Note: Descriptions are shown in the official language in which they were submitted.
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HETEROCYCLIC SUBSTITUTED PIPERIDINES AND USES THEREOF
Throughout this application, various references are
referred to within parentheses. Disclosures of these
publications in their entireties are hereby incorporated
by reference into this application to more fully
describe the state of the art to which this invention
pertains.
Background of the Invention
The designation "alA" is the appellation recently
approved by the IUPHAR Nomenclature Committee for the
previously designated "ale" cloned subtype as outlined
in the 1995 Receptor and Ion Channel Nomenclature
Supplement (Watson and Girdlestone, 1995). The
designation alA is used throughout this application and
the supporting tables and figures to refer to this
receptor subtype. At the same time, the receptor
formerly designated alA was renamed alD. The new
nomenclature is used throughout this application.
Stable cell lines expressing these receptors are
described herein; however, these cell lines were
deposited with the American Type Culture Collection
(ATCC) under the old nomenclature (in ra).
Benign Prostatic Hyperplasia (BPH), also called Benign
Prostatic Hypertrophy, is a progressive condition which
is characterized by a nodular enlargement of prostatic
tissue resulting in obstruction of the urethra. This
results in increased frequency of urination, nocturia, a
poor urine stream and hesitancy or delay in s~carting the
urine flow. Chronic consequences of BPH can include
hypertrophy of bladder smooth muscle, a decompensated
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bladder and an increased incidence of urinary tract
infection. The specific biochemical, histological and
pharmacological properties of the prostate adenoma
leading to the bladder outlet obstruction are not yet
known. However, the development of BPH is considered to
be an inescapable phenomenon for the aging male
population. BPH is observed in approximately 70g of
males over the age of 70. Currently, in the United
States, the method of choice for treating BPH is surgery
IO (Lepor, H., Urol. Clinics North Amer., 17, 651 (1990)).
Over 400,000 prostatectomies are performed annually
(data from 1986).
Transurethral resection of the prostate (TURP) was used
in approximately 180,000 men in the United States in
1996. This surgical procedure results in significant
benefit. However, because of its potential adverse
consequences, surgery is an unattractive alternative for
many patients and is not recommended for elderly
patients due to the potential for complications.
Another surgical procedure, transurethral needle
ablation (TUNA), was recently approved by the FDA and
may have the advantage of possible use on an out-patient
basis under local anesthesia. However, initial results
of a recent study comparing TURP and TUNA show a lower
level of efficacy in TUNA than in TURP with respect to
increasing urinary flow.
A medicinal alternative to surgery is clearly very
desirable. The limitations of surgery for treating BPH
include the morbidity rate of an operative procedure in
elderly men, persistence or recurrence of obstructive
and irritative symptoms, as well as the significant cosi:
of surgery.
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a-Adrenergic receptors (McGrath, et. al. Med. Res. Rev.,
9, 407-533, 1989) are specific neuroreceptor proteins
located in the peripheral and central nervous systems on
tissues and organs throughout the body. These receptors
are important switches for controlling many
physiological functions and, thus, represent important
targets for drug development. In fact, many a-
adrenergic drugs have been developed over the past 40
years. Examples include clonidine, phenoxybenzamine and
prazosin (treatment of hypertension), naphazoline (nasal
decongestant), and apraclonidine (treating glaucoma).
a-Adrenergic drugs can be broken down into two distinct
classes: agonists (clonidine and naphazoline are
agonists), which mimic the receptor activation
properties of the endogenous neurotransmitter
norepinephrine, and antagonists (phenoxybenzamine and
prazosin are antagonists), which act to block the
effects of norepinephrine. Many of these drugs are
effective but also produce unwanted side effects (for
example, clonidine produces dry mouth and sedation in
addition to its antihypertensive effects).
During the past 15 years a more precise understanding of
a-adrenergic receptors and their drugs has evolved
through increased scientific scrutiny. Prior to 1977,
only one a-adrenergic receptor was known to exist.
Between 1977 and 1988, it was accepted by the scientific
community that at least two a-adrenergic receptors--al
and az--existed in the central and peripheral nervous
systems. Since 1988, new techniques in molecular
biology have led to the identification of at least six
a-adrenergic receptors which exist throughout the
central and pezipherai nervous systems: alA il~ew
nomenclature) , a18, alp (new nomenclature) , azA, az8 and azc
(Bylund, D.B., FASEB J., 6, 832 (1992)). In many cases,
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it is not known precisely which physiological responses
in the body are controlled by each of these receptors.
In addition, current a-adrenergic drugs are not
selective for any particular a-adrenergic receptor.
Many of these drugs produce untoward side effects which
may be attributed to their poor a-adrenergic receptor
selectivity.
Since the mid 1970's, nonselective a-antagonists have
been prescribed to treat BPH. In 1976, M. Caine, et al.
(Brit. J. Urol., 48, 255 (1976)), reported that the
nonselective a-antagonist phenoxybenzamine was useful in
relieving the symptoms of BPH. This drug may produce
its effects by interacting with a-receptors located on
the prostate. However, this drug also produces
significant side effects such as dizziness and asthenia
which severely limit its use in treating patients on a
chronic basis. More recently, the a-adrenergic
antagonists prazosin and terazosin have also been found
to be useful for treating BPH. However, these drugs
also produce untoward side effects. It has recently
been discovered that the alA receptor is responsible for
mediating the contraction of human prostate smooth
muscle (Gluchowski, C. et. al., WO 94/10989, 1994;
Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994).
This discovery indicates that the alA antagonists may be
effective agents for the treatment of BPH with decreased
side effects. Further studies have indicated that the
alA receptor may also be present in other lower urinary
tract tissues, such as urethral smooth muscle (Ford et
al. Br. J. Pharmacol., 114, 24P, (1995)).
This invention is directed to oxazolidinone compounds
which are selective antagonists for cloned human alA
receptors. This invention is also related to uses of
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these compounds for lowering intraocular pressure (than,
et. al. Ophthalmol. Vis. Sci., 34 Abst. #1133, 928,
1993), inhibiting cholesterol synthesis (D'Eletto and
Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) S1-
S4, 1989), benign prostatic hyperplasia, impotency
(Milne and Wyllie, EP 0 459 666 A2, 1991),
sympathetically mediated pain (Campbell, WO 92/14453,
1992), cardiac arrhythmia (Spiers, et. al.,~T.
Cardiovascular Pharmacol., 16, 824-830, 1990) and for
the treatment of any disease where antagonism of the cxlA
receptor may be useful.
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Svmmarv of the Invention
This invention is directed to a compound having the
structure:
R ~ 2
or
R
wherein each X is independently O or S;
wherein q is 1 or 2;
wherein each RZ i s independent ly H ; - ( CHz ) tXR3 ; -
( CHZ ) tC ( X ) NR3 ; - ( CHz ) tCOzR3 ; -COzR3 ; s traight chained or
branched C1-C~ alkyl, aminoalkyl, carboxamidoalkyl;
straight chained or branched CZ-C~ alkenyl, or alkynyl;
or C3-C~ cycloalkyl or C5-C., cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or
branched C1-C., alkyl , straight chained or branched CZ-C,
alkenyl, or alkynyl; or C3-C? cycloalkyl or CS-C~
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cycloalkenyl;
wherein R4 is aryl, heteroaryl, C1-C, alkyl substituted
with one or two aryl, or C1-C., alkyl substituted with
one or two heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F, Cl, Br, I, -
CN, -NOz , -N ( R3 ) 2 , -COR3 , - ( CH2 ) tXR3 , - ( CHz ) nC ( X ) NR3 , -
( CHZ ) nCOzR3 , s traight chained or branched C1-C~ alkyl ,
monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or
straight chained or branched Cz-C., aminoalkyl, alkenyl
or alkynyl, or C3-C, cycloalkyl or CS-C~ cycloalkenyl;
wherein each n independently is an integer from 0 to 7
inclusive;
wherein RS is H; aryl, C1-C, alkyl substituted with aryl,
heteroaryl, or C1-C7 alkyl substituted with heteroaryl;
wherein the aryl or heteroaryl may be substituted with
one or more of F, C1, Br, I, -CN, -NO2, -N(R3)2, -COR3, -
2 0 ( CHZ ) tXR3 , - ( CHz ) nC ( X ) NR3 , - ( CHZ ) nCOzR3 , s traight
chained or
branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl
or carboxamidoalkyl, or straight chained or branched CZ-
C, aminoalkyl, alkenyl or alkynyl, or C3-C., cycloalkyl or
CS-C~ cycloalkenyl;
where RS and one Rz on adjacent carbon atoms together
may form aryl, heteroaryl, indane or tetrahydronaphthyl,
C3-C~ cycloalkyl, or heterocycloalkyl wherein one or two
heteroatoms may be 0, N or S;
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_g_
wherein R1 is
Rlo
R10
s [ m R6
Z-N
R~
m '
R1
Rlo
15 RloRla
R1o R1o
q
~Z N N R 11
R qRlo
20
RloRlo
so [ m Rs
25 q ~R7
or
35
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_g_
R1o
s'10
~ L /~\ Rl o\ ~ /~
t N N-R11
~qR ~m
~lo to
to
where each R6 is independently H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched Cz-C., alkenyl or alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, C1, Br, I, -(CHz)nXR3,
-COR3 . - ( CHZ ) nC ( X ) N ( R3 ) z , - { CHz ) nCOzR3 , -CN , -N02 , -N (
R3 ) 2 , -
SOZR3, straight chained or branched C1-C~ alkyl,
monofluoroalkyl or polyfluoroalkyl, straight chained or
branched CZ-C., alkenyl or alkynyl, or C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C~
cycloalkenyl;
where each R., is independently H; F; Cl; Br;. I; -COR3; -
3 0 COzR3 ; - ( CHZ ) nXR3 ; -COR3 ; - ( CH2 ) ~C { X ) N { R3 ) 2 ; - ( CHz )
nCOzR3 ; -
CN; -NO2; -N{R3)2; straight chained or branched C1-C~
alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched CZ-C~ alkenyl or alkynyl;
C3-C., cycloalkyl, monofluorocycloalkyl,
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polyfluorocycloalkyl or CS-C., cycloalkenyl, wherein the
alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl,
cycloalkyl or cycloalkenyl may be substituted with one
or more aryl or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more of F, Cl,
Br , I , - ( CH2 ) nXR3 , -COR3 , - ( CHZ ) nC ( X ) N ( R3 ) 2 , - ( CHz )
nCOzR3 , -
CN, -N02, -N(R3)2. -SOzR3, straight chained or branched
C1-C., alkyl, monofluoroalkyl or polyfluoroalkyl,
straight chained or branched CZ-C, alkenyl or alkynyl,
or C3-C., cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or ~5-C7 cycloalkenyl; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, Cl, Br, I, -(CHz)nXR3,
-COR3 , - ( CHZ ) nC ( X ) N ( R3 ) z . - ( CHz ) "COzR3 , -CN , -NO2 . -N (
R3 ) z .
SOzR3, straight chained or branched C1-C~ alkyl, straight
chained or branched C1-C, monofluoroalkyl or
polyfluoroalkyl, straight chained or branched CZ-C~
alkenyl or alkynyl, or C3-C., cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C~
cycloalkenyl;
wherein each Rlo is independently H; (CHZ) CXR3;
( CHZ ) tC ( X ) NR3 ; ( CHz ) tCOzR3 ; straight chained or branched
C1-C., alkyl or carboxamidoalkyl; straight chained or
branched CZ-C., aminoalkyl, alkenyl, or alkynyl; or Cj-C~
cycloalkyl or CS-C~ cycloalkenyl;
wherein R11 is aryl, heteroaryl, C1-C., alkyl substituted
with one or two aryl, or C1-C, alkyl substituted with
one or two heteroaryl; wherein any aryl or heteroaryl
independently may be substituted with one or more of F,
Cl, Br, I, -CN, -NOz, -N(R3)z, -COR3, -(CHZ)nXR3, -
( ~Ii2 ) nC ( X ) NR3 , - ( CH2 ) nCO2R3 , straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl, straight chained or branched CZ-C~
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aminoalkyl, alkenyl, or alkynyl, or C3-C~ cycloalkyl or
CS-C~ cycloalkenyl;
wherein each m independently is an integer from 0 to 3
inclusive;
wherein Z is
15
10
R2 ~~ R10
R9
30
R9 __
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10
20
0 Rlo Rlo
R
m 8R9 Rl o
3a
~m
~m~m ~~
Rlo R1 R9 Rlo
_a
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or
15
O Rg
R2 RZ Rio
n
m ~t ~ t
Rg
R2 R2 Rlo
or CZ-C~ alkenyl, wherein the Cz-C., alkenyl may be
unsubstituted or substituted with one or more R9 groups;
where Re i s H ; ( CHZ ) tXR3 ; ( CHz ) CC ( X ) NR3 ; ( CHZ ) tCOzR3 ;
straight chained or branched C1-C~ alkyl,
carboxamidoalkyl; straight chained or branched CZ-C,
aminoalkyl, alkenyl, or alkynyl; or C3-C., cycloalkyl or
CS-C., cycloalkenyl;
wrere caeh R9 is iizciepemderic.ly H; F; Cl; Fr; I;
( CHZ ) mXR3 ; ( CHz ) mC ( X ) NR3 ; ( CHZ ) mCOzR3 ; s traight chained or
branched C1-C., alkyl, monofluoroalkyl, polyfluoroalkyl,
J
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aminoalkyl, or carboxamidoalkyl; straight chained or
branched CZ-C~ alkenyl, or alkynyl; or C3-C~ cycloalkyl
or CS-C7 cycloalkenyl;
wherein Y is S, O, or NRB;
or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a
compound having the structure:
F
02CH3
This invention is additionally directed to a compound
having the structure:
X
3 o X ~N~RZ
W
X . R5
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wherein each W is an integer from 0 to 3 inclusive;
wherein each W1 is an integer from 0 to 3 inclusive;
wherein each X is independently O or S;
wherein X1 is 0, S, NR3;
wherein each RZ is independently H; - (CH2 ) tXR3; -
( CHZ ) tC ( X ) NR3 ; - ( CHZ ) tCO2R3 ; -COZR3 ; straight chained or
branched C1-C~ alkyl, aminoalkyl, carboxamidoalkyl;
straight chained or branched CZ-C~ alkenyl, or
alkynyl; or C3-C~ cycloalkyl or CS-C~ cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained
or branched C1-C~ alkyl, straight chained or branched
Cz-C~ alkenyl, or alkynyl; or C3-C~ cycloalkyl or CS-C~
cycloalkenyl;
wherein RQ is aryl, heteroaryl, C1-C~ alkyl substituted
with one or two aryl, or C1-C., alkyl substituted with
one or two heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F, C1, Br, I, -
CN , -NOZ , -N ( R3 ) 2 , -CORj , - ( CHZ ) ~XR3 , - ( CHZ ) nC ( X ) NR3 , -
( CHZ ) nCOZR3 , straight chained or branched C1-C~ alkyl ,
monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl,
or straight chained or branched CZ-C~ aminoalkyl,
alkenyl or alkynyl, or C3-C., cycloalkyl or CS-C.,
cycloalkenyl;
wherein each n independently is an integer from 0 to 7
inclusive;
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wherein RS is H; aryl, C1-C., alkyl substituted with
aryl, heteroaryl, or C1-C., alkyl substituted with
heteroaryl; wherein the aryl or heteroaryl may be
substituted with one or more of F, C1, Br, I, -CN, -
NOz , -N ( R3 ) 2 , -COR3 , - ( CHz ) tXR3 , - ( CHZ ) nC ( X ) NR3 , -
(CHz ) nCO2R3 , straight chained or branched C1-C, alkyl ,
monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl,
or straight chained or branched C2-C~ aminoalkyl,
alkenyl or alkynyl, or C3-C~ cycloalkyl or CS-C~
cycloalkenyl;
wherein R1 is
R1
R1
~Z-N ~)
2 0 ~r~R ~ ,
R10
25
35
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.fl n ,
1'101'10
R1o R1o
q
,~Z N R 11
o R1o qRlo
RloRlo
( m R6 or
'
~m 7
Rl o
RZO
~ ~R10 ~ m
N N N-R1~
~ qR ~ m
R10 10
where each R6 is independently H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched CZ-C~ alkenyl or alkynyl;
C3-C., cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or CS-C~ cycloalkenyl; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, C1, Br, I, -(CHZ)nXR3,
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-COR3 , - ( CHz ) nC ( X ) N ( R3 ) z , - ( CHz ) nCOZR3 , -CN, -NOz , -N ( R3
) z , -
SOZR3 , straight chained or branched C1-C., alkyl ,
monofluoroalkyl or polyfluoroalkyl, straight chained or
branched Cz-C~ alkenyl or alkynyi, or C3-C? cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C.,
cycloalkenyl;
where each R~ is independently H; F; C1; Br; I;.-COR3; -
COZR3 ; - ( CHz ) nXR3 : ( CHz ) nC ( X ) N ( R3 ) z ; - ( CHz ) nCO2R3 ; -CN
; -NOz ;
-N ( R3 ) z ; straight chained or branched C1-C., alkyl ,
hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched Cz-C-, alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C~
cycloalkenyl, wherein the alkyl, aminoalkyl,
carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or
cycloalkenyl may be substituted with one or more aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, C1, Br, I, -(CHz)nXR3,
2 0 -COR3 . - ( CHz ) nC ( X ) N ( R3 ) z , - ( CHz ) nCOzR3 , -CN , -NOz . -N
( R3 ) z , -
SOzR3, straight chained or branched C1-C~ alkyl,
monofluoroalkyl or polyfluoroalkyl, straight chained or
branched Cz-C~ alkenyl or alkynyl, or C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C~
cycloalkenyl; aryl or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more of F, C1,
Br , I , - ( CHz ) nXR3 , -COR3 , - ( CHz ) nC ( X ) N ( R3 ) z , - ( CHz )
nCOzR3 , -
CN, -NOz, -N(R3)z, -SOzR3, straight chained or branched
C1-C~ alkyl, straight chained or branched C1-C~
monofluoroalkyl or polyfluoroalkyl, straight chained or
branched Cz-C~ alkenyl or alkynyl, or C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C7
cycloalkenyl;
wherein each Rlo is independently H; (CHz) tXR3;
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( CH2 ) tC (X ) NR3 ; ( CHz ) tCO2R3 ; straight chained or branched
C1-C, alkyl or carboxamidoalkyl; straight chained or
branched CZ-C, aminoalkyl , alkenyl , or alkynyl ; or C3-C.,
cycloalkyl or CS-C~ cycloalkenyl;
wherein R11 is aryl, heteroaryl, C1-C~ alkyl substituted
with one or two aryl, or C1-C~ alkyl substituted with
one or two heteroaryl; wherein any aryl or heteroaryl
independently may be substituted with one or more of F,
C1, Br , I , -CN, -NO2 , -N ( R3 ) 2 , -COR3 , - ( CHz ) nXR3 , -
(CHz) nC (X)NR3, - (CH2) nCOzR3, straight chained or branched
C1-C., alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl, straight chained or branched Cz-C~
aminoalkyl, alkenyl, or alkynyl, or C3-C., cycloalkyl or
CS-C., cycloalkenyl ;
wherein each m independently is an integer from 0 to 3
inclusive;
wherein Z is
30
__
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10
20
30
__
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J
15
25 p R1 o Rl o
R
8R9 RZ o
N
m m o
'
R1o R R9 Rlo
35
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-22-
O Rg
R2 R2 Rlo
n
m ~ t~ t
9
2 2 10
or Cz-C., alkenyl , wherein the Cz-C, alkenyl may be
unsubstituted or substituted with one or more R9 groups;
where R8 i s H ; ( CHz ) tXR3 ; ( CHZ ) CC ( X ) NR3 ; ( CHz ) CCOZR3 ;
straight chained or branched C1-C~ alkyl,
carboxamidoalkyl; straight chained or branched CZ-C.,
aminoalkyl, alkenyl, or alkynyl; or C3-C., cycloalkyl or
CS-C~ cycloalkenyl;
where each R9 is independently H; F; C1; Br; I;
( CHZ ) mXR3 ; ( CH2 ) mC ( X ) NR3 ; ( CHz ) mCO2R3 ; s traight chained or
branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched Cz-C~ alkenyl, or alkynyl; or C3-C., cycloalkyl
or CS-C., cycloalkenyl;
wherein Y is S, O, or NRe;
or a pharmaceutically acceptable salt thereof.
This invention is also related to uses of these
compounds for lowering intraocular pressure, inhibiting
cholesterol synthesis, relaxing lower urinary tract
tissue, the treatment of benign prostatic hyperplasia,
impotency, cardiac arrhythmia and for the treatment of
any disease where antagonism of the alA receptor may be
useful. The invention further provides pharmaceutical
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compositions comprising a therapeutically effective
amount of the above-defined compounds and a
pharmaceutically acceptable carrier.
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Brief Descrivtion of the Ficrures
Ficrure 1 Figures 1A-1M show the structures of the
compounds described hereinbelow in the
Examples.
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-25
Detailed Desc~it~tion of the Invention
The present invention is directed to compounds having
the structure:
R ~ 2 ;
R
or
wherein each X is independently 0 or S;
wherein q is 1 or 2;
wherein each RZ is independently H; - (CHZ) tXR3;
( CHZ ) tC ( X ) NR3 ; - ( CH2 ) tCOzR3 ; -COzR3 ; straight chained or
branched C1-C~ alkyl, aminoalkyl, carboxamidoalkyl;
straight chained or branched CZ-C, alkenyl, or alkynyl;
or C3-C., cycloalkyl or CS-C~ cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
whereiiz each R3 is independeni:ly H; s traiylW chained or
branched C1-C., alkyl, straight chained or branched CZ-C~
alkenyl, or alkynyl; or C3-C-, cycloalkyl or CS-C,
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cycloalkenyl;
wherein R4 is aryl, heteroaryl, C1-C, alkyl substituted
with one or two aryl, or C1-C~ alkyl substituted with
one or two heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F, C1, Br, I, -
CN , -NOZ , -N ( R3 ) z , -COR3 , - ( CHz ) CXR3 , - ( CHZ ) nC ( X ) NR3 , -
( CHZ ) nCO2R3 , s traight chained or branched C1-C~ alkyl ,
monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or
straight chained or branched CZ-C., aminoalkyl, alkenyl
or alkynyl, or C3-C~ cycloalkyl or CS-C., cycloalkenyl;
wherein each n independently is an integer from 0 to 7
inclusive;
wherein RS is H; aryl, C1-C~ alkyl substituted with aryl,
heteroaryl, or C1-C~ alkyl substituted with heteroaryl;
wherein the aryl or heteroaryl may be substituted with
one or more of F, Cl, Br, I, -CN, -NO~, -N(R3)2, -COR3, -
2 0 ( CHZ ) tXR3 , - ( CHz ) nC ( X ) NR3 , - ( CHZ ) nCOzR3 , straight
chained or
branched C1-C., alkyl, monofluoroalkyl, polyfluoroalkyl
or carboxamidoalkyl, or straight chained or branched CZ-
C., aminoalkyl, alkenyl or alkynyl, or C3-C., cycloalkyl or
CS-C, cycloalkenyl;
where RS and one Rz on adjacent carbon atoms together
may form aryl, heteroaryl, indane or tetrahydronaphthyl,
C3-C., cycloalkyl, or heterocycloalkyl wherein one or two
heteroatoms may be O, N or S;
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wherein Rz is
R1
~Z-
R~
R10
15
1'10r'10
R1o R1o
q
~--z N N R11
R1o qRlo
RloRlo
O
~/~Rlo ~ m
N/ ~~'N -
~, q ~ ItR7 or
35
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10
0
R11
1V
where each R6 is independently H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
.straight chained or branched C2-C., alkenyl or alkynyl;
C3-C., cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, C1, Br, I, - (CH2)nXR3,
2 0 -COR3 , - ( CHz ) "C ( X ) N ( R3 ) z , - ( CHz ) nCOZR3 , -CN , -N02 , -N
( R3 ) z , -
SOzR3, straight chained or branched C1-C., alkyl,
monofluoroalkyl or polyfluoroalkyl, straight chained or
branched CZ-C., alkenyl or alkynyl , or C3-C~ cycloalkyl ,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C.,
cycloalkenyl;
where each R~ is independently H; F; C1; Br; I; -COR3; -
COZR3 : - ( CHz ) nXR3 ; -COR3 ; - ( CH2 ) nC ( X ) N ( R3 ) z ; - ( CHZ )
nCOzRj ; -
CN; -N02 ; -N ( R3 ) 2 ; s traight chained or branched C1-C.,
alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched CZ-C7 alkenyl or alkynyl;
C3-C., cycloalkyl, monofluorocycl~dlkyl,
polyfluorocycloalkyl or CS-C., cycloalkenyl, wherein the
alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl,
n Ran
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cycloalkyl or cycloalkenyl may be substituted with one
or more aryl or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more of F, C1,
Br , I , - ( CH2 ) nXR3 , -COR3 , - ( CHZ ) nC ( X ) N ( R3 ) 2 , - ( CHz )
nCOzR3 , -
CN, -NOZ, -N(R3)2, -SOZR3, straight chained or branched
C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl,
straight chained or branched CZ-C~ alkenyl or alkynyl,
or C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or CS-C~ cycloalkenyl; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, Cl, Br, I, -(CH2)nXR3,
-COR3 , - ( CHZ ) nC ( X ) N ( R3 } 2 , - ( CHZ ) nCO2R3 , -CN , -NOZ , -N (
R3 ) 2 . -
SOzR3, straight chained or branched C,-C7 alkyl, straight
chained or branched C1-C~ monofluoroalkyl or
polyfluoroalkyl, straight chained or branched CZ-C,
alkenyl or alkynyl, or C3-C., cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C.,
cycloalkenyl;
wherein each Rlo is independently H; (CHZ)CXR3;
( CHz ) tC ( X} NR3 ; ( CHz ) tCO2R3 ; straight chained or branched
C1-C~ alkyl or carboxamidoalkyl; straight chained or
branched CZ-C~ aminoalkyl , alkenyl , or alkynyl ; or C3-C~
cycloalkyl or C5-C~ cycloalkenyl;
wherein R11 is aryl, heteroaryl, C1-C~ alkyl substituted
with one or two aryl, or C1-C~ alkyl substituted with
one or two heteroaryl; wherein any aryl or heteroaryl
independently may be substituted with one or more of F,
3 0 C 1, Br , I , -CN, -NOz , -N { R3 ) z , -COR3 , - ( CHZ ) nXR3 , -
CHZ ) nC (X) NR3 , - ( CHZ ) nCO2R3 , s traight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl, straight chained or brancr~ed CZ-C~
aminoalkyl, alkenyl, or alkynyl, or C3-C~ cycloalkyl or
CS-C, cycloalkenyl;
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wherein each m independently is an integer from 0 to 3
inclusive;
wherein Z is
10
20
J
J
,
__
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10
20
30
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O Rlo Rlo
R
m 8R9 Rlo
N ~m
~~~ T~~m W
R10 R10 Rg R10 or
0 Rg
R2 R2 R1o
n
m t~ t
9
2 2 H10
or Cz-C~ alkenyl, wherein the C2-C, alkenyl may be
unsubstituted or substituted with one or more R9 groups;
where R8 i. s H ; ( CHZ ) tXR3 ; ( CHz ) tC ( X ) NR3 ; { CHz } tCOzR3 ;
straight chained or branched C1-C, alkyl,
carboxamidoalkyl; straight chained or branched C2-C~
aminoalkyl, alkenyl, or alkynyl; or C3-C., cycloalkyl or
CS-C~ cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I;
CH2 ) mXR3 ; ( CH2 ) mC ( X ) NR3 ; ( CHZ ) mCO2R3 ; s traight chained or
branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched CZ-C7 alkenyl, or alkynyl; cr C3-C., cycloalkyl
or CS-C., cycloalkenyl;
wherein Y is S, O, or NRe;
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or a pharmaceutically acceptable salt thereof.
The invention further provides for the (+) enantiomer of
any of the compounds described herein which maybe a cis
isomer or a traps isomer. The invention also provides
for the (-) enantiomer of any of the compounds described
herein which may be a cis or a traps isomer.
The compounds of the present invention are preferably at
least 80~ pure, more preferably at least 90~ pure, and
most preferably at least 95~ pure.
In the present invention the term "aryl" is used to
include phenyl, benzyl, benzoyl or naphthyl and the term
"heteroaryl" is used to include pyrazinyl, pyrryl,
furanyl, thiophenyl, pyridyl, imidazolyl, indolyl,
aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl,
benzfuranyl, 2-keto-1-benzimidazolinyl or quinolyl.
The compounds of this invention exhibit at least ten-
fold greater affinity for the human alA receptor than
for the human alB or human a1D receptor.
In one embodiment of the present invention R1 is
30
R1
~Z-
R-
R4 is aryl or heteroaryl, where the aryl may be
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substituted with one or more of F, C1, - (CHz) tOR3, -
( CHZ ) nCONR3 , - ( CHz ) nCO2R3 , s traight chained or branched C1-
C., alkyl or monof luoroalkyl ; and
Z is
15
K9
t L ~ J t .
-n
R2 ~ R10
Rg
or
O R1 o R10
R
8Rg Rl o
N
m
~~m ~~
m
Rlo R1o Rg Rlo
In another embodiment of the present invention R4 is
pyridyl or phenyl, where the phenyl may be substituted
g __
R2 R10
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wi th one or more o f F , C1, - ( CHz ) tOR3 , - ( CHZ ) nC ( O ) NR3 , -
( CHZ ) nCOZR3 , s traight chained or branched C1-C~ alkyl or
monofluoroalkyl.
In yet another embodiment of the present invention each
R6 is independently aryl or heteroaryl, where the aryl
or heteroaryl may be substituted with one or more of F,
C 1, Br , I , - ( CHZ ) nXR3 , -COR3 , - ( CHz ) nC ( X ) N ( R3 ) 2 , -
( CHz ) nCOZR3 , -CN, -NOZ , -N ( R3 ) z , - SO2R3 , s traight chained
or branched Cl-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl.
In a further embodiment of the present invention R, is
H; -CN; -COzR3; -C(O)NR;; -(CHZ)mXR3; unsubstituted or
substituted aryl; C1-C3 alkyl; or -OCOR3.
In another embodiment of the present invention R4 is
phenyl which may be substituted with at least one of F
or C1.
In yet another embodiment of the present invention the
compound has the structure:
R 2 R
or
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In another embodiment of the present invention Z is:
R2 R1o
i o NH
t~ t
R9
O R2 Rlo
20 In a further embodiment of the present invention q is 1
and R1 is
/Z-
7
.
In a further embodiment of the present inveneioii ai:
least one Rz is C1-C3 alkyl.
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In another embodiment of the present invention R4 is
phenyl substituted with at least one of F or C1.
In a further embodiment of the present invention RQ is
phenyl substituted with at least two F.
In an embodiment of the present invention R9 is 3,4-
difluorophenyl.
In an additional embodiment of the present invention R6
is pyridyl, phenyl, or phenyl substituted with one or
more of F, C1, Br, I, - (CHZ) nXR3, -COR3, -
(CHZ)nC(X)N(R3)2.-(CHZ)nCOzR3, -CN, -NO,i -N(R3)z, -S02R3i
straight chained or branched C1-C, alkyl,
monofluoroalkyl or polyfluoroalkyl.
In a further embodiment of the present invention R., is
H; -CN; or -COZR3.
In another embodiment of the present invention R9 is F;
-OH; C1-C3 alkyl ; or -.:kCH2 ) mXR3 .
In an embodiment, when R9 is -OH or F, the other R9 on
the same carbon atom is not -OH. In yet another
embodiment, when R9 is F, the other R9 on the same
carbon atom is C1-C3 alkyl, F, C1, Br, or I.
In yet another embodiment of the present invention R6 is
4-fluorophenyl.
In one embodiment of the invention,
the compound is a trans (+) isomer having the structure:
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H3
F
This invention is additionally directed to a compound
having the structure:
O
25
This invention is additionally directed to a compound
having the structure:
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F
10
This invention is additionally directed to a compound
having the structure:
0
0 N N
i
CN
This invention is additionally directed to a compound
having the structure:
0 0
0
F CN
~~-~F
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This invention includes a compound having the structure:
X
X N~R1
W
X ~ R.5
W1
25 wherein each W is an integer from 0 to 3 inclusive;
wherein each W1 is an integer from 0 to 3 inclusive;
wherein each X is independently O or S;
wherein each X1 is O; S, NR3;
wherein each R2 is independently H; - (CHZ) tXR3; -
( CH2 ) tC ( X ) NR3 ; - ( CH2 ) tC02Rj ; -C02R3 ; s traight chained or
branched C1-C~ alkyl, aminoalkyl, carboxamidoalkyl;
straight chained or branched CZ-C~ alkenyl, or alkynyl;
or C3-C~ cycloalkyl or CS-C., cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or
branched C1-C, alkyl, straight chained or branched Cz-C~
alkenyl, or alkynyl; or C3-C~ cycloalkyl or CS-C~
cycloalkenyl;
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wherein R4 is aryl, heteroaryl, C1-C, alkyl substituted
with one or two aryl, or C1-C., alkyl substituted with
one or two heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F, C1, Br, I, -
CN, -NOZ , -N ( R3 ) 2 , -COR3 , - ( CHZ ) tXR3 , - ( CH2 ) nC ( X ) NR3 , -
(CH2)nCOzR3, straight chained or branched C1-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or
straight chained or branched CZ-C., aminoalkyl, alkenyl
or alkynyl, or C3-C~ cycloalkyl or CS-C., cycloalkenyl;
wherein each n independently is an integer from 0 to 7
inclusive;
wherein RS is H; aryl, C1-C., alkyl substituted with aryl,
heteroaryl, or C1-C~ alkyl substituted with heteroaryl;
wherein the aryl or heteroaryl may be substituted with
one or more of F, Cl, Br, I, -CN, -NOz, -N(R3)z, -COR3, -
( CHZ ) tXR3 , - ( CHZ ) nC ( X ) NR3 , - ( CHZ ) nCO2R~ , straight chained or
branched C1-C., alkyl, monofluoroalkyl, polyfluoroalkyl
or carboxamidoalkyl, or straight chained or branched Cz-
C, aminoalkyl, alkenyl or alkynyl, or C3-C, cycloalkyl or
CS-C, cycloalkenyl;
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wherein R1 is
R1
6
~Z-
7
R'
15
1'10j~10
R1o R1o
ao
~Z N N R11
R1o
R1o
RloRlo
10 [ m R6
R
Irl ~ o r
35
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R11
n10
wherein each R6 is independently H; straight chained
or branched C1-C, alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched CZ-C~ alkenyl or alkynyl;
C3-C., cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or CS-C~ cycloalkenyl; aryl or
heteroaryl, wherein the aryl or heteroaryl may be
substituted with one or more of F, C1, Br, I, -
2 0 ( CHz ) nXR3 , -COR3 , - ( CHZ ) nC ( X ) N ( R3 ) z , - ( CH2 ) nCOzR3 , -
CN , -
NO2 , -N ( R3 ) 2, -SOZR3 , straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl, straight
chained or branched CZ-C~ alkenyl or alkynyl, or C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or CS-C~ cycloalkenyl ;
wherein each R., is independently H; F; Cl; Br; T; -
COR3 ; -COzR3 ; - ( CHz ) nXR3 ; ( CHZ ) nC ( X ) N ( R3 ) 2 ; - ( CHz )
nCOzR3 ; -
CN; -NOz; -N(R3)2; straight chained or branched C1-C~
alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched CZ-C7 alkenyl or alkynyl;
C3-C~ cycloalkyl, monofluorocyc:loalkyl,
polyfluorocycloalkyl or C5-C, cycloalkenyl, wherein
the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl,
R1o
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alkynyl, cycloalkyl or cycloalkenyl may be substituted
with one or more aryl or heteroaryl, wherein the aryl
or heteroaryl may be substituted with one or more of
F , C 1, Br , I . - ( CHZ ) nXR3 , -COR3 , - ( CH2 ) nC ( X ) N ( R3 ) 2 , -
(CHZ)nCOzR3, -CN, -NO2, -N(R3)z, -SOzR3, straight chained
or branched C1-C., alkyl, monofluoroalkyl or
polyfluoroalkyl, straight chained or branched Cz-C,
alkenyl or alkynyl, or C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or CS-C.,
cycloalkenyl; aryl or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more of F,
C1. Br, I, -(CHz)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-
( CHz ) nC02R3 , -CN, -N02 , -N ( R3 ) z , - SOZR3 , s traight chained
or branched C1-C., alkyl, straight chained or branched
C1-C., monofluoroalkyl or polyfluoroalkyl, straight
chained or branched CZ-C., alkenyl or alkynyl , or C3-C7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or CS-C., cycloalkenyl;
wherein each Rlo is independently H; (CH2)tXR3;
( CHz ) tC ( X ) NRj ; ( CHz ) tCOzR3 ; straight cha fined or branched
C1-C~ alkyl or carboxamidoalkyl; straight chained or
branched CZ-C~ aminoalkyl, alkenyl, or alkynyl; or C3-
C., cycloalkyl or CS-C., cycloalkenyl;
wherein R11 is aryl, heteroaryl, C1-C~ alkyl
substituted with one or two aryl, or C1-C~ alkyl
substituted with one or two heteroaryl; wherein any
aryl or heteroaryl independently may be substituted
with one or more of F, C1, Br, I, -CN, -NO2, -N(R3)z, -
COR3 , - ( CHz ) nXR3 , - ( CH2 ) nC ( X ) NR3 , - ( CHZ ) nCOzR3 , S tra i
ght
chained or branched C1-C., alkyl, monofluoroalkyl,
polyfluoroalkyl, or carboxawidoalkyl, straight chained
or branched C2-C., aminoalkyl , alkenyl , or alkynyl , or
C3-C~ cycloalkyl or CS-C~ cycloalkenyl;
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wherein each m independently is an integer from 0 to 3
inclusive;
wherein Z is
10
2 K10
K9
~ t
-n
R2 ~ R10
R9 ,
30
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10
20 ,
O R1 o Rl o
R
m 8R9 RZ o
N
m m
m
' I\
Rl o R1 o R-~ Rl o
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10 or
v rig
F~2 R2 R1o
n
tl t
R9
H2 2 10
or CZ-C~ alkenyl , wherein the CZ-C~ alkenyl may be
unsubstituted or substituted with one or more R9 groups;
where RB i s H ; ( CHz ) tXR3 ; ( CHZ ) tC ( X ) NR3 ; ( CHz ) tCOzR3 ;
straight chained or branched C1-C~ alkyl,
carboxamidoalkyl; straight chained or branched CZ-C,
aminoalkyl, alkenyl, or alkynyl; or C3-C., cycloalkyl or
C~ cycloalkenyl;
where each R9 is independently H; F; C1; Br; I;
( CHZ ) mXR3 ; ( CHZ ) mC ( X ) NR3 ; ( CHz ) mCO2R3 ; s t raight chained or
branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or.' carboxainidoalkyl; straight chained or
branched CZ-C, alkenyl, or alkynyl; or C3-C, cycloalkyl
or CS-C~ cycloalkenyl;
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wherein Y is S, O, or NRe;
or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a
compound having the structure:
02CH3
The invention also encompasses the (-) and (+)
enantiomers of all compounds described herein. The
invention further includes cis and trans isomers of all
of the compounds described herein, the terms "cis" and
"traps" corresponding to relative stereochemistry, as
determined, for example, by NOE (Nuclear Overhauser
Effect) experiments. In one embodiment, cis and traps
designate the relative positions of aryl and alkyl on
adjacent carbons in the oxazolidinone ring (see Examples
18 and 19).
Included in this invention are pharmaceutically
acceptable salts and complexes of all of the compounds
described herein. The salts include but are not limited
to the following acids and bases: iriorganic acids such
as hydrochloric acid, hydrofluoric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid and boric acid;
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organic acids such as acetic acid, trifluoroacetic acid,
formic acid, oxalic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, malefic acid, citric acid,
methanesulfonic acid, trifluoromethanesulfonic acid,
benzoic acid, glycolic acid, lactic acid and mandelic
acid; inorganic bases such as ammonia and hydrazine; and
organic bases such as methylamine, ethylamine,
hydroxyethylamine, propylamine, dimethylamine,
diethylamine, trimethylamine, triethylamine,
ethylenediamine, hydroxyethylamine, morpholine,
piperazine and guanidine. This invention further
encompasses hydrates and polymorphs of all of the
compounds described herein.
The invention further provides pharmaceutical
compositions comprising a therapeutically effective
amount of any of the compounds described above and a
pharmaceutically acceptable carrier. In the subject
invention a "therapeutically effective amount" is any
amount of a compound which, when administered to a
subject suffering from a disease against which the
compounds are effective, causes reduction, remission, or
regression of the disease. In one embodiment, the
therapeutically effective amount is an amount from about
0.01 mg to about 800 mg. In another embodiment, the
therapeutically effective amount is an amount from about
0.01 mg to about 500 mg. In another embodiment, the
therapeutically effective amount from about 0.01 mg to
about 250 mg. In another embodiment, the
therapeutically effective amount is an amount from about
0.1 mg to about 60 mg. In another embodimen'~, the
therapeutically effective amount is an amount from about
1 mg to about 20 mg. In one embodiment the
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therapeutically effective amount is an amount from about
0.01 mg per subject per day to about 500 mg per subject
per day, preferably from about 0.1 mg per subject per
day to about 100 mg per subject per day, e.g., from
about 1 mg per subject per day to about 50 mg per
subject per day. In the practice of this invention the
"pharmaceutically acceptable carrier" is any
physiological carrier known to those of ordinary skill
in the art as being useful in formulating pharmaceutical
compositions.
In one embodiment the pharmaceutical carrier may be a
liquid and the pharmaceutical composition would be in
the form of a solution. In another embodiment, the
pharmaceutically acceptable carrier is a solid and the
composition is in the form of a powder or tablet. In a
further embodiment, the pharmaceutical carrier is a gel
and the composition is in the form of a suppository or
cream. In a further embodiment the compound may be
formulated as a part of a pharmaceutically acceptable
transdermal patch.
A solid carrier can include one or more substances which
may also act as flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating
agents; it can also be an encapsulating material. In
powders, the carrier is a finely divided solid which is
in admixture with the finely divided active ingredient.
In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in
suitable proportions and compacted in the shape and size
desired. The powders and tablets preferably corncain up
to 99~ of the active ingredient. Suitable solid carriers
include, for example, calcium phosphate, magnesium
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stearate, talc, sugars, lactose, dextrin, starch,
gelatin, cellulose, polyvinylpyrrolidine, low melting
waxes and ion exchange resins.
Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved or
suspended in a pharmaceutically acceptable liquid
carrier such as water, an organic solvent, a mixture of
both or pharmaceutically acceptable oils or fats. The
liquid carrier can contain other suitable pharmaceutical
additives such as solubilizers, emulsifiers, buffers,
preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of
liquid carriers for oral and parenteral administration
include water (partially containing additives as above,
e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including
monohydric alcohols and polyhydric alcohols, e.g.
glycols) and their derivatives, and oils (e. g.
fractionated coconut oil and arachis oil). For
parenteral administration, the carrier can also be an
oily ester such as ethyl oleate and isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid
form compositions for parenteral administration. The
liquid carrier for pressurized compositions can be
halogenated hydrocarbon or other pharmaceutically
acceptable propellent.
Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by for example,
intramuscular, intrathecal, epidural, intraperii:eneal or
subcutaneous injection. Sterile solutions can also be
administered intravenously. The compounds may be
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prepared as a sterile solid composition which may be
dissolved or suspended at the time of administration
using sterile water, saline, or other appropriate
sterile injectable medium. Carriers are intended to
include necessary and inert binders, suspending agents,
lubricants, flavorants, sweeteners, preservatives, dyes,
and coatings.
The invention also provides a method of treating a
subject suffering from benign prostatic hyperplasia
which comprises administering to the subject any one of
the compounds described herein in an amount effective to
treat benign prostatic hyperplasia. In a preferred
embodiment the compound of the pharmaceutical
composition additionally does not cause a fall in blood
pressure at dosages effective to alleviate benign
prostatic hyperplasia. In one preferred embodiment the
compound effects treatment of benign prostatic
hyperplasia by relaxing lower urinary tract tissue and
in particular where lower urinary tract tissue is
prostatic smooth muscle.
The invention further provides a method of treating a
subject suffering from elevated intraocular pressure
which comprises administering to the subject one of the
compounds described herein effective to lower
intraocular pressure.
The invention further provides a method of treating a
subject suffering from a disorder associated with
elevated blood cholesterol which comprises administering
to the subject one of the compounds described herein
effective to inhibit cholesterol synthesis.
The invention also provides a method of treating a
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disease which is susceptible to treatment by antagonism
of the alA receptor which comprises administering to the
subject one of the compounds described herein effective
to treat the disease.
The invention further provides a method of treating a
subject suffering from impotency which comprises
administering to tr~e subject one of the compound]
described herein effective to treat impotency.
The invention further provides a method of treating a
subject suffering from sympathetically mediated pain
which comprises administering to the subject one of the
compounds described herein effective to treat
sympathetically mediated pain.
The invention provides a method of treating a subject
suffering from cardiac arrhythmia which comprises
administering to the subject one of the compounds
described herein effective to treat cardiac arrhythmia.
The invention provides a method of treating a subject
suffering from benign prostatic hyperplasia which
comprises administering to the subject one of the
compounds described herein in combination with a 5
alpha-reductase inhibitor effective to treat benign
prostatic hyperplasia. In one preferred embodiment the
5-alpha reductase inhibitor is finasteride. The dosage
administered to the subject is about 0.01 mg per subject
per day to 50 mg per subject per day of finasteride in
combination with an alA antagonist. A more preferred
dosage administered to the subject is about 1 mg per
subject per day to 7 mg per subject per day of
finasteride in combination with an alA antagonist. The
most preferred dosage administered to the subject is
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about 5 mg per subject per day of finasteride in
combination with an alA antagonist.
The invention also provides a pharmaceutical composition
comprising a therapeutically effective amount of a
combination of any of the compounds described herein in
combination with finasteride and a pharmaceutically
acceptable carrier. Tn one embodiment the
pharmaceutical composition is a therapeutically
effective amount of a combination comprising an amount
from about 0.01 mg per subject per day to about 500 mg
per subject per day of any one of the compounds
described herein and an amount of finasteride of about 5
mg per subject per day. A more preferred embodiment of
the pharmaceutical composition is a therapeutically
effective amount of a combination comprising an amount
from about 0.1 mg per subject per day to about 60 mg per
subject per day of any one of the compounds described
herein and an amount of the finasteride of about 5 mg
per subject per day. The most preferred embodiment of
the pharmaceutical composition is a therapeutically
effective amount of a combination comprising from about
1 mg per subject per day to about 20 mg per subject per
day of any one of the compounds described herein and an
amount of finasteride of about 5 mg per subject per day.
The invention further.provides a method of relaxing
lower urinary tract tissue which comprises contacting
the lower urinary tract tissue with an amount of one of
the compounds described herein effective to relax lower
urinary tract tissue. In one embodiment the lower
urinary tract tissue is prostatic smooth muscle. In one
preferred embodiment the compound additionally does not
cause a fall in blood pressure when it is effective to
relax lower urinary tract tissue.
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The invention provides a method of relaxing lower
urinary tract tissue in a subject which comprises
administering to the subject an amount of one of the
compounds described herein effective to relax lower
urinary tract tissue. In one preferred embodiment the
compound does not cause a fall in blood pressure and the
lower urinary tract tissue is prostatic smooth muscle.
The invention further provides for a method of
inhibiting contraction of prostatic tissue, which
comprises administering to the subject an amount of any
of the compounds described herein effective to inhibit
contraction of prostatic tissue. In one preferred
embodiment the prostatic tissue is prostatic smooth
muscle and the compound additionally does not cause a
fall in blood pressure.
The invention provides for the use of the compounds
described herein for the preparation of a pharmaceutical
composition for lowering intraocular pressure,
inhibiting cholesterol synthesis, and the treatment of:
benign prostatic hyperplasia, impotency, cardiac
arrhythmia and any disease where antagonism of the a.~A
receptor may be useful. The invention provides for the
use of the compounds described herein for the
preparation of a pharmaceutical composition for relaxing
lower urinary tract tissue and in particular prostatic
smooth muscle. The invention further provides for the
use of any of compounds described herein for the
preparation of a pharmaceutical composition, where the
compound additionally does not cause a fall in blood
pressure at dosages effective to lower intraocular
pressure, to inhibit cholesterol synthesis, arid for 4he
treatment of: benign prostatic hyperplasia, impotency,
cardiac arrhythmia and any disease where antagonism of
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the alA receptor may be useful.
The invention provides for the use of the compounds
described herein in the preparation of a medicament for
lowering intraocular pressure, inhibiting cholesterol
synthesis, and for the treatment of: benign prostatic
hyperplasia, impotency, cardiac arrhythmia and any
disease where antagonism of the alA receptor may be
useful. The invention provides for the use of the
compounds described herein in the preparation of a
medicament for relaxing lower urinary tract tissue and
in particular prostatic smooth muscle. The invention
further provides for the use of any of compounds
described herein in the preparation of a medicament,
where the compound additionally does not cause a fall in
blood pressure at dosages effective to lower intraocular
pressure, to inhibit cholesterol synthesis, and for the
treatment of: benign prostatic hyperplasia, impotency,
cardiac arrhythmia and any disease where antagonism of
the alA receptor may be useful.
The invention provides a drug which is useful for
lowering intraocular pressure, inhibiting cholesterol
synthesis, and the treatment of: benign prostatic
hyperplasia, impotency, cardiac arrhythmia and any
disease where antagonism of the alA receptor may be
useful, the effective ingredient of the said drug being
any of the compounds described herein. The invention
further provides the drug described herein additionally
does not cause a fall in blood pressure at dosages
effective to lower intraocular pressure, to inhibit
cholesterol synthesis, and for the treatment of: benign
prostatic hyperplasia, impotency, cardiac arrhythiziia acid
any disease where antagonism of the alA receptor may be
useful.
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The invention provides a drug which is useful for
relaxing lower urinary tract tissue and in particular
prostatic smooth muscle, the effective ingredient of the
drug being any of the compounds described herein. The
invention further provides a drug which is useful for
relaxing lower urinary tract tissue additionally does
not cause a fall in blood pressure at dosages effective
to relax lower urinary tract tissue.
In the preceding methods the compound may be
administered orally in the form of a sterile solution or
suspension containing other solutes or suspending
agents, for example, enough saline or glucose to make
the solution isotonic, bile salts, acacia, gelatin,
sorbitan monoleate, polysorbate 80 (oleate esters of
sorbitol and its anhydrides copolymerized with ethylene
oxide) and the like.
The compound may also be administered orally either in
liquid or solid composition form. Compositions suitable
for oral administration include solid forms, such as
pills, capsules, granules, tablets, and powders, and
liquid forms, such as solutions, syrups, elixirs, and
suspensions. Forms useful for parenteral administration
include sterile solutions, emulsions, and suspensions.
Optimal dosages to be administered may be determined by
those skilled in the art, and will vary with the
particular compound in use, the strength of.the
preparation, the mode of administration, and the
advancement of the disease condition. Additional
factors depending on the particular subject being
treated will result in a need to adjust dosages,
including subject age, weight, gender, diet, and time of
administration.
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In the practice of this invention, the term "lower
urinary tract tissue" is used to include prostatic
capsule, prostate urethra, and bladder neck.
One skilled in the art will readily appreciate
that appropriate biological assays will be used to
determine the therapeutic potential of the claimed
compounds for the treating the above noted disorders.
This invention will be better understood from the
Experimental Details which follow. However, one skilled
in the art will readily appreciate that the specific
methods and results discussed are merely illustrative of
the invention as described more fully in the claims
which follow thereafter.
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Experimental Details
Example 1: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-(3',4',5',6'-tetrahydro-2'H-
(2,4']bipyridinyl-1'-yl)-propyl~-amide (Schemes 5 and 6)
It is a typical procedure for the synthesis of
oxazolidinone compounds which are described below.
METHOD A:
a. Amino-(3,4-difluorophenyl)-acetonitrile
Through a solution of 3,4-difluorobenzaldehyde (25.0 g,
0.18 mol) in MeOH (500 mL)in a round bottom flask, was
bubbled ammonia gas for two hours at room teperature. The
flask was then cooled to 0°C and trimethylsilyl cyanide
(1.3 eq., 0.23 mmol) was then added slowly. The reaction
mixture was stirred for 2 h when TLC analysis indicated
that the reaction was complete (Rf - 0.35, 3:2
hexane/EtOAc). Solvent was removed in vacuo and the
residue was subjected to flash column chromatography on
silica gel to obtain 25.0 g (81~) of amino-(3,4-
difluorophenyl)-acetonitrile as a yellow syrup.
b. Amino-(3,4-difluorophan~-1)--acetic acid methyl ester
To a well stirred solution of amino-(3,4-difluorophenyl)-
acetonitrile (22.0 g, 0.130 mol), a solution of HC1 in
MeOH(200 mL) was added at room temperature. The resulting
yellow solution was stirred at room temperature for 10 h
and then heated to reflux for 1.5 h. After cooling, the
solvent was removed in vacuo and the resulting yellow
solid was dissolved in water (200 mL). The aqueous
solution was then carefully basified with 20~ NaOH
solution to pH 9. The aqueous layer was extracted with
CHzCl2 (3 x 100 mL). The organic layer was separated and
dried over Na2S04, filtered and the solvent was removed in
vacuo to obtain 22.2 g (84~)oF amino-(3,4-difluorophenyl)-
acetic acid methyl ester as a brownish yellow liquid. It
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was used in the next step without purification.
c. 2-Amino-2-(3,4-difluorophenyl)-ethanol
To a well stirred suspension of LiAlH4 (4.7 g, 0.125 mol)
in THF (120 mL) in a 3-necked round bottom flask fitted
with a condenser and a dropping funnel, was added a
solution of amino-(3,4-difluorophenyl)-acetic acid methyl
ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0°C.
The.resulting greenish brown suspension was then heated to
reflux for 2 h. The reaction mixture was cooled to 0°C
and then carefully quenched sequentially with 5 mL of
water, 5 mL of 3N NaOH followed by 15 mL of water. The
resulting suspension was filtered through a fritted glass
funnel. To the residue was added 100 mL EtzO and the
suspension was heated to reflux for 20 min. The
suspension was filtered and was combined with the previous
filtrate, dried over MgS09, filtered and the solvent was
removed in vacuo. 2-amino-2-(3,4-difluorophenyl)-ethanol
was obtained as a yellow glassy syrup (8.6 g, 99~) which
was used in the next step without further purification.
METHOD B' Synthesis of 2-amino-2-l3 4-difluorophenvl)-
ethanol by different route. (Scheme 6)
a. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone
To a solution of KOH (56 g, 1.0 mol) in ~~IeOH (500 mL)
was added 3,4-difluoroacetophenone (15.6 g, 0.1 mol)
dropwise over 15 min at 0°C. Phenyliodosodiacetate (64.4
g, 0.2 mol) was added in small portions over 20 min
period and the resulting yello-orange solution was
stirred overnight at room temperature. The solvent was
removed in vacuo to obtain yellow-orange gum. The
residue was dissolved in 100 mL of water and 100 mL of
brine and was thoroughly extracted with ethyl acetate (3
X 150 mL). The organic layer was dried over NazS04 and
was decanted. The solvent was removed in vacuo to obtain
31.0 g of the acetal as thick yellow oil. It was
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dissolved in 200 mL of acetone and about 10 drops of
conc. sulfuric acid. The reaction mixture was stirred at
room temperature for 2 h till tlc analysis showed
complete cosumption of the starting material. The
solvent was removed in vacuo and the solid that was
obtained was basified by adding sat. NaHC03 solution and
then it was extracted with ethyl acetate (300 mL). The
organic layer was separated and washed with brine. The
organic layer was dried over MgS09, filtered and the
solvent was removed in vacuo to obtain yellow solid. The
yellow solid was washed with cold hexane ( to remove
iodobenzene impurities) and dried to obtain 11.4 g (66~
yield) of 1-hydroxy-(3,4-difluorophenyl)-acetophenone as
pale yellow solid. The product was shown to be > 90~
pure by NMR and was used in the next step without
further purification.
b. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone oxime
To a solution of 1-hydroxy-(3,4-difluorophenyl)-
acetophenone (6.0 g, 34.9 mmol) in 150 mL of MeOH was
added hydroxylamine hydrochloride (3.16 g, 45.6 mmol)
and sodium acetate (~9.6 g, 69.6 mmol) at room
temperature and the resulting solution was stirred
overnight. The solvent was removed and the residue was
dissolved in methylene chloride (150 mL) and was washed
with 100 mL of sat. NaHC03 solution followed by brine.
The organic layer was separated and dried over MgS04,
filtered and the solvent was removed in vacuo to obtain
1-hydroxy-(3,4-difluorophenyl)-acetophenone-oxime as a
yellow solid (5.6 g, 86~). It was used in the next step
without any purification.
c. Z-Amino-2-(3,4-difluorophenyl)-ethanol
To a well stirred suspension of LiAlH9 (3.4 g, 89.5
mmol ) in THF ( 12 0 n~L j in a 3 -necked round bottom f lask.
fitted with a condenser and a dropping funnel, was added
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a solution of 1-hydroxy-(3,4-difluorophenyl)-
acetophenone-oxime (4.6 g, 24.6 mmol) in THF (50 mL)
dropwise at 0°C. The resulting greyish yellow
suspension was then heated to reflux for 2 h. The
reaction mixture was cooled to 0°C and then carefully
quenched sequentially with 3.4 mL of water, 3.4 mL of 3N
NaOH followed by 10 mL of water. The resulting
suspension was filtered thro' a fritted glass funnel.
To the residue was added 100 mL Et20 and the suspension
was heated to reflux for 20 min. The suspension was
filtered and was combined with the previous filtrate,
dried over MgS04, filtered and the solvent was removed
in vacuo. 2-Amino-2-(3,4-difluorophenyl)-ethanol was
obtained as a yellow glassy syrup (4.1 g, 960) which was
used in the next step without further purification.
d. [1-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic
acid-tart-butyl ester
To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol
(8.6 g, 49.7 mmol) in CHC13 (150 mL) at 0°C was added a
solution of di-tart-butyl Bicarbonate (11.4 g, 52.0
mmol) in CHC13 (50 mL) in one portion and the resulting
solution was stirred overnight at room temperature. The
solvent was removed in vacuo and the residue was
subjected to column chromatography on silica gel (2:1
hexane-EtOAc followed by EtOAc) to obtain [1-(3,4-
difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-
butyl ester as white solid (10.0 g,74~).
e. (+)-4-(3,4-Difluorophenyl)-oxazolidin-2-one
To a well stirred suspension of NaH (1.1 g, 45.8 mmol)
in THF (40 mL) at room temperature was added a solution
of [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic
acid-tart-butyl ester (5.0 g, 18.3 mmol) in THF 20 mL
via a dropping funnel at room temperature. 'rhe
resulting suspension was stirred for 3 h and then
quenched carefully with 10 mL of water. The biphasic
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mixture was extracted with 200 mL of Et20, washed with
brine, filtered and the solvent was removed in vacuo.
The gummy residue thus obtained was purified by column
chromatography over silica gel (Rf = 0.15, 3:2 hexane-
EtOAc) to obtain (+)-4-(3,4-difluorophenyl)-oxazolidin-
2-one as a white flaky solid (2.8 g, 77~). The
enantiomers were separated by using Chiralcel OD (4.6 x
250 mm) using 80~ hexane/20~ isopropyl alcohol/ 0.1
~Diethylamine as the eluting system under isothermal
conditions (U.V. 254 nM). The retention times for the
two isomers were 16.19 min and 20.08 min respectively.
First isomer:[a]D = + 62.9 (c = 0.67, acetone); Anal.
Calcd. for C9H~NOzF2: C, 54.28; H, 3.54; N, 7.03. Found:
C, 54.16; H, 3.44; N, 6.96. Second isomer:[a]D = - 56.9
(c = 0.75, acetone) ; Anal. Calcd. for C9H.,NOzFz: C,
54.28; H, 3.54; N, 7.03. Found: C, 54.31; H, 3.46; N,
6.98. The first isomer was used in the next step.
f. 4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic
acid-4-aitro-phenyl ester
To a suspension of NaH (0.14 g, 5.30 mmol) in 20 mL of
anhydrous THF under argon, a solution of (+)-4-(3,4-
difluorophenyl)-oxazolidin-2-one (0.88 g, 4.42 mmol) in
THF was added dropwise via an dropping funnel. The
resulting suspension was stirred at room temperature for
30 min. This suspension was then added dropwise via
cannula into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (1.11 g, 5.30
mmol) in 25 mL of THF and cooled at -78°C over a period
of 15 min. The stirring was continued for 2 h after
which the solvent was removed and the residue was
purified by column chromatography on silica gel with
1:1 hexane/CHZClZ followed by CHzClz (Rf= 0.4, CHZC12) to
obtain 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid-4-nitro-phenyl ester as a white solid
(1.558, 86~).
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g. 3-Amino -propyl-4-pyridyl-piperidine
1-(3-Aminopropyl)-4-(pyrid-2-yl)pyridinium bromide
hydrobromide
Method A: A solution of 2,4'-dipyridyl {5.0 g, 32.0
mmol) and 3-bromopropylamine hydrobromide (7.0 g, 32.0
mmol) in DMF (50.0 mL) and acetonitrile (50.0 mL) was
heated at 90-95°C for 1 h. After cooling, the white
solid that came out was filtered, washed with EtzO and
dried. The mother liquor was concentrated to remove
EtzO and then heated to 90-95°C for 4 h. The solvent
was evaporated and the white residue was triturated with
Et20 (100.0 mL) and filtered. The combined weight of
the salt was 11.6 g {97~).
Method B: A well-stirred solution of 2,4'-dipyridyl
(12.8 g, 0.08 mol) and N-tert-butoxycarbonyl-3-bromo-
propylamine {21.3 g, 0.09 mol) in acetonitrile {40.0 mL)
was heated to reflux for 6 h. The reactior~ mixture was
cooled to room temperature and filtered. The white
solid thus obtained was washed with acetone (2 x 20.0
mL) and chloroform (2 x 20.0 mL) to yield 10.9 g as the
first crop. Anal. Calcd. for C13H1sN3Br.HBrØ5 H20: C,
40.65; H, 4.72; N, 10.94. Found: C, 40.83; H, 4.37; N,
11.05.
3-(3',6'-Dihydro-2'-H-[2;4']bipyridinyl-1'-yl)-
propylamiae
To a solution of 1-(3-aminopropyl)-4-[pyrid-2-
yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol)
in 20.0 mL MeOH was added NaBH4 (0.101 g, 2.62 mmol) in
small portions. The reaction mixture was stirred for 30
min and then quenched with 6M HC1 solution. The
solution was concentrated to 20.0 mL and basified with
50~ NaOH solution to pH 12. Extracted with CHC13 (5 x
30.U mL), dried over MgS04 and the solvent was removed
to give 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-
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propylamine as an oil (0.37 g, 96~ yield). It is used
in the next step immediately without purification.
3-(3',4',5',6'-Tetrahydro-2'-H-[2,4']bipyridinyl-1'-yl)-
propylamine
To a solution of 3-(3',6'-Dihydro-2'-H-
[2,4')bipyridinyl-1'-yl)-propylamine (3.48 g crude, 15.9
mmol) in MeOH (40 mL), was added 1.0 g of Pearlman's
catalyst. The suspension was hydrogenated under 120 psi
for 10 h after which the reaction mixture was filtered
thro' a pad of celite and the solvent was removed. The
residue was purified by column chromatography over
silica gel using CHZC12/methanol/2M NH3 in MeOH (90:8:4
to 90:40:40) as the eluting system. The product was
obtained as a pale yellow oil (3.21 g, 91~).
3-(3',4',5',6'-Tetrahydro-2'-H-[2,4']bipyridinyl-1'-yl)-
propylamine
To a solution of 1-(3-aminopropyl)-4-[pyrid-2-
yl]pyridinium bromide hydrobromide (0.53 g) 10.0 mL of
2M NH3 in MeOH was added PtOz (0.1 g) and the reaction
mixture was hydrogenated at 110 psi for 6 h and then at
130 psi for 12 h. The catalyst was removed via
filtration thro' a pad of celite, washed with MeOH and
the solvent was removed. The NMR showed it to be the
required product although the accurate weight of the
product was not determined due to the presence of
ammonium bromide generated during the course of the
reaction.
h. (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [3-(3',4',5',6'-tetrahydro-2'H-
[2,4']bipyridinyl-1'-y1)-propyl]-amide
To a solution of 3-amino-propyl-4-pyridyl piperidine
(1.1 g, 5.1 mmol) in 100 mL of THF 4-(3,4-
ditluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-
nitro-phenyl ester (1.55 g, 4.24 mmol) was added and the
resulting yellow solution was stirred under argon
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atmosphere for 10 h at room temperature. The solvent
was removed in vacuo and the residue was purified by
column chromatography over silica gel with EtOAC
followed by 15o MeOH in EtOAC as the eluting systems (Rf
- 0.4, 1:1 MeOH/EtOAC) to obtain a pale yellow glassy
oil. It was dissolved in EtOAc (150 mL) and washed
throughly with 5~ KOH solution (4 x 25 mL) in order to
remove traces of 4-nitrophenol in the product. . The
organic layer was separated, washed with brine (25 mL)
and then dried over Na2S04. The solvent was removed and
4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic
acid [3-(3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-
1'-yl)-propyl]-amide was obtained as a colorless glassy
oil(1.55 g, 82~) which develops some brownish color
after 2 h.
To a solution of 4-(3,4-Difluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid [3-(3',4',5',6'-
tetrahydro-2'H-(2,4']bipyridinyl-1'-yl)-propyl]-amide
(1.53 g, 3.45 mmol) in 10.0 mL of anhydrous EtOH was
added a warm solution of 95~ fumaric acid (0.48 g, 4.06
mmol) in 8.0 mL EtOH and the resulting solution was kept
under a gentle stream of argon for 30 min. Hexane (5 x
1.0 mL) was added over 2 h and the solution was kept
under argon atmosphere overnight. Pale yellowish-white
small crystals thus obtained were filtered, washed
successively with EtOH (10.0 mL) and hexane (10.0 mL).
The crystals were pulverized and dried under vacuum at
40°C. The white non-hygroscopic powder (1.6 g, 84~) was
found out to be the monofumarate salt after NMR and
elemental analysis as shown below. M.P. 142-144°C; [a]D
- + 47.4 (c = 0.52, MeOH); Anal. Calcd. for
Cz.,H3aN407Fz.HzO: C, 56.05; H, 5.57; N, 9.68. Found: C,
56.18; H, 5.51; N, 9.54.
Example 2: 4-(3,4-Difluorophenyl)-3-(5-(4-(2-methoxy-
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phenyl)-piperazin-1-yl]-pentyl)-oxazolidin-2-one
a. 4-(3,4-Difluorophenyl)-1-(5-bromopentyl)
oxazolidinone
To a stirred suspension of sodium hydride (203 mg, 8.04
mmol) in THF(5 mL) at 0°C under argon, was added a
solution of 4-(3,4-difluorophenyl)oxazolidinone (800 mg,
4.02 mmol) in the mixed solvent of THF(4 ml) and
HMPA(0.7 ml, 4.02 mmol) and stirred for 30 min. To this
1,5-dibromopentane (2.17 ml, 16 mmol) was added and the
mixture was heated to reflux for 70 min, after which the
reaction mixture was cooled to room temperature and the
solvent was removed in vacuo. The residue was purified
by column chromatography over silica gel with CHzCl2
followed by 5~ EtOAc in CHzClz as the eluting system (Rf
- 0.72, CH2C12:Et0Ac = 3:1) to obtain 4-(3,4-
difluorophenyl)-1-(5-bromopentyl) oxazolidinone as a
brown liquid (0.70 g, 50~).
b. 4-(3,4-Difluorophenyl)-3-~5-~4-(2-methoxy-phenyl)-
piperazin-1-yl]-pentyl)-oxazolidin-2-one
To a solution of 4-(3,4-difluorophenyl)-1-(5--
bromopentyl) oxazolidinone (60 mg, 0.17 mmol) in 1,5-
dioxane (20 ml) at room temperature, were added 1-(2-
methoxyphenyl)-piperazine (33.8 mg, 0.17 mmol) and KzC03
(23.8 mg, 0.52 mmol). The resulting mixture was heated
to reflux for 12 h after which the reaction mixture was
cooled to room temperature and the solvent was removed
in vacuo. The residue was dissolved in water and
extracted with CHzCl2 ( 2 X 3 0 ml ) , dried over NazSOA . The
solvent was then removed in vacuo and the residue was
purified by column chromatography over silica gel with
EtOAc followed by 5~ MeOH in EtOAc as the eluting system
(Rf = 0.24, MeOH:EtOAc = 1:8) to obtain 4-(3,4-
difluorophenyl)-3-{5-[4-(2-methoxy-phenyl)-piperazin-1-
yl]-pentyl}-oxazolidin-2-one as a brown oil (69 mg,
88~). The compound was dissolved in CHZCI2 (3 mL) and
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was treated with 1N HC1 in ether (1 mL). The solvent
was removed in vacuo to give the corresponding
hydrochloride salt as a yellow solid. M.P. 174-178°C;
Anal . Calcd. For Cz5H33N3O3FzClz ~ 0 . 65 CHzCl2: C, 52 . 43 ; H,
5.88; N, 7.15. Found: C, 52.12; H, 6.36; N, 6.84.
Example 3: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid ~3-[4-(5-bromo-2-methoxy-phenyl)-4-
phenyl-piperidin-1-yl]-propyl)-amide
a. 4-(5-bromo-2-methoxy)-phenyl-4-phenyl-piperidine
hydrochloride
To a 100 mL round bottom flask equipped with a rubber
septum and a stirring bar was added 4-hydroxy-4-phenyl-
piperidine (5 g, 30.0 mmol) followed by 30 mL of 4-
bromoanisole. The resulting solution was stirred at room
temperature under argon atmosphere and then A1C13 (8.0
g, 60.0 mmol) was added in one portion. An exotherm was
observed. The reaction mixture was stiired for 8 h
(brownish green color), then poured carefully over 600
ml of ice-water and stirred for 10 h. The white
suspension was diluted with 100 mL of diethyl ether. The
white solid that precipitated out was filtered and
washed thoroughly with water (600 mL) followed by
diethyl ether (500 mL) to obtain 4-(5-bromo-2-methoxy)-
phenyl-4-phenyl-piperidine hydrochloride as a greyish
white solid (6.0 g, 52~).
b. 3-[4-(5-bromo-2-methoxy)phenyl-4-phenyl-piperidin-1-
yl]propylamine
To a solution of 4-(5-bromo-2-methoxy)-phenyl-4-phenyl-
piperidine hydrochloride (2.5 g, 6.3 mmol) in 100 mL
dioxane was added 3-bromo-N-tert-butoxycarbonyl-
propylamine (2.25 g, 9.4 mmol) and KZC03 (3.48 g, 25.2
mmol) and the resulting suspension was heated to reflex
f or 10 h. The suspension was allowed to cool, filtered
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and the solvent was evaporated to obtain yellow residue
which was purified by column chromatography (Rf = 0.4,
3:1 EtOAc/MeOH) to obtain 3-[4-(5-bromo-2-
methoxy)phenyl-4-phenyl-piperidin-1-yl]-N-tert-
butoxycarbonyl-propylamine as a yellow oil (3.15 g). It
was dissolved in 35 mL of CHZC12 and 6.0 mL of
trifluoroacetic acid was added with stirring at room
temperature under argon atmosphere. After 1 h the
solvent was evaporated in vacuo and the residue was
basified to pH 10 by adding minimum amount of 1 N KOH
solution. The product was extracted with CHZC12 (3 X 35
mL), dried over MgS04, filtered and the solvent was
removed in vacuo to obtain 3-[4-(5-bromo-2-
methoxy)phenyl-4-phenyl-piperidin-1-yl]propylamine as a
viscous yellow oil (2.26 g, 89~ for two steps). It was
used in the next step without further purification. The
above mentioned steps a and b are representative
examples of synthesis of all the 4,4-diaryl piperidine
containing side chains described in this document.
c. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid ~3-[4-(5-bromo-2-methoxy-phenyl)-4-
phenyl-piperidin-1-yl~-propyl)-amide
To a solution of 3-amino-propyl-4-(5-bromo-2-
methoxy)phenyl-4-phenyl piperidine (2.0 g, 4.96 mmol) in
100 mL of THF was added 4-(3,4-difluorophenyl)-2-oxo-
oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (1.81
g, 4.96 mmol) and the resulting yellow solution was
stirred under argon atmosphere for 3 h at room
temperature. The solvent was removed in vacuo and the
residue was purified by column chromatography over
silica gel with 50~ hexane/EtOAC followed by 5~ MeOH in
EtOAC as the eluting systems (Rf = 0.4, 2:3 MeOH/EtOAC)
to obtain the product as white foam (wt= 2.2 g). It was
dissolved in EtOAc (150 mL) and washed throughly with 5~
NaOH solution (4 x 25 mL) in order to remove traces of
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4-nitrophenol from the product. The organic layer was
separated, washed with brine (25 mL) and then dried over
Na2S09. The solvent was removed after filtration and
(+)-1-{3-{3,4-difluorophenyl)-2-oxo-oxazolidine-3-
carbonyl)-amino-propyl}(5-bromo-2-methoxy)phenyl-4-
phenyl-piperidine was obtained as a colorless glassy
oil(1.84 g, 60~). [a]D = + 34.3 (c = 0.3, MeOH); The
compound was dissolved in CHC13 (10 mL) and was treated
with 1N HC1 in ether (5 mL). The solvent was removed in
vacuo to give the corresponding hydrochloride salt as a
white solid {2.0 g). M.P. 142-144°C; Anal. Calcd. for
C31H33N4~4BrClFz . 0 . 3 CHC13 : C, 53 . 65 ; H, 4 . 79 ; N, 6 . 00 .
Found: C, 53.89; H, 4.73; N, 5.74.
Example 4: 1-{3-((2-Oxo-4-phenyl-(1,3]oxazinane-3-
carbonyl)-amino-propyl}-4-phenyl-piperidine-4-carboxylic
acid methyl ester (Scheme 7)
a. 3-Amino-3-phenyl-propan-1-of
To a well stirred suspension of LiAlH4 (1.3 g, 35.0
mmol) in THF (75 mL) in a round bottom flask fitted with
a condenser was added 3-amino-3-phenyl-propionic acid
(2.5 g, 15.0 mmol) in small portions at 0°C. The
resulting grey suspension was then heated to reflux for
2 h. The reaction mixture was cooled to 0°C and then
carefully quenched sequentially with 1.3 mL of water,
1.3 mL of 3N NaOH followed by 4.0 mL of water. The
resulting suspension was filtered thro' a fritted glass
funnel. To the residue was added 100 mL Et20 and the
suspension was heated to reflux for 20 min. The
suspension was filtered and was combined with the
previous filtrate, dried over MgS04, filtered and the
solvent was removed in vacuo. 3-amino-3-phenyl-propan-1-
ol was obtained as a white solid (2.30 g, 1000 which
was used in the next step without further purification.
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b. (3-8ydroxy-1-phenyl-propyl)-carbamic acid-tart-butyl
ester
To a solution of 3-amino-3-phenyl-propan-1-of (2.30 g,
15.0 mmol) in CHC13 (50 mL) at 0°C was added a solution
of di-tart-butyl dicarbonate (3.75 g, 17.1 mmol) in
CHC13 (25 mL) in one portion and the resulting solution
was stirred overnight at room temperature. The solvent
was removed in vacuo and the residue was subjected to
column chromatography on silica gel (2:1 hexane-EtOAc
followed by EtOAc) to obtain (3-hydroxy-1-phenyl-
propyl)-carbamic acid-tent-butyl ester as white solid
( 4 . 0 g, 1000 .
c. 4-Phenyl-oxazinan-2-one
To a well stirred suspension of 95~ NaH (0.24 g, 10.0
mmol) in THF (20 mL) at r.t. was added a solution of (3-
hydroxy-1-phenyl-propyl)-carbamic acid-tart-butyl ester
(1.0 g, 4.0 mmol) in 10 mL THF via a dropping funnel at
room temperature. The resulting suspension was stirred
for 3 h and then quenched carefully with 10 mL of water.
The biphasic mixture was extracted with 100 mL of Et20,
washed with brine, filtered and the solvent was removed
in vacuo. The gummy residue thus obtained was purified
by column chromatography over silica gel (Rf = 0.2, 3:2
hexane-EtOAc) to obtain 4-phenyl-oxazinan-2-one as a
white flaky solid (0.44 g, 62~).
d. 2-Oxo-4-phenyl-[1,3]-oxazinane-3-carboxylic acid-4-
nitro-phenyl ester
To a suspension of NaH (0.07 g, 2.78 mmol) in 10 mL of
anhydrous THF under argon, a solution of 4-phenyl-
oxazinan-2-one (0.41 g, 2.31 mmol) in THF was added
dropwise via an dropping funnel. The resulting
suspension was stirred at room temperature for 30 min.
This suspension was tluen added dropwise via cannula into
another round bottom flask containing a solution of 4-
nitrophenylchloroformate (0.60 g, 3.0 mmol) in 20 mL of
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THF and cooled at -78°C over a period of 15 min. The
stirring was continued for 2 h after which the solvent
was removed and the residue was purified by column
chromatography on silica gel with 1:1 hexane/CHZCIz
followed by CHzClz (Rf= 0.4, CHZCIz) to obtain 2-oxo-4-
phenyl-[1,3]-oxazinane-3-carboxylic acid-4-nitro-phenyl
ester as a white solid (0.65 g, 82~).
e. 1-~3-[(2-Oxo-4-phenyl-[1,3)oxazinane-3-carbonyl)-
amino-propyl}-4-phenyl-piperidine-4-carboxylic acid
methyl ester
To a solution of 3-amino-propyl-(4-carbomethoxy-4-
phenyl) piperidine (55 mg, 0.20 mmol) in 5 mL of THF, 2-
oxo-4-phenyl-[1,3]-oxazinane-3-carboxylic acid-4-nitro-
phenyl ester(51 mg, 0.15 mmol) was added and the
resulting yellow solution was stirred under argon
atmosphere for 10 h at room temperature. The solvent
was removed in vacuo and the residue was purified by
column chromatography over silica gel with EtOAC
followed by 15~ MeOH in EtOAC as the eluting systems (Rf
- 0.4, i:1 MeOH/EtOAC) to obtain 2-oxo-4-phenyl-[1,3]-
oxazinane-3-carboxylic acid-3-(4-carbomethoxy-4-phenyl)-
piperidin-1-yl]-propyl amide as a pale yellow glassy oil
(35 mg, 49~ yield). It was converted into hydrochloride
salt for characterization. Hygroscopic yellow solid.
Anal. Calcd. for CZ~H39N3OSC1.2.5 H20: C, 57.80; H, 7.01;
N, 7.49. Found: C, 57.98; H, 6.68; N, 6.86.
Example 5: 4-(3,5-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [3-(3~,4~,5~,6~-tetrahydro-2~H-
[2,4~~bipyridinyl-1~-yl)-propyl]-ester
a. 1-(3-hydroxypropyl)-4-[pyrid-2-yl]pyridinium bromide.
A solution of 2,4'-dipyridyl (3.0 g, 18.6 mmol) and 3-
bromo-1-propanol (2.02 ml, 22.4 mnlUl) in ace-conitrile
(100 mL) was heated to reflux for 2 days. After
cooling, the solvent was removed in vacuo and the
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yellow-brown liquid (8.0 g) was directly used for next
step without further purification.
b. 3-(3',6'-Dihydro-2'-H-(2,4'~bipyridinyl-1'-yl)-
propanol.
To a solution of 1-(3-hydroxypropyl)-4-[pyrid-2-
yl]pyridinium bromide (8 g) in 100 mL EtOH was added
NaBH4 (1.41 g, 37.2 mmol) in small portions. The
reaction mixture was stirred at room temperature for 12
h and then quenched with drops of water. The solvent was
removed in vacuo and the residue was purified by column
chromatography over silica gel with 1:4 MeOH/EtOAc
followed by 2:4 (2M NH3 in MeOH) /EtOAc as the eluting
system (Rf = 0.6, (2M NH3 in MeOH) /EtOAc = 1:4) to
obtain 3-(3',6'-dihydro-2'-H-[2,4')bipyridinyl-1'-yl)-
propanol as an oil (1.58 g, 39~ over two steps).
c. 3-hydroxy-propyl-4-pyridyl-piperidine.
To a solution of 3-(3',6'-dihydro-2'-H-
[2,4']bipyridinyl-1'-yl)-propanol (1.30 g, 5.93 mmol) in
mixed solvent (40 mL) of MeOH and 2N Hcl (1:1), was
added 0.5 g of Pearlman's catalyst. The suspension was
hydrogenated under 80 psi at 50~C for 10 h after which
the reaction mixture was_filtered through a pad of
celite and the solvent was removed. The residue was
basified by 20~ NaOH and extracted by CHClj (7 X 40 ml),
dried over NazS04. The solvent was removed in vacuo to
obtain a brown oil (785 mg, 60~).
d. 4-(3,5-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [3-(3',4',5',6'-tetrahydro-2'H-
L2,4'~bipyridinyl-1'-yl)-propyl]-ester
To a solution of 4-(3,5-difluorobenzyl)-2-oxo-
oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (50
mg, 0.137 mmol) in 1,6-dioxane (20 ml) at room
temperature, were added 3-hydroxy-propyl-4-pyridyl-
piperidine (30 mg, 0.136 mmol) and KzC03 (23.8 mg, 0.52
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mmol). The resulting mixture was heated to reflux for 12
h after which the reaction mixture was cooled to room
temperature and the solvent was removed in vacuo. The
residue was purified by column chromatography over
silica gel with EtOAc followed by 15~ MeOH in EtOAc as
the eluting system (Rf = 0.30, MeOH:EtOAc = 1:1) to
obtain 4-(3,5-difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [3-(3',4',5',6'-tetrahydro-2'H-.
[2,4']bipyridinyl-1'-yl)-propyl]-ester (20 mg, 33~).
The compound was dissolved in anhydrous EtOH (1 mL) and
was treated with a warm solution of 95~ fumaric acid
(5.3 mg, 0.045 mmol) in EtOH (3 ml). The resulting
solution was kept under gentle stream of argon for 30
min after which hexane (2 ml) was added over lh and the
solution was kept under argon overnight. Grey small
crystals thus obtained were filtered, washed with EtOH
(1 ml) and hexane (1 ml) and dried under vacuum. M.P.
171-173°C; Anal. Calcd. For Cz~Hz9N308Fz ~ 0 .27CHC13: C,
55.16; H, 4.97; N, 7.08. Found: C, 55.17; H, 4.98; N,
6.53.
Example f: 2-Oxo-4-(3,4,5-trifluoro-phenyl)-oxazolidine-
3-carboxylic acidt3-[4-(2-carbamoyl-phenyl)-piperazin-1-
yl]-propyl}-amide
a. 2-L4-(3-amino-propyl)-piperazin-1-yl]-benzamide
Concentrated sulfuric acid (15 mL) was added to 1-(2-
cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a
round bottom flask and. the resulting slurry was stirred
at room temperature for 48 h. The reaction mixture was
poured on crushed ice very slowly and then basified (pH
9) with 50~ solution of NaOH. The aqueous layer was
extracted several times with EtOAc, dried over KZC03,
filtered and the solvent was evaporated. 1-(2-
carboxamidophenyl)piperazine was obtained as an off-
white solid (1.2 g, 73~). It was used in the next step
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without further purification.
b. 2-Oxo-4-(3,4,5-trifluoro-phenyl)-oxazolidine-3-
carboxylic acid{3-[4-(2-carbamoyl-phenyl)-piperazin-1-
yl~-propyl~-amide
To a solution of 1-(3-amino-propyl)-4-(2-carboxamido)-
phenyl-piperazine (100 mg, 0.38 mmol) in 10 mL of THF,
4-(3,4,5-trifluorophenyl)-2-oxo-oxazolidine-3-carboxylic
acid-4-nitro-phenyl ester(130 mg, 0.34 mmol) was added
and the resulting yellow solution was stirred under
argon atmosphere for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.64,
MeOH/EtOAc=1:3 ) to obtain (+)-1-{3-{3,4,5-
trifluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{3-
[4-(2-carbomoyl-phenyl)-piperazin-1-yl]-propyl}-amide
(135 mg, 79~). The compound was dissolved in CHZC12 (3
mL) and was treated with 1N HC1 in ether (1 mL). The
solvent was removed in vacuo to give the corresponding
hydrochloride salt as a yellow solid. M. P. 164-168°C;
[a]fl = +50.5, (c = 0:28, MeOH); Anal. Calcd. For
C24H28NSO4F3C12' 0.25 CHC13: C, 47 .89; H, 4.68; N, 11.51.
Found: C, 48.18; H, 5.03; N, 11.14.
Example 7: 2-[4-(3-~[4-(3,5-Difluoro-phenyl)-2-oxo-
oxazolidine-3-carbonyl]-amino}-propyl)-piperazin-1-yl]-
benzoic acid methyl ester (Schemes 1 and 5)
a. 1-(2-Carbomethoxyphenyl)-piperazine
To a solution of methyl 2-bromobenzoate (1.63 g, 17.8
mmol) in 1,4-dioxane (100 ml) at room temperature, were
added piperazine (15.3 g, 178 mmol) and KZC03 (4.92 g,
mmol). The resulting mixture was heated to reflux for
7 days after which the reaction mixture was cooled to
room temperature and the solvent and the excess
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piperazine were removed in vacuo and heating with a hot
water bath. The residue was dissolved in 1N NaOH
solution and extracted with CHzClz (6 X 30 m1), dried
over Na2S04. The solvent was removed in vacuo to obtain
1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0
g, 26~).
b. 2-[4-(3-~[4-(3,5-Difluoro-phenyl)-2-oxo-oxazolidine-
3-carbonyl]-amino?-propyl)-piperazin-1-yl]-benzoic acid
methyl ester
To a solution of 1-(3-amino-propyl)-4-(2-
carbomethoxyphenyl)-piperazine (25 mg, 0.090 mmol) in 10
mL of THF, 4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid-4-nitro-phenyl ester(30 mg, 0.082 mmol)
was added and the resulting yellow solution was stirred
under argon atmosphere for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.75,
MeOH/EtOAc=1:3 ) to obtain 2-[4-(3-{[4-(3,5-difluoro-
phenyl)-2-oxo-oxazolidine-3-carbonyl]-amino}-propyl)-
piperazin-1-yl]-benzoic acid methyl ester (31 mg, 69~).
The compound was dissolved in CHzCl2 (3 mL) and was
treated with 1N HC1 in ether (1 mL). The solvent was
removed in vacuo to give the corresponding hydrochloride
salt as a yellow solid. M. P. 93-96°C; [a]D = +45.3, (c
- 0 .29, MeOH) ; Anal . Calcd. For CZSH3oN9OSF2CIz ~ 0 . 58 CHZC12:
C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56;
N,8.91.
Example 8: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [4-(4-phenyl-piperidin-1-yl)-butyl]-
amide
To a solution of 1-(4-amino-butyl)-4-phenyl-piperidine
(35 mg, 0.151 mmol) in 10 mL of THF, 4-(3,5-
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difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-
nitro-phenyl ester(40 mg, 0.110 mmol) was added and the
resulting yellow solution was stirred under argon
atmosphere for 2 h at room temperature. The solvent was
removed in vacuo and the residue was purified by column
chromatography over silica gel with 1:1 hexane/EtOAc
followed by 1:19 MeOH/EtOAc (Rf= 0.33, MeOH/EtOAc=1:3 )
to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [4-(4-phenyl-piperidin-1-yl)-butyl]-
amide (42 mg, 83~). The compound was dissolved in CHZC12
(3 mL) and was treated with 1N HC1 in ether (1 mL). The
solvent was removed in vacuo to give the corresponding
hydrochloride salt as a yellow solid. M.P. 80-84°C;
Anal . Calcd. For Cz5H3oN303FzCl ~ 0 . 5 CHZC12 : C, 57 . 09; H,
5.82; N, 7.83. Found: C, 57.08; H, 6.21; N, 7.36.
Example 9: 1-(3-~[5-i3-(3,4-Difluorophenyl)-2-oxo-
oxazolidine-3-carbonyl -amino?-propyl)-4-phenyl-
piperidine-4-carboxylic acid methyl ester (Scheme 8)
a. Hydroxy-(3,4-difluorophenyl)-acetonitrile
To a solution of 3,4-difluorobenzaldehyde (2.86 g, 20.0
mmol) in MeOH (20 mL)in a round bottom flask was added
trimethylsilyl cyanide (4.0 mL., 30.0 mmol) at 0°C. The
reaction mixture was stirred at room temperature for 10
h when TLC analysis indicated that the reaction was
complete (Rf = 0.4, 3:2 hexane/EtOAc). Solvent was
removed in vacuo and hydroxy-(3,4-difluorophenyl)-
acetonitrile was obtained as a colorless liquid (crude
wt. - 3.4 g). It was used in the next step. without
purification.
b. 2-Amino-1-(3,4-difluorophenyl)-ethanol
To a well stirred solution of hydroxy-(3,4-
difluorophenyl)-acetonitrile (3.34 g, 20 mmol), was
added a 1.0 M solution of LiAlH9 in ether (40 mL, 40
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mmol) dropwise at 0°C. The resulting yellow solution was
then stirred at room temperature for 2 h. The reaction
mixture was cooled to 0°C and then carefully quenched
sequentially with 1.5 mL of water, 1.5 mL of 3N NaOH
followed by 4.5 mL of water. The resulting suspension
was filtered thro' a fritted glass funnel. To the
residue was added 100 mL EtzO and the suspension was
heated to reflux for 20 min. The suspension was
filtered and was combined with the previous filtrate,
dried over MgS04, filtered and the solvent was removed
in vacuo. 2-amino-1-(3,4-difluorophenyl)-ethanol was
obtained as a yellow glassy syrup (3.3 g, 99~) which was
used in the next step without further purification.
c. [1-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic
acid-tart-butyl aster
To a solution of 2-amino-1-(3,4-difluorophenyl)-ethanol
(3.2 g, 19.8 mmol) in CHC13 (15 mL) at 0°C was added a
solution of di-tert-butyl dicarbonate (4.36 g, 20.0
mmol) in CHC13 (10 mL) in one portion and the resulting
solution was stirred overnight at room temperature. The
solvent was removed in vacuo and the residue was
subjected to column chromatography on silica gel (2:1
hexane-EtOAc followed by EtOAc) to obtain [2-(3,4-
difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-
butyl ester as white solid (3.2 g, 59.40 .
d. 5-(3,4-Difluorophenyl)-oxazolidin-2-one
To a well stirred suspension of 95~ NaH (0.55 g, 11.8
mmol) in THF (20 mL) at room temperature was added a
solution of [2-(3,4-difluorophenyl)-2-hydroxy-ethyl]-
carbamic acid-tert-butyl ester (3.2 g, 23.0 mmol) in THF
via a dropping funnel at room temperature. The
resulting suspension was stirred for 3 h and then
quenched carefully with 10 mL of water. The biphasic
mixture was extracted with 100 mL of Et20, washed with
brine, filtered and the solvent was removed in vacuo.
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The gummy residue thus obtained was purified by column
chromatography over silica gel (Rf = 0.15, 3:2 hexane-
EtOAc) to obtain 5-(3,4-difluoro-phenyl)-oxazolidin-2-
one as a white solid (1.1 g, 47~).
e. 5-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic
acid-4-vitro-phenyl ester
To a suspension of 95~ NaH (0.08 g, 3.0 mmol) in 5.0 mL
of anhydrous THF under argon, a solution of 5-(3,4-
difluorophenyl)-oxazolidin-2-one (0.5 g, 2.51 mmol) in
5.0 mL THF was added dropwise via an dropping funnel.
The resulting suspension was stirred at room temperature
for 30 min. This suspension was then added dropwise via
cannula into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (0.07 g, 3.26
mmol) in 20 mL of THF, cooled at -78°C,~ over a period of
15 min. The stirring was continued for 2 h after which
the solvent was removed and the residue was purified by
column chromatography on silica gel with 1:1
hexane/CHZCIz followed by CHZC12 (Rf= 0.4, CHZC12) to
obtain 5-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid-4-vitro-phenyl ester as a white solid
(0.7 g, 76~).
f. 1-(3-([5-(3-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-
carbonyl]-amino?-propyl)-4-phenyl-piperidine-4-
carboxylic acid methyl ester
To a solution of 3-amino-propyl-4-carbomethoxy-4-phenyl
piperidine (0.04 g, 0.13 mmol) in 10 mL of THF 5-(3,4-
difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-
nitro-phenyl ester (0.04 g, 0.10 mmol) was added and the
resulting yellow solution was stirred under argon
atmosphere for 10 h at room temperature. The solvent
was removed in vacuo and the residue was purified by
column chromatography over silica gel with EtOAC
followed by 15~ MeOH in EtOAC as the eluting systems (Rf
- 0.4, 1:1 MeOH/EtOAC) to obtain 1-(3-{[5-t3-(3,4-
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difluorophenyl)-2-oxo-oxazolidine-3-carbonyl]-amino}-
propyl)-4-phenyl-piperidine-4-carboxylic acid methyl
ester as a pale yellow glassy oil(0.03 g, 60~). It was
converted into its hydrochloride salt. M.P. - 121-
125°C; Anal. Calcd. for C26HBON3O9F2C1zØ2 HzO: C, 57.66;
H, 5.66; N, 7.76. Found: C, 57.80; H, 6.15; N, 7.95.
Example 10: 4-(3-Chloro-4-fluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid [3-(4,4-diphenyl-
piperidin-1-yl)-propyl]-amide (Schemes 2 and 5)
To a solution of 3-amino-propyl-4,4-diphenyl piperidine
(0.04 g, 0.1 mmol) in 5 mL of THF was added 4-(3-chloro-
4-fluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-
nitro-phenyl ester (0.04 g, 0.12 mmol) and the resulting
yellow solution was stirred under argon atmosphere for 3
h at room temperature. The solvent was removed in vacuo
and the residue was purified by column chromatography
over silica gel with 50~ hexane/EtOAC followed by 5~
MeOH in EtOAC as the eluting systems (Rf = 0.45, 1:3
MeOH/EtOAC) to obtain 4-(3-Chloro-4-fluoro-phenyl)-2-
oxo-oxazolidine-3-carboxylic acid [3-(4,4-diphenyl-
piperidin-1-yl)-propyl]-amide as white foam (wt = 0.03
g). It was converted into its hydrochloride salt. M.P.
112-115°C; Anal. Calcd. for C3oH32N3O3C12FØ5 CHC13: C,
57.95; H, 5.18; N, 6.65. Found: C, 58.06; H, 5.74; N,
6.30.
Example il: 4-(3,4-Difluoro-phenyl)-2-thioxo-
oxazolidine-3-carboxylic acid [3-(4-o-toluyl-4-p-toluyl-
piperidin-1-yl)-propyl]-amide (Scheme 9)
a. 4-(3,4-Difluorophenyl)-oxazolidine-2-thione
To a solution of 2-amino-2-(3,4-difluorophenyl)-
ethanol (600 mg, 3 .46 mmol) in CHzCl2 (20 ml) at room
temperature, was added 1,1'-thiocarbonyldiimadazole (755
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mg, 3.81 mmol). The resulting solution was heated by a
pre-heated oil-bath (110°C) to reflux for 10 h after
which the reaction mixture was cooled to room
temperature and the solvent was removed in vacuo. The
residue was purified by column chromatography over
silica gel with CHZC12 as the eluting system (Rf = 0.68,
CHZCI2:EtOAc = 3:1) to obtain 4-(3,4-difluorophenyl)-
oxazolidine-2-thione a brown oil (290 mg, 39~).
b. 4-(3,4-Difluorophenyl)-2-thione-oxazolidine-3-
carboxylic acid-4-nitro-phenyl ester.
To a suspension of NaH (41 mg, 1.62 mmol) in 20 mL of
anhydrous THF under argon, a solution of 4-(3,4-
difluorophenyl)-oxazolidine-2-thione (290 mg, 1.35 mmol)
in THF was added dropwise via an dropping funnel. The
resulting suspension was stirred at room temperature for
30 min. This suspension was then added dropwise via
cannula into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (336 mg, 1.62
mmol) in 20 mL of THF and cooled at -78°C over a period
of 15 min. The stirring was continued for 2 h after
which the solvent was removed and the residue was
purified by column chromatography on silica gel with
1:1 hexane/CHZCIz , then 3:7 hexane/CHzClz followed by
CHzClz (Rf= 0 . 50 ) to obtain 4- ( 3 , 4-difluorophenyl ) -2-
thione-oxazolidine-3-carboxylic acid-4-vitro-phenyl
ester as a yellow solid (130 mg, 25~).
c. 4-(3,4-Difluoro-phenyl)-2-thioxo-oxazolidine-3-
carboxylic acid (3-(4-o-toluyl-4-p-toluyl-piperidin-1-
yl)-propyl]-amide
To a solution of 1-(3-amino-propyl)-4-(4-methyl)-phenyl-
4-(2-methyl)-phenyl-piperidine (60 mg, 0.186 mmol) in 10
mL of THF,4-(3,4-Difluorophenyl)-2-thione-oxazolidine-3-
carboxylic acid-4-vitro-phenyl ester(30 mg, 0.079 mmol)
was added and the resulting yellow solution was stirred
under argon atmosphere for 2 h at room temperature. The
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solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (Rf= 0.66,
MeOH/EtOAc=1:3 ) to obtain 4-(3,4-Difluoro-phenyl)-2-
thioxo-oxazolidine-3-carboxylic acid [3-(4-o-toluyl-4-p-
toluyl-piperidin-1-yl)-propyl]-amide (16 mg, 36~). The
compound was dissolved in CH2Clz (3 mL) and was treated
with 1N HC1 in ether (1 mL). The solvent was removed in
vacuo to give the corresponding hydrochloride salt as a
yellow solid. M.P.= 132-136°C; Anal. Calcd. for
C32H36N3~2SC1 ~ 0 . 60 CHzCl2: C, 60 .14; H, 5 .76; N, 6.45.
Found: C, 59.97; H, 6.14; N, 6.12.
Example 12: 4-phenyl-2-thioxo-thiazolidine-3-carboxylic
acid (3-(3',4',5',6'-tetrahydro-2'H-(2,4']bipyridinyl-
1'-yl)-propyl]-amide (Scheme 9)
a. 4-(S)-Phenyl-thiazolidine-2-thione
To a solution of (S)-(+)-2-Phenylglycinol(1.40 g, 10
mmol) in 1N KOH/H~O (10 ml) at room temperature, was
added carbon disulfide (3 ml, 50 mmol). The resulting
solution was heated by a pre-heated oil-bath (110°C) to
reflux for 20 h after which the reaction mixture was
cooled to room temperature and extracted with CHzClz (3
X 30 ml), dried over NazS04. The solvent was removed in
vacuo and the residue was purified by column
chromatography over silica gel with 1:1 hexane/CHZCIz
followed by CHZC12 as the eluting system (Rf = 0.09,
CHzCl2:hexane = 7:3) to obtain 4(S)-phenyl-thiazolidine-
2-thione (170 mg, 9~).
b. 4-(S)-Phenyl-2-thione-thiazolidine-3-carboxylic acid-
4-nitro-phenyl ester.
To a suspension of NaH (26 mg, 1.04 mmol) in 10 mL of
anhydrous THF under argon, a solution of 4(S)-Phenyl-
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thiazolidine-2-thione (170 mg, 0.87 mmol) in THF was
added dropwise via an dropping funnel. The resulting
suspension was stirred at room temperature for 30 min.
This suspension was then added dropwise via cannula into
another round bottom flask containing a solution of 4-
nitrophenylchloroformate (217 mg, 1.04 mmol) in 20 mL of
THF and cooled at -78°C over a period of l5 min. The
stirring was continued for 2 h after which the solvent
was removed and the residue was purified by column
chromatography on silica gel with 1:1 hexane/CHZC12 ,
then 3 :7 hexane/CHZC12 followed by CHzCl2 (Rf= 0 . 50 ) to
obtain (+)-4(S)-phenyl-2-thione-thiazolidine-3-
carboxylic acid-4-nitro-phenyl ester as a pale yellow
solid (200 mg, 64~).
c. 4-phenyl-2-thioxo-thiazolidine-3-carboxylic acid [3-
(3',4',5',6'-tetrahydro-2'H-[2,4']biphenyl-1'-yl)-
propyl ] -amide
To a solution of 3-amino-propyl-4-pyridyl-piperidine (35
mg, 0.159 mmol) in 10 mL of THF,(+)-4(S)-Phenyl-2-
thione-thiazolidine-3-carboxylic acid-4-nitro-phenyl
ester (50 mg, 0.139 mmol) was added and the resulting
yellow solution was stirred under argon atmosphere for 2
h at room temperature. The solvent was removed in vacuo
and the residue was purified by column chromatography
over silica gel with 1:1 hexane/EtOAc followed by 1:9
MeOH/EtOAc (Rf= 0.21, MeOH/EtOAc=1:3 ) to obtain 4-(3,4-
Difluoro-phenyl)-2-thioxo-thiazolidine-3-carboxylic acid
[3-(3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-
propyl]-amide (10 mg, 14~). The compound was. dissolved
in CHZCIz (3 mL) and was treated with 1N HC1 in ether (1
mL}. The solvent was removed in vacuo to give the
corresponding hydrochloride salt as a yellow solid.
M. P . = 6'7-70°C; Anal . Calcd. for Cz3H31N4OS2C12 ~ 0 . 67 CHC13
C, 47.82; H, 5.37; N, 9.42. Found: C, 47.85; H, 6.12; N,
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6.52.
Example 13: (-)-2-Oxo-8,8a-dihydro-3aH-1-(S)-oxa-3-(R)-
aza-cyclopent[l~indene-3-carboxylic acid-[3-(1-4-cyano-
4-phenyl-piperidin-1-yl)-propyl-amide (Scheme 10)
a. Synthesis of (+)-3,3a,8,8a-tetrahydro-1(S)-oxa-3(R)-
aza-cyclopenta[a~inden-2-one
To a solution of (1R,2S)-(+)-cis-1-amino-2-indanol (1.0
g, 6.7 mmol) in 30 ml methylene chloride in 100-ml round
bottom flask equipped with a stirring bar, was added
1,1'-carbonyldimidazole (1.20 g, 7.4 mmol) at room
temperature. The resulting solution was heated by a pre-
heated oil-bath (110°C) to reflux for 10 h after which
the reaction mixture was cooled to room temperature and
the formation of white crystal was observed. The white
crystal was filtered off , washed with minmum CHzCl2 (2
mL} and then dried in vacuo. (+)-3,3a,8,8a-Tetrahydro-
1(S)-oxa-3(R)-aza-cyclopenta[a]inden-2-one was obtained
as a white crystal (500 mg, 43~).[a]p = -71.1 (c = 0.28,
acetone) . M.P. 203-204°C. Anal. Calcd. for CloH9N0z: C,
68.56; H, 5.18; N, 8.00. Found: C, 58.44; H, 5.12; N,
7.98.
b.2-Oxo-1,3a,8,8a-tetrahydro-2H-3-aza-
cyclopenta[a]indene-3-carboxylic acid 4-vitro-phenyl
ester.
To a suspension of NaH (73 mg, 2.88 mmol} in 20 mL of
anhydrous THF under argon, a solution of 3,3a,8,8a-
tetrahydro-1(R)-oxa-3(S)-a~a-cyclopenta[a]inden-2-one
(420 mg, 2.40 mmol) in THF was added dropwise via an
dropping funnel. The resulting suspension was stirred
at room temperature for 30 min. This suspension was
then added dropwise via cannula into another round
bottom flask containing a solution of 4-
nitrophenylchloroformate (598 mg, 2.88 mmol) in 25 mL of
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THF and cooled at -78°C over a period of 15 min. The
stirring was continued for 2 h after which the solvent
was removed and the residue was purified by column
chromatography on silica gel with 4:1 hexane/EtOAc
followed by 3:2 hexane/EtOAc (Rf= 0.51,
hexane/EtOAc=1:1) to obtain a white solid (680 mg, 83~).
c. (-)-2-Oxo-8,8a-dihydro-3aH-1-(S)-oxa-3-(R)-aza-
cyclopent[1]indene-3-carboxylic acid-[3-(1-4-cyano-4-
phenyl-piperidin-1-yl)-propyl-amide
To a solution of 1-(3-amino-propyl)-4-cyano-4-phenyl-
piperidine (25 mg, 0.103 mmol) in 10 mL of THF, 2-Oxo-
1,3a,8,8a-tetrahydro-2H-3-aza-cyclopenta[a]indene-3-
carboxylic acid 4-vitro-phenyl ester (40 mg, 0.118 mmoi)
was added and the resulting yellow solution was stirred
under argon atmosphere for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
1:1 hexane/EtOAc followed by EtOAc (Rf= 0.35 ) to obtain
(-)-2-Oxo-8,8a-dihydro-3aH-1-(S)-oxa-3-(R)-aza-
cyclopent[1]indene-3-carboxylic acid-[3-(1-4-cyano-4-
phenyl-piperidin-1-yl)-propyl-amide (19 mg, 35~). The
compound was dissolved in CHzClz (3 mL) and was treated
with 1N HC1 in ether (1 mL). The solvent was removed in
vacuo to give the corresponding hydrochloride salt as a
white solid. M. P. 98-102°C; [a]D = -96.5, (c = 0.21,
MeOH) ; Anal. Calcd. For C26HZ9N4O3C1 ~ 0.48 CHzClz: C,
60.96; H, 5.79; N, 10.74. Found: C, 60.94; H, 6.69; N,
8.02.
Example 14: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-[2-methyl-4-(2-vitro-phenyl)-
piperazin-1-yl)-propyl)-amide
a. (S)-(+)-3-men:hy1-1-(2-r~itra~henyl)-piperazine
To a solution of 2-bromo-nitrobenzene (0.6 g, 3.0 mmol)
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in 1,4-dioxane (15 mL) was added (S)-(+)-2-
methylpiperazine (0.5 g, 0.5 mmol) and powdered KzC03
(15.0 mmol, 1.5 g) and the resulting suspension was
heated at reflux for 10 h. After the suspension was
cooled, it was filtered through a sintered glass funnel
and the solvent was evaporated in vacuo. The resulting
residue was purified by column chromatography on silica
gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to
yield (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as
an orange oil (0.53 g, 80~). It was converted into (S)-
(+)-3-methyl-1-(2-nitrophenyl)-4-(3-aminopropyl)-
piperazine by the usual procedure.
b. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid ~3-[2-methyl-4-(2-vitro-phenyl)-
piperazin-1-yl)-propyl)-amide
To a solution of (S)-(+)-3-methyl-1-(2-nitrophenyl)-4-
(3-aminopropyl)-piperazine (35 mg, 0.126 mmol) in 10 mL
of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid-4-vitro-phenyl ester (50 mg, 0.137 mmol)
was added and the resulting yellow solution was stirred
under argon atmosphere for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf= 0.58,
MeOH:EtOAc=1:3 ) to obtain 4-(3,4-Difluoro-phenyl)-2-
oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2-
nitro-phenyl)-piperazin-1-yl)-propyl}-amide (55 mg,
87~). The compound was dissolved in CHZC12 (3 mL) and
was treated with 1N HCl in ether (1 mL). The solvent
was removed in vacuo to give the corresponding
hydrochloride salt as a pale yellow solid. M. P. 115-
119°C; [a]D = +38.3, (c = 0.22, CHZClz); Anal. Calcd. For
CZQHz$NSOSFZC1 ~ 0 . 72 C6H12: C, 56.50; H, 6.38; N, il . 63 .
Found: C, 56.63; H, 6.35; N, 10.08.
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Example 15: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid {3-(4-methyl-4-phenyl-piperidin-1-yl)-
propyl?-amide
a. 1-Benzyl-4-methyl-4-piperidinol
To a solution of 1-benzyl-4-piperidone (5.6 mL, 30.0
mmol) in 50 mL THF was added a solution of methyllithium
in THF (24.0 mL, 36 mmol) dropwise at 0°C over 15 min.
The reaction mixture was allowed to warm to room
temperature over 3 h and then quenched with 30 mL of
sat. NHQC1 solution. The oragnic layer was extracted
with diehtyl ether (2 X 100 mL) and the combined organic
layer was washed with brine (100 mL). The organic layer
was separated, dried over NazS04, filtered and the
solvent was removed in vacuo to obtain yellow gum. It
was purified by column chromatography over silica gel
with 9:1 EtOAc-MeOH as the eluting system to obtain 1-
benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6
g, 59~ yield) .
b. 1-Benzyl-4-methyl-4-phenyl piperidine
To a solution of 1-benzyl-4-methyl-4-piperidinol (3.6 g,
17.5 mmol) in 75 mL of benzene was added A1C13 (11.7 g,
87.7 mmol) in one portion at room temperature. After
stirring at room temperaure for 30 min, the reaction
mixture was heated to reflux for 8 h. The red colored
solution was allowed to cool and then poured over 100 g
of ice-water. It was extracted with EtOAc (2 X 100 mL)
and the organic layer was washed with solution of
Rochelle's salt. The organic layer was separated, dried
over NaZSOg, filtered and the solvent was removed in
vacuo to obtain 1-benzyl-4-methyl-4-phenyl piperidine as
a red oil (4.5 g, 97~ yield). It was used in the next
step without further purification.
c . 4-~e~:lr~yl-~-ph~nyl pi~dridirxe
To a cooled suspension of 10~ Pd-C (0.5 g) in 10 mL
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methanol was added a solution of 1-benzyl-4-methyl-4-
phenyl piperidine (4.5 g, 17.0 mmol) in 40 mL of
methanol and the resulting suspension was hydrogenated
in a Parr bomb under 250 psi of hydrogen for two days.
The suspension was filtered through a pad of celite and
the solvent was removed from the filtrate to obtain 4-
methyl-4-phenyl piperidine as a yellow solid (3.3 g, 99~
yield) .
d. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-f4-methyl-4-phenyl-piperidin-1-yl)-
propyl)-amide
To a solution of 1-(3-amino-propyl)-4-methyl-4-phenyl-
piperidine (60 mg, 0.258 mmol) in 10 mL of THF, 4-(3,4-
difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-
nitro-phenyl ester (60 mg, 0.165 mmol) was added and the
resulting yellow solution was stirred under argon
atmosphere for 2 h at room temperature. The solvent was
removed in vacuo and the residue was purified by column
chromatography over silica gel with 1:1 hexane/EtOAc
followed by MeOH:EtOAc=1:19 (Rf= 0.45, MeOH:EtOAc=1:3 )
to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid {3-[4-methyl-4-phenyl-piperidin-1-yl)-
propyl}-amide (56 mg, 74~). The compound was dissolved
in CHZC12 (3 mL) and was treated with 1N HC1 in ether (,1
mL). The solvent was removed in vacuo to give the
corresponding hydrochloride salt as a pale yellow solid.
M. P. 176-178°C; [a]D = +76.9, (c = 0.23, MeOH); Anal.
Calcd. For CzSHsoN303FzCl ~ 0.60 CHzClz: C, 56.32; H, 5.94;
N, 7.70. Found: C, 56.30; H, 5.80; N, 7.35.
Example 16: 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-
oxazolidine-3-carboxylic acid {3-(4-(2-methylphenyl)-4-
(4-methylphenyij-pxperidin-1-girl)-p~~~yijamida (Scheme
11)
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a. 2-(3,4-Difluorophenyl)propan-2-of
To a solution of ethylmagnesium bromide in ether (38.0
mL, 38.0 mmol) at 0°C, was added a solution of 3',4'-
difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl ether
(35mL). The reaction mixture was stirred at 0°C for 1 h
when TLC analysis indicated that the reaction was
complete (Rf = 0.3, 3:1 hexane/EtOAc). The reaction was
quenched carefully by adding 38 mL of water. It was
extracted with diethyl ether (2 X 30 mL), washed with
Rochelle's salt followed by brine and the organic layer
was dried over Na2S04. The solvent was removed in vacuo
after filtration and 2-(3,4-difluorophenyl)propan-2-of
was obtained as a colorless oil (crude wt. - 5.4 g, 97~)
which looked > 90~ pure by NMR. It was used in the next
step without purification.
b. 1,2-Difluoro-4-isopropenyl-benzene
To a solution of 2-(3,4-difluorophenyl)propan-2-of (1.0
g, 5.8 mmol) in 40 mL benzene was added 0.1 g of p-
toluenesulfonic acid and the solution was heated to
60°C. TLC analysis showed disappearance of the starting
material. After cooling, the solution was extracted
with EtOAc, washed with saturated NaHC03, dried over
Na2SOq, filtered and the solvent was removed in vacuo.
1,2-difluoro-4-isop~openyl-benzene was obtained as a
yellow oil (0.82 g, 92~ yield).
c. 2-(3,4-Difluorophenyl)-2-methyl-oxirane
To a biphasic solution ,of 1,2-difluoro-4-isopropenyl-
benzene (0.81 g, 5.1 mmol) in CHZC12 (50 mL) and 50 mL
of phosphate buffer (made by dissolving 0.3 g of NaHP04
and 0.35 g of NaH2P04 in 50 mL water, pH = 8) at 0°C,
was added a solution of 3-chloroperoxybenzoic acid
(approx. 75~ solid, 3.32 g, 10.2 mmol) via a dropping
funnel fitted with a cotton plug dropwise in two
batches. The solution was stirred at room temperature
overnight. It was extracted with CHZC1~, washed with
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sat. Na2Sz04 solution followed by water. The organic
layer was finally washed with sat. NaHC03, separated,
dried over Na2S04, filtered and solvnt was removed in
vacuo. 2-(3,4-Difluorophenyl)-2-methyl-oxirane was
obtained as a pale yellow oil (0.65 g, 74~ yield). It
was used in the next step without purification.
d. 1-Amino-2-(3,4-difluorophenyl)-propan-2-of and 2-
Amino-2-{3,4-difluorophenyl)-propan-1-of
To a solution of 2-(3,4-difluorophenyl)-2-methyl-oxirane
(1.2 g, 7.06 mmol) in 10 mL of acetonitrile was added
sodium azide (0.69g, 10.6 mmol) followed by lithium
perchlorate (1.13 g, 10.6 mmol). and the suspension was
heated to reflux overnight. After cooling, it was
extraced with EtOAc, washed with saturated NaHC03, dried
over Na2S04, filtered and the solvent was removed in
vacuo. The light bron oil that was obtained was a 10:1
mixture of 1-azido-2-(3,4-difluorophenyl)-propan-2-of
and 2-azido-2-(3,4-difiuorophenyl)-propan-1-of (crude wt
2.0 g). It was dissolved in 40 mL of diethyl ether,
cooled to 0°C and then treated with a solution of
lithium aluminum hydride (20.0 mL, 20 mmol). The
resulting yellow suspension was then stirred at room
temperature for 2 h. The reaction mixture was cooled to
0°C and then carefully quenched sequentially with 0.8 mL
of water, 0.8 mL of 3N NaOH followed by 2.5 mL of water.
The resulting suspension was filtered thro' a fritted
glass funnel. To the residue was added 100 mL EtzO and
the suspension was heated to reflux for 20 min. The
suspension was filtered and was combined with the
previous filtrate, dried over MgS04, filtered and the
solvent was removed in vacuo. 1-Amino-2-(3,4-
difluorophenyl)-propan-2-of and 2-amino-2-(3,4-
difluorophenyl)-propan-1-of was obtained as a yellow
glassy syrup (1.16 g, 87~) which was used in the next
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step immediately without further purification.
e. (2-(3,4-Difluorophenyl)-2-hydroxy-propyl~-carbamic
acid-tart-butyl ester and (1-(3,4-Difluorophenyl)-2-
hydroxy-propyl~-carbamic acid-tart-butyl ester
To a solution of 1-amino-2-(3,4-difluorophenyl)-propan-
2-0l and 2-amino-2-(3,4-difluorophenyl)-propan-1-of (1.2
- g, 6.4 mmol) in CHC13 (50 mL) at 0°C was added a
solution of di-tart-butyl Bicarbonate (1.74 g, 7.9 mmol)
in CHC13 (i0 mL) in one portion and the resulting
solution was stirred overnight at room temperature. The
solvent was removed in vacuo and the residue was
subjected to column chromatography on silica gel (2:1
hexane-EtOAc followed by EtOAc) to obtain [2-(3,4-
difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-
butyl ester and [1-(3,4-Difluorophenyl)-2-hydroxy-
propyl]-carbamic acid-tart-butyl ester as a white solid
(1.1 g, 60.10 .
f. 5-(3,4-Difluorophenyl)-5-methyl-oxazolidin-2-one and
4-(3,4-Difluorophenyl)-4-methyl-oxazolidin-2-one
To a well stirred solution of [2-(3,4-difluorophenyl)-2-
hydroxy-propyl]-carbamic acid-tart-butyl ester and [1-
(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic acid-
tert-butyl ester (1.1 g, 3.8 mmol) THF (50 mL) was added
95~ NaH (0.23 g, 9.6 mmol) at room temperature. The
resulting suspension was heated to reflux for 1 h and
then stirred at room temperature overnight. It was
quenched carefully with ice. The biphasic mixture was
extracted with 100 mL of EtOAc, washed with brine, dried
over NaZS04, filtered and the solvent was removed in
vacuo. The two diastereomers were separated by column
chromatography over silica gel. The first diastereomer
that came out was 4-(3,4-difluorophenyl)-4-methyl-
oxazolidin-2-one (0.05 g, kf = U.3, 3:2 hexane-EtOAc)
and the second isomer was 5-(3,4-difluorophenyl)-5-
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methyl-oxazolidin-2-one (0.61 g, Rf = 0.2, 3:2 hexane-
EtOAc).
g. 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-3-
carboxylic acid-4-vitro-phenyl ester
To a a solution of 4-(3,4-Difluorophenyl)-4-methyl-
oxazolidin-2-one(0.05 g, 0.23 mmol) in 5.0 mL THF was
added 95~ NaH (0.01 g, 0.28 mmol) in one portion. The
resulting suspension was stirred at room temperature for
20 min. This suspension was then added dropwise via a
syringe into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (0.06 g, 0.28
mmol) in 5 mL of THF, cooled at -78°C, over a period of
min. The stirring was continued for 1 h after which
the solvent was removed and the residue was purified by
15 column chromatography on silica gel with 3:2
hexane/EtOAc (Rf= 0.5) to obtain 4-(3,4-difluorophenyl)-
4-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-
phenyl ester as a white solid (0.06 g, 69~).
h. 5-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-
carboxylic acid-4-vitro-pheayl ester
To a a solution of .~-{3,4-Difluorophenyl)-4-methyl-
oxazolidin-2-one (0.61 g, 2.86 mmol) in 20 mL THF was
added 95~ NaH (0.07 g, 3.0 mmol) in one portion. The
resulting suspension was stirred at room temperature for
20 min. This suspension was then added dropwise via a
cannula into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (0.62 g, 3.1
mmol) in 20 mL of THF, cooled at -78°C, over a period of
15 min. The stirring was continued for 1 h after which
the solvent was removed and the residue was purified by
column chromatography on silica gel with 3:2
hexane/EtOAc (Rf= 0.6) to obtain 4-(3,4-difluorophenyl)-
4-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-
phenyl ester as a white solid (0.7 g, 67~).
i. 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-3-
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carboxylic acid ~3-[4-(2-methylphenyl)-4-(4-
methylphenyl)-piperidin-1-yl~-propyl~amide
To a solution of 3-amino-propyl-4-(2-methyl)phenyl-4-(4-
methyl)phenyl-piperidine (0.09 g, 0.27 mmol) in 10 mL of
THF, 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-
3-carboxylic acid-4-nitro-phenyl ester (0.06 g, 0.15
- mmol) was added and the resulting yellow solution was
stirred under argon atmosphere for 10 h at room
temperature. The solvent was removed in vacuo and the
residue was purified by column chromatography over
silica gel with EtOAC followed by 15~ MeOH in EtOAC as
the eluting systems (Rf = 0.3, 1:3 MeOH/EtOAC) to obtain
4-(3,4-difluorophenyl)-4-methyl-2-oxo-oxazolidine-3-
carbonyl)-amino-propyl}-4-(2-methyl)phenyl-4-(4-
methyl)phenyl-piperidine as a pale yellow glassy oil
(0.06 g, 73~) as a viscous oil. It was converted into
its hydrochloride salt. M.P. - 98-101°C; Anal. Calcd.
for C33H3gN3O3FzC1.1.0 CHZC12: C, 59.79; H, 5.90; N, 6.15.
Found: C, 59.40; H, 5.99; N, 5.92.
Example 17: 5-(3,4-Difluorophenyl)-5--methyl-2-oxo-
oxazolidine-3-carboxylic acid {3-[4-(2-methoxy-5-
methyl)phenyl-4-(4-methylphenyl)-piperidin-1-
yl~propyl?amide (Scheme 11)
To a solution of 3-amino-propyl-4-(2-methoxy-5-
methyl)phenyl-4-(4-methyl)phenyl-piperidine (0.09 g,
0.27 mmol) in 10 mL of THF, 5-(3,4-Difluorophenyl)-5-
methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-
phenyl ester (0.04 g, 0.11 mmol) was added and the
resulting yellow solution was stirred under argon
atmosphere for 10 h at room temperature. The solvent
was removed in vacuo and the residue was purified by
column chromatography over silica gel with EtOAC
followed by 15~ MeOH in EtOAC as the eluting systems (Rf
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0.3, 1:3 MeOH/EtOAC) to obtain 4-(3,4-difluorophenyl)-
4-methyl-2-oxo-oxazolidine-3-carboxylic acid (3-[4-(2-
methoxy-5-methyl)phenyl-4-(4-methylphenyl)-piperidin-1-
yl]propyl}amide as a pale yellow glassy oil (0.06 g,
850) as a viscous oil. It was converted into its
hydrochloride salt. M.P. - 82-85°C; Anal. Calcd. for
C34HQON304FzC1Ø7 CHZC12: C, 60.61; H, 6.07; N, 6.11.
Found: C, 60.73; H, 6.46; N, 6.12.
Example 18: ris (+)-4-(3,4-Difluorophenyl)-5-methyl-2-
oxo-oxazolidine-3-carboxylic acid(3-[4-(4-fluorophenyl)-
piperidin-1-yl]propyl)amide (Scheme 12)
a. 1-(3,4-Difluorophenyl)propan-1-of
To a solution of 3,4-difluorobenzaldehyde (5.0 g, 35.2
mmol) in diethyl ether (35 mL)in a round bottom flask
was added a solution of ethylmagnesium bromide in THF
(38.0 mL, 38.0 mmol) at 0°C. The reaction mixture was
stirred at 0°C for 1 h when TLC analysis indicated that
the reaction was complete (Rf = 0.5, 8:1 hexane/EtOAc).
The reaction was quenched carefully by adding 38 mL of
water. It was extracted with diethyl ether (2 X 30 mL),
washed with brine and the organic layer was dried over
NazS04. The solvent was removed in vacuo after
filtration and 1-(3,4-difluorophenyl)propan-1-of was
obtained as a yellow oil (crude wt. - 6.0 g) which
looked > 90~ pure by NMR. It was used in the next step
without purification.
b. 1-(3,4-Difluorophenyl)propan-1-one
In a round bottom flask containing pyridinium
chlorochromate (12.5 g, 58.1 mmol) was added celite 545
(25 g) and with the help of a magnetic stirrer the
solids were mixed together. 200 mL of CHZC12 was added
followed by a solution of 1-(3,4-difluoro-phenyl)propan-
1-0l ( 5 . 0 g, 29 . 2 mmol ) in 10 mL of CHzCl2 and the
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resulting brown suspension was stirred overnight at room
temperature. The suspension was filtered through a
sintered glass funnel and the solvent was removed in
vacuo from the pale green colored filtrate. The green
oil was then diluted with diethyl ether (200 mL) and it
was filtered through a pad of celite to remove the metal
impurities. The solvent was removed in vacuo to obtain
1-(3,4-difluorophenyl)propan-1-one as a pale yellow oil
(3.4 g, 69~ yield). It was used in the next step without
purification.
c. 1-(3,4-Difluorophenyl)-2-hydroxy-propan-1-one
In a round bottom flask containing 200 mL of MeOH was
added pellets of potassium hydroxide (23.0 g, 410.0
mmol). The solution was cooled to 0°C and 1-(3,4-
difluorophenyl)-2-hydroxy-propan-1-one (7.0 g, 41.2
mmol) in 10 mL MeOH was added dropwise. The solution
was stirred for 10 min and then iodobenzene diacetate
(22.5 g, 70 mmol) vaas added in two portions. The
solution first became orange and then turned yellow. It
was stirred overnight at room temperature and then
solvent was removed in vacuo. The residue was dissolved
in water and was extracted with ethyl acetate (3 X 100
mL). The combined organic extracts were washed with
brine and then dried over Na2S04. After filteration, the
solvent was removed in vacuo to get 1-(3,4-
difluorophenyl)-2-hydroxy-propan-1-one dimethyl acetal
as a yellow viscous oil. (crude wt. - 9.2 g). It was
dissoled in 150 mL of acetone and 10 drops of
concentrated sulfuric acid were added. After stirring
for 3 h, TLC analysis indicated that the reaction was
complete. Acetone was removed in vacuo and after
basification with saturated NaHC03, the residue was
extracted in EtOAc and was washed with brine. The
organic layer was separated, dried over NazS09 and then
filtered. The solvent was removed in vacuo and the
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residue was purified by silica gel chromatography (Rf =
0.4, 3:2 hexane/EtOAc) to obtain 1-(3,4-difluorophenyl)-
2-hydroxy-propan-1-one as a pale yellow oil (3.3 g, 51~
yield over two steps).
d. 1-(3,4-Difluorophenyl)-2-hydroxy-propan-1-one-oxime
To a well stirred solution of 1-(3,4-difluorophenyl)-2-
hydroxy-propan-1-one (5.5 g, 29.6 mmol) in MeOH (200 mL)
was added hydroxylamine hydrochloride (2.6 g, 38.4 mmol)
and sodium acetate (8.1 g, 59.2 mmol) and the the turbid
solution was stirred overnight at room temperature. The
solvent was evaporated and the residue was extracted
with CHZC12. The organic layer was washed with sat.
NaHC03, separated, dried over NazS09 and then filtered.
The solvent was removed in vacuo to obtain 1-(3,4-
difluorophenyl)-2-hydroxy-propan-1-one-oxime as an
orangish yellow oil (5.8 g, 97~). It was used in the
next step without purification.
e. 1-Amino-1-(3,4-difluorophenyl)-propan-2-of
To a well stirred solution of 1-(3,4-difluorophenyl)-2-
hydroxy-propan-1-one-oxime (5.8 g, 28.4 mmol), was added
a 1.0 M solution of LiAlH4 in ether (90 mL, 90 mmol)
dropwise at 0°C. The resulting yellow solution was then
stirred at room temperature for 2 h. The reaction
mixture was cooled to 0°C and then carefully quenched
sequentially with 3.5 mL of water, 3.5 mL of 3N NaOH
followed by 10.5 mL of water. The resulting suspension
was filtered thro' a fritted glass funnel. To the
residue was added 100 mL Et20 and the suspension was
heated to reflux for 20 min. The suspension was
filtered and was combined with the previous filtrate,
dried over MgS04, filtered and the solvent was removed
in vacuo. 1-amino-1-(3,4-difluorophenyl)-propan-2-of was
obtained as a yellow glassy syrup (3.6 g, 60'x) which was
used in the next step without further purification.
f. [1-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic
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acid-tart-butyl ester
To a solution of 1-amino-1-(3,4-difluorophenyl)-propan-
2-0l (3.5 g,~ 19.1 mmol) in CHC13 (15 mL) at 0°C was
added a solution of di-tart-butyl Bicarbonate (5.1 g,
23.6 mmol) in CHC13 (10 mL) in one portion and the
resulting solution was stirred overnight at room
temperature. The solvent was removed in vacuo and the
residue was subjected to column chromatography on silica
gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1-
(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-
tert-butyl ester as a viscous oil (3.3 g, 60.20 .
g. 4-(3,4-Difluorophenyl)-5-methyl-oxazolidin-2-one
To a well stirred solution of [1-(3,4-difluorophenyl)-2-
hydroxy-propyl]-carbamic acid-tart-butyl ester (0.43 g,
1.5 mmol) THF (20 mL) was added 95~ NaH (0.09 g, 3.8
mmol) at room temperature. The resulting suspension was
stirred for 3 h at about 35°C (warm water bath) and then
quenched carefully with ice. The biphasic mixture was
extracted with 100 mL of EtOAc, washed with brine, dried
over Na2S04, filtered and the solvent was removed in
vacuo. The two diastereomers were separated by column
chromatography over silica gel (First isomer: 0.11 g, Rf
- 0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf =
0.5, 3:1 hexane-EtOAc). NOE experiment suggested that
the first diastereomer had the methyl and the aryl group
in trans configuration while the second diastereomer had
cis relationship between the two groups.
Enantiomers of each of these diastereoisomers were
separated by HPLC by using Chiralcel OD (4.6 x 250 mm)
using 80~ hexane/20~ isopropyl alcohol/ 0.1~
diethylamine as the eluting system (12 mL/min) under
isothermal conditions (U. V. 254 nM). The retention
times for the two isomers of the trans-oxazolidinone
were 12.1 min {[a]D = + 36.4 (c = 0.25, acetone)} and
15.6 min {[a]D = - 30.8 (c = 0.20, acetone)},
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respectively. The retention times for the two isomers of
the cis-oxazolidinone were 13.7 min {[a]D = + 65.8 (c =
0.92, acetone)} and 19.9 min {[a]D = - 65.8 (c = 0.74,
acetone)} respectively. The next steps may be performed
on each of the four enantiomers individually in the
following manner, which describes the synthesis of the
cis (+) enantiomer.
h. 4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-
carboxylic acid-4-vitro-phenyl ester
To a suspension of 95o NaH (0.01 g, 0.38 mmol) in 5.0 mL
of anhydrous THF under argon, a solution of 4-(3,4-
difluorophenyl)-5-methyl-oxazolidin-2-one (0.07 g, 0.33
mmol) in 5.0 mL THF was added dropwise via a syringe.
The resulting suspension was stirred at room temperature
for 20 min. This suspension was then added dropwise via
a syringe into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (0.08 g, 0.4
mmol) in 10 mL of THF, cooled at -78°C, over a period of
15 min. The stirring was continued for 1 h after which
the solvent was removed and the residue was purified by
column chromatography on silica gel with 1:1
hexane/CHZCIz followed by CHZC12 (Rf= 0.4, CHZC12) to
obtain 4-(3,4-difluorophenyl)-5-methyl-2-oxo-
oxazolidine-3-carboxylic acid-4-vitro-phenyl ester as a
white solid (0.07 g, 56~).
i. 3-[4-(4-Fluoro-phenyl)-piperidin-1-yl~-propylamine
To a solution of 4-fluorophenylmagnesium bromide (110.0
mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0°C
was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL)
dropwise. The resulting solution was stirred under argon
atmosphere for 1.5 h and then quencYlEd with 100.0 mL of
saturated NH4C1 solution. The organic layer was
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separated and the aqueous layer was extracted with 100.0
mL of EtZO. The combined organic extracts were washed
with brine, separated and dried over NaZS04. The
solution was filtered and the solvent was removed in
vacuo to obtain a yellow oil which was purified by
passing through a silica gel column with 4:1
hexane/EtOAc followed by 1:1 hexane/EtOAc as the eluting
system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-of was
obtained as a pale yellow oil in 89~ yield (13.9 g). It
was dissolved in 150.0 mL of toluene and p-
toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was
added. The resulting suspension was heated to reflux for
8 h. After the suspension was cooled, it was basified
with 3 N NaOH solution and was extracted with Et20 (2 X
50 mL). The organic extracts were combined, washed with
brine and the oraganic layer was dried over Na2S04. The
solvent was removed in vacuo to obtain 1-benzyl-4-(4-
fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellow
viscous oil (12.0 g, 92~ yield) which was used in the
next step without further purification.
To a solution of 1-benzyl-4-(4-fluoro-phenyl)-
1,2,3,6-tetrahydro-pyridine (45.0 mmol, 12.0 g) in 100
mL MeOH was added 1.0 g of Pd(OH)2 and the resulting
suspension was hydrogenated under 200 psi of HZ in a
stainless steel bomb for two days. The suspension was
passed through a pad of celite and the filterate was
concentrated in vacuo to obtain 4-(4-fluoro)-phenyl-
piperidine (7.5 g, 94~) as a viscous oil. It was
converted into 3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-
propylamine by the route described previously in Example
1.
j. cis (+)-(4-(3,4-Difluorophenyl)-5-methyl-2-oxo-
oxazolidine-3-carboxylic acid{3-[4-(4-fluorophenyl)-
piperidin-1-yl]propyl?amide
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To a solution of 3-amino-propyl-4-(4-fluoro)phenyl-
piperidine (0.04 g, 0.12 mmol) in 10 mL of THF (+)-4-
(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-
carboxylic acid-4-nitro-phenyl ester (0.03 g, 0.08 mmol)
(made from the (+}-enantiomer from HPLC of the cis
diastereomer separated by column chromatography) was
added and the resulting yellow solution was stirred
under argon atmosphere for 10 h at room temperature.
The solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
EtOAC followed by 15o MeOH in EtOAC as the eluting
systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain (+}-(4-
(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-
carboxylic acid{3-[4-(4-fluorophenyl)-piperidin-1-
yl]propyl}amide as a pale yellow glassy oil(0.03 g,
66~). It was converted into its hydrochloride salt. M.
P. 108-112°C; [a]D = +56.7, (c = 0.20, MeOH); Anal.
Calcd. For CZSHZ9PJ3O3F3C1 ~ 0.36 CH2C12: C, 56. 14; H, 5.52;
N, 7.75. Found: C, 56.17; H, 5.90; N, 7.20.
Example 19: trans (+)-4-(3,4-Difluorophenyl)-5-methyl-2-
oxo-oxazolidine-3-carboxylic acid~3-I4-(4-fluorophenyl)-
piperidin-1-yl7propyl)amide (Scheme 12)
In an analogous manner as described above for Example
18, Steps h-j, the traps (+)-4-(3,4-difluorophenyl)-5-
methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-
phenyl ester ( 0 . 03 g, 0 . 08 mmol ) (made from the (+) -
enantiomer from HPLC of the traps diastereomer separated
by column chromatography) was converted into traps (+)-
4-(3,4-difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-
carboxylic acid{3-[4-(4-fluorophenyl)-piperidin-1-
yl]propyl}amide in 70~ yield. It was converted into
hydrochloride salt.
M.P. - 80-83°C (shrinks around 58°C); [a]D = + 27.4 (c =
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0.49, MeOH) ; Anal . Calcd. for CZSHZ9N3O3F3C1.1.0 H20: C,
56.55; H 6.07; N 7.91 Found: C, 56.49; H, 5.88; N 7.80.
Example 20: 4-(3,4-Difluoro-benzyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-[4-(2-carbamoylphenyl)-piperazin-1-
yl~-propyl)amide
a. 2-Amino-3-(3,4-difluoro)-phenyl-propan-1-of
To.a well stirred suspension of LiAlH4 (0.48 8,.12.5
mmol) in THF (30 mL) in a round bottom flask fitted with
a condenser was added 3,4-difluorophenyl alanine (1.0 g,
5.0 mmol) in small portions at 0°C. The resulting grey
suspension was then heated to reflux for 2 h. The
reaction mixture was cooled to 0°C and then carefully
quenched sequentially with 0.5 mL of water, 0.5 mL of 3N
NaOH followed by 1.5 mL of water. The resulting
suspension was filtered through a fritted glass funnel.
To the residue was added 50 mL Et20 and the suspension
was heated to reflux for 20 min. The suspension was
filtered and was combined with the previous filtrate,
dried over MgS04, filtered and the solvent was removed
in vacuo. 2-Amino-3-(3.4-difluoro)-phenyl-propan-1-of
was obtained as a white solid (0.5 g, 1000 which was
used in the next step.without further purification.
b. (+)-[2-(3,4-Difluorobenzyl)-2-hydroxy-ethyl -carbamic
acid-tart-butyl ester
To a solution of 2-amino-3-(3.4-difluoro)-phenyl-propan-
1-0l (0.5 g, 2.62 mmol,) in CHC13 (20 mL) at 0°C was
added a solution of di-tert-butyl dicarbonate (0.64 g,
2.90 mmol) in CHC13 (10 mL) in one portion and the
resulting solution was stirred overnight at room
temperature. The solvent was removed in vacuo and the
residue was subjected to column chromatography on silica
gel (2:1 hexane-EtUAc followed by EtOAc) to obtain (+)-
[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-
tert-butyl ester as white solid (0.64 g, 99~).
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c.(+)-4-(3,4-Difluoro-benzyl)-oxazolidin-2-one
To a well stirred suspension of 95~ NaH (0.12 g, 5.0
mmol) in THF (20 mL) at r.t. was added a solution of
(+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic
acid-tert-butyl ester (1.0 g, 4.0 mmol) in 10 mL THF via
a dropping funnel at room temperature. The resulting
suspension was stirred for 3 h and then quenched
carefully with 10 mL of water. The biphasic mixture was
extracted with 50 mL of Et20, washed with brine,
filtered and the solvent was removed in vacuo. The
gummy residue thus obtained was purified by column
chromatography over silica gel (Rf = 0.25, 3:2 hexane-
EtOAc) to obtain (+)-4-(3,4-difluoro-benzyl)-oxazolidin-
2-one as a white solid (0.32 g, 76~).
d.(+)-4-(3,4-Difluoro-benzyl)-oxazolidin-2-one-3-
carboxylic acid-4-nitro-phenyl ester
To a suspension of NaH (0.03 g, 1.30 mmol) in 10 mL of
anhydrous THF under argon, a solution of (+)-4-(3,4-
difluoro-benzyl)-oxazolidin-2-one (0.21 g, 1.0 mmol) in
10 mL THF was added dropwise via an dropping funnel.
The resulting suspension was stirred at room temperature
for 30 min. This suspension was then added dropwise via
cannula into another round bottom flask containing a
solution of 4-nitrophenylchloroformate (0.30 g, 1.5
mmol) in 20 mL of THF and cooled at -78°C over a period
of 15 min. The stirring was continued for 2 h after
which the solvent was removed and the residue was
purified by column chromatography on silica gel with
1:1 hexane/CHZC12 followed by CH2Clz (Rf= 0.4, CHZCIz) to
obtain (+)-4-(3,4-difluoro-benzyl)-oxazolidin-2-one-3-
carboxylic acid-4-nitro-phenyl ester as a yellow solid
(0.35 g, 82~).
e. 4- (3, 4-Difluorv-benzyl) -2-c~~o-oxazolic~i~rs-~3-
carboxylic acid (3-[4-(2-carbamoylphenyl)-piperazin-1-
yl]-propyl?amide
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To a solution of 1-(3-amino-propyl)-4-(2-carboxamido)-
phenyl-piperazine (30 mg, 0.114 mmol) in 10 mL of THF,
4-(3,4-difluorobenzyl)-2-oxo-oxazolidine-3-carboxylic
acid-4-nitro-phenyl ester (30 mg, 0.079 mmol) was added
and the resulting yellow solution was stirred under
argon atmosphere for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (Rf= 0.70,
MeOH/EtOAc=1:3 ) to obtain 4-(3,4-Difluoro-benzyl)-2-
oxo-oxazolidine-3-carboxylic acid {3-[4-(2-
carbamoylphenyl)-piperazin-1-yl]-propyl~amide (20 mg,
44~). The compound was dissolved in CHZC12 (3 mL) and
was treated with 1N HC1 in ether (1 mL). The solvent
was removed in vacuo to give the corresponding
hydrochloride salt as a yellow solid. M. P. 82-85°C;
[a]D = +34.3, (c = 0.49, MeOH); Anal. Calcd. For
C25H31N5~4F2C12 ~ 3 . 5 H20 : C, 47 .10 ; H, 6 . 01; N, 10 . 99 .
Found: C, 47.12; H, 5.94; N,10.94.
Example 21: 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid(2-L4-phenylpiperidine-4-(carboxylic acid
methyl ester)]ethyl)amide (Scheme 5)
To a solution of 2-amino-ethyl-4-carbomethoxy-4-phenyl
piperidine (0.03 g, 0.12 mmol) in 5 mL of THF was added
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic
acid-4-nitro-phenyl ester (0.04 g, 0.10 mmol) and the
resulting yellow solution was stirred under argon
atmosphere for 3 h at room temperature. The solvent was
removed in vacuo and the residue was purified by column
chromatography over silica gel with 50~ hexane/EtOAC
followed by 5~ MeOH in EtOAC as the eluting systems (Rf
- 0.5, 1:3 MeOH/EtOAC) to obtain the product as
colorless oil (wt= 0.02 g). The Compound was converted
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into its hydrochloride salt. M.P. 80-85°C; [a]D = +
51.6, (c = 0.11, MeOH); Anal. Calcd. for
CzsHzaN30sC1F2Ø5 CHC13: C, 52.48; H, 4.92; N, 7.20.
Found: C, 52.54; H, 5.13; N, 7.27.
Example 22: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid~3-[4-(4-fluoro-2-methyl-phenyl)-
piperidin-1-yl]-propyl? amide
a. 1-Benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol
To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 20
mL THF was added 2-Bromo-5-fluoro toluene (1.9 mL, 15.0
mmol) dropwise at -78°C over 15 min. The reaction
mixture was allowed to warm to 0°C over 1 h and then
cooled to -78°C. 1-Benzyl-4-piperidone (1.48 mL, 8.0
mmol) was added the white slurry and the reaction
mixture was warmed to 0°C over 2 h. The reaction was
then quenched with 10 mL of sat. NHQC1 solution. The
oragnic layer was extracted with diehtyl ether (2 X 50
mL) and the combined organic layer was washed with brine
(100 mL). The organic layer was separated, dried over
Na2S04, filtered and the solvent was removed in vacuo to
obtain yellow oil. It was purified by column
chromatography over silica gel with 3:2 hexane-EtOAc as
the eluting system to obtain 1-benzyl-4-(5-fluoro-2-
methyl)-phenyl-4-piperidinol as a yellow thick oil (1.1
g, 46~ yield).
b. 1-Benzyl-4-(4-Fluoro-2-methyl)-phenyl-1,2,3,6-
tetrahydropyridine
To a solution of 1-benzyl-4-(5-fluoro-2-methyl)-phenyl-
4-piperidinol (1.1 g, 3.68 mmol) in 100 mL toluene was
added p-toluenesulfonic acid monohydrate (1.39 g, 7.35
mmol) and the resulting solution was heated to reflux
for 8 h. The suspension was cooled and the basified with
10~ KOH solution and extracted with EtOAc (2 X 50 mL).
The organic layer was washed with brine (30 mL). The
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organic layer was separated, dried over NazS04, filtered
and the solvent was removed in vacuo to obtain 1-benzyl-
4-(4-Fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine
as a pale yellow oil (0.9 g, 87~ yield). It was used in
the next step without further purification.
c. 3-amino-propyl-4-(4-fluoro-2-methyl)phenyl-piperidine
To. a cooled suspension of 10~ Pd-C (0.1 g) in 10 mL
methanol was added a solution of 1-benzyl-4-(4-Fluoro-2-
methyl)-phenyl-1,2,3,6-tetrahydropyridine (0.9 g, 3.2
mmol) in 20 mL of methanol and the resulting suspension
was hydrogenated at room temperature under 1 atm of
hydrogen for 10 h. The suspension was filtered through a
pad of celite and the solvent was removed from the
filtrate to obtain 4-(4-fluoro-2-methyl)-phenyl-
. piperidine which was converted into its hydrochloride
salt (0.62 g, 99~ yield). It was used in the next step
without further purification. It was converted into 3-
amino-propyl-4-(4-fluoro-2-methyl)phenyl-piperidine by
the usual procedure.
d. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid(3-[4-(4-fluoro-2-methyl-phenyl)-
piperidin-1-yl~-propyl?amide
To a solution of 3-amino-propyl-4-(4-fluoro-2-
methyl)phenyl-piperidine (0.03 g, 0.11 mmol) in 5 mL of
THF was added 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-
3-carboxylic acid-4-nitro-phenyl ester (0.04 g, 0.10
mmol) and the resulting yellow solution was stirred
under argon atmosphere for 8 h at room temperature. The
solvent was removed in vacuo and the residue was
purified by column chromatography over silica gel with
50~ hexane/EtOAC followed by 5~ MeOH in EtOAC as the
eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain the
product as colorless oil (wt= 0.02 g). The compound was
converted into its hydrochloride salt. Off-white solid.
M.P. - 60-64°C; [a]D= + 36.6 (c = 0.15, MeOH); Anal.
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Calcd. for CzSHa9N30sF3C1Ø25 CHC13: C, 55.97; H, 5.44; N,
7.76. Found: C, 55.91; H, 5.66; N, 7.87.
Preparation of Side Chains.
1. 3-(4,4-Diphenylpiperidin-1-yl)propylamine.
a. 4,4-Diphenylpiperidine hydrochloride. A mixture of
4-piperidone monohydrate hydrochloride (15.0 g, 0.0976
mol) and A1C13 (130 g, 0.976 mol, 10.0 eq) in anhydrous
benzene (600 mL) were stirred at reflux for 4 hours.
The mixture was cooled to room temperature, poured into
ice (300 g) and water (50 mL), and filtered. The solid
was washed with toluene and dried to afford 19.2 g (72~)
of an off-white solid, which was characterized
spectroscopically.
b. 3-(4,4-Diphenylpiperidin-1-yl)propionitrile. To a
suspension of 4,4-diphenylpiperidine hydrochloride
(0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et3N
(0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile
(0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution
was stirred at room temperature under argon for 15 min
and then concentrated. Water was added, and the mixture
was extracted with EtOAc (3 X 10 mL). The combined
organic extracts were dried (MgS04) and concentrated to
give 170 mg (87%) of a tan solid, which was
characterized spectroscopically and used in the next
reaction without purification.
c. 3-(4,4-Diphenylpiperidin-1-yl)propylamine. To a
stirred solution of 3-(4,4-diphenylpiperidin-1-
yl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF
(20 mL) under argon was added a solution of BH3 in THF
(1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature.
The mixture was refluxed for 4.5 hours and then cooled
to room temperature. Aqueous HCl (6 N, 50 mL) was added
and stirring was continued for 1 hour. The mixture was
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basified to pH 9 by addition of 6 N aq. NaOH, extracted
with CHZC12 (3 X 10 mL), dried (MgS04) and concentrated.
The residue was purified by flash chromatography (Si02,
EtOAc-MeOH-isopropylamine 9:1:0 to 4:1:0.2) to give 1.35
g (66~) of tan solid, which was characterized
spectroscopically.
2..3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine.
a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthalimide.
A mixture of 4-cyano-4-phenylpiperidine hydrochloride
(111 g, 0.5 mol), 3-bromopropylphthalimide (135.39 g,
0.505 mol), potassium carbonate (276.42 g, 2 mol), and
potassium iodide (5.4 g) in DMF (1 L) was stirred and
heated at 100-110 °C for 8 h. About 80~ of the solvent
was evaporated at reduced pressure, the residue was
diluted with dichloromethane (1 L) and washed with brine
(3 X 300 mL) and dried (NazS04). Solvent was evaporated
from the dichloromethane solution and the residue was
treated with isopropanol (400 mL) and cooled. The pale
yellow crystalline product formed was filtered, washed
with ice-cold isopropanol and dried (168.6 g, 90~); M.p.
96-98 °C .
b. 3-(4-Cyano-4-phenyl,piperidin-1-yl)propylamine.
To a solution of 3-(4-cyano-
4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3
mol) in methanol (1. 5 L), hydrazine (30 mL) was added
and the mixture was stirred and refluxed for 20 h. It
was cooled, the white solid formed was filtered and
washed with more methanol (200 mL). Solvent was
evaporated from the filtrate and residue was dried under
vacuum for 4 h. Chloroform (500 mL) was added to this,
stirred for 1 h and filtered. The white solid was washed
with more chloroform (200 mL), the solvent was
evaporated from the combined filtrates to leave the
product as an oil (70
g, 96~).
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3. 3 -(4-Methoxycarbonyl-4-phenylpiperidin-1-
yl)propylamine.
a. 4-Methoxycarbonyl-4-phenylpiperidine. To a
stirred solution of HzS04 (16 mL) in MeOH (400 mL), 4-
phenyl-4-piperidinecarboxylic acid 4-
methylbenzenesulfonate (37.7 g, 0.1 mole) was added and
the mixture was stirred and refluxed for 8 hours.
Excess methanol was evaporated at reduced pressure and
the residue was poured into a mixture of ice and 6 N
NaOH. The pH was adjusted to 10-11 by adding more 6 N
NaOH and extracted with CHzCl2 (3 X 150 mL). The
combined CHzClz extracts were dried (MgS04) and the
solvent evaporated to leave the desired product as a
viscous oil. The product (20.2 g, 920) was used without
further purification.
b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1-
yl)propylamine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5
g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g,
0.058 mol), potassium carbonate (13.475 g, 0.0957 mole),
and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was
stirred and refluxed for 24 hours. Dioxane was
evaporated at reduced pressure, the residue was treated
with ice-cold 6 N NaOH (400 mL) and extracted with
CHZC12 (4 X 120 mL). Solvent was evaporated from the
combined dried (KZC03) extracts and the residue was
purified by column chromatography on silica gel using
CHC13/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent to
afford the product as a viscous oil (7.8 g, 72~).
4. 3-Aminopropyl-4-pyridyl-piperidine
a. 1- ( 3-~rminopropyl j -4- [pyrid-2-ylJ Fryridiniu~n bromit~e
hydrobromide.
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A solution of 2,4'-dipyridyl (5.0 g, 32.0 mmol) and 3-
bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF
(50.0 mL) arid acetonitrile (50.0 mL) was heated at 90-95
°C for 1 h. After cooling, the white solid that came
out was filtered, washed with Et20 and dried. The
mother liquor was concentrated to remove EtzO and then
heated at 90-95°C for 4 h. The solvent was evaporated
and the white residue was triturated with Et20 (100.0
mL) and filtered. The combined weight of the salt was
11.6 g (97~).
b. 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-
propylamine.
To a solution of 1-(3-aminopropyl)-4-[pyrid-2-
yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol)
in 20.0 mL MeOH was added NaBH4 (0.101 g, 2.62 mmol) in
small portions. The reaction mixture was stirred for 30
min and then quenched with 6M HC1 solution. The
solution was concentrated to 20.0 mL and basified with
50~ NaOH solution to pH 12. Extracted with CHC13 (5 x
30.0 mL), dried over MgS04 and the solvent was removed
to give 3-(3',6'-dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-
propylamine as an oil (0.37 g, 96~ yield). It is used
in the next step immediately without purification.
c. 3-Aminopropyl-4-(2-pyridyl)piperidine.
To a solution of 3-(3',6'-dihydro-2'-H-
[2,4']bipyridinyl-1'-yl)-propylamine (3.48 g crude, 15.9
mmol) in MeOH (40 mL), was added 1.0 g of Pearlman's
catalyst. The suspension was hydrogenated under 120 psi
for 10 h after which the reaction mixture was filtered
through a pad of celite and the solvent was removed.
The residue was purified by column chromatography over
silica gel using CHZCIz/methanol/2M NH3 in MeOH (90:8:4
to 90:40:4U) as the eluting system. The product was
obtained as a pale yellow oil (3.21 g, 91~).
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5. 3-(4-Acetoxy-4-phenylpiperidin-1-yl)propylamine.
a. N-Benzyloxycarbonyl-3-(4-hydroxy-4-phenylpiperidin-1-
yl)propylamine.
A mixture of 4-hydroxy-4-phenylpiperidine (5 g, 0.0282
mol), N-benzyloxycarbonyl-3-bromopropylamine (8.445 g,
0:031 mol), and potassium carbonate (7.795 g, 0.0564
mole) in acetone (200 mL) was stirred and refluxed for
l2 hours. Acetone was evaporated at reduced pressure,
the residue was treated with ice-cold water (400 mL) and
extracted with CHzCl2 (4 X 120 mL). Solvent was
evaporated from the combined dried (sodium sulfate)
extracts and the residue was found to be almost pure
desired product (9.5 g, 91~) by tlc and 1H-NMR and was
used as such without any further purification.
b. N-Benzyloxycarbonyl-3-(4-acetoxy-4-phenylpiperidin-1-
yl)propylamine.
To a solution of N-benzyloxycarbonyl-3-
(4-hydroxy-4-phenylpiperidin-1-yl)propylamine (0.5 g,
1.36 mmol) in THF (20 mL) at 0 °C, sodium hydride (60~
suspension in paraffin, 65 mg, 1.63 mmol, 1.2 eq.) was
added and the mixture was stirred for 1.5 h. To this
acetyl bromide (0.12 mL, 1.63 mmol) was injected and the
mixture was stirred at O °C for 30 minutes and at room
temperature for 3 h. Solvent was evaporated, the
residue was mixed with dichloromethane (100 mL), and
washed with water (2 X 20 mL). Solvent was evaporated
from the dried dichloromethane solution gave the product
as a viscous oil (0.485 g, 87~). The 1H-NMR showed this
product to be pure and was used in the next. step without
any further purification.
c. 3-(4-Acetoxy-4-phenylpiperidin-1-yl)propylamine.
A mixture of N-benzyloxycarbonyi-3-
(4-acetoxy-4-phenylpiperidin-1-yl)propylamine (3.0 g,
7 . 3 mmol ) and 10 o Pd-C ( 0 . 3 g) in 1M ammonia in
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methanol(50 mL) was hydrogenated at 70 psi at room
temperature for 4 h. The catalyst was removed by
filtration and the solvent was evaporated to leave the
product as a viscous oil (2.01 g, 99$), the 1H-NMR
showed it to be very pure and was used in the next step
without any purification.
6. 3-(4-Cyano-4-phenylpiperidin-1-yl)-2-
hydroxypropylamine.
a. 3 -(4-Cyano-4-phenylpiperidin-1-yl)(2-
hydroxypropyl)phthalimide
A mixture of 4-cyano-4-phenylpiperidine (10.0 g, 45
mmol) and 2,3-epoxypropylphthalimide (10.94 g, 54 mmol)
in DMF (100 mL) was stirred and heated at 70 °C for 72
h. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography on
silica gel using chloroform-methanol-2M ammonia in
methanol (1000/28/14) as the eluent, to obtain the
desired product as a viscous oil (16.45 g, 86~).
b. 3-(4-Cyano-4-phenylpiperidin-1-yl)-2-
hydroxypropylamine.
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-
hydroxypropyl)phthalimide (l0 g, 23.48 mmol) and
hydrazine (6.01 g, 188 mmol, 8 eq.) in methanol (100 mL)
was stirred and refluxed for 4.5 h. It was cooled,
filtered, and the solid was washed with methanol (30
mL). Evaporation of solvent from the filtrate gave the
product as a viscous oil (5.53 g, 94~).
7. 3-(4-Cyano-4-phenylpiperidin-1-yl)-2-
fluoropropylamine.
a. 3 -(4-Cyano-4-phenylpiperidin-1-yl)(2-
fluoropropyl)phthalimide
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-
hydroxypropyl)phthalimide (2.60 g, 6.1 mmol) and
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diethylaminosulfur trifluoride (DAST, 1.96 g, 12.2 mmol)
in benzene (100 mL) was stirred and heated at 70 °C
under argon atmosphere for 24 h. The solvent was
evaporated under reduced pressure and the residue was
purified by column chromatography on silica gel using
chloroform-methanol-2M ammonia in methanol (1000/28/14)
as the eluent, to obtain the desired product as a
viscous oil (1.30 g, 50~).
b. 3-(4-Cyano-4-phenylpiperidin-1-yl)-2-
fluoropropylamine.
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-
fluoropropyl)phthalimide (3.80.g, 8.88 mmol) and
hydrazine (2.27 g, 71.04 mmol, 8 eq.) in methanol (100
mL) was stirred and refluxed for 4.5 h. It was cooled,
filtered, and the solid was washed with methanol (30
mL). Evaporation of solvent from the filtrate gave the
product as a viscous oil (1.9 g, 85$).
8. 3-[4-(2-Pyridyl)-piperidin-1-yl)-3-methylpropylamine.
a. 3-[4-(2-Pyridyl)-piperidin-1-yl)-2-
methylpropionitrile. A mixture of 4-(2-pyridyl)-
piperidine (1.56 g, 10 mmol) and crotononitrile (1.34 g,
20 mmol, 2 eq) in ethanol (100 mL) was strirred and
refluxed for 16 h and the solvent and excess
crotononitrile were evaporated under vacuum. The
residue was purified by column chromatography on silica
gel using dichloromethane-methanol-2M ammonia in
methanol (45/4/2) as the eluent to give the desired
product as a viscous oil (2.09 g, 94~), which got
solidified on standing.
b. 3-[4-(2-Pyridyl)-piperidin-1-yl)-3-methylpropylamine.
To a stirred solution of 3-[4-(2-pyridyl)-piperidin-1-
yl)-3-methylpropionitrile (0.446 g, 2 mmol) in anhydrous
THF (10 mL) under argon was added a solution of BH3 in
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THF (1.0 M, 10 mL, 10 mmol, 5 eq) at room temperature.
The mixture was refluxed for 4.5 hours and then cooled
to room temperature. Aqueous HC1 (6 N, 50 mL) was added
and stirring was continued for 1 hour. The mixture was
basified to pH 9 by addition of 6 N aq. NaOH, extracted
with CHZC12 (3 X 10 mL), dried (potassium carbonate) and
the solvent evaporated to leave the product as a viscous
oil (0.42 g, 93~) the 1H-NMR of it showed it to, be pure
enough to use it in the next step.
9. 3-[4-(2-Pyridyl)-piperidin-1-y1)-2-methylpropylamine.
a. 3-[4-(2-Pyridyl)-piperidin-1-yl)-2-
methylpropionitrile. A mixture of 4-(2-pyridyl)-
piperidine (3.12 g, 20 mmol) and 1-methylacrylononitrile
(5 mL) in methanol (100 mL) was strirred and refluxed
for 48 h and the solvent and excess 1-
methylacrylonitrile were evaporated under vacuum. The
residue was purified by column chromatography on silica
gel using dichloromethane-methanol-2M ammonia in
methanol (45/4/2) as the eluent to give the desired
product as a viscous oil (3.30 g, 74~), which got
solidified on standing.
b. 3-[4-(2-Pyridyl)-piperidin-1-yl)-2-methylpropylamine.
To a stirred solution of 3-[4-(2-pyridyl)-piperidin-1-
yl)-2-methylpropionitrile (0.446 g, 2 mmol) in anhydrous
THF (10 mL) under argon was added a solution of BH3 in
THF (1.0 M, 10 mL, 10 ~nmol, 5 eq) at room temperature.
The mixture was refluxed for 4.5 hours and then cooled
to room temperature. Aqueous HCl (6 N, 50 mL) was added
and stirring was continued for 1 hour. The mixture was
basified to pH 9 by addition of 6 N aq. NaOH, extracted
with CHZC12 (3 X 10 mL), dried (potassium carbonate) and
the solvent evaporated to leave the product as a viscous
oil (0.436 g, 96~) the 1H-NMR of it showed it to be pure
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enough to use it in the next step.
Examples 23 and 24.
N3-[3-(4-Cyano-4-phenylpiperidino)propyl]-2-oxo-4,4-
diphenyl-oxazolidine-3-carboxamide hydrochloride and N3-
[3-(4,4-Diphenylpiperidino)propyl]-2-oxo-4,4-diphenyl-
oxazolidine-3-carboxamide hydrochloride
a) 1,1-biphenyl-2-hydroxyethylamine.
To stirred a solution of 2,2-diphenylglycine (5.0 g, 22
mmol) in THF (100 mL) at 0°C under argon atmosphere, a
solution of LAH in THF (2M, 50 mL, 50 mmol) was added
over a period of 15 minutes and the mixture was allowed
to warm to room temperature. After 12 h, it was poured
onto a mixture of ice (300 g) and 6N HC1 (20 mL) and
stirred for 1h. The mixture was basified to pH 10-11 by
the addition of 6N NaOH and extracted with
dichloromethane {4 X 100 mL). The combined extracts
were dried (sodium sulfate) and the solvent evaporated
to leave the product as a pale yellow viscous oil, which
on trituration with hexane became white powder (4.7 g,
~100~). The 1H-NMR showed this product to be pure and
was used as is in the next step.
b) 4,4-biphenyl-2-oxo-oxazolidine.
A mixture o~ 1,1-diphenyl-2-hydroxyethylamine (4.26 g,
20 mmol), CDI (3.24 g, 20 mmol.) in dichloromethane (200
mL) was refluxed for 20 h and the solvent evaporated.
The residue was purified by column chromatography on
silica gel using dichloromethane/ethyl acetate (9:1) to
give the product as a viscous oil which solidified on
standing (4.25 g, 89~).
c) 4,4-biphenyl-1-(4-nitrophenyloxycarbonyl)-2-oxo-
oxazolidine.
To a stirred suspension of sodium hydride (60~
suspension in paraffin, 0.6 g, 15 mmol, 1.5 eq.) in THF
(20 mL) at 0 °C, a solution of 4,4-diphenyl-2-oxo-
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oxazolidine (2.39 g, 10 mmol) in THF (5 mL) was added
and stirred for 30 minutes. This suspension was added
to a solution of 4-nitrophenyl chloroformate (2.41 g, 12
mmol) in THF (20 mL) at -78 °C under argon and the
stirring was continued for 2 h. It was slowly warmed to
room temperature and after 4 h the solvent was
evaporated. The residue was mixed with dichloromethane
(150 mL), washed with 0.05 N sodium hydroxide (3 X 10
mL), and dried (sodium sulfate). Solvent was evaporated
and the residue was purified by column chromatography on
silica gel using chloroform/ethyl acetate (9:1) as the
eluent to give the product as a white powder (3.72 g,
92~).
d) General procedure: Examples 23 and 24.
A mixture of 4,4-diphenyl-3-(4-nitrophenyloxycarbonyl)-
2-oxo-oxazolidine (40 mg, 0.1 mmol) and an appropriate
amine (0.15 mmol, 1.5 eq.) in THF (5 mL) was stirred at
room temperature and the product formed was purified by
preparative TLC cn silica gel using ethyl acetate as the
eluent. The HC1 salt was made by treatment with 1N HC1
in ether.
N3-[3-(4-Cyano-4-phenylpiperidino)propyl]-2-oxo-4,4-
diphenyl-oxazolidine-3-carboxamide hydrochloride
Yield 93~; m.p.139-141 °C; Anal. Calcd. For:
C31H32N4~3 ~ HC1 . 0 . 8CHZC12 : C, 60 . 77 ; H, 5 . 92 ; N, 9 . 51.
Found: C, 60.90; H, 5.80; N, 9.66.
N3-[3-(4,4-Dipheaylpiperidino)propyl]-2-oxo-4,4-
diphenyl-oxazolidine-3-carboxamide hydrochloride
Yield 92~; m.p.145-148 °C; Anal. Calcd. For:
3O C39H3.,N3O3.HC1 .1.3CHZC12: C, 62.12; H, 6.00; N, 6.16.
Found: C, 62.19; H, 5.64; N, 6.14.
Examples 25, 2ti, 2 i , 2& ~xmc'~ 29 .
a. 1-(3,4-Difluorophenyl)-2-methyl-2-hydroxypropylamine.
To a well-stirred solution of methyl 2-amino-2-(3,4-
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difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous
ether (200 mL) at 0°C a solution of methylmagnesium
bromide (3M, 87 mL, 261 mmol) in ether was added in 10
minutes. The mixture was stirred at 0°C for 2.5 h and
allowed to warm to room temperature. After 12 h, the
mixture was carefully poured onto a mixture of ice (300
g) and saturated ammonium chloride (50 g). The ether
layer was separated and the aqueous layer was extracted
with more ether (4 X 200 mL). The combined extracts
were dried with magnesium sulfate and the solvent
evaporated. The crude product was purified by column
chromatography on silica gel using
chloroform/methanol/2M ammonia in methanol (1000:20:10
mL, 1000:40:20 mL, 1000:80:40 mL) as eluents to give the
product as an oil (6.5 g, 62~). The 1H-NMR and MS
confirmed this to be the desired product.
b. 4-(3,4-Difluorophenyl)-5,5-dimethyl-2-oxo-
oxazolidine.
A mixture of 1-(3,4-difluorophenyl)-2-methyl-2-
hydroxypropylamine (3.00 g, 14.9 mmol), CDI (2.418 g,
14.9 mmol) in dichloromethane (150 mL) was refluxed for
36 h and the solvent evaporated. The residue was
purified by column chromatography on silica gel using
chloroform/ethyl acetate (9:1) to give the product as a
viscous oil which solidified on standing (1.80 g, 50~).
c. 4-(3,4-Difluorophenyl)-5,5-dimethyl-2-oxo-3-(4-
nitrophenyloxycarbonyl)oxazolidine.
To a stirred suspension of sodium hydride (600
suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL)
at 0 °C, a solution of 4-(3,4-difluorophenyl)-5,5-
dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF
(5 mL) was added and stirred for 30 minutes. This
suspension was added to a solution of 4-nitrophenyl
chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at -78
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°C under argon and the stirring was continued for 2 h.
It was slowly warmed to room temperature and after 4 h
the solvent was evaporated. The residue was mixed with
dichloromethane (150 mL), washed with 0.05 N sodium
hydroxide (3 X 10 mL), and dried (sodium sulfate).
Solvent was evaporated and the residue was purified by
column chromatography on silica gel using
chloroform/ethyl acetate (9:1) as the eluent to give the
product as a white powder (860 mg, 59~).
d. General procedure:
A mixture of 4-(3,4-difluorophenyl)-5,5-dimethyl-3-(4-
nitrophenyloxycarbonyl)-2-oxo-oxazolidine (50 mg, 0.123
mmol) and an appropriate amine (0.16 mmol, 1.3 eq.) in
dichloromethane (6 mL) was stirred at room temperature
and the product formed was purified by preparative TLC
on silica gel using two elutions, first with
chloroform/ethyl acetate (9:1) and then with
chloroform/methanol (9:1) as eluents. The HC1 salt was
made by treatment with 1N HC1 in ether.
Example 25:
Methyl 1-[3-([4-(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-
oxazolidine-3-yl]carbonylamino)propyl]-4-phenyl-4-
piperidinecarboxylate hydrochloride
Yield 56~; m.p. 208-210 °C; Anal. Calcd. For:
CZeH33F2N3O5.HCl . C, 59.42; H, 6.05; N, 7.42. Found: C,
59.06; H, 5.83; N, 7.27.
Example 26:
1-[3-([4-(3,4-Difluorophenyl)-5,5-dimethyl-2-oxo-
oxazolidine-3-yl]carbonylamino)propyl]-4-phenyl-4-
piperidyl acetate hydrochloride
Yield 29~; m.p. 116-118 °C; Anal. Calcd. For:
CZaH33F2N3C5.HC1 Ø3CHzC12: C, 5'7.46; H, 5.90; N, 7.50.
Found: C, 57.38; H, 6.18; N, 7.67.
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Example 27:
N3-3-[4-(2-Pyridyl)piperidino]-3-methylpropyl-4-(3,4-
difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine-3-
carboxamide dihydrochloride
Yield 64~; m.p. 87-90 °C; Anal. Calcd. For:
C26H32F2N4~3 ~ 2HC1 . 1 . 1CHC13 . 1. 1H20: C, 45 . 81; H, 5 . 29; N,
7.88. Found: C, 45.73; H, 5.50; N, 8.07.
Example 28:
N3-[3-(4-Cyano-4-phenylpiperidino)-2-hydroxypropyl]-4-
(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine-3-
carboxamide hydrochloride
Yield 63~; m.p. 135-137 °C; Anal. Calcd. For:
Cz.,H3aF2N404.HC1 .1.2H20: C, 56.83; H, 5.90; N, 9.82.
Found: C, 56.88; H, 5.98; N, 9.58.
Example 29:
N3-[3-(4-Cyano-4-phenylpiperidino)-2-fluoropropyl]-4-
(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine-3-
carboxamide hydrochloride
Yield 39~; m.p. 120-122 °C; Anal. Calcd. For:
CZ.,H29F3N4O3.HC1 Ø8CHZC12: C, 53.95; H, 5.15; N, 9.05.
Found: C, 53.89; H, 5.33; N, 8.95.
Example 30:
Methyl 1-5-[4-(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-
oxazolidin-3-yl]pentyl-4-phenyl-4-piperidinecarboxylate
hydrochloride
a. 4-(3,4-Difluorophenyl)-5,5-dimethyl-1-(5-
bromopentyl)-2-oxo-oxazolidine.
To a stirred suspension of sodium hydride (60~
suspension in paraffin 205 mg, 1.4 eq) in THF (20 mL) at
0 °C, a solution of 4-(3,4-difluoroplienyl)-5,5-dimethyl-
2-oxo-oxazolidine (880 mg, 3.622 mmol) in THF (5 mL) was
added and stirred for 30 minutes. To this 1,5-
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dibromopentane (3.37 g, 14.64 mmol, 4 eq.) and HMPA (179
mg, 3.66 mmol) were added and the mixture was warmed to
room temperature. It was heated at 55-60 °C for 12 h
and the solvent evaporated. The residue was purified by
column chromatography on silica gel using
chloroform/ethyl acetate (9:1) as the eluent to give the
product as a viscous oil (1.1 g).
b. Methyl 1-5-L4-(3,4-difluorophenyl)-5,5-dimethyl-2-
oxo-oxazolidin-3-yl]pentyl-4-phenyl-4-
piperidinecarboxylate hydrochloride
A mixture of 4-(3,4-difluorophenyl)-5,5-dimethyl-1-(5-
bromopentyl)oxazolidinone (50 mg, 0.123 mmol),
4-phenyl-4-methoxycarbonylpiperidine (0.16 mmol, 1.3
eq.), potassium iodide (11.6 mg), and potassium
carbonate (58 mg, 0.42 mmol, 3 eq.) in acetone (6 mL)
was stirred and refluxed for 12 h and the product formed
was purified by preparative TLC on silica gel using
ethyl acetate as the eluent. The HC1 salts were made by
treatment with 1N HC1 in ether. Yield 50~; m.p. 58-60
°C ; Anal . Calcd . For : CZ9H36F2NzO9 . HCl . 0 . 8CHZC12 : C ,
57.82; H, 6.28; N, 4.53. Found: C, 58.01; H, 6.53; N,
4.45.
Example 31:
N3-2- [4- (2-Oxo-2, 3-dihydro-l.Fi-benzo [d] imidazol-1-
yl)pi.peridino]ethyl-4-(3,4-difluorophenyl)-5,5-dimethyl-
2-oxo-oxazolidine-3-carboxamide hydrochloride
a. N-(2-It4-(2-Keto-1-benzimidazolinyl)piperidin-1-yl]-
ethyl)phthalimide.
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine
(5 g, 23 mmol) and N-(2-bromoethyl)phthalimide (5.85 g,
23 mmol) in DMF (100 mL) was added potassium carbonate
(10 g') and potassium iodide (250 mg~) an3 the mixture was
stirred and heated at 65-70 °C for 2h. It was poured
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into ice-water (500 mL), extracted with ether (4 X 75
mL) and dried (sodium sulfate). Solvent was evaporated
and the product was crystallized from methanol (8 g,
89~).
b. N-(2-[(4-(2-Keto-1-benzimidazolinyl)piperidin-1-yl]-
ethyl)amine
A mixture of N-(2-[{4-(2-keto-1-
benzimidazolinyl)piperidin-1-yl]-ethyl)phthalimide (3.9
g, 10 mmol) and hydrazine (2 mL) in methanol was
refluxed for 10 h and the solvent was evaporated. The
residue was suspended in chloroform (50 mL) and
filtered. The residue was washed with more chloroform
(50 mL). Solvent was evaporated from the combined
filtrate and the residue was dried under vacuum to leave
the desired product, which was used in the next step
without further characterization.
c. N3-2-[4-(2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-
yl)piperidino]ethyl-4-(3,4-difluorophenyl)-5,5-dimethyl-
2-oxo-oxazolidine-3-carboxamide hydrochloride
Prepared from 4-(3,4-difluorophenyl)-5,5-dimethyl-3-(4-
nitrophenyloxycarbonyl)-2-oxo-oxazolidine (20 mg) and N-
(2-[{4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]-
ethyl)amine (20 mg) as described earlier. Yield 25 mg;
[a]p = +58.8 (c = 0.40 g, methanol); m.p. 227-230 °C;
Anal. Calcd. For: C26H29F2N5~3~HC1Ø4 CHZC12: C, 54.30; H,
5.32; N, 11.99. Found: C, 54.52; H, 5.40; N, 11.82.
Example 32:
4-(3,4-Difluorophenyl)-3-[(3-[4-(2-
pyridyl)piperidino]methylpiperidino)carbonyl]-
oxazolidine-2-one dihydrochloride.
a. 1-Henzyl-4-[pyrid-2-yl]pyridinium bromide.
A solutiori of 2,4'-uipyridyl (15.62 g, 0.1 mol) and
benzyl bromide (17.104 g, 0.lmol) in anhydrous EtOAc
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(600 mL) for 24 h. The pale yellow crystalline product
formed was filtered and dried (32.7 g, 1000 .
b. 1-Benzyl-'4-(2-pyridyl)-1,2,3,6-tetrahydropyridine.
To a stirred solution of 1-benzyl-4-[pyrid-2-
yl]pyridinium bromide (50 g, 0.152 mol) in ethanol (500
mL) at 0-5 °C, was added NaBH9 (23 g) in small portions
over a period of 4 h. The mixture was allowed to warm
to room temperature and the stirring continued for
overnight. Solvent was evaporated the residue was mixed
with ether (500 mL), washed with 6N sodium hydroxide
solution (200 mL), brine (500 mL), and dried (potassium
carbonate). Solvent was evaporated and the oily residue
was used in the next step immediately without
purification (33.4 g, 88~).
c. 4-(2-Pyridyl)piperidine.
To a solution of 1-benzyl-4-(2-pyridyl)-1,2,3,6-
tetrahydropyridine (25 g, 0.1 mol) in MeOH (400 mL) and
2M ammonia in methanol (100 mL), was added Pearlman's
catalyst (6 g). The suspension was hydrogenated under
200 psi for 24 h after which the reaction mixture was
filtered through a pad of celite and the solvent was
removed. The residue was purified by column
chromatography over silica gel using CH~Clz/methanol/2M
NH3 in MeOH (45:4:2 to 9:4:4) as the eluting system.
The product was obtained as a pale yellow oil (12.4 g,
79~) .
d. N-(t-Butyl-carbonate)-nipecotic acid. To a solution
of nipecotic acid (3.865 g, 29.9 mmol)in dioxane (20
mL)at 0°C was added (Boc)ZO (6.53 g, 29.9 mmol) and a
solution of NaOH (2.63 g, 6.60 mmol)in water (10 mL).
The resulting mixture was stirred overnight while warmed
up to room temperature. The mixture was concentrated
and the residue was acidified to pII=3 wit~i 1 Iv HC1 and
then extracted with EtOAc (3 X 50 mL), dried (MgS04) to
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afford crude product which was used in the next step
without further purification.
e. 4-(2-Pyridyl)piperidine-N-(t-butyl-carbonate)-
nipecotamide. To a solution of N-(t-butyl-carbonate)-
nipecotic acid (6.85 g, 29.8 mmol) in CHZC12 (40 mL) was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (DMAPECD) (11.426 g, 59.6 mmol)and DMAP
(9.102 g, 74.5 mmol), then 4-(2-pyridyl)piperidine
(4.834g, 29.8 mmol) was added. The resulting mixture
was stirred for 24 hours and quenched with water (40
mL). The mixture was extracted with CHZC12 (3 X40 mL)
and the combined extracts was dried (KZC03) and
concentrated. The residue was purified by flash
chromatography on silica gel(CHC13-MeOH-NH3 100:4:1) to
afford the product as an oil (5.469 g, 49~).
f. 4-(2-Pyridyl)-N-(2-piperidinyl)methyl-piperidine. A
solution of 4-(2-pyridyl)piperidine-N-(t-butyl-
carbonate)-nipecotamide (2.904 g, 5.084 mmol) in TFA
5.0 mL) was stirred at 0 °C overnight. The mixture was
concentrated and the residue was dissolved in THF (30
mL). The mixture was cooled to 0 °C and lithium
aluminium hydride (LAH) (193 mg, 5.084 mmol) was added
slowly. The reaction mixture was stirred for 12 hours
while warmed to r.t. before quenched with water (1.0 mL)
and 1 N NaOH (0.5 mL). The mixture was basified to
pH=10 with 1 N NaOH and extracted with CHZC12 (5 X 20
mL), dried (KZCO3) and concentrated. The residue was
purified by flash chromatography (CHC13-MeOH-NH3
200:10:2 to 100:20:5) to afford the product as an oil
(0.804 g, 61~).
g. 4-(3,4-Difluorophenyl)-3-((3-(4-(2-
pyridyl ) pipericiino 7.cmthylpiperxdir~o ) CiiY~:lUiljY1 ] -
oxazolidine-2-one dihydrochloride.
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Prepared from 4-(3,4-difluorophenyl)-3-(4-
nitrophenyloxycarbonyl) -2-oxo-oxazolidine and 4-(2-
pyridyl)-N-(2-piperidinyl)methyl-piperidine following
the procedure described earlier.
Yield 90~; m.p.= 176-178 °C; Anal. Calcd. For
C26H31N403F2.2HC1. l.2Hz0. 1 .2CHzC12: C, 47 . 90; H, 5 . 59,
N,8.21. Found: C, 47.27; H, 5.41; N, 8.21.
Example 33:
N1-[2-(4-Cyano-4-phenylpiperidino)ethyl]-2-[4-(3,4-
difluorophenyl)-2-oxo-oxazolidin-3-yl]acetamide
hydrochloride
a. (+)-~2-[(4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-1
acetic acid benzyl ester. To a stirred a solution of 4
(3,4-difluorophenyl)-2-oxo-oxazolidinone (398 mg, 2
mmol) in THF (20 mL) at 0 °C under argon atmosphere,
LiHMDS (1M solution in THF, 2.2 mL, 2.2 mmol) was added
and the mixture was warmed to room temperature. After 30
minutes it was cooled to 0 °C and to this benzyl
bromoacetate (0.504 g, 2.2 mmol, 1.1 eq.) was added and
the mixture was warmed to room temperature. After 12 h,
solvent was evaporated and the residue was purified by
column chromatography on silica gel using
chloroform/ethyl acetate (9:1) as the eluent to give the
product as a viscous oil (0.695 g, 88a).
b. (+)-(2-[(4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-1-
acetic acid
The product obtained from the above reaction (0.592 g,
1.5 mmol) was dissolved in methanol/water (25/5 mL),
mixed with Pearlman's catalyst (120 mg) and hydrogenated
at 100 psi for 3 h. The catalyst was removed by
filtration and washed with methanol (20 mL). Solvent
was evaporated from the combined filtzate to obcaim the
product as a white powder (0.375 g, 97~).
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c. N1-[2-(4-Cyano-4-phenylpiperidino)ethyl]-2-[4-(3,4-
difluorophenyl)-2-oxo-oxazolidin-3-yl]acetamide
hydrochloride
A mixture of
(+)-{2-[(4-(3,4-difluorophenyl)-2-oxo-oxazolidine-1-
acetic acid (51.4 mg, 0.2 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(100 mg), and 4-(N,N-dimethylamino)pyridine (100 mg), 2-
[(4-cyano-4-phenyl)piperidin-1-yl]propylamine (55 mg) in
anhydrous dichloromethane (15 mL) was stirred at room
temperature for 12 h. The mixture was diluted with 10 mL
of dichloromethane and washed with saturated aqueous
ammonium chloride solution (6 X 10 mL). Solvent was
evaporated from the dried (sodium sulfate)
dichloromethane solution and the residue was purified by
column chromatography on silica gel using chloroform-
methanol-2M ammonia in methanol (100/2/1) as the eluent,
to obtain the desired product as a white powder (82 mg);
[a]D = +168.40 (c = 0.42 g, methanol). The HC1 salt was
prepared by treatment of a solution of the free base in
ether with 1N HC1 in ether. M.p. 136-139 °C; Anal.
Calcd. for Cz5H2~N403F2C1. 0 . 4CHzC12 : C, 5 6 . 3 8 ; H, 5 . 2 0 ; N,
10.40. Found: C, 56.38; H; 5.30; N, 10.52.
Example 34:
4-(4-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carbonyl]-piperazin-1-yl}-1-phenyl-
cyclohexanecarbonitrile
a. 1-Phenyl-4-piperazin-1-yl-cyclohexanecarbonitrile
A mixture of 4-cyano-4-phenyl-cyclohexanone (0.23 g, 1.2
mmol) and piperazine (0.30 g, 3.5 mmol) in 20 ml of
toluene was stirred at reflux for 2 h in presence of
catalytic amount of p-toluenesulfonic acid. 'hhe
reaction mixture was concentrated in vacuo to provide a
white solid, which was redissolved in 20 ml of EtOH and
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stirred with NaBH4 (0.30 g, 80 mmol) for 12 h at 25 °C.
Reaction mixture was diluted with 100 ml of EtOAc and
washed with brine several times. Organic layer was
dried over MgS04 and concentrated in vacuo, to provide
oily residue, which was subjected to column
chromatography (10~ MeOH/EtOAc) to yield 0.13 g (40~) of
the desired product as an oil.
b..4-(4-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carbonyl~-piperazin-1-yl)-1-phenyl-
cyclohexanecarbonitrile
To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid 4-nitrophenyl ester (80
mg, 0.21 mmol) in 5 ml of THF was added 1-phenyl-4-
piperazin-1-yl-cyclohexanecarbonitrile (80 mg, 0.29
mmol) in a portion and the resulting solution was
stirred for 12 h at 25 °C. Reaction mixture was
concentrated in vacuo yielding a yellow oil, which was
subjected to column chromatography (50~ Hexane/EtOAc) to
provide 53 mg (51'x) of the desired product as a
colorless oil. The product obtained was converted to
the HC1 salt and recrystallized from EtOAc-Et20 to
afford 43 mg of the product as white solid: mp 148-151
°C; Anal . Calc . For Cz,H2aF2N40j . 1. OHC1 requires C, 61. 07 ;
H, 5.50; N, 10.55. Found: C, 59.48; H, 5.41; N, 10.34.
Example 35:
(+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-(4-furan-2-yl-4-phenyl-piperidin-1-
yl ) -propyl 3 -wide
a. 4-Phenyl-4-furan-2-yl-piperidine
To a solution of 4-hydroxy-4-phenyl-piperidine(0.50 g,
2.8 mmol) in 10 ml of CHZC12 at 25 °C was added furan
(0.40 ml, 5.6 mmol) and aluminum chloride (0.75 g, 5.6
mmol) in a portion and the resulting heterogeneous
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solution was stirred for 3 h. Reaction mixture was
poured into cold aqueous NaHC03 and extracted with
EtOAc. Organic layer was dried over NazS04 and
concentrated in vacuo to provide oily residue, which was
purified by column chromatography (30~ NH3 sat'd
MeOH/EtOAc) to yield 0.48 g (76~) of the desired product
as an oil.
b. 3-[4-(4-furan-2-yl-4-Phenyl-phenyl)-piperidin-1-yl)~-
propyl-1-amine
A solution of the amine (0.15 g, 0.66 mmol), (3-bromo-
propyl)-carbamic acid tent-butyl ester (0.30 g, 1.3
mmol ) and KzC03 ( 2 . 0 g, 7 . 4 mmol ) in 10 ml of dioxane
was stirred at reflux for 12 h. Reaction mixture was
diluted with EtOAc and washed with brine several times.
Organic layer was dried over Na2S04 and concentrated in
vacuo to provide oily residue, which was purified by
column chromatography (EtOAc, neat) to yield 120 mg of
the desired product as tert-butyl carbamic ester. The
ester was diluted in 5 ml of CH2C12 and 1 ml of
trifluoroacetic acid, and stirred for 2 h at 25 °C.
Reaction mixture was concentrated in vacuo, yielding an
oil, which was diluted with EtOAc and washed with
aqueous NaHC03. Organic layer was dried over NazS04 and
concentrated in vacuo to provide 86 mg (33~) of the
desired product as a colorless oil.
c. (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid [3-(4-furan-2-yl-4-phenyl-piperidin-1-
yl)-propyl~amide
To a solution of (+}-4-(3,4-difluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid 4-nitrophenyl ester (19
mg, 0. 05 mmol) in 5 ml of CHzCl2 was added 3- [4- (4-
Phenyl-4-furan-2-yl-phenyl)-piperidin-1-yl)]-propyl-1-
amine (12 mg, 0.04 mmol) in a portion and the resulting
solution was stirred for 4 h at 25 °C. Reaction mixture
was concentrated in vacuo yielding a yellow oil, which
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was subjected to column chromatography (5~ MeOH/CHC13)
to provide 18 mg (88~) of the desired product as a
colorless oil. The product obtained was converted to
the HCl salt and recrystallized from EtOAc-Et20 to
afford 19 mg of the product as white solid: mp 149-151
°C; [a)D = + 49.4 (c=0.11, MeOH); Anal. Calc. For
C28H29F2N3OQ.1.OHC1 requires C, 62.42; H, 5.42; N, 7.53.
Found: C, 60.79; H, 5.49; N, 7.43.
Example 36:
(+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-[4-(1-methyl,-1H-pyrrol-2-yl)-4-
phenyl-piperidin-1-yl]-propyl)-amide
a. 4-Phenyl-4-(1-methyl-pyrrol)-2-y1-piperidine
To a solution of 4-hydroxy-4-phenyl-piperidine(0.50 g,
2.8 mmol) in 10 ml of CHzClz was added 1-methyl-pyrrole
(0.51 ml, 5.6 mmol) and aluminum chloride (0.75 g, 5.6
mmol) in a portion and the resulting heterogeneous
solution was stirred for 4 h at -78 °C. Reaction
mixture was poured into cold aqueous NaHC03 and
extracted with EtOAc. Organic layer was dried over
Na2S04 and concentrated in vacuo to provide oily residue
(0.81 g), which was identified as the desired product by
NMR analysis and subjected to the following reaction
without any further purification.
b. 3-[4-(1-methyl-1H-pyrrol-2-yl)-4-phenyl-piperidin-1-
yl]-propyl-1-amine
A solution of the amine (0.81 g, 2.8 mmol), (3-bromo-
propyl)-carbamic acid tert-butyl ester (1.0 g, 4.2
mmol) , KZC03 (1.0 g, 7 .4 mmol) and NaI (0. 05 g) in 10 ml
of dioxane was stirred at reflux for 12 h. Reaction
mixture was diluted with EtOAc and washed with brine
several times. Organic layer was dried over ZvazS09 and
concentrated in vacuo to provide oily residue, which was
purified by column chromatography (2~ MeOH/CHC13) to
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yield 0.87 g (78~) of the desired product as tert-butyl
carbamic ester. The ester was diluted in 10 ml of
CHzCl2 and 1 ml of trifluoro-acetic acid, and stirred
for 2 h at 25 °C. Reaction mixture was concentrated in
vacuo, yielding an oil, which was diluted with EtOAc and
washed with aqueous NaHC03. Organic layer was dried
over NazS04 and concentrated in vacuo to provide 0.63 g
(75~ for two steps) of the desired product as a
colorless oil.
c. (+)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-[4-(1-methyl-1H-pyrrol-2-yl)-4-
phenyl-piperdin-1-yl~-propyl)-amide
To a solution of (+)-4-(3,4-difluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid 4-nitrophenyl ester (30
mg, 0.08 mmol) in 5 ml of CHzCl2 was added 3-{[4-phenyl-
4-(1-methyl-pyrrol)-2-yl-phenyl]-piperidin-1-yl}-propyl-
1-amine (24 mg, 0.08 mmol) in a portion and the
resulting solution was stirred for 4 h at 25 °C.
Reaction mixture was concentrated in vacuo yielding a
yellow oil, which was subjected to column chromatography
(5~ MeOH/CHC13) to provide 14.4 mg (34~) of the desired
product as a colorless oil. The product obtained was
converted to the HCl salt and recrystallized from EtOAc-
Et20 to afford 13.0 mg of the product as white solid: mp
135-138 °C; [a]D = + 34.1 (c=0.11, MeOH); Anal. Calc.
For Cz$H29FZN304. 1 . OHC1 requires C, 62 . 42 ; H, 5 .42; N,
7.53. Found: C, 60.?9; H, 5.49; N, 7.43.
Example 37:
(+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid ~3-[4-(5-methyl-thiophen-2-yl)-
piperidin-1-yl]-propyl)-amide
a. 4- [4-Hydroxy-4- (5-methyl-thiophen-2-yl) ~ -px~rc~ridirm
To a solution of 2-methyl-thiophene (1.0 ml, 10 mmol) in
40 ml of dry THF was added tert-butyl lithium (1.7 M
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solution in ether, 6.5 ml, 11 mmol) dropwise and the
resulting solution was stirred for 1 h at -40 °C. To
the solution was added N-tert-butoxycarbonyl-4-
piperidinone (1.0 g, 5.0 mmol) in a portion and the
resulting solution was stirred for 2 h. Reaction was
quenched by adding a few drops of water. Reaction
mixture was diluted with EtOAc and washed with brine
several times. Organic layer was dried over NaZSOq and
concentrated in vacuo to provide an oil, which was
identified as the desired product by NMR analysis and
subjected to the following reaction without any further
purification.
b. 4-(5-Methyl-thiophen-2-yl)-piperidine
A solution of the carbamic ester (1.3 g, 4.4 mmol) and
triisopropylsilane (1.0 ml, 8.2 mmol) in 10 ml of CHzClz
was added 10 ml of trifluoroacetic acid and the
resulting solution was stirred for 2 h at 0 °C.
Reaction mixture was concentrated in vacuo, yielding a
dark oil, which was redissolved in EtOAc and washed with
aqueous NaHC03. Organic layer was dried over Na2S04 and
concentrated in vacuo to provide oily residue, which was
purified by column chromatography (5~ MeOH/CHC13) to
yield 0.73 g (870) of the desired product as an oil.
c. 3-[4-(5-methyl-thiophene-2-yl)-piperidin-1-yl~-
propyl-1-amine
A solution of the amine (0.73 g, 4.0 mmol), (3-bromo-
propyl)-carbamic acid tert-butyl ester (1.8 g, 7.5
mmol) , KZC03 (1.0 g, 7.4 mmol) and NaI (0.05 g) in 25 ml
of acetone was stirred at reflux for 12 h. Reaction
mixture was diluted with EtOAc and washed with brine
several times. Organic layer was dried over NazS04 and
concentrated in vacuo to provide oily residue, which was
purif led by column chrorciatography ( 5~ i~eOH/CHC13 ) to
yield 0.60 g (44~) of the desired product as tert-butyl
carbamic ester. The ester was diluted in 10 ml of
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CHZC12 and 1 ml of trifluoroacetic acid, and stirred for
2 h at 25 °C. Reaction mixture was concentrated in
vacuo, yielding an oil, which was diluted with EtOAc and
washed with aqueous NaHC03. Organic layer was dried
over NazS04 and concentrated in vacuo to provide 0.40 g
of the desired product as a colorless oil.
d. (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-
carboxylic acid (3-[4-(5-methyl-thiophen-2-yl)-
piperidin-1-yl~-propyl)-amide
To a solution of (+)-4-(3,4-difluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid 4-nitrophenyl ester (46
mg, 0 . 12 mmol ) in 5 ml of CHzCl.2 was added 3- [ 4- ( 5-
methyl-thiophen-2-yl)-piperidin-1-yl]-propyl-1-amine (30
mg, 0.13 mmol) in a portion and the resulting solution
was stirred for 22 h at 25 °C. Reaction mixture was
concentrated in vacuo yielding a yellow oil, which was
subjected to column chromatography (5~ MeOH/CHZCIz) to
provide 41 mg (74~) of the desired product as a
colorless oil. The product obtained was converted to
the HC1 salt and recrystallized from EtOAc-Et20 to
afford 43 mg of the product as white solid: mp 143-146
°C; [a]D = + 41.0 (c=0.11, MeOH); Anal. Calc. For
Cz3Hz.,FzN304.1.OHC1 requires C, 55.25; H, 5.64; N, 8.40.
Found: C, 57.01; H, 5.54; N, 8.29.
General Procedure for the Preparation of the 4,4-Diaryl
Piperidines: A mixture of 0.5 g of 4-aryl-4-hydroxy
piperidine, 3 mL of the aromatic substrate, and 1 g of
aluminum chloride were stirred at room temperature for 3
days. The reaction mixture was poured over 10 mL of
ice, diluted with t-butyl-methyl ether, the resulting
hydrochloride salt was filtered, washed with water and
ether, dried, and used in the next step after spectral
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characterization.
4-Phenyl-4-(4-thiomethoxy-phenyl)-piperidine,
Hydrochloride: From 4-phenyl-4-hydroxy-piperidine and
thioanisole ( 82~ ) , Anal . Calc . for C1gH21N1S1+HC1+0 . 2H20
C, 66.83; H, 6.98; N, 4.33. Found: C, 66.71; H, 6.81; N,
4.24.
4-(4-Fluoro-phenyl-4-(4-thiomethoxy-phenyl)-piperidine,
Hydrochloride: From 4-(4-fluoro-phenyl-4-hydroxy-
piperidine and thioanisole (590), Anal. Calc. for
ClBHZOF1N1S1+HCl+0.35CHZC12: C, 60..14; H, 5.56; N, 3.90.
Found: C, 59.96; H, 5.95; N, 3.81.
4-(4-Fluoro-phenyl-4-(2-methoxy-5-fluoro-phenyl)-
piperidine, Hydrochloride: From 4-(4-fluoro-phenyl)-4-
hydroxy-piperidine and 4-fluoroanisole (78~), Anal.
Calc . for C18H19N1Fz01+HC1+0 . 2Hz0: C, 62 . 96 ; H, 5 . 99; N,
4.08. Found: C, 62.72; H, 6.06; N, 4.06.
Bis-(4-fiuoro-phenyl)pip~ridine, Hydrochloride: From 4-
(4-fluoro-phenyl)-4-hydroxy-piperidine and 3 mL of
fluorobenzene (69~).
4-(4-Bromo-phenyl-4-(4-methoxy-phenyl)-pip~ridine,
Hydrochloride: From 4-(4-bromo-phenyl-4-hydroxy-
piperidine and thioanisole (66~), Anal. Calc. for
ClaHZOBr1N1S1+HC1: C, 54.21; H, 5.30; N, 3.51. Found: C,
54.43; H, 5.22; N, 3.41.
General Procedure for the Preparation of the 4,4-Diaryl-
1-(3-amino-propyl)Piperidines: A solution of 1.00 mmol
of diarylpiperidine, 1.30 mmol of N-BUC-3-
bromopropylamine, 1.00 mL of diisopropylethylamine and 2
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mL of dioxane were heated at reflux temperature for 36
hours, cooled, applied to prep-tlc plates and eluted
with the appropriate solvent. The product was used in
the next step after spectral characterization. A
solution of the N-BOC protected amine in 1:1 TFA-water
was stirred at room temperature for 2 hours (monitored
by tlc), solvent removed in vacuo, the product was
dissolved in dichloromethane, washed with saturated
Na2C03 solution, dried (Na2S09 ) , solvent removed in
vacuo, and the product was used after spectral
characterization.
(4-(4-methanesulfonyl-phenyl)-4-phenyl]-3-
aminopropyl-piperidine: A mixture of 644 mg of [4-
(4-thiomethyl-phenyl)-4-phenyl]-3-aminopropyl-piperidine
(TFA salt, 1.13 mmol), 853 mg of 50-60~ 3-
chlorophenylperbenzoic acid (2.72 mmol, assuming 55~
purity), 2 mL of trifluoroacetic acid and 10 mL of
chloroform were stirred at room temperature for 36
hours, solvent removed in vacuo, and the product was
chromatographed (X2) (NH3-MeOH-CHC13) to give 270 mg of
the desired product.
General procedure for the synthesis of Examples 38, 39,
40, 41 and 42.
A solution of (+)-4x(3,4-difluoro-phenyl)-2-oxo-
oxazolidine-3-carboxylic acid 4-vitro-phenyl ester (25
mg, 0.069 mmol), the 4,4-diaryl-1-(3-amino-propyl)
piperidine (1.2 eqiv.) in 5 ml of methylene chloride
were stirred at room temperature for 12 hours. The
reaction mixture was washed with 3 N KOH solution. The
organic phase was chromatographed on preparative TLC
(CHZCIz/methanol/ 2 N NH3 in methanol = 40 /2/1) Lo
obtain the title compound. The hydrochloride salt of
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the free base was prepared by addition of 1 N HCl in
ether to a solution of the free base in ethyl acetate
until no more precipitate was observed.
Example 38:
4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic
acid (3-[4-(4-bromo-phenyl)-4-(4-methoxy-phenyl)-
piperidin-1-yl~-propyly-amide
33 mg of the free base was obtained (55~ yield). Anal.
Calc. For C31H32BrF2N3o4 + 1.5 HCl: C, 54.50 ~; H, 4.94
N, 6.15 ~. Found: C, 54.62 ~; H, 4.88 ~; N,
5.88 ~. M.p. of the salt: 123 126 °C. [a]Daz - +
53.93 .
Example 39:
4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic
acid t3-L4-(4-fluoro-phenyl)-4-(4-methylsulfanyl-
phenyl)-piperidin-1-yl)-propyl}-amide
mg of the free base was obtained (55~ yield). Anal.
20 Calc . For C31H32F3N3~3~ + 1. 75 HC1 + 0 . 75 EtOAc : C, 57 .23
H, 5.61 ~; N, 5.89 ~. Found: C, 57.28 ~; H, 5.73
N, 5.83 ~. M.p. of the salt: 121 -- 124 °C [a]Da2 - +
33.33.
Example 40:
4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic
acid (3-[4,4-bis-(4-fluoro-phenyl)-piperidin-1-yl]-
propyl)-amide. 24 mg of the free base was obtained (63
yield) . Anal . Calc . For C3oH2IFQN303 + 2 . 0 HCl + 0 .125
CHC13: C, 56.24 ~; H, 4.88 0; N, 6.52 ~. Found: C,
56.39 ~; H, 4.88 ~; N, 6.10 ~. M.p. of the salt: 124 -
126 °C. [a]DZ~ - + 47.33
Example 41:
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4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic
acid (3-[4-(4-fluoro-phenyl)-4-(2-methoxy-5-fluoro-
phenyl)-piperidin-1-yl]-propyly-amide
24 mg of the free base of the tittle product was
obtained ( 59~ yield) . Anal . Calc . For C31H31F4N3~4 + 2 . 0
HCl + 0.5 EtOAc: C, 56.42 ~; H, 5.31 ~; N, 5.98
Found: C, 56.61 ~; H, 5.18 $; N, 5.77 ~. M.p. of the
salt: 130 - 133 °C [a)DZZ= + 38.86.
Example 42:
(+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxyl
is acid
(3-[4-(4-methanesulfonyl-phenyl)-4-phenyl-piperidin-1-yl
]- propyl)- amide, hydrochloride
18 mg of the free base was obtained: Anal. Calc. For
Cj1H31F4N304 + 2.0 HC1 + EtOAc: C, 55.41 0; H, 5.71 ~; N,
5.54 ~. Found: C, 55.82 ~; H, 5.19 ~; N, 5.49 ~.
Example 43:
4-(3,4-Difluorophenyl)-1-(3-(4-(2-pyridyl)piperidin-1-
yl)-propyl)aminocarbonyl-2-imidazolidone.
a. 2-Amino-2-(3,4-difluorophenyl)-acetonitrile:
To a mixture of 3,4-difluorobenzaldehyde (2.0 g, 14.07
mmol) and trimethylsilylcyanide (2.34 ml, 17.59 mmol),
catalytic amount of Zinc Iodide was added at 0°C. After
stirring for 15 minutes at room temperature a saturated
solution of methanolic ammonia (15 ml) was added in one
lot at 0°C. The reaction mixture was then stirred for 4
hours at 40 °C. After evaporation of the solvent the
residue was purified by column chromatography
(hexanes:ethyl acetate;3:2) to yield 1.98 g of the
product as a brown syrup.
b. 1-(3,4-Ditluorop~aen~rl)ethane-1,2-diamina:
To Lithium aluminium hydride in ether (50.7 ml, 50.76
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mmol), at 0°C, cyano amine in ether (80 ml) slowly over
a period of 10 minutes. The solution was then allowed
to stir at room temperature for 1 hour. The reaction
mixture was cooled to 0°C and quenched with water (2
ml), 15~ NaOH (2 ml) and water (10 ml). The mixture was
then filtered, the residue was repeatedly washed with
ethylacetate. The solution was then concentrated to
yied 2.71 g (93~) of the crude product as an oil which
was then used for the subsequent step.
c. 4-(3,4-Difluorophenyl)-2-imidazolidone:
To the diammine (1.667 g, 9.68 mmol) in dichloromethane
(20m1), triethylamine (1.34 ml, 9.68 mmol) was added
slowly and the reaction was cooled to -78°c. Then
triphosgene (3.01 g, 10.16 mmol) was added to the
solution over a period of 30 minutes. The reaction
mixture was then stirred at -78°C for 5 minutes. The
reaction mixture was quenched with water and partitioned
between dichloromethane (20 ml) and water, washed with
10 ml 10~ KOH solution, dried over sodium sulfate,
filtered and concentrated. The product was then
purified by column purified (hexanes:ethyl acetate 2:3)
to yield 0.995 g (52~) of a yellow solid.
d. 4-(3,4-Difluorophenyl)-2-imidazolidone-1-carboxylic
acid 4-nitrophenyl ester:
To sodium hydride (0.069 g, 2.74 mmol) in THF (10 ml),
4-(3,4-difluorophenyl)-2-imidazolidone (0.5g, 2.49 mmol)
was added at 0°C. The solution was then stirred at room
temperature for 15 minutes. It was then added to a
solution of 4-nitrophenyl chloroformate (0.5528, 2.74
mmol) at -78°C via a cannula. The reaction mixture was
then allowed to stir at room temperature for 8 hours.
It was then concentrated and partitioned between ethyl
acetate (20 ml) and water (5 ml), washed with 10 ~KOH
(10 ml), dried over sodium sulfate, filtered and
concentrated. Purification by column chromatography
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(hexanes:ethylacetate 2:3) yielded 0.04 g (4.4 ~) of the
product as a light brown syrup.
e. 4-(3,4-Difluorophenyl)-1-(3-(4-(2-pyridyl)piperidin-
1-yl)-propyl)aminocarbonyl-2-imidazolidone:
To 4-(3,4-difluorophenyl)-1-(4-nitrophenoxy)carbonyl-2-
imidazolidone (0.05 g, 0.137 mmol) in THF (10 mL) was
added 1-(3-aminopropyl)-4-(2-pyridyl}piperidine (0.036
g, 0.165 mmol) and the solution was stirred at room
temperature for 16 hours. Tyre solution was then
concentrated and the residue flash chromatographed
(ethyl acetate:methanol 4:1) to yield 0.038 g (59~} of
the product as a brown syrup. It was dissolved in
dichloromethane (2 mL) and treated with 1N HCl in ether
(0.5 mL). The solution was concentrated under reduced
pressure. Recrystallization of the residue from ether
gave 0.029 g (60 ~) of the hydrochloride salt as a brown
solid: mp 148-150°C. Anal. Calcd. for C23HZ9FzN4O3C1z-0.5
CC14: C, 51.90; H,4.90; N, 11Ø Found: C, 54.23; H
5.17; N, 10.84.
Example 44:
3-(4-(4-Cyano-4-phenylpiperidin-1-yl)piperidin-1-
yl)carbonyl-4-(3,4-difluorophenyl)-2-imidazolidone.
a. 4-(3,4-Difluorophenyl)-2-imidazolidone-3-carboxylic
acid 4-nitrophenyl ester:
To sodium hydride (0.069 g, 2.74 mmol) in THF (10 ml),
4-(3,4-difluorophenyl)-imidazolidin-2-one (0.5g, 2.49
mmol) was added at 0°C. The solution was then stirred
at room temperature for 15 minutes. It was then added
to a solution of 4-nitrophenylchloroformate (0.552g,
2.74 mmol) at -78°C via a cannula. The reaction mixture
was then allowed to stir at room temperature for 8
hours. It was then concentrated and partitioned between
ethyl acetate (20 ml} and water (5 ml), washed with 10
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~KOH (10 ml), dried over sodium sulfate, filtered and
concentrated. Purification by column chromatography
(hexanes:ethylacetate; 2:3) to yield 0.04 g (4.4 ~) of
the product as a light brown syrup.
b. 3-(4-(4-Cyano-4-phenylpiperidin-1-yl)piperidin-1-
yl)carbonyl-4-(3,4-difluorophenyl)-2-imidazolidone:
To 4-(3,4-difluorophenyl)-3-(4-nitrophenoxy)carbonyl-2-
imidazolidone.(0.04 g, 0.110 mmol) in THF (10 mL) was
added 4-(4-cyano-4-phenylpiperidin-1-yl)piperidine
(0.0355 g, 0.132 mmol) and the solution was stirred at
room temperature for 16 hours. The solution was then
concentrated and the residue flash chromatographed
(ethyl acetate:methanol 4:2) to yield 0.024 g (44~) of
the product as a brown syrup. It was dissolved in
dichloromethane (2 mL) and treated with 1N HC1 in ether
(0.5 mL). The solution was concentrated under reduced
pressure. Recrystallization of the residue from ether
gave 0.029 g (96~) of the hydrochloride salt as a white
solid: mp 243-245°C. Anal. Calcd. for CZ.,H3oC1F2N50z'0.4
CHC13: C,56.96; H,5.30; N, 12.22. Found: C, 57.08; H
5.20; N, 11.90.
Example 45
4-(3,4-Difluorophenyl)-3-methyl-1-(3-(4-(2-
pyridyl)piperidin-1-yl)propyl)aminocarbonyl-2-
imidazolidone.
a. 2-(3,4-Difluorophenyl)-2-methylamiao-acetonitrile:
To a mixture of 3,4-difluorobenzaldehyde (4.0 g, 28.0
mmol) and trimethylsilylcyanide (4.69 mL, 35.1 mmol),
catalytic amount of Zinc Iodide was added at 0°C. After
stirring for 15 minutes at room temperature a saturated
solution of methylammonia (15 niL) was added in one lot
at 0°C. The reaction mixture was then stirred for 4
hours at 40°C. After evaporation of. the solvent the
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residue was purified by column chromatography
(hexanes:ethylacetate 3:2) to yield 4.719 g (92~) of the
product as a brown syrup.
b. 2-(3,4-Difluorophenyl)-2-methylamino-ethylamine:
To Lithium aluminum hydride in ether (49.41 mL, 49.4
mmol), at 0°C, 2-(3,4-difluorophenyl)-2-methylamino-
acetonitrile (3.0 g, 16.47 mmol) in ether (80 mL) slowly
over a period of 10 minutes. The solution was then
allowed to stir at room temperature for 1 hour. The
reaction mixture was cooled to 0°C and quenched with
water (2 mL), 15~ NaOH (2 mL) and water (10 mL). The
mixture was then filtered, the residue was repeatedly
washed with ethylacetate. The solution was then
concentrated to yield 2.71 g (93~) of the crude product
as an oil.
c. 4-(3,4-Difluorophenyl)-3-methyl-2-imidazolidoae:
To 2-(3,4-difluorophenyl)-2-methylamino-ethylamine
(1.048 g, 5.68 mmol) in dichloromethane (20mL), 1,1-
carbonyldiimidazole (1.09 g, 6.75 mmol) was added slowly
and the reaction was stirred at room temperature for 24
hours. It was then concentrated and purified by column
chromatography (hexanes:ethylacetate; 1:4) to yield
0.876 g (73~) of a yellow solid.
d. 4-(3,4-Difluorophenyl)-3-methyl-1-(3-(4-(2
pyridyl)piperidin-1-yl)propyl)aminocarbonyl-2
imidazolidone.
To a solution of 4-(3,4-difluorophenyl)-3-methyl-2-
imidazolidone (0.15 g, 0.706 mmol) in THF (10 mL) cooled
at 0°C, lithium bis(trimethylsilyl)amide in THF (0.848
mL, 0.848 mmol) was added slowly and the solution was
stirred at room temperature for 15 minutes. After
cooling to -78°C, phosgene (0.729 g, 7.06 mmol) was
added and the solution was s~.irred at -78°C for 1 hour.
It was then concentrated to give an intermediate
(0.1948, 0.703 mmol) which was immediately dissolved. in
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THF (10 mL) at -78°C and treated with 1-(3-aminopropyl)-
4-(2-pyridyl)piperidine (0.231 g, 1.05 mmol) and
triethylamine (0.106 g, 1.055 mmol), and the solution
was stirred at room temperature for 24 hours. It was
then concentrated, and the residue partitioned between
dichloromethane (25 mL) and water (5 mL). The organic
layer was washed with 10~ KOH solution (5 mL), dried
over sodium sulfate, filtered and concentrated.
Purification of the residue by flash chromatography
(ethyl acetate: methanol 24:1) yielded 0.030 g (9~) of
the product as a syrup. It was dissolved in
dichloromethane (2 mL) and treated with 1N HC1 in ether
(0.5 mL). The solution was concentrated under reduced
pressure. Recrystallization of the residue from ether
gave 0.030 g (88~) of the dihydrochloride salt as a pale
yellow solid: mp 120-122°C. Anal. Calcd. for
Cz4H31C1FzN50z'0.95 CHC13: C, 46 . 54; H, 5 . 00; N, 10. 88 .
Found: C, 46.30; H 5.35; N, 11.20.
Example 46:
4-(3,4-Difluorophenyl)-3-(3-(4-(2-mothoxyl-5-
methyl)phenyl-4-phenylpiperidin-1-
yl)propyl)aminocarbonyl-2-imidazolidone.
a. 1-(3,4-Difluorophenyl)-2-tritylamino-ethylamine:
To a solution of 1-(3,4-difluorophenyl)-ethane-1,2-
diamine (6 g, 35.6 mmol) in dichloromethane (100 ml),
diazabicycloundecane (DBU)(5.87 mL, 39.2 mmol) was added
and the solution cooled to 0°C. Trityl chloride (10.94
g, 39.2 mmol) in dichloromethane (100 ml) was added
slowly.to the cooled solution. After addition the
solution was stirred at room temperature for 24 hours.
The soution was then concentrated, partitioned between
chloroform (100 ml) and water (25 ml), washed with 1N
KOH (10 mL), filtered, and concentrated. Purification
by column chromatography (hexanes:ethyl acetate 3:2)
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yielded 6.75 g (46 ~} of the product as a brown syrup.
b. 4-(3,4-Difluorophenyl)-1-trityl-2-imidazolidone:
To a solution of 1-(3,4-difluorophenyl)-2-tritylamino-
ethylamine (6.75g, 16.44 mmol) in THF (200 mL), 1,1-
carbonyldiimidazole (3.2 g, 19.7 mmol) was added and the
solution was stirred at room temperature for 12 hours.
The solution was concentrated and purified by column
chromatography (hexanes:ethylacetate 3:2) to yield 5.55
g (77~) of the product as a white solid.
c. 4-(3,4-Difluorophenyl)-1-trityl-2-imidazolidone-3-
carboxylic acid 4-nitrophenyl ester:
To sodium hydride (95 0 (0.189 g, 7.49 mmol) in THF (150
ml), 4-(3,4-Difluorophenyl)-~-trityl-2-imidazolidone
(3.0 g, 6.81 mmol) was added at 0°C. The solution was
then stirred at room temperature for 15 minutes. It was
then added to a solution of 4-nitrophenylchloroformate
(1.647 g, 8.17 mmol) at -78°C via a cannula. The
reaction mixture was then allowed to stir at room
temperature for 12 hours. It was then concentrated and
partitioned between ethyl acetate (30 ml) and water (5
ml), washed with 10 ~KOH (10 ml), dried over sodium
sulfate, filtered and concentrated. Purification by
column chromatography (hexanes:ethylacetate; 2:3) to
yield 2.1 g (51~) of the product as a light brown syrup.
d. 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxy-5-
methyl)phenyl-4-phenylpiperidin-1-
yl)propyl)aminocarbonyl-1-trityl-2-imidazolidone:
To 4-(3,4-difluorophenyl)-3-(4-nitrophenoxy)carbonyl-1-
trityl-2-imidazolidone (0.089, 0.147 mmol) in THF (5 mL)
was added 3-(4-(2-methoxy-5-methyl)phenyl-4-
phenylpiperidin-1-yl)propylamine (0.055 g, 0.162 mmol)
and the solution was stirred at room temperature for 16
hours. The solution was then concentrated and i:he
residue flash chromatographed (hexanes:ethyl acetate
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1:4) to yield 0.08 g (68~) of the product as a syrup.
e. 4-(3,~-Difluorophenyl)-3-(3-(4-(2-methoxyl-5-
methyl)phenyl-4-phenylpiperidin-1-
yl)propyl)aminocarbonyl-2-imidazolidone:
To 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxyl-5-
methyl)phenyl-4-phenylpiperidin-1-
yl)propyl)aminocarbonyl-1-trityl-2-imidazolidone (0.100
g, 0.124 mmol) in dichloromethane (2 mL) at 0°C,
trifluoroacetic acid (4 mL) in dichloromethane (2 mL)
was slowly added and the solution was stirred at room
temperature for 20 minutes. The solution was then
concentrated, neutralized with 10~ KOH and extracted
into dichloromethane (20 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated.
Purification of the residue by flash chromatography
(ethyl acetate) yielded 0.06 g (87~) of a white foam. To
it in dichloromethane (2 mL), 1N HC1 in ether (0.5 mL)
was added, and the solution concentrated under reduced
pressure. Recrystallization of the residue from ether
gave 0.061 g (96 ~) of a hydrochloride salt as a white
solid: mp 173-175°C. Anal. Calcd. for C3zH36C1F2NgO3~1.20
CHC13: C, 53.72; H,5.19; N, 7.55. Found: C, 53.76; H
5.01; N, 7.36.
Example 47:
(-)-3-(3-(4-Cyano-4-phenylpiperidin-1-yl)-2(S)-
methylpropyl)-aminocarbonyl-4-(3,4-difluorophenyl)-2-
imidazolidone.
a. 4-Cyano-1-(3-hydroxy-2(S)-methylpropyl)-4-
phenylpiperidine:
A mixture of 4-cyano-4-phenylpiperidine hydrochloride
(1.89 g, 8.49 mmol) and (S)-3-bromo-2-methyl-1-propanol
(1.0 g, 6.53 mmol), potassium carbonate (2.709 g, 19.6
mmol) and sodium iodide (1.17 g, 7.84 mmol) in acetone
(20 mL) was refluxed for 12 hours. The solution was
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cooled to room temperature and concentrated. The
residue was partitioned between ethyl acetate (25 mL)
and water (10 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated. Purification
of the residue by flash chromatography (hexanes:ethyl
acetate 2:3) yielded 1.45 g (86~) of the product as a
syrup.
b. 1-(3-Azido-2(S)-mathylpropyl)-4-cyano-4-
phenylpiperidiae:
To a solution of 4-cyano-1-(3-hydroxy-2(S)-
methylpropyl)-4-phenylpiperidine (1.0 g, 3.87 mmol),
triphenyl phospine (1.01 g, 3.87 mmol)and diethyl
azodicarboxylate (0.609 g, 3.87 mmol) in THF (20 mL) was
slowly added diphenylphosporylazide (0.83 mL, 3.87 mmol)
and the solution was stirred at room temperature for 24
hours_ The solution was then concentrated and flash
chromatographed (hexanes:ethyl acetate 3:2) to yield
0.963 g (88~) of the product as a light brown syrup.
c. 1-(3-Amino-2(S)-methylpropyl)-4-cyaao-4-
phenylpiperidine:
To a solution of 1-(3-azido-2(S)-methylpropyl)-4-cyano-
4-phenylpiperidine (0.96 g, 3.39 mmol) in ethyl acetate
(10 mL) was added trimethylphosphine (8.4 mL, 8.49 mmol)
and water (0.30 mL, 16.9 mmol) and the solution was
stirred at roomtemperature for 24 hours. The solution
was then concentrated and flash chromatographed (ethyl
acetate: methanol:methanolic ammonia 3:1:1) to yield 0.60
g (69~) of the crude product as a syrup.
d. (-)-3-(3-(4-Cyano-4-phenylpiperidine-1-yl)-2(S)-
methylpropyl)-aminocarbonyl-4-(3,4-difluoro)phenyl-1-
trityl-2-imidazolidone:
To 4-(3,4-difluoro)phenyl-3-(4-nitrophenoxy)carbonyl-1-
trityl-2-imidazolidone (0.49 g, 0.809 mmol) in THF (10
mL) was added 1-(3-amino-2(S)-methyl)propyl-4-cyano-4-
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phenylpiperidine (0.250 g, 0.92 mmol) and the solution
was stirred at room temperature for 16 hours. The
solution was then concentrated and flash chromatographed
(ethyl acetate:methanol 4:1) to yield 0.441 g (73~) of
the product as a syrup.
e. (-)-3-(3-(4-Cyano-4-phenylpiperidin-1-yl)-2(S)-
methyl)propyl-aminocarbonyl-4-(3,4-difluorophenyl)-2-
imidazolidone:
To (-)-3-(3-(4-Cyano-4-phenylpiperidine-1-yl)-2(S)-
methylpropyl)-aminocarbonyl-4-(3,4-difluoro)phenyl-1-
trityl-2-imidazolidone (0.441 g, 0.607 mmol) in
dichloromethane (2 mL) at 0°C was added trifluoroacetic
acid (4 mL) in dichloromethane (2 mL) and the solution
was stirred at room temperature for 20 minutes. The
solution was then concentrated, neutralized with 10~ KOH
and extracted into dichloromethane (20 mL). The organic
layer was dried over sodium sulfate, filtered and
concentrated. Purification of the residue by column
chromatography (ethyl acetate) yielded 0.293 g (100~)of
the product as a syrup. The two diastereomers were
seperated by using Chiralcel OD (20 x 250 mm) column
with hexanes/2-propanol/diethylamine (60:40:0.1)as the
eluent.
To the desired diastereomer (0.016 g, 0.0332 mmol)
in dichloromethane (2 mL) was added 1N HC1 in ether (0.5
mL) and the solution concentrated under reduced
pressure. Recrystallization of the residue from ether
gave 0.016 g (94~) of the hydrochloride salt as a white
solid: [a]D = - 5.32 (8.0 mg/mL MeOH); mp 265-267°C.
Anal.Calcd. for C26H30C1FZN5O2~0.15 CHC13: C, 58.61; H,
5.67; N, 12.07. Found: C, 58.50; H 5.90; N, 12.10.
~:xample 4~8:
(+)-3-(3-(4-cyano-4-(2,4-dichloro)phenylpiperidin-1-
yl)propyl)aminocarbonyl-4-(3,4-difluorophenyl)-2-
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oxazolidinoae.
a. 4-Cyaao-4-(2,4-dichlorophenyl)-piperidine-1-
carboxylic acid tart-butyl ester:
To bis(2-chloroethyl)-carbamic acid tert-butyl ester
(l.Og, 3.8 mmol) and (2,4-dichloro)phenyl
acetonitrile(0.708 g, 3.8 mmol) in DMF (35 mL) was added
NaH (95 0 (0.258 g, 9.68 mmol) in one lot at 0°C. The
solution was stirred for 10 minutes at room temperature.
When the foaming subsided, the solution was heated at
60°C for 24 hours. It was then quenched with water at
0°C and concentrated. The residue was extracted with
ethyl acetate (25 mL) and washed with water (3 x 15 mL).
The organic layer was dried over sodium sulfate,
filtered and concentrated. Purification of the residue
by column chromatography (hexane: ethyl acetate 4:1)
yielded 0.620 g (45~) of the product as a syrup.
b. t3-I4-Cyano-4(2,4-dichlorophenyl)-piperidin-1-yl?-
propyl~-carbamic acid tart-butyl ester:
To 4-cyano-4-(2,4-dichlorophenyl)-piperidine-1-
carboxylic acid tert-butyl ester (0.620 g, 1.74 mmol) in
dichloromethane (5 mL), trifluoroacetic acid (2 mL) was
added and the solution stirred at room temperature for 1
hour. The solution was concentrated, neutralized with
10 ~ KOH solution and extracted into 25 ml of
dichloromethane. The organic layer was dried over
sodium sulfate, filtered and concentrated to give 0.442
g (99~) of 4-(2,4-dichlorophenyl)-piperidine-4-
carbonitrile which was used as such for the subsequent
step.
To a stirred solution of the 4-(2,4-
dichlorophenyl)piperidine-4-carbonitrile (0.736 g, 2.88
mmol) in acetone (20 mL) was added N-(tert-
butoxycarbonyl)-3-br~mopropylamine (0.754 g, 3.17 mmol,
potassium carbonate (1.594 g, 11.53 mmol) and sodium
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iodide (0.865 g, 5.7 mmo1) and the solution refluxed for
24 hours. The reaction mixture was cooled to room
temperature; concentrated and partitioned between
chloroform (30 mL) and water (5 mL). The organic layer
was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by column
chromatography (ethyl acetate) to yield 0.925 g (78 ~)
of the required product as a colorless oil.
c. (+)-3-(3-(4-cyano-4-(2,4-dichloro)phenylpiperidin-1-
yl)propyl)ami.nocarbonyl-4-(3,4-difluorophenyl)-2-
oxazolidinone:
To 3-[4-cyano-4-(2,4-dichlorophenyl)-piperidin-1-yl]-
propyl-carbamic acid tert-butyl ester (0.589, 1.42 mmol)
in dichloromethane (5 mL), trifluoroacetic acid (1 mL)
was added and the solution stirred at room temperature
for 1 hour. The solution was concentrated, neutralized
with 10 ~ KOH solution and extracted into 25 mL of
dichloromethane. The organic layer was dried over
sodium sulfate, filtered and concentrated to give 0.423
g (93~) of 1-(3-aminopropyl)-4-(2,4-dichlorophenyl)-
piperidine-4-carbonitrile which was used as such for the
subsequent step.
To 4-(3,4-difluorophenyl)-2-oxazolidinone-3-
carboxylic acid 4-nitrophenyl ester (0.03 g, 0.0823
mmol) in dry THF (10 mL) was added 1-(3-aminopropyl)-4-
(2,4-dichlorophenyl)piperidine-4-carbonitrile(0.03 g,
0.0823 mmol) and the solution was stirred at room
temperature for 24 hours. The reaction mixture was
concentrated and purified by column chromatography
(hexanes:ethyl acetate 1:4) to yield 0.04 g (91~) of the
product as a foamy syrup. To the syrup (0.040 g, 0.0744
mmol) in 4 mL of dichloromethane, 5 mL of 1N HC1 in
ether was added, and the solution concentrated under
reduced pressure. Recrystallization of the residue from
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ether gave 0.040 g (94 ~) of the product as a white
solid: mp 204-206 °C; [a]D = 48.8 (1.55 mg/mL MeOH).
Anal . Calcd. for CzSHasFzNa03Clz - 0 . 60 CH2C12 : C, 49 . 21; H,
4.21; N, 8.97. Found: C, 49.44; H 4.39; N, 8.66.
Example 49:
(+)-3-(3-(4-Aminocarbonyl-4-(4-chloro)phenylpiperidin-1-
yl)-propyl)aminocarbonyl-4-(3,4-difluoro)phenyl-2-
oxazolidinone.
a. 3-(4-Cyano-4(4-chlorophenyl)piperidin-1-
yl)propylcarbamic acid tart-butyl ester:
To bis(2-chloroethyl)-carbamic acid tart-butyl ester
(1.0 g, 3.8 mmol) and (4-chloro)phenyl acetonitrile
(0.624 g, 4.12 mmol) in DMF (35 mL) was added NaH (95
$)(0.260 g, 10.30 mmol) in one lot at 0°C. The solution
was stirred for 10 minutes at room temperature. When
the foaming subsided, the solution was heated at 60°C
for 45 minutes. It was then quenched with water at
0°C,. partitioned between ethyl acetate (25 mL) and
brine (3 x 20 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated to yield 0.76
g (56 ~) of the crude product which was used as such for
the subsequent step.
To 4-cyano-4-(4-chlorophenyl)piperidine-1-carboxylic
acid tart-butyl ester (0.85 g, 2.64 mmol) in
dichloromethane (2 mL) was added 2 mL of trifluoroacetic
acid and the solution stirred at room temperature for 1
hour. The solution was concentrated, neutralized with
10 ~ KOH solution and extracted into 25 mL of
dichloromethane. The organic layer was dried over
sodium sulfate, filtered and concentrated under reduced
pressure. iPurification of the residue by column
chromatography (ethyl acetate: methanol:methanolic
ammonia 8:1:1) yielded 0.482 g (82 ~) of the product as
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a syrup.
b. 3-(4-(4-Chloroph~nyl)-4-cyanopiperidin-1-
yl)propylcarbamic acid tart-butyl ester:
To a stirred solution of the 4-(4-
chlorophenyl)piperidine-4-carbonitrile (0.482 g, 2.18
mmol) in acetone (20 mL) was added N-(tert-
butoxycarbonyl)-3-bromopropylamine (0.572 g, 2.4 mmol,
potassium carbonate (1.20 g, 8.7 mmol) and sodium iodide
(0.655 g, 4.36 mmol) and the solution refluxed for 24
hours. The reaction mixture was cooled to room
temperature, concentrated and partitioned between
chloroform (20 mL) and water (5 mL). The organic layer
was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by column
chromatography (ethyl acetate) to yield 0.655 g (71 ~)
of the required product as a colorless oil.
c. (+)-3-(3-(4-Aminocarbonyl-4-(4-
chloro)phenylpiperidin-1-yl)-propyl)aminocarbonyl-4-
(3,4-difluoro)phenyl-2-oxazolidinone:
3-(4-(4-chlorophenyl)-4-cyanopiperidin-1-
yl)propylcarbamic acid tent-butyl ester (0.150 g, 5.39
mmol) in conc. HZS04 (1 mL) was stirred at room
temperature for 30 hours. The solution was
concentrated, neutralized with 10 ~ KOH solution and
extracted into 25 mL of dichloromethane. The organic
layer was dried over sodium sulfate, filtered and
concentrated to give 0.185 g (79~) of 1-(3-aminopropyl)-
4-(4-chlorophenyl)piperidine-4-carboxamide which was
used as such for the subsequent step.
To 4-(3,4-difluorophenyl)-3-(4-
nitrophenoxy)carbonyl-2-oxazolidinone (0.040 g, 0.109
mmol) in 10 mL of dry THF was added 1-(3-aminopropyl)-4-
(4-chlorophenyl)-piperidine-4-carboxamide (0.042 g,
0.141 mmol) and the solution was stirred at room
temperature for 24 hours. The reaction mixture was
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concentrated and purified by column chromatography
(ethyl acetate: MeOH 9:1) to yield 0.025 g (44~) of the
product as a foamy syrup. To the syrup (0.025 g, 0.048
mmol) in dichloromethane (2 mL) was added 1N HCl in
ether (0.5 mL) and the solution concentrated under
reduced pressure. Recrystallization of the residue from
ether gave 0.021 g (80 ~) of the product as a white
solid: mp 140-142 °C; [a]D = 52.0(1.3 mg/mL MeOH).
Anal. Calcd. for CZSHz~C12F2N404'1.7 CHZCIz: C, 45.70; H,
4.51; N, 7.96. Found: C, 45.75; H 4.64; N,7.96.
Example 50:
(+)-3-(5-(4-Cyano-4-phenylpiperidin-1-yl)pent-2(E)-en-1-
yl)-4-(3,4-difluoro)phenyl-2-oxazolidinone.
To a solution of 4-(3,4-difluorophenyl)-2-oxazolidinone
(0.2 g, 1 mmol) and HMPA (0.18 g, 1 mmol) in THF (6 mL)
was added NaH (44 mg, 1.1 mmol, 60~ in mineral oil) at
room temperature. After 30 min, 1,5-dibromo-2-pentene
(0.34 g, 1.5 mmol) was added to the mixture. the mixture
was stirred at room temperature for 4 h. After removal
of solvent, the residue was flash chromatographed over
silica gel (1:1 hexane-ethyl acetate) to give a mixture
of two isomers in 40~ yield as a yellow oil.
This oil (0.14 g, 0.4 mmol) was mixed with 4-cyano-
4-phenylpiperidine hydrochloride (0.18 g, 0.8 mmol),
potassium carbonate (0.2 g, 1.4 mmol), sodium iodide (61
mg, 0.4 mmol) in acetone (6 mL) and was refluxed
overnight. After removal of the solvent, the residue was
flash chromatographed over silica gel (ethyl acetate) to
give a mixture of two isomers in 22~ yield as a yellow
oil. HPLC separation (column: Primesphere Si02 Sum, 21.2
x 250 mm, eluent: 75:25:0.1 ethyl acetate-hexane-
triei:hylamine) gave the desired product (20 mg) as a
yellow oil. It was treated with 1.0 equivalent of HC1 to
give a salt as a yellow solid: mp 168-170°C; ESMS m/e =
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452 (MH+) ; [a]D = 45.0 (0.4 mg/mL CHZCIz) . Anal. Calcd.
for CZ6HZ.,F2N30z'HC1'1.OH20: C, 61.72; H, 5.98; N, 8.30.
Found: C, 61.79; H, 5.88; N, 8.26.
Example 51: trsas (+)-4-(3,4-Difluorophenyl)-5-methyl-2-
oxo-oxazolidine-3-carboxylic acid(3-[4-(4-fluoro-2-
methylphenyl)-piperidin-1-yl~propyl)amide
a. .3-[4-(4-fluoro-2-methylphenyl)-piperidin-1-y~]-
propylamine was synthesized as described in Example 22,
Step c, and was used in the next step without further
purification.
b. traas (+)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-
oxazolidine-3-carboxylic acidi3-(4-(4-fluoro-2-
methylphenyl)-piperidin-1-yl]propyl)amide
As described in Example 18, step i, the trans (+)-4-
(3,4-difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-
carboxylic acid-4-vitro-phenyl ester (0.03 g, 0.08 mmol)
was converted into trans (+)-4-(3,4-difluorophenyl)-5-
methyl-2-oxo-oxazolidine-3-carboxylic acid{3-[4-(4-
fluoro-2-methylphenyl)-piperidin-1-yl]propyl}amide,
using the side chain described in step a above, with 75~
yield. It was converted into the hydrochloride salt.
M.P. - 80-83°C; [a]D = + 23.0 (c = 0.12, MeOH); Anal.
Calcd. for Cz5H29N3~3F3C1Ø23 HzO: C, 58.91; H, 5.98; N,
7.93. Found: C, 58.91; H, 6.37; N, 7.73.
Example 52: (+)-8-(3,4-Difluorophenyl)-6-oxo-5-oxa-7-
aza-spiro(3.4]octan-7-carboxylic acid-{3-[4-(4-
fluoro)phenyl)-piperidin-1-yl]-propyl~-amide
a. Benzhydrylindene-(3,4-difluoro-benzyl)-amine
To a solution of 3,4-difluorobenzylamine (9.8 g, 69
mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene
(200 mL) was added a catalytic amount of BF3.OEtz and
the resulting solution was stirred at reflux for 12 h.
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The reaction mixture was concentrated in vacuo, yielding
an oil (21 g, >95~), which was characterized by NMR
analysis and subjected to the following reaction without
any further purification.
b. 1-((Benzhydryliden-amino)-(3,4-difluoro-
phenyl)methyl)-cyclobutanol
To a solution of the imine (2.5 g, 8.1 mmol) in 50 mL of
dry THF was added tent-butyllithium (1.7 M, 6.2 mL)
dropwise and the resulting solution was stirred at -78°C
for 0.5 h. To the solution was added cyclobutanone
(0.74 ml, 9.9 mmol) in 20 ml of THF and the solution was
stirred at -78 °C for 2 h and 25 °C for 1 h. The
reaction was quenched by adding 1.0 mL of dilute acetic
acid. Reaction mixture was diluted with 100 ml of EtzO
and washed with brine. The organic layer was dried over
Na2S04 and concentrated in vacuo, yielding 1-
[(benzhydryliden-amino)-(3,4-difluoro-phenyl)methyl]-
cyclobutanol as an oil, which was subjected to the
following reaction without purification.
c. 1-(Amino-(3,4-difluoro-phenyl)methyl]-cyclobutanol
The crude batch of 1-[(benzhydryliden-amino)-(3,4-
difluoro-phenyl)methyl]-cyclobutanol obtained from the
above reaction and MeONH2.HC1 (1.35 g, 16.2 mmol) was
dissolved in 125.0 mL of MeOH and stirred for 12 h. The
reaction mixture was concentrated in vacuo, yielding
oily residue which was redissolved in 100 ml of EtOAc
and was washed with 2.0 M NaOH followed by brine. The
organic layer was separated, dried over Na2S09 and then
concentrated in vacuo to give 1-[amino-(3,4-Difluoro-
phenyl)methyl]-cyclobutanol as an oil which was used in
the next step without any purification.
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d. [(3,4-Difluorophenyl)-(1-hydroxy-cyclobutyl)-methyl~-
carbamic acid-tart-butyl ester
To a solution of 1-[amino-(3,4-difluoro-phenyl)methyl]
cyclobutanol (approximately 8.1 mmol) in CHzCl2 (50 mL)
at 0°C was added a solution of di-tart-butyl dicarbonate
(3.5 g, 16.2 mmol) in one portion and the resulting
solution was stirred for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
subjected to column chromatography on silica gel (9:1
cyclohexane-EtOAc followed by 4:1 cyclohexane-EtOAc) to
obtain [(3,4-difluorophenyl)-(1-hydroxy-cyclobutyl)-
methyl]-carbamic acid-tart-butyl ester as a viscous oil
(1.0 g, 40~ yield over four steps).
e. 8-(3,4-Difluorophenyl)-5-oxa-7-aza-spiro[3.4]octan-6-
one
To a well stirred solution of [(3,4-difluorophenyl)-(1-
hydroxy-cyclobutyl)-methyl]-carbamic acid-tart-butyl
ester (1.0 g, 3.2 mmol) in THF (20 mL) was added 95~ NaH
(0.2 g, 8.3 mmol) at room temperature. The resulting
suspension was stirred for 3 h at about 35°C (warm water
bath) and then quenched carefully with ice. The
biphasic mixture was extracted with 100 mL of EtOAc,
washed with brine, dried over NaZS04, filtered and the
solvent was removed in vacuo to yield 8-(3,4-
difluorophenyl)-5-oxa-7-aza-spiro[3.4]octan-6-one in
racemic form as a white solid.
The (+) and (-) enantiomers were separated by HPLC
by using Chiralcel OD (4.6 x 250 mm) using 80~
hexane/20~ isopropyl alcohol/ 0.1 ~ diethylamine as the
eluting system (12 mL/min) under isothermal conditions
(U. V. 254 nM). The retention times for the two isomers
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of were 12.1 min {[a]D = - 20.0 (c = 0.35, MeOH)} and
15.6 min {[a]D = + 23.7 (c = 0.52,MeOH)}respectively.
The (-)-enantiomer was used in the next step (0.308, 35~
yield).
f. (+)-8-(3,4-Difluorophenyl)-6-oxo-5-oxa-7-aza-
spiro[3.4]octan-7-carboxylic acid-4-nitrophenyl]aster
To a solution of (-)-8-(3,4-difluorophenyl)-5-oxa-7-aza-
spiro[3.4]octan-6-one (0.25 g, 0.63 mmol) in 10 mL THF
was added a solution of n-butyllithium in hexane (0.47
mL, 0.76 mmol) dropwise via a syringe under argon
atmosphere at -78°C. The resulting yellow solution was
stirred at -78°C for 50 min. This solution was then
added dropwise via a cannula into another round bottom
flask containing a solution of 4-
nitrophenylchloroformate (0.15 g, 0.76 mmol) inl0 mL of
THF, cooled at -78°C, over a period of 15 min. After
five minutes, the flask was removed from the cooling
bath and stirring was continued for 1 h. The reaction
was quenched by adding ice and it was extracted with
EtOAc. The organic extracts were washed with brine and
the organic layer was dried over NaZS04. The solvent was
removed after filtration and the residue was purified by
column chromatography on silica gel with 4:1
cyclohexane-ethyl acetate to obtain (+)-8-(3,4-
difluorophenyl)-6-oxo-5-oxa-7-aza-spiro[3.4]octan-7-
carboxylic acid-4-nitrophenyl]ester as a thick syrup
which solidified upon standing (0.19 g, 75~). [a]D = +
42.0 (c = 0.65, MeOH).
g. (+)-8-(3,4-Difluorophenyl)-6-oxo-5-oxa-7-aza-
spiro[3.4~octan-7-carboxylic acid-(3-[4-(4-
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fluoro)phenyl)-piperidin-1-yl]-propyl)-amide
To a solution of 3-[4-(4-
fluorophenyl)piperidin-1-yl]propylamine (0.02 g, 0.08
mmol) in 10 mL of THF (+)-8-(3,4-difluorophenyl)-6-oxo-
5-oxa-7-aza-spiro[3.4]octan-7-carboxylic acid-4-
nitrophenyl]ester (0.02 g, 0.05 mmol) was added and the
resulting yellow solution was stirred under argon
atmosphere for 10 h at room temperature. The solvent
was removed in vacuo and the residue was purified by
column chromatography over silica gel with EtOAC
followed by 15~ MeOH in EtOAC as the eluting systems (Rf
- 0.4, 1:3 MeOH/EtOAC) to obtain (+)-8-(3,4-
difluorophenyl)-6-oxo-5-oxa-7-aza-spiro[3.4]octan-7-
carboxylic acid-{3-[4-(4-fluoro)phenyl)-piperidin-1-yl]-
propyl}-amide as a pale yellow oil(0.02 g, 89~). It was
converted into its hydrochloride salt by dissolving it
into 5 mL of EtOAc and then treating it with 1.0 mL of
HCl in Et20 (1.0 M). Mass spectrum showed M+1 peak.
Example 53: (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-
oxo-oxazolidine-3-carboxylic acid-(3-[4-(4-fluoro-2-
methyl-phenyl)-piperidini-yl]-propyl)-amide
a. 2-(Benzhydryliden-amino)-1-cyclopropyl-2-(3,4-
difluoro-phenyl)-ethanol
To a solution of benzhydrylindene-(3,4-difluoro-benzyl)-
amine (2.5 g, 8.1 mmol) in 50 mL of dry THF was added
tert-butyllithium (1.7 M, 6.2 mL) dropwise and the
resulting solution was stirred at -78°C for 0.5 h. To
the solution was added cyclopropanecarboxaldehyde (0.90
ml, 1?..0 mmol) in 1.0 ml of THF and the solution was
stirred at -78 °C for 2 h and 25 °C for 1 h. The
reaction was quenched by adding 1.0 mL of dilute acetic
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acid. Reaction mixture was diluted with 100 ml of EtzO
and washed with brine. The organic layer was dried over
NazSOq and concentrated in vacuo, yielding 2-
(benzhydryliden-amino)-1-cyclopropyl-2-(3,4-difluoro-
phenyl)-ethanol as a yellow oil, which was subjected to
the following reaction without purification.
b. 2-Amino-1-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol
The crude batch of 2-(benzhydryliden-amino)-1-
cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol obtained
from the above reaction (approximately 16.2 mmol) and
MeONH2.HC1 (4.0 g, 48.0 mmol) was dissolved in 125.0 mL
of MeOH and stirred for 12 h. The reaction mixture was
concentrated in vacuo, yielding oily residue which was
redissolved in 100 ml of EtOAc and was washed with 2.0 M
NaOH followed by brine. The organic layer was
separated, dried over Na2S04 and then concentrated in
vacuo to give the crude product as a yellow oil. It was
purified by column chromatography over silica gel (95:5
CHC13/10~ ammonia in MeOH} to yield 3.2 g (93o yield) of
2-amino-1-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol as
a pale yellow oil.
c. [2-Cyclopropyl-1-(3,4-difluorophenyl)-2-hydroxy-
ethyl]-carbamic acid-tart-butyl ester
To a solution of 2-amino-1-cyclopropyl-2-(3,4-difluoro-
phenyl)-ethanol (1.7 g, 8.1 mmol) in CHzCl2 (50 mL) at
0°C was added a solution of di-tert-butyl dicarbonate
(3.5 g, 16.2 mmol) in one portion and the resulting
solution was stirred for 2 h at room temperature. The
solvent was removed in vacuo and the residue was
subjected to column chromatography on silica gel (4:1
cyclohexane/EtOAc) to obtain [2-cyclopropyl-1-(3,4-
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difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-
butyl ester as a viscous oil (1.7 g, 68~ yield).
e. 5-Cyclopropyl-4-(3,4-Difluorophenyl)-oxazolidin-2-one
To a well stirred solution of [2-cyclopropyl-1-(3,4-
difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-
butyl ester (1.7 g, 5.4 mmol) in THF (20 mL) was added
95~ NaH (0.4 g, 16.2 mmol) at room temperature. The
resulting suspension was stirred for 3 h at about 35°C
(warm water bath) and then quenched carefully with ice.
The biphasic mixture was extracted with 100 mL of EtOAc,
washed with brine, dried over Na2S04, filtered and the
solvent was removed in vacuo to yield 5-cyclopropyl-4-
(3,4-difluorophenyl)-oxazolidin-2-one (1.3 g, 93~ yield)
as a 3:1 mixture of the trans:cis diastereomers. The
diastereomers were separated by column chromatography
over silica gel with 7:3 cyclohexane/ethyl acetate as
the eluting system. The trans isomer eluted first (Rf =
2.5, 0.65 g) followed by the cis isomer (Rf = 2.0, 0.2
g). The relative streochemistry was assigned by
comparing the 1H NMR of the two isomers of 5-
cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one to
the corresponding isomers of 4-(3,4-difluorophenyl)-5-
methyl-oxazolidin-2-one as described in Example 19.
The (+) and (-) enantiomers of the trans-isomer
were separated by HPLC by using Chiralcel OD (4.6 x 250
mm) using 80~ hexane/20~ isopropyl alcohol/ 0.1 ~
diethylamine as the eluting system (12 mL/min) under
isothermal conditions (U. V. 254 nM). The retention
times for the two enantiomers were 12.0 min {[a]D = +
1.8 (c = 0.35, MeOH)} and 15.5 min respectively. The
(+)-enantiomer was used in the next step.
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f. (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo
oxazolidine-3-carboxylic acid-4-nitrophenylyester
To a solution of (+)-5-cyclopropyl-4-(3,4-
Difluorophenyl)-oxazolidin-2-one (0.16 g, 0.66 mmol) in
10 mL THF was added a solution of n-butyllithium in
hexane (0.49 mL, 0.79 mmol) dropwise via a syringe
under argon atmosphere at -78°C. The resulting yellow
solution was stirred at -78°C for 50 min. This solution
was then added dropwise via a cannula into another round
bottom flask containing a solution of 4-
nitrophenylchloroformate (0.16 g, 0.79 mmol) inl0 mL of
THF, cooled at -78°C, over a period of 15 min. After
five minutes, the flask was removed from the cooling
bath and stirring was continued for 1 h. The reaction
was quenched by adding ice and it was extracted with
EtOAc. The organic extracts were washed with brine and
the organic layer was dried over Na2S09. The solvent was
removed after filtration and the residue was purified by
column chromatography on silica gel with 4:1
cyclohexane-ethyl acetate to obtain (+)-5-cyclopropyl-4-
(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic
acid-4-nitrophenyl]ester as a thick syrup (0.17 mg,
58g).
g. (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-
oxazolidine-3-carboxylic acid-(3-[4-(4-fluoro-2-methyl-
phenyl)-piperidinl-yl~-propyl}-amide
To a solution of 3-[4-(4-fluoro-2-methyl-phenyl)-
piperidin-1-yl]propylamine (0.02 g, 0.05 mmol) in 10 mL
of CH2Clz, (+) -5-cyclopropyl-4- (3, 4-difluorophenyl) -2-
oxo-oxazolidine-3-carboxylic acid-4-
nitrophenyl]ester(0.01 g, 0.03 mmol) was added and the
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resulting yellow solution was stirred for 10 h at room
temperature. The solvent was removed in vacuo and the
residue was purified by column chromatography over
silica gel with EtOAC followed by 15~ MeOH in EtOAC as
the eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain
(+)-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-
oxazolidine-3-carboxylic acid-{3-[4-(4-fluoro-2-methyl-
phenyl)-piperidinl-yl]-propyl}-amide as a pale yellow
oil(0.01 g, 80~). It was converted into its
hydrochloride salt by dissolving it into 5 mL of EtOAc
and then treating it with 1.0 mL of HCl in Et20 (1.0 M).
Mass spectrum showed M+1 peak.
Example 54: Asymmetric Synthesis of 4-(3,4-
Difluorophenyl)-5-methyl-oxazolidin-2-one
a. 2-Hydroxy-1-pyrrolidin-1-yl-propan-1-one (The
procedure reported by Vilarrasa et al. Tetrahedron Lett.
1997, 38, 1633 was used; see also Scheme 31)
S-(+)-Methyl lactate (48.03 mmol, 5.0 g) and pyrrolidine
(52.8 mmol, 4.4 mL) were. mixed in a round bottom flask
and the reaction mixture was allowed to stir at room
temperature for four days. Methanol was distilled off
using a short path distillation apparatus to obtain 2-
hydroxy-1-pyrrolidin-1-yl-propan-1-one as a yellow oil.
It was used in the next reaction without further
purification.
b. 2-(tart-Butyl-dimethyl-silanyloxy)-1-pyrrolidin-I-yl-
propan-1-one
~0 To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-
one (47.0 mmol, 6.72 g) in DMF (25 mL) was added
imidazole (70.5 mmol, 4.8 g), N,N-dimethyl-4-
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aminopyridine (4.7 mmol, 0.57 g) at room temperature.
Tert-butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g)
was then added while stirring. Some exotherm was
observed. The initial pale yellow solution turned brwn-
red in color and some precipitate was observed after 30
min. The reaction mixture was allowed to stir overnight
and then filtered through a sintered glass funnel. The
solid was washed with some Et20. The filtrate was
diluted with water (150 mL) and it was extracted with
Et20 (2 X 100 mL). The organic extrats were combined and
washed successively with water (100 mL), sat. NHQCl
solution and the organic layer was separated. It was
dried over Na2S04, filtered and the solvent was removed
in vacuo to obtain 2-(tert-butyl-dimethyl-silanyloxy)-1-
pyrrolidin-1-yl-propan-1-one as a golden yellow oil
(10.4 g, 86~ yield). The product was judged to be > 95~
pure by NMR and was used in next step without any
purification.
c. 2-(tart-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-
phenyl)-1-yl-propan-1-one
To a round bottom flask containing 72.0 mL of THF at -
78°C was added a solution of n-butyllithium in hexane
(72.0 mmol, 45.0 mL) under an argon atmosphere followed
by 1-bromo-3,4-difluorobenzene (72.0 mmol, 8.1 mL). A
solution of 2-(tert-butyl-dimethyl-silanyloxy)-1-
pyrrolidin-1-yl-propan-1-one (60.0 mmol, 15.4 g) in 10.0
mL THF was then added ina steady stream and.the orange
colored solution was stirred for 35 min at -78°C. It was
quenched with 20.0 mL of sat. NH9C1 solution and was
allowed to attain room temperature. The solution was
extracted with Et20 (2 X 50 mL), washed with brine and
the organic layer was dried over NaZS04. The solution
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was filtered and the solvent was removed in vacuo to
obtain the product as an orange oil. The crude product
was subjected to silica gel flash column chromatography
(9:1 hexane/EtOAc to 4:1 hexane/EtOAc as the eluent
system). 2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-
difluoro-phenyl)-1-yl-propan-1-one was obtained as a
pale yellow oil (14.1 g, 78~ yield, 96~ based on the
recovered starting material).
d. 2-(tart-Butyl-dimethyl-silanyloxy)-1-(3,4-~difluoro-
phenyl)-1-yl-propan-1-one-oxime
To a solution of 2-(tert-Butyl-dimethyl-silanyloxy)-1-
(3,4-difluoro-phenyl)-1-yl-propan-1-one (13.7 mmol, 4.1
g) in 60.0 mL of methanol was added sodium acetate
mmol, 3.76 g) and hydroxylamine hydrochloride ( mmol,
1.24 g) and the resulting solution was stirred at room
temperature overnight. Methanol was then removed in
vacuo and the resultind residue was extracted with EtOAc
(2 X 50 mL) and brine. The organic layer was separated,
dried over Na2S04, filtered and the solvent was remoced
in vacuo. 2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-
difluoro-phenyl)-1-yl-propan-1-one-oxime was obtained as
a colorless oil (4.04 g, 94~ yield). It was used in the
next step without further purification.
e. 1-Amino-1-(3,4-difluorophenyl)-propan-2-of
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-1-
(3,4-difluoro-phenyl)-1-yl-propan-1-one-oxime (12.2
mmol, 3.84 g) in 20.0 mL of EtzO was added a 1.0 M
solution of lithium aluminum hydride (25.0 mmol, 25.0
mL) at 0°C under an argon atmosphere. After 1 h, the
solution was heated to reflux for 2 h at which time some
solid was observed. The reaction mixture was cooled to
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0°C and then quenched sequentially with water (1.0 mL),
1.0 N KOH (1.0 mL) and water (3.0 mL). The residue was
filtered and the solid was washed with warm EtzO (20.0
mL). The filtrates were combined and dried'over Na2S09.
The solution was filtered and the solvent was removed in
vacuo to obtain 1-amino-1-(3,4-difluorophenyl)-propan-2-
ol as a colorless oil as a mixture of two diastereomers
which solidified into a low melting solid (2.1 g, 92~
yield). It was used in the next step without
purification.
It was converted into 4-(3,4-difluorophenyl)-5-methyl-
oxazolidin-2-one by the general procedure as described
before .
f. [1-(3,4-Difluorophenyl)-2-hydroxy-propyl~-carbamic
acid-tart-butyl ester
To a solution of 1-amino-1-(3,4-difluorophenyl)-propan-
2-0l ( 3 . 5 g, 19 . 1 mmol ) in CHC13 ( 15 mL ) at 0°C was
added a solution of di-tert-butyl dicarbonate (5.1 g,
23.6 mmol) in CHC13 (10 mL} in one portion and the
resulting solution was stirred overnight at room
temperature. The solvent was removed in vacuo and the
residue was subjected to column chromatography on silica
gel (2:1 hexane-EtOAc followed by EtOAc} to obtain [1-
(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-
tert-butyl ester as a viscous oil (3.3 g, 60.20 .
g. 4-(3,4-Difluorophenyl)-5-methyl-oxazolidin-2-one
To a well stirred solution of [1-(3,4-difluorophenyl)-2-
hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g,
1.5 mmol) THF (20 mL) was added 95o NaH (0.09 a. 3_A
mmol) at room temperature. The resulting suspension was
stirred for 3 h at about 35°C (warm water bath) and then
quenched carefully with ice. The biphasic mixture was
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extracted with 100 mL of EtOAc, washed with brine, dried
over Na2S04, filtered and the solvent was removed in
vacuo. The two diastereomers were separated by column
chromatography over silica gel (First isomer: 0.11 g, Rf
- 0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf =
0.5, 3:1 hexane-EtOAc). NOE experiment suggested that
the first diastereomer had the methyl and the aryl group
in trans configuration while the second diastereomer had
cis relationship between the two groups.
Each diastereomer was subjected to chiral HPLC
analysis using Chiralcel OD (4.6 x 250 mm) using 80~
hexane/20~ isopropyl alcohol/ 0.1~ diethylamine as the
eluting system (12 mL/min) under isothermal conditions
(U. V. 254 nM). The retention time for the trans-
oxazolidinone was 13.0 min. This corresponds to the (+)-
isomer of the trans oxazolidinone that was synthesized
by a separate method as described in Example 19 (the
retention time for the (+)-trans-oxazolidinone was 12.1
min). The HPLC analysis also confimed that the
enantiomeric purity of the diastereomer was >99a because
no peak corresponding to-(-)-isomer was observed. Since
the absolute stereochemistry of the starting material
[(S)-(+)-methyl lactate] is known, the absolute
stereochemistry of the (+}-isomer of the trans-
oxazolidinone must be (S, S) at the two stereocenters.
This enantiomerically pure oxazolidinone can be
converted into the required final products by using
similar methodology as described before in example 19.
General svnt~,tic schemes: In addition to the specific
examples of compounds described above, typical
procedures for the synthesis of the compounds of this
invention are shown in Schemes 32-35. In Scheme 34, the
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synthesis may be carried out using a procedure similar
to Koo, J. (J. Am. Chem. Soc., 1953, 75, 723), Anderson,
P. (Tetrahedron Lett., 1971, 2787), and Bean, N. P. et
al. (Tetrahedron, 1993, 49, 3193). In Scheme 35, the
synthesis may be carried out using a procedure similar
t~o Belkon, Y. et al. ( J. Chem. Soc. Perkin Trans. I,
1986, 1865), Novikov, M. S. et al. (Tetrahedron Lett.,
1997, 38, 4187), and Meyers, A. et al. (J. Amer. Chem.
Soc., 1984, 106, 1146).
~~le 55
As a specific embodiment of am oral composition of a
compound of this invention, 100mg of one of the
compounds described herein is formulated with sufficient
finely divided lactose to provide a total amount of 580
to 590 mg to fill a size O hard gel capsule.
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Pharmaco~2Qical Profiles of the Compounds in Cloned
Human Adrenergic Receptors.
Binding affinities were measured for selected compounds
of the invention at six cloned human alpha-1 and alpha-2
receptor subtypes, as well as at the L-type calcium
channel. The protocols for these experiments are given
below.
Protocol for the Determination of the Potencv of al
Antagonists
The activity of compounds at the different human
receptors was determined in vitro using cultured cell
lines that selectively express the receptor of interest.
Z5 These cell lines were prepared by transfecting the
cloned cDrdA or cloned genomic DNA or constructs
containing both genomic DNA and cDNA encoding the human
a-adrenergic receptors as follows:
alD Human Adrenergic Receptor: The entire coding region
of a1D (1719 bp), including 150 base pairs of 5'
untranslated sequence (5' UT) and 300 by of 3'
untranslated sequence (3' UT), was cloned into the BamHI
and ClaI sites of the polylinker-modified eukaryotic
expression vector pCEXV-3, called EXJ.HR. The construct
involved the ligation of partial overlapping human
lymphocyte genomic and hippocampal cDNA clones: 5'
sequence were contained on a 1.2 kb SmaI-XhoI genomic
fragment (the vector-derived BamHI site was used for
subcloning instead of the internal insert-derived SmaI
site) and 3' sequences were contained on an 1.3 kb XhoI-
ClaI cDNA fragment (the Clal site was from the vector
polylinker). Stable cell lines were obtained by
cotransfection with the plasmid a1A/EXJ (expression
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vector containing the a1A receptor gene (old
nomenclature)) and the plasmid pGCcos3neo (plasmid
containing the aminoglycoside transferase gene) into
LM(tk-) cells using calcium phosphate technique. The
cells were grown, in a controlled environment (37°C., 5~
COZ), as monolayers in Dulbecco's modified Eagle's
Medium (GIBCO, Grand Island, NY) containing 25mM glucose
and supplemented with 10~ bovine calf serum, 100
units/ml penicillin g, and 100 ug/ml streptomycin
sulfate. Stable clones were then selected for
resistance to the antibiotic G-418 (1 mg/ml), and
membranes were harvested and assayed for their ability
to bind [3H]prazosin as described below (see
"Radioligand Binding assays").
The cell line expressing the human a1D receptor used
herein was designated L-alA (old nomenclature) and was
deposited with the American Type Culture Collection,
12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the
International Recognition of the Deposit of
Microorganisms for the Purposes of Patent Procedure.
The cell line expressing the human a1D receptor, was
accorded ATCC Accession No. CRL 11138, and was deposited
on September 25, 1992.
al$ Human Adrenergic Receptor: The entire coding region
of a1B (1563 bp), including 200 base pairs and 5'
untranslated sequence (5' UT) and 600 by of 3'
untranslated sequence (3' UT), was cloned into the EcoRI
site of pCEXV-3 eukaryotic expression vector. The
construct involved ligating the full-length containing
EcoRI brainstem cDNA fragment from h ZapII into the
expression vector. Stable cell lines were selected as
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described above. The cell line used herein was
designated L-al$ and was deposited with the American
Type Culture Collection, 12301 Parklawn Drive,
Rockville, Maryland 20852, U.S.A. under the provisions
of the Budapest Treaty for the International Recognition
of the Deposit of Microorganisms for the Purposes of
Patent Procedure. The cell line L-a18 was accorded
ATCC Accession. No. CR 11139, on September 29, 1992.
a~ Human Adrenergic Receptor: The entire coding region
of alA (1401 bp), including 400 base pairs of 5'
untranslated sequence (5' UT) and 200 by of 3'
untranslated sequence (3' UT), was cloned into the Kpnl
site of the polylinker-modified pCEXV-3-derived
eukaryotic expression vector, EXJ.RH. The construct
involved ligating three partial overlapping fragments: a
5' 0.6kb HincII genomic clone, a central 1.8 EcoRI
hippocampal cDNA clone, and a 3' 0.6Kb PstI genomic
clone. The hippocampal cDNA fragment overlaps with the
5' and 3' genomic clones so that the HincII and PstI
sites at the 5' and ~3' ends of the cDNA clone,
respectively, were utilized for ligation. This full-
length clone was cloned into the KpnI site of the
expression vector, using the 5' and 3' KpnI sites of the
fragment, derived from vector (i.e., pBluescript) and
3'-untranslated sequences, respectively. Stable cell
lines were selected as. described above. The stable cell
line expressing the human alA receptor used herein was
designated L-ale (old nomenclature) and was deposited
with the American Type Culture Collection, 12301
Parklawn Drive, Rockville, Maryland 20852, U.S.A. under
the provisions of the Budapest Treaty for the
International Recognition of the Deposit of
Microorganisms for the Purposes of Patent Procedure.
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The cell line expressing the human alA receptor was
accorded Accession No. CR 11140, on September 25, 1992.
Radioligand Binding Assays: Transfected cells from
culture flasks were scraped into 5m1 of 5mM Tris-HC1,
5mM EDTA, pH 7.5, and lysed by sonication. The cell
lysates were centrifuged at 1000 rpm for 5 min at 4°C,
and the supernatant was centrifuged at 30,000 x g for 20
min at 4°C. The pellet was suspended in 50mM Tris-HC1,
1mM MgClz, and 0.1~ ascorbic acid at pH 7.5. Binding of
the a1 antagonist [3H)prazosin (0.5 nM, specific
activity 76.2 Ci/mmol) to membrane preparations of
LM(tk-) cells was done in a final volume of 0.25 ml and
incubated at 37°C for 20 min. Nonspecific binding was
determined in the presence of 10 uM phentolamine. The
reaction was stopped by filtration through GF/B filters
using a cell harvester. Inhibition experiments,
routinely consisting of 7 concentrations of the tested
compounds, were analyzed using a non-linear regression
curve-fitting computer program to obtain Ki values.
az human Adrenergic Receptors: To determine the potency
of al antagonists at the az receptors, LM(tk-) cell
lines stably transfected with the genes encoding the
a2A, oc2H, and a2~ receptors were used. The cell line
expressing the a2A receptor is designated L-a2A, and was
deposited on November 6, 1992 under ATCC Accession No.
CRL 11180. The cell line expressing the azB receptor is
designated L-NGC-azB, and was deposited on October 25,
1989 under ATCC Accession No. CRL10275. The cell line
expressing the az~ receptor is designated L-a2C, and was
deposited on November 6, 1992 under ATCC Accession No.
CRL-11181. All the cell lines were deposited with the
American Type Culture Collection, 12301 Parklawn Drive,
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Rockville, Maryland 20852, U.S.A. under the provisions
of the Budapest Treaty for the International Recognition
of the Deposit of Microorganisms for the Purposes of
Patent Procedure. Cell lysates were prepared as
described above (see Radioligand Binding Assays), and
suspended in 25 mM glycylglycine buffer (pH 7.6 at room
temperature). Equilibrium competition binding assay
were performed using [3H]rauwolscine (0.5nM), and
nonspecific binding was determined by incubation with
lOUM phentolamine. The bound radioligand was separated
by filtration through GF/B filters using a cell
harvester.
Determination of the Activity of al Antagonists at
Calcium Channels
The potency of al antagonists at calcium channels may be
determined in competition binding assays of
[3H]nitrendipine to membrane fragments of rat cardiac
muscle, essentially as described by Glossman and Ferry
(Methods in Enzymology 109:513-550, 1985). Briefly, the
tissue is minced and homogenized in 50mM Tris-HC1 (pH
7.4) containing 0.lmM phenylmethylsulfonyl fluoride.
The homogenates are centrifuged at 1000 g for 15
minutes, and the resulting supernatant centrifuged at
45,000 g for 15 minutes. The 45,000 g pellet is
suspended in buffer and centrifuged a second time.
Aliquots of membrane protein are then incubated for 30
minutes at 37°C in the presence of [3H]nitrendipine (1
nM), and nonspecific binding determined in the presence
of 10/,cM nifedipine. The bound radioligand is separated
by filtration through GF/B filters using a cell
harvester.
The compounds described above were assayed using cloned
human alpha adrenergic receptors. The preferred
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compounds were found to be selective alA antagonists.
The binding affinities of several compounds are
illustrated in the following table.
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Binding affinities of selected compounds of the present
invention at cloned human alD, a1B and alA receptors .
Example halD halB halA
Ki Ki Ki
2 11 21 0.5
21 2455 891 21
28 3660 4012 0.7
h = human
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-170-
Scheme 1
NH,
0
coat. H~SO~
Vp f'
O!!e Ohle
Diox~e O
\--/ ' Sz
O~N
NOZ
_ Heat
f' Hr ' ~ HAG .J
H~
R. R.
1. Hr-ICH213NHBoc ~~
HIJ~ I ~ H2H~
2. TFJ1
R R
Scbaa~ l: General Synthesis of Piperazine side chains
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-171-
Scheme 2
0
A: OH
l~.Li ~ P-TsOH.H~O
.... N ~ N _ N
'Ph ~Ph 'Ph ~ C ~Ph
xr off u'
Ar'-H
A1C1 N
3
H H
0 HjC OH HjC Ph H3C Ph
Ph H ~ H2
rieLi N ~ N _.---~ N.
N ~ A1C13 ~ Pd-C
Ph Ph H
~Ph
Ph Cppv Ph COOMe
coat. u250~
h N
MeOH H
:. 8:-(CH2)n-NHBoc pr
~NH ~N~~2
R '-r ~ . TFA R
n = 2. 3. 4. . R = H. MG. Ar'
Scbam~ 2: General Synthesis of Piperidine Side Chains
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/I2668
-172-
i~
w H ~ 1 a
w N 3~laHH~ w H HZ H
N o_- Br- ICH~ ) 3~I~i~ ~tOH Pd-C
N 8 N N
H:
N'd 2 ~ Z P1F! Z
w N ~ i i ~ c
3_-- (CHI ) 3-OH ~ N Na8H~ w N H w H
2
I , f ._ E.--.r ~ F-..
'N A N
8_
~OH OH OH
Schema 3: Syn~hesis o= ?y:idyy p:peridine conta:ring side chains
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-173-
r
a
z
f. Z
m
O O
z ~"~
O 4. O
X
7
w
o N
O \
m d
°' °' E
s =
0
r,
y
~r N
a
n~
0
z
z
o i
v
~. \ I ~. \ ~
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-174-
~c
v z s
.
O
~ Z r1
u
0
d
s ~ a
O _ N IC
E'
Z 5C
4
Z
V
C
O
n O ...r
s _ Z 2 'C7
O
.r
rC Z Z
V O
U N
Z b
X
O O O
O~ O w
CL Z ~ O
Z
/
\
, v
' o
y
i
i _ __ ,~ >.
l:
C.:
2 Z C ~1
v i6
V
C .-.
a L it ~.
~ y N
C ~ ~ N
~ r 4.
C
a L H d "
w ~ V n
o ~ c
'~ v N ~ z
a
'' . ~ o
x ~ '~' W
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-175-
d
E
m
s
o a
o ~
..
a c _
\ / a
o s
er
m° ° V
o m
d
C n r,~ 'D
ar ~ s z
o m
i a ! O
v
a
\ / ~ x
c ~' .~ n O
N
O
\ / eW. w
'' O
w
w _ ~ m
..
iJ
C
Y O
N Z F:.
a C
p - \ / Z y
'' ..a
a. 4
~ ~" ' o o to
a (~ v m
o ~ Z = i
z
\ /
n ~ \ / V
w
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-176-
0
z
0
o~ ~~o
Z
'p ~O ...
J a
d
a
E
X
o "~.,
0
V
a
° .. 0
c
..,
L
E. o X
O
w
C ~a 0
z a
.. ' N
N N
n
i.
2 Z
Z ~ Q O ~ ?~
Z
C
p
_ 1r
G
41
C7
O
O E"
x
Z
Z
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-177-
x
s.
o~
z
o~ °'
o -r
e~ o /
a
0
m X
.. m
d
C
0
z s~t C
E p, "''
ar 'C
Ir ' O Z
Z ~
S Z ~ ~ N
r' H ~' O
O
N U
..r
_ d
Z O
J C
O / O
Z
C:
w
O
O
w N
L
is y
Z
Z
U
N
Z t
E a
0
m_ ao
a
0
\ / o ago
\ /
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-178- _.
N
r1
C
Z Z
Z Z
o ~ / tx
Z Z d
C
O ~ -.a
Z
y
i
H D w~
fl
Z
i r. 1~/
N
v i °u i a
-. ' ..a
v ~ V
E~
N ~ N
-
a
d
0
..
z
c:~ ~ i
o ~'
.Q
...,
o O
N
a
n X v_ 7 X
U
O rr
v ~' ~c a~ w
°' ~ O
a' N
a
v -..
a~
d
y
o »
o~
c~
Z ,,1
A
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-179-
0 1 0
x
s~ x~
\ /
N N
z
_i
d b
_ ~ ~_
V V
~ N
O
= z 1 x z
1
x
W
\ / ~ /
01
..a
N
41
O n y
N
a
m 2 m Z V1
~ N
,.n N
", o r ~ w
o
_ 1
\ /
CA 02294549 1999-12-14
WO 98/57940 ~CT/US98/12668
-180-
o '
"~ ~ ~i
z x
x m
\ m
a
E
a
\ /
m
x i s m
o ~ v~ s : O
a z o o s o~ C
o ..
_. s = ..,
o ~. c ~ a 'G
m
E \ / n, o
a ~. ': v ~ I
~ o ~, a
m 4
_C -. E
_ O O
C: .. r Q1
i x ~ C~ L
c ' a
°.: a a
m ~ rr
\ / z ~ > >'
a ,o -. -
z .. o
.a a
ii ~ ''
s
r. 2 s \ ~ O
''
o v _ ~ m
N
is: . z \ / Z \ / O ~ ':~ 4)
O i
o :, y
m
s H
N O
.Z
y - ..
_ 4~ E oL.
v a n . ~ =
ax
< m Z .r Z d
\ / V ~; H ~ ..: n
a
E
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
181-
0
r.
w
~ o
r
a ,
a
x
z
o E ..~~
v aJ
x O 4
w o w 0j
o wm d
y ,o
\ / ° 4 ' E
x / > d ~ 'C X
O O~ 1 V .~ W Z ...
W~1 r 11 i ~ ..~~
o~C a z s sy. ~
v e~ ° ~ / ° o
o =_ \ / s ~ v C
E a ~ . ° ~ ' -''
a a .fl
G. x V y 4 ~ C ..r
d o° a .'- ''
o
rr a V O
C c QE a a ..., = tC
~° o o _u ~, ~, x
.r V C
G ~ ~ ~ 1~ G.
w d V
- i0 ~ ~. ~ E C!
,~ ~ A ° c ~ . a .~c
ev O~ ~' ~p ~' a ~~1
~'
c°'n c°r ~ v
rv ~ ~. ' r. ,,~,~ d
1
_ a C m g
C Ir \ _ 1
° 1 / a O o
c~' "' Z 1 Z
?. O
v.~ J t O .n ffl -rl
\ O x~ ° = D fll
O 4
4: c. y
N
N U
L1 4.
w
d
V
N O = rt
O = ~ y
\ I z n
V
w
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-182-
n
0
:_ .
O
N
d
O ,..
a
E
x
O O ca,
C)
t O
4~ it C
y 't7
o "
r,, ..s
O 0
s' N
O
'u O
m° ?~
y N
C
w m
0
...
a _n
i = a N
..,
- ... e~ . N
d
z x
o ~ j,
z~
r 4.
i
w
O ~ d
i v
L
C O n E ~ a
2 w Z O
Z ~' V
CD
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-183-
K=C0~
0
~ KI Ph /~-~ \
Ph ~ ~ Br~N / ----~ NC\~~/N~N I
NC's
O
O
H~'~z
Ph~~
NC N~~z
A1C1~ 1. RCN
O~~ ~ I / ~ ph~~~~ -.. Ph N~"
2. HH Ph~~~/
Ar
ps ~ ~ Ar Ar CDI
~N~i2 -... ~N'H
HOC NHz ~ O
OH p
~ ~ O I \ N0~ R-~= ~. Ar O
1. NaH / THF ~ ~ _~ ~N~N.R
~N O ' H
2 . 4 -Ni trophenyl O ~ O---
chloroformate O O
Scheme lt. Preparation of ~xnu~ples 23 and 24
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-184-
0
o R,~o, off
Ph ~ N KI Ph ~ N
NC'~NH . O / ~ '---i NC ~N O
O
0
F ~' W
DAST Ph ~N ~ N
NC
OH
Ph ~N
NC
F
Ph ~~
NC N~W
RZ'0, NaH
NH . 3r ~ N-COzBn . R~ HO ~N ~ N' COzBn ~~C--1
..O ~ H H
?d(OH)=/C Pr.
P:~~N~N.CO=Bn --~ AcO~N~
AcO H
RICO,
Ph KI Ph
Me0 C ~~ ' 8r ~ ~ ~ MeOzC N
s
Scbsm~ 15. Prepara:ion of Side Chaias
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-185-
O O RzCO, O 0
'-'rN -~ H ~ N -~ ~ ~N N ~/'' N
N Nx + / \
/ \
0 \rJ 0
O
~ ~N N .~/''
1
sx,
--~ \ . N -~ -
\ N N CN
\ . N
N
Schema 16. Preparation o. Side Chains tcontd.)
CA 02294549 1999-12-14
WO 98/57940 PCT/US98112668
-186-
~nr
Ar MeMgBz
MeOzC ~ NFi~ ~ p .-
OH p
NOz
1. NaH/THF ~ N ~ 0 f ~ R-~Z ~ N :l N.R
2.4-Nitrophenyl p ~ p
chlorofarznate O o
Scha~ 17. Prepa_-ation of Examples 25-29 and 31.
Ar ~i Ar
1 . r3al-I / THF n
N v/~ $_ ---r N ~~~W
p 2.:,~-Dibromopentane 0 ~ 0 p
Schams 18. Preparation of example 30.
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-187- _
/ ' ~. ..---r \ . / 'N - Br ~ NaHx~
\ ~ N ~ Ph Hr N Ph
N CO=H
N
_ Pd(OH)=/C BOC
/ ~ . NH
N ~ \
\ N Ph N DMAPECD
_ p LiAlH~
0 Tf'A \ ~ N
\ ~ N
N
N80C
F
/ F
F
'N .~ J \ N0~ / ' F
0
' ~~N
h N
O -~ '~ N
O
,N
\j
Scheme 19: Prepara=ion of Exa=aple 32
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-188-
0 ~CO~ O
Ph Br ~ N ~ pb ~I'' r./~ N
NC'~NFi ~ ~ ~ ~ NC
O p
NC'~N ~
gch~,s 20: Preparation of Side Chain
F g
/ F / F
LiHi~S ~ ~ pd (OH) =/C
BrCH=CO=CHZPh
O~ ~0'-Ph
0 O 0
F F
F F
~N~~
N~OH '
N~N~
0-~ O DMAPECD. DMAP p ~ OII N
0 0 Ph
CN
Scheme 21: Preparation of Example 33
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-189-
Z
°~ O
' ~'~ '~ ~ ~
/
L
a
t
K
3
a :::
~= Z
- c~Wi
a.
3~
z o
4
a
i ~ ~ G
N
O O N
V
t
V
I L
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-190-
2
Z
z
a.
. i ~'
G ~ U
Z~Z
N
X T
G
Z.
c
z
a v
_ _ V Z
ZL- C~ ..
V
r
V Z ~
V
c
°'
z ~ ~ 'n
x
- a
- ~ v
x ". o
1 / z + o
X s
Z
r
~ ~ ~ G
t
- N
Ir
a
Z Z
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-191-
1
HO 1 R2
xi ~ / ~ A1C13
N
H H
x
1. B_-~N 0
diisopropylethylamine
dioxa.-:e, reflex _
2. T:::luoroacetis acid
F
F
..,.,
0
0 ~. NOZ
N_ 'N
0 / 0 ' ~; i
t '0
0~0
R, - ::, 4-F, 4-Hr, 4-SCH3
RZ = H. SOZCH3, 4-F. (2-OCH3,5-F) , 4-Br
Schems24 : preparation of Examples 38-42
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-192
h
N
Z
,T-Z
I
~' ~ z
p ~ ~O
v I ~o
0
a ~I Z ~o
I ~, .~ -z
i
z o
Q
'' i
i
l Z Z
\ i C'
~, 2 ~ f-
-s C 'D
N ~ G
2 ~ ~ c0
Z v c~
:? _
V:
~o p °o
z
0
W
y ' O
O
p
d
Z Z ~p m
U ~ Z a'
Z
tz O~ ~ u. ~ Z
1 ,
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-193
U
~O
H
Z
Z
~O
m
Z c O
l
Z~ o
s
a
1
i H
'c
N
Z
U ~ °'
., a
E
eo
~o
0
= o
O a
m
a
~ I ~J
0
E
°~z~1 ~ s
~z
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-194-
' N
I
Z
z O
= Z
1
O
C~
°' / ~o
s ~ ~ \ z
i i ~ ~o
v Z
N
H
H
r
N
I 2 N
0
s
a
z O
u.
U ti 2 G
n LL i a cd
Z N u.
i
v ~ H ~O o
Z
O Z
m Z
tL
Z
o
- o
Z
es
O a
N
V
\ z~ _ = U
Z
< m
o~Z~ ~ ~ -'
~z cn
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-195-
Z
U
Z
~O
V
o
m
O
d
' E
~a
x
0
m c
0
0
a
m
a
N
m
Z
N
V
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-196-
x1
( W ]W1
OH
i I NHZ . Benzophenone~ i I N ~ ~ 1. t-BuLi / THF .~ ' N
R PhCH3, BF3.OEt2 ~~ ~ 0
x Rx ~ 2. Rx w
( W ~i
(For example 52, R = fluoro group, x = 2, Xlrt']Wl
W = 0 , W1 = 0 , and X1 = CH 2 )
0
NH2 NHBoc ~
MeONH2 . HC1 ~H O"NH
off Boc20, CHC13 ~ NaH, THF
--. ( ] W .,
Rx I( J~~ JWl Rx I( ]~,a~ ]Wl Xl ]Wl /
X Rx
Enantiomers separated 0 1. n-BuLi/THF 0 O ~NOZ
by chiral HPLC column. ~ 2. C1COOPh-N02
O NH 0 r7 O
( ]~ ~ ( ]~
X1 l W1 / Xl l Wl
Rx Rx
0 0
H2N-R p~N ~LN ~R
H
( ]~ i
For example 52, R = X1 jW~
tcx
F
Scheme 29: Synthesis of Example 52 and related compounds
CA 02294549 1999-12-14
WO 98/57940 PCT/US98112668
-197-
OH
I NH2 Benzophenone ~ N I ~ 1. t-BuLi / THF N
F F ~ I
F PhCH3, BF3.OEt2 ~ F
F I / 2. ~-CHO F
0
NH2 Iv.-'_3oc
MeONH .HC1 / OH Boc20, CHC13 ~ OH O~NH
NaH, THF
68% yield F ~ I ~ 91% F ~ I
(three steps) F
F F
Diastereomers separated O 1. n-BLLi/THF O O .,~ N02
by chiral HPLC column. O~j,Nf; 2. C1C00Ph-NOZ
0 N 0
Enantiomers separated
by chiral sPLC column. ' ~ F F
\
F F
O O
H2N'~N ~ ~ F ~ ~L
0 N NON
H
~F ~ F
F
Schome 30: Synthesis of Example 53.
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-198-
H
N
0
0 TBDMSC1
~OH ~N ~N
OH OH ~ TBDMS-O
F
F ~ I O N,OH
Li / HZNOH.HCl
i
TBDMS-O ~ ~ F TBDMS-O
F
F F
LAH, Et20 OH NHZ 1. Boc20, CH2C12
F 2. NaH / THF
3. Separate diastereomers
F by column chromatography
O
\' O
O ~NH O ~NH ~N.R
.~ 1. C1COOPh-N02 O~N H
i
- ~ ' F _ w ~ F 2 . R-NH 2
F F ' ~ F
F
Only the traps isomer shown.
Scheme 31: General synthesis of methylated oxazolidinone.
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-199-
(Y, u,
O
z r~ o c~ z rx
z r~ z N
x vx
o _ x ~ c~ o >~
o ~ °~
z z ~,
x °z
° ° z ~x
oz z ~z
z Ux ~'x ~ NM
r-I N M '~ N M ,L;
U
u, (n
x N
N
Z ~ f~ ~ ~ N
°
__ x~_
S~ U7
O
r1
O cd
x ~ z
U '~-a Cl~ ~
N V ~ U O ~ ~-I N
x ~
U ~ ~ ..
x f x t~ N Z N U1 (r1
°
II II
x >~ x ~ ~
x
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-200-
N
d'
'z x z _ x
0
v
N x ~ x
N ~ N
N
u, E-i U E~ U
z .~ z
0 0~
0 0 '. x o
x U ~ x ~
N
0 O
w H z z
N p.,
p p
N O N N
z ~ ~~ x ~~ z
zo ~ zU x
U
w c-i N O CJW-I N Ul
'-' II U
_ I I
H ~ xx ~ ~ a
o z ~ ~I A z
O
U z ~ _ cx z ~ to
x
~ z
z~
c-1 N
~C N
N U H C7
o x ~' z
..
N ~ ~~ U M
z
If
as ~ N ~ v _
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
-201-
N
O
z
I
0
ow
xUz
N
zUx
c-i N M
c ~ z
I
u~ v
3 c0
,n x O ~y
rt ~ z O
2 U x
O ~-I N r~ O
v
x
x x
U
x
w
N ~ U
x -z -
w
a
o rx
z
x ..
w ~'
m
m
x
U
CA 02294549 1999-12-14
WO 98/57940 PCT/US98/12668
N
-202- O
z
o ~ x
0
ox
z
O 0 c~ z U x
O ~ U ,
(Lf rl Z '~-' c-I N .M
z U x ~
a
v-1 N cY1 ~ N
" O
~~'' ~ N m ~ Z tx
x
z
0
va N ~Z ~~z z
z c~ o zUx o
x ~,
r-I N ~''~ . .
O -~ N
~Z x °u z
~S r-~ N 'r'I
o z U x z
~,
N M v
cx a ~
x
N U
x
O
c~
v
N
N r-I
N
O
v
z O
x
f~ U
+ U
m
O O
U
W
