist NR D2 agonist NR antagonist NR D3 agonist NR
antagonist NR D5 agonist NR antagonist NR Histamine 1 agonist NR
Inv. agonist NR Histamine 2 agonist NR antagonist NR Histamine 3
agonist NR antagonist NR alpha-1A(a/c) agonist NR antagonist NR
alpha-1B agonist NR In. Agonist NR alpha-2A agonist NR antagonist
NR alpha-2B agonist NR antagonist NR alpha-2C agonist NR antagonist
NR beta 1 agonist NR antagonist NR beta 2 agonist NR antagonist NR
endothelinB agonist NR CCK-A agonist NR NK-1 agonist NR
Vasopressin1A agonist NR K-opiod agonist NR
Example 139
In Vivo Pharmacology of
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methyl-
piperidin-4-yl)acetamide hydrochloride (AC-90,179)
[0667] Methods
[0668] Animals and Apparatus
[0669] Instruments) were used for rat experiments (details on
startle apparatus and measures, see Male Non-Swiss Albino mice and
male Sprague-Dawley rats (Harlan Sprague-Dawley) were housed (4
mice/cage; 2 rats/cage) in rooms with temperature and humidity
controlled and water and food (Harlan Teklad) freely available.
Mice were kept on a 12-hr light:dark cycle, whereas rats were kept
on a 12-hr reverse light:dark cycle. For locomotor and observation
experiments in mice, plastic 200.times.30 cm activity cages were
equipped with photocell beams (AccuScan Instruments). Startle
chambers (San Diego Instruments) were used for rat experiments (for
details on startle apparatus and measures, see Mansbach et al.,
(1988) Psychopharmacology 94:507-14).
[0670] Procedure
[0671] Observation for Head Twitches
[0672] Mice were treated with 2.5 mg/kg DOI i.p. Five min later,
mice were treated with AC-90179 s.c. and placed into activity
cages. Ten min later, mice were observed using a repeated sampling
technique. Each mouse was observed for 10 sec and rated for
presence (1) or absence (0) of head twitch behavior for a total of
6 observations in 15 min and a total head twitch score of 0-6. Each
dose combination was tested in a separate group of animals (n=8)
and the experimenter was blind to drug conditions.
[0673] Head twitch scores were averaged followed by analysis of
variance (ANOVA) and post-hoc Dunnett's t-test comparisons.
[0674] Locomotor Activity
[0675] For hyperactivity experiments, mice were treated with 0.3
mg/kg dizocilpine or 3.0 mg/kg d-amphetamine i.p. 15 min before the
session. Five minutes after the pretreatment, mice were treated
with AC-90179 s.c. and placed into the activity cages. For
spontaneous activity, AC-90179 was administered alone. Locomotor
data were collected during a 15 min session without habituation in
a lit room. Each dose combination was tested in a separate group of
animals (n=8). Distance traveled (cm) was calculated and averaged
followed by ANOVA and post-hoc Dunnett's t-test comparisons.
[0676] Startle Testing
[0677] Rats were tested and groups (n=10) matched for levels of
startle reactivity and prepulse inhibition (PPI; see Mansbach et
at., (1988) Psychopharmacology 94:5.07-14). Two days later, test
sessions started and consisted of a 5-min acclimation period with a
constant background noise (65 dB), followed by 60 presentations of
acoustic stimuli to measure acoustic startle responses. The 60
trials consisted of: twenty two 40-ms presentations of a 120 dB
broadband pulse, ten 20-ms presentations of each prepulse intensity
(68, 71, 77 dB) 100 ms prior to a 40-msec presentation of a 120 dB
broadband pulse, and 8 NOSTIM trials in which no stimuli were
delivered in order to assess general motor activation in the rats.
Thirty min before testing, rats were treated with sterile water
(s.c.), risperidone (1.0 mg/kg, i.p.), or AC-90179 (s.c.). Five min
later, rats were administered DOI (0.5 mg/kg, s.c.) or 0.9% saline
(s.c.). One-week later, rats were administered the same
pretreatment drug or vehicle and crossed over to receive the
treatment opposite to that they received the previous week. Startle
magnitudes and percent PPI for the three prepulse intensities were
calculated as described elsewhere (Bakshi, et al., (1994) J.
Pharmacol. Exp. Ther. 271:787-94) and ANOVAs with repeated measures
performed.
[0678] Results
[0679] To further characterize the clinical utility of a selective
5-HT2A receptor inverse agonist as a novel antipsychotic agent,
AC-90179 was tested in head twitch, locomotor and pre pulse
inhibition behavioral models. DOI-treated (2.5 mg/kg, i.p., 15 min)
mice exhibited an average head twitch score of 2.6 (.+-.0.3,
S.E.M.). AC-90179 (0.1-30 mg/kg, s.c., 10 min) caused a
dose-related decrease in DOI-induced head-twitches with a minimum
effective dose of 1 mg/kg and with higher doses completely
eliminating head twitch behavior (FIG. 2A).
[0680] In the locomotor experiments (FIG. 2B), mice traveled an
average of 794 cm (.+-.122 S.E.M.) after vehicle administration.
Dizocilpine (0.3 mg/kg, i.p., 15 min) and d-amphetamine (3.0 mg/kg,
i.p., 15 min) caused increases in distance traveled with averages
of 2625 cm (.+-.312) and 3367 cm (.+-.532), respectively. AC-90179
(0.3-10 mg/kg, s.c., 10 min) attenuated the hyperactivity induced
by dizocilpine, but not by d-amphetamine. The minimum effective
dose against dizocilpine was 1 mg/kg, whereas AC-90179 reduced
spontaneous locomotor activity only at the highest dose tested (30
mg/kg).
[0681] The 3-way repeated measures ANOVA on the PPI data from the
AC-90179 groups revealed an overall effect of treatment
[F(1,37)=27.73, p<0.01] and a treatment by pretreatment
interaction [F(3,37)=8.22, p<0.01] (FIG. 2C). DOI significantly
disrupted PPI, and AC-90179 was effective in restoring this
disruption especially at the higher doses. AC-90179 did not affect
PPI on its own, with no significant effect of pretreatment
(p>0.05) on percent PPI. Risperidone was used as a positive
control because previous studies in our laboratory have suggested
that it is effective in blocking the PPI-disruptive effects of DOI.
The 3-way repeated measures ANOVA on the PPI data from the
risperidone group also revealed a significant effect of treatment
[F(1,18)=14.08, p<0.01] and a treatment by pretreatment
interaction [F(1,18)=24.48, p<0.01). As predicted, risperidone
was also effective in restoring PPI in DOI-treated rats.
Risperidone also had no effect on PPI by itself, as evidenced by a
lack of a pretreatment effect (p>0.05). Since there were no
significant interactions with prepulse intensity, the data were
collapsed across the three prepulse intensities for graphical
purposes.
[0682] Since there was a significant pretreatment by treatment
interaction, pair-wise 2-way repeated measures ANOVAs were
conducted on the saline- and DOI-treated groups. In the
vehicle-treated rats, there was no effect of AC-90179 (p>0.025)
or risperidone (p>0.025) on PPI. In the DOI-treated groups,
there were significant effects of AC-90179 [F(3,37)=5.68,
p<0.01] and risperidone [F(1,18)=16.73, p<0.01) on percent
PPI.
[0683] The 3-way repeated measures ANOVA on startle magnitude from
the AC-90179 groups revealed a significant effect of pretreatment
[F(3,37)=2.89, p=0.048) and treatment [F(1,37)=10.27, p<0.01] on
startle magnitude, but no treatment by pretreatment interaction
(p>0.05; FIG. 1, panel C inset). Risperidone, on the other hand,
had no effect on startle magnitude (p>0.05).
Example 140
In Vivo Pharmacology of Additional Compounds
[0684] The effect of various compounds on head twitch behavior in
mice treated with DOI was observed as described above in Example
139. The results are summarized below in Table 5.
[0685] The effect of various compounds on head twitch behavior in
mice treated wth DOI was observed as described in Example 139.
Animals received 0.1-30 mg/kg of the compound indicated via
subcutaneous injection. MED indicates the minimum effective dose at
which a statistically significant reduction in head twitching score
(described above) was observed. MED=minimum effective dose in
vivo.
5TABLE 5 Comparison Of Analogs For Their Ability To Attenuate
DOI-Induced Head Twitches In Mice. Compound MED 26HCH17 30 44ELH45
30 50ELH27 1 42ELH80 .ltoreq.10 42ELH79 .ltoreq.10 47AKU-7
.ltoreq.10 42ELH85 .ltoreq.10 47AKU-8 .ltoreq.10 47AKU-12
.ltoreq.10 47AKU-13 .ltoreq.10 42ELH91 >10 42ELH90 .about.10
47AKU-20 .ltoreq.10 47AKU-19 >10 47AKU-22 .ltoreq.10 47AKU-21
>10 42ELH75 .ltoreq.10 47AKU-11 .about.10 47AKU-14 .ltoreq.10
47AKU-18 .gtoreq.10 50ELH6 .ltoreq.10 47AKU-33 .gtoreq.10 47AKU-25
>10 50ELH65 .ltoreq.10 50ELH68 .ltoreq.10 47AKU-49 .ltoreq.10
47AKU-44 .ltoreq.10 58AKU-4 .ltoreq.10 58AKU-5 .ltoreq.1 50ELH93A
.ltoreq.10 58AKU-6 .ltoreq.10 63ELH20 .ltoreq.10 63ELH21 .ltoreq.10
MED = minimum effective dose in vivo.
[0686] The invention described and claimed herein is not to be
limited in scope by the specific embodiments herein disclosed,
since these embodiments are intended as illustrations of several
aspects of the invention. Any equivalent embodiments are intended
to be within the scope of this invention. Indeed, various
modifications of the invention in addition to those shown and
described herein will become apparent to those skilled in the art
from the foregoing description. Such modifications are also
intended to fall within the scope of the appended claims.
[0687] The disclosures of all references cited herein are
incorporated by reference in their entireties.
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