U.S. patent application number 12/095906 was filed with the patent office on 2009-01-08 for oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Joshua Clayton, Ian Egle, Methvin Isaac, Babu Joseph, Fupeng Ma, Abdelmalik Slassi, Krzysztof Swierczek.
Application Number | 20090012089 12/095906 |
Document ID | / |
Family ID | 38030087 |
Filed Date | 2009-01-08 |
United States Patent
Application |
20090012089 |
Kind Code |
A1 |
Slassi; Abdelmalik ; et
al. |
January 8, 2009 |
Oxazolidinone Compounds and Their Use as Metabotropic Glutamate
Receptor Potentiators
Abstract
The present invention is directed to compounds of Formula I:
##STR00001## Wherein R.sup.1, R.sup.2, Y, m and n are further
defined in the description. The invention also relates to processes
for the preparation of the compounds and to new intermediates
employed in the preparation, pharmaceutical compositions containing
the compounds, and to the use of the compounds in therapy.
Inventors: |
Slassi; Abdelmalik;
(Mississauga, CA) ; Joseph; Babu; (Oakville,
CA) ; Ma; Fupeng; (Melrose, MA) ; Egle;
Ian; (North York, CA) ; Clayton; Joshua;
(Oakville, CA) ; Isaac; Methvin; (Brampton,
CA) ; Swierczek; Krzysztof; (West Jordan,
UT) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
ASTRAZENECA AB
Sweden
SE
|
Family ID: |
38030087 |
Appl. No.: |
12/095906 |
Filed: |
December 6, 2006 |
PCT Filed: |
December 6, 2006 |
PCT NO: |
PCT/US06/46344 |
371 Date: |
July 30, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60750347 |
Dec 15, 2005 |
|
|
|
Current U.S.
Class: |
514/236.8 ;
514/254.02; 514/340; 514/376; 544/137; 544/364; 544/386; 546/271.4;
548/229 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 25/08 20180101; A61P 25/22 20180101; A61P 25/14 20180101; A61P
25/12 20180101; A61P 27/02 20180101; A61P 25/16 20180101; A61P
27/16 20180101; C07D 413/12 20130101; A61P 25/18 20180101; A61P
21/00 20180101; C07D 413/08 20130101; A61P 25/24 20180101; C07D
263/20 20130101; A61P 25/06 20180101; A61P 25/00 20180101; A61P
9/10 20180101; A61P 25/28 20180101; A61P 29/00 20180101; A61P 13/00
20180101; A61P 25/20 20180101; A61P 25/10 20180101 |
Class at
Publication: |
514/236.8 ;
548/229; 544/364; 544/386; 544/137; 546/271.4; 514/376; 514/254.02;
514/340 |
International
Class: |
A61K 31/421 20060101
A61K031/421; A61P 25/00 20060101 A61P025/00; C07D 263/20 20060101
C07D263/20; C07D 401/14 20060101 C07D401/14; A61K 31/496 20060101
A61K031/496; A61K 31/4439 20060101 A61K031/4439; C07D 401/10
20060101 C07D401/10; C07D 413/10 20060101 C07D413/10; A61K 31/5377
20060101 A61K031/5377 |
Claims
1. A compound according to Formula I: ##STR00276## wherein: R.sup.1
is selected from the group consisting of H, hydroxy, F, Cl, Br, I,
nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,
O-alkenyl, alkynyl, O-alkynyl, cycloalkyl, alkylene-cycloalkyl,
O-cycloalkyl, O-alkylene-cycloalkyl, heterocycloalkyl,
alkylene-heterocycloalkyl, O-heterocycloalkyl,
O-alkylene-heterocycloalkyl, aryl, alkylenearyl, O-aryl,
O-alkylenearyl, heteroaryl, alkyleneheteroaryl, O-heteroaryl,
O-alkyleneheteroaryl, (CO)cycloalkyl, (CO)heterocycloalkyl,
(CO)aryl, (CO)heteroaryl, alkyleneOR.sup.4, O-alkyleneOR.sup.4,
(CO)R.sup.7, O(CO)R.sup.7, alkyleneO(CO)R.sup.7,
alkylene(CO)R.sup.7, O-alkylene(CO)R.sup.7, CO.sub.2R.sup.7,
alkyleneCO.sub.2R.sup.7, O-alkyleneCO.sub.2R.sup.7, alkylenecyano,
O-alkylenecyano, NR.sup.4R.sup.5, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O--(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, NR.sup.4(CO)R.sup.3,
alkyleneNR.sup.4(CO)R.sup.3, O-alkyleneNR.sup.4(CO)R.sup.5,
NR.sup.4(CO)NR.sup.4R.sup.5, alkyleneNR.sup.4(CO)NR.sup.4R.sup.5,
SR.sup.4, alkyleneSR.sup.4, O-alkyleneSR.sup.4, (SO)R.sup.3,
alkylene(SO)R.sup.3, O-alkylene(SO)R.sup.3, SO.sub.2R.sup.3,
alkyleneSO.sub.2R.sup.3, O-alkyleneSO.sub.2R.sup.3,
(SO.sub.2)NR.sup.4R.sup.5, alkylene(SO.sub.2)NR.sup.4R.sup.5,
O-alkylene(SO.sub.2)NR.sup.4R.sup.5, NR.sup.4(SO.sub.2)R.sup.5,
alkyleneNR.sup.4(SO.sub.2)R.sup.5,
O-alkyleneNR.sup.4(SO.sub.2)R.sup.5,
NR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
alkyleneNR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
O-alkyleneNR.sup.4(SO.sub.2)NR.sup.4R.sup.5, NR.sup.4OR.sup.5,
NR.sup.4(CO)OR.sup.7, alkylNR.sup.4(CO)OR.sup.7,
O-alkylNR.sup.4(CO)OR.sup.7 and any cyclic moiety is optionally
substituted by one or more independently selected substituents
R.sup.6; R.sup.2 is selected from the group consisting of H,
hydroxy, F, Cl, Br, I, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo,
cycloalkyl, alkylene-cycloalkyl, O-cycloalkyl,
O-alkylene-cycloalkyl, heterocycloalkyl, alkylene-heterocycloalkyl,
O-heterocycloalkyl, O-alkylene-heterocycloalkyl, aryl,
alkylenearyl, O-aryl, O-alkylenearyl, heteroaryl,
alkyleneheteroaryl, O-heteroaryl, O-alkyleneheteroaryl,
alkyleneOR.sup.4, O-alkyleneOR.sup.4, (CO)R.sup.7,
alkylene(CO)R.sup.7, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O-alkylene(CO)NR.sup.4R.sup.5,
alkyleneNR.sup.4(CO)R.sup.3, and any cyclic moiety is optionally
substituted by one or more independently selected substituents
R.sup.6; R.sup.3 is, in each instance, selected from the group
consisting of H and alkyl, R.sup.4 and R.sup.5 are independently
selected from the group consisting of H, alkyl, alkylhalo, alkenyl,
alkynyl, cycloalkyl, alkylenecycloalkyl, heterocycloalkyl,
alkyleneheterocycloalkyl, aryl, alkylenearyl, heteroaryl, and
alkyleneheteroaryl, NR.sup.7R.sup.8, alkyleneNR.sup.7R.sup.8,
OR.sup.7, alkyleneOR.sup.7, and any cyclic moiety is optionally
substituted with a substituent selected from the group consisting
of alkyl, halo, haloalkyl O-alkyl, O-haloalkyl, aryl, alkylenearyl,
heteroaryl and alkyleneheteroaryl; R.sup.6 is, in each instance,
selected from the group consisting of H, hydroxy, F, Cl, Br, I,
nitro, CN, oxo, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,
O-alkenyl, alkynyl, O-alkynyl, cycloalkyl, alkylene-cycloalkyl,
O-cycloalkyl, O-alkyl-cycloalkyl, heterocycloalkyl,
alkylene-heterocycloalkyl, O-heterocycloalkyl,
O-alkylene-heterocycloalkyl, aryl, alkylenearyl, O-aryl,
O-alkylenearyl, heteroaryl, alkyleneheteroaryl, O-heteroaryl,
O-alkyleneheteroaryl, (CO)R.sup.3, O(CO)R.sup.3,
alkyleneO(CO)R.sup.3, alkylene(CO)R.sup.3, O-alkylene(CO)R.sup.3,
CO.sub.2R.sup.4, alkyleneCO.sub.2R.sup.3,
O-alkyleneCO.sub.2R.sup.3, alkylenecyano, O-alkylenecyano,
NR.sup.4R.sup.5, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O--(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, NR.sup.4(CO)R.sup.3,
alkyleneNR.sup.4(CO)R.sup.3, O-alkyleneNR.sup.4(CO)R.sup.3,
NR.sup.4(CO)NR.sup.4R.sup.13, SR.sup.4, alkyleneSR.sup.5,
O-alkyleneSR.sup.4, (SO)R.sup.3, alkylene(SO)R.sup.3,
O-alkylene(SO)R.sup.3, SO.sub.2R.sup.3, alkyleneSO.sub.2R.sup.3,
O-alkyleneSO.sub.2R.sup.3, (SO.sub.2)NR.sup.4R.sup.5,
alkylene(SO.sub.2)NR.sup.4R.sup.5,
O-alkylene(SO.sub.2)NR.sup.7R.sup.8, NR.sup.7(SO.sub.2)R.sup.8,
alkyleneNR.sup.7(SO.sub.2)R.sup.8,
O-alkyleneNR.sup.4(SO.sub.2)R.sup.5, NR.sup.4(CO)OR.sup.5,
alkylNR.sup.4(CO)OR.sup.5, O-alkylNR.sup.4(CO)OR.sup.5,
SO.sub.3R.sup.4 and any cyclic moiety is optionally substituted
with a substituent selected from the group consisting of halo,
alkyl, O-alkyl, haloalkyl, O-haloalkyl and NR.sup.4R.sup.5; R.sup.7
and R.sup.8 are independently selected from the group consisting of
H and alkyl; Y is selected from the group consisting of alkylene,
alkenylene and alkynylene wherein any hydrogen atom of Y may be
independently substituted with one or more substituents selected
from the group consisting of hydroxy, F, Cl, Br, I, alkyl,
alkylhalo and O-alkyl; and m and n are independently selected from
the group consisting of 0, 1, 2, 3 and 4; with the proviso that the
compound is not selected from the group consisting of:
3-Benzyl-5-phenyl-2-oxazolidinone,
3-(.alpha.-Methylbenzyl)-5-phenyl-2-oxazolidinone,
3-(.alpha.-Methyl-(4-methylbenzyl))-5-phenyl-2-oxazolidinone,
3-((2-Thienyl)methyl)-5-phenyl-2-oxazolidinone,
5-(3,4-Dimethoxyphenyl)-3-benzyl-2-oxazolidinone,
5-(3,4-Dimethoxyphenyl)-3-(2-(3,4-dimethoxyphenylethyl))-2-oxazolidinone,
Methyl 4[2-[5-(3-chlorophenyl)-2-oxazolidin-3-yl]propyl]phenoxy
ethanoate, 4[2-[5-(3-Chlorophenyl)-2-oxazolidin-3-yl]propyl]phenoxy
ethanoic acid,
3-[1-(4-Methylphenyl)ethyl]-5-phenyl-2-oxazolidinone,
5-(3-Chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidin-
one and
5-(3-Chlorophenyl)-3-[(3,4-dimethoxyphenyl)-butan-2-yl]-2-oxazolid-
inone.
2. A compound according to claim 1 wherein Y is a CH.sub.2
group.
3. A compound according to claim 2 wherein R.sup.2 is selected from
the group consisting of alkyl, alkoxy, trifluoromethoxy and
halo.
4. A compound according to claim 3 wherein R.sup.2 is halo.
5. A compound according to claim 4 wherein R.sup.2 is chloro.
6. A compound according to claim 2 wherein R.sup.1 is selected from
the group consisting of optionally substitute aryl, O-aryl,
heteroaryl and O-heteroaryl.
7. A compound according to claim 6 wherein R.sup.1 is an optionally
substituted phenyl group.
8. A compound according to claim 6 wherein R.sup.1 is an optionally
substituted pyridyl group.
9. A compound selected from the group consisting of:
5-(R)-Phenyl-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
3-(4-Trifluoromethoxybenzyl)-5-[3-(4-trifluoromethoxybenzyloxy)phenyl]-ox-
azolidin-2-one,
5-(4-Methoxyphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-(4-Methylphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-(4-Chlorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
3-(4-Trifluoromethoxy-benzyl)-5-(4-trifluoromethoxy
phenyl)-oxazolidin-2-one,
5-(4-Methoxyphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-p-Tolyl-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-o-Tolyl-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-(3,5-Dichlorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-(3,4-Dichlorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one,
5-(3,5-Dimethoxyphenyl)-3-(4-trifluoromethoxy
benzyl)-oxazolidin-2-one,
3-(4-Trifluoromethoxybenzyl)-5-(S)-phenyl-oxazolidin-2-one,
3-(4-Phenoxybenzyl)-5-(R)-phenyl-oxazolidin-2-one,
3-(3,5-Difluorobenzyl)-5-(R)-phenyl-oxazolidin-2-one,
3-(3,4-Dichlorobenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
3-(4-Iodobenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
3-(4-Difluoromethoxbenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
3-(4-Chlorobenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
3-(4-Ethylbenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
3-Biphenyl-4-ylmethyl-5-(R)-phenyl)-oxazolidin-2-one,
3-(4-Benzyloxybenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
3-(4-Methoxybenzyl)-5-(R)-phenyl)-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-(4-iodobenzyl)-oxazolidin-2-one,
4-5[(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-benzoic acid
methyl ester,
5-(4-Fluorophenyl)-3-(4-methoxybenzyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(4-Iodobenzyl)-oxazolidin-2-one,
3-(3-Iodo-benzyl)-5-(R)-phenyl-oxazolidin-2-one,
5-(4-Bromo-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one,
5-(3-Bromo-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one,
5-(4-Bromo-phenyl)-3-(4-chloro-benzyl)-oxazolidin-2-one,
3-(4-Hydroxybenzyl)-5-(R)-phenyl-oxazolidin-2-one,
5-(4-Fluorophenyl-3-[4-(4-pyridin-2-yl-piperazine-1-carbonyl)-benzyl]-oxa-
zolidin-2-one,
5-(4-Fluorophenyl)-3-[4-(4-pyridin-3-ylmethyl-piperazine-1-carbonyl)-benz-
yl]-oxazolidin-2-one,
3-[4-(4-Benzyl-piperazine-1-carbonyl)-benzyl]-5-(4-fluorophenyl)-oxazolid-
in-2-one, 3-(4-Bromomethylbenzyl)-5-(R)-phenyl-oxazolidin-2-one,
3-(4-Bromomethyl-benzyl)-5-(R)-(4-chlorophenyl)-oxazolidin-2-one,
3-(4-Bromomethylbenzyl)-5-(4-fluorophenyl)-oxazolidin-2-one,
4-(Morpholin-4-ylmethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one,
4-[4-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-benzyl]-piperazine-1-carb-
oxylic acid tert-butyl-ester,
3-[4-(4-Methyl-piperazin-1-ylmethyl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e,
5-(R)-Phenyl-3-[4-(4-phenyl-piperazin-1-ylmethyl)-benzyl]-oxazolidin-2--
one,
5-(R)-Phenyl-3-(4-piperazin-1-ylmethyl-benzyl)-oxazolidin-2-one,
5-(R)-Phenyl-3-(4-{[(pyridine-2-yl
methyl)-amino]-methyl}-benzyl)-oxazolidin-2-one,
3-{4-[(Methyl-pyridin-2-ylmethyl-amino)-methyl]-benzyl}-5-(R)-phenyl-oxaz-
olidine-2-one,
5-(R)-Phenyl-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-[4-(pyridine-2-yloxymethyl)-benzyl]-oxazolidin-2-one-
,
5-(4-Fluorophenyl)-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-on-
e,
5-(4-Fluorophenyl)-3-[4-(pyridine-4-yloxymethyl)-benzyl]-oxazolidin-2-o-
ne,
5-(R)-(4-Chlorophenyl)-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidi-
n-2-one, 3-(4-Phenoxymethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one,
5-(R)-Phenyl-3-(4-Pyridin-4-yl-benzyl)-oxazolidin-2-one,
5-(R)-Phenyl-3-(4-Pyridin-3-yl-benzyl)-oxazolidin-2-one,
3-{4-[6-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-benzyl}-5-(R)-phenyl-oxaz-
olidin-2-one,
3-[4-(6-Morpholin-4-yl-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e,
5-(R)-Phenyl-3-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-oxazolidin--
2-one,
3-[4-(6-Amino-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one,
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide,
5-(R)-Phenyl-3-[4-(6-piperazin-1-yl-pyridin-3-yl)-benzyl]-oxazolidin-2-on-
e,
3-[4'-(4-Methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-5-(R)-pheny-
l-oxazolidin-2-one,
3-[3'-(4-Methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-5-(R)-phenyl--
oxazolidin-2-one, 3-{4-[6-(2-Morpholin-4-yl-ethyl
amino)-pyridin-3-yl]-benzyl})-5-(R)-phenyl-oxazolidin-2-one,
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)biphenyl-4-carboxylic
acid (2-dimethylamino-ethyl)-amide, 3-{4-[6-(3-Dimethyl
amino-propoxy)-pyridin-3-yl]-benzyl})-5-(4-fluorophenyl-oxazolidin-2-one,
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid (2-dimethylamino-ethyl)-amide,
5-(4-Fluorophenyl)-3-(2'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-oxazol-
idin-2-one, 4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid,
5-(4-Fluorophenyl)-3-[3'-(4-methyl-piperazine-1'-carbonyl)-biphenyl-4-ylm-
ethyl]-oxazolidin-2-one, 3-(4'-Dimethylamino
methyl-biphenyl-4-ylmethyl)-5-(4-fluorophenyl)-oxazolidin-2-one,
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide,
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid (2-hydroxyethyl)-amide,
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid ethylamine,
4'-[5-(R)-(4-Chlorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid (2-dimethylamino-ethyl)-amide,
3-[3-(6-Morpholin-4-yl-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e,
3'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide,
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-biphenyl-4-carboxylic
acid (1-benzyl-pyrrolidin-3-(S)-yl)-amide,
5-(4'-Dimethylaminomethyl-biphenyl-3-yl)-3-(4-trifluoromethoxy-benzyl)-ox-
azolidin-2-one, 4'-[5-(S)-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide,
4'-[5-(R)-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide,
5-(R)-(4-Chlorophenyl)-3-(2'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one, 4'-[5-(R)-(4-Chlorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide,
3-[4'-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-yl
methyl]-5-phenyl-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-[3'-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmet-
hyl]-oxazolidin-2-one, 5-(4-Fluorophenyl)-3-(3'-morpholin-4-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-(3'-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl)-oxazo-
lidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(3'-diethylaminomethyl-biphenyl-4-ylmethyl)-oxaz-
olidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(3'-{[dimethylaminoethyl)-methylamino]-methyl}bi-
phenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(3'-piperidin-1-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(3'-morpholin-4-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-[3'-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-y-
lmethyl]-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(3'-dimethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(3'-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl)-o-
xazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(2'-dimethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(2'-{[(2-dimethylaminoethyl)-methyl-amino]-methy-
l}-biphenyl-4-yl methyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-[2'-(4-methyl-piperazin-1-yl
methyl)-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-[2'-(3-(S)-dimethylamino-pyrrolidin-1-yl
methyl)-1-biphenyl-4-ylmethyl]-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(2'-piperidin-1-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-[2'-(3-(R)-dimethylamino-pyrrolidin-1-yl
methyl)-1-biphenyl-4-ylmethyl]-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(2'-piperazin-1-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(4'-dimethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(4'-{[(2-dimethylaminoethyl)-methyl-amino]-methy-
l}-biphenyl-4-yl methyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(4'-morpholin-4-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(4'-piperidin-1-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-[4'-(4-methyl-piperazin-1-yl
methyl)-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-(4'-piperazin-1-yl
methyl-biphenyl-4-ylmethyl)-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-(3'-hydroxymethyl-biphenyl-4-ylmethyl)-oxazolidin-2--
one,
5-(4-Fluorophenyl)-3-[4-(pyrazin-2-yloxy)-benzyl]-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-[4-(pyrimidin-2-yloxy)-benzyl]-oxazolidin-2-one,
3-[4-(4-Fluorophenoxy)-benzyl]-5-(4-fluorophenyl)-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-[4-(pyridin-2-yloxy)-benzyl]-oxazolidin-2-one,
5-(4-Fluorophenyl)-3-(4-phenoxy-benzyl)-oxazolidin-2-one,
5-(R)-(4-Chlorophenyl)-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-benzyl]-
-oxazolidin-2-one,
3-(4-Morpholin-4-yl-benzyl)-5-(R)-phenyl-oxazolidin-2-one,
3-[4-(4-Methyl-piperazin-1-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one,
5-(R)-Phenyl-3-[4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one,
5-(R)-Phenyl-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-benzyl]-o-
xazolidin-2-one,
5-(R)-Phenyl-3-[4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one,
3-[3-(4-Methyl-piperazin-1-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2--
one,
5-(R)-Phenyl-3-[3-(4-pyridin-4-ylmethyl-piperazin-1-yl)-benzyl]-oxazo-
lidin-2-one,
3-(3-Morpholin-4-yl-benzyl)-5-(R)-phenyl-oxazolidin-2-one,
5-(R)-Phenyl-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-ylmethyl)-benzyl]-oxa-
zolidin-2-one,
5-(R)-Phenyl-3-[4-(4-pyridin-3-ylmethyl-piperazin-1-ylmethyl)-benzyl]-oxa-
zolidin-2-one,
5-[4-(5-Methoxy-pyridin-3-yl)-phenyl]-3-(4-trifluoro-methoxy-benzyl)-oxaz-
olidin-2-one, and
4'-[3-(4-Chloro-benzyl)-2-oxo-oxazolidin-5-yl]-biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide.
10. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier or excipient.
11. (canceled)
12. (canceled)
13. (canceled)
14. A method for the treatment or prevention of neurological and
psychiatric disorders associated with glutamate dysfunction in an
animal in need of such treatment, comprising the step of
administering to said animal a therapeutically effective amount of
a compound according to claim 1.
15. A method for the treatment or prevention of neurological and
psychiatric disorders associated with glutamate dysfunction in an
animal in need of such treatment, comprising the step of
administering to said animal a therapeutically effective amount of
a pharmaceutical composition according to claim 10.
16. The method according to claim 14, wherein the neurological and
psychiatric disorders are selected from cerebral deficit subsequent
to cardiac bypass surgery and grafting, stroke, cerebral ischemia,
spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest,
hypoglycemic neuronal damage, dementia, AIDS-induced dementia,
Alzheimer's disease, Huntington's Chorea, amyotrophic lateral
sclerosis, ocular damage, retinopathy, cognitive disorders,
idiopathic and drug-induced Parkinson's disease, muscular spasms
and disorders associated with muscular spasticity including
tremors, epilepsy, convulsions, cerebral deficits secondary to
prolonged status epilepticus, migraine, migraine headache, urinary
incontinence, substance tolerance, substance withdrawal, psychosis,
schizophrenia, anxiety, generalized anxiety disorder, panic
disorder, social phobia, obsessive compulsive disorder, and
post-traumatic stress disorder (PTSD), mood disorders, depression,
mania, bipolar disorders, circadian rhythm disorders, jet lag,
shift work, trigeminal neuralgia, hearing loss, tinnitus, macular
degeneration of the eye, emesis, brain edema, pain, acute pain,
chronic pain, severe pain, intractable pain, neuropathic pain,
inflammatory pain, and post-traumatic pain, severe dyskinesia,
sleep disorders, narcolepsy, attention deficit/hyperactivity
disorder, and conduct disorder.
17. The method according to claim 16, wherein the neurological and
psychiatric disorders are selected from Alzheimer's disease,
cerebral deficits secondary to prolonged status epilepticus,
substance tolerance, substance withdrawal, psychosis,
schizophrenia, anxiety, generalized anxiety disorder, panic
disorder, social phobia, obsessive compulsive disorder, and
post-traumatic stress disorder (PTSD), mood disorders, depression,
mania, and bipolar disorders.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel compounds which are
potentiators of glutamate receptors, methods for their preparation,
pharmaceutical compositions containing them and their use in
therapy.
[0002] The metabotropic glutamate receptors (mGluR) constitute a
family of GTP-binding-protein (G-protein) coupled receptors that
are activated by glutamate, and have important roles in synaptic
activity in the central nervous system, including neural
plasticity, neural development and neurodegeneration.
[0003] Activation of mGluRs in intact mammalian neurons elicits one
or more of the following responses: activation of phospholipase C;
increases in phosphoinositide (PI) hydrolysis; intracellular
calcium release; activation of phospholipase D; activation or
inhibition of adenyl cyclase; increases or decreases in the
formation of cyclic adenosine monophosphate (cAMP); activation of
guanylyl cyclase; increases in the formation of cyclic guanosine
monophosphate (cGMP); activation of phospholipase A.sub.2;
increases in arachidonic acid release; and increases or decreases
in the activity of voltage- and ligand-gated ion channels (Schoepp
et al., 1993, Trends Pharmacol. Sci., 14:13; Schoepp, 1994,
Neurochem. Int., 24:439; Pin et al., 1995, Neuropharmacology 34:1,
Bordi & Ugolini, 1999, Prog. Neurobiol. 59:55).
[0004] Eight mGluR subtypes have been identified, which are divided
into three groups based upon primary sequence similarity, signal
transduction linkages, and pharmacological profile. Group-I
includes mGluR1 and mGluR5, which activate phospholipase C and the
generation of an intracellular calcium signal. The Group-II (mGluR2
and mGluR3) and Group-III (mGluR4, mGluR6, mGluR7, and mGluR8)
mGluRs mediate an inhibition of adenylyl cyclase activity and
cyclic AMP levels. For a review, see Pin et al., 1999, Eur. J.
Pharmacol., 375:277-294.
[0005] Members of the mGluR family of receptors are implicated in a
number of normal processes in the mammalian CNS, and are important
targets for compounds for the treatment of a variety of
neurological and psychiatric disorders. Activation of mGluRs is
required for induction of hippocampal long-term potentiation and
cerebellar long-term depression (Bashir et al., 1993, Nature,
363:347; Bortolotto et al, 1994, Nature, 368:740; Aiba et al.,
1994, Cell, 79:365; Aiba et al., 1994, Cell, 79:377). A role for in
GluR activation in nociception and analgesia also has been
demonstrated (Meller et al., 1993, Neuroreport, 4: 879; Bordi &
Ugolini, 1999, Brain Res., 871:223). In addition, mGluR activation
has been suggested to play a modulatory role in a variety of other
normal processes including synaptic transmission, neuronal
development, apoptotic neuronal death, synaptic plasticity, spatial
learning, olfactory memory, central control of cardiac activity,
waking, motor control and control of the vestibulo-ocular reflex
(Nakanishi, 1994, Neuron, 13:1031; Pin et al., 1995,
Neuropharmacology, supra; Knopfel et al., 1995, J. Med. Chem.,
38:1417).
[0006] Recent advances in the elucidation of the neurophysiological
roles of mGluRs have established these receptors as promising drug
targets in the therapy of acute and chronic neurological and
psychiatric disorders and chronic and acute pain disorders. Because
of the physiological and pathophysiological significance of the
mGluRs, there is a need for new drugs and compounds that can
modulate mGluR function.
SUMMARY OF THE INVENTION
[0007] The invention satisfies this need and others by providing,
as one object, compounds of Formula I,
##STR00002##
wherein: [0008] R.sup.1 is selected from the group consisting of H,
hydroxy, F, Cl, Br, I, nitro, CN, alkyl, allylhalo, O-alkyl,
O-allylhalo, alkenyl, O-alkenyl, alkynyl, O-alkynyl, cycloalkyl,
alkylene-cycloalkyl, O-cycloalkyl, O-alkylene-cycloalkyl,
heterocycloalkyl, alkylene-heterocycloalkyl, O-heterocycloalkyl,
O-alkylene-heterocycloalkyl, aryl, alkylenearyl, O-aryl,
O-alkylenearyl, heteroaryl, alkyleneheteroaryl, O-heteroaryl,
O-alkyleneheteroaryl, (CO)cycloalkyl, (CO)heterocycloalkyl,
(CO)aryl, (CO)heteroaryl, alkyleneOR.sup.4, O-alkyleneOR.sup.4,
(CO)R.sup.7, O(CO)R.sup.7, alkyleneO(CO)R.sup.7,
alkylene(CO)R.sup.7, O-alkylene(CO)R.sup.7, CO.sub.2R.sup.7,
alkyleneCO.sub.2R.sup.7, O-alkyleneCO.sub.2R.sup.7, alkylenecyano,
O-alkylenecyano, NR.sup.4R.sup.5, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O--(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, NR.sup.4(CO)R.sup.3,
alkyleneNR.sup.4(CO)R.sup.3, O-alkyleneNR.sup.4(CO)R.sup.5,
NR.sup.4(CO)NR.sup.4R.sup.5, alkyleneNR.sup.4(CO)NR.sup.4R.sup.5,
SR.sup.4, alkyleneSR.sup.4, O-alkyleneSR.sup.4, (SO)R.sup.3,
alkylene(SO)R.sup.3, O-alkylene(SO)R.sup.3, SO.sub.2R.sup.3,
alkyleneSO.sub.2R.sup.3, O-alkyleneSO.sub.2.sup.3,
(SO.sub.2)NR.sup.4R.sup.5, alkylene(SO.sub.2)NR.sup.4R.sup.5,
O-alkylene(SO.sub.2)NR.sup.4R.sup.5, NR.sup.4(SO.sub.2)R.sup.5,
alkyleneNR.sup.4(SO.sub.2)R.sup.5,
O-alkyleneNR.sup.4(SO.sub.2)R.sup.5,
NR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
alkyleneNR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
O-alkyleneNR.sup.4(SO.sub.2)NR.sup.4R.sup.5, NR.sup.4OR.sup.5,
NR.sup.4(CO)OR.sup.7, alkylNR.sup.4(CO)OR.sup.7,
O-alkylNR.sup.4(CO)OR.sup.7 and any cyclic moiety is optionally
substituted by one or more independently selected substituents
R.sup.6; [0009] R.sup.2 is selected from the group consisting of H,
hydroxy, F, Cl, Br, I, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo,
cycloalkyl, alkylene-cycloalkyl, O-cycloalkyl,
O-alkylene-cycloalkyl, heterocycloalkyl, alkylene-heterocycloalkyl,
O-heterocycloalkyl, O-alkylene-heterocycloalkyl, aryl,
alkylenearyl, O-aryl, O-alkylenearyl, heteroaryl,
alkyleneheteroaryl, O-heteroaryl, O-alkyleneheteroaryl,
alkyleneOR.sup.4, O-alkyleneOR.sup.4, (CO)R.sup.7,
alkylene(CO)R.sup.7, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, alkylene(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, alkyleneNR.sup.4(CO)R.sup.3, and any
cyclic moiety is optionally substituted by one or more
independently selected substituents R.sup.6; [0010] R.sup.3 is, in
each instance, selected from the group consisting of H and alkyl,
[0011] R.sup.4 and R.sup.5 arc independently selected from the
group consisting of H, alkyl, alkylhalo, alkenyl, alkynyl,
cycloalkyl, alkylenecycloalkyl, heterocycloalkyl,
alkyleneheterocycloalkyl, aryl, alkylenearyl, heteroaryl, and
alkyleneheteroaryl, NR.sup.7R.sup.8, alkyleneNR.sup.7R.sup.8,
OR.sup.7, alkyleneOR.sup.7, and any cyclic moiety is optionally
substituted with a substituent selected from the group consisting
of alkyl, halo, haloalkyl O-alkyl, O-haloalkyl, aryl, alkylenearyl,
heteroaryl and alkyleneheteroaryl; [0012] R.sup.6 is, in each
instance, selected from the group consisting of H, hydroxy, F, Cl,
Br, I, nitro, CN, oxo, allyl, alkylhalo, O-alkyl, O-alkylhalo,
alkenyl, O-alkenyl, alkynyl, O-alkynyl, cycloalkyl,
alkylene-cycloalkyl, O-cycloalkyl, O-alkyl-cycloalkyl,
heterocycloalkyl, alkylene-heterocycloalkyl, O-heterocycloalkyl,
O-alkylene-heterocycloalkyl, aryl, alkylenearyl, O-aryl,
O-alkylenearyl, heteroaryl, alkyleneheteroaryl, O-heteroaryl,
O-alkyleneheteroaryl, (CO)cycloalkyl, (CO)heterocycloalkyl,
(CO)aryl, (CO)heteroaryl, alkyleneOR.sup.4, O-alkyleneOR.sup.4,
(CO)R.sup.3, O(CO)R.sup.3, alkyleneO(CO)R.sup.3,
alkylene(CO)R.sup.3, O-alkylene(CO)R.sup.3, CO.sub.2R.sup.4,
alkyleneCO.sub.2R.sup.3, O-alkyleneCO.sub.2R.sup.3, alkylenecyano,
O-alkylenecyano, NR.sup.4R.sup.5, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O--(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, NR.sup.4(CO)R.sup.3,
alkyleneNR.sup.4(CO)R.sup.3, O-alkyleneNR.sup.4(CO)R.sup.3,
NR.sup.4(CO)NR.sup.4R.sup.13, SR.sup.4, alkyleneSR.sup.5,
O-alkyleneSR.sup.4, (SO)R.sup.3, alkylene(SO)R.sup.3,
O-alkylene(SO)R.sup.3, SO.sub.2R.sup.3, alkyleneSO.sub.2R.sup.3,
O-alkyleneSO.sub.2R.sup.3, (SO.sub.2)NR.sup.4R.sup.5,
alkylene(SO.sub.2)NR.sup.4R.sup.5,
O-alkylene(SO.sub.2)NR.sup.7R.sup.8, NR.sup.7(SO.sub.2)R.sup.8,
alkyleneNR.sup.7(SO.sub.2)R.sup.8,
O-alkyleneNR.sup.4(SO.sub.2)R.sup.5, NR.sup.4(CO)OR.sup.5,
alkylNR.sup.4(CO)OR.sup.5, O-alkylNR.sup.4(CO)OR.sup.5,
SO.sub.3R.sup.4 and any cyclic moiety is optionally substituted
with a substituent selected from the group consisting of halo,
alkyl, O-alkyl, haloalkyl, O-haloalkyl and NR.sup.4R.sup.5; [0013]
R.sup.7 and R.sup.8 are independently selected from the group
consisting of H and alkyl; [0014] Y is selected from the group
consisting of alkylene, alkenylene and alkynylene wherein any
hydrogen atom of Y may be independently substituted with one or
more substituents selected from the group consisting of hydroxy, F,
Cl, Br, I, alkyl, alkylhalo and O-alkyl; and m and n are
independently selected from the group consisting of 0, 1, 2, 3 and
4; with the proviso that the compound is not selected from the
group consisting of: [0015] 3-Benzyl-5-phenyl-2-oxazolidinone,
[0016] 3-(.alpha.-Methylbenzyl)-5-phenyl-2-oxazolidinone, [0017]
3-(.alpha.-Methyl-(4-methylbenzyl))-5-phenyl-2-oxazolidinone,
[0018] 3-((2-Thienyl)methyl)-5-phenyl-2-oxazolidinone, [0019]
5-(3,4-Dimethoxyphenyl)-3-benzyl-2-oxazolidinone, [0020]
5-(3,4-Dimethoxyphenyl)-3-(2-(3,4-dimethoxyphenylethyl))-2-oxazolidinone,
[0021] Methyl
4[2-[5-(3-chlorophenyl)-2-oxazolidin-3-yl]propyl]phenoxy ethanoate,
[0022] 4[2-[5-(3-Chlorophenyl)-2-oxazolidin-3-yl]propyl]phenoxy
ethanoic acid, [0023]
3-[1-(4-Methylphenyl)ethyl]-5-phenyl-2-oxazolidinone, [0024]
5-(3-Chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidin-
one and [0025]
5-(3-Chlorophenyl)-3-[(3,4-dimethoxyphenyl)-butan-2-yl]-2-oxazolidinone.
[0026] Another object of the invention is to provide a
pharmaceutical composition comprising a compound according to
Formula I together with a pharmaceutically acceptable carrier or
excipient.
[0027] Yet another object of the invention is a method for the
treatment or prevention of neurological and psychiatric disorders
associated with glutamate dysfunction in an animal in need of such
treatment. The method comprises the step of administering to the
animal a therapeutically effective amount of a compound of Formula
I or a pharmaceutical composition thereof. Preferably, the animal
is a mammal; more preferably a human being.
[0028] Still another object of the invention is the use of a
compound according to Formula I, or a pharmaceutically acceptable
salt or solvate thereof for the manufacture of a medicament for the
treatment of any of the conditions discussed herein.
[0029] Another object of the invention provides a compound of
Formula I; or a pharmaceutically acceptable salt or solvate
thereof, for use in therapy.
[0030] The invention additionally provides processes for the
preparation of compounds of Formula I. General and specific
processes are discussed in more detail below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] The present invention is based upon the discovery of
compounds that exhibit activity as pharmaceuticals, in particular
as modulators of metabotropic glutamate receptors. More
particularly, the compounds of the present invention exhibit
activity as potentiators of the mGluR2 receptor, and are useful in
therapy, in particular for the treatment of neurological and
psychiatric disorders associated with glutamate dysfunction.
DEFINITIONS
[0032] Unless specified otherwise within this specification, the
nomenclature used in this specification generally follows the
examples and rules stated in Nomenclature of Organic Chemistry,
Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979,
which is incorporated by references herein for its exemplary
chemical structure names and rules on naming chemical structures.
Optionally, a name of a compound may be generated using a chemical
naming program: ACD/ChemSketch, Version 5.09/September 2001,
Advanced Chemistry Development, Inc., Toronto, Canada.
[0033] The term "alkyl" as used herein means a straight- or
branched-chain hydrocarbon radical having from one to six carbon
atoms, and includes methyl, ethyl, propyl, isopropyl, t-butyl and
the like.
[0034] The term "alkenyl" as used herein means a straight- or
branched-chain alkenyl radical having from two to six carbon atoms,
and includes ethenyl, 1-propenyl, 1-butenyl and the like.
[0035] The term "alkynyl" as used herein means a straight- or
branched-chain alkynyl radical having from two to six carbon atoms,
and includes 1-propynyl (propargyl), 1-butynyl and the like.
[0036] The term "cycloalkyl" as used herein means a cyclic group
(which may be unsaturated) having from three to seven carbon atoms,
and includes cyclopropyl, cyclohexyl, cyclohexenyl and the
like.
[0037] The term "heterocycloalkyl" as used herein means a three- to
seven-membered cyclic group (which may be unsaturated) having at
least one heteroatom selected from the group consisting of N, S and
O, and includes piperidinyl, piperazinyl, pyrrolidinyl,
tetrahydrofuranyl and the like.
[0038] The term "alkoxy" as used herein means a straight- or
branched-chain alkoxy radical having from one to six carbon atoms
and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and
the like.
[0039] The term "halo" as used herein means halogen and includes
fluoro, chloro, bromo, iodo and the like, in both radioactive and
non-radioactive forms.
[0040] The term "alkylene" as used herein means a difunctional
branched or unbranched saturated hydrocarbon radical having one to
six carbon atoms, and includes methylene, ethylene, n-propylene,
n-butylene and the like.
[0041] The term "alkenylene" as used herein means a difunctional
branched or unbranched hydrocarbon radical having two to six carbon
atoms and having at least one double bond, and includes ethenylene,
n-propenylene, n-butenylene and the like.
[0042] The term "alkynylene" as used herein means a difunctional
branched or unbranched hydrocarbon radical having two to six carbon
atoms and having at least one triple bond, and includes ethynylene,
n-propynylene, n-butynylene and the like.
[0043] The term "aryl" as used herein means an aromatic group
having five to twelve atoms, and includes phenyl, naphthyl and the
like.
[0044] The term "heteroaryl" means an aromatic group which includes
at least one heteroatom selected from the group consisting of N, S
and O, and includes groups and includes pyridyl, indolyl, furyl,
benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl and the
like.
[0045] The term "pharmaceutically acceptable salt" means either an
acid addition salt or a basic addition salt which is compatible
with the treatment of patients.
[0046] A "pharmaceutically acceptable acid addition salt" is any
non-toxic organic or inorganic acid addition salt of the base
compounds represented by Formula I or any of its intermediates,
Illustrative inorganic acids which form suitable salts include
hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid
metal salts such as sodium monohydrogen orthophosphate and
potassium hydrogen sulfate. Illustrative organic acids which form
suitable salts include the mono-, di- and tricarboxylic acids.
Illustrative of such acids are, for example, acetic, glycolic,
lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic,
tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,
hydroxybenzoic, phenylacetic, cinnamic, salicylic,
2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids
such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
Either the mono- or di-acid salts can be formed, and such salts can
exist in either a hydrated, solvated or substantially anhydrous
form. In general, the acid addition salts of these compounds are
more soluble in water and various hydrophilic organic solvents, and
generally demonstrate higher melting points in comparison to their
free base forms. The selection criteria for the appropriate salt
will be known to one skilled in the art. Other non-pharmaceutically
acceptable salts e.g. oxalates may be used for example in the
isolation of compounds of Formula I for laboratory use, or for
subsequent conversion to a pharmaceutically acceptable acid
addition salt.
[0047] A "pharmaceutically acceptable basic addition salt" is any
non-toxic organic or inorganic base addition salt of the acid
compounds represented by Formula I or any of its intermediates.
Illustrative inorganic bases which form suitable salts include
lithium, sodium, potassium, calcium, magnesium or barium
hydroxides. Illustrative organic bases which form suitable salts
include aliphatic, alicyclic or aromatic organic amines such as
methylamine, trimethyl amine and picoline or ammonia. The selection
of the appropriate salt may be important so that an ester
functionality, if any, elsewhere in the molecule is not hydrolyzed.
The selection criteria for the appropriate salt will be known to
one skilled in the art.
[0048] The term "solvate" means a compound of Formula I or the
pharmaceutically acceptable salt of a compound of Formula I wherein
molecules of a suitable solvent are incorporated into a crystal
lattice. A suitable solvent is physiologically tolerable at the
dosage administered as the solvate. Examples of suitable solvents
are ethanol, water and the like. When water is the solvent, the
molecule is referred to as a hydrate.
[0049] The term "treat" or "treating" means to alleviate symptoms,
eliminate the causation of the symptoms either on a temporary or
permanent basis, or to prevent or slow the appearance of symptoms
of the named disorder or condition.
[0050] The term "therapeutically effective amount" means an amount
of the compound which is effective in treating the named disorder
or condition.
[0051] The term "pharmaceutically acceptable carrier" means a
non-toxic solvent, dispersant, excipient, adjuvant or other
material which is mixed with the active ingredient in order to
permit the formation of a pharmaceutical composition, i.e., a
dosage form capable of administration to the patient. One example
of such a carrier is a pharmaceutically acceptable oil typically
used for parenteral administration.
Compounds
[0052] Compounds of the invention conform generally to Formula
I;
##STR00003##
wherein: [0053] R.sup.1 is selected from the group consisting of H,
hydroxy, F, Cl, Br, I, nitro, CN, alkyl, alkylhalo, O-alkyl,
O-allylhalo, alkenyl, O-alkenyl, alkynyl, O-alkynyl, cycloalkyl,
alkylene-cycloalkyl, O-cycloalkyl, O-alkylene-cycloalkyl,
heterocycloalkyl, alkylene-heterocycloalkyl, O-heterocycloalkyl,
O-alkylene-heterocycloalkyl, aryl, alkylenearyl, O-aryl,
O-alkylenearyl, heteroaryl, alkyleneheteroaryl, O-heteroaryl,
O-alkyleneheteroaryl, (CO)cycloalkyl, (CO)heterocycloalkyl,
(CO)aryl, (CO)heteroaryl, alkyleneOR.sup.4, O-alkyleneOR.sup.4,
(CO)R.sup.7, O(CO)R.sup.7, alkyleneO(CO)R.sup.7,
alkylene(CO)R.sup.7, O-alkylene(CO)R.sup.7, CO.sub.2R.sup.7,
alkyleneCO.sub.2R.sup.7, O-alkyleneCO.sub.2R.sup.7, alkylenecyano,
O-alkylenecyano, NR.sup.4R.sup.5, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O--(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, NR.sup.4(CO)R.sup.3,
alkyleneNR.sup.4(CO)R.sup.3, O-alkyleneNR.sup.4(CO)R.sup.5,
NR.sup.4(CO)NR.sup.4R.sup.5, alkyleneNR.sup.4(CO)NR.sup.4R.sup.5,
SR.sup.4, alkyleneSR.sup.4, O-alkyleneSR.sup.4, (SO)R.sup.3,
alkylene(SO)R.sup.3, O-alkylene(SO)R.sup.3, SO.sub.2R.sup.3,
alkyleneSO.sub.2R.sup.3, O-alkyleneSO.sub.2R.sup.3,
(SO.sub.2)NR.sup.4R.sup.5, alkylene(SO.sub.2)NR.sup.4R.sup.5,
O-alkylene(SO.sub.2)NR.sup.4R.sup.5, NR.sup.4(SO.sub.2)R.sup.5,
alkyleneNR.sup.4(SO.sub.2)R.sup.5,
O-alkyleneNR.sup.4(SO.sub.2)R.sup.5,
NR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
alkyleneNR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
O-alkyleneNR.sup.4(SO.sub.2)NR.sup.4R.sup.5, NR.sup.4OR.sup.5,
NR.sup.4(CO)OR.sup.7, alkylNR.sup.4(CO)OR.sup.7,
O-alkylNR.sup.4(CO)OR.sup.7 and any cyclic moiety is optionally
substituted by one or more independently selected substituents
R.sup.6; [0054] R.sup.2 is selected from the group consisting of H,
hydroxy, F, Cl, Br, I, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo,
cycloalkyl, alkylene-cycloalkyl, O-cycloalkyl,
O-alkylene-cycloalkyl, heterocycloalkyl, alkylene-heterocycloalkyl,
O-heterocycloalkyl, O-alkylene-heterocycloalkyl, aryl,
alkylenearyl, O-aryl, O-alkylenearyl, heteroaryl,
alkyleneheteroaryl, O-heteroaryl, O-alkyleneheteroaryl,
alkyleneOR.sup.4, O-alkyleneOR.sup.4, (CO)R.sup.7,
alkylene(CO)R.sup.7, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O-alkylene(CO)NR.sup.4R.sup.5,
alkyleneNR.sup.4(CO)R.sup.3, and any cyclic moiety is optionally
substituted by one or more independently selected substituents
R.sup.6; [0055] R.sup.3 is, in each instance, selected from the
group consisting of H and alkyl, [0056] R.sup.4 and R.sup.5 are
independently selected from the group consisting of H, alkyl,
alkylhalo, alkenyl, alkynyl, cycloalkyl, alkylenecycloalkyl,
heterocycloalkyl, alkyleneheterocycloalkyl, aryl, alkylenearyl,
heteroaryl, and alkyleneheteroaryl, NR.sup.7R.sup.8,
alkyleneNR.sup.7R.sup.8, OR.sup.7, alkyleneOR.sup.7, and any cyclic
moiety is optionally substituted with a substituent selected from
the group consisting of alkyl, halo, haloalkyl O-alkyl,
O-haloalkyl, aryl, alkylenearyl, heteroaryl and alkyleneheteroaryl;
[0057] R.sup.6 is, in each instance, selected from the group
consisting of H, hydroxy, F, Cl, Br, I, nitro, CN, oxo, alkyl,
alkylhalo, O-alkyl, O-alkylhalo, alkenyl, O-alkenyl, alkynyl,
O-alkynyl, cycloalkyl, alkylene-cycloalkyl, O-cycloalkyl,
O-alkyl-cycloalkyl, heterocycloalkyl, alkylene-heterocycloalkyl,
O-heterocycloalkyl, O-alkylene-heterocycloalkyl, aryl,
alkylenearyl, O-aryl, O-alkylenearyl, heteroaryl,
alkyleneheteroaryl, O-heteroaryl, O-alkyleneheteroaryl,
(CO)cycloalkyl, (CO)heterocycloalkyl, (CO)aryl, (CO)heteroaryl,
alkyleneOR.sup.4, O-alkyleneOR.sup.4, (CO)R.sup.3, O(CO)R.sup.3,
alkyleneO(CO)R.sup.3, alkylene(CO)R.sup.3, O-alkylene(CO)R.sup.3,
CO.sub.2R.sup.4, alkyleneCO.sub.2R.sup.3,
O-alkyleneCO.sub.2R.sup.3, alkylenecyano, O-alkylenecyano,
NR.sup.4R.sup.5, alkyleneNR.sup.4R.sup.5,
O-alkyleneNR.sup.4R.sup.5, (CO)NR.sup.4R.sup.5,
alkylene(CO)NR.sup.4R.sup.5, O--(CO)NR.sup.4R.sup.5,
O-alkylene(CO)NR.sup.4R.sup.5, NR.sup.4(CO)R.sup.3,
alkyleneNR.sup.4(CO)R.sup.3, O-alkyleneNR.sup.4(CO)R.sup.3,
NR.sup.4(CO)NR.sup.4R.sup.13, SR.sup.4, alkyleneSR.sup.5,
O-alkyleneSR.sup.4, (SO)R.sup.3, alkylene(SO)R.sup.3,
O-alkylene(SO)R.sup.3, SO.sub.2R.sup.3, alkyleneSO.sub.2R.sup.3,
O-alkyleneSO.sub.2R.sup.3, (SO.sub.2)NR.sup.4R.sup.5,
alkylene(SO.sub.2)NR.sup.4R.sup.5,
O-alkylene(SO.sub.2)NR.sup.7R.sup.8, NR.sup.7(SO.sub.2)R.sup.8,
alkyleneNR.sup.7(SO.sub.2)R.sup.8,
O-alkyleneNR.sup.4(SO.sub.2)R.sup.5, NR.sup.4(CO)OR.sup.5,
alkylNR.sup.4(CO)OR.sup.5, O-alkylNR.sup.4(CO)OR.sup.5,
SO.sub.3R.sup.4 and any cyclic moiety is optionally substituted
with a substituent selected from the group consisting of halo,
alkyl, O-alkyl, haloalkyl, O-haloalkyl and NR.sup.4R.sup.5; [0058]
R.sup.7 and R.sup.8 are independently selected from the group
consisting of H and alkyl; [0059] Y is selected from the group
consisting of alkylene, alkenylene and alkynylene wherein any
hydrogen atom of Y may be independently substituted with one or
more substituents selected from the group consisting of hydroxy, F,
Cl, Br, I, alkyl, alkylhalo and O-alkyl; and m and n are
independently selected from the group consisting of 0, 1, 2, 3 and
4; with the proviso that the compound is not selected from the
group consisting of: [0060] 3-Benzyl-5-phenyl-2-oxazolidinone,
[0061] 3-(.alpha.-Methylbenzyl)-5-phenyl-2-oxazolidinone, [0062]
3-(.alpha.-Methyl-(4-methylbenzyl))-5-phenyl-2-oxazolidinone,
[0063] 3-((2-Thienyl)methyl)-5-phenyl-2-oxazolidinone, [0064]
5-(3,4-Dimethoxyphenyl)-3-benzyl-2-oxazolidinone, [0065]
5-(3,4-Dimethoxyphenyl)-3-(2-(3,4-dimethoxyphenylethyl))-2-oxazolidinone,
[0066] Methyl
4[2-[5-(3-chlorophenyl)-2-oxazolidin-3-yl]propyl]phenoxy ethanoate,
[0067] 4[2-[5-(3-Chlorophenyl)-2-oxazolidin-3-yl]propyl]phenoxy
ethanoic acid, [0068]
3-[1-(4-Methylphenyl)ethyl]-5-phenyl-2-oxazolidinone, [0069]
5-(3-Chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidin-
one and [0070]
5-(3-Chlorophenyl)-3-[(3,4-dimethoxyphenyl)-butan-2-yl]-2-oxazolidinone.
[0071] In one embodiment Y is a CH.sub.2 group.
[0072] In another embodiment R.sup.2 is selected from the group
consisting of alkyl, alkoxy, trifluoromethoxy and halo. In other
embodiments R.sup.2 is a 4-halo group; in yet another it is a
4-chloro group.
[0073] In still other embodiments R.sup.1 is selected from the
group consisting of optionally-substituted aryl, O-aryl, heteroaryl
and O-heteroaryl groups. In another embodiment R.sup.1 is an
optionally-substituted phenyl group, in another it is an
optionally-substituted O-pyridyl group.
[0074] In other embodiments R.sup.1 is an aryl group further
substituted with a substituent selected from the group consisting
of alkyleneNR.sub.4R.sub.5, (CO)NR.sub.4R.sub.5 and
O-alkyleneNR.sub.4R.sub.5.
[0075] It will be understood by those of skill in the art that when
compounds of the present invention contain one or more chiral
centers, the compounds of the invention may exist in, and be
isolated as, enantiomeric or diastereomeric forms, or as a racemic
mixture. The present invention includes any possible enantiomers,
diastereomers, racemates or mixtures thereof of a compound of
Formula I. The optically active forms of the compound of the
invention may be prepared, for example, by chiral chromatographic
separation of a racemate, by synthesis from optically active
starting materials or by asymmetric synthesis based on the
procedures described thereafter.
[0076] It will also be appreciated by those of skill in the art
that certain compounds of the present invention may exist as
geometrical isomers, for example E and Z isomers of alkenes. The
present invention includes any geometrical isomer of a compound of
Formula I. It will further be understood that the present invention
encompasses tautomers of the compounds of Formula I.
[0077] It will also be understood by those of skill in the art that
certain compounds of the present invention may exist in solvated,
for example hydrated, as well as unsolvated forms. It will further
be understood that the present invention encompasses all such
solvated forms of the compounds of Formula I.
[0078] Within the scope of the invention are also salts of the
compounds of Formula I. Generally, pharmaceutically acceptable
salts of compounds of the present invention are obtained using
standard procedures well known in the art, for example, by reacting
a sufficiently basic compound, for example an alkyl amine with a
suitable acid, for example, HCl or acetic acid, to afford a
physiologically acceptable anion. It is also possible to make a
corresponding alkali metal (such as sodium, potassium, or lithium)
or an alkaline earth metal (such as a calcium) salt by treating a
compound of the present invention having a suitably acidic proton,
such as a carboxylic acid or a phenol with one equivalent of an
alkali metal or alkaline earth metal hydroxide or alkoxide (such as
the ethoxide or methoxide), or a suitably basic organic amine (such
as choline or meglumine) in an aqueous medium, followed by
conventional purification techniques.
[0079] In one embodiment of the present invention, the compound of
Formula I may be converted to a pharmaceutically acceptable salt or
solvate thereof, particularly, an acid addition salt such as a
hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,
tartrate, citrate, methanesulphonate or p-toluenesulphonate.
[0080] Specific examples of the present invention include the
compounds 1 to 125 as illustrated in the following table, their
pharmaceutically acceptable salts, hydrates, solvates, optical
isomers, and combinations thereof:
TABLE-US-00001 No. Structure Name 1 ##STR00004##
5-(R)-Phenyl-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 2
##STR00005##
3-(4-Trifluoromethoxybenzyl)-5-[3-(4-trifluoromethoxybenzyloxy)
phenyl]-oxazolidin-2-one 3 ##STR00006##
5-(4-Methoxyphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 4
##STR00007##
5-(4-Fluorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 5
##STR00008##
5-(4-Methylphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 6
##STR00009##
5-(4-Chlorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 7
##STR00010## 3-(4-Trifluoromethoxy-benzyl)-5-(4-trifluoromethoxy
phenyl)-oxazolidin-2-one 8 ##STR00011##
5-(4-Methoxyphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 9
##STR00012##
5-p-Tolyl-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 10
##STR00013##
5-o-Tolyl-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one 11
##STR00014##
5-(3,5-Dichlorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one
12 ##STR00015##
5-(3,4-Dichlorophenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one
13 ##STR00016##
5-(3,5-Dimethoxyphenyl)-3-(4-trifluoromethoxybenzyl)-oxazolidin-2-one
14 ##STR00017##
3-(4-Trifluoromethoxybenzyl)-5-(S)-phenyl-oxazolidin-2-one 15
##STR00018## 3-(4-Phenoxybenzyl)-5-(R)-phenyl-oxazolidin-2-one 16
##STR00019## 3-(3,5-Difluorobenzyl)-5-(R)-phenyl-oxazolidin-2-one
17 ##STR00020##
3-(3,4-Dichlorobenzyl)-5-(R)-phenyl)-oxazolidin-2-one 18
##STR00021## 3-(4-Iodobenzyl)-5-(R)-phenyl)-oxazolidin-2-one 19
##STR00022##
3-(4-Difluoromethoxbenzyl)-5-(R)-phenyl)-oxazolidin-2-one 20
##STR00023## 3-(4-Chlorobenzyl)-5-(R)-phenyl)-oxazolidin-2-one 21
##STR00024## 3-(4-Ethylbenzyl)-5-(R)-phenyl)-oxazolidin-2-one 22
##STR00025## 3-Biphenyl-4-ylmethyl-5-(R)-phenyl)-oxazolidin-2-one
23 ##STR00026##
3-(4-Benzyloxybenzyl)-5-(R)-phenyl)-oxazolidin-2-one 24
##STR00027## 3-(4-Methoxybenzyl)-5-(R)-phenyl)-oxazolidin-2-one 25
##STR00028## 5-(4-Pluorophenyl)-3-(4-iodobenzyl)-oxazolidin-2-one
26 ##STR00029##
4-5[-(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-benzoic acid
methyl ester 27 ##STR00030##
5-(4-Fluorophenyl)-3-(4-methoxybenzyl)-oxazolidin-2-one 28
##STR00031##
5-(R)-(4-Chlorophenyl)-3-(4-Iodobenzyl)-oxazolidin-2-one 29
##STR00032## 3-(3-Iodo-benzyl)-5-(R)-phenyl-oxazolidin-2-one 30
##STR00033##
5-(4-Bromo-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
31 ##STR00034##
5-(3-Bromo-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
32 ##STR00035##
5-(4-Bromo-phenyl)-3-(4-chloro-benzyl)-oxazolidin-2-one 33
##STR00036## 3-(4-Hydroxybenzyl)-5-(R)-phenyl-oxazolidin-2-one 34
##STR00037##
5-(4-Fluorophenyl-3-[4-(4-pyridin-2-yl-piperazine-1-carbonyl)-benzyl]-oxa-
zolidin-2-one 35 ##STR00038##
5-(4-Fluorophenyl)-3-[4-(4-pyridin-3-ylmethyl-piperazine-1-carbonyl)-benz-
yl]-oxazolidin-2-one 36 ##STR00039##
3-[4-(4-Benzyl-piperazine-1-carbonyl)-benzyl]-5-(4-fluorophenyl)-oxazolid-
in-2-one. 37 ##STR00040##
3-(4-Bromomethylbenzyl)-5-(R)-phenyl-oxazolidin-2-one 38
##STR00041##
3-(4-Bromomethyl-benzyl)-5-(R)-(4-chlorophenyl)-oxazolidin-2-one 39
##STR00042##
3-(4-Bromomethylbenzyl)-5-(4-fluorophenyl)-oxazolidin-2-one 40
##STR00043##
4-(Morpholin-4-ylmethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one 41
##STR00044##
4-[4-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-benzyl]-piperazine-1-carb-
oxylic acidtert-butyl-ester. 42 ##STR00045##
3-[4-(4-Methyl-piperazin-1-ylmethyl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e 43 ##STR00046##
5-(R)-Phenyl-3-[4-(4-phenyl-piperazin-1-ylmethyl)-benzyl]-oxazolidin-2-on-
e 44 ##STR00047##
5-(R)-Phenyl-3-(4-piperazin-1-ylmethyl-benzyl)-oxazolidin-2-one 45
##STR00048## 5-(R)-Phenyl-3-(4-{[(pyridine-2-yl
methyl)-amino]-methyl}-benzyl)-oxazolidin-2-one 46 ##STR00049##
3-{4-[(Methyl-pyridin-2-ylmethyl-amino)-methyl]-benzyl}-5-(R)-phenyl-oxaz-
olidine-2-one 47 ##STR00050##
5-(R)-Phenyl-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-one
48 ##STR00051##
5-(4-Fluorophenyl)-3-[4-(pyridine-2-yloxymethyl)-benzyl]-oxazolidin-2-one
49 ##STR00052##
5-(4-Fluorophenyl)-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-one
50 ##STR00053##
5-(4-Fluorophenyl)-3-[4-(pyridine-4-yloxymethyl)-benzyl]-oxazolidin-2-one
51 ##STR00054##
5-(R)-(4-Chlorophenyl)-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-
-one 52 ##STR00055##
3-(4-Phenoxymethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one 53
##STR00056##
5-(R)-Phenyl-3-(4-Pyridin-4-yl-benzyl)-oxazolidin-2-one 54
##STR00057##
5-(R)-Phenyl-3-(4-Pyridin-3-yl-benzyl)-oxazolidin-2-one 55
##STR00058##
3-{4-{6-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-benzyl}-5-(R)-phenyl-oxaz-
olidin-2-one 56 ##STR00059##
3-[4-(6-Morpholin-4-yl-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e 57 ##STR00060##
5-(R)-Phenyl-3-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-oxazolidin-2--
one 58 ##STR00061##
3-[4-(6-Amino-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one
59 ##STR00062##
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide 60 ##STR00063##
5-(R)-Phenyl-3-[4-(6-piperazin-1-yl-pyridin-3-yl)-benzyl]-oxazolidin-2-on-
e 61 ##STR00064##
3-[4'-(4-Methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-5-(R)-phenyl--
oxazolidin-2-one 62 ##STR00065##
3-[3'-(4-Methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-5-(R)-phenyl--
oxazolidin-2-one 63 ##STR00066## 3-{4-[6-(2-Morpholin-4-yl-ethyl
amino)-pyridin-3-yl]-benzyl}-5-(R)-phenyl-oxazolidin-2-one 64
##STR00067##
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)biphenyl-4-carboxylic
acid (2-dimethylamino-ethyl)-amide 65 ##STR00068##
3-{4-[6-(3-Dimethyl
amino-propoxy)-pyridin-3-yl]-benzyl}-5-(4-fluorophenyl-oxazolidin-2-one
66 ##STR00069##
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide 67 ##STR00070##
5-(4-Fluorophenyl)-3-(2'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-oxazol-
idin-2-one 68 ##STR00071##
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxylic
acid. 69 ##STR00072##
5-(4-Fluorophenyl)-3-[3'-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylme-
thyl]-oxazolidin-2-one. 70 ##STR00073## 3-(4'-Dimethylamino
methyl-biphenyl-4-ylmethyl)-5-(4-fluorophenyl)-oxazolidin-2-one. 71
##STR00074##
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-methyl-amide 72 ##STR00075##
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxylic
acid (2-hydroxyethyl)-amide 73 ##STR00076##
4'-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxylic
acid ethylamine 74 ##STR00077##
4'-[5-(R)-(4-Chlorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid (2-dimethylamino-ethyl)-amide 75
##STR00078##
3-[3-(6-Morpholin-4-yl-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e 76 ##STR00079##
3'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide 77 ##STR00080##
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-biphenyl-4-carboxylic
acid (1-benzyl-pyrrolidin-3-(S)-yl)-amide 78 ##STR00081##
5-(4'-Dimethylaminomethyl-biphenyl-3-yl)-3-(4-trifluoromethoxy-benzyl)-ox-
azolidin-2-one
79 ##STR00082## 4'-[5-(S)-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide 80 ##STR00083##
4'-[5-(R)-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide 81 ##STR00084##
5-(R)-(4-Chlorophenyl)-3-(2'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 82 ##STR00085##
4'-[5-(R)-(4-Chlorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide 83 ##STR00086##
3-[4'-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-yl
methyl]-5-phenyl-oxazolidin-2-one 84 ##STR00087##
5-(4-Fluorophenyl)-3-[3'-(4-methyl-piperazin-1-ylmethyl)-bipheny]-4-ylmet-
hyl]-oxazolidin-2-one 85 ##STR00088##
5-(4-Fluorophenyl)-3-(3'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-oxazol-
idin-2-one 86 ##STR00089##
5-(4-Fluorophenyl)-3-(3'-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl)-oxazo-
lidin-2-one 87 ##STR00090##
5-(R)-(4-Chlorophenyl)-3-(3'-diethylaminomethyl-biphenyl-4-ylmethyl)-oxaz-
olidin-2-one 88 ##STR00091##
5-(R)-(4-Chlorophenyl)-3-(3'-{[dimethylaminoethyl)methylamino]methyl}biph-
enyl-4-ylmethyl)-oxazolidin-2-one 89 ##STR00092##
5-(R)-(4-Chlorophenyl)-3-(3'-piperidin-1-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 90 ##STR00093##
5-(R)-(4-Chlorophenyl)-3-(3'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 91 ##STR00094##
5-(R)-(4-Chlorophenyl)-3-[3'-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-y-
lmethyl]-oxazolidin-2-one 92 ##STR00095##
5-(R)-(4-Chlorophenyl)-3-(3'-dimethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one 93 ##STR00096##
5-(R)-(4-Chlorophenyl)-3-(3'-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 94 ##STR00097##
5-(R)-(4-Chlorophenyl)-3-(2'-dimethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one. 95 ##STR00098##
5-(R)-(4-Chlorophenyl)-3-(2'-{[(2-dimethylaminoethyl)-methyl-amino]-methy-
l}-biphenyl-4-yl methyl)-oxazolidin-2-one. 96 ##STR00099##
5-(R)-(4-Chlorophenyl)-3-[2'-(4-methyl-piperazin-1-yl
methyl)-biphenyl-4-ylmethyl)-oxazolidin-2-one 97 ##STR00100##
5-(R)-(4-Chlorophenyl)-3-[2'-(3-(S)-dimethylamino-pyrrolidin-1-yl
methyl)-1-biphenyl-4-ylmethyl]-oxazolidin-2-one 98 ##STR00101##
5-(R)-(4-Chlorophenyl)-3-(2'-piperidin-1-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 99 ##STR00102##
5-(R)-(4-Chlorophenyl)-3-(2'-(3-(R)-dimethylamino-pyrrolidin-1-yl
methyl)-1-biphenyl-4-ylmethyl]-oxazolidin-2-one 100 ##STR00103##
5-(R)-(4-Chlorophenyl)-3-(2'-piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 101 ##STR00104##
5-(R)-(4-Chlorophenyl)-3-(4'-dimethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one. 102 ##STR00105##
5-(R)-(4-Chlorophenyl)-3-(4'-{[(2-dimethylaminoethyl)-methyl-amino]-methy-
l}-biphenyl-4-yl methyl)-oxazolidin-2-one. 103 ##STR00106##
5-(R)-(4-Chlorophenyl)-3-(4'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one. 104 ##STR00107##
5-(R)-(4-Chlorophenyl)-3-(4'-piperidin-1-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 105 ##STR00108##
5-(R)-(4-Chlorophenyl)-3-[4'-(4-methyl-piperazin-1-yl
methyl)-biphenyl-4-ylmethyl)-oxazolidin-2-one 106 ##STR00109##
5-(R)-(4-Chlorophenyl)-3-(4'-piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 107 ##STR00110##
5-(4-Fluorophenyl)-3-(3'-hydroxymethyl-biphenyl-4-ylmethyl)-oxazolidin-2--
one 108 ##STR00111##
5-(4-Fluorophenyl)-3-[4-(pyrazin-2-yloxy)-benzyl]-oxazolidin-2-one
109 ##STR00112##
5-(4-Fluorophenyl)-3-[4-(pyrimidin-2-yloxy)-benzyl]-oxazolidin-2-one
110 ##STR00113##
3-[4-(4-Fluorophenoxy)-benzyl]-5-(4-fluorophenyl)-oxazolidin-2-one
111 ##STR00114##
5-(4-Fluorophenyl)-3-[4-(pyridin-2-yloxy)-benzyl]-oxazolidin-2-one
112 ##STR00115##
5-(4-Fluorophenyl)-3-(4-phenoxy-benzyl)-oxazolidin-2-one 113
##STR00116##
5-(R)-(4-Chlorophenyl)-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-benzyl]-
-oxazolidin-2-one 114 ##STR00117##
3-(4-Morpholin-4-yl-benzyl)-5-(R)-phenyl-oxazolidin-2-one 115
##STR00118##
3-[4-(4-Methyl-piperazin-1-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one
116 ##STR00119##
5-(R)-Phenyl-3-[4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 117 ##STR00120##
5-(R)-Phenyl-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 118 ##STR00121##
5-(R)-Phenyl-3-[4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 119 ##STR00122##
3-[3-(4-Methyl-piperazin-1-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one
120 ##STR00123##
5-(R)-Phenyl-3-[3-(4-pyridin-4-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 121 ##STR00124##
3-(3-Morpholin-4-yl-benzyl)-5-(R)-phenyl-oxazolidin-2-one 122
##STR00125##
5-(R)-Phenyl-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-ylmethyl)-benzyl]-oxa-
zolidin-2-one 123 ##STR00126##
5-(R)-Phenyl-3-[4-(4-pyridin-3-ylmethyl-piperazin-1-ylmethyl)-benzyl]-oxa-
zolidin-2-one 124 ##STR00127##
5-[4-(5-Methoxy-pyridin-3-yl)-phenyl]-3-(4-trifluoro-methoxy-benzyl)-oxaz-
olidin-2-one 125 ##STR00128##
4'-[3-(4-Chloro-benzyl)-2-oxo-oxazolidin-5-yl]-biphenyl-3-carboxylic
acid (2-dimethylamino-ethyl)-amide
Pharmaceutical Composition
[0081] The compounds of the present invention may be formulated
into conventional pharmaceutical composition comprising a compound
of Formula I, or a pharmaceutically acceptable salt or solvate
thereof, in association with a pharmaceutically acceptable carrier
or excipient. The pharmaceutically acceptable carriers can be
either solid or liquid. Solid form preparations include, but are
not limited to, powders, tablets, dispersible granules, capsules,
cachets, and suppositories.
[0082] A solid carrier can be one or more substances, which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or table disintegrating agents. A solid
carrier can also be an encapsulating material.
[0083] In powders, the carrier is a finely divided solid, which is
in a mixture with the finely divided compound of the invention, or
the active component. In tablets, the active component is mixed
with the carrier having the necessary binding properties in
suitable proportions and compacted in the shape and size
desired.
[0084] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture is then poured
into convenient sized moulds and allowed to cool and solidify.
[0085] Suitable carriers include, but are not limited to, magnesium
carbonate, magnesium stearate, talc, lactose, sugar, pectin,
dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl
cellulose, low-melting wax, cocoa butter, and the like.
[0086] The term composition is also intended to include the
formulation of the active component with encapsulating material as
a carrier providing a capsule in which the active component (with
or without other carriers) is surrounded by a carrier which is thus
in association with it. Similarly, cachets are included.
[0087] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0088] Liquid form compositions include solutions, suspensions, and
emulsions. For example, sterile water or water propylene glycol
solutions of the active compounds may be liquid preparations
suitable for parenteral administration. Liquid compositions can
also be formulated in solution in aqueous polyethylene glycol
solution.
[0089] Aqueous solutions for oral administration can be prepared by
dissolving the active component in water and adding suitable
colorants, flavoring agents, stabilizers, and thickening agents as
desired. Aqueous suspensions for oral use can be made by dispersing
the finely divided active component in water together with a
viscous material such as natural synthetic gums, resins, methyl
cellulose, sodium carboxymethyl cellulose, and other suspending
agents known to the pharmaceutical formulation art. Exemplary
compositions intended for oral use may contain one or more
coloring, sweetening, flavoring and/or preservative agents.
[0090] Depending on the mode of administration, the pharmaceutical
composition will include from about 0.05% w (percent by weight) to
about 99% w, more particularly, from about 0.10% w to 50% w, of the
compound of the invention, all percentages by weight being based on
the total weight of the composition.
[0091] A therapeutically effective amount for the practice of the
present invention can be determined by one of ordinary skill in the
art using known criteria including the age, weight and response of
the individual patient, and interpreted within the context of the
disease which is being treated or which is being prevented.
Medical Use
[0092] It has been discovered that the compounds of the present
invention exhibit activity as pharmaceuticals, in particular as
modulators of metabotropic glutamate receptors. More particularly,
the compounds of the present invention exhibit activity as
potentiators of the mGluR2 receptor, and are useful in therapy, in
particular for the treatment of neurological and psychiatric
disorders associated with glutamate dysfunction in an animal.
[0093] More specifically, the neurological and psychiatric
disorders include, but are not limited to, disorders such as
cerebral deficit subsequent to cardiac bypass surgery and grafting,
stroke, cerebral ischemia, spinal cord trauma, head trauma,
perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage,
dementia (including AIDS-induced dementia), Alzheimer's disease,
Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,
retinopathy, cognitive disorders, idiopathic and drug-induced
Parkinson's disease, muscular spasms and disorders associated with
muscular spasticity including tremors, epilepsy, convulsions,
cerebral deficits secondary to prolonged status epilepticus,
migraine (including migraine headache), urinary incontinence,
substance tolerance, substance withdrawal (including, substances
such as opiates, nicotine, tobacco products, alcohol,
benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,
schizophrenia, anxiety (including generalized anxiety disorder,
panic disorder, social phobia, obsessive compulsive disorder, and
post-traumatic stress disorder (PTSD)), mood disorders (including
depression, mania, bipolar disorders), circadian rhythm disorders
(including jet lag and shift work), trigeminal neuralgia, hearing
loss, tinnitus, macular degeneration of the eye, emesis, brain
edema, pain (including acute and chronic pain states, severe pain,
intractable pain, neuropathic pain, inflammatory pain, and
post-traumatic pain), tardive dyskinesia, sleep disorders
(including narcolepsy), attention deficit/hyperactivity disorder,
and conduct disorder.
[0094] The invention thus provides a use of any of the compounds
according to Formula I, or a pharmaceutically acceptable salt or
solvate thereof, for the manufacture of a medicament for the
treatment of any of the conditions discussed above.
[0095] Additionally, the invention provides a method for the
treatment of a subject suffering from any of the conditions
discussed above, whereby an effective amount of a compound
according to Formula I or a pharmaceutically acceptable salt or
solvate thereof is administered to a patient in need of such
treatment. The invention also provides a compound of Formula I or
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined for use in therapy.
[0096] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The term "therapeutic" and
"therapeutically" should be construed accordingly. The term
"therapy" within the context of the present invention further
encompasses the administration of an effective amount of a compound
of the present invention, to mitigate either a pre-existing disease
state, acute or chronic, or to mitigate a recurring condition. This
definition also encompasses prophylactic therapies for prevention
of recurring conditions and continued therapy for chronic
disorders. In use for therapy in a warm-blooded animal such as a
human, the compounds of the present invention may be administered
in the form of a conventional pharmaceutical composition by any
route including orally, intramuscularly, subcutaneously, topically,
intranasally, intraperitoneally, intrathoracially, intravenously,
epidurally, intrathecally, intracerebroventricularly and by
injection into the joints. In preferred embodiments of the
invention, the route of administration is oral, intravenous, or
intramuscular.
[0097] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, who
determines the individual regimen and dosage level for a particular
patient.
[0098] As mentioned above, the compounds described herein may be
provided or delivered in a form suitable for oral use, for example,
in a tablet, lozenge, hard and soft capsule, aqueous solution, oily
solution, emulsion, and suspension. Alternatively, the compounds
may be formulated into a topical administration, for example, as a
cream, ointment, gel, spray, or aqueous solution, oily solution,
emulsion or suspension. The compounds described herein also may be
provided in a form that is suitable for nasal administration, for
example, as a nasal spray, nasal drops, or dry powder. The
compounds can be administered to the vagina or rectum in the form
of a suppository. The compounds described herein also may be
administered parentally, for example, by intravenous,
intravesicular, subcutaneous, or intramuscular injection or
infusion. The compounds can be administered by insufflation (for
example as a finely divided powder). The compounds may also be
administered transdermally or sublingually.
[0099] In addition to their use in therapeutic medicine, the
compounds of Formula I, or salts thereof, are useful as
pharmacological tools in the development and standardization of in
vitro and in vivo test systems for the evaluation of the effects of
inhibitors of mGluR-related activity in laboratory animals as part
of the search for new therapeutics agents. Such animals include,
for example, cats, dogs, rabbits, monkeys, rats and mice.
Process for Preparing
[0100] Compounds of the present invention can be prepared by
various synthetic processes. The selection of a particular process
to prepare a given compound is within the purview of the person of
skill in the art. The choice of particular structural features
and/or substituents may therefore influence the selection of one
process over another.
[0101] Within these general guidelines, the following processes can
be used to prepare exemplary subsets of compounds of this
invention. Unless indicated otherwise, the variables described in
the following schemes and processes have the same definitions as
those given for Formula I above.
[0102] In one process, for example, compounds of Formula I wherein
R.sup.1 is a phenyl group may be prepared as shown in Scheme 1,
below:
##STR00129##
[0103] Compounds of Formula I wherein R.sup.1 is a (CO)piperazine
group may be prepared as shown in Scheme 2, below:
##STR00130##
[0104] Compounds of Formula I wherein R.sup.1 is an
alkyleneNR.sup.7R.sup.8 group may be prepared as shown in Scheme 3,
below:
##STR00131##
[0105] Compounds of Formula I wherein R.sup.1 is an
alkyleneOR.sup.7 group may be prepared as shown in Scheme 4,
below:
##STR00132##
[0106] Compounds of Formula I wherein R.sup.1 is an O-aryl group
may be prepared as shown in Scheme 5, below:
##STR00133##
[0107] Compounds of Formula I wherein R.sup.1 is a heterocycloalkyl
group may be prepared as shown in Scheme 6, below:
##STR00134##
[0108] Many variations of the foregoing processes and additions
thereto appear throughout the examples that follow. The person of
ordinary skill in the art thus will appreciate that the compounds
of this invention can be prepared by following or adapting one or
more of the processes disclosed herein.
[0109] The invention is further illustrated by way of the following
examples, which are intended to elaborate several embodiments of
the invention. These examples are not intended to, nor are they to
be construed to, limit the scope of the invention. It will be clear
that the invention may be practiced otherwise than as particularly
described herein. Numerous modifications and variations of the
present invention are possible in view of the teachings herein and,
therefore, are within the scope of the invention.
General Methods
[0110] All starting materials are commercially available or earlier
described in the literature. The .sup.1H and .sup.13C NMR spectra
were recorded either on Bruker 300, Bruker DPX400 or Varian +400
spectrometers operating at 300, 400 and 400 MHz for .sup.1H NMR
respectively, using TMS or the residual solvent signal as
reference, in deuterated chloroform as solvent unless otherwise
indicated. All reported chemical shifts are in ppm on the
delta-scale, and the fine splitting of the signals as appearing in
the recordings (s: singlet, br s: broad singlet, d: doublet, t:
triplet, q: quartet, m: multiplet).
[0111] Analytical in line liquid chromatography separations
followed by mass spectra detections, were recorded on a Waters LCMS
consisting of an Alliance 2795 (LC) and a ZQ single quadropole mass
spectrometer. The mass spectrometer was equipped with an
electrospray ion source operated in a positive and/or negative ion
mode. The ion spray voltage was .+-.3 kV and the mass spectrometer
was scanned from m/z 100-700 at a scan time of 0.8 s. To the
column, X-Terra MS, Waters, C8, 2.1.times.50 mm, 3.5 mm, was
applied a linear gradient from 5% to 100% acetonitrile in 10 mM
ammonium acetate (aq.), or in 0.1% TFA (aq.).
[0112] Preparative reversed phase chromatography was run on a
Gilson preparative HPLC with UV detection at 254 nm, using a
Chiralpak.RTM. AD 0.46.times.25 cm column (Daicel Chemical
Industries, Ltd.).
[0113] Purification of products were also done using Chem Elut
Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut
Silica) SPE Columns (Varian, cat #12256018; 12256026; 12256034), or
by flash chromatography in silica-filled glass columns.
[0114] The pharmacological properties of the compounds of the
invention can be analyzed using standard assays for functional
activity. Examples of glutamate receptor assays are well known in
the art as described in, for example, Aramori et al., 1992, Neuron,
8:757; Tanabe et al., 1992, Neuron, 8:169; Miller et al., 1995, J.
Neuroscience, 15:6103; Balazs, et al., 1997, J. Neurochemistry,
1997, 69:151. The methodology described in these publications is
incorporated herein by reference. Conveniently, the compounds of
the invention can be studied by means of an assay that measures the
mobilization of intracellular calcium, [Ca.sup.2+].sub.i in cells
expressing mGluR2
[0115] A [.sup.35S]-GTP.gamma.S binding assay was used to
functionally assay mGluR2 receptor activation. The allosteric
activator activity of compounds at the human mGluR2 receptor were
measured using a [.sup.35S]-GTP.gamma.S binding assay with
membranes prepared from CHO cells which stably express the human
mGluR2. The assay is based upon the principle that agonists bind to
G-protein coupled receptors to stimulate GDP-GTP exchange at the
G-protein. Since [.sup.35S]-GTP.gamma.S is a non-hydrolyzable GTP
analog, it can be used to provide an index of GDP-GTP exchange and,
thus, receptor activation. The GTP.gamma.S binding assay therefore
provides a quantitative measure of receptor activation.
[0116] Membranes were prepared from CHO cells stably transfected
with human mGluR2. Membranes (30 .mu.g protein) were incubated with
test compound (3 nM to 300 .mu.M) for 15 minutes at room
temperature prior to the addition of 1 .mu.M glutamate, and
incubated for 30 min at 30.degree. C. in 500 .mu.l assay buffer (20
mM HEPES, 100 mM NaCl, 10 mM MgCl.sub.2), containing 30 .mu.M GDP
and 0.1 nM [.sup.35S]-GTP.gamma.S (1250 Ci/mmol). Reactions were
carried out in triplicate in 2 ml polypropylene 96-well plates.
Reactions were terminated by vacuum filtration using a Packard
96-well harvester and Unifilter-96, GF/B filter microplates. The
filter plates were washed 4.times.1.5 ml with ice-cold wash buffer
(10 mM sodium phosphate buffer, pH 7.4). The filter plates were
dried and 35 .mu.l of scintillation fluid (Microscint 20) was added
to each well. The amount of radioactivity bound was determined by
counting plates on the Packard TopCount. Data was analyzed using
GraphPad Prism, and EC.sub.50 and E.sub.max values (relative to the
maximum glutamate effect) were calculated using non-linear
regression.
[0117] Generally, compounds of the present invention were active in
the assays described herein at concentrations (or with EC.sub.50
values) of less than about 10 .mu.M, Preferred compounds of the
invention have EC.sub.50 values of less than 1 .mu.M; more
preferred compounds of less than about 100 nM. For example,
compounds of Examples 3.1, 13.5, 10.29, 17.2 and 17.3 have
EC.sub.50 values of 1.96, 0.39, 0.12, 0.91 and 3.1 .mu.M,
respectively.
EXAMPLES
Example 1.1
5-(R)-phenyl-oxazolidin-2-one
##STR00135##
[0119] General Procedure (1): A solution of
(R)-2-Amino-1-phenylethanol (0.675 g, 4.92 mmol) and di-2-pyridyl
carbonate (1.06 g, 4.92 mmol) in anhydrous dichloromethane (50 ml)
was stirred at RT overnight. The resultant reaction mixture was
diluted with ethyl acetate (60 mL), washed with water (2.times.25
mL), brine (25 mL), dried over anhydrous sodium sulphate and
concentrated in vacuo to get the product as a white solid. It was
purified by chromatography on silica gel, eluting with 5-15% ethyl
acetate in hexanes, to yield 0.695 g (87%) of the desired product
as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.42
(m, 5H), 6.19 (bs, 1H) 5.64 (t, 1H), 4.0 (t, 1H), 3.56 (dd,
1H).
[0120] In a similar fashion the following compounds were
synthesized. Triethyl amine was used as a base to neutralize, where
the starting material (amino alcohol) was available as a salt.
TABLE-US-00002 Ex. No. Structure Name Form 1.2 ##STR00136##
5-(R)-(4-Chloro-phenyl)-oxazolidin-2-one 85 mg (95%)white solid NMR
7.35 (m, 4 H), 6.78 (bs, 1 H) 5.6 (t, 1 H), 3.97 (t, 1 H), 3.51
(dd, 1 H). 1.3 ##STR00137## 5-(4-Methyl-phenyl)-oxazolidin-2-one 69
mg (99%)white solid NMR 7.28 (dd, 2 H), 7.219 (dd, 2 H), 6.79 (bs,
1 H) 5.8 (t, 1 H), 3.95 (t, 1 H), 3,53 (dd, 1 H), 2.4 (s, 3 H) 1.4
##STR00138## 5-(4-Methoxy-phenyl)-oxazolidin-2-one 74 mg (97%)white
solid NMR 7.28 (dd, 2 H), 6.94 (dd, 2 H), 6.57 (bs, 1 H) 5.57 (t, 1
H), 3.94 (t, 1 H), 3.83 (s, 3 H), 3.53 (dd, 1 H 1.5 ##STR00139##
5-(4-Fluoro-phenyl)-oxazolidin-2-one 907 mg, 96%white solid NMR
7.39 (m, 2 H), 7.12 (m, 2 H), 5.66 (bs, 1 H) 5.63 (t, 1 H), 4 (t, 1
H), 3.54 (dd, 1 H) 1.6 ##STR00140##
5-(4-Chloro-phenyl)-oxazolidin-2-one 85 mg, 95%White solid NMR 7.31
(m, 4 H), 6.78 (bs, 1 H) 5.6 (t, 1 H), 3.97 (t, 1 H), 3.51 (dd, 1
H). 1.7 ##STR00141## 5-(4-Bromo-phenyl)-oxazolidin-2-one 582 mg,
78%colourless solid NMR 7.59-7.54 (d, 2 H), 7.30-7.27 (d, 2 H),
5.61 (t, 1 H), 5.51 (br s, 1 H), 4.01 (t, 1 H), 3.45- 3.46 (m, 1 H)
1.8 ##STR00142## 5-(3-Bromo-phenyl)-oxazolidin-2-one 610 mg,
54%colourless solid NMR 7.56-7.52 (m, 2 H), 7.33-7.30 (m, 2 H),
5.79 (br s, 1 H), 5.61 (t, 1 H), 3.56 (t, 1 H).
Example 2
5-(R)-(4-chlorophenyl)-oxazolidin-2-one
##STR00143##
[0122] General Procedure (2): To a solution of
(2R)-(4-chlorophenyl)(hydroxy) ethane nitrile (0.5 g, 2.98 mmol) in
anhydrous THF (6 mL), was added BH3.THF complex (6 mL, 1M in THF, 6
mmol) drop wise at RT and refluxed for 3 h. The reaction mixture
was quenched by the drop wise addition of Methanol (6 mL). After 20
min. of stirring, the reaction mixture was concentrated in vacuo to
get the amino alcohol. This was dissolved in anhydrous
dichloromethane (5 mL) and stirred with di-2-pyridyl carbonate (613
mg, 2.83 mmol,) at RT overnight. The resultant reaction mixture was
diluted with ethyl acetate (25 mL), washed with water (2.times.10
mL), brine (10 mL), dried over sodium sulphate (anhydrous) and
concentrated in vacuo to yield the desired product, with good
purity, as a white solid (573 mg, 97% over 2 steps). .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 7.4 (m, 2H), 7.35 (m, 2H), 5.8 (bs,
1H) 5.62 (t, 1H), 4.15 (t, 1H), 3.52 (t, 1H).
[0123] 5-substituted oxazolidin-2-one compounds were made by using
one of the above two methods, based on the availability of the
starting material. The product so obtained was used for the
subsequent step without further purification.
Example 3.1
5-(R)-Phenyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
##STR00144##
[0125] General Procedure (3): A suspension of
5-(R)-Phenyl-oxazolidin-2-one (74 mg, 0.45 mmol), 4-(trifluoro
methoxy) benzyl bromide (173 mg, 0.68 mmol) and Cesium carbonate
(443 mg, 1.36 mmol) in anhydrous acetonitrile (3 mL) was stirred at
70.degree. C. for 4 h. The resulting suspension was diluted with
ethyl acetate (6 mL), washed with water (3 mL), brine (3 mL), dried
over anhydrous sodium sulphate and concentrated in vacuo to give
the product as a pale brown oil. Purification by chromatography on
silica gel using 20-25% ethyl acetate/hexanes as eluent yielded a
colorless oil as the title compound (128 mg, 84%). .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 7.36 (m, 7H), 7.22 (d, 2H), 5.5 (t, 1H),
4.49 (dd, 3H), 3.8 (t, 1H), 3.34 (dd, 1H).
[0126] In a similar fashion, the following compounds were made:
TABLE-US-00003 Ex. No. Structure Name Form 3.2 ##STR00145##
3-(4-Trifluoromethoxy
benzyl)-5-[3-(4-trifluoromethoxy-benzyloxy)phenyl]-oxazolidin-2-one
67 mg (33%),colorless oil NMR 7.47 (d, 2 H), 7.3 (m, 7 H), 6.95 (m,
3 H), 5.5 (t, 1 H), 5.06 (s, 2 H), 4.49 (dd, 2 H), 3.8 (t, 1 H),
3.32 (dd, 1 H). 3.3 ##STR00146##
5-(4-Methoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
103 mg (73%)Pale yellow solid NMR 7.35 (d, 2 H), 7.23 (m, 4 H),
6.90 (d, 2 H), 5.45 (t, 1 H), 4.56 (d, 1 H), 4.42 (d, 1 H), 3.81
(s, 3 H), 3.76 (t, 1 H), 3.33 (dd, 1 H). 3.4 ##STR00147##
5-(4-Fluoro-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
96 mg (67%)Pale yellow oil NMR 7.32 (m, 4 H), 7.23 (m, 2 H), 7.07
(m, 2 H), 5.48 (t, 1 H), 4.56 (d, 1 H), 4.41 (d, 1 H), 3.80 (t, 1
H), 3.31 (dd, 1 H). 3.5 ##STR00148##
5-(4-Methyl-phenyl)-3-(4-trifluoro methoxy-benzyl)-oxazolidin-2-one
108 mg, (79%)White solid NMR 7.34 (dd, 2 H), 7.23 (m, 6 H), 5.48
(t, 1 H), 4.58 (d, 1 H), 4.42 (d, 1 H), 3.78 (t, 1 H), 3.32 (dd, 1
H), 2.36 (s, 3 H) 3.6 ##STR00149##
5-(4-Chloro-phenyl)-3-(4-trifluoro methoxy-benzyl)-oxazolidin-2-one
127 mg, 88%Colorless oil NMR 7.31 (m, 8 H), 5.48 (t, 1 H), 4.57
(dd, 1 H), 4.39 (d, 1 H), 3.80 (t, 1 H), 3.29 (dd, 1 H). 3.7
##STR00150##
3-(4-Trifluoromethoxy-benzyl)-5-(4-trifluoromethoxy-phenyl)-oxazolidin-2--
one 130 mg, 80%Colorless oil NMR 7.65 (d, 2 H), 7.45 (d, 2 H), 7.33
(d, 2 H), 7.20 (d, 2 H), 5.48 (t, 1 H), 4.57 (dd, 1 H), 4.39 (d, 1
H), 3.87 (t, 1 H), 3.30 (dd, 1 H). 3.8 ##STR00151##
5-(4-Methoxyphenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
142 mg, 79%Pale yellow oil NMR 7.34 (d, 2 H), 7.24 (m, 4 H), 6,91
(d, 2 H), 5.45 (t, 1 H), 4.56 (dd, 1 H), 4.42 (d, 1 H), 3.81 (s, 3
H), 3.76 (t, 1 H), 3.33 (dd, 1 H). 3.9 ##STR00152##
5-p-Tolyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one 108 mg,
99%White solid NMR 7.34 (d, 2 H), 7.22 (m, 6 H), 5.47 (t, 1 H),
4.54 (d, 1 H), 4.42 (d, 1 H), 3.78 (t, 1 H), 3.33 (t, 1 H), 2.37
(s, 3 H)). 3.10 ##STR00153##
5-o-Tolyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one 106 mg,
64%Off white solid NMR 7.41 (m, H), 7.35 (d, 2 H), 7.23 (m, 5 H),
5.7 (dd, 1 H), 4.56 (d, 1 H), 4.42 (d, 1 H), 3.85 (t, 1 H), 3.25
(dd, 1 H). 3.11 ##STR00154## 5-(3,5-Dichloro-phenyl)-3-(4-trifluoro
methoxy-benzyl)-oxazolidin-2-one 129 mg, 75%Colorless oil NMR 7.33
(m, 3 H), 7.21 (m, 4 H), 5.45 (dd, 1 H), 4.56 (d, 1 H), 4.39 (d, 1
H), 3.83 (t, 1 H), 3.28 (dd, 1 H). 3.12 ##STR00155##
5-(3,4-Dichloro-phenyl)-3-(4-trifluoro
methoxy-benzyl)-oxazolidin-2-one 131 mg, 63%Colorless oil NMR 7.43
(m, 2 H), 7.33 (m, 2 H), 7.20 (m, 3 H), 5.45 (dd, 1 H), 4.46 (d, 1
H), 4.39 (d, 1 H), 3.83 (t, 1 H), 3.28 (dd, 1 H). 3.13 ##STR00156##
5-(3,5-Dimethoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
83 mg, 47%White solid NMR 7.35 (dd, 2 H), 7.25 (dd, 2 H), 6.43 (m,
3 H), 5.44 (dd, 1 H), 4.54 (d, 1 H), 4.41 (d, 1 H), 3.78 (m, 7 H),
3.17 (dd, 1 H). 3.14 ##STR00157##
3-(4-trifluoro-methoxy-benzyl)-5-(S)-Phenyl-oxazolidin-2-one 57 mg,
28%Off white solid NMR 7.37 (m, 7 H), 7.21 (d, 2 H), 5.51 (dd, 1
H), 4.57 (d, 1 H), 4.42 (d, 1 H), 3.81 (t, 1 H), 3.34 (dd, 1 H).
3.15 ##STR00158##
3-(4-phenoxy-benzyl)-5-(R)-Phenyl-oxazolidin-2-one 27 mg, 88%Brown
oil NMR 7.38 (m, 7 H), 7.28 (dd, 2 H), 7.14 (t, 1 H), 7.02 (m, 4
H), 5.50 (t, 1 H), 4.53 (d, 1 H), 4.40 (d, 1 H), 3.81 (t, 1 H),
3.34 (dd, 1 H). 3.16 ##STR00159##
3-(3,5-Difluoro-benzyl)-5-(R)-Phenyl-oxazolidin-2-one 41 mg,
43%White solid NMR 7.38 (m, 5 H), 6.83 (m, 3 H), 5.54 (t, 1 H),
4.55 (d, 1 H), 4.39 (d, 1 H), 3.84 (t, 1 H), 3.35 (dd, 1 H). 3.17
##STR00160## 3-(3,4-Dichloro-benzyl)-5-(R)-phenyl)-oxazolidin-2-one
45 mg, 57%White solid NMR 7.39 (m, 7 H), 7.17 (d, 1 H), 5.52 (t, 1
H), 4.50 (d, 1 H), 4.37 (d, 1 H), 3.82 (t, 1 H), 3.33 (dd, 1 H).
3.18 ##STR00161## 3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one
60 mg, 64%White solid NMR 7.68 (dd, 2 H), 7.35 (m, 5 H), 7.05 (d, 2
H), 5.47 (t, 1 H), 4.49 (d, 1 H), 4.37 (d, 1 H), 3.78 (t, 1 H),
3.31 (dd, 1 H). 3.19 ##STR00162##
3-(4-Difluoromethoxy-benzyl)-5-(R)-phenyl)-oxazolidin-2-one 39 mg,
52%Colorless oil NMR 7.34 (m, 7 H), 7.12 (d, 2 H), 6.53 (t, 1 H),
5.50 (t, 1 H), 4.55 (d, 1 H), 4.40 (d, 1 H), 3.80 (t, 1 H), 3.32
(dd, 1 H). 3.20 ##STR00163##
3-(4-Chloro-benzyl)-5-(R)-phenyl)-oxazolidin-2-one 60 mg, 64%White
solid NMR 7.37 (m, 9 H), 5.51 (t, 1 H), 4.53 (d, 1 H), 4.40 (d, 1
H), 3.79 (t, 1 H), 3.32 (dd, 1 H). 3.21 ##STR00164##
3-(4-Ethyl-benzyl)-5-(R)-phenyl)-oxazolidin-2-one 69 mg, 75%Off
white solid NMR 7.33 (m, 9 H), 5.47 (dd, 1 H), 4.58 (d, 1 H), 4.39
(d, 1 H), 3.79 (t, 1 H), 3.32 (dd, 1 H), 2.66 (q, 2 H), 1.26 (t, 3
H) 3.22 ##STR00165##
3-Biphenyl-4-ylmethyl-5-(R)-phenyl)-oxazolidin-2-one 52 mg,
64%White solid NMR 7.60 (m, 4 H), 7.40 (m, 10 H), 5.52 (t, 1 H),
4.62 (d, 1 H), 4.48 (d, 1 H), 3.84 (t, 1 H), 3.38 (dd, 1 H). 3.23
##STR00166## 3-(4-Benzyloxy-benzyl)-5-(R)-phenyl)-oxazolidin-2-one
61 mg, 69%White solid NMR 7.25 (m, 12 H), 6.98 (d, 2 H), 5.47 (t, 1
H), 5.08 (s, 2 H), 4.50 (d, 1 H), 4.37 (d, 1 H), 3.77 (t, 1 H),
3.31 (dd, 1 H). 3.24 ##STR00167##
3-(4-Methoxy-benzyl)-5-(R)-phenyl)-oxazolidin-2-one 344 mg,
99%Colorless oil NMR 7.32 (m, 7 H), 7.89 (d, 2 H), 5.48 (dd, 1 H),
4.50 (d, 1 H), 4.36 (d, 1 H), 3.83 (s, 3 H), 3.77 (t, 1 H), 3.30
(dd, 1 H). 3.25 ##STR00168##
5-(4-Fluoro-phenyl)-3-(4-Iodo-benzyl)-oxazolidin-2-one 1.5 g,
98%Off white solid NMR 7.66 (m, 2 H), 7.28 (m, 2 H), 7.05 (m, 4 H),
5.45 (t, 1 H), 4.46 (d, 1 H), 4.35 (d, 1 H), 3.76 (t, 1 H), 3.27
(dd, 1 H). 3.26 ##STR00169##
4-5[-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-ylmethyl]-benzoic
acidmethyl ester 124 mg, 46%White solid NMR 8.02 (m, 2 H), 7.35 (d,
2 H), 7.29 (m, 2 H), 7.05 (m, 2 H), 5.48 (t, 1 H), 4.58 (d, 1 H),
4.47 (d, 1 H), 3.91 (s, 3 H), 3.79 (t, H), 3.29 (dd, 1 H). 3.27
##STR00170##
5-(4-Fluoro-phenyl)-3-(4-methoxy-benzyl)-oxazolidin-2-one 510 mg,
77%Colorless oil NMR 7.30 (m, 4 H), 7.08 (m, 2 H), 6.89 (m, 2 H),
5.45 (t, 1 H), 4.50 (d, 1 H), 4.37 (d, 1 H), 3.83 (s, 3 H), 3.76
(t, 1 H), 3.27 (dd, 1 H). 3.28 ##STR00171##
5-(R)-(4-Chloro-phenyl)-3-(4-Iodo-benzyl)-oxazolidin-2-one 186 mg,
90%White solid NMR 7.70 (m, 2 H), 7.37 (m, 2 H), 7.26 (m, 2 H),
7.04 (m, 2 H), 5.48 (t, 1 H), 4.50 (d, 1 H), 4.37 (d, 1 H), 3.78
(t, 1 H), 3.27 (dd, 1 H). 3.29 ##STR00172##
3-(3-Iodo-benzyl)-5-(R)-phenyl-oxazolidin-2-one 786 mg, 100%yellow
oil NMR 7.66 (d, 2 H), 7.41-7.27 (m, 6 H), 7.12 (t, 1 H), 5.52 (t,
1 H), 4.52 (d, 1 H), 4.37 (d, 1 H), 3.81 (t, 1 H), 3.33 (t, 3 H)
3.30 ##STR00173##
5-(4-Bromo-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
374 mg, 96%colourless oil NMR 7.52 (d, 2 H), 7.33 (d, 2 H),
7.23-7.18 (m, 4 H), 5.47 (t, 1 H), 4.57 (d, 1 H), 4.41 (d, 1 H),
3.81 (t, 1 H), 3.29 (t, 1 H) 3.31 ##STR00174##
5-(3-Bromo-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-2-one
424 mg, 99%yellow oil NMR 7.50-7.48 (m, 2 H), 7.34 (d, 2 H),
7.27-7.20 (m, 4 H), 5.47 (t, 1 H), 4.57 (d, 1 H), 4.41 (d, 1 h),
3.82 (t, 1 H), 3.30 (t, 1 H). 3.32 ##STR00175##
5-(4-Bromo-phenyl)-3-(4-chloro-benzyl)-oxazolidin-2-one 139 mg,
73%colourless oil NMR 7.51 (d, 2 H), 7.32 (d, 2 H), 7.23-7.14 (m, 4
H), 5.45 (t, 1 H), 5.48 (d, 1 H), 4.38 (d, 1 H), 3.76 (t, 1 H),
3.25 (t, 1 H).
Example 4
3-(4-hydroxy-benzyl)-5-(R)-phenyl-oxazolidin-2-one
##STR00176##
[0128] To a solution of
3-(4-Methoxy-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (60 mg, 0.21
mmol, prepared according to procedure 3) in dichloromethane (2 mL)
at -78.degree. C., was added BBr.sub.3 (1M in dichloromethane) drop
wise and the reaction mixture was allowed to warm up slowly to RT.
After 1.5 h of stirring, the reaction mixture was quenched with
saturated aqueous sodium bicarbonate solution and extracted with
dichloromethane (3.times.4 mL). The combined organic phase was
dried over anhydrous sodium sulfate and concentrated in vacuo to
get the product. Purification by chromatography on silica gel,
eluting with 1-2% methanol in dichloromethane yielded the title
compound (32 mg, 56%) as a white powder. .sup.1H NMR (300 MHz,
CDCl.sub.3): 7.34 (m, 5H), 7.18 (d, 2H), 6.83 (m, 2H), 5.48 (t,
1H), 5.12 (bs, 1H), 4.50 (d, 1H), 4.36 (d, 1H), 3.78 (t, 1H), 3.31
(dd, 1H).
Example 5.1
5-(4-fluoro-phenyl-3-[4-(4-pyridin-2-yl-piperazine-1-carbonyl)-benzyl]-oxa-
zolidin-2-one
##STR00177##
[0130] The carboxylic acid (35 mg, 111 mmol) obtained by the
hydrolysis of 4-[5-(4-Fluorophenyl)-2-oxo-oxazolidin-3-yl
methyl]-benzoic acid methyl ester was coupled with the
1-pyridin-2-yl-piperazine (1.1 eq.) using EDCI (1.1 eq) and HOBT
(1.1 eq) in DMF (1 mL) at RT, overnight. The reaction mixture was
diluted with dichloromethane (7 mL), washed with water (3 mL), aq.
saturated sodium bicarbonate solution (3 mL), brine (3 mL), dried
over anhydrous sodium sulphate and concentrated in vacuo to get the
product. It was purified by chromatography on silica gel, eluting
with dichloromethane containing 1-3% 2M ammonic in methanol, to
yield the desired product as white powder (47 mg, 93%). .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 8.22 (d, 1H), 7.54 (m, 1H), 7.46 (d,
2H), 7.32 (m, 4H), 7.10 (t, 2H), 6.69 (m, 2H), 5.50 (t, 1H), 4.62
(d, 1H), 4.47 (d, 1H), 3.90 (bs, 2H), 3.80 (t, 1H), 3.58 (bs 6H),
3.32 (dd, 1H).
[0131] In a similar fashion the following compounds were
synthesized:
TABLE-US-00004 Ex. No. Structure Name Form 5.2 ##STR00178##
5-(4-Fluoro-phenyl)-3-[4-(4-pyridin-3-ylmethyl-piperazine-1-carbonyl)-ben-
zyl]-oxazolidin-2-one 51 mg, 97%.White solid. NMR 8.53 (m, 2 H),
7.65 (m, 1 H), 7.33 (m, 7 H), 7.06 (t, 2 H), 5.46 (t, 1 H), 4.56
(d, 1 H), 4.42 (d, 1 H), 3.76 (m, 3 H), 3.55 (s, 2 H), 3.41 (bs, 2
H), 3.28 (dd, 1 H), 2.53 (bs, 2 H), 2.39 (bs, 2 H). 5.3
##STR00179##
3-[4-(4-Benzyl-piperazine-1-carbonyl)-benzyl]-5-(4-fluoro-phenyl)-oxazoli-
din-2-one. 49 mg, 93%White solid NMR 7.34 (m, 11 H), 7.08 (m, 2 H),
5.47 (t, 1 H), 4.57 (d, 1 H), 4.43 (d, 1 H), 3.77 (m, 3 H), 3.55
(s, 2 H), 3.32 (bs, 2 H), 3.29 (dd, 1 H), 2.54 (bs, 2 H), 2.39 (bs,
2 H).
Example 6.1
3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one
##STR00180##
[0133] General Procedure (4): A suspension of
5-(R)-Phenyl-oxazolidin-2-one (400 mg, 2.45 mmol), .alpha.{acute
over (.alpha.)}-dibromo-p-xylene (5.1 g, 19.6 mmol) and Cesium
carbonate (2.4 g, 7.35 mmol) in anhydrous acetonitrile (200 mL) was
heated with at 70.degree. C. for 4 h. The solid was filtered off
and the filtrate was concentrated in vacuo. The residue was taken
up in dichloromethane (35 mL), washed with water (10 mL), brine (10
mL), dried over anhydrous sodium sulphate and concentrated in vacuo
to get the product. Purification of the product by chromatography
on silica gel, eluting with 5-30% ethyl acetate/hexanes, yielded
the title compound (595 mg, 70%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.38 (m, 9H), 5.51 (t, 1H), 4.58 (d, 1H), 4.51
(s, 2H), 4.41 (d, 1H), 3.80 (t, 1H), 3.3 (dd, 1H).
[0134] The following compounds were made in a similar manner:
TABLE-US-00005 Ex. No. Structure Name Form 6.2 ##STR00181##
3-(4-Bromomethyl-benzyl)-5-(R)-(4-chloro-phenyl)-oxazolidin-2-one
69 mg, 39%,white solid NMR 7.40 (m, 4 H), 7.26 (m, 4 H), 5.47 (t, 1
H), 4.55 (d, 1 H), 4.52 (s, 2 H), 4.40 (d, 1 H), 3.79 (t, 1 H),
3.28 (dd, 1 H). 6.3 ##STR00182##
3-(4-bromomethyl-benzyl)-5-(4-fluoro-phenyl)-oxazolidin-2-one 212
mg, 53%,white powder NMR 7.39 (m, 4 H), 7.30 (m, 4 H), 7.08 (m, 2
H), 5.48 (t, 1 H), 4.56 (d, 1 H), 4.49 (s, 2 H), 4.41 (d, 1 H),
3.79 (t, 1 H), 3.29 (dd, 1 H).
Example 7.1
3-(morpholin-4-ylmethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one
##STR00183##
[0136] A solution of
3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (30 mg,
0.086 mmol) and morpholine (0.038 mL, 0.433 mmol) in acetonitrile
(2 mL) was heated at 70.degree. C. for 4 hours. The reaction
mixture was diluted with ethyl acetate (6 mL), washed with water (4
mL), brine (4 mL), dried over anhydrous sodium sulfate and
concentrated to get the product. It was purified by chromatography
on silica gel, eluting with 30-60% ethyl acetate in hexanes, to
yield the title compound as a white solid (21 mg, 69%).
[0137] Note: where N-Boc protected precursors were prepared, the
final free base was obtained by cleaving off the Boc protection
using trifluoro acetic acid in dichloromethane. .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 7.37 (m, 9H), 5.49 (t, 1H), 4.56 (d, 1H),
4.41 (d, 2H), 3.79 (t, 1H), 3.72 (m, 4H), 3.50 (s, 2H), 3.33 (dd,
1H), 2.45 (m, 4H).
[0138] The following compounds were made in a similar fashion:
TABLE-US-00006 Ex. No. Structure Name Form 7.2 ##STR00184##
4-[4-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)-benzyl]-piperazine-1-carb-
oxylicacid tert-butyl-ester. 28 mg, 72%White solid NMR 7.37 (m, 9
H), 5.49 (t, 1 H), 4.56 (d, 1 H), 4.40 (d, 1 H), 3.79 (t, 1 H),
3.50 (s, 2 H), 3.44 (m, 4 H), 3.33 (dd, 1 H), 2.38 (m, 4 H), 1.47
(s, 9 H). 7.3 ##STR00185##
3-[4-(4-Methyl-piperazin-1-ylmethyl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e 28 mg, 88%White solid NMR 7.37 (m, 9 H), 5.49 (1, 1 H), 4.56 (d,
1 H), 4.40 (d, 1 H), 3.78 (t, 1 H), 3.51 (s, 2 H), 3.32 (dd, 1 H),
2.48 (m, 8 H), 2.31 (s, 3 H). 7.4 ##STR00186##
5-(R)-Phenyl-3-[4-{4-phenyl-piperain-1-ylmethyl)-benzyl]-oxazolidin-2-one
37 mg,quantitativeyield.White solid NMR 7.36 (m, 11 H), 6.96 (m, 3
H), 5.50 (t, 1 H), 4.57 (d, 1 H), 4.42 (d, 1 H), 3.80 (t, 1 H),
3.58 (s, 2 H), 3.34 (dd, 1 H), 3.22 (m, 4 H), 2.62 (m, 4 H). 7.5
##STR00187##
5-(R)-Phenyl-3-(4-piperazin-1-ylmethyl-benzyl)-oxazolidin-2-one 28
mg, 88%White solid NMR 7.37 (m, 9 H), 5.49 (t, 1 H), 4.56 (d, 1 H),
4.40 (d, 1 H), 3.79 (t, 1 H), 3.49 (s, 2 H), 3.32 (dd, 1 H), 2.90
(m, 4 H), 2.42 (bs, 4 H). 7.6 ##STR00188##
5-(R)-Phenyl-3-(4-{[(pyridine-2-yl
methyl)-amino]-methyl}-benzyl)-oxazolidin-2-one 36 mg, 83%Pale
yellow oil. NMR 8.57 (d, 1 H), 7.65 (m, 1 H), 7.37 (m, 10 H), 7.27
(m, 1 H), 5.48 (t, 1 H), 4.55 (d, 1 H), 4.40 (d, 1 H), 3.93 (s, 2
H), 3.84 (s, 2 H), 3,78 (t, 1 H), 3.31 (dd, 1 H), 2.18 (bs, 1 H).
7.7 ##STR00189##
3-{4-[(Methyl-pyridin-2-ylmethyl-amino)-methyl]-benzyl}-5-(R)-phenyl-oxaz-
olidin-2-one 27 mg, 61%Colorless oil. NMR 8.54 (d, 1 H), 7.67 (m, 1
H), 7.53 (d, 1 H), 7.37 (m, 9 H), 7.17 (m, 1 H), 5.48 (1, 1 H),
4.55 (d, 1 H), 4.39 (d, 1 H), 3.78 (t, 1 H), 3.69 (s, 2 H), 3.59
(s, 2 H), 3.31 (dd, 1 H), 2.25 (s, 3 H).
Example 8.1
5-(R)-phenyl-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-one
##STR00190##
[0140] A solution of 3-hydroxypyridine (23 mg, 0.24 mmol) in DMF (1
mL) was added to a suspension of
3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (70 mg, 0.20
mmol) (synthesized according to procedure 4) and sodium hydride
(60%) (9 mg, 0.22 mmol) in DMF (1.5 mL) and the reaction mixture
was stirred overnight at RT. It was diluted with dichloromethane (6
mL), washed with water (2.times.5 mL), dried over anhydrous sodium
sulfate and concentrated in vacuo. The product was purified by
chromatography on silica gel, eluting with dichloromethane
containing 0.25-1% of methyl alcohol, to yield the title compound
as a white solid (33 mg, 45%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 8.40 (s, 1H), 8.25 (s, 1H), 7.38 (m, 11H), 5.50 (dd, 1H),
5.11 (s, 2H), 4.59 (d, 1H), 4.43 (d, 1H), 3.80 (t, 1H), 3.34 (dd,
1H).
[0141] The following compounds were made in a similar fashion:
TABLE-US-00007 Ex. No. Structure Name Form 8.2 ##STR00191##
5-(4-Fluoro-phenyl)-3-4-(pyridine-2-yloxymethyl)-benzyl]-oxazolidin-2-one
38 mg, 73%White solid. NMR 7.30 (m, 8 H), 7.07 (m, 2 H), 6.64 (m, 1
H), 6.19 (t, 1 H), 5.45 (t, 1 H), 5.14 (s, 2 H), 4.55 (d, 1 H),
4.38 (d, 1 H), 3.76 (t, 1 H), 3.28 (dd, 1 H). 8.3 ##STR00192##
5-(4-Fluoro-phenyl)-3-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2-on-
e 25 mg, 48%.White solid. NMR 8.40 (d, 1 H), 8.25 (d, 1 H), 7.45
(d, 2 H), 7.27 (m, 6 H), 7.08 (t, 2 H), 5.48 (t, 1 H), 5.18 (s, 2
H), 4.58 (d, 1 H), 4.44 (d, 1 H), 3.79 (t, 1 H), 3.31 (dd, 1 H).
8.4 ##STR00193##
5-(4-Fluoro-phenyl)-3-[4-(pyridine-4-yloxymethyl)-benzyl]-oxazolidin-2-on-
e 20 mg, 39%.White solid. NMR 7.33 (m, 6 H), 7.19 (d, 2 H), 7.08
(m, 2 H), 6.40 (m, 2 H), 5.49 (t, 1 H), 4.95 (s, 2 H), 4.58 (d, 1
H), 4.41 (d, 1 H), 3.79 (t, 1 H), 3.31 (dd, 1 H). 8.5 ##STR00194##
5-(R)-(4-Chloro-phenyl)-[4-(pyridine-3-yloxymethyl)-benzyl]-oxazolidin-2--
one 12 mg, 17%.White solid. NMR 8.40 (d, 1 H), 8.26 (m, 1 H), 7.28
(m, 10 H), 5.46 (t, 1 H), 5.12 (s, 2 H), 4.56 (d, 1 H), 4.43 (d, 1
H), 3.80 (t, 1 H), 3.29 (dd, 1 H).
Example 9
3-(4-phenoxymethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one
##STR00195##
[0143] A suspension of
3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (30 mg,
0.086 mmol, prepared according to procedure 4), phenol (10 mg, 0.1
mmol), potassium carbonate (25 mg, 0.18 mmol), potassium iodide (3
mg, 0.008 mmol) and 2-butanone was heated at 80.degree. C.
overnight. The reaction mixture was allowed to cool down to RT,
mixed with water (5 mL), organic phase was separated and the aq.
phase was extracted with ethyl acetate (3.times.8 mL). The combined
organic phase was washed with brine (5 mL), dried over anhydrous
sodium sulfate and concentrated in vacuo to get the product.
Purification by chromatography on silica gel, eluting with 5-20%
ethyl acetate in hexanes yielded the title compound (22 mg, 59%) as
a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.38 (m,
11H), 6.99 (m, 3H), 5.50 (t, 1H), 5.08 (s, 2H), 4.59 (d, 1H), 4.44
(d, 1H), 3.80 (m, 1H), 3.34 (m, 1H).
Example 10.1
5-(R)-Phenyl-3-(4-Pyridin-4-yl-benzyl)-oxazolidin-2-one
##STR00196##
[0145] General Procedure (5): To a solution of
3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (30 mg, 79 mmol)
and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (24
mg, 118 mmol) in dimethoxy ethane (1 mL), was added 2M aq. sodium
carbonate solution (1 mL) and tetrakis(triphenyl
phosphine)palladium(0). The reaction mixture was heated at
100-110.degree. C. for 1.5 h. It was then cooled to room
temperature, diluted with dichloromethane (6 mL), washed with water
(2.times.3 mL), brine (3 mL), dried over anhydrous sodium sulphate
and concentrated in vacuo to yield the product, which was purified
by chromatography on silica gel, eluting with either hexane/ethyl
acetate solvent system or dichloromethane/ammonia in methanol
solvent system to yield the desired product as an off white solid.
(13.5 mg, 52%). Note: where N-Boc protected precursors were
prepared, the final free base was obtained by cleaving off the Boc
protection using trifluoro acetic acid in dichloromethane. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 8.67 (m, 2H), 7.66 (m, 2H), 7.45
(m, 9H), 5.53 (t, 1H), 4.63 (d, 1H), 4.50 (d, 1H), 3.84 (t, 1H),
3.38 (t, 1H).
[0146] In a similar fashion the following compounds were
synthesized:
TABLE-US-00008 Ex. No. Structure Name Form 10.2 ##STR00197##
5-(R)-Phenyl-3-(4-Pyridin-3-yl-benzyl)-oxazolidin-2-one 14 mg,
54%Waxy solid NMR 8.85 (m, 1 H), 8.62 (d, 1 H), 7.90 (d, 1 H), 7.59
(d, 1 H), 7.38 (m, 8 H), 5.53 (t, 1 H), 4.63 (d, 1 H), 4.49 (d, 1
H), 3.85 (t, 1 H), 3.38 (t, 1 H). 10.3 ##STR00198##
3-{4-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-benzyl}-5-(R)-phenyl-oxaz-
olidin-2-one 22 mg, 49%Off whitesolid NMR 8.44 (d, 1 H), 7.71 (m, 1
H), 7.51 (d, 1 H), 7.36 (m, 7 H), 6.73 (d, 1 H), 5.49 (t, 1 H),
4.59 (d, 1 H), 4.43 (d, 1 H), 3.81 (t, 1 H), 3.63 (m, 4 H), 3.35
(dd, 1 H), 2.55 (m, 4 H), 2.37 (s, 3 H). 10.4 ##STR00199##
3-[4-(6-Morpholin-4-yl-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e 28 mg, 64%White solid NMR 8.46 (d, 1 H), 7.74 (dd, 1 H), 7.51 (d,
1 H), 7.37 (m, 7 H), 6.73 (d, 1 H), 5.51 (t, 1 H), 4.60 (d, 1 H),
4.45 (d, 1 H), 3.83 (m, 5 H), 3.57 (m, 4 H), 3.36 (t, 1 H). 10.5
##STR00200##
5-(R)-Phenyl-3-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-oxazolidin-2--
one 24 mg, 40%White solid NMR 7.35 (m, 9 H), 6.16 (m, 1 H), 5.49
(t, 1 H), 4.55 (d, 1 H), 4.40 (d, 1 H), 3.78 (t, 1 H), 3.55 (m, 2
H), 3.32 (dd, 1 H), 3.12 (t, 2 H), 2.46 (m, 2 H), 1.88 (bs, 1 H).
10.6 ##STR00201##
3-[4-(6-Amino-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one
21 mg, 58%Off whitesolid NMR 8.33 (m, 1 H), 7.68 (m, 1 H), 7.50 (m,
2 H), 7.38 (m, 7 H), 6.60 (m, 1 H), 5.52 (t, 1 H), 4.61 (d, 1 H),
4.53 (bs, 2 H), 4.45 (d, 1 H), 3.83 (t, 1 H), 3.36 (dd, 1 H). 10.7
##STR00202##
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)biphenyl-3-carboxylicacid
(2-dimethylamino-ethyl)-amide 33 mg, 71%White solid NMR 8.05 (s, 1
H), 7.34 (m, 2 H), 7.63 (m, 2 H), 7.52 (t, 1 H), 7.36 (m, 7 H),
6.90 (bs, 1 H), 5.53 (t, 1 H), 4.63 (d, 1 H), 4.48 (d, 1 H), 3.85
(t, 1 H), 3.56 (m, 2 H), 3.38 (t, 1 H), 2.56 (t, 2 H), 2.30 (s, 6
H). 10.8 ##STR00203##
5-(R)-Phenyl-3-[4-(6-piperazin-1-yl-pyridin-3-yl)-benzyl]-oxazolidin-2-on-
e 32 mg, 74%Off whitesolid NMR 8.44 (d, 1 H), 7.71 (m, 1 H), 7.51
(m, 2 H), 7.37 (m, 8 H), 6.72 (d, 1 H), 5.50 (t, 1 H), 4.60 (d, 1
H), 4.43 (d, 1 H), 3.82 (t, 1 H), 3.57 (m, 4 H), 3.35 (dd, 1 H),
3.02 (m, 4 H). 10.9 ##STR00204##
3-[4'-(4-Methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-5-(R)-phenyl--
oxazolidin-2-one 31 mg, 65%White solid NMR 7.61 (m, 4 H), 7.51 (m,
2 H), 7.38 (m, 8 H), 5.53 (t, 1 H), 4.63 (d, 1 H), 4.48 (d, 1 H),
3.85 (m, 3 H), 3.53 (m, 2 H), 3.38 (dd, 1 H), 2.45 (m, 4 H), 2.36
(s, 3 H). 10.10 ##STR00205##
3-[3'-(4-Methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-5-(R)-phenyl--
oxazolidin-2-one 34 mg, 71%White solid NMR 7.61 (m, 4 H), 7.40 (m,
1 H), 7.38 (m, 9 H), 5.53 (t, 1 H), 4.60 (d, 1 H), 4.48 (d, 1 H),
3.84 (m, 3 H), 3.50 (m, 2 H), 3.37 (dd, 1 H), 2.52 (m, 2 H), 2.35
(s, 5 H). 10.11 ##STR00206## 3-{4-[6-(2-Morpholin-4-yl-ethyl
amino)-pyridin-3-yl]-benzyl}-5-(R)-phenyl-oxazolidin-2-one 16 mg,
54%White solid NMR 8.36 (d, 1 H), 7.66 (m, 1 H), 7.50 (m, 2 H),
7.37 (m, 7 H), 6.50 (m, 1 H), 5.52 (t, 1 H), 5.21 (m, 1 H), 4.60
(d, 1 H), 4.45 (d, 1 H), 3.83 (t, 1 H), 3.76 (m, 4 H), 339 (m, 3
H), 2.67 (t, 2 H), 2.53 (m, 4 H). 10.12 ##STR00207##
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-ylmethyl)biphenyl-4-carboxylicacid
(2-dimethylamino-ethyl)-amide 34 mg, 73%White solid NMR 7.89 (d, 2
H), 7.63 (m, 4 H), 7.39 (m, 7 H), 6.88 (bs, 1 H), 5.53 (t, 1 H),
4.63 (d, 1 H), 4.48 (d, 1 H), 3.84 (t, 1 H), 3.56 (m, 2 H), 3.38
(dd, 1 H), 2.56 (t, 2 H), 2.30 (s, 6 H). 10.13 ##STR00208##
3-{4-[6-(3-Dimethylamino-propoxy)-pyridin-3-yl]-benzyl}-5-(4-fluoro-pheny-
l-oxazolidin-2-one 55 mg, 98%Off whitesolid NMR 8.36 (m, 1 H), 7.76
(m, 1 H), 7.51 (d, 2 H), 7.33 (m, 4 H), 7.07 (m, 2 H), 6.82 (m, 1
H), 5.48 (t, 1 H), 4.59 (d, 1 H), 4.40 (m, 3 H), 3.81 (t, 1 H),
3.52 (dd, 1 H), 2.46 (m, 2 H), 2.27 (s, 6 H), 1.98 (m, 2 H). 10.14
##STR00209##
4'-[5-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxyli-
c acid (2-dimethylamino-ethyl)-amide 40 mg, 69%white solid NMR 8.05
(s, 1 H), 7.71 (m, 2 H), 7.63 (m, 2 H), 7.53 (m, 1 H), 7.40 (m, 2
H), 7.33 (m, 2 H), 7.10 (m, 2 H), 6.88 (bs, 1 H), 5.51 (t, 1 H),
4.62 (d, 1 H), 4.48 (d, 1 H), 3.83 (t, 1 H), 3.56 (m, 2 H), 3.35
(t, 1 H), 2.57 (t, 2 H), 2.30 (s, 6 H). 10.15 ##STR00210##
5-(4-Fluoro-phenyl)-3-(2'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-oxazo-
lidin-2-one 37 mg, 66%Colorlessoil NMR 7.43 (m, 1 H), 7.36 (m, 2
H), 7.29 (m, 7 H), 7.10 (m, 2 H), 5.52 (t, 1 H), 4.63 (d, 1 H),
4.48 (d, 1 H), 3.87 (1, 1 H), 3.65 (m, 4 H), 3.37 (m, 3 H), 2.36
(m, 4 H). 10.16 ##STR00211##
4'-[5-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxyli-
c acid. 92 mg, 37%white solid NMR 13.14 (bs, 1 H), 8.18 (m, 1 H),
7.95 (m, 2 H), 7,73 (m, 2 H), 7.62 (m, 1 H), 7.44 (m, 4 H), (DMSO-
7.25 (m, 2 H), 5.64 (t, 1 H), 4.53 (d, 1 H), 4.42 (d, 1 H), 3.89
(t, 1H), 3.35 (m, 1 H). D6) 10.17 ##STR00212##
5-(4-Fluoro-phenyl)-3-[3'-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylm-
ethyl]-oxazolidin-2-one. 55 mg, 93%white solid NMR 7.62 (m, 4 H),
7.47 (m, 1 H), 7.39 (m, 3 H), 7.30 (m, 2 H), 7.07 (m, 2 H), 5.49
(t, 1 H), 4.58 (d, 1 H), 4.46 (d, 1 H), 3.82 (m, 3 H), 3.49 (m, 2
H), 3.33 (dd, 1 H), 2.51 (m, 2 H), 2.35 (m, 5 H). 10.18
##STR00213##
3-(4'-Dimethylaminomethyl-biphenyl-4-ylmethyl)-5-(4-fluoro-phenyl)oxazoli-
din-2-one. 36 mg, 89%white solid NMR 7.58 (m, 4 H), 7.36 (m, 6 H),
7.08 (m, 2 H), 5.49 (t, 1 H), 4.60 (d, 1 H), 4.47 (d, 1 H), 3.82
(t, 1 H), 3.50 (s, 2 H), 3.33 (dd, 1 H), 2.30 (s, 6 H). 10.19
##STR00214##
4'-[5-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxyli-
c acid (2-dimethylamino-ethyl)-methyl-amide 49 mg, 82%colorlessoil
NMR 7.62 (m, 4 H), 7.48 (m, 1 H), 7.37 (m, 5 H), 7.10 (m, 2 H),
5.50 (t, 1 H), 4.59 (d, 1 H), 4.47 (d, 1 H), 3.82 (t, 1 H), 3.69
(m, 1 H), 3.38 (m, 2 H), 3.09 (d, 3 H), 2.61 (bs, 1 H), 2.39 (m, 4
H), 2.05 (s, 3 H). 10.20 ##STR00215##
4'-[5-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxyli-
c acid (2-hydroxy-ethyl)-amide 27 mg, 50%pale yellowsolid. NMR 8.04
(s, 1 H), 7.75 (m, 2 H), 7.61 (m, 2 H), 7.53 (m, 1 H), 7.32 (m, 4
H), 7.07 (m, 2 H), 6.85 (bs, 1 H), 5.49 (1, 1 H), 4.60 (d, 1 H),
4.46 (d, 1 H), 3,87 (m, 3 H), 3.79 (m, 2 H), 3.34 (t, 1 H), 2.77
(bs, 1 H). 10.21 ##STR00216##
4'-[5-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-ylmethyl]-biphenyl-3-carboxyli-
c acidethylamine 27 mg, 50%white solid NMR 8.02 (s, 1 H), 7.71 (m,
2 H), 7.62 (m, 2 H), 7.52 (m, 1 H), 7.32 (m, 4 H), 7.10 (m, 2 H),
6.23 (bs, 1 H), 5.50 (t, 1 H), 4.60 (d, 1 H), 4.47 (d, 1 H), 3.83
(m, 1 H), 3.55 (m, 2 H), 3.34 (t, 1 H), 1.27 (m, 3 H). 10.22
##STR00217## 4'-[5-(R)-(4-Chloro-phenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylicacid (2-dimethylamino-ethyl)-amide 32
mg, 55%white solid NMR 8.05 (s, 1 H), 7.63 (m, 2 H), 7.56 (m, 2 H),
7.52 (m, 1 H), 7.38 (m, 4 H), 7.28 (m, 2 H), 6.94 (bs, 1 H), 5.49
(t, 1 H), 4,60 (d, 1 H), 4.47 (d, 1 H), 3.83 (t, 1 H), 3.55 (m, 2
H), 3.31 (t, 1 H), 2.52 (m, 2 H), 2,28 (s, 6 H). 10.23 ##STR00218##
4'-[5-(S)-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylicacid (2-dimethylamino-ethyl)-amide 102
mgPale brown solid NMR Obtained by the HPLC separation of Example
10n on chiralpak AD column. 8.06 (s, 1 H), 7.73 (m, 2 H), 7.62 (m,
2 H), 7.52 (m, 1 H), 7.33 (m, 4 H), 7.05 (m, 3 H), 5.49 (t, 1 H),
4.60 (d, 1 H), 4.46 (d, 1 H), 3.82 (t, 1 H), 3.56 (m, 2 H), 3.33
(t, 1 H), 2.56 (t, 2 H), 2.29 (s, 6 H). 10.24 ##STR00219##
4'-[5-(R)-(4-Fluoro-phenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylicacid (2-dimethylamino-ethyl)-amide 112
mgPale brown solid NMR Obtained by the HPLC separation of Example
10n on chiralpak AD column. 8.06 (s, 1 H), 7.62 (m, 4 H), 7.50 (m,
1 H), 7.33 (m, 4 H), 7.05 (m, 3 H), 5.47 (t, 1 H), 4.58 (d, 1 H),
4.46 (d, 1 H), 3.81 (t, 1 H), 3.70 (m, 2 H), 3.33 (t, 1 H), 2.50
(t, 2 H), 2.29 (s, 6 H). 10.25 ##STR00220##
5-(R)-(4-Chloro-phenyl)-3-(2'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 43 mg, 97%Colorless oil NMR 7.42 (m, 1 H), 7.36 (m,
11 H), 5.51 (t, 1 H), 4.62 (d, 1 H), 4.48 (d, 1 H), 3.88 (t, 1 H),
3.65 (m, 4 H), 3.38 (m, 3 H), 2.36 (m, 4 H). 10.26 ##STR00221##
4'-[5-(R)-(4-Chloro-phenyl)-2-oxo-oxazolidin-3-yl
methyl]-biphenyl-3-carboxylicacid
(2-dimethylamino-ethyl)-methyl-amide 49 mg, 82%white solid NMR 7.59
(m, 4 H), 7.45 (m, 1 H), 7.37 (m, 5 H), 7.28 (m, 2 H), 5.48 (t, 1
H), 4.57 (d, 1 H), 4.45 (d, 1 H), 3.82 (t, 1 H), 3.68 (m, 1 H),
3.38 (m, 1 H), 3.30 (dd, 1 H), 3.02 (d, 3 H), 2.61 (m, 1 H), 2.38
(m, 4 H), 2.07 (s, 3 H). 10.27 ##STR00222##
3-[3-(6-Morpholin-4-yl-pyridin-3-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-on-
e 60 mg, 73%brown solid NMR 8.44 (d, 1 H), 7.71 (d, 1 H), 7.47-7.33
(m, 9 H), 7.25 (d, 1 H), 6.72 (d, 1 H), 5.51 (t, 1 H), 4.62 (d, 1
H), 4.47 (d, 1 H), 3.88-3.81 (m, 5 H), 3.59-3.56 (m, 4 H), 3.36 (t,
1 H). 10.28 ##STR00223## 3'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-yl
methyl)-biphenyl-3-carboxylicacid (2-dimethylamino-ethyl)-amide 90
mg, 100%colourlessgum NMR 8.05 (s, 1 H), 7.80-7,70 (dd, 2 H),
7.56-7.46 (m, 9 H), 6.92 (br s, 1 H) 5.50 (t, 1 H), 4.64 (d, 1 H),
4.47 (d, 1 H), 3.84 (t, 1 H), 3.56 (q, 2 H), 3.36 (t, 1 H), 2.56
(t, 2 H), 2.29 (s, 6 H). 10.29 ##STR00224##
4'-(2-Oxo-5-(R)-phenyl-oxazolidin-3-yl
methyl)-biphenyl-4-carboxylicacid
(1-benzyl-pyrrolidin-3-(S)-yl)-amide 19 mg, 34%off whitesolid NMR
7.86 (d, 2 H), 7.63 (t, 4 H), 7.42-7.32 (m, 11 H), 6.67 (d, 1 H),
5.53 (t, 1 H), 4.636 (br s, 1 H), 4.63 (d, 1 H), 4.48 (d, 1 H),
3.84 (t, 1 H), 3.67 (s, 2 H), 3.37 (t, 1 H), 2,98 (m, 1 H), 2.75
(m, 1 H), 2.69-2.64 (m, 1 H), 2.41-2.32 (m, 2 H), 2.13 (br s, 1 H),
1.77 (br s, 1 H). 10.30 ##STR00225##
5-(4'-Dimethylaminomethyl-biphenyl-3-yl)-3-(4-trifluoromethoxy-benzyl)-ox-
azolidin-2-one 10 mg 17%yellow oil NMR 7.58-7.51 (m, 4 H),
7.49-7.29 (m, 6 H), 7.28 (d, 1 H), 7.22 (d, 1 H), 5.58 (t, 1 H),
4.69 (d, 1 H), 4.43 (d, 1 H), 3.85 (t, 1 H), 3.50 (s, 2 H), 2.29
(s, 6 H).
Example 11.1
3-[4'-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-5-phenyl-oxazol-
idin-2-one
##STR00226##
[0148] General Procedure (6): A solution of
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(60 mg, 212 mmol) in N-methyl piperazine (0.5 mL) was heated at
70-75.degree. C. for 3 h. The reaction mixture was cooled down to
RT, diluted with dichloromethane (6 mL), washed with water
(2.times.2 mL), brine (2 mL), dried over anhydrous sodium sulphate
and concentrated in vacuo to yield
1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxborolan-2-yl)-benzyl]-piper-
azine in reasonably good purity. This boronate ester was used for
Suzuki coupling reaction with
3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (40 mg, 105 mmol),
without any purification, as described in General Procedure (5).
The desired product was isolated as a white solid (28 mg, 60%) by
silica gel column chromatography. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.56 (m, 4H), 7.38 (m, 9H), 5.52 (t, 1H), 4.61
(d, 1H), 4.46 (d, 1H), 3.83 (t, 1H), 3.57 (s, 2H), 3.37 (dd, 1H),
2.53 (bs, 8H), 2.32 (s, 3H). (Note: where N-Boc protected
piperazine was used as the base, the final product was obtained by
cleaving off the Boc group using trifluoro acetic acid in
dichloromethane.)
[0149] In a similar fashion the following compounds were
synthesized:
TABLE-US-00009 Ex. No. Structure Name Form 11.2 ##STR00227##
5-(4-Fluoro-phenyl)-3-[3'-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-ylme-
thyl]-oxazolidin-2-one 29 mg, 60%Colorless oil. NMR 7.45 (m, 4 H),
7.32 (m, 6 H), 7.08 (t, 2 H), 5.49 (t, 1 H), 4.60 (d, 1 H), 4.48
(d, 1 H), 3.82 (t, 1 H), 3.60 (s, 2 H), 3.31 (dd, 1 H), 2.39 (bs, 8
H), 2.33 (s, 3 H). 11.3 ##STR00228##
5-(4-Fluoro-phenyl)-3-(3'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-oxazo-
lidin-2-one 23 mg, 48%Colorless oil. NMR 7.56 (m, 4 H), 7.36 (m, 6
H), 7.09 (t, 2 H), 5.50 (t, 1 H), 4.61 (d, 1 H), 4.48 (d, 1 H),
3.82 (t, 1 H), 3.74 (m, 4 H), 3.58 (s, 2 H), 3.34 (dd, 1 H), 2.50
(m, 4 H). 11.4 ##STR00229##
5-(4-Fluoro-phenyl)-3-(3'-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl)-oxaz-
olidin-2-one 18 mg, 25%Colorless oil. NMR 7.55 (m, 4 H), 7.38 (m, 6
H), 7.09 (t, 2 H), 5.50 (t, 1 H), 4.61 (d, 1 H), 4.48 (d, 1 H),
3.82 (t, 1 H), 3.58 (s, 2 H), 3.34 (dd, 1 H), 2.95 (m, 4 H), 2.59
(bs, 1 H), 2.50 (bs, 4 H). 11.5 ##STR00230##
5-(R)-(4-Chloro-phenyl)-3-(3'-diethylaminomethyl-biphenyl-4-ylmethyl)-oxa-
zolidin-2-one 31 mg, 71%Waxy whitesolid NMR 7.60 (m, 3 H), 7.45 (m,
1 H), 7.38 (m, 6 H), 7.28 (m, 2 H), 5.48 (t, 1 H), 4.60 (d, 1 H),
4.47 (d, 1 H), 3.82 (t, 1 H), 3.65 (s, 2 H), 3.31 (dd, 1 H), 2.58
(q, 4 H), 1.09 (t, 6 H). 11.6 ##STR00231##
5-(R)-(4-Chloro-phenyl)-3-(3'-{[dimethylamino-ethyl)-methyl-amino]-methyl-
}biphenyl-4-ylmethyl)-oxazolidin-2-one 27 mg, 58%Pale brown oil NMR
7.59 (m, 3 H), 7.39 (m, 1 H), 7.37 (m, 6 H), 7.27 (m, 2 H), 5.48
(t, 1 H), 4.59 (d, 1 H), 4.47 (d, 1 H), 3.82 (t, 1 H), 3.60 (s, 2
H), 3.31 (dd, 1 H), 2.51 (m, 4 H), 2.29 (s, 3 H), 2.24 (s, 6 H).
11.7 ##STR00232##
5-(R)-(4-Chloro-phenyl)-3-(3'-piperidin-1-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 37 mg, 83%Pale brown oil. NMR 7.61 (m, 2 H), 7.55
(s, 1 H), 7.40 (m, 1 H), 7.38 (m, 6 H), 7.28 (m, 2 H), 5.49 (t, 1
H), 4.60 (d, 1 H), 4.47 (d, 1 H), 3.83 (t, 1 H), 3.55 (s, 2 H),
3.11 (dd, 1 H), 2.42 (m, 4 H), 1.60 (m, 4 H), 1.47 (m, 2 H). 11.8
##STR00233##
5-(R)-(4-Chloro-phenyl)-3-(3'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 37 mg, 83%White solid. NMR 7.62 (m, 2 H), 7.55 (s,
1 H), 7.51 (m, 1 H), 7.42 (m, 6 H), 7.27 (m, 2 H), 5.49 (t, 1 H),
4.60 (d, 1 H), 4.47 (d, 1 H), 3.83 (t, 1 H), 3.74 (m, 4 H), 3.58
(s, 2 H), 3.32 (dd, 1 H), 2.50 (m, 4 H). 11.9 ##STR00234##
5-(R)-(4-Chloro-phenyl)-3-[3'-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4--
ylmethyl]-oxazolidin-2-one 38 mg, 89%Brown oil NMR 7.59 (m, 3 H),
7.47 (m, 1 H), 7.37 (m, 8 H), 5.49 (t, 1 H), 4.59 (d, 1 H), 4.47
(d, 1 H), 3.83 (t, 1 H), 3.59 (s, 2 H), 3.31 (dd, 1 H), 2,39 (m, 8
H), 2.31 (s, 3 H). 11.10 ##STR00235##
5-(R)-(4-Chloro-phenyl)-3-(3'-dimethylaminomethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 43 mg, 53%Pale brown oil. NMR 7.61 (m, 2 H), 7.55
(s, 1 H), 7.46 (m, 1 H), 7.36 (m, 6 H), 7.28 (m, 2 H), 5.48 (t, 1
H), 4.59 (d, 1 H), 4.47 (d, 1 H), 3.82 (t, 1 H), 3.51 (s, 2 H),
3.31 (dd, 1 H), 2.30 (s, 6 H). 11.11 ##STR00236##
5-(R)-(4-Chloro-phenyl)-3-(3'-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl)--
oxazolidin-2-one 53 mg, 59%White foamysolid. NMR 7.60 (m, 2 H),
7.55 (s, 1 H), 7.47 (m, 1 H), 7.38 (m, 6 H), 7.27 (m, 2 H), 5.48
(t, 1 H), 4.59 (d, 1 H), 4.47 (d, 1 H), 3.82 (t, 1 H), 3.57 (s, 2
H), 3.31 (dd, 1 H), 2.91 (hs, 4 H), 2.47 (bs, 4 H). 11.12
##STR00237##
5-(R)-(4-Chloro-phenyl)-3-(2'-dimethylaminomethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one. 30 mg, 69%Pale yellow oil. NMR 7.40 (d, 1 H), 7.36
(m, 11 H), 5.52 (t, 1 H), 4.62 (d, 1 H), 4.48 (d, 1 H), 3.88 (t, 1
H), 3.35 (m, 3 H), 2.16 (s, 6 H). 11.13 ##STR00238##
5-(R)-(4-Chloro-phenyl)-3-(2'-{[(2-dimethylamino-ethyl)-methyl-amino]-met-
hyl}-biphenyl-4-yl methyl)-oxazolidin-2-one. 40 mg, 87%Colorless
oil. NMR 7.39 (d, 1 H), 7.33 (m, 10 H), 7.28 (d, 1 H), 5.51 (t, 1
H), 4.64 (d, 1 H), 4.46 (d, 1 H), 3.87 (t, 1 H), 3.53 (s, 2 H),
3.35 (dd, 1 H), 2.35 (m, 4 H), 2.18 (s, 6 H), 2 H (s, 3 H). 11.14
##STR00239## 5-(R)-(4-Chloro-phenyl)-3-[2'-(4-methyl-piperazin-1-yl
methyl)-biphenyl-4-ylmethyl)-oxazolidin-2-one 38 mg, 83%Colorless
oil. NMR 7.42 (d, 1 H), 7.33 (m, 11 H), 5.51 (t, 1 H), 4.63 (d, 1
H), 4.46 (d, 1 H), 3.86 (t, 1 H), 3.42 (s, 2 H), 3.34 (dd, 1 H),
2.33 (bs, 8 H), 1.27 (s, 3 H). 11.15 ##STR00240##
5-(R)-(4-Chloro-phenyl)-3-[2'-(3-(S)-dimethylamino-pyrrolidin-1-yl
methyl)-1-biphenyl-4-ylmethyl]-oxazolidin-2-one 42 mg, 87%Pale
yellow oil. NMR 7.42 (d, 1 H), 7.38 (m, 11 H), 5.51 (t, 1 H), 4.62
(d, 1 H), 4.45 (d, 1 H), 3.87 (t, 1 H), 3.50 (s, 2 H), 3.34 (dd, 1
H), 2.73 (m, 2 H), 2.62 (m, 1 H), 2.43 (m, 1 H), 2.28 (d, 2 H),
1.92 (s, 6 H), 1.67 (m, 1 H). 11.16 ##STR00241##
5-(R)-(4-Chloro-phenyl)-3-(2'-piperidin-1-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 20 mg, 45%Waxy whitesolid NMR 7.43 (d, 1 H), 7.33
(m, 11 H), 5.51 (t, 1 H), 4.62 (d, 1 H), 4.48 (d, 1 H), 3.87 (t, 1
H), 3.34 (m, 3 H), 2.28 (bs, 4 H), 1.39 (m, 4 H), 1.27 (m, 2 H).
11.17 ##STR00242##
5-(R)-(4-Chloro-phenyl)-3-[2'-(3-(R)-dimethylamino-pyrrolidin-1-yl
methyl)-1-biphenyl-4-ylmethyl]-oxazolidin-2-one 32 mg, 66%Pale
yellow oil. NMR 7.41 (d, 1 H), 7.37 (m, 11 H), 5.51 (t, 1 H), 4.63
(d, 1 H), 4.44 (d, 1 H), 3.87 (t, 1 H), 3.49 (s, 2 H), 3.35 (dd, 1
H), 2.72 (m, 2 H), 2.62 (m, 1 H), 2.42 (m, 1 H), 2.27 (d, 2 H),
1.92 (s, 6 H), 1.67 (m, 1 H). 11.18 ##STR00243##
5-(R)-(4-Chloro-phenyl)-3-(2'-piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 55 mg, 84%White foamysolid. NMR 7.43 (d, 1 H), 7.34
(m, 11 H), 5.51 (t, 1 H), 4.62 (d, 1 H), 4.47 (d, 1 H), 3.87 (t, 1
H), 3.34 (m, 3 H), 2.81 (m, 4 H), 2.31 (bs, 4 H). 11.19
##STR00244##
5-(R)-(4-Chloro-phenyl)-3-(4'-dimethylaminomethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one. 40 mg, 98%White solid. NMR 7.60 (m, 4 H), 7.38 (m,
6 H), 7.27 (m, 2 H), 5.48 (t, 1 H), 4.60 (d, 1 H), 4.46 (d, 1 H),
3.82 (t, 1 H), 3.49 (s, 2 H), 3.31 (dd, 1 H), 2.3 (s, 6 H). 11.20
##STR00245##
5-(R)-(4-Chloro-phenyl)-3-(4'-{[(2-dimethylamino-ethyl)-methyl-amino]-met-
hyl}-biphenyl-4-yl methyl)-oxazolidin-2-one. 28 mg, 54%Yellow
solid. NMR 7.55 (m, 4 H), 7.37 (m, 6 H), 7.25 (m, 2 H), 5.48 (t, 1
H), 4.59 (d, 1 H), 4.46 (d, 1 H), 3.82 (t, 1 H), 3.54 (s, 2 H),
3.31 (dd, 1 H), 2.44 (t, 2 H), 2.33 (t, 2 H), 2.23 (s, 3 H), 2.21
(s, 6 H). 11.21 ##STR00246##
5-(R)-(4-Chloro-phenyl)-3-(4'-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one. 17 mg, 38%White solid. NMR 7.57 (m, 4 H), 7.38 (m,
6 H), 7.27 (m, 2 H), 5.49 (t, 1 H), 4.60 (d, 1 H), 4.47 (d, 1 H),
3.84 (t, 1 H), 3.75 (m, 4 H), 3.56 (s, 2 H), 3.32 (dd, 1 H), 2.50
(m, 4 H). 11.22 ##STR00247##
5-(R)-(4-Chloro-phenyl)-3-(4'-piperidin-1-ylmethyl-biphenyl-4-ylmethyl)-o-
xazolidin-2-one 30 mg, 67%White solid. NMR 7.56 (m, 4 H), 7.38 (m,
6 H), 7.28 (m, 2 H), 5.48 (t, 1 H), 4.60 (d, 1 H), 4.46 (d, 1 H),
3.83 (t, 1 H), 3.53 (s, 2 H), 3.32 (dd, 1 H), 2.42 (bs, 4 H), 1.61
(m, 4 H), 1.48 (m, 2 H). 11.23 ##STR00248##
5-(R)-(4-Chloro-phenyl)-3-[4'-(4-methyl-piperazin-1-yl
methyl)-biphenyl-4-ylmethyl)-oxazolidin-2-one 31 mg, 67%White
solid. NMR 7.56 (m, 4 H), 7.37 (m, 6 H), 7.27 (m, 2 H), 5.47 (t, 1
H), 4.60 (d, 1 H), 4.46 (d, 1 H), 3.83 (t, 1 H), 3.57 (s, 2 H),
3.31 (dd, 1 H), 2.51 (bs, 8 H), 2.31 (s, 3 H). 11.24 ##STR00249##
5-(R)-4-Chloro-phenyl)-3-(4'-piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-ox-
azolidin-2-one 37 mg, 51%White solid. NMR 7.56 (m, 4 H), 7.38 (m, 6
H), 7.27 (m, 2 H), 5.48 (t, 1 H), 4.60 (d, 1 H), 4.46 (d, 1 H),
3.83 (t, 1 H), 3.55 (s, 2 H), 3.31 (dd, 1 H), 2.92 (m, 4 H), 2.46
(bs, 4 H).
Example 12
5-(4-fluoro-phenyl)-3-(3'-hydroxymethyl-biphenyl-4-ylmethyl)-oxazolidin-2--
one
##STR00250##
[0151] To a solution of
4'-[5-(4-Fluoro-phenyl)-2-oxo-oazolidin-3-ylmethyl]-biphenyl-3-carbaldehy-
de (40 mg, 0.1 mmol, synthesized by the Suzuki coupling protocol
described in General Procedure (5) in methanol was added 0.13 mL
(0.13 mmol) of sodium cyanoborohydride (1 M in THF) and the
reaction flask was stirred overnight at RT. The reaction mixture
was concentrated; the residue was taken up in dichloromethane (4
mL), washed with saturated aqueous sodium bicarbonate solution (2
mL), dried over anhydrous sodium sulfate and concentrated in vacuo.
Purification of the product by chromatography on silica gel,
eluting with 10-40% ethyl acetate yielded the title compound as a
white solid (29 mg, 73%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.61 (m, 3H), 7.50 (m, 2H), 7.38 (m, 5H), 7.08 (m, 2H),
5.48 (t, 1H), 4.78 (s, 2H), 4.59 (d, 1H), 4.46 (d, 1H), 3.81 (t,
1H), 3.33 (dd, 1H).
Example 13.1
5-(4-fluoro-phenyl)-3-[4-(pyrazin-2-yloxy)-benzyl]-oxazolidin-2-one
##STR00251##
[0153] Sodium cyanoborohydride (0.62 mL, 1 M in THF) was added to a
solution of 2-amino-1-(4-fluoro-phenyl)-ethanol (80 mg, 0.52 mmol),
4-(Pyrazin-2-yloxy)-benzaldehyde (103 mg, 0.52 mmol) and glacial
acetic acid (0.5 mL), in methanol (3 mL) at RT and the flask was
stirred overnight. The reaction mixture was concentrated in vacuo;
the residue was quenched with saturated aqueous sodium bicarbonate
solution and then extracted with dichloromethane (3.times.4 mL).
The combined organic phases were dried over anhydrous sodium
sulfate and concentrated again in vacuo to yield
1-(4-fluoro-phenyl)-2-[4(pyrazin-2-yloxy)-benzyl amino]-ethanol as
a white solid 62 mg, 35%).
[0154] To a solution of the intermediate obtained above in
dichloromethane (3 mL) at 5.degree. C., was added diisopropyl
ethylamine (0.1 mL, 60 mmol) followed by Tri phosgene (60 mg, 0.2
mmol) and the flask was stirred overnight at RT. The reaction
mixture was quenched with 1 N HCl, then neutralized with saturated
aqueous sodium bicarbonate solution and extracted with
dichloromethane (2.times.4 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue is
purified by chromatography on silica gel, eluting with 30-50% ethyl
acetate in hexanes, to yield the title compound as a white solid
(31 mg, 46%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.46 (s,
1H), 8.36 (d, 1H), 8.11 (m, 1H), 7.37 (m, 4H), 7.2 (m, 4H), 5.49
(t, 1H), 4.60 (d, 1H), 4.43 (d, 1H), 3.84 (t, 1H), 3.35 (dd,
1H).
[0155] The following compounds were made in a similar manner:
TABLE-US-00010 Ex. No. Structure Name Form 13.2 ##STR00252##
5-(4-fluoro-phenyl)-3-[4-(pyrimidin-2-yloxy)-benzyl]-oxazolidin-2-one
38 mg, 40%.Colorless oil. NMR 8.57 (d, 2 H), 7.34 (m, 4 H), 7.22
(m, 2 H), 7.08 (m, 3 H), 5.49 (t, 1 H), 4.60 (d, 1 H), 4.41 (d, 1
H), 3.84 (t, 1 H), 3.35 (dd, 1 H). 13.3 ##STR00253##
3-[4-(4-fluoro-phenoxy)-benzyl]-5-(4-fluoro-phenyl)
-oxazolidin-2-one 65 mg, 63%.Colorless oil. NMR 7.27 (m, 4 H), 7.05
(m, 8 H), 5.47 (t, 1 H), 4.52 (d, 1 H), 4.39 (d, 1 H), 3.80 (t, 1
H), 3.31 (dd, 1 H). 13.4 ##STR00254##
5-(4-Fluoro-phenyl)-3-[4-(pyridin-2-yloxy)-benzyl]-oxazolidin-2-one
25 mg, 42%.Colorless oil. NMR 8.19 (m, 1 H), 7.70 (m, 1 H), 7.35
(m, 4 H), 7.05 (m, 5 H), 6.95 (d, 1 H), 5.48 (t, 1 H), 4.58 (d, 1
H), 4.41 (d, 1 H), 3.83 (t, 1 H), 3.34 (dd, 1 H). 13.5 ##STR00255##
5-(4-Fluoro-phenyl)-3-(4-phenoxy-benzyl)-oxazolidin-2-one 69 mg,
75%.Colorless oil. NMR 7.37 (m, 6 H), 7.05 (m, 7 H), 5.48 (t, 1 H),
4.54 (d, 1 H), 4.40 (d, 1 H), 3.80 (t, 1 H), 3.31 (dd, 1 H).
Example 14
5-(R)-(4-chlorophenyl)-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-benzyl]--
oxazolidin-2-one
##STR00256##
[0157] To a suspension of
5-(R)-(4-Chloro-phenyl)-3-(4-Iodo-benzyl)-oxazolidin-2-one (50 mg,
0.12 mmol), lead acetate (3 mg, 0.012 mmol), 2-(dicyclohexyl
phosphino) biphenyl (5 mg, 0.014 mmol) and cesium carbonate (118
mg, 0.36 mmol) in toluene (2.5 mL), was added 2-pyridyl methyl
piperazine and the reaction flask was heated at 100.degree. C. for
3 h. The reaction mixture was diluted with dichloromethane (6 mL),
washed with water (3 mL), brine (3 mL), dried over anhydrous sodium
sulfate and concentrated in vacuo. The residue was purified by
chromatography on silica gel, eluting with dichloromethane
containing 0.5-2% ammonia (2 M) in methanol The title compound was
isolated as an off white solid (30 mg, 54%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 8.6 (m, 1H), 7.69 (m, 1H), 7.44 (d, 1H), 7.35
(m, 2H), 7.25 (m, 5H), 6.88 (m, 2H), 5.42 (t, 1H), 4.45 (d, 1H),
4.33 (d, 1H), 3.75 (m, 3H), 3.24 (m, 5H), 2.69 (m, 4H).
Example 15
3-(4-Morpholin-4-yl-benzyl)-5-(R)-phenyl-oxazolidin-2-one
##STR00257##
[0159] Palladium Acetate (3 mg, 0.013 mmol) and BINAP (8 mg, 0.013
mmol) were suspended in Toluene (2 mL) and stirred under argon for
10 minutes. The suspension was then added to a stirring suspension
of 3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (50 mg, 0.132
mmol), morpholine (14 .mu.L, 0.158 mmol), and cesium carbonate (43
mg, 0.396 mmol) in toluene (1 mL). Stirring continued for 5 minutes
at room temperature and the mixture was then heated at 115.degree.
C. for 2 hours. The mixture was then cooled to room temperature,
diluted with dichloromethane, filtered and concentrated in vacuo.
The residue was purified by chromatography on silica gel, eluting
with 30-40% ethyl acetate in hexanes. The title compound was
isolated as a yellow solid (14 mg, 31%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.40-7.31 (m, 5H), 7.23 (d, 2H), 6.89 (d, 2H),
5.47 (t, 1H), 4.50-4.33 (q, 2H), 3.89-3.86 (m, 4H), 3.76 (t, 1H),
3.30 (t, 1H), 3.19-3.16 (m, 4H).
Example 16.1
3-[b
4-(4-Methyl-piperazin-1-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one
##STR00258##
[0161] To a stirring suspension of palladium acetate (3 mg, 0.011
mmol), cesium carbonate (103 mg, 0.318 mmol),
3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (40 mg, 0.106
mmol), and Biphenyl-2-yl-dicyclohexyl-phosphane (4 mg, 0.011 mmol)
in toluene was added 1-Methyl-piperazine (14 .mu.L, 0.126 mmol).
The mixture stirred at 100.degree. C. for 3 hours and was then
cooled to room temperature, diluted with water and extracted with
ethyl acetate. The organics were washed with brine, dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by chromatography on silica gel, eluting with
30-40% ethyl acetate in hexanes. The title compound was isolated as
a brown solid (14 mg, 38%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.40-7.30 (m, 5H), 7.21 (d, 2H), 6.91 (d, 2H), 5.46 (t,
1H), 4.50-4.31 (q, 2H), 3.76 (t, 1H), 3.30 (t, 1H), 3.27-3.21 (m,
4H), 2.61-2.58 (m, 4H), 2.37 (s, 3H).
[0162] The following compounds were made in a similar manner:
TABLE-US-00011 16.2 ##STR00259##
5-(R)-Phenyl-3-[4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 32 mg, 38%brown oil NMR 8.58 (d, 2 H), 7.39-7.29 (m, 7 H),
7.20 (d, 2 H), 6.90 (6, 2 H), 5.46 (t, 1 H), 4.49 (d, 1 H), 4.36
(d, 1 H), 3.76 (t, 1 H), 3.58 (s, 2 H), 3.30 (t, 1 H), 3.27-3.21
(m, 4 H), 2.64-2.61 (m, 4 H) 16.3 ##STR00260##
5-(R)-Phenyl-3-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 41 mg, 48%brown oil NMR 8.60 (6, m), 7.68 (t, 1 H), 7.45
(d, 1 H), 7.39-7.29 (m, 5 H), 7.28-7.17 (m, 3 H), 6.89 (d, 2 H),
5.46 (t, 1 H), 4.48 (d, 1 H), 4.34 (d, 1 H), 3.78-3.72 (m, 3 H),
3.31-3.23 (m, 5 H), 2.70-2.67 (m, 4 H) 16.4 ##STR00261##
5-(R)-Phenyl-3-[4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 39 mg, 46%yellow solid NMR 8.55 (d, 2 H), 7.72 (d, 1 H),
7.39-7.28 (m, 6 H), 7.19 (6, 2 H), 6.89 (6, 2 H), 5.46 (t, 1 H),
4.49 (d, m), 4.35 (d, 1 H), 3.75 (t, 1 H), 3.59 (s, 1 H), 3.28 (t,
1 H), 3.26-3.19 (m, 4 H), 2.64-2.60 (m, 4 H) 16.5 ##STR00262##
3-[3-(4-Methyl-iperazin-1-yl)-benzyl]-5-(R)-phenyl-oxazolidin-2-one
21 mg, 30%brown oil NMR 7.39-7.32 (m, 5 H), 7.25 (t, 1 H), 6.85 (d,
2 H), 6.77 (d, 1 H), 5.49 (t, 1 H), 4.48 (d, 1 H), 4.34 (d, 1 H),
3.79 (t, 1 H), 3.33 (t, 1 H), 3.21-3.18 (m, 4 H), 2.59-2.56 (m, 4
H), 2.37 (s, 3 H) 16.6 ##STR00263##
5-(R)-Phenyl-3-[3-(4-pyridin-4-ylmethyl-piperazin-1-yl)-benzyl]-oxazolidi-
n-2-one 24 mg, 29%brown oil NMR 8.58 (d, 2 H), 7.45-7.22 (m, 8 H),
6.84 (d, 2 H), 6.76 (d, 1 H), 5.49 (t, 1 H), 4.48 (d, 1 H), 4.34
(d, 1 H), 4.13 (t, 1 H), 3.33 (t, 1 H), 3.20-3.18 (m, 4 H),
2.63-2.60 (m, 4 H). 16.7 ##STR00264##
3-(3-Morpholin-4-yl-benzyl)-5-(R)-phenyl-oxazolidin-2-one 25 mg,
37%brown oil NMR 7.40-7.33 (m, 5 H), 7.27 (t, 1 H), 6.85-6.80 (m, 3
H), 5.50 (t, 1 H), 4.49-4.40 (dd, 2 H), 3.88-3.78 (m, 5 H), 3.35
(t, 1 H), 3.16-3.12 (m, 4 H) 16.8 ##STR00265##
5-(R)-Phenyl-3-[4-(4-pyridin-2-lmethyl-piperazin-1-yl
methyl)-benzyl]-oxazolidin-2-one 45 mg, 49%yellow solid NMR 8.56
(d, 1 H), 7.65 (t, 1 H), 7.41-7.32 (m, 8 H), 7.29 (d, 2 H), 7.23
(m, 1 H), 5.48 (t, 1 H), 4.55 (d, 1 H), 4.39 (d, 1 H), 3.78 (t, 1
H), 3.68 (s, 2 H), 3.52 (s, 2 H), 3.31 (t, 1 H), 2.53 (br s, 8 H)
16.9 ##STR00266##
5-(R)-Phenyl-3-[4-(4-pyridin-3-ylmethyl-piperazin-1-ylmethyl)-benzyl]-oxa-
-zolidin-2-one 49 mg, 53%yellow oil NMR 8.55-8.50 (m, 2 H), 7.65
(d, 1 H), 7.39-7.22 (m, 10 H), 5.48 (t, 1 H), 4.55, (d, 1 H), 4.39
(d, 1 H), 3.78 (t, 1 H), 3.53 (d, 4 H), 3.32 (t, 1 H), 2.34 (br s,
8 H).
Example 17.1
5-(R)-Phenyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-o-
xazolidin-2-one
##STR00267##
[0164] A flask containing
3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (390 mg, 1.03
mmol),
4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (339
mg, 1.34 mmol),
1,1'-bis(diphenylphosphinoferrocene-dichloropalladium(II) (84 mg,
0.103 mmol), and potassium acetate (303 mg, 3.04 mmol) in DMF was
heated at 110.degree. C. for 2 hours. The mixture was then cooled
to room temperature, diluted with water and extracted with ethyl
acetate. The organics were washed with water (2.times.) and brine,
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by chromatography on silica gel,
eluting with 30-50% ethyl acetate in hexanes. The title compound
was isolated as a colourless solid (205 mg, 53%). .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 7.81 (d, 2H), 7.39-7.29 (m, 7H), 5.47 (t,
1H), 4.52-4.48 (dd, 2H), 3.76 (t, 1H), 3.29 (t, 1H), 1.35
(12H).
[0165] The following compounds were made in a similar manner:
TABLE-US-00012 17.2 ##STR00268##
5-[4-(5-Methoxy-pyridin-3-yl)-phenyl]-3-(4-trifluoromethoxy-benzyl)-oxa-z-
olidin-2-one 48 mg, 91%beige solid NMR 8.44 (d, 1 H), 8.33 (d, 1
H), 7.60 (d, 2 H), 7.43 (d, 2 H), 7.37-7.34 (m, 3 H), 7.24 (d, 2
H), 5.58 (t, 1 H), 4.59 (d, 1 H), 4.44 (d, 1 H), 3.93 (s, 3 H),
3.85 (t, 1 H), 3.37 (t, 1 H). 17.3 ##STR00269##
4'-[3-(4-Chloro-benzyl)-2-oxo-oxa-zolidin-5-yl]-biphenyl-3-carboxylic
acid(2-dimethylamino-ethyl)-amide 8 mg, 15%yellow oil NMR 8.05 (s,
1 H), 7.75-7.64 (m, 5 H), 7.53 (t, 1 H), 7.42-7.34 (m, 4 H), 7.26
(d, 2 H), 6.95 (br s, 1 H), 5.56 (t, 1 H), 4,55 (d, 1 H), 4.42 (d,
1 H), 3.82 (t, 1 H), 3.57 (q, 2 H), 3.36 (t, 1 H), 2.56 (q, 2 H),
2.30 (s, 6 H).
Example 18
(3-S)-4-Iodo-N-(1-benzyl-3-pyrrolidinyl)benzamide
##STR00270##
[0167] To a solution of 4-iodobenzoyl chloride (10 g, 37 mmol) in
ether (400 mL) at 0.degree. C. was added triethylamine (4.7 g, 45
mmol). (3-S)-1-Benzyl-3-aminopyrrolidine (7.3 g, 41 mmol) in ether
(100 mL) was then added slowly via dropping funnel at 0.degree. C.
After the addition was complete, the mixture was further stirred
for 18 hrs. Water (200 mL) was added and the mixture extracted with
methylene chloride (3.times.200 mL) dried and concentrated to give
the title compound (9.7 g, 64%) as beige powder. 1H NMR (CDCl3)
.delta.: 7.79 (m, 2H), 7.47 (m, 2H), 7.26-7.35 (m, 5H), 6.51 (d,
1H, J=8.8 Hz), 4.62-4.68 (m, 1H), 3.63 (s, 2H), 2.91-2.96 (m, 1H),
2.70-2.74 (m, 1H), 2.58-2.63 (m, 1H), 2.25-2.44 (m, 2H), 1.68-1.77
(m, 1H).
Example 19.1
2-Amino-1-(4-bromo-phenyl)-ethanol
##STR00271##
[0169] Sodium borohydride (227 mg, 6.00 mmol) was dissolved in
methanol (10 mL) and 5% potassium hydroxide in methanol (4.49 mL,
4.00 mmol) was carefully added. To this solution was added
2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (1.0 g, 4.00
mmol) dissolved in methanol (10 mL) and stirring continued for 0.2
hours at room temperature. The mixture was concentrated, and
quenched with saturated sodium bicarbonate (10 mL) and extracted
with dichloromethane several times. The organics were combined,
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The title compound was isolated as a yellow solid (677 mg,
77%). .sup.1H NMR (300 MHz, CDCl.sub.3): 7.51-7.47 (d. 2H),
7.27-7.23 (d, 2H), 4.63-4.59 (m, 1H), 3.03 (dd, 1H), 2.76 (dd,
1H)
[0170] The following compound was made in a similar manner:
TABLE-US-00013 19.2 ##STR00272## 2-Bromo-1-(3-bromo-phenyl)-ethanol
4.72 g, 94%yellow oil NMR 7.59 (s, 1 H), 7.50-7.47 (m, 1 H),
7.33-7.23 (m, 2 H), 4.95-4.90 (m, 1 H), 3.68-3.63 (dd, 1 H),
3.56-3.50 (dd, 1 H), 2.69 (d, 1 H).
Example 20
[2-Bromo-1-(3-bromo-phenyl)-ethoxy]trimethyl-silane
##STR00273##
[0172] To a solution of 2-Bromo-1-(3-bromo-phenyl)-ethanol (4.72 g,
16.9 mmol), imidazole (5.75 g, 84.5 mmol) and dimethylaminopyridine
(1.03 g, 8.45 mmol) in DMF at 0.degree. C. was added
Chloro-trimethyl-silane (4.56 mL, 3.90 mmol) dropwise. Stirring
continued at 0.degree. C. for 2 hours and was then warmed to RT.
The mixture was diluted with saturated sodium bicarbonate and
extracted with ethyl acetate. The organics were washed with water
and brine, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The title compound was isolated as a yellow
oil (5.85 g, quantitative). .sup.1H NMR (300 MHz, CDCl.sub.3): 7.52
(s, 1H), 7.44 (d, 1H), 7.28-7.23 (m, 2H), 4.83 (t, 1H), 3.43 (d,
2H) 0.109 (s, 9H).
Example 21
2-Azido-1-(3-bromo-phenyl)-ethanol
##STR00274##
[0174] [2-Bromo-1-(3-bromo-phenyl)-ethoxy]-trimethyl-silane (5.85
g, 16.6 mmol and tetrabutyl sodium iodide (613 mg, 1.66 mmol) were
dissolved in DMSO and sodium azide (2.16 g, 33.2 mmol) was slowly
added. The mixture stirred at 80.degree. C. for 4 hours and then at
room temperature for 18 hours. The mixture was quenched with
saturated sodium bicarbonate and extracted with ethyl acetate. The
organics were washed with water brine and 1M HCl, then again with
water and brine, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by chromatography
on silica gel, eluting with 5-10% ethyl acetate in hexanes. The
title compound was isolated as a yellow oil (3.38 g, 83%). .sup.1H
NMR (300 MHz, CDCl.sub.3): 7.57 (s, 1H), 7.48 (d, 1H), 7.31-7.29
(m, 2H), 4.87 (m, 1H), 3.49 (d, 2H), 2.45 (d, 1H).
Example 22
2-Amino-1-(3-bromo-phenyl)-ethanol
##STR00275##
[0176] To a solution of 2-Azido-1-(3-bromo-phenyl)-ethanol (3.38 g,
13.8 mmol) in THF (40 mL) was added water (2.48 ml, 138 mmol) and
triphenylphosphine (7.26 g, 27.7 mmol). The mixture stirred for 2
hours at 50.degree. C. and was then cooled to room temperature,
diluted with water and extracted with ethyl acetate. The organics
were washed with 1M HCl (2.times.) and the aqueous washes were
combined and neutralized with 1N sodium hydroxide. The aqueous
mixture was extracted with ethyl acetate and the organics were
washed with water and brine, dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The title compound was isolated
as a yellow oil (2.53 g, 85%). .sup.1H NMR (300 MHz, CDCl.sub.3):
7.55 (s, 1H), 7.41 (d, 1H), 7.31-7.20 (m, 2H), 4.62 (m, 1H), 3.02
(d, 1H), 2.79 (m, 1H).
* * * * *