U.S. patent application number 09/770513 was filed with the patent office on 2001-07-26 for pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists.
Invention is credited to Ito, Fumitaka, Kondo, Hiroshi.
Application Number | 20010009921 09/770513 |
Document ID | / |
Family ID | 11004480 |
Filed Date | 2001-07-26 |
United States Patent
Application |
20010009921 |
Kind Code |
A1 |
Ito, Fumitaka ; et
al. |
July 26, 2001 |
Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa
agonists
Abstract
A compound of the following formula: 1 and the salts thereof,
wherein A is hydrogen, halo, hydroxy, or the like; the broken line
represents an optional double bond with proviso that if the broken
line is a double bond, then A is absent; Ar.sup.1 is optionally
substituted phenyl or the like; Ar.sup.2 is aryl or heteroaryl
selected from phenyl, napththyl, pyridyl, and the like, the aryl or
heteroaryl being optionally substituted; R.sup.1 is hydrogen,
hydroxy, C.sub.1-C.sub.4 alkyl, or the like; and R.sup.2 and
R.sup.3 are independently selected from optionally substituted
C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkenyl, and the like or R.sup.2 and
R.sup.3, together with the nitrogen atom to which they are
attached, form an optionally substituted pyrrolidine, piperidine or
morpholine ring. These compounds are useful as kappa agonists.
Inventors: |
Ito, Fumitaka; (Chita-gun,
JP) ; Kondo, Hiroshi; (Handa-shi, JP) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc.
235 East 42nd street
New York
NY
10017
US
|
Family ID: |
11004480 |
Appl. No.: |
09/770513 |
Filed: |
January 26, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09770513 |
Jan 26, 2001 |
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09254805 |
Mar 12, 1999 |
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6201007 |
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09254805 |
Mar 12, 1999 |
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PCT/IB97/01021 |
Aug 21, 1997 |
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09254805 |
Mar 12, 1999 |
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PCT/IB96/00957 |
Sep 18, 1996 |
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Current U.S.
Class: |
514/424 ;
514/408; 548/541; 548/566 |
Current CPC
Class: |
A61P 1/06 20180101; A61P
25/28 20180101; C07D 207/10 20130101; A61P 19/02 20180101; A61P
25/04 20180101; C07D 207/20 20130101; C07D 409/12 20130101; A61P
43/00 20180101; C07D 213/82 20130101; A61P 25/00 20180101; A61P
23/00 20180101; C07D 207/12 20130101; C07D 401/12 20130101; Y02P
20/55 20151101; C07D 403/12 20130101; C07D 405/12 20130101; C07D
207/24 20130101; A61P 29/00 20180101 |
Class at
Publication: |
514/424 ;
514/408; 548/541; 548/566 |
International
Class: |
A61K 031/40 |
Claims
1. A compound of the following formula 34and the salts thereof,
wherein A is hydrogen, halo, hydroxy, C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo C.sub.1-C.sub.6
allcoxy, oxo, OY wherein Y is a hydroxy protecting group, or
absent; the broken line represents an optional double bond with
proviso that if the broken line is a double bond, then A is absent;
Ar.sup.1 is phenyi optionally substituted by one or more
substituents selected from halo, hydroxy, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkoxy, CF.sub.3, carboxy-C.sub.1-C.sub.4 alkoxy and
C.sub.1-C.sub.4 alkoxy-carbonyl-C.sub.1-C.sub.4 alkoxy; Ar.sup.2 is
aryl or heteroaryl selected from phenyl, naphthyl, pyridyl,
thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl
being optionally substituted by one or more substituents selected
from halo, hydroxy, amino, nitro, carboxy, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylamino, di
C.sub.1-C.sub.4 alkylamino, halo C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylthio and sulfonyl methyl, R.sup.1 is hydrogen,
hydroxy, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy or OY
wherein Y is a hydroxy protecting group; and R.sup.2 and R.sup.3
are independently selected from hydrogen, hydroxy, C.sub.1-C.sub.7
alkyl optionally substituted by one or more hydroxy or halo,
C.sub.3-C.sub.6 cycloaikyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.7 alkoxy, phenyl optionally
substituted by halo, phenyl C.sub.1-C.sub.7 alkyl halo substituted
phenyl C.sub.1-C.sub.7 alkyl, and (CH.sub.2)nX--R.sup.4 wherein n
is one or two, X is O, NH or S and R.sup.4 is C.sub.1-C.sub.3
alkyl, or when Ar.sup.2 is phenyl, --Ar.sup.2--C(=O)--N(R.sup.2)--
is a phthalimide group and R.sup.3 is C.sub.1-C.sub.7 alkyl, or
R.sup.2 and R.sup.3, together with the nitrogen atom to which they
are attached, form a pyrrolidine, piperidine or morpholine nrg,
optionally substituted by C.sub.1-C.sub.3 alkyl or halo.
2. A compound according to claim 1, wherein A is hydrogen, halo,
hydroxy, oxo or OY, or if the broken line is a double bond, then A
is absent, Ar.sup.1 is phenyl optionally substituted by one to
three substituents selected from halo, hydroxy, C.sub.1-C.sub.4
alkoxy, carboxy C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4
alkoxy-carbonyl-C.sub.1-C.sub.- 4 alkoxy; Ar.sup.2 is phenyl,
pyridyl or thienyl, optionally substituted by one to two halo or
C.sub.1-C.sub.4 alkoxy; R.sup.1 is hydrogen, hydroxy or
C.sub.1-C.sub.4 alkyl; and R.sup.2 and R.sup.3 are independently
selected from hydrogen, C.sub.1-C.sub.7 alkyl optionally
substituted by one or more hydroxy or halo, C.sub.3-C.sub.6
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.4 alkoxy phenyl and halo substituted phenyl
C.sub.1-C.sub.7 alkyl, when Ar.sup.2 is phenyl,
--Ar.sup.2--C(=O)--N(R.sup.2)-- is a phthalimide group and R.sup.3
is C.sub.1-C.sub.7 alkyl, or R.sup.2 and R.sup.3, together with the
nitrogen atom to which they are attached, form a pyrrolidine or
morpholine ring.
3. A compound according to claim 2, wherein A is hydrogen,
fluorine, chlorine, hydroxy or OY wherein Y is methoxymethyl or
tetrahydropyranyl; or if the broken line is a double bond, then A
is absent, Ar.sup.1 is phenyl optionally substituted by chlorine,
hydroxy, methoxy or carboxymethoxy; Ar.sup.2 is phenyl, pyridyl or
thienyl, optionally substituted by chlorine, fluorine or methoxy;
R.sup.1 is C.sub.1-C.sub.4 alkyl; R.sup.2 is C.sub.1-C.sub.7 alkyl
optionally substituted by hydroxy or fluorine, C.sub.2-C.sub.6
alkenyl, halo substituted phenylmethyl or phenyl; and R.sup.3 is
hydrogen or methyl; or R.sup.2 and R.sup.3, together with the
nitrogen atom to which they are attached, form a pyrrolidine or
morpholine ring.
4. A compound accroding to claim 3, wherein A is hydroxy, fluorine
or chlorine, or if the broken line is a double bond, then A is
absent; Ar.sup.1 is phenyl optionally substituted by
carboxymethoxy; Ar.sup.2 is phenyl optionally substituted by
methoxy or pyridyi; R.sup.1 is C.sub.1-C.sub.4 alky, R.sup.2 is
C.sub.1-C.sub.7 alkyd optionally substitute by hydroxy; and R.sup.3
is hydrogen.
5. A compound according to claim 4 selected from
4-{N-[2-(3-(S)-hydroxypyr-
rolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}--
2-methoxy-N'-propylbenzamide; 6-{N-[2-(3
-(S)-hydroxypyrrolidin-1-yl)-1-(S-
)-phenylethyl]-N-methylamino}-N'-propylnicotinamide;
5-{N-[1-(S)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-eth-
yl]-N-methylamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-fluoropyrrolidin-1-y-
l)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}--
N'-(2-(S)-hydroxypropyl)benzamide; 5-{N-[2-(3
-(S)-fluoropyrrolidin-1-yl)--
1-(S)-phenylethyl]-N-methylamiino}-N'-propylpicolinamide;
4-{N-methylamino-N-[2-(3-pyrrolin-1-y)-1-(S)-phenylethyl]-N'-propylbenzam-
ide; and 4-{N-[2-(3
-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methy-
lamino}-N'-(2-(S)-hydroxypropyl)benzamide.
6. A compound according to claim 3 selected from
4-{N-[2-(3-(S)-hydroxypyr-
rolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-isopropylbenzamide;
3-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylainp}-N-
'-propylbenzamide;
2-chloro4{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phe-
nylethyl]-N-methylamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrroid-
in-1-yl)-1-(S)-phenylethyl]-N-methylamino}-3-methoxy-N'-propylbenzamide;
3-chloro4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methy-
lamino}-N'-propylbenzamide;
4-{N-[1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxy-
pyrroiidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyI]-N-m-
ethylamino}-N'-propylbenzamide;
4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl)ethy-
l]-N-methylamino}-N'-propylbenzamide;
4-{N-[1-(S)-(3-chlorophenyl)-2-(3-S)-
-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}--
N'-propylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenyleth-
yl]-N-methylamino}-pyrrolidinebenzamide,
4-{N-[2-(3-(S)-hydroxypyrrolidin--
1-yl)-1-(S)-phenylethyl]-N-methylamino}-morpholinebenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(
S)-phenylethyl]-N-methylamino}- -N'-(2-(R)-hydroxypropyl)benzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-
-1-(S)-phenylethyl]-N-methylamino}-N'-isobutylbenzamide;
4-{N-[2-(3-S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N-
'-allylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-
]-N-methylamino}-N'-(3,3,3,-trifluoropropyl)benzamide;
3-fluoro-4-{N-[2-(3
-(S)-hydroxypyrroiidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylb-
enzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-meth-
ylamino}-N'-(2,2,3,3,3,-pentafluoropropyl)benzamide,
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}--
N'-tert-amylbenzamide;
5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenyl-
ethyl]-N-methylamino}-N'-propylpicolinamide,
4-{N-[2-(3-(S)-fluoropyrrolid-
in-1-yl)-1-(S)-phenylethyl]-N-methytamino}-N'-(2-(S)-hydroxypropyl)benzami-
de; 2-chloro4-{N-[2-(3
-(S)-fluotopyrrolidin-1-yl)-1-(S)-phenylethyl]-N-me-
thylamino}-N'-propylbenzamde; and
4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1--
(S)-phenylethyl]-N-methylamino}-N-propylbenzamide.
7. A compound according to claim 2 selected from
4-{N-[2-(3-(S)-hydroxypyr-
rolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-methylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}--
N'-ethylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethy-
l]-N-methylamino}-N'-butylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrroildin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-pentylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}--
N'-phenylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenyleth-
yl]-N-methylamino}-N'-(2-chlorobenzyl)benzamide;
4-{N-[2-(3-(S)-hydroxypyr-
rolidin-1-yl)-1-(S)-phenylethyl]-N-methyiamino}-N',N'-dimethylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolbdin-1-yl)-1-(S)-phenylethyl]-N-methyiamino}--
N'-methyl-N'-propylbenzamide;
5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-
-phenylethyl]-N-methylamino}-N'-propyl-2-thiophenecarboxamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenyethyl]amino}-N'-propylb-
enzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenytethyl]-N-meth-
ylamino}-N'-propylphthalimide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S-
)-phenylethyl]-N-methylamino}-N'-ethoxybenzamide;
4-{N-[2-(3-(S)-hydroxypy-
rrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(3-hydroxypropyl)benza-
mide,
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylam-
ino}-N'-cyclopropylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-
-phenytethyl]-N-methylamino}-N'-(S)-sec-butylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}--
N'-(R)-sec-butylbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-ph-
enylethyl]-N-methylamino}-N'-propargylbenzamide;
4-{N-[1(R)-(3-carboxymeth-
oxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propy-
lbenzamide;
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-me-
thylamino}-N'-tert-butylbenzamide; 4-
{N-hydroxy-N-[2-(3-(S)-hydroxypyrrol-
idin-1-yl)-1-(S)-phenylethyl]amino}-N'-propylbenzamide; 4-{N-[2-(3
-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-hydroxyamino}-N'-propylb-
enzamide;
4-{N-[2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methy-
lamino}-N'-propylbenzamide;
4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-ph-
enylethyl]-N-methylanmno}-N'-propylbenzamide;
4-{N-[2-(3-(S)-chloropyrroli-
din-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(2-(R)-hydroxypropyl)benzar-
mide; and
4-{N-[2-(3-oxopyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-
-N'-propylbenzamide.
8. A pharmaceutical composition for the prevention or treatment of
a medical condition for which agonist activity toward opioid kappa
receptor is needed, in a mammalian subject, which comprises a
therapeutically effective amount of a compound according to claim
1, and a pharmaceutically inert carrier.
9. A pharmaceutical composition according to claim 8, which is
useful as an analgesic, anesthetic, anti-inflammatory or
neuroprotective agent, or usefil in the treatment of arthritis,
stroke or functional bowel disease.
10. A method for the treatment of a medical condition for which
agonist activity toward opioid kappa receptor is needed, in a
mammalian subject, when comprises administering to said subject a
therapeutically effective amount of a compound according to claim
1.
11. A compound of the following formula: 35wherein Ar.sup.2a is
phenyl, pyridyl to thienyl; X is hydrogen, halo or C.sub.1-C.sub.7
alkoxy; R.sup.1 is hydrogen, optionally protected hydroxy or
C.sub.1-C.sub.4 alkyi; and R.sup.2 and R.sup.3 are independently
hydrogen or C.sub.1-C.sub.7 alkyl optionally substituted by hydroxy
or halo.
12. A compound according to claim 11 selected from
4-methylamino-N'-propyl- benzamide;
5-N-methylamino-N'-propylpicolinamide; 2-chloro-4-methylarnino--
N'-propylbenzamide;
4-methylamino-N'-(2-(S)-hydroxypropyl)benzamide;
4-methylamino-N'-(2-(R)-hydroxypropyl)benamide,
4-methylamino-N'-(2,2,3,3- ,3-pentafluoropropyl)benzamide; and
4-methylamino-N'-tert-amylbezaside.
13. A compound selected from
2-(3-(S)-fluoropyrroldin-1-yl)-1-(S)-phenylet- hanol;
2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol;
2-(R)-phenyl-2-(3-pyrroline-1-yl) ethanol;
2-(3-(R)-fluoropyrrolidin-1-y)- -1-(S)-phenylethanol;
2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol;
2-(3-(R)-fluoropyrrolidin-1-yl)-1-phenylethanol;
2-(3-(S)-fluoropyrrolidi- n-1-yl)-2-(S)-phenylethanol;
2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenyle- thanol; and
2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol.
14. A process for producting a compound of formula (I), which
comprises reacting an amide compound of the formula (VId): 36with
an ethanol compound selected from compounds (Va), (Vb) and (Vc),
and a mixture of compounds (Va) and (Vb): 37in the absence or
presence of a base in a reaction inert solevent.
Description
TECHNICAL FIELD
[0001] This invention relates to novel pyrrolidinyl and pyrrolinyl
ethylamine compounds and their pharmaceutically acceptable salts,
and to pharmaceutical compositions containing them. The
pharmaceutically active compounds of tics invention can be used as
a selective kappa-receptor agonist.
BACKGROUND ART
[0002] Opioid analgesics such as morphine are therapeutically
useful, but their usage is strictly limited because of their side
effects such as drug dependency and abuse. Thus, analgesics with
high usefulness and reduced tendency to cause drug dependency are
desired. Considerable pharmacological and biochemical studies have
been carried out to discover the opioid peptides and opioid
receptors, and the discovery of the subtype of opioid receptor such
as mu (.mu.), delta (.delta.), kappa (.kappa.) in a variety of
species, including human, has made a beginning towards creating new
analgesics. As it is thought that opioid analgesics such as
morphine act as a mu-receptor agonist, separating the action based
on a kappa-receptor agonist from the action based on mu-receptor
agonist has been investigated. Recently kappa-selective agonists
(kappa-agonists) have been reported from the above viewpoint for
example, EMD-61753: A. Barber et al., Br. J Pharmacol., Vol. 113,
pp. 1317-1327, 1994. Some of them actually have been studied in
clinical trials (Med Res. Rev., Vol. 12, p. 525, 1992).
[0003] European Patent No. EP 0254545 B1 discloses a variety of
ethylenediamine compounds. European Patent No. EP 0483580 A2
discloses a vanity of pyrrolidine compounds as analgesics.
International Publication WO 96/30339 discloses a wide variety of
pyrrolidinyl hydroxamic acid compounds as selective kappa-receptor
agonists
BRIEF DISCLOSURE OF THE INVENTION
[0004] The present invention provides a compound of the following
formula: 2
[0005] and the salts thereof, wherein
[0006] A is hydrogen, halo, hydroxy, C.sub.1-C.sub.6 (preferably
C.sub.1-C.sub.4) alkyl, halo C.sub.1-C.sub.6 (preferably
C.sub.1-C.sub.4) alkyl, C.sub.1-C.sub.6 (preferably
C.sub.1-C.sub.4) alkoxy, halo C.sub.1-C.sub.6 (preferably
C.sub.1-C.sub.4) alkoxy, oxo, OY wherein Y is a hydroxy protecting
group, or absent;
[0007] the broken line represents an optional double bond with
proviso that if the broken line is a double bond, then A is
absent;
[0008] Ar.sup.1 is phenyl optionally substituted by one or more
(preferably one to two) substituents selected from halo, hydroxy,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkoxy, CF.sub.3, carboxy-C.sub.1-C.sub.4
alkoxy and C.sub.1-C.sub.4 alkoxy-carbonyl-C.sub.1-C.sub.4
alkoxy;
[0009] Ar.sup.2 is aryl or heteroaryl selected from phenyl,
naphthyl, pyridyl, thienyl, furyl pyrrolyl and pyrimidyl, the aryl
or heteroaryl being optionally substituted by one or more
(preferably one to two) substituents selected from halo, hydroxy,
amino, nitro, carboxy, C.sub.1-C.sub.4 alkyl C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 alkylamino, di C.sub.1-C.sub.4 alkylamino,
halo C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkythio and sulfonyl
methyl;
[0010] R.sup.1 is hydrogen, hydroxy, C.sub.1-C.sub.4 alkyl
C.sub.1-C.sub.4 alkoxy or OY wherein Y is a hydroxy protecting
group; and
[0011] R.sup.2 and R.sup.3 are independently selected from
hydrogen, hydroxy, C.sub.1-C.sub.7 alkyl optionally substituted by
one or more (preferably one to five) hydroxy or halo,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.7 (preferably
C.sub.1-C.sub.5) alkoxy, phenyl optionally substituted by halo
(preferably substituted by one or two halogen atoms), phenyl
C.sub.1-C.sub.7 (preferably C.sub.1-C.sub.5) alkyl, halo
substituted phenyl C.sub.1-C.sub.7 alkyl, and (CH.sub.2)nX--R.sup.4
wherein n is one or two, X is O, NH or S and R.sup.4 is
C.sub.1-C.sub.3 alkyl, or when Ar.sup.2 is phenyl
--Ar.sup.2--C(=O)--N(R.sup.2)-- is a phthalimide group and R.sup.3
is C.sub.1-C.sub.7 alkyl, or
[0012] R.sup.2 and R.sup.3, together with the nitrogen atom to
which they are attached, form a pyrroildine, piperidine or
morpholine ring, optionally substituted by C.sub.1-C.sub.3 alkyl or
halo.
[0013] When Ar.sup.2 is phenyl, R.sup.2R.sup.3N--C(=O)-- is
preferably at the meta or para position on the phenyl ring with
respect to 2-(A-pyrrolydinyl)-1-Ar.sup.1-ethyl-N(R.sup.1)--. When
oxo is selected as "A" group, it is apparent that the oxygen atom
should be attached to the pyrrolidinyl group through a double
bond.
[0014] The pyrrolidinyl and pyrrolinyl ethylamine compounds of the
present invention of formula (I) exhibit good kappa-receptor
agonist activity, and thus are useful as an analgesic, anesthetic,
anti-inflammatory or neuroprotective agent, and also useful in the
treatment of arthritis, stroke or functional bowel disease such as
abdominal pain, for the treatment of a mammalian subject,
especially a human subject. Specifically, these compounds are
useful as an analgesic for acute and chronic pain. Especially,
these compounds are useful as an analgesic at central nervous
system in the mammalian subject. Also, these compounds are useful
as an analgesic for peripheral mediated inflammatory pain caused,
for example by burns (induced by a contact with heat, acid or the
other agents), scald (induced by a contact by hot liquid or steam),
rheumatism or the like, in the said subject.
[0015] Accordingly, the present invention provides a pharmaceutical
composition, which is useful as an analgesic, anesthetic,
anti-inflammatory or neuroprotective agent, and also usefull in the
treatment of the above-mentioned diseases, which comprises a
therapeutically effective amount of the compound of the formula
(I), and a pharmaceutically inert carrier.
[0016] The present invention also provides a method for the
treatment of a medical condition for which agonist activity toward
opioid kappa-receptor is needed, in a mammalian subject, which
comprises administering to said subject a therapeutically effective
amount of the compound of the formula (I).
DETAILED DISCLOSURE OF THE INVENTION
[0017] In this specification, the term "hydroxy protecting group"
means a functional group to protect a hydroxy group against
undesirable reactions during synthetic procedures, including, but
not limited to benzyl, benzoyl, methoxymethyl, tetrahydropyranyl
and trialkylsilyl.
[0018] The term "C.sub.1-C.sub.6 alkyl" is used herein means a
straight or branched alkyl including but not limited to methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the
like.
[0019] The term "C.sub.1-C.sub.6 alkoxy" is used herein to mean a
straight or branched --OR (R is C.sub.1-C.sub.6 alkyl) including,
but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
iso-butoxy, tert-butoxy and the like.
[0020] The term "halo" means F, Cl, Br or I, preferably F or
Cl.
[0021] The term "halo C.sub.1-C.sub.6 alkyl" means a straight or
branched, halo-substituted alkyl of 1 to 6 carbon atoms including,
but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl and tert-butyl, substituted by 1 to 13 (preferably one to
five) halogen atoms.
[0022] The term "halo C.sub.1-C.sub.6 alkoxy" means C.sub.1-C.sub.6
alkoxy substituted by 1 to 13 (preferably one to three) halogen
atoms.
[0023] The term "halo substituted phenyl C.sub.1-C.sub.7 alkyl"
means C.sub.1-C.sub.7 alkyl having a phenyl group attached to its
terminal carbon atom, the phenyl group being substituted by one to
five (preferably one to two) halogen atoms.
[0024] A preferred group of compounds of this invention includes
the compounds of the formula (I) wherein
[0025] A is hydrogen, halo, hydroxy, oxo or OY, or if the broken
line is a double bond then A is absent;
[0026] Ar.sup.1 is phenyl optionally substituted by one to three
substituents selected from halo, hydroxy, C.sub.1-C.sub.4 alkoxy,
carboxy C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4
alkoxy-carbonyl-C.sub.1-C.sub.- 4 alkoxy;
[0027] Ar.sup.2 is phenyl, pyridyl or thienyl, optionally
substituted by one to two halo or C.sub.1-C.sub.4 alkoxy;
[0028] R.sup.1 is hydrogen, hydroxy or C.sub.1-C.sub.4 alkyl;
and
[0029] R.sup.2 and R.sup.3 are independently selected from
hydrogen, C.sub.1-C.sub.7 alkyl optionally substituted by one or
more hydroxy or halo, C.sub.3-C.sub.6 (preferably C.sub.3-C.sub.4)
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 (preferably
C.sub.2-C.sub.3) alkenyl, C.sub.1-C.sub.4 alkoxy phenyl and halo
substituted phenyl C.sub.1-C.sub.7 alkyl when Ar.sup.2 is phenyl,
--Ar.sup.2--C(=O)--N(R.sup- .2)-- is a phthalimide group and
R.sup.3 is C.sub.1-C.sub.7 alkyl, or
[0030] R.sup.2 and R.sup.3, together with the nitrogen atom to
which they are attached, form a pyrrolidine or morpholine ring.
[0031] A more preferred group of this invention includes the
compounds of the formula (I) wherein
[0032] A is hydrogen, fluorine, chlorine, hydroxy or OY wherein Y
is methoxymethyl or tetrahydropyranyl; or if the broken line is a
double bond their A is absent or;
[0033] Ar.sup.1 is phenyl optionally substituted by chlorine,
hydroxy, methoxy or carboxymethoxy;
[0034] Ar.sup.2 is phenyl pyridyl or thienyl, optionally
substituted by chlorine, fluorine or methoxy;
[0035] R.sup.1 is C.sub.1-C.sub.4 alkyl;
[0036] R.sup.2 is C.sub.1-C.sub.7 (preferably C.sub.1-C.sub.5)
alkyl optionally substituted by hydroxy or fluorine,
C.sub.2-C.sub.6 (preferably C.sub.2-C.sub.3) alkenyl, halo
substituted phenylmethyl or phenyl; and
[0037] R.sup.3 is hydrogen or methyl; or
[0038] R.sup.2 and R.sup.3, together with the nitrogen atom to
which they are attached, form a pyrrolidine or morpholine ring.
[0039] A more preferred group of this invention includes the
compounds of the formula (I) wherein
[0040] A is hydroxy, fluorine or chlorine, or if the broken line is
a double bond, then A is absent; Ar.sup.1 is phenyl optionally
substituted by carboxymethoxy; Ar.sup.2 is phenyl optionally
substituted by methoxy or pyridyl; R.sup.1 is C.sub.1-C.sub.4
alkyl, R.sup.2 is C.sub.1-C.sub.7 alkyl optionally substitute by
hydroxy; and R.sup.3 is hydrogen.
[0041] Preferred individual compounds are:
[0042]
4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylam-
ino}-N'-propylbenzamide;
[0043]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-2-methoxy-N'-propylbenzamide;
[0044]
6{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylam-
ino}-N'-propylnicotinamide;
[0045]
4-{N-[1-(S)-(3-carboxymethoxyphenyl)-2-(3(S)-hydroxypyrrolidin-1-yl-
)-ethyl]-N-methylamino}-N'-propylbenzamide,
[0046]
4-{N-[2-(3(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylami-
no}-N'-propylbenzamide;
[0047]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(2-(S)-hydroxypropyl)benzamide;
[0048]
5-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylam-
ino}-N'-propylpicolinamide;
[0049]
4{N-methylamino-N-[2-(3-pyrrolin-1-yl)-1-(S)-phenylethyl}-N'-propyl-
benzamide; and
[0050]
4-{N-[2-(3-S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylami-
no}-N'-(2-(S)-hydroxypropyl)benzamide.
[0051] Other preferre individual compounds are:
[0052]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-isopropylbenzamide;
[0053]
3-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-propylbenzamide;
[0054]
2-chloro-4-(N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]--
N-methylamino}-N'-propylbenzamide;
[0055] 4-
{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyl-
amino}-3-methoxy-N'-propylbenzamide;
[0056]
3-chloro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]--
N-methylamino}-N'-propylbenzamide;
[0057] 4-{N-[1-(S)-(3
-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-eth-
yl]-N-methylamino}-N'-propybenzamide;
[0058]
4-(N-(2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-3-metboxyphenyl)-ethyl-
]-N-methylamino}-N'-propylbenzamide;
[0059]
4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}-N'-prop-
ylbenzamide;
[0060] 4-{N-[1-(S)(3
-chlorophenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl-
]-N-methylamino}-N'-propylbenzamide;
[0061]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)phenylethyl]-N-methyami-
no}-N'-propylbenzamide;
[0062]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1(S)-phenylethyl]-N-methylam-
ino}-pyrrolidinebenzamide;
[0063] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)
1-(S)-phenylethyl]-N-methyla- mino}-morpholinebenzamide;
[0064]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(2-(R)hydroxypropyl)benzamide;
[0065]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-isobutylbenzamide;
[0066]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-allylbenzamide;
[0067]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(3,3,3,-trifluoropropyl)benzamide;
[0068]
3-fluoro-4{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-
-methylamino}-N'-propylbenzamide;
[0069] 4-{N-[2-(3
-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyl-
amino}-N'-(2,2,3,3,3,-pentafluoropropyl)benzamide;
[0070]
4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylam-
ino}-N'-tert-amylbenzamide;
[0071]
5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-propylpicolinamide;
[0072]
4-{N-(2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylam-
ino}-N'-(2-(S)-hydroxypropyl)benzamide;
2-chloro-4-{N-(2-(3-(S)-fluoropyrr-
olidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;
and
[0073]
4-{N-[2-3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylami-
no}-N'-propylbenzamide.
[0074] Other preferred compounds are
[0075]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-methylbenzamide;
[0076]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-ethylbenzamide;
[0077]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-butylbenzamide;
[0078]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-pentylbenzamide;
[0079]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-phenylbenzamide;
[0080]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(2-chlorobenzyl)benzamide;
[0081]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N',N'-dimethylbenzamide;
[0082]
4-{N-[2-(3-(S)-hylroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-methyl-N'-propylbenzamide;
[0083]
5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-propyl-2-thiophenecarboxamide;
[0084]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N'--
propylbenzamide;
[0085]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-propylphthalimide;
[0086]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-ethoxybenzamide;
[0087]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(3-hydroxypropyl)benzamide;
[0088]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-cyclopropylbenzamide;
[0089]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(S)-sec-butylbenzamide;
[0090]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-(R)-sec-butylbenzamide;
[0091]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-propargylbenzamide;
[0092]
4-{N-[1-(R)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-y-
l)-ethyl]-N-methylamino}-N'-propylbenzamide;
[0093]
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N-tert-butylbenzamide;
[0094]
4-{N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-
amino}-N'-propylbenzamide;
[0095]
4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-hydroxya-
mino}-N'-propylbenzamide;
[0096] 4-{N-[2-(3
-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyla-
mino}-N'-propylbenzamide;
[0097]
4-{N-[2-3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylami-
no}-N'-propylbenzamide;
[0098]
4-{N-[2-3-(S)-chloropyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylamin-
o}-N'-(2-(R)-hydroxypropyl)benzamide; and
[0099]
4-{N-[2-(3-oxopyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-
-propylbenzamide.
[0100] Further, the present invention provides a compound of the
following formula: 3
[0101] wherein
[0102] Ar.sup.2 is phenyl, pyridyl or thienyl;
[0103] X is hydrogen, halo or C.sub.1-C.sub.7 alkoxy;
[0104] R.sup.1 is hydrogen, optionally protected hydroxy or
C.sub.1-C.sub.4 alkyl; and
[0105] R.sup.2 and R.sup.3 are independently hydrogen or
C.sub.1-C.sub.7 alkyl optionally substituted by hydroxy or
halo.
[0106] Preferred individual compounds of the formula (Vld) are:
[0107] 4-methylamino-N'-propylbenzamide;
[0108] 5-N-methyamino-N'-propylpicolinamide;
[0109] 2-chloro4-methylamino-N'-propylbenzamide;
4methylamino-N'-(2-(S)-hy- droxypropyl)benzamide;
[0110] 4-methylamino-N'-(2-(R)-hydroxypropyl)benzamide;
[0111] 4-methylamino-N'-(2,2,3,3,3-pentafluoropropyl)benzamide;
and
[0112] 4-methylamino-N'-tert-amylbezamide.
[0113] Further, the present invention provides compounds selected
from
[0114] 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol;
[0115] 2-(3-(S)-fluoropyrrolidin-1-yl)-2(R)-phenylethanol;
[0116] 2-(R)-phenyl-2-(3-pyrroline-1-yl)ethanol;
[0117] 2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol
[0118] 2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol;
[0119] 2-(3-(S)-fluoropyrroihdin-1-yl)-1-(R)-phenylethanol;
[0120] 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol;
[0121] 2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethanol; and
[0122] 2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol.
[0123] Further, the present invention provides processes for
producing a compound of formula (I), which comprises reacting an
aride compound of the formula (VId): 4
[0124] with an ethanol compound selected from compounds (Va), (Vb)
and (Vc), and a mixture of compounds (Va) and (Vb): 5
[0125] in the absence or presence of a base in a reaction inert
solvent.
[0126] General Synthesis
[0127] The kappa agoniists (kappa-receptor agonists) of formula (I)
of this invention can be prepared as described in the following
schemes. Unless otherwise indicated, in the reaction schemes that
follow, A, Ar.sup.1, Ar.sup.2, R.sup.1, R.sup.2 and R.sup.3 are
defined as above. 6
[0128] In the above Scheme la, an optionally substituted styrene
oxide (II) or an optionally substituted phenyl-1,2-ethanediol
2-tosylate (III) can be reacted with a pyrrolidine compound (IV) in
the absence or presence of a base such as K.sub.2CO.sub.3 to form a
mixture of substituted pyrrolidinyl ethanols (Va) and (Vb) This
reaction may be carried out in the absence or presence of a
reaction inert solvent (e.g., methanol (MeOH), ethanol (EtOH),
isopropylalcohol, tetrahydrofuran (TH), dioxane,
N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene
chloride (CH.sub.2Cl.sub.2), water, benzene, toluene, n-hexane or
cyclohexane). This reaction can be carried out at a temperature
from -78.degree. C. to the reflux temperature of the solvent,
preferably at from room temperature to a reflux temperature of the
solvent for 5 minutes to 48 hours, preferably from 0.5 to 12 hours.
The compound (Va) or the mixture of the compounds (Va) and (Vb),
can be treated with methaaesuulfonyl chloride in the presence of a
base such as triethylamine in a proper solvent such as
dichloroethane, followed by coupling with a methyl ester compound
of formula (VIa) to give an intermediate compound (VII). This
coupling reaction can be carried out, in the absence or presence of
a base such as sodium hydride (NaM), in a suitable polar solvent
such as water, EtOH or DMF, at from room temperature to reflux
temperature of the solvent, for 15 minutes to 6 hours
[0129] Then, the intermediate compound (VII) may be treated with a
base such as NaOH in a reaction inert solvent such as methanol, at
a temperature from 0 to 100.degree. C. for 5 minutes to 12 hours to
give a carboxylic acid compound (VIII).
[0130] The carboxylic acid (VIII) can be reacted with an alkyl
amine in the presence of a carbodiimide compound to give the
pyrrolydinyl ethylaraine compound (I). A convenient carbodiimide
compound is 1-ethyl-3-(3-dimeythylaminopropyl)carbodiimide (WSC).
This reaction may be carried out by contacting substantially
equivalent amounts of the carboxylic acid and alkylamine witl a
small exces, amount of the carbodiimide in an appropriate solvent
Appropriate solvents are inert aromatic hydrocarbons, ethers,
halogenated hydrocarbons, especially dichloromethane The reaction
may take place at a temperature in the range from -30 to
100.degree. C., usually from 0 to 30.degree. C. for 30 minutes to
24 hours, usually 12 to 16 hours at room temperature. The resulting
product can be isolated and purified by standard techniques.
[0131] If required, the hydroxy protecting group in A of the
compound (I) obtained (i.e., Y of --OY), can be removed by the
appropriate method for the particular protecting group chosen. For
example, a typical protecting group methoxymethyl, can be removed
by acid catalyzed hydrolysis in the presence of acid catalyst such
as HCl A further convenient protecting group in A is the
tetrahydropyanyl group (THP). This can be also removed by
acid-catalyzed hydrolysis. Appropriate acid catalysts are organic
acids, inorganic acids, or Lewis acids such as acetic acid (AcOH),
p-toluenesulfonic acid (p--TsOH), hydrochloric acid (HCl), and
dimethylaluminium chloride (Me.sub.2AlCl). Preferred acid catalyst
is HCl.
[0132] An optically inactive compound (I) wherein Ar.sup.1 is
optionally substituted phenyl, can be prepared by subjecting a
corresponding optically inactive 1-phenyl-1, 2-ethanediol
2-tosylate of the formula (III) or 1-phenyl-2-pyrrolidinylethanol
(Vb) to the reactions described in Scheme 1a. Optically inactive
compounds (III), wherein Ar.sup.1 is optionally substituted phenyl,
may be prepared according to the procedures described in for
example Tetrahedron, Vol. 47, pp. 9861-9866, 1991, Cehm. Rev., Vol.
80, pp. 187-213, 1980 or J. Org. Chem., Vol. 47, pp. 1229-1232,
1982, followed by tosylation such as reaction with ptoluanesulfonyl
chloride in pyridine at 0.degree. C. Optically inactive (Vb) can be
prepared according to the procedures described for example in
Tetrahedron Lett., Vol. 35, pp. 1511-1514, 1994 followed by a
conventional reduction.
[0133] A compound of the formula (I) wherein A is hydroxy, R.sup.2
is alkoxy and R.sup.3 is hydrogen, can be obtained from a
methylbenzoate of formula (VII) wherein A is hydroxy. First the
hydroxy group of the methylbenzoate compound may be protected with
a suitable protecting group such as tert-butyldimethysilyl group.
Second the hydroxy-protected methyl ester compound can be subjected
to hydrolysis to give the corresponding carboxylic acid. Then the
carboxylic acid can be subjected to amidation to give the compound
(I). The hydroxy protection can be conducted by subjecting the
icompound of the formula (VII) in DMF to a reaction with
tert-butyldimethylsilylchloride and immidazole solution at about
0.degree. C. for 1 to 6 hours. The hydrolysis can be carried out in
the presence of a base such as sodium hydroxide in a polar solvent
such as methanol at about the reflux temperature of the solvent for
from 1 to 10 hours. The amidation can be carried out with a desired
O-alkythydroxylamine in the presence of a carbod.,imide such as WSC
at room temperature for from 1 to 24 hours. If deprotection is
required, a conventional procedures can be employed. For example,
when the hydroxy group is protected with tert-butyldimethylsilyl
group, the amide compound can be treated with tetrabutylammonium
fluoride in a proper solvent such as THF at room temperature.
[0134] A compound of formula (I), wherein A is absent and the
broken line is a double bond, can be also prepared by subjecting a
2-phenyl-2-(3-pyrrolin-1-yl)ethanol compound (Vc) and a benzamiide
compound to the coupling reactions illusrated in Scheme 1a. 7
[0135] The ethanol coompound (Vc) can be prepared by reacting a
corresponding phenylglicinol and 1, 4-dichlorobutene in the
presence of base such as Et.sub.3N in a reaction inert solvent such
as ethanol at the reflux temperature of the solvent for 1 to 24
hours
[0136] A compound of the formula (I) wherein A is oxo (=O), can be
prepared by oxidation of the corresponding pyrrolidinot compound. A
suitable oxidation is Swern oxidation.
[0137] Further, the compounds of the formula (I) wherein
--Ar.sup.2--C(=O)--N(R.sup.2)--, is a phthalimide group, can be
prepared by usinc, a compound of the formula (VIb): 8
[0138] instead of the compound (VIa) in the above-mentioned Scheme
1a.
[0139] Compounds of the formula (I) wherein Ar.sup.2 is thienyl,
can be prepared by using a methylarninothiophenecarboxamide of the
fornnifia (VIc): 9
[0140] instead of the compound (VIa) in the above-memioned Scheme
1a. Compounds (VIc) can be prepared, first, by reacting a
nitrothiophenecarboxaldehyde with the Jones reagent to give a
nitrothiophenecarboxylic acid. Then, the carboxylic acid obtained
can be subjected to condensation with a compound of the formula:
NHR.sup.2R.sup.3, and then to reduction of the nitro group with
iron powder and ammonium chloride, followed by methylation of the
amino group.
[0141] The compounds of formula (II), (III) and (IV) are either
known compounds, which can be made by the known methods, or they
are analogs of known compounds, which can be prepared by methods
analogous to the known methods.
[0142] According to the well known procedures or the following
procedures, R, S configuration of compounds (Va) and (Vb) can be
selectively determined by subjecting a 3-pyrrolidinol with the
corresponding R,S configuration.
[0143] Compounds of the fromula (Va) and (Vb) wherein A is fluorine
and Ar.sup.1 is phenyl, can be prepared from a commercially
available 1-benzyl-3-pyrrolidinol. First, hydroxy group of the
pyrrolidinol can be converted to an appropriate leaving group such
as p-toluenesulfonate. The conversion can be achieved by subjecting
the ptrrolidinol to the reaction with p-toluenesulfonyl chloride in
pyridine. Second, the leaving group may be replaced by fluorine by
a reaction with a suitable fluorinating agent such as
tetrabutylammonium fluoride in a reaction inert solvent such as
THF. Then, the 3-fluoropyrrolidine can be subjected to
hydrogenation followed by a coupling with a stylene oxide of
formula (II). The hydrogenation can be carried out in the presence
of a suitable catalyst such as palladiu hydroxide on carbon under
hydrogen atmosphere in a reaction inert solvents such as EtOH at
from 0.degree. C. to a room temperature for 5 minutes to 48 hours
preferably 12 to 36 hours. The coupling reaction can take place in
the absence or presence of a reaction inert solvent such as
EtOH.
[0144] Compounds of the fromula (Va) and (Vb) wherein A is chlorine
and Ar.sup.1 is phenyl can also be prepared from
1-benzyl-3-pyrrolidinol. For enanple, the 1-benzyl-3-pyrrolidinol
can be subjected to chlorination to give
1-benzyl-3-chloropyrrolidine. The benzyl group of the
1-benzyl-3-chloropyrrolidine can be removed by treating the
1-benzyl-3-chloropyrrolidine with 1-chloroethyl chloroformate
followed by coupling with styreneoxide of the formula (II). The
chlorination 1-benzyl-3-pyrrolidinol can be carried out under a
conventional condition, for example in the presence of a suitable
reagent such as triphenylphosphine in a suitable solvent such as
CCl.sub.4 at room temperature. The debenzylation can be carried out
accroding to the well known methods. The debenzylation is typically
carried out in a reaction inert solvent such as dichloroethane at
the reflux temperature of the solvent for 5 minutes to 3 hours.
Then the solvent may be evapolated and the residue can be subjected
to the coupling reaction with styrene oxide in a suitable solvent
such as EtOH at the reflux temperature of the solvent for 5 minutes
to 4 hours.
[0145] Compounds (Va) and (Vb) wherein A is halo and Ar.sup.1 is a
optionally substituted phenyl, can be prepared from a desired
N-protected 3-pyrrolidinol compound via the corresponding
N-protected 3-halopyrrolidine. First, 1-benzyl-3-pyrrolidinol can
be treated with a suitable halogenation reagent in a reaction inert
solvent for exarnple, triphenylphosphine in CCl.sub.4 at the reflux
temperature of the solvent for from 3 to 36 hours. Second, the
1-benzyl-3-chloropyrrolidin can be purifed, and deprotection can be
carried out under conditions known to skilled in the art (e.g.,
with 1-chloroethyl chloroformate in dichloroethane at 0.degree. C.
for 30 minutes to 6 hours). Third, the 3-chloropyrrolidine can be
treated with a styreneoxide compound to give the ethanols (Va) and
(Vb) according to the procedures illustrated in Scheme 1a.
[0146] Methyl ester compounds of the formula (VIa), wherein
Ar.sup.2 is optionally substituted phenyl, are known compounds or
can be prepared by treating a substituted 4-aminobenzoic acid
compound with an aklhalide in the presence of a base such as NaH or
Na.sub.2CO.sub.3 in a reaction inert solvent such as DMF.
[0147] More specifically, the compounds of the formula (VIa) can be
prepared by the following methods.
[0148] A: Methyl 3-methylarinobenzoate of the formula (VIa) can be
prepared by first subjecting 3-acetarnidebenzoic acid to
methylation in the presence of a base such as NaH in a reaction
inert solvent such as DNF, followed by deacetylation in the
presence of an acid catalyst such as conc. sulfuric acid
(H.sub.2SO.sub.4).
[0149] B: A compound of the formula (VIa) wherein Ar.sup.2 is
substituted by fluorine and R.sup.1 is hydrogen, can be prepared
from a nitrobntnzoic acid by subjecting the nitrobenzoic acid to
esterification followed by reduction. The esterification can be
achieved in the presence of acid catalyst such as sulfuric acid in
MeOH at the reflux tempetate of the solvent for 1 to 17 hours. The
reduction can be carried out in the presence of a reducing agent
such as iron powder in a suitable solvent such as acetic acid at
from room temperature to 60.degree. C. for 0.5 to 6 hours. If
desired, the amino group can be alkylated by a well known method.
For example, first the methyl ester can be treated with
trifluoroacetic anhydride in the presence of base such as
Na.sub.2CO.sub.3 in a suitable solvent such as CH.sub.2Cl.sub.2,
then can be alkylated with a suitable alkylating agent such as
iodomethane. A compound of the formula (VIa) wherein Ar.sup.2 is
substituted by chlorine and R.sup.1 is alkyl, can be prepared from
a chlorobenzoic acid by alkylation . The alkylation can be take
place in the presence of a base such as NaH with a suitable alkyl
halide in a reaction inert solvent such as DMF at about 0.degree.
C. for 1 to 24 hours.
[0150] C: A compound of the formula (VIa), wherein Ar.sup.2 is
pyridyl; the methylester group is on the 3-position and the
R.sup.1HN- is on the 6-position of the pyridine ring respectively,
can be prepared by esterification of a 6-arninoncotic acid. The
crude residue of the methyl ester obtained may be subjected to
methylation of the amino group. A suitable esterificating agent is,
for example, trimethylsilyldiazomethane- . The methylation of the
amino group can be carried out according to the same procedures of
the above mentioned preparation of compounds (VIa).
[0151] Alternatively, an amide compound of the general formula
(VId) 10
[0152] wherein A.sup.2a, X, R.sup.1, R.sup.2 and R.sup.3 are
defined as above, can be subjected to the coupling reaction with
compounds (Va) and (Vb) to directly give a compound (I). This
coupling reaction can be carried out in the absence or presence of
a base such as NaH in a reaction inert solvent. The preferred
solvents include EtOi and DMF. The reaction can be carried out at a
temperature in the range of -78.degree. C. to the reflux
temperature of the solvent, preferably from room temperature to the
reflux temperature, for 5 minutes to 48 hours, preferably 0.5 to 24
hours.
[0153] The aniide compounds of the formula (VId) can be prepared
according to the procedures described below,
[0154] A: A compound of the formula (VId) wherein Ar.sup.1 is
phenyl; R.sup.1 is hydroxy and X is hydrogen, can be obtained by
reduction of a known nitro N-alkylbenzamide compound. Suitable
reducing. agents include for example, zinc powder. This reduction
can be caied out by adding the reducing agent to a mixture of the
nitro N-alkylbenzamide compound and ammonium chloride at about room
temperature (e.g., 20-25.degree. C.) for from 1 to 3 hours.
[0155] B: A compound of the formula (VId) wherein Ar.sup.2a is
phenyl; R.sup.1 is hydrogen or C.sub.1-C.sub.4 alky; R.sup.2 is
C.sub.1-C.sub.7 alkyl optionally substituted by hydroxy; R.sup.3
:is hydrogen and X is hydrogen or halo, may be prepared from a
known amino benzoic acid compound, wherein the phenyl ring is
optionally substituted by halo. The benzoic acid can be subjected
to amidation under the similar conditions to those illustrated in
Scheme 1a. If desired, the amino group of the benzamide compound
obtained can be allylated. For example, preferable ailating agent
is alkylhalide, and this alkylation can be carried out in the
presence of base such as potassium carbonate at about room
temperature for 12 to 24 hours.
[0156] C: An amide compound (VId) wherein Ar.sup.2a is pyridyl, and
--NHR.sup.1 group is on the 5-position and the amide group is on
the 2-position of the pyridine ring respectively, can be prepared
by treating an amino-protected picolinic acid with oxalyl chloride
followed by aridation with an desired alkyl amine. The treatyi of
the 5-protectde-ama picolic acid at oxalyl chloride can be
performed in a reaction inert solvent such as CH.sub.2Cl.sub.2 or
DMF/CH.sub.2Cl.sub.2 in the presence of a base such as
triethylamine at room temperature. The amidation can be carried out
in the presence of a base in a reaction inert solvent. The base is
preferably triethyiamine and the reaction may be conducted in a
suitable solvent, e.g., dichloroethane at about 15.degree. C. If
required, the amino protecting group can be removed by the
procedures known to those skilled in the art.
[0157] An alternative method to prepare the compounds of the
formula (I) is illustrated in the following Scheme 1b. 11
[0158] The mixture of the compounds (Va) and (Vb) can be treated
with methanesulfonyl chloride in a similar way as shown in Scheme
1a, followed by coupling with a cyano compound (VIe) to give the
compound of the formula (VIIb). This coupling reaction can be
carried out in a reaction inert solvent such as DMF or ethanol, in
the presence or absence of base such as NaK NaNH.sub.2 or
2,6-lutidine. This reaction may take place at from room temperature
to the reflux temperature of the solvent for 30 minutes to 12
hours.
[0159] Then, the compound (VIIb) may be reacted with a suitable
alkoxide such as T-BuOK in the presence of water, in a polar
solvent such as t-BuOH. This reaction may take place at reflux
tempa ofiboivent fnbr 5 minutes to6 hors. Then, a proper alkyl
halide can be added to the resulting reaction mixture. The mixture
thus obtained is refluxed for 5 minutes to 5 hours. The target
compound (I) can be isolated and purified from a resulting reaction
mixture by standard techniques.
[0160] Cyano compounds of the formula (Vle), wherein Ar.sup.2 is a
substituted phenyl can be prepared by treating known substituted
4-inobennomtrie compounds with NaH or K.sub.2CO.sub.3, followed by
alkylation with an alkylhalide in a reaction inert solvent such as
DMF.
[0161] The compounds of formula (I) of this invention are basic,
and therefore they will form acid-addition salts. All such salts
are within the scope of this invention. However, it is necessary to
use an acid addition salts which is pharmaceutically-acceptable for
administration to a mammal. The acid-addition salts can be prepared
by standard methods, e.g., by contacting the basic and acidic
compounds in substantially equivalent proportions in water or an
organic solvent such as methanol or ethanol, or a mixture thereof
The salts can be isolated by evaporation of the solvent. Typical
salts which can be formed are the hydrochloride, nitrate, sulfate,
bisulfate, phosphate, acetate, lactate, citrate, tartrate,
succinate, malate, fumarate, gluconate, saccharate, benzta, t
methanesulfonate, p-toluenesulfonate, oxalate and pamoate
(1,1'-methyiene-bis-(2-hydroxy-3-naphtoate)) salts.
[0162] The compounds of formula (I) of this invention, wherein
Ar.sup.1 is phenyl substituted by carboxy-C.sub.1-C.sub.4 alkoxy
are acidic, and they will form base salts. All such salts are
within the scope of this invention. However, it is necessary to use
a base salt which is pharmaceutically-acceptable for administration
to a mammal. The base salts can be prepared by standard methods,
e.g., by contacting the acidic and basic compounds in substantially
equivalent proportions in water or an organic solver. sue as
methanol or ethanol, or a mixnire thereof. The salts can be formed
are the sodium, potassium, calcium and magnesium salts, and also
salts with ammonia and amines, sucn as ethylannine, diethylamine,
cyclohexylamine, piperidine or morpholine salts.
[0163] Also included within the scope of this invention are
bioprecursors (also cailed as pro-drugs) of the kappa agonist
compounds of the formula (I). A bioprecursor of a kappa agonist of
formula (I) is a chemical derivative thereof which is readily
conve-,Led back into the parent compound of formula (I) in
biological systems. In particular, a bioprecursor of a kappa
agonist of formula (I) is converted back to the parent compound of
formula (I) after the bioprecuroo has be administered to, and
absorbed by, a mammalian subject, e.g., a human subject. For
example, it is possible to make a bioprecursor of a kappa agonist
of the invention of formula (I) in which one or both of A and
R.sup.1 is hydroxy groups by making an ester of the hydroxy group.
When only one of A and R.sup.1 is a hydroxy group, only mono-esters
are possible. When both A and R.sup.1 are hydroxy, mono- and
di-esters (which can be the same or different) can be made. Typical
esters are simple allcanoate esters, such as acetate, propionate,
butyrate, etc In addition, when A or R.sup.1 is a hydroxy group,
bioprecursors can be made by converting the hydroxy group to an
acyloxymethyl derivative (e. g., a pivaloyfoxymethyl derivative) by
reaction with an acylaxymnethyl halide (e. g., pivaloyloxymethyl
chloride).
[0164] The kappa agonists compounds of the present invention of
formula (I) exhibit significant agonist activity toward opioid
kappa-receptor and are thus useful as an analgesic, anesthetic,
anti-inflammatory agent or neuroprotective agent, and also useful
in the treatment of arthritis, stroke or functional bowel disease
such as abdominal pain, for the treatment of a mammalian subject,
especially a human subject.
[0165] The activity of the kappa-agonists compounds of formula (I)
of the present invention, is demonstrated by the opioid receptor
binding activity. Such activity mav be determined in homogenate
from guinea pig whole brain, as described by Regina, A. et al.,. in
J. Receptor Res., Vol. 12: pp. 171-180, 1992. In summary, tissue
homogenate is incubated at 25.degree. C. for 30 min in the presence
of labelled ligand and test compounds The mu-sites are labelled by
1 nM of (3H)-[D-Ala2,MePhe4,Gly-ol- 5]enkephalin (DAMGO), the
delta-sites by 1 nM of (3H)-(D-Pen2,5]enkephalin (DPDPE) and the
kappa-sites by 0.5 nM (3H)-CI-977. The non specific binding is
measured by use of 1 .mu.M CI-977 (kappa), 1 .mu.M (DAMGO) (mu), 1
.mu.M (DPDPE) (delta). Data are expressed as the IC.sub.50 values
obtained by a non-linear fitting program using the Cheng and
Prusoff equation Some compounds prepared in the Examples showed a
potent ICso value against kappa receptor in the range of 0.01 to
100 nM.
[0166] The analgesic activity of the kappa-agonist compounds at the
central nervous system can also be demonstrated by the Formalin
Test as described by Wheeler-Aceto, H. et al. in
Psychopharmacology, Vol. 104: pp. 35-44, 1991. In this testing,
male SD rats (80-100 g) are injected s.c. with a test compound
dissolved in 0.1% methyl cellulose saline or vehicle. After 30
min., 50 .mu.l of a 2% formalin are injected into a hind paw. The
number of licking the injected paw per observation period is
measured 15-30 min. after the injecio of fbmaain and expressed as %
inhibition compared to the respective vehicle group. Some compounds
prepared in the Examples showed a potent ED.sub.50 value in the
range of less than 25 mg/kg p.o.
[0167] The activity of the kappa agonists, against peripheral
acute-pain, can be demonstrated by the Randall-Selitto assay (M. E.
Planas, Pain, Vol.60, pp. 67-71, 1995). lathis testing, MaleSD rats
(100-120 g) were used and the nocceptive threshold at the right paw
was measured by Randall-Selitto (Ugo Basile) method. After three
days of acclimation of assay condition, experiments were carried
out. Hyperalgesia was induced by the intraplantar injection of a
0.1 ml/right paw of 1% solution of carrageenin. Painful pressure
were delivered to the right plantar via a wedge-shaped piston and
the level of response were measured at 3.5 and 4.5 hr later the
carrageenin injection. Some compounds, prepared in the working
examples as described below, were tested in accordance with the
above procedures, and showed good activity against acute-pain
(i.e., ED.sub.50 value of less than 10 mg/kg p.o.).
[0168] The activity of the kappa agonists, against chronic pain at
the periphery, can be demonstrated by the adjuvant-induced
hyperalgesia, according to the procedure described by Judith S.
Waker el al., as reported in Life Sciences, Vol. 57, PP. 371-375,
1995. In this testing, male SL rats, weighing 180-230 g at the time
of inoculation, were used. To produce adjumant arthritis, rats were
anesthetized with ether and inoculated intradermahly into the
footpad of the right hindpaw with 0.05 ml of Mycobacteriun
butyricum suspended in paraffin oil (2 mg/ml). Nociceptive
threshold was evaluated by paw pressure test, using same procedures
of the Randall-Selitto assay (as being described above), and edema
was measured as the width of foot. Assays were done through the
whole period.
[0169] The sedation function of kappa agonists can be determined by
the Rotarod Tes; as described by Hayes, A. G. et al. in Br. J.
Pharmacol., Vol. 79, pp. 731-736, 1983. In this testing, a group of
6-10 male SD rats (100-120 g) are selected for their ability to
balance on a rotating rod (diameter 9 cm, rate of rotation 5
r.p.m.). The selected rats are then injected s.c. with a test
compound dissolved in 0.1% methyl cellulose saline The animals are
tested again 30 min. after treatment; a rat falling off the bar
more tha twice within 150 seconds is considered to be showing motor
impairment and the animal's perform ance (i. time on the-rotarod)
are recorded. The ED.sub.50 value, defined as the dose of the drug
which have the performance time is observed in the control group
Some compounds prepared in the working examples as described below,
were tested n accordance with the above procedures.
[0170] The diuresis function of the kappa agonists can be
determined according to the procedure described by A. Barber et
ai., (Br. J. Pharmacol., Vol. III, pp. 843-851, 1994). Some
compounds, prepared in the working examples as descnbed below, were
tested in accordance with the above procedures.
[0171] The kappa agonists compounds of formuil (I) of this
invention can DC administered in either the oral, parenteral or
tropical routes to mammals. A preferable dosage level may be in a
range of from 0 01 mg to 10 mg per kg of body weight per dab,
although variations will necessarily occur depending upon the
weight and condition of the subject being treated, the disease
state being treated and the particular route of administration
chosen. However, a dosage level that is in the range of from 0.01
mg to 1 mg per kg of body weight per day, single or divided dosage
is most desirably employed in humans for the treatment of pain in a
postoperative patient and a pain tlke hyperalgesia caused by
chronic diseases.
[0172] The compounds of the present invention may be administered
alone or in combination with pharmaceutically acceptable carriers
or diluents by either of the above routes previously indicated, and
such administration can be carried out in single or multiple doses.
More particularly, the novel therapeutic agents of the invention
can be administered in a wide variety of different dosage forms,
i.e., they may be combined with various pharmaceutically acceptable
inert carriers in the form of tablets, capsules, lozenges,
trochees, hard candies, powders, sprays, creams, salves,
suppositories, jellies, gels, pastes, lotions, ointments, aqueous
suspensions, injectable solutions, elixirs, syrups, and the like.
Such carriers include solid diluents or fillers, sterile aqueous
media and various nontoxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective compounds of
this invention are present in such dosage forms at concentration
levels ranging 5% to 70% by weight, preferably 10% to 50% by
weight.
[0173] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dipotassium phosphate and glycine may be
employed along with various disintegrants such as starch and
preferably corn, potato or tapioca starch, alginic acid and certain
complex silicates; together with granulation binders like
polyvinyipyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating ag such mar stmme, so lsuixiyl sulte and talc are often
very useful for tabletting purposes. Solid compositions of a
similar type may also be employed as fillers in gelatine capsules;
preferred materials in this connection also include lactose or milk
sugar as well as high molecular weight polyethylene grycols. When
aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient may be combined wit varous
sweetening or flavoring agents, coloring matter or dyes, and, if so
desired, emulsifying and/or suspending agents as well, together
with such diluents as water, ethanol, propylene glycol, glycerin
and various like combinations thereof.
[0174] For parenteral adrninistration, solutions of a compound of
the present invention in either sesame or peanut oil or in aqueous
propylene glycol may be employed. The aqueous solutions should be
suitably buffered (preferably pH>8) if necessary and the liquid
diluent first rendered isotonic. These aqueous solutions are
suitable for intravenous injection purposes. The oily solutions are
suitable for intra-articular, intra-muscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well-known to those skilled in the art.
Additionally, it is also possible to administer the compounds of
the present invention topically when treating inflammatory
conditions of the skin and this may preferably be done by way of
creams, jeffies, gels, pastes, ointments and the like, in
accordance with standard pharmaceutical practice.
EXAMPLES AND PREPARATIONS
[0175] The present invention is illustrated by the following
examples and preparations. However, it should be understood that
the invention is not limited to the specific details of these
examples and preparations. Melting points were taken wfth a Buchi
micro melting point apparatus and uncorrected. Inrared Pay
absorption spectra (IR) were measured by a Shimadzu infrared
spectrometer (IR470). .sup.1H and .sup.13 C nuclear magnetic
resonance spectra (NMR) were measured in CDCl.sub.3 by a JEOL NMR
spectrometer (JNM-GX270, 270 MHz) unless otherwise indicated and
peak positions are expressed in parts per million (ppm) downfield
from tetramethylsilane. The peak shapes are denoted as follows a,
singlet; d, doublet; t, triplet; m, multiplet; br, broad.
Preparation 1
[0176]
2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol
[0177] To a stirred solution of (S)-( )1,2,4-butanetriol (10.61 g,
0.1 mol) in pyridine (50 ml) was added toluenesulfouyl chloride
(38.13 g 0.2 mol) by portions at 0.degree. C. After 14h stirring,
the reaction mixture was poured into conc. HCl aqueous solution
including ice and acidified to pH2. The manure was extracted with
ether (100 ml.times.3). The extract combined was washed with brine,
dried (Na.sub.2SO.sub.4), and concentrated to give 18.58 g of
colorless od. To a stirred solution of this crude ditosylate (18.58
g, 45.7 mmol) and dimnesoxyxmtbh (50 ml) in CH.sub.2Cl.sub.2 (50
ml) was added P.sub.2O.sub.5 by portions at rt (room temperature)
and stirred for 26h. The CH.sub.2Cl.sub.2 layer was separated and
the P.sub.2O.sub.5 (50 g) solid was washed with CH.sub.2Cl.sub.2
(50 ml.times.4). The CH.sub.2Cl.sub.2 layer combined was washed
with saturated NaHCO.sub.3 aqueous solution and brine. After dry
(Na.sub.2SO.sub.4), the solvent was evaporated to afford 18.01 g of
brown viscous oil. A mixture of this oil (18.00 g,40 mmol),1-(-)
2-phenylglycin 1(4.80 g, 35 mm, and Et.sub.3N(11.3 ml, 80 mmol) in
ethanol (20 ml) was refluxed with stirring for 8. The solvent was
evaporated and the residue was dissolved in CH.sub.2Cl.sub.2 (200
ml). This solution was washed with saturated NAHCO.sub.3 aqueous
solution and brine, dried (Na.sub.2SO.sub.4), and concentrated to
give 16.69 g of brown viscous oil, which was purified by column
chromatography (silica gel 200 g, CH.sub.2Cl.sub.2MeOH: 20/1) to
afford 5.13 g (20.4%, over all yield) of clear brown viscous
oil.
[0178] .sup.1H NM (270 MHz, CDCl.sub.3) .delta. 7.40-7.25 (5H, m),
4.62 (1H, d, J=7.0 Hz), 4.58(1H, d, J=7.0 Hz), 4.25-4.15 (1H, m),
3.88 (1H, dd, J=5.9, 10.6 Hz), 3.80 (1H, dd, J=5 9, 10.6 Hz), 3.50
(1H, t, J=5.9 Hz), 3.33 (3H, s), 2.76 (1H, dt, J=6.2, 8.4 Hz), 2.71
(1H, dd, J=5.9, 10.3 Hz), 2.63 (1H, dd, J=3.3, 10.3 Hz), 2.45 (1H,
dt, J=6.2, 8.1 Hz), 2.18 (1H, br s), 2.16-2.02 (1H, m), 1.87-1.75
(1H, m).
[0179] IR(neat): 3450cm.sup.-1.
Preparation 2
[0180] 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol
and 2-(3-(S)-Methoxymethoxpyrrolidin-1-yl)-2-(R)-phenylethanol
[0181] A mixture of 3-(S)-methoxymethoxypyrrolidine (4.37 g, 33.3
mmol) and (S)-(-)-styrene oxide (4.00 g, 33.3 mmol) in EtOH (40 ml)
was refluxed with siirring for 2h. After evaporation of the
solvent, the residue was purified by column chromatography
(slicagel: 120 g, CH.sub.2Cl.sub.2:MeOH=40:1-20:1) to give 4.91 g
(58.7%) of pale yellow oil as 0.65 to 0.35 mixture oftitle
compounds.
[0182] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.40-7.27 (5H, m),
4.68-4.63 (2.65H, m), 4.35-4.15 (1H, m), 3.90-3.75 (0.7H, m), 3.49
(0.35H, t, J=5.9 Hz), 3.38 (1.95H,s), 3.32 (1.05H, s), 3.10-2.90
(1.3H, m), 2.80-2.40 (4H, m), 2.20-2.00 (1H, m), 1.95-1.75 (2H,
m)
Preparation 3
[0183] 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenyethanol
and 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol
[0184] A mixture of 3-(S)-methoxymethoxypyrrolidine (6.10 g, 46.5
mmol), (S)-(+)-1-phenyl-1,2-ethanediol-2-tosylate (13.6 g, 46.5
mmol) and K.sub.2CO.sub.3 (7.06 g, 51.1 mmol) in EtOH (80 ml) was
refluxed with stirring for 4.5h. After evaporation of the solvent,
CH.sub.2Cl.sub.2 was added to the residue and washed with saturated
NaHCO.sub.3 aqueous solution, brine, dried (Na.sub.2SO.sub.4), and
concentrated to give 14.94 g of crude products, which was purified
by column chromatography (slicagel: 150 g,
CH.sub.2Cl.sub.2/MeOH=50:1-20:1) to afford 7.75 g (66.4%) of brown
oil as 0.65 to 0.35 mixture of title compounds.
[0185] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.40-7.27 (5H, m),
4.68-4.63 (2.65H, m), 4.35-4.15 (1H, m), 3.90-3.75 (0.7H, m), 3.49
(0.35H, t, J=5 9 Hz), 3.38 (1.95H,s), 3.32 (1.05H, s), 3 10-2.90
(1.3H, m), 2.80-2 40 (4H, m), 2.20-2 00 (1H, m), 1.95-1.75 (2H,
m)
Preparation 4
[0186]
2-(R)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethano-
l and
1-(S)-Phenyl-2-(3-(S)-tetrahydropvran-2-yloxypyrrolidin-1-yl)ethanol
[0187] This was prepared from 3-(S)-tetrahydropyranyloxypyrrolidine
(300 g, 17.5 mmol) and (S)-(-)-styrene oxide (2.10 g, 17.5 mmol) in
50% yield as 0.35 to 0 65 mrixture of title compounds according to
a procedure sirnilar to that described in Preparation 2.
[0188] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.50-7.20 (5H, m),
4 71 (0.65H, dd, J=3 3, 10 6 Hz), 4.65-4.50 (1H, m), 4.45-4.25 (1H,
m), 3.95-3.75 (1.7H, m), 3.60 - 3.42 (1.35H, m), 3.20-2.40 (5.3H,
m), 2.25-1.45 (9H, m).
Preparation 5
[0189] 2-(R)-Phenyl-2-pyrrolidin-1-yl-ethanol and
1-(S)-Phenyl-2-pyrrolidi- n-1-ethanol
[0190] This was prepared from pyrrolidine (592 mg, 8.32 mmol) and
(S)-(-)-styrene oxide (1.00 g, 8.32 mmol) in 96% yield as 0.3 to
0.7 mixture of title compounds according to a procedure similar to
that described in Preparation 2.
[0191] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.45-7.27 (5H, m),
4 70 (0.7H dd, J=3 3, 10 6 Hz), 3 87 (0.3H, dd, J=5.9, 10.6 Hz),
3.81 (0.3H, dd, J=5.9, 10.6 Hz), 3.47 (0.3H, t, J=5.9 Hz),
2.90-2.70 (1.4H, m), 2.65-2.40 (4H, m), 1.90-1.60(5H, m).
Preparation 6
[0192] Methyl 3-methoxy-4-methylaminobenzoate
[0193] To a suspension of NaH (2.43 g, 60.7 ml. i. DMF (20 ml) was
added a solution of 4-amino-3-hydroxybenzoic acid (3.00 g, 19.6
mmol) in MF(20 ml) at 0.degree. C. After stirring at room
temperature for 1H, iodomethane (3.78 ml, 60.7 mmol) was added to
this mixture at 0.degree. C. and stirred at room temperature for
16h. The mixture was poured into ice water and extracted with nHex:
AcOEt: Et.sub.2O=1:1:1 (300 ml) The extract was washed with water,
brine, dried (Na.sub.2SO.sub.4), and concentrated to give brown
oil, which was purified by column chromato-graphy (silica gel 190
g, nHex/AcOEt=10/1 and silica gel 35 g, CH.sub.2Cl.sub.2 only) to
afford 481 mg (I 3%) of title compound.
[0194] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.66 (1H, dd,
J=1.8, 8.4 Hz), 7.40 (1H, d, J=1.8 Hz), 6.52 (1H, d, J=8.4 Hz),
4.72 (1H, br. s), 3.89 (3H, s), 3.86 (3H, s), 2.91 (3H, d, J=5.1
Hz).
Preparation 7
[0195] Methyl 2-methoxy-4-methylaminobenzoate
[0196] This was prepared from 4-amino-2-hydroxybenzoic acid (3.00
g, 19.6 mmol) in 22% yield according to a procedure similar to that
described in Preparation 6.
[0197] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.77 (1H, d, J=8.8
Hz), 6.16 (1H, dd, J=2.2, 8.8 Hz), 6 08 (1H, d, J=1.8 Hz), 4.19
(1H, br. s), 3.88 (3H, s), 3.82 (3H, s), 2.89 (3H, d, J=5.1
Hz).
Preparation 8
[0198] Methyl 2-chloro-4-methylaminobenzoate
[0199] This was prepared from 4-amino-2-chlorobenzoic acid (2.00 g,
11.7 mmol) in 13% yield-according to a procedure similar to that
described in Preparation 6.
[0200] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.80 (1H, d, J=8.8
Hz), 6.59 (1H, d, J=2.6 Hz), 6.44 (1H, dd, J=2.6, 8.8 Hz), 4.21
(1H, br. s), 3.86 (3H, s), 2.87 (3H, d, J=5.1 Hz).
Preparation 9
[0201] 3-Chloro-4-thylaminobenzonitrile
[0202] This was prepared from 4-amino-3-chlorobenzonitlile (2.00 g,
13.1 mmol) in 42% yield according to a procedure similar to that
described in Preparation 6.
[0203] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.50 (1H, d, J=1.8
Hz), 7.43 (1H, dd, J=1.8, 8.4 Hz), 6.61 (1H, d, J=8.4 Hz),4.92 (1H,
br. s), 2.96 (3H, d, J=5.1 Hz).
Preparation 10
[0204] Methyl 6-methylaminonicotinate
[0205] To a suspension of 6-aminonucotinic acid (1.00 g, 7.24 mmol)
in MeOH (20 ml) and MeCN (10 ml) was added 10% solution of
trimethylsilyldiazoraiethane in CH.sub.2Cl.sub.2 (25 ml) at room
temperature. After stirring at room ten perarure for 0.5 h the
solvent was evaporated to give crude methyl 6-aminonicotinate as a
yellow solid. Title compound was prepared from this crude methyl
6-arninonicotinate in 17% yield according to a procedure similar to
that described in Preparation 6.
[0206] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.75 (1H, d, J=2.2
Hz), 8.01 (1H, dd, J=2.2, 8 8 Hz), 6.36(1H, d, J=9.2 Hz), 5.11(1H,
br. s), 3.87(3H, s), 2.99(3H, d, J=5.5 Hz).
Preparation 11
[0207] Methyl 3-methylaminobenzoate
[0208] To a suspension of NaH (1.54 g, 38.5 mmol) in DMF (20 ml)
was added a solution of 3-acetamidebenzoic acid (3.00 g, 16.7 mmol)
in DMF (20 ml) at 0.degree. C. After stirring at room temperaure
for 0.5 h, iodomethane (2.40 ml, 38.5 mmol) was added to this
mixture at 0.degree. C. and stirred at room temperature for 1.5 h.
The mixture was poured into ice 6N--HCl aqueous solution and
extracted with AcOEt: toluene=2:1 (200 ml.times.3). The extract was
washed with water, brine, dried (Na.sub.2SO.sub.4), and
concentrated to give 3.08 g of brown oil. A mixture of this brown
oil and cH.sub.2SO.sub.4 (5 ml) in MeOH (30 ml) was refluxed with
stirring for 7h. After cooling down to room temperature, the
sulvent was evaporated. The residue was basified with saturated
NaHCO.sub.3 aqueous solution and extracted with CH.sub.2Cl.sub.2.
The extracted was washed with water, brine, dried
(Na.sub.2SO.sub.4), and concentrated to give 2.31 g (84%) of brown
oil.
[0209] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.37 (1H, dt,
J=1.4, 7.5 Hz), 7.28-7.20 (2H, m), 6.73 (1H, ddd, J=0.73, 2.6, 8.1
Hz), 3.89 (3H, s), 2.87 (3H, s).
Preparation 12
[0210] 4-Amino-N'- pronylethahalimide
[0211] To a suspension or NaH (493 g, 12.3 mmol) in DMF (10 ml) was
added a solution of 4-aminophthalimide (2.00 g, 12.3 mmol) in DMF
(10 ml) at 0.degree. C. After stirring at room temperature for 1 h,
iodopropane (1.20 ml, 12.3 mmol) was added to this mixture at
0.degree. C. and stirred at room temperature for 28 h. The mixture
was poured into water and umated with AcOEt: toluene=2:1 (150
ml.times.3). The extract was washed with water, brine, dried
(Na.sub.2SO.sub.4), and concentrated to give yellow solid, which
was purified by column chromatography (silica gel: 130 g,
CH.sub.2Cl.sub.2 only to CH.sub.2Cl.sub.2/MeOH=75/1) to give 1.14 g
(45%) of yellow solid.
[0212] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.59 (1H, d, J=8.1
Hz), 7.03 (1H, d, J=2.2 Hz), 6.81 (1H, dd, J=2.2, 8.1 Hz), 4.32
(2H, br. s), 3.65-3.55 (2H, m), 1.80-1.60 (2H, m), 0.93(3H, t,
J=7.3 Hz).
Preparation 13
[0213] 4-Methylamino-N'-propylphthalimide
[0214] This was prepared from 4-amino-N'-propylphthalimide in 11%
yield according to a procedure similar to that described in
Preparation 12.
[0215] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.59 (1H, d, J=8.4
Hz), 6.96 (1H, d, J=2.2 Hz), 6.71 (1H, dd, J=2.2, 8.4 Hz), 4.50
(1H, br. s), 3.65-3.55 (2H, m), 2.95 (3H, d, J=5.1 Hz), 1.80-1.60
(2H m), 0.93 (3H,t, J=7.3 Hz).
Preparatiosr14
[0216] 5-Nitro-2-thiophenecarboxylic acid
[0217] To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g,
6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in
acetone, 8.12 ml, 65 mmol) at -20.degree. C. After stirring for 1H,
30 ml of isopropanol was added to the mixture. H.sub.2O was added
to the mbtire and eracted with CH.sub.2Cl.sub.2. The extract was
washed with water, brine, dried (Na.sub.2SO.sub.4), .nd
concentrated to give 967 mg (90%) of yeUow amorphous.
[0218] .sup.1H N (270 MHz, CDCl.sub.3) .delta. 7.88 (1H, d, J=4.4
Hz), 7.66 (1H, d, J=4.0 Hz), 5.14 (1H, br. s).
Preparation 15
[0219] 5-Nitro-N-propyl-2-thiophenecarboxamide
[0220] To a solution of 5-nitro-2-thiophenecarboxylic acid (967 mg,
5.59 mmol) in DMF (0.745 ml) and CH.sub.2Cl.sub.2 (4 ml) was added
oxalyl chloride at 0.degree. C. After stirring for 0.5h at rt (room
temperature), the solvent was evaporated below 30.degree. C. to
give yellow oil and solid. To a solution of n-propylamine (0 551
ml, 6. 71 mmol) in Et.sub.3N (1.87 ml, 13 4 mmol) and
CH.sub.2Cl.sub.2 (25 ml) was added a solution of crude acid
chloride in CH.sub.2Cl.sub.2 (10 ml) below 20.degree. C. After
stirring for 4h at rt, the mixture was washed with water, saturated
NaHCO.sub.3 aqueous solution. water, brine, dned
(Na.sub.2SO.sub.4), and concentrated to give brown solid, which was
purified by column chromatography (silica gel 50 g,
CH.sub.2Cl.sub.2/MeOH=100/1-30/1) to afford 815 mg (68%) of white
solid.
[0221] .sup.1H NMR (270, CDCl.sub.3) .delta. 7 85 (1H, d, J=4.0
Hz), 7 35 (1H, d, J=4.4 Hz), 6.12 (1H, br s), 3 50-3 35 (2H, m), 1
75-1 55 (2H, m), 0 99 (3H,t, J=7 3 Hz)
Preparation 16
[0222] 5-Amino-N'-propyl-2-thiophenecarboxamide
[0223] A mixture of 5-nitro-N-propyl-2-thiophenecarboxamide (815
mg, 3 81 mmol), iron powder (1.06 g, 19 0 mmol) and NH.sub.4Cl (102
mg, 1.90 mmol) in EtOH (12 ml) and H.sub.2O (6 ml) was refluxed
with stirring for 2h. The reaction mixture was filtered and washed
with EtOH. The combined filtrate was evaporated. The residue was
dissolved in AcOEt and washed with water, brine, dried
(Na.sub.2SO.sub.4), and concentrated to give brown amorphous, which
was purified by column chromatography (silica gel 40 g,
CH.sub.2Cl.sub.2/MeOH=40/1) to afford 411 mg (59%) of brown
amorphous.
[0224] .sup.1H NMR (270 Mz, CDCl.sub.3) .delta. 7 09 (1H, d, J=3 7
Hz), 6 07 (1H, d, J=4 0 Hz), 5 80-5 60 (1H, m), 4 14 (2H, br. s), 3
40-3 25 (2H, m), 1 70-1 50 (2H, m), 0 96 (3H,t, J=7 3 Hz)
Preparation 17
[0225] 5-Methylamino-N'-propyl-2-thiophenecarboxamide
[0226] To a solution of 5-amino-N'-propyl-2-thiophenecarboxamide
(411 mg, 2 23 nmnol) in CH.sub.2Cl.sub.2(12 ml) was added
Na.sub.2CO.sub.3 (710 mg, 6 70 mmol) and trifluoroacetic anhydride
(0.631 ml, 4.47 mmol) at rt After stirring for 5h, the solid was
filtered off The filtrate was washed with water and brine, dried
Na.sub.2SO.sub.4) and concentrated to give 396 mg of yellow oil To
a solution of this oil in DMF (6 5 ml) was added Na.sub.2CO.sub.3
(2.35 g, 22.2 mmol) and iodomethane (2.90 ml, 46 6 mmol) at rt.
After stirring for 22h, the mixture was poured into ice 1N--HCl and
extracted with AcOEt: toluene=2 1 The extract was washed with
water, brine, dried(Na.sub.2SO.sub.4), and concentrated to give 298
mg of orange solid. To a solution of this solid in MeOH (3.5 ml)
was added 7% K.sub.2CO.sub.3 aqueous solution (1.8 ml) at rt. After
stirring for 18h, the solvent was evaporated. The residue was
dissolved in AcOEt and water. lhe organic layer was washed with
water, brine, dried (Na.sub.2SO.sub.4), and concentrated to give
brown oil, which was purified by column chromatography(silica gel
15 g, CH.sub.2Cl.sub.2/MeOH=60/1 -40/1) to afford 122.5 mg (44%) of
title compound.
[0227] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.16 (1H, d, J=4.0
Hz), 5.89 (1H, d, J=4.4 Hz), 5.68 (1H, br. s), 4.32 (1H, br. s),
3.40-3.30 (2H, m), 2.91 (3H, d, J=5.1 Hz), 1.70-1.50 (2H, m), 0.96
(3H,t, J=7.3 Hz).
Preparation 18
[0228] (S)-1-(3 -Methoxymethoxyphenyl)-1,2-ethanediol
[0229] A mixture of 3-methoxymethoxystyrene (prepared by
methoxymethylation of 3-hydroxystyrene in a standard manner) (1.54
g, 9.39 mmol), and AD-mix-.alpha. (13.18 g, 9.41 mmol) in water (48
ml) and t-BuOH (48 ml) was stirred at 0.degree. C. for 6.5h. To
this reaction mixture was added Na.sub.2SO.sub.3 (14.13 g) and the
mixture was stirred at rt for 1H. The reaction mixture was
extracted with ethyl acetate. The extract was washed with brine,
dried (Na.sub.2SO.sub.4), and concentrated to give light brown oil,
which was purified by column chromatography (silica gel: 90 g,
ethyl acetate/hexane:1/2-3/1) to afford 1.69 g (91%) of desired
product as colorless oil.
[0230] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.25 (1H dd,
J=7.7, 8.1 Hz), 7.03 (1H, d, J=1.8 Hz), 6.98-6.92 (2H, m), 5.15
(2H, s), 4.74 (1H, dd, J=3.3, 8.1 Hz), 3.71 (1H, br. d, J=9 9 Hz),
3.65-3.55 (2H, m, including 1H, dd, J=8.1, 11.0 Hz at 3.61 ppm
CHCH2OH), 3.44 (3H, s), 3.14 (1H, br.s, OH).
Preparation 19
[0231] (S)-1-(3-Methoxymethoxyphenyl)-1,2-ethanediol-2-tosylate
[0232] To a stirred solution of
(S)-1-(3-methoxymethoxyphenyl)-1,2-ethaned- iol (1.69 g, 8.54 mmol)
in pyridine (20 ml) was added p-toluenesulfonyl chloride (1.63 g,
8.54 mmol) and 4-dimethylaminopyridine (1.04 g, 8.54 mmol) at
0.degree. C. and the reaction mixture was stirred at 0.degree. C.
to rt for 16h at 60.degree. C. for 1h. The reaction mixture was
acidified with 2N HCl aqueous solution and extracted with ethyl
acetate The extract was washed with water and brine, dried
(Na.sub.2SO.sub.4), and concentrated to give brown oil, which was
punified by column chromatography (silica gel: 150 g, ethyl
acetatelhexane 1/2 to 2/1) to afford 2 01, (67%) of desired product
as colorless oil. Its optical purity was 98% ee by HPLC.
[0233] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.77 (2H, d, J=8 4
Hz), 7.34 (2H, d, J=8.1 Hz), 7.25 (1H, dd, J=7.7, 8.4 Hz),
7.00-6.92 (3H, m), 5.15 (2H, s), 4.95 (1H, ddd, J=3 3, 3.3, 8 4
Hz), 4 15 (1H, dd, J=3.3, 10.3 Hz), 4 03 (1H, dd, J=8 4, 10 3 Hz),
3 46 (3H, s), 2 65 (1H, d, J=3.3 Hz), 2.45 (3H, s).
Preparation 20
[0234]
2-(R)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1--
yl)ethanol and
1-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrro-
lidin-1yl)ethanol
[0235] This was prepared from
(S)-1-(3-methoxymethyloxyphenyl)-1,2-ethaned- iol-2-tosylate in 79%
yield as 0.25 to 0.75 mixture of title compounds according to a
procedure similar to that described in Preparation 3.
[0236] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 29-7.21 (1H, m),
7 09-6.91 (3H, m), 5 22-5.13 (2H, m), 4 80-4.55 (2.75H, m),
4.33-4.15 (1H, m), 3.90-3.72 (0.5H, m), 3 51-3 45 (0 25H, m), 3 48
(3H, s), 3.38 (2.25H, s), 3.33 (0.75H, s), 3.05-2.90 (1 5H, m),
2.80-2 43 (4H, m), 2.23-2.02 (1H, m), 1.95-1.70 (2H, m).
Preparation 21
[0237] (S)-1-(3-Chloronhenyl)-1,2--ethanediol
[0238] This was prepared from 3-chlorostyrene in 100% yield
according to a procedure similar to that described in Preparation
18.
[0239] .sup.1H NMR(270 MHz, CDCl.sub.3) .delta. 7.40-7.20 (4H, m),
4 90-4 75 (1H, m), 3 85-3 75 (1H, m), 3 75-3 60 (1H, m), 2.66 (1H,
d, J=2.9 Hz), 2.20-2.05 (1H, m)
Preparation 22
[0240] (S)-1-(3-Chlorophenyl-1,2-ethanediol-2-tosylate
[0241] This was prepared from (S)-1-(3-chlorophenyl)-1,2-ethanediol
in 74% yield according to a procedure similar to that described in
Preparation 19. Its optical purity was 98%ee by HPLC.
[0242] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.76 (2H, d, J=8.1
Hz), 7.32 (2H, d, J=8.4 Hz), 7.31-7.17 (4H, m), 5.00-4.92 (1H, m),
4.14 (1H, dd, J=3.3, 10.6 Hz), 4.02 (1H, dd, J=8.4, 10.6 Hz), 2.63
(1H, d, J=3.7 Hz), 2.46 (3H, s).
Preparation 23
[0243] 2-(R)-(3 -Chlorophenyl)-2-(3
-(S)-methoxymethoxypyrrolidin-1-yl)eth- anol and 1-(S)-(
3-Chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1yl)eth- anol
[0244] This was prepared from
(S)-1-(3-chlorophenyl)-1,2-ethanediol-2-tosy- late in 62% yield as
0.15 to 0.85 mixture of title compounds according to a procedure
similar to that described in Preparation 3.
[0245] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.40-7.20 (4H, m),
4.80-4.57 (2.85H, m), 4.32-4.15 (1H, m), 3.85-3.80 (0.3H, m),
3.48-3.40 (0.15H, m), 3.38 (2.55H, s), 3.34 (0.45H, s), 2.92.(1.7H,
m), 2.80-2.62 (2H, m), 2.58-2.40 (2H, m), 2.23-2.05 (1H, m),
1.95-1.80 (1H, m).
Preparation 24
[0246] (R)- -Benzyl-3 -prolidinol-tosylate
[0247] To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (1.77
g, 10 mmol) in pyridine(30 ml) was added p-toluenesulfonyl chloride
(9.53 g, 50 mmol) by portions at 0.degree. C. Afer 90h stirring at
room temperature, water was added to the reaction mixture and the
miture was extracted with ether (150 ml). The extract was washed
with water, brine, dried(Na.sub.2SO.sub.4), and concentrated to
give 3.06 g (92%) of brown oil.
[0248] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.76 (2H, d, J=8.4
Hz), 7.31 (2H, d, J=8.4 Hz), 7.3 5-7.29 (5H, m), 5.05-4.90 (1H, m),
3.61 (1H, d, J=12.8 Hz), 3.54 (1H, d, J=12.8 Hz), 2.76 (1H, dd,
J=6.0, 11.2 Hz), 2.75-2.60 (1H, m), 2.55-2.35 (2H, m), 2.44(3H, s),
2.12-2.05 (1H, m), 2.03-1.90 (1H, m).
Preparatlon 25
[0249] (S)-1-Benzyl-3-fluoropyrrolidine
[0250] To a solution of (R)-1-benzyl-3-pyrrolidinol-tosylate (3 06
g 9 24 mmol) THF (30 ml) was added 10M solution
oftetrabutylammonium fluoride in THF (370 ml 370 mmol) at room
temperature After 15h stirrng at retlux temperature, water (150 ml)
was added to the reaction mixture and the mixture was extracted
with ethyl acetate (100 ml.times.2). The combined extract was
washed with water, brine, dried (Na.sub.2SO.sub.4), and
concentrated to give brown oil, which was purified by column
chromatography (silica gel. 80 g, CH.sub.2Cl.sub.2/MeOH 50/1) to
afford 118 g (71%) of brown oil
[0251] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 45-7 20 (5H, m),
5 29-5.00 (1H, m), 3 68 (1H, d J=13.2 Hz), 3.63 (1H, d, J=12.8 Hz)
2.95-2.60 (3H, m), 2.55-2.38 (1H, m), 2 30-1 90 (2H, m).
Preparation 26
[0252] 2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and
2-(3-(S)-Fluoropyrrolidin-1-yl)-2-(R)-2phenylethanol
[0253] A suspension mixture of (S)-1-benzyl-3-fluoropyrrolidine (1
18 g, , 5 58 mmol) and 20% palladium hydroxide on carbon (354 mg)
in EtOH (20 ml) was stirred under hydrogen atmosphere at room
temperature for 21.5h. After removal of the catalyst by Celite
filtration, to this solution was added a solution of
(S)-(-)-styrene oxide (791 mg, 6.58 mmol) in EtOH (5 ml) The
mixture was refluxed with stirring for 3 5h After evaporation of
the solvent, the residue was purified by column chromatography
(slicagel: 80 g, CH.sub.2Cl.sub.2:MeOH=40 1-30 l) to give 713 mg
(51.8%) of yellow oil as 0.7 to 0.3 mixture of title compounds
[0254] .sup.1H NM R (270 MHz, CDCl.sub.3) .delta. 7 45-7 20 (5H.
m), 535-5 05 (0 7H, m), 5 25-4 95 (0 3H, m), 4 71 (0.7H, dd, J=3 3,
10 6 Hz), 3 95-3 75 (0.6H, m), 3 52 (0 3H, t, J=5 9 Hz 3 15-2 40
(5.4H m), 2.30-1 80 (3H, m)
Preparation 27
[0255] 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol
and 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol
[0256] This was prepared from 3-(S)-methoxymethoxypyrrolidine and
(R)-(-)-styrene oxide in 53% yield as 0.7 to 0.3 mixture of title
compounds according to a procedure similar to that described in
Preparation 2.
[0257] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.40-7.20 (5H, m),
4.72 (0.7H, dd, J=3.3, 10.6 Hz), 4.66 (0.7H, d, J=7.0 Hz), 4.63
(0.7H, d, J=7.0 Hz),4.63-4.56 (0.6H, m), 4.35-4.17 (1H, m),
3.92-3.77 (0.6H, m), 3.50 (0.3H, t, J=5.5 Hz), 3.37 (2.1H,s), 3.33
(0.9H, s), 3.10-2.50 (5.4H, m), 2.25-2.00 (1H, m), 1.95-1.70 (2H,
m)
Preparation 28
[0258] (R)-1-(3 -Methoxymethoxyphenyl)-1,2-ethanediol
[0259] This was prepared from 3-methoxymethoxystyrene and
AD-mix-.beta. in 100% yield according to the procedures similar to
those described in Preparation 18.
[0260] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.31-7.25 (1H, m),
7.06-6.96 (3H, m), 5.18 (2H, s), 4.80 (1H, dd, J=3.7, 8.1 Hz), 3.78
(1H, dd, J=3.7, 11.4 Hz), 3.66 (1H, dd, J=8.1, 11.4 Hz), 3.48 (3H,
s).
Preparation 29
[0261] (R)-1-(3-Methoxymethoxphenyl)-1,2-ethanediol-2-tosylate
[0262] This was prepared from
(R)-1-(3-methoxymethoxyphenyl)-1,2-ethanedio- l in 77% yield
according to the procedures similar to those described in
Preparation 19.
[0263] .sup.1H NMR (210 MHz, CDCl.sub.3) .delta. 7.77 (2H, d, J=8.4
Hz), 7.33 (2H, d, J=7.7 Hz), 7.28-7.18 (1H, m), 7.00-6.92 (3H, m),
5.15 (2H, s), 5.00-4.90 (1H, m), 4.20-4.00(2H, m), 3 46 (3H, s),
2.80-2.60 (1H, m), 2.45 (3H, s)
[0264] 97%ee(by HPLC)
Preparation 30
[0265] 2-(R)-Phenyl-2-(3-pyrroline-1-yl)ethanol
[0266] This was prepared from R-(-)-2-phenylglycinol and
cis-1,4-dichloro-2-butene in 58% yield according to the procedures
similar to those described in Preparation 1
[0267] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.36-7.29(5H, m),
5 77(2H, s), 3 83(2H, d, J=5 9 Hz) 3 66(1H,m), 3 50(4H, s).
Preparation 31
[0268] (S)-1-Benzyl-3-pyrrolidinol-tosylate
[0269] This was prepared from (S)-1-benzyl-3-pyrrolidinol and
p-toluenesulfonyl chloride in 98% yield according to the procedures
similar to those described in Preparation 24.
[0270] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.76(2H, d, J=8.4
Hz), 7.33-7 26(7H, m), 4 97(1H, t, J=2 9 Hz), 3.69-3.58(2H, m),
2.89-2.83(1H, m), 2.73-2.68(2H, m), 2.58-2.55(1H, m), 2.44(3H, s),
2.20-2.12(1H, m), 1.99-1.93(1H, m).
Preparation 32
[0271] (R)-1-Benzyl-3 -fluorolpyrrolidine
[0272] This was prepared from (S)-1-benzyl-3-pyrrolidinol-tosylate
in 61% yield according to the procedures similar to those described
in Preparation 25.
[0273] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 33-7 23(5H, m),
5 28-5 04(1H, m), 3.71-3 61(2H, m), 2.91-2.67(3H, m), 2.50-2.42(1H,
m), 2.24-2.00(2H, m).
Preparation 33
[0274] 2-(3-(R)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and
2-(3-(R)-Fluoropyrrolidin-1-yl)-2-(R)-phenylethanol
[0275] This was prepared (R)-1-benzyl-3-fluoropyrrolidine in 76%
over all yield as 0 6 to 0 4 mixture of title compounds according
to the procedures similar to those described in Preparation 26.
[0276] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 40-7 24(5H, m),
5 32-5 27(0.3H, m), 5 25-5 21(0 2H, m), 5.11-5.07(0.3H, m),
5.07-5.01(0.2H. m), 471(0.6H, dd, J=3.3, 10.3 Hz). 390-3.78(0.6H,
m), 3.55-3.51(0.4H, m), 3.13-2.44(5.4H, m), 2.23-1.94(2H, m).
Preparation 34
[0277] 2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(R)-phenylethanol and
2-(3-(S)-Fluoropyrrolidin-1-yl)-2-(S)-phenylethanol
[0278] This was prepared from 3-(S)-fluoropyrrolidine and
(R)-(+)-styreneoxide in 72% yield as 0.7 to 0.3 mixture of the
title compounds according to the procedures similar to those
described in Preparation 26.
[0279] .sup.1H NMR (270 MHZ, CDCl.sub.3) .delta. 7.39-7.24(5H, m),
5.31-5.28(0.35H, m), 5 28-5.22(0.15H, m), 5.12-5.07(0.35H, m),
5.06-5.01(0.15H, m), 4.73-4.68(0.7H, m), 3 88-3.79(0.7H, m),
3.54-3.50(0.3H, m), 3.13-2.44(5.3H, m), 2.20-1.93(2H, m).
Preparation 35
[0280] (S)-1-Benzyl-3-chloropyrrolidine
[0281] To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886
mg, 5.0 mmol) in CCl.sub.4(20 ml) was added
triphenylphosphine(1.574 g, 6.0 mmol) at rt. After 20h stirring at
reflux temperature, the solvent was evapolated. Saturated
NaHCO.sub.3 aqueous solution and water was added to the residue,
and the mixture was extracted with AcOEt. The extract was brine,
dried(Na.sub.2SO.sub.4), and concentrated to give brown oil, which
was purified by column chromatography (silica gel; 100 g,
CH.sub.2Cl.sub.2/MeOH: 50/1-45/1) to give 706 mg(72%) of pale
yellow oil.
[0282] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.33-7.23(5H, m),
4.42-4.33(1H, m), 3.73-3.61(2H, m), 3.09(1H, dd, J=6.6, 10.6 Hz),
2.81-2.61(3H, m), 2.48-2.35(1H, m), 2.13-2.03(1H,
Preparation 36
[0283] 2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylethanol and
2-(3-(S)-Chloropyrrolidin-1-yl)-2-(R)-phenylethanol
[0284] To a stirred solution of
(S)-1-benzyl-3-chloropyrrolidine(695 mg, 3.55 mmol) in
dichloroethane(10 ml) was added 1-chloroethyl chloroformate(0.38
ml, 3.53 mmol) at 0.degree. C. The mixture was stirred at 0.degree.
C. for 10 min and refluxed for 1.5h. After cooling down to rt, the
solvent was evaporated. The residue was dissolved in MeOH(5 ml) and
refluxed for 1h. After cooling down to rt, the solvent was
evapolated to give 787 mg of brown solid.
[0285] Title compounds were prepared from the above solid and
(S)-(-)-styreneoxide in 39% over all yield as 0.67 to 0.33 mixture
ofthe title compounds according to the procedures similar to those
described in Preparation 2
[0286] .sup.1H NMR (270 MHZ, CDCl.sub.3) .delta. 7.39-7 27(5H, m),
4 70(0 67H, dd, J=3.3, 10 3 Hz), 4 45-4 40(0.67H, m), 4 38-4
32(0.33H, m), 391-3 02(2.33H, m), 2.88-256(4H, m), 2.50-2.31(1H,
m), 2.17-2.03(1H, m).
Preparation 37
[0287] Methlyl 3-fluoro4-nitrobenzoate
[0288] A mixture of 3-fluoro-4-nitrobenzoic acid(2 07 g, 11 2 mmol)
and CH.sub.2SO.sub.4(0.5 ml) in MeOH(10 ml) was refuxed for 8h The
solvent was evapolated The residue was dissolved in AcOEt and
washed with saturated NaHCO.sub.3 aqueous solution, water, brine,
dried (Na.sub.2SO.sub.4), and concentrrated to give 2.14 g(96%) of
ivory solid.
[0289] .sup.1H NMR (270 Mz, CDCl.sub.3) .delta. 8.15-8.07(1H, m),
7.99-7.96(1H, m), 7.95-7.92(1H, m), 3 99(3H, S).
Preparation 38
[0290] Methlyl 4-amino-3-fluorobenzoate
[0291] A mixture of methlyl 3-fluoro4nitrobenzoate(2.14 g, 10.8
mmol) and iron powder(2 63 g) in acetic acid(22 ml) was stirred at
50.degree. C. for 2.5h. After cooling dorn to room temperature,
CH.sub.2Cl.sub.2(100 ml) and water(300 ml) was added to the mixture
and filtered to remove iron powder. The organic layer was separated
and the aqueous layer was extracted with CH.sub.2Cl.sub.2(70
ml.times.2). The CH.sub.2Cl.sub.2 solution was combined, washed
with water, brine, dried(Na.sub.2SO.sub.4), and concentrated to
give 1.77g(97% ) of pale brown solid
[0292] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 70-7 62(2H, m),
6 79-6.70(1H, m), 4 13(2H, br s), 3.86(3H, S).
Preparation 39
[0293] Methlyl 3-fluoro4-methylaminobenzoate
[0294] To a solution of methlyl 4-amino-3-fluorobenzoate(1.77 g,
10.5 mmol) in CH.sub.2Cl.sub.2(50 ml) was added
Na.sub.2CO.sub.3(3.33 g, 31.4 mmol) and trifluoroacetic
anhydride(2.96 ml, 20.9 mmol) at room temperature. After stirring
for 2.5h, the solid was filtered off. The filtrate was washed with
water, brine, dried(Na.sub.2SO.sub.4), and concentrated to give
2.70 g(97%) of white solid. To a solution of this solid(2.70 g,
10.2 mmol) in DMF(48 ml) was added Na.sub.2CO.sub.3(16.9 g, 160
mmol) and iodomethane(20.8 ml, 334 mmol) at 0.degree. C. After
stirrng for 2h at 0.degree. C., for 1h at room temperature, the
mixture was poured into 2NHCl with ice and extracted with AcOEt:
toluene=2:1(200 ml.times.2). The extract was washed with water,
brine, dried(Na.sub.2SO.sub.4), and concentrated to give 3.06
g(quant) of brown oil. This oil was dissolved in MeOH(25 ml) and
7%K.sub.2CO.sub.3 solution(12.5 ml) was added at 0.degree. C. After
stirrinc for 2h at 0.degree. C., for 4h at room temperature,
7%K.sub.2CO.sub.3 solution(12.5 ml) was added. After stirring for
1.5h at room temperature, the mixture was acidified with 5NHCl and
MeOH was evapolated. The residue was extracted with AcOEt. The
extract was washed with water, brine, dried(Na.sub.2SO.sub.4), and
concentrated to give 1.83 g(98%) of pale brown solid.
[0295] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.80-7.72(1H, m),
7.62(1H, dd, J=1.8, 12.5 Hz), 6.63(1H, t, J=8.6 Hz), 4.40(1H, br.
s), 3.86(3H, S), 2.94(3H, d, J=5.1 Hz).
Preparation 40
[0296]
5-[N-tert-Butoxycarbonyl)-N-methylamino]-N'-2propylpicolinamide
[0297] To a solution of
5-[N-(tert-butoxycarbonyl)-N-methylamino]picolinic acid(1.93 g,
7.66 mmol) and triethylamine(1.60 ml, 11.5 mmol) in DMF(0 678 ml)
and CH.sub.1Cl.sub.2(14 ml) was adied oxalyi chloride(0.989 ml,
11.3 mmol) dropwise at room temperature. After stirring for 30 min
at room temperature, the solvent was evapolated The residue was
dissolved in CH.sub.2Cl.sub.2(14 ml). This solution was added
dropwise to a stirried, cooled solution of n-propylamine(0.756 ml,
9.19 mmol) and triethylamine(3.20 ml, 23.0 mmol) in
CH.sub.2Cl.sub.2(28 ml) while the temperature was kept below
15.degree. C. After stirring for 15h at room temperature, the
mixture was washed with water, brine, dried(Na.sub.2SO.sub.4), and
concentrated to give brown oil, which was purified by column
chromatography (silica gel, 100 g, CH.sub.2Cl.sub.2/MeOH: 60/1) to
give 1.82 g(81%) of pale brown oil.
[0298] .sup.1H NMR (270MHz, CDCl.sub.3) .delta. 8.49(1H, d, J=2 6
Hz), 8 16(1H, d, J=8 4 Hz), 7 95(1H, br s), 7 71(1H, dd, J=2.6, 8.4
Hz), 3 50-3 40(2H, m), 3.32(3H, S), 1 75-1 55(2H, m), 1 48(9H, s),
1 00(31H, t, J=7.3 Hz)
Preparation 41
[0299] 5-N-Methylamino-N'-2propylpicolinamide
[0300] A solution of
5-[N-(tert-butoxycarbonyl)-N'-methylamino-N'-propylpi-
colinamide(1.82 g, 6 21 mmol) in trifluoroacetic acid(30 ml) was
stirred at 0.degree. C. for 2h. After removal of the solvent, the
residue was dissolved in CH.sub.2Cl.sub.2 and 25% ammonia solution.
The organic layer was separated and washed with brine,
dried(Na.sub.2SO.sub.4), and concentrated to give 1.20 g(100%) of
brown solid.
[0301] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.01(1H, d, J=8.4
Hz), 7 88(1H, d, J=2.9 Hz), 7 78(1H, br s), 6 90(1H, dd, J=2.9, 8.4
Hz), 4.17(1H, br. s), 3 45-3.35(2H. m), 2.91(3H, d, J=5 1 Hz),
1.75-1.55(2H, m), 0.98(3H, t, J=7 3 Hz).
Preparation 42
[0302] 4-N-Hydroxyamino-N'-propylbenzamide
[0303] To a solution of 4-nitro-N-propylbenzamide(2.75 g,13.2 mmol)
and ammomuum chloride(812 mg, 15.2 mmol) in EtOH(20 ml) and
water(10 ml) was added zinc powder(1.70 g, 26.0 mmol) portionwise
with water cooling After stirring for 30 min at room temperature,
zinc powder(0.50 g, 7 65 mmol) was added to the mixture and stirred
for 30 min at room temperature The solid was removed through celite
and washed with MeOH. The filtrate and washings were combined and
concentrated to give yellow solid, which was purified by column
chromatography (silica ,el, 130 g, CH.sub.2Cl.sub.2/MeOH:
25/1-10/1) to give 2 06 g(80%) of ivory solid.
[0304] .sup.1H NMR (270 MHz, CDCl.sub.3-DMSO-d6) .delta. 8.32(1H,
d, J=2 2 Hz), 7 72(2H, d, J=8 4 Hz). 7.25-7 10(1H, m), 6.95(2H, d,
J=8 8 Hz). 3 45-3.30(2H, m), 2.91(1H, s), 1.70-1 55(2H, m), 0
96(3H, t, J=7,3 Hz).
Preparation 43
[0305] 4-Amino-2-chloro-N'-propylbenzamide
[0306] A mixture of 4-amino-2-chlorobenzoic acid(3.00 g, 17.5
mmol), n-propylamine(2.88 ml, 35.0 mmol) and WSC(6.71 g, 35.0 mmol)
in CH.sub.2Cl.sub.2(35 ml) was stirred at room temperature for 16h.
The mixture was washed with water, brine, dried(Na.sub.2SO.sub.4),
and concentrated to give brown oil, which was purified by column
chromatography (silica gel; 180 g, CH.sub.2Cl.sub.2/MeOH:
30/1-10/1) to give 2.32 g(62%) of pale ivory solid.
[0307] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.64(1H, d, J=8.4
Hz), 6.64(1H, d, J=2.6 Hz), 6.57(1H, dd, J=2.6, 8.4 Hz), 6.44(1H,
br. s), 3.97(2H, br. s), 3.50-3.30(2H m), 1.75-1.55(2H, m),
0.99(3H, t, J=7.3 Hz).
Preparation 44
[0308] 2-Chloro4-methylamino-N'-propylbenzamide
[0309] A mixture of 4-amino-2-chloro-N'-propylbenzamide(2.32 g,
10.9 mmol), iodomethane(0.68 ml, 0.9 mmol) and K.sub.2CO.sub.3(1.51
g, 10.9 mmol) in DMF(50 ml) was stirred at room temperature for
20h. Water was added to the mixture and extracted with AcOEt:
toluene=1:1. The extract was washed with water, brine,
dried(Na2SO.sub.4), and concentrated to give pale brown solid,
which was purified by column chromatography (silica gel; 120 g,
CH.sub.2Cl.sub.2/MeOH: 40/1) to give 887 mg(36%) of pale brown
solid.
[0310] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.57(1H, d, J=8.4
Hz), 6.80(1H, br. s), 6.53(1H, d, J=2.2 Hz), 6.50(1H, dd, J=2.2,
8.4 Hz), 5.00-4.80(1H, m), 3.45-3.30(2H, m), 2.82(3H, d, J=5.1 Hz),
1.75-1.55(2H, m), 0.99(3H. t, J=7.3 Hz).
Preparation 45
[0311] 4-Methylamino-N'-(2-(S)-hydroxypropyl)benzamide
[0312] This was prepared from 4-(methylamino)benzoic acid and
(S)-(+)-1-amino-2-propanol in 22% yield according to the procedures
similar to those described in Preparation 43.
[0313] .sup.1H NMR (270 MHz, CDCl.sub.3-DMSO-d6) .delta. 7.69(2H,
d, J=8.4 Hz), 7.14(1H, br. s), 6.56(2H, d, J=8.8 Hz), 4 60-4 30(2H,
m), 3.98-3 94(1H, m), 3 64-3 55(1H, m), 3.28-3.18(1H, m), 2 85(3H,
s), 1 20(3H, d, J=6 2 Hz)
Preparation 46
[0314] 4-Methylamino-N'-(2-(R)-hydroxypropyl)benzamide
[0315] This was prepared from 4-(methylamino)benzoic acid and
(R)-(-)-1-amino-2-propanol in 41% yield according to the procedures
stmilar to those described in
Preparation 43.
[0316] .sup.1H NMR (270 MHz, CDCl.sub.3-DMSO-d6) .delta. 7.68(2H
dd, J=1.8, 7.0 Hz), 7.12(1H br s), 6.55(2H, dd, J=1.8, 7.0 Hz), 4
50(1H, br s), 4 37(1H, br. s), 3.98-3.93(1H, m), 3 64-3 55(1H, m),
3.28-3.18(1H, m), 2.85(3H, d, J=4 8 Hz), 1 20(3Hz d, J=6.2 Hz).
Preparation 47
[0317] 4-Methylamino-N'-propylbenzamide
[0318] This was prepared from 4-(methylamino)benzoic acid and
n-propyiamime in 82% yield according to the procedures similar to
those described in Preparation 43
[0319] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 63(2H d, J=88
Hz), 6 56(2H, d, J=88 Hz), 6 05(1H, br s), 4.11(1H, br. s), 3.45-3
30(2H, m), 2.86(3H, s), 1.70-1.50(2H, m), 0.97(3H, t, J=7 3
Hz).
Preparation 48
[0320]
4-[N-(Benzyloxycarbonyl)-N-methylamino]-N'-(2,2,3,3,3,-pentafluorop-
ropyl)benzamide
[0321] To a solution of
4-[N-(benzyloxycarbonyl)-N-methylarnino]benzoic acid (100 mg, 0.351
mmol) in CH.sub.2Cl.sub.2(1 ml) was added oxalyl chloride(0 122 ml,
1 40 mmol) and DMF(0.026 ml) at room temperature. After stirring
for 4h at room temperature. the solvent was evapolated. The residue
was dissolved in CH.sub.2Cl.sub.2(10 ml) To this solution was added
2,2,3,3,3-pentafluoropropylamine(523 mg, 3 51 mmol) and
triethylarnine(0.372 ml, 2.67 mmol) at room temperature. After
stirring for 18h at room temperature, saturated NAHCO.sub.3 aqueous
solution was added to the mixture and extracted with
CH.sub.2Cl.sub.2. The extract was washed with brine,
dried(Na.sub.2SO.sub.4), and concentrated to give brown oil, which
was purified by column chromatography (silica gel; 30 g,
CH.sub.2Cl.sub.2 only--CH.sub.2Cl.sub.2/MeOH: 50/1) to give 532
mg(72%) of title compound.
[0322] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.75(2H, d, J=8.8
Hz), 7.39-7.31(7H, m), 6.42-6 31(1H, m), 5.19(2H, s), 4.17(2H, ddd,
J=6.2, 14.7, 14.7 Hz ), 3.36(3H, s).
Preparation 49
[0323]
4-[N-(Benzyloxycarbonyl)-N-methylamino]-N'-tert-amylbenzamide
[0324] This was prepared from
4-[N-(benzyloxycarbonyl)-N-methylamino]benzo- ic acid and
tert-amylamine in 22% yield according to the procedures similar to
those described in Preparation 48.
[0325] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.69 (2H, d, J=8.4
Hz), 7.32-7.29 (7H, m), 5.86-5.75 (1H, m), 5.17(2H, s), 3.33(3H,
s), 1.88-1.80(2H, m), 1.40(6H, s), 0.89(3H, t, J=7.3 Hz).
Preparation 50
[0326]
4-[N-(Benzyloxycarbonyl)-N-methylamino]-N'-tert-butylbenzamide
[0327] This was prepared from
4-N-(benzyioxycarbonyl)-N-methylamino]benzoi- c acid and
tert-butylamine in 93% yield according to the procedures similar to
those described in Preparation 48.
[0328] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.69(2H, d, J=8.8
Hz), 7.32-7.29 (7H, m), 5.89 (1H, br s), 5.17(2H, s), 3.33(3H, s),
1.46(9H, s).
Preparation 51
[0329] 4-Methylamino-N'-(2,2,3,3,3,-pentafluoropropyl)benzamide
[0330] A suspension mixture of
4-[N-(benzyloxycarbonyl)-N-methylamino]-N'--
(2,2,3,3,3,-pentafluoropropyl)benzamide(532 mg, 1.28 mmol) and 10%
palladium carbon(41 mg) in MeOH(5 ml) was stirred under hydrogen
atmosphere at room temperature for 6h. The catalyst was removed
through Celite and washed with MeOH. The filtrate and washings were
combined and concentrated to give 345 mg(96%) of title
compound.
[0331] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 66 (2H, d, J=8 4
Hz), 6.58 (2H, d; J=8 4 Hz). 6 15-6.12(1H, m), 4 23-4 09(3H, m),
2.89(3H, d, J=4 4 Hz).
Preparation 52
[0332] 4-Methylamino-N'-tert-amylbenzamide
[0333] This was prepared from
4-[N-(benzyloxycarbonyi)-N-methylamino]-N'-t- ert-amylbenzamide in
88% yield according to the procedures similar to those descnbed in
Preparation 51.
[0334] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 58(2H, d, J=8.4
Hz), 6 56(2H, d, J=9.8 Hz), 5.70(1H, br s), 4 00(1H, br. s),
2.87(3H, s), 1.83(2H, q, J=7.7 Hz), 1.39(6H, s), 0.89(3H, t, J=7.7
Hz).
Preparation 53
[0335] 4-Methylamino-N'-tert-butylbenzamide
[0336] This was prepared from
4-[N-(benzyloxycarbonyl)-N-methylamino]-N'-t- ert-butylbenzamide in
100% yield according to the procedures similar to those descrbed in
Preparation 51.
[0337] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.58(2H, d, J=8.4
Hz), 6.56(2H, d, J=8.8 Hz), 5.78(1H, br s), 2.86(3H, s), 1.45(9H,
s).
EXAMPLE 1
[0338] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-propylbenzamide
[0339] (i) Methyl
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phen-
ylethyl]-N-methylamino}benzoate
[0340] To a stirred solution of the mixture of
2-(3-(S)-methoxymethoxypyrr- olidin-1-yl)-1-(S)-phenylethanol and
2-(3 -(S)-methoxymethoxypyrrolidin-1-- yl)-2-(R)-phenylethanol
(2.01 g, 8.00 mmol) and triethylartune (1.34 ml, 9 60 mmol) in
CH.sub.2Cl.sub.2 (35 ml) was added methanesulfonyl chlonde (0.744
ml, 9.60 mmol) dropwise at 0.degree. C. (ice bath). After 5.5h
stirring at room remperature, the reaction mixture was washed with
saturated NaHCO.sub.3 aqueous solution, brine, dried
(Na.sub.2SO.sub.4), and concentrated to give 2.16 g of brown
viscous oil. To this oil was added Methyl 4-methylaminobenzoate
(1.45 g, 8.80 mmol) and ethanol (16 ml) and the mixture was stirred
at reflux temperature for 1.5h. The solvent was evaporated. The
residue was dissolved in CH.sub.2Cl.sub.2 and washed with saturated
NaHCO.sub.3 aqueous solution and brine, dnred (Na.sub.2SO.sub.4),
and concentrated to give brown oil, which was purified by column
chromato-graphy (silica gel 150 g, CH.sub.2Cl.sub.2/MeOH:
100/1-35/1) to afford 1.99 g(62.5%) of brown oil.
[0341] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.89 (2H, d, J=9.2
Hz), 7.35-7.20 (5H, m), 6.78 (2H, d J=9.2 Hz), 5.17 (1H, dd, J=6.6,
8.1 Hz), 4.59 (1H, d, J=7.0 Hz), 4.55 (1H, d, J=7.0 Hz), 4.22-4.12
(1H, m), 3.85 (3H, s), 3.30 (3H, s), 3.10 (1H, dd, J=6.2, 12.8 Hz),
3.03 (1H, dd, J=8.4, 12.8 Hz), 2.86 (3H, s), 2.85-2.80 (1H, m),
2.77-2.67 (1H, m), 2.65-2.53(2H, m), 2.05 (1H, ddd, J=7.5, 13.9,
13.9 Hz), 1.83-1.70(1H, m).
[0342] (ii) 4-{N-[2-(3
-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenyleth-
yl]-N-methylamino}benzoic acid
[0343] A mixture of methyl
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-
-(S)-phenylethyl]-N-methylamino} benzoate (1.99 g, 5.00 mmol) and
4N--NaOH (12.5 ml, 50.0 mmol) in MeOH (35 ml) was stirred at
75.degree. C. for 3h. The mixture was neutrallized with 5N--HCl at
0.degree. C. The solvent was removed in vacuo. CH.sub.2Cl.sub.2 was
added to the residue and insoluble solid was removed by filtration.
The filtrate was concentrated to give 2.04 g (quant) of pale brown
amorphous.
[0344] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.93 (2H, d, J=8.8
Hz), 7.40-7.10 (5H, m), 6.81 (2H, d, J=9.2 Hz), 5.85 (1H, br. s),
5.26(1H, dd, J=6.2, 8.1 Hz), 4.60(1H, d, J=70 Hz), 4 56 (1H, d,
J=7.0 Hz), 4.25-4.15 (3H, m), 3.30 (3H, s), 3.20-3.05 (2H, m), 2.97
(1H, dd, J= 6.2, 9.9 Hz), 2.87 (3H, s), 2.80-2.65 (3H, m),
2.15-2.00 (1H, m), 1.90-1.75 (1H, m)
[0345] (iii)
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)phenyletht-
l]-N-methylamino}-N'-propylbenzamide
[0346] To a stirred solution of 4-{(N-[2-(3
-(S)-methoxymethoxypyrrolidin--
1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid (2.04 g, 5.00
mmol) and n-propylamine (0.822 ml, 10.0 mmol) in CH.sub.2Cl.sub.2
(35 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (1.92 g, 10 mmol) at room temperature.
[0347] After 15 5hr stirring, the reaction mixture was washed with
water and brine. dried(Na.sub.2SO.sub.4), and concentrated to give
brown oil, which was purified by column chromatography (silica gel;
100 g, CH.sub.2Cl.sub.2/MeOH 25/1) to give 1 52 g(72%) of pale
brown amorphous.
[0348] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.65 (2H, d, J=8 8
Hz), 7.35-7 20 (5H, m), 6 79 (2H, d, J=9 2 Hz), 6.05-5.90 (1H, m),
5.14 (1H, dd, J=6.6, 8.1 Hz), 4.59 (1H, d, J=70 Hz), 455 (1H, d,
J=7.0 Hz), 4.24-4.10 (1H, m), 3 39 (2H, dd, J=6.6, 13.9 Hz), 3 30
(3H, s), 3.14-2.96 (2H, m), 2.90-2.80 (1H, m), 2.85 (3H, s),
2.78-2.52 (3H, m), 2.14-1 96 (1H, m), 1 84-1 70 (1H, m), 1.68-1 56
(2H, m), 0.97 (3H, t, J=7 3 Hz)
EXAMPLE 2
[0349] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propylbenzamide
[0350] A mixture of
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-ph-
enylethyl]-N-methylamino}-N-propylbenzamide (1.52 g, 3.58 mmol) and
10% HCl in MeOH (25ml) was stirred at room temperature for 6h. The
solvent was evaporated The residue was basified with 25% ammonium
hydroxide, extracted with CH.sub.2Cl.sub.2. The extract was washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated to give pale
brown amorphous, which was purified by column chromatography
(silica gel, 65 g, CH.sub.2Cl.sub.2/MeOH. 20/1-15/1) to give 1 21 g
(89%) of pale brown amorphous
[0351] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.66
(2H, d, J=9.2 Hz), 7 40-7.20 (1H, m), 6.81 (2H, d, J=9 2 Hz),
6.05-5 90 (1H, m), 5 15 (1H, dd, J=5 9, 9 2 Hz), 4 28-4 16 (1H, m),
3.46-3.32 (2H, m), 3.13 (1H, dd, J=9 2, 12.8 Hz), 3.03 (1H, dd, J=5
9, 12 8 Hz), 2.90 (1H, ddd, J=5.0, 8.5, 8.5 Hz), 2 84 (3H, s), 2.73
(1H, d, J=9.9 Hz), 2.56 (1H, dd, J=4 6, 9 7 Hz), 2.32 (1H, ddd,
J=6.1, 90, 90 Hz), 2.18-2.00 (1H, m), 1 90-150 (4H, m), 0 98 (3H,
t, J=7.3 Hz)
[0352] 600 mg of this amorphous was dissolved in 10% HCl in MeOH
(10 ml) The solvent was concentrated to give 625 mg of HCI salt as
pale brown amorphous.
[0353] IR(KBr): 3300, 1610 cm.sup.-1.
[0354] MS m/z: 382(M+H).sup.+
[0355] Anal. Calcd for
C.sub.23H.sub.3N.sub.3O.sub.2.multidot.HCl.multidot- .1.5H.sub.2O
C, 62.08; H, 7.93; N, 944.
[0356] Found: C, 62.29; H, 8.01; N, 9.42.
EXAMPLE 3
[0357] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-methylbenzamide
[0358] This was prepared from
4-(N-[2-(3-S)-methoxymethoxypyrrolidin-1-yl)-
-1-(S)-phenylethyl]-N-methyiamino}benzoic acid and methylamine
hydrochlorde in 26% yield according to a procedure similar to that
described in Example 1 (iii).
[0359] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.64 (2H, d, J=8.8
Hz), 7.40-7.20 (5H, m), 6.79(2H, d, J=8.8 Hz), 6.02 (1H, br. s),
5.13 (1H, dd, J=6.6, 8.1 Hz), 4.59 (1H, d, J=7.0 Hz), 4.55 (1H, d,
J=6.6 Hz), 4.20-4.13 (1H, m), 3.30 (3H, s), 3.15-3.00 (2H, m), 2.97
(1H, d, J=5.1 Hz), 2.90-2.80 (1H, m), 2.83 (3H, s), 2.75-2.55 (3H,
m), 2.05 (1H, ddd, J=7.7, 14.3, 13.9 Hz), 1.90-1.70 (1H, m)
EXAMPLE 4
[0360] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-methylbenzamide
[0361] This was prepared from
4-{N-[2-(3-(S)-methoxyrnethoxypyrrolidin-1-y-
l)-1-(S)-phenylethyl]-N-methyiamino}-N'-methylbenzamide in 82%
yield according to a procedure similar to that described in Example
2.
[0362] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.66
(2H, d, J=9.2 Hz),.7.40-7.20 (5H, m), 6.81 (2H, d, J=8.8 Hz),
6.00-5.95 (1H, m), 5.15 (1H, dd, J=6.0, 9.0 Hz), 4.25-4.20 (1H, m),
3.13 (1H, dd, J=9.2, 12.8 Hz), 3.03 (1H, dd, J=5.9, 12.8 Hz), 2.98
(3H, d, J=5.1 Hz), 2.95-2.80 (1H, m), 2.83 (3H, s), 2.74 (1H, d,
J=9.9 Hz), 2.55 (1H, dd, J=4.6, 9.7 Hz), 2.35-2.25 (1H, m),
2.17-2.05 (1H, m), 1.80-1.60 (2H, m)
[0363] HCl salt: amorphous solid.
[0364] IR(KBr): 3350, 1610 cm.sup.-1.
[0365] Anal. Calcd for
C.sub.21H.sub.27N.sub.3O.sub.2.multidot.HCl.multido- t.1.2H2O: C,
61.29; H, 7.45 ; N, 10.21
[0366] Found: C, 61.68; H, 7.84; N, 10.20.
EXAMPLE 5
[0367] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxyyprrolidin-1yl)-1-(S)-p-
henylethyl-N-methylamino}-N'-ethylbenzamide
[0368] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and ethylamine
hydrochloride in 33% yield according to a procedure similar to that
described in Example 1 (iii).
[0369] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 64 (2H, d, J=8.8
Hz), 7.34-7 24 (5H, m), 6.79 (2H, d, J=8.8 Hz), 5.95-5.83 (1H, m),
5.13 (1H, dd, J=7.0, 7.5 Hz), 4.59 (1H, d, J=7.0 Hz), 4.55 (1H, d,
J=6.6 Hz), 4.25-4.14 (1H, m), 3.52-3.42 (2H, m), 3.30 (3H, s),
3.10-3 01 (2H, m), 2.89-2.80 (1H, m), 2.83 (3H, s), 2.75-2.53 (3H,
m), 2.11-2.01 (1H, m), 1 80-1 74 (1H, m), 1.23 (3H, t, J=7.1
Hz)
EXAMPLE 6
[0370] Preparation of
4-{N-[2-(3-(S)-Hydroxpyrrolidin-1-yl)-1-(S)-phenylet-
hyl]-N-methylamino}-N'-ethylbenzamide
[0371] This was prepared from
4-N-(2-(3-(S)methoxymethoxypyrrolidin-1-yl)--
1-(S)-phenylethyl]-N-methylamino}-N'-ethylbenzamide in 43% yield
according to a procedure similar to that described in Example
2.
[0372] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.65
(2H d, J=8.8 Hz), 7.34-7.23 (5H, m), 6.80 (2H, d, J=8.8 Hz), 6.01
(1H, br.s), 5.14 (1H, dd, J=6.2, 8.8 Hz), 4.22-4 18 (1H, m), 3.50-3
40 (2H, m), 3.11 (1H, dd, J=8 8, 12 8 Hz), 3.02 (1H, dd, J=5.9, 12
8 Hz), 2 92-2.85 (1H, m), 2.82 (3H, s), 2.70 (1H, d, J=9.5 Hz),
2.57 (1H, dd, J=4.8, 9 9 Hz), 2.37-2.29 (1H, m), 2.12-2.01 (2H, m),
1 68-1 60 (1H, m), 1.21 (3H, t, J=7.3Hz)
[0373] HCl salt: amorphous solid.
[0374] IR(KBr): 3350, 1610 cm.sup.-1.
[0375] Anal. Calcd for
C.sub.22H.sub.29N.sub.3O.sub.2.multidot.HCl.multido- t.4H.sub.2O C,
55.72, H. 7 70, N, 8.97
[0376] Found: C, 55.51; H, 8.05; N, 8.83.
EXAMPLE 7
[0377] Preparation of 4-{N-[2 -(3
-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S
)-phenylethyl]-N-methylamino}-N'-butylbenzamide
[0378] This was prepared from
4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and n-butylarnine
in 40% yield according to a procedure similar to that described in
Example 1 (iii).
[0379] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.63 (2H, d, J=9.2
Hz), 7.34-7.24 (5H, m), 6.79 (2H, d, J=9.2 Hz), 6.00-5.85 (1H, m),
5.12 (1H, dd, J=6.6, 7.1 Hz), 4.59 (1H, d, J=6.6 Hz), 4 55 (1H, d,
J=6.6 Hz), 4.19-4.15 (1H, m), 3.50-3.40 (2H, m), 3.29 (3H, s),
3.07-3.02 (2H, m), 2.90-2.80 (1H, m), 2.84 (3H, s), 2.72-2.57 (3H,
m), 2.08-2.01 (1H, m), 1.78-1 60 (1H, m), 1.58-1.36 (4H m), 0.94
(3H, t, J=7.3 Hz)
EXAMPLE 8
[0380] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-2phenyl-
ethyI]-N-methylamino}-N'-butylbenzamide
[0381] This was prepared from
4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamnino}-N'-butylbenzamide in 59% yield
according to a procedure similar to that descnbed in Example 2.
[0382] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.65
(2H, d, J=8.8 Hz), 7.35-7.24 (5H, m), 6.80 (2H, d, J=8.8 Hz),
5.82-5.78 (1H, m), 5.15 (1H, dd, J=5.9, 8.8 Hz), 4.26-4.24 (1H, m),
3.43 (2H, dd, J=7.0, 12.8 Hz), 3.13 (1H, dd, J=8.8, 12.8 Hz), 3.03
(1H, dd, J=6.2, 12.8 Hz), 2.93-2.85 (1H, m), 2.84 (3H, s), 2.73
(1H, d, J=9.5 Hz), 2.56 (1H, dd, J=4.8, 9.5 Hz), 2.37-2.28 (1H, m),
2.10-2.06 (1H, m), 1.72-1.52 (4H, m), 1.47-1 25 (2H, m), 0.95 (3H,
t, J=7.3 Hz)
[0383] HCl salt: amorphous solid.
[0384] IR(KBr): 3350, 1610 cm.sup.-1.
[0385] MS nmz: 396(M+H).sup.+.
[0386] Anal. Calcd for C.sub.24H.sub.33N.sub.3O.sub.2.multidot.HCl
1 4H.sub.2O C, 63.05; 8.1 1; N, 9.19
[0387] Found: C, 63.06; H, 8.04; N, 8.98.
EXAMPLE 9
[0388] Preparation of
4-{N-[1-(S)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxyp-
yrrolidin-1-yl)-ethyl]-N-methylamino}-N'-pentylbenzamide
[0389] This was prepared from
2-(R)-phenyl-2-(3-(S)-tetrahydropyrar-2-ylox-
ypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3
-(S)-tetrahydropyran-2-ylox- ypyrrolidin-1-yl)ethanol in 33% over
all yield according to a procedure similar to that described in
Example 1 (i)-(iii)
[0390] .sup.1H NMR (270 MHz, CDCI.sub.3) .delta. 7 70-7 60 (2H, m),
7 40-7 20 (5H, m), 6 79 (2H, d, J=8.8 Hz), 6.00-5.90 (1H, m), 5
20-5.10 (1H, m), 4 60-4.55 (0 6H, m), 4.50-4 40 (0 4H, m), 4
35-4.20 (1H, m), 3.90-3.72 (1H, m), 3 50-3,35 (3H, m), 3 15-2 90
(3H, m), 2 84 (1.8H, s), 2.83 (1.2H, s), 2.80-2.50 (3H, m),
220-1.95 (1H, m), 1 90-1 25 (13H, m), 0 91 (3H, t, J=7 0 Hz).
EXAMPLE 10
[0391] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-pentylbenzamide
[0392] This was prepared from
4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran--
2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}-N'-pentylbenzamnide in
98% yield according to a procedure similar to that described in
Example 2.
[0393] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.65
(2H, d, J=9.2 Hz), 7 40-7 20 (5H, m), 6.81 (2H, d, J=8.8 Hz), 6
00-5.90 (1H, m), 5 16 (1H, dd, J=6 0, 9.0 Hz), 4 26-4 18 (1H, m),
3.50-3.37 (2H, m), 3.13 (1H, dd, J=9 2, 12.8 Hz), 3 03 (1H dd, J=6
3, 12 8 Hz) 2.93-2.80 (1H, m), 2.84 (3H, s), 2 73 (1H, d, J=9 2 Hz
), 2.56 (1H, dd, J=4 8, 9 5 Hz), 2 37-2.28 (1H, m), 2.17-2.00 (1H,
m), 1 90-1 55 (4H, m), 1.50-1 30 (4H, m), 0 93 (3H, t, J=7 3
Hz)
[0394] HCl salt amorphous solid.
[0395] IR(KBr): 3350, 1610 cm.sup.-1
[0396] Anal. Calcd for
C.sub.25H.sub.35N.sub.3O.sub.2.multidot.HCl.multido- t.0 25H.sub.2O
C, 6665, b, 8.17,N, 9 33
[0397] Found: C, 6657; H, 847; N, 9 31
EXAMPLE 11
[0398] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl-1-(S)-p-
henylethyl]-N-methylamino}-N'-isopropylbenzamide
[0399] This was prepared from
4-(N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino} benzoic acid and isopropylamine
in 15% yield according to a procedure similar to that described in
Example 1 (iii).
[0400] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.63 (2H, d, J=9.2
Hz), 7.34-7.21 (5H, m), 6.78 (2H, d, J=9.6 Hz), 5.75-5.72 (1H, m),
5.12 (1H, dd, J=6.2, 8.8 Hz), 4.59 (1H, d, J=6.6 Hz), 4.55 (1H, d,
J=6.6 Hz), 4.30-4.23 (1H, m), 4.18-4.14 (1H, m), 3.30 (3H, s),
3.06-3.03 (2H, m), 2.90-2.80 (1H, m), 2.85 (3H, s), 2.81-2.72 (1H,
m), 2.66-2.57 (2H, m), 2.08-2.01 (1H, m), 1.79-1.76 (1H, m), 1.23
(6H, d, J=6.6 Hz)
EXAMPLE 12
[0401] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thy]-N-methylamino}-N'-isopropylbenzamide
[0402] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-isopropylbenzamide in 80%
yield according to a procedure similar to that described in Example
2.
[0403] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.64
(2H d, J=8.8 Hz), 7.34-7.22 (5H, m), 6.90 (2H, d, J=8.8 Hz),
5.79-5.77 (1H, m), 5.15 (1H, dd, J=6.2, 8.8 Hz), 4.30-4 19 (2H, m),
3.13 (1H, dd, J=9.2, 12.8 Hz), 3.03 (1H, dd, J=6.2, 12.8 Hz),
2.93-2.84 (1H, m), 2.82 (3H, s), 2.72 (1H, d, J=9.5 Hz), 2.57 (1H,
dd, J=4.8, 9.9 Hz), 2.38-2.29 (1H, m), 2.14-2.02 (2H, m), 1.68-1.58
(1H, m), 1.23 (6H, d, J=6.6 Hz)
[0404] HCl salt: amorphous solid.
[0405] IR(KBr): 3350, 1610 cm.sup.-1.
[0406] MS m/z: 382(M+H).sup.+.
[0407] Anal. Calcd for
C.sub.23H.sub.31N.sub.3O.multidot.HCl.multidot.1.0H- .sub.2O: C,
61-09 ; H, 7.98; N, 9.29
[0408] Found: C, 61.16; H, 7 61; N, 9.12.
EXAMPLE 13
[0409] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-phenylbenzamide
[0410] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino} benzoic acid and aniline in 48%
yield according to a procedure similar to that described in Example
1 (iii)
[0411] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 63 (2H, d, J=8 8
Hz), 7 69 (1H, br s), 7 62 (2H, d, J=7 7 Hz), 7.40-7.24 (7H, m), 7
11 (1H, t, J=7 3 Hz), 6 88-6 80 (2H, m), 5 18 (1H, dd, J=7 7, 15 0
Hz), 4 60 (1H, d, J=7 0 Hz), 4 56 (1H, d, J=7 0 Hz), 425-4.10 (1H,
m),3 31 (3H, s), 3.15-3.05 (2H, m), 2.89 (3H, s), 2.95-2.80 (1H,
m), 2.80-2.55 (3H, m), 2.15-2 00 (1H, m), 1.90-1.70 (1H, m)
EXAMPLE 14
[0412] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-phenylbenzamide
[0413] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-phenylbenzamide in 16% yield
accordin, to a procedure similar to that described in Example
2.
[0414] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7 84
(1H, br. s), 7.76 (2H, d, J=8.8 Hz), 7 66-7 60 (2H, m), 7.40-7.24
(7H, m), 7.10 (1H, t, J=7 3 Hz), 6.84 (2H, d, J=9.2 Hz), 5 18 (1H,
dd, J=6.2, 8.8 Hz), 4.30-4.17 (1H, m), 3.15 (1H, dd, J=9.2, 12.8
Hz), 3.05 (1H, dd, J=5.9, 12.8 Hz), 3.00-2.85 (1H, m), 2.85 (3H,
s), 2.74 (1H, d, J=9 5 Hz), 2 59 (1H, dd, J=4.8, 9.5 Hz), 2.45-2.30
(1H, m), 2.25 (1H, br. s), 2.15-2.00 (1H, m), 1 80-1,60 (1H, m)
[0415] HCl salt: amorphous solid.
[0416] IR(KBr): 3400, 1600 cm.sup.-1.
[0417] Anal. Calcd for
C.sub.2H.sub.29N.sub.3O.sub.2.multidot.HCl.multidot- .H.sub.2O C,
66 44; H, 6.86; N, 8.94
[0418] Found: C, 66.33; H, 7.16; N, 8.86.
EXAMPLE 15
[0419] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-(2-chlorobenzyl)benzamide
[0420] This was prepared from
4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
2-chlorobenzylarnine in 88% yield according to a procedure similar
to that descnbed in Example 1 (iii)
[0421] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.68 (2H, d, J=9.2
Hz), 7.50-7.20 (9H, m), 6.80 (2H, d, J=9 2 Hz), 6.50-6.40 (1H, m),
5 13 (1H, dd, J=6.6, 8.1 Hz), 4 71 (2H, d, J=5 9 Hz), 4 59 (1H, d,
J=7.0 Hz), 4.54 (1H, d, J=7.0 Hz), 4.22-4.10 (1H, m), 3.29 (3H, s),
3.15-2.97 (2H, m), 2.87-2.80 (1H, m), 2.85 (3H, s), 2.75-2.52 (3H,
m), 2.13-1.98 (1H, m), 1 85-1.70 (1H, m)
EXAMPLE 16
[0422] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-(2-chlorobenzyl)benzamide
[0423] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
-1-(S)-phenylethyl]-N-methylamino}-N'-(2-chlorobenzyl)benzamide in
98% yield according to a procedure similar to that described in
Example 2.
[0424] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.68
(2H, d, J=8.8 Hz), 7.50-7.20 (9H, m), 6.79 (2H, d, J=8.8 Hz),
6.50-6.40 (1H, m), 5.14 (1H, dd, J=6.0, 9.0 Hz), 4.71 (2H, d, J=5.9
Hz), 4.25-4.20 (1H, m), 3.12 (1H, dd, J=8.8, 12.8 Hz), 3.03 (1H,
dd, J=6 2, 12.8 Hz), 2.95-2.80 (1H, m), 2.84 (3H, s), 2.72 (1H, d,
J=9.9 Hz), 2.56 (1H, dd, J=4.4, 9.9 Hz), 2.40-2.32 (1H, m),
2.16-2.00 (1H, m), 1.80-1.55 (2H, m)
[0425] HCl salt: amorphous solid.
[0426] IR(KBr): 3300, 1630, 1605 cm.sup.-1.
[0427] Anal. Calcd for
C.sub.27H.sub.30N.sub.3O.sub.2Cl.multidot.HCl.multi- dot.H.sub.2O
0.3C.sub.3H.sub.8O. C, 62.46 H, 6.65; N, 7.83
[0428] Found: C, 62.51; H, 7.02; N, 7.94.
EXAMPLE 17
[0429] Preparation of
4-{N-[2-(3-(S)-Methoxyethoxypyrrolidin-1-yl)-1-(S)-p-
henylethyl]-N-methylamino}-N',N'-dimethylbenzamide
[0430] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino} benzoic acid and dimethylamine
hydrochloride in 71% yield according to a procedure similar to that
described in Example 1 (iii).
[0431] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.50-7.20 (7H, m),
7.00-6.75 (2H m), 5.35-5.25 (1H, m), 4 62 (1H, d, J=7.0 Hz), 4.58
(1H, d, J=6.6 Hz), 4.35-4.20 (1H, m), 3.40-3.20 (2H, m), 3.32 (3H
s), 3.15-3.30 (1H, m), 3.07 (6H, s), 2.95-2.70 (2H, m), 2.81 (3H,
s), 2.25-2 05 (1H, m), 2 00-1.80 (1H, m), 1 80-1 55 (1H, m)
EXAMPLE 18
[0432] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N',N'-dimethylbenzamide
[0433] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N',N'-dimethylbenzamide in 88%
yield accordimg to a procedure similar to that described in Example
2.
[0434] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7 37
(2H, d, J=8 8 Hz), 7 35-7 20 (5H, m), 6 79 (2H, d, J=9.2 Hz), 5.13
(1H, dd, J=6.0, 9 0 Hz), 4.25-4.17 (1H, m), 3.18-2 98 (2H, m), 3 07
(6H, s), 2.91 (1H, ddd, J=5.1, 8 4, 8 4 Hz), 2.81 (3H, s), 2.74
(1H, d, J=9 2 Hz), 2.55 (1H, dd, J=4.8, 9.5 Hz), 2.37-2.25 (1H, m),
2.20-2.00 (1H, m), 1 80-1 55 (2H, m)
[0435] HCl salt: amorphous solid.
[0436] IR(KBr): 3400, 1610 cm.sup.-1.
[0437] Anal. Calcd for
C.sub.22H.sub.29N.sub.3O.sub.2.multidot.HCl.multido- t.H.sub.2O C,
62.62 , H, 7 64, N,9 96
[0438] Found: C, 62.52; H, 7.86; N, 9 98
EXAMPLE 19
[0439] Preparation of
4-{N-[1-(S)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxyp-
yrroildin-1-yl)-ethyl]-N-methylamino}-N-methyl-N'-propoylbenzamide
[0440] This was prepared from
2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-ylox-
ypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3
-(S)-tetrahydropyran-2-ylox- ypyrrolidin-1-yl)ethanol in 32% over
all yield according to a procedure similar to that described in
Example 1 (i)-(iii).
[0441] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.40-7 20 (7H, m),
6 77 (2H, d, J=8 8 Hz), 5 11 (1H, dd, J=7 0, 7.7 Hz), 4.60-4.55
(0.6H, m), 4 53-4 47 (0 4H, m), 4.38-4 25 (1H, m), 3.90-3 75 (1H,
m), 3 55-3.30(3H, m), 3.15-292 (2H, m), 3 03(3H, s), 2,81 (1 8H,
s),280 (1 2H, s), 2 80-2 70 (1H, m), 2.68-2.50 (3H, m), 2 15-1 95
(1H, m), 1 90-1 45 (9H, m), 100-0.80 (3H, m).
EXAMPLE 20
[0442] Preparation of 4-{N-[2-(3
-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyl-
ethyl]-N-methylamino}-N'-methyl-N'-propylbenzamide
[0443] This was prepared from
4-(N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran--
2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}-N'-methyl-N'-propylbenzamide
in 83% yield according to a procedure sinilar to that described in
Example 2.
[0444] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.40-7.20 (7H, m), 6.79 (2H, d, J=8.8 Hz), 5 11 (1H, dd, J=6.2, 8.8
Hz), 4.28-4.16 (1H, m), 3.46-3.32 (2H, m), 3.18-2.98 (1H, m), 3.03
(3H, s), 2.90 (1H, ddd, J=5.1, 8.4, 8.5 Hz), 2.81 (3H s), 2.78-2.70
(1H, m), 2.56 (1H, dd, J=4.6, 9.7 Hz), 2.32 (1H, ddd, J=6.2, 9.2,
9.2 Hz), 2.18-2.00 (1H, m), 1.90-1.50 (4H, m), 1.00-0.80 (3H,
m)
[0445] HCl salt: amorphous solid.
[0446] IR(KBr): 3350, 1610 cm.sup.-1.
[0447] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.2.multidot.HCl.multido-
t.0.75H.sub.2O: C, 64.70; H, 8.03; N,9.43
[0448] Found: C, 64.68; H,8.39;N, 9.49.
EXAMPLE 21
[0449] Preparation of
3-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-propylbenzamide
[0450] (i)
Methyl-3-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl))-1-(S)-phe-
nylethyl]-N-methylamino}benzoate
[0451] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1yl)-2-(R)- -phenylethanol and
methyl 3-methylaniinobenzoate in 78% yield according to a procedure
similar to that described in Example 1 (i).
[0452] .sup.1H NMR (270 Mz CDCl.sub.3) .delta. 7.51-7,48 (1H, m),
7.39-7.34 (1H, m), 7.33-7.20 (6H, m), 7.04-6 98 (1H, m), 5.15-5.05
(1H, m), 4.59 (1H, d, J=7.0 Hz), 4.55 (1H, d, J=7 0 Hz), 4,20-4.10
(1H, m), 3.89 (3H, s), 3.30 (3H, s), 3.15-2.97 (2H, m), 2.90-2.80
(1H, m), 2.82 (3H, s), 2.77-2.55 (3H, m), 2.12-1.98 (1H, m),
1.83-1.60 (1H, m)
[0453] (ii) 3-{N-[2-(3 -(S)-Methoxymethoxypyrrolidin-1-yl)-1(
S)phenylethyl]-N-methylamino}benzoic acid
[0454] This was prepared from methyl
3-{N-[2-(3-(S)-methoxymethoxypyrroidi-
n-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate in 100% yield
according to a procedure similar to that described in Example 1
(ii).
[0455] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 98 (1H, br s), 7
47 (1H, d, J=7 7 Hz), 7 30-7 10 (6H, m), 6 82 (1H, d, J=2.2, 8.4
Hz), 5.70-5 60 (1H, m), 4.63 (1H, d, J=6 6 Hz), 4 59 (1H, d, J=6.6
Hz), 4.40-4.30 (1H, m), 4.04 (1H, br. s), 3.77 (1H, dd, J=5 9, 11.7
Hz), 3 68-3 58 (1H, m), 3 48-3.28 (2H, m), 3.32 (3H, s), 3.12-3.00
(1H, m), 2.96-2:84 (1H, m), 2 71
[0456] (iii)
3-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-S)-phenylethy-
l]-N-methylamino}-N'-propylbenzamide
[0457] This was prepared from
3-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and n-propylamine
in 78% yield according to a procedure similar to that described in
Example 1 (iii).
[0458] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 34-7.19 (7H, m),
6.98 (1H, d, J=7.3 Hz), 6 91 (1H, dd, J=2.2, 8 1 Hz), 6.22 (1H, br.
s), 5.16-5.06 (1H, m), 4.57 (1H, d, J=6.6 Hz), 4 53 (1H, d, J=6.6
Hz), 4.22-4.12 (1H, m), 3.46-3.32 (2H, m), 3.28 (3H, s), 3.16-2.96
(1H, m), 2.81 (3H, s), 2.86-2.52 (4H, m), 2.14-1.98 (1H, m),
1.82-1.56 (4H, m), 0.98 (3H, t, J=7 3 Hz)
EXAMPLE 22
[0459] Preparation of
3-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propylbenzamide
[0460] This was prepared from
3-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide in 90% yield
according to a procedure similar to that described in Example
2.
[0461] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.42-7 37 (1H, m),
7.36-7 19 (6H, m), 6.97 (1H, d, J=7 7 Hz), 6.92 (1H, dd, J=2.6, 8 1
Hz), 6 21 (1H, br. s), 5.13 (1H, dd, J=5 9. 3 8 Hz), 4 26-4.14 (1H,
m), 3.48-3.32 (2H, m), 3 18-3.00 (2H, m), 2 92 (1H, ddd, J=4 8, 8
4, 8 4 Hz), 2.86-2.72 (1H, m), 2.78 (3H, s), 2.50 (1H, dd, J=4 8,
9.9 Hz), 2.36-2.22 (1H, m), 2.20-2.02 (1H, m), 2.00-1.70 (2H, m),
1.63 (2H, ddd, J=7 3, 14 7, 14 7 Hz), 0 98 (3H, t, J=7.3 Hz)
[0462] HCl salt: brown powder.
[0463] mp: 105-114.degree. C.
[0464] IR(KBr): 3350, 1635 cm.sup.-1.
[0465] MS m/z: 381(M.sup.+).
[0466] Anal. Calcd for
C.sub.23H.sub.31N.sub.3O.sub.2.multidot.HCl.multido-
t.0.7H.sub.2O.multidot.0.3C.sub.6H.sub.14O: C,64.58 H, 8.22; N,
9.11
[0467] Found: C, 64.42; H,8.54; N, 9.34.
EXAMPLE 23
[0468] Preparation of
2-Chloro4-{N-[1-(S)-2benyl-2-(3-(S)-tetrahyaropyran--
2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}-N'-propylbenzamide
[0469] (i) Methyl
2-chloro4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yl-
oxvpyrrolidin-1-yl)-ethyl-N-methylamino}benzoate
[0470] This was prepared from
2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-ylox-
ypyrrolidin-1-yl)ethanol and
1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxy-
pyrrolidin-1-yl)ethanol and methyl 2-chloro-4- methylaminobenzoate
in 40% yield according to a procedure similar to that described in
Example 1 (i).
[0471] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.86-7.80 (1H, m),
7.38-7.22 (5H, m), 6.83-6.78 (1H, m), 6.72-6.65 (1H, m), 5.10 (1H,
dd, J=6.6, 7.7 Hz), 4.60-4.55 (0.6H, m), 4.50-4.45 (0.4H, m),
4.38-4.22 (1H, m), 3.86 (3H, s), 3.85-3.75 (1H m), 3.50-3.37 (1H,
m), 3.13-2 90 (3H, m), 2.85 (1.8H, s), 2.84 (1.2H, s), 2.80-2.50
(3H, m), 2.20-1.95 (1H, m), 1 95-1.40 (7H, m).
[0472] (ii)
2-Chloro-1-{N-[1-(S)-2benyl-2-(3-(S)-tetrahydropyran-2-yloxypy-
rrolidin-1-yl)ethyl]-N-methylamino}benzoic acid
[0473] This was prepared from methyl
2-chloro4-{N-[1-(S)-phenyl-2-(3-(S)-t-
etrahydropyran-2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}benzoate
in 100% yield according to a procedure similar to that described in
Example 1 (ii).
[0474] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.86-7.75 (1H, m),
7.38-7.22 (5H, m), 6.80-6.60 (2H, m), 5.20-5.10 (1H, m), 4,60-4.55
(0 6H, m), 4.50-4.45 (0.4H, m), 4.38-4.22 (1H, m), 3 85-3.37 (3H,
m), 3.20-3.00 (2H, m), 2 80-2.50 (4H, m), 2.69 (3H, s), 2.20-1.95
(1H, m), 1.95-1.40 (7H, m).
[0475] (iii)
2-Chloro-4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxyp-
yrrolidin-1yl)-ethyl]-N-methylamino}-N'-propvlbenzamide
[0476] This was prepared from
2-chloro-4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahy-
dropyran-2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino} benzoic acid
and n-propylamine in 68% yield according to a procedure similar to
that described in Example 1 (iii).
[0477] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 78-7 72 (1H, m),
7 38-7 22 (5H, m), 6 79-6 70 (2H, m), 6 60-6.48 (1H, m), 5.07 (1H,
dd, J=6 6, 7 3 Hz), 4.60-4 55 (0.6H, m), 4 50-4 45 (0 4H, m),
4.38-4.22 (1H, m), 3.90-3.75 (1H, m), 3 50-3 37 (3H, m), 3.13-2.90
(2H, m), 2 82 (3H, s), 2.80-2.50 (4H, m), 2.20-1.95 (1H, m),
1.95-1.40 (9H, m), 0 99 (3H, t, J=7 3 Hz).
EXAMPLE 24
[0478] Preparation of
2-Chloro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl-1-(S)-
-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0479] This was prepared from
2-chloro4-{N-[1-(S)phenyl-2-3-(S)-tetrahydro-
pyran-2-yloxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
in 89% yield according to a procedure similar to that described in
Example 2.
[0480] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7 76
(1H, d, J=8 8 Hz), 7 40-7 20 (5H, m), 6 75 (1H, dd, J=2.6, 8.8 Hz),
6.72 (1H, d, J=2.6 Hz), 6.54 (1H br. s), 5 07 (1H, dd, J=5.9, 9 2
Hz), 4.30-4 20 (1H, m), 3 46-3 35 (2H, m), 3 12 (1H, dd, J=9 2. 12
3 Hz), 3.01 (1H, dd, J=6.0, 13.0 Hz), 2.95-2.78 (1H, m), 2.83 (3H,
s), 2.72 (1H, d, J=9 9 Hz), 2 58 (1H, dd, J=4 8, 9 5 Hz), 2.35 (1H,
ddd, J=6 0, 8 9, 9 0 Hz), 2 18-2.00 (1H, m), 1 90-1 50 (4H, m), 0
99(3H, t, J=7 7 Hz)
[0481] HCl salt. amorphous solid.
[0482] IR(KBr): 3350, 1600 cm.sup.-1.
[0483] Anal. Calcd for
C.sub.23H.sub.30N.sub.3O.sub.2Cl.multidot.HCl.multi- dot.0
2H.sub.2O C, 60 58, H, 6 94, N, 9.21
[0484] Found: C, 60.29; H, 7 13; N, 9.13
EXAMPLE 25
[0485] Preparation of
2-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1--
yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0486] (i) Methyl
2-methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)--
1-(S)-phenylethyl]-N-methylamino}benzoate
[0487] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
methyl 2-methoxy4-methylaminobenzoate in 41% yield according to a
procedure similar to that described in Example 1 (i).
[0488] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.79 (1H, d, J=9.2
Hz), 7.36-7.20 (5H, m), 6.40 (1H, dd, J=2.4, 8.9 Hz), 6.27 (1H, d,
J=2.6 Hz), 5.13 (1H, dd, J=7.0, 8.1 Hz), 4.60 (1H, d, J=7.0 Hz),
4.56 (1H, d, J=6.6 Hz), 4.25-4.15 (1H, m), 3.86 (3H, s), 3.82 (3H,
s), 3.30 (3H, s), 3.14-2.96 (2H, m), 2.87 (3H, s), 2.90-2.80 (1H,
m), 2.78-2.52 (3H, m), 2.14-1.96 (1H, m), 1.84-1.70 (1H, m)
[0489] (ii)
2-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrroldin-1-yl)-1-(S)-p-
henylethyl]-N-methylamino}benzoic acid This was prepared from
methyl
2-methoxy4{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]--
N-methylamino} benzoate in 100% yield according to a procedure
similar to that described in Example 1 (ii).
[0490] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.98 (1H, d, J=8.8
Hz), 7.38-7.16 (5H, m), 6.54 (1H, dd, J=2.4, 9.0 Hz), 6.35-6.25
(1H, m), 5.20-5.05 (1H, m), 4.60 (1H, d, J=7.0 Hz), 4 56 (1H, d,
J=7.0 Hz), 4.25-4.15 (1H, m), 3.99 (3H, s), 3.30 (3H, s), 3.14-3.05
(2H, m), 2.91 (3H, s), 2.90-2.52 (4H, m), 2.14-2.00 (1H, m),
1.90-1.70 (1H, m),
[0491] (iii) 2-Methoxy-4-{N-[2-(3
-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S-
)-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0492] This was prepared from
2-methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrro-
lidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
n-propylamine in 84% yield according to a procedure similar to that
described in Example 1 (iii).
[0493] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.07 (1H, d, J=8.8
Hz), 7.78-7 68 (1H, m),7 36-7 20 (5H, m), 6 51 (1H, dd. J=2 4, 9 0
Hz), 6 27 (1H, d, J=2.2 Hz), 5 11 (1H, dd, J=6 6, 8 1 Hz), 4 60
(1H, d, J=7.0 Hz), 4 56 (1H, d, J=6.6 Hz), 4 25-4 15 (1H, m), 3.89
(3H, s). 3 45-3 35 (2H, m),3 30 (3H, s), 3 14-2.96 (2H, m), 2 86
(3H, s), 2 90-2 80 (1H, m), 2.78-2 52 (3H, m), 2.14-1 96 (1H, m), 1
84-1 70 (1H, m), 1 68-1 50 (2H, m), 0 97 (3H, t, J=7 3 Hz)
EXAMPLE 26
[0494] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyet-
hyl]-N-methylamino}-2-methoxy-N'-propylbenzamide
[0495] This was prepared from
2-methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrro-
lidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide in
85% yield according to a procedure similar to that described in
Example 2.
[0496] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 8 07
(1H, d, J=8.8 Hz), 7.78-7 68 (1H, m), 7 38-7 22 (5H, m), 6.53 (1H,
dd, J=2.2, 8.8 Hz), 6.27 (1H, d, J=2 2 Hz), 5.13 (1H, dd, J=6.2,
8.4 Hz), 4.30-4.20 (1H, m), 3.89 (3H, s), 3.45-3.35 (2H m),
3.20-3.00 (2H, m), 2 95-2 80 (1H, m), 2.85 (3H, s), 2.74 (1H, d,
J=9 5 Hz), 2.58 (1H, dd, J=4 8, 9 5 Hz), 2.40-2.27(1H, m),
2.18-2.02 (1H, m), 1.95-1.55 (4H, m), 0 97(3H, t, J=7 3 Hz)
[0497] HCl salt: amorphous solid.
[0498] IR(KBr): 3400, 1600 cm.sup.-1.
[0499] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.3.multidot.HCl.multido-
t.0.8CH.sub.4O: C, 62.89; H, 7.92; N, 8.87
[0500] Found: C, 63.16; H, 8.32; N, 9 20.
EXAMPLE 27
[0501] Preparation of
3-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1--
yl)-1-(S)-phenylethyl]-N-methylamino}-N-'propylbenzamide
[0502] (i) Methyl
3-methoxy-4{-N-[-(3-(S)-methoxymethoxpyrrolidin-1-yl)-1--
(S)-phenylethyl]-N-methylamino}benzoate
[0503] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
methyl 3-methoxy-4-methylaminobenzoate in 60% yield according to a
procedure similar to that described in Example 1 (i).
[0504] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.58-7.53 (2H, m),
7.31-7.20 (5H, m), 6.71 (1H, d, J=8.4 Hz), 5.13 (1H, t, J=7.3 Hz),
4.59 (1H, d, J=7.0 Hz), 4.55 (1H, d, J=7 0 Hz), 4.15-4.05 (1H, m),
3.95 (3H, s), 3.89 (3H, s), 3.30 (3H, s), 3.09 (2H, d, J=7.3 Hz),
2.87 (1H, dd, J=6.2, 9.9 Hz), 2.60 (3H, s), 2.60-2.52 (2H, m), 2.47
(1H, dd, J=4.0, 9.9 Hz), 2.08-1.92 (1H, m), 1.73-1.60 (1H, m)
[0505] (ii)
3-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}benzoic acid
[0506] This was prepared from methyl
3-methoxy4-{N-[2-(3-(S)-methoxymethox-
ypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate in 100%
yield according to a procedure similar to that described in Example
1 (ii).
[0507] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.52-7.4S(2H, m),
7.32-7.12 (5H, m), 6.65 (1H, d, J=8.4 Hz), 5.47 (1H, dd, J=6.6, 7.0
Hz), 4.64 (1H, d, J=7.0 Hz), 4.60 (1H, d, J=6.6 Hz), 4.45-4.35 (1H,
m), 4.02 (3H, s), 3.85-3.70 (3H, m), 3.68-3.57 (1H, m), 3.32 (3H,
s), 3.30-3.05 (2H, m), 2.64 (3H, s), 2.40-2.23 (1H, m), 2.15-2.00
(1H, m)
[0508] (iii)
3-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-
-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0509] This was prepared from
3-methoxy-4{N-[2-(3-(S)-methoxymethoxypyrrol-
idin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
n-propylamine in 64% yield according to a procedure similar to that
described in Example 1 (iii).
[0510] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.45 (1H, d, J=1.8
Hz), 7.32-7.18 (5H, m), 7.11 (1H, dd, J=1.8, 8.4 Hz), 6.66 (1H, d,
J=8.1 Hz), 6.15-6.05 (1H, m), 5.03 (1H, t, J=7.7 Hz), 4.59 (1H, d,
J=7.0 Hz), 4.54 (1H, d, J=7.0 Hz), 4.15-4.05 (1H, m), 3.96 (3H, s),
3.45-3.35 (2H, m), 3.30 (3H, s), 3.08 (2H, d, J=7.7 Hz), 2.95-2.85
(1H, m), 2.65-2.50 (2H, m), 2.57 (3H, s), 2.46 (1H, dd, J=4.4, 9.9
Hz), 2.10-1.90 (1H, m), 1.75-1.55 (3H, m), 0.99 (3H, t, J=7.3
Hz)
EXAMPLE 28
[0511] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-3-methoxy-N'-propylbenzamide
[0512] This was prepared from
3-methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrro-
lidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide in
77% yield according to a procedure similar to that described in
Example 2.
[0513] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7 48
(1H, d, J=22 Hz), 7 37-722 (5H, m, 7.12 (1H, dd, J=2.2, 8.4 Hz),
6.72 (1H, d, J=8.4 Hz), 6.15-6.05 (1H, m), 5.16 (1H, dd, J=6.6, 8.8
Hz), 4.15-4.05 (1H, m), 3 97 (3H, s), 3.45-3 35 (2H, m), 3.23 (2H,
dd, J=8 8, 12 5 Hz), 2.99 (1H, dd, J=6.4, 12.3 Hz), 2 80-2.70 (1H,
m), 2.59 (3H, s), 2.45 (1H, dd, J=4.4, 9.9 Hz), 2.20-1.90 (2H, m),
1.75-1.40 (4H, m), 0.99 (3H, t, J=7.3 Hz)
[0514] HCl salt: amorphous solid.
[0515] IR(KBr): 3350, 1630 cm.sup.-1.
EXAMPLE 29
[0516] Preparation of
3-chloro-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-y-
l)-1-(S-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0517] (i) 3-chloro4-{N-[2-(3
-(S)-methoxymethoxpyrrolidin-1-yl)-1-(S)-phe-
nylethyl]-N-methylamino}benzonitrile
[0518] To a stirred solution of the midture of
2-(3-(S)-methoxymethoxypyrr- olidin-1-yl)-1-(S)-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-y- l)-2-(R)-phenylethanol (251
mg, 1.00 mmol) and triethylamine (0.167 ml, 1 20 mmol) in
CH.sub.2Cl.sub.2 (4 ml) was added methanesulfonyl chloride (0 093
ml, 1.20 mmol) dropwise at 0.degree. C. (ice bath). After 15.5h
stirring at room temperature, the reaction mixture was washed with
saturated NAHCO, aqueous solution, brine, dried (Na.sub.2SO.sub.4),
and concentrated to give 238 mg of brown viscous oil-(i) To a
suspension of NaH (48 mg, 1.20 mmol) in N,N-dimethylformaamide (2
ml) was added a solution of 3-chloro-4-methylaminobenzonitrine (200
mg, 1 20mmol) at room temperature After stirring for 45 min, to
this mixture was added a solution of the above brown viscous
oil-(i) in N,N-dimethylformamide (2 ml) at room temperature and the
mixture was stirred at room temperature for 4.5h. H.sub.2O was
added to this mnixture, basified with 25% --NH.sub.4OH and
extracted with CH.sub.2Cl.sub.2 The extract was washed with water,
brine, dried (Na.sub.2SO.sub.4), and concentrated to give brown
oil, which was purified by column chromatography (silica gel 20 g,
CH.sub.2Cl.sub.2/MeOH 100/1-50/1) to afford 244 mg (61%) of brown
oil.
[0519] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.61 (1H, d, J=2.2
Hz), 7.43-7.25 (6H, m), 6.98 (1H, d, J=8.4 Hz), 5.03 (1H, dd,
J=7.3, 7.7 Hz), 4.58 (1H, d, J=6.6 Hz), 4.54 (1H, d, J=6.6 Hz),
4.10-3.97 (1H, m), 3.31 (3H, s), 3.10 (2H, dd, J=1.5, 7.7 Hz),
2.75-2.65 (1H, m), 2.69 (3H, s), 2.55-2.43 (3H, m), 2.03-1.85 (1H,
m), 1.70-1.60 (1H, m)
[0520] (ii)
3-Chloro-4{N-[2-(3-(S)methoxymethoxypyrrolidin-1-yl-1-(S)-phen-
ylethyl]-N-methylyamino}-N'-propylbenzamide
[0521] To a suspension of t--BuOK (381 mg, 3.05 mmol) and H.sub.2O
(0.055 ml, 3.05 mmol) in t--BuOH (1.0 ml) was added a solution of
3-chloro4{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-
-methylamino}benzonitrile (244 mg, 0.611 mmol) in t--BuOH (1.0 ml)
at room temperature. After refluxing for 0.5h, the mixture was
allowed to cool to room temperature. n-Propyliodide (0.298 ml, 3.05
mmol) was added to the mixture, and the mixture was refluxed for
3h. Arfer cooling down to room temperature, the solvent was
evaporated. The residue was dissolved in CH.sub.2Cl.sub.2 and
washed with water and brine, dried (Na.sub.2SO.sub.4), and
concentrated to give pale brown oil, which was purified by column
chromatography (silice gel, 15 g, CH.sub.2Cl.sub.2/MeOH: 80/1-50/1)
to give 206 mg (73%) of ivory amorphous.
[0522] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.77 (1H, d, J=2.2
Hz), 7.52 (1H, dd, J=2.2, 8 4 Hz), 7.36-7.20 (5H, m), 6.92 (1H, d,
J=8.4 Hz), 6.15-6.00 (1H, m), 4.91 (1H, dd, J=7 3, 7.7 Hz), 4.57
(1H, d, J=7.0 Hz), 4.53 (1H, d, J=7.0 Hz), 4.10-3.98 (1H, m),
3.45-3 35 (2H, m), 3.29 (3H, s), 3.14 (1H, dd, J=7.7, 12.5 Hz),
3.05 (1H, dd, J=7.3, 12.5 Hz), 2.73 (1H, dd, J=6.2, 9.9 Hz), 2.64
(3H, s), 2.55-2.43 (3H, m), 2.05-1.88 (1H, m), 1.75-1 55 (3H, m),
0.96 (3H, t, J=7.3 Hz)
EXAMPLE 30
[0523] Preparation of
3-Chloro4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-
-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0524] This was prepared from
3-chloro4-{N-[2-(3-(S)-methoxymethoxypyrroli-
din-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide in
9.6% yield according to a procedure similar to that described in
Example 2
[0525] .sup.1H NMR (270 Mz, free amine, CDCl.sub.3) .delta. 7 81
(1H, d, J=2 2 Hz), 7 51 (1H, dd, J=2 2, 8 4 Hz), 7.42-7.22 (5H, m),
6.93 (1H, d, J=8 4 Hz), 6.15-6 00 (1H, m), 4 99 (1H, dd, J=7.3, 7.9
Hz), 4.20-4.05 (1H, m), 3.45-3.35 (2H, m), 3.16 (1H, dd, J=7 7, 12
5 Hz), 3 08 (1H, dd, J=7.3, 12.5 Hz), 2.75-2.60 (2H, m), 2.65 (3H,
s), 2.41 (1H; dd, J=4 4, 9 5 Hz), 2.25-2.15 (1H, m), 2.08-1.93 (1H,
m), 1.90-1.40 (4H, m), 0.99 (3H, t, J=7 3 Hz)
[0526] Fumaric acid salt: amorphous solid.
[0527] IR(K,Br): 3350, 1630 cm.sup.-1.
[0528] MS m/z: 416, 418 (M+H).sup.+.
[0529] Anal. Calcd for
C.sub.23H.sub.30N.sub.3O.sub.2Cl.multidot.C.sub.4H.-
sub.4O.sub.4.multidot.H.sub.2O: C, 58.96; H, 6 60; N, 7 64
[0530] Found: C, 59.35; H,6.64; N, 7.55.
EXAMPLE 31
[0531] Preparation of
6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-propynicotinamide
[0532] (i) Methyl
6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phen-
yethyl]-N-methylamino}nicotinate
[0533] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
methyl 6-methylaminonicotinate in 60% yield according to a
procedure similar to that described in Example 29 (i).
[0534] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.83 (1H, d, J=2.2
Hz), 8.01 (1H, dd, J=2 2, 9 2 Hz), 7 35-7.20 (5H, m), 6.48 (1H, d,
J=9 2 Hz), 6.44-6 32 (1H, m), 4 59 (1H, d, J=7 0 Hz), 4 56 (1H, d,
J=6.6 Hz), 4.22-4.12 (1H, m), 3.86 (3H, s), 3.30 (3H, s), 3.17-2.92
(3H, m), 2.83 (3H, s), 2.80-2.70 (1H, m), 2.65-2 50 (2H, m), 2.12-1
95 (1H, m), 1 80-1 65 (1H, m).
[0535] (ii)
6-{-N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenyleth-
yl]-N-methylamino}nicotinic acid
[0536] This was prepared from methyl
6-{N-[2-(3-(S)-methoxymethoxypyrrolid-
in-1-yl)-1-(S)-phenylethyl]-N-methylamino}nicotinate in 100% yield
according to a procedure similar to that described in Example 1
(ii).
[0537] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.80-8.75 (1H, m),
7 95-7.87 (1H, m), 7.35-7 15 (5H. m), 6.57 (1H, br. s), 6.42 (1H,
d, J=9.2 Hz), 4.62 (1H d, J=6.6 Hz), 4.59 (1H, d, J=7.0 Hz),
4.35-4.00 (2H, m), 3.50-3.25 (2H, m), 3.32 (3H, s), 3.18-3.08 (1H,
m), 3.02-2.70 (3H, m), 2.79 (3H, s), 2.20-2.05 (1H, m), 1.90-1.80
(1H, m).
[0538] (iii)
6-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-N-phenyle-
thyl]-N-methylamino}-N'-propylnicotinamide
[0539] This was prepared from
6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino} nicotinic acid and
n-propylamine in 65% yield according to a procedure similar to that
described in Example 1 (iii).
[0540] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.57 (1H, d, J=2.6
Hz), 7.89 (1H, dd, J=2.6, 9.2 Hz), 7.35-7.20 (5H, m), 6.50 (1H, d,
J=9.2 Hz), 6.40-6.35 (1H, m), 6.00-5.90 (1H, m), 4.59 (1H, d, J=7.0
Hz), 4.56 (1H, d, J=7.0 Hz), 4.20-4.10 (1H, m), 3.45-3.35 (2H, m),
3.30 (3H, s), 3.17-2.92 (3H, m), 2.82 (3H, s), 2.80-2.70 (1H, m),
2.65-2.50 (2H, m), 2.12-1.95 (1H, m), 1.80-1.55 (3H, m), 0.99 (3H,
t, J=7.3 Hz).
EXAMPLE 32
[0541] Preparation of
6-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propylnicotinamide
[0542] This was prepared from
6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-propynicotinamide in 73%
yield according to a procedure similar to that described in Example
2.
[0543] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 8.58
(1H, d, J=2.6 Hz), 7.89 (1H, dd, J=2 6, 8.8 Hz), 7.35-7.20 (5H, m),
6.50 (1H, d, J=9.5 Hz), 6.36 (1H, dd, J=5.9. 9 9 Hz), 6.00-5.92
(1H, m), 4.25-4.15 (1H, m), 3.45-3 35 (2H, m), 3.17 (1H, dd, J=9.9,
12.5 Hz), 3.05-2.95 (2H, m), 2.81 (3H, s), 2.72 (1H, d, J=9.5 Hz),
2.62 (1H, dd, J=4 8, 9 9 Hz), 2.40-2.25 (1H, m), 2.17-2.02 (1H, m),
1.95-1.75 (2H, m), 1.70-1.55 (2H, m), 0 98 (3H, t, J=7.3 Hz).
[0544] Fumaric acid salt: amorphous solid.
[0545] IR(KBr): 3350, 1630 cm.sup.-1
[0546] MS m/z 383(M+H).sup.+
[0547] Anal Calcd for
C.sub.22H.sub.30N.sub.4O.sub.2.multidot.C.sub.4H.sub-
.4O.sub.4.multidot.1 5H.sub.2O. C, 59.42, H, 7 10, N, 10 66
[0548] Found C, 59 50; H, 7.43; N, 10 73
EXAMPLE 33
[0549] Preparation of
4{N-[1-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxy-
methoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0550] (i) Methyl
4-{N-[1-(S-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymeth-
oxypyrrolidin-1 -yl)-ethyl]-N-methylamino}benzoate
[0551] This was prepared from the mixture of
2-(R)-(3-methoxymethoxyphenyl-
)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and
1-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)eth-
anol and methyl 4-methylaminobenzoate in 60% yield according to a
procedure similar to that described in Example 1 (i).
[0552] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 89 (2H, d, J=9 2
Hz), 7 27-7.19 (1H, m), 6 98-6 88 (3H, m), 6.77 (2H, d, J=9.2 Hz),
5.14 (2H, s), 5.14-5.08 (1H, m), 4.59 (1H, d, J=6 6 Hz), 4 55 (1H,
d, J=7.0 Hz), 4 22-4 12 (1H, m), 3.85 (3H, s), 3.46 (3H, s), 3 30
(3H, s), 3.04 (2H, d, J=8.1 Hz), 2.88 (3H, s), 2.85-2.53 (4H, m),
2.10-1.98 (1H, m), 1 83-1 70 (1H, m).
[0553] (ii) 4-
{N-[1-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxyp-
yrrolidin-1-yl)-ethyl]-N-methylamino}benzoic acid
[0554] This was prepared from methyl
4-{N-[1-(S)-(3-methoxymethoxyphenyl)--
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benroate
in 100% yield according to a procedure similar to that described in
Example 1 (ii).
[0555] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.88 (2H, d, J=8 8
Hz), 7.30-7.12 (1H, m), 6.98-6 84 (3H, m), 6.68 (2H, d, J=8.8 Hz),
5 15-5 05 (1H, m), 5.10 (2H, s), 4.55 (1H, d, J=6.6 Hz), 4 51 (1H,
d, J=7 0 Hz), 4 18-4 03 (1H, m), 3.42 (3H, s), 3.25 (3H, s), 3
10-2.92 (2H, m), 2.85 (1H, dd, J=6.4, 9 9 Hz), 2.74 (3H, s),
2.70-2.53 (3H, m), 2 10-1 93 (1H, m), 1.80-1.65 (1H, m).
[0556] (iii) 4-{N-[1-(S)-(3
-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxy-
pyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0557] This was prepared from
4-{N-[1-(S)-(3-methoxymethoxyphenyl)-2-(3-(S-
)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoic acid
and n-propylamine in 80% yield according to a procedure similar to
that described in Example 1 (iii).
[0558] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.65 (2H, d, J=9.2
Hz), 7.28-7.18 (1H, m), 6 98-6 88 (3H, m), 6.76 (2H, d, J=8.8 Hz),
6.05-5.90 (1H, m), 5.14 (2H, s), 5.08 (1H, dd, J=7.0, 7.7 Hz), 4.59
(1H, d, J=6.6 Hz), 4.55 (1H, d, J=7.0 Hz), 4.22-4.12 (1H, m), 3 46
(3H, s), 3.45-3.35 (2H, m), 3.30 (3H, s), 3.03 (2H, d, J=7.7 Hz),
2.86 (3H, s), 2.85-2.80 (1H, m), 2.75-2.50 (3H, m), 2.12-1.95 (1H,
m), 1.85-1.52 (3H, m), 0.97 (3H, t, J=7.3 Hz).
EXAMPLE 34
[0559] Preparation of
4-{N-[1-(S)-(3-Hydroxyphenyl)-2-(3-(S)-hvdroxypyrrol-
idin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0560] This was prepared from
4-{N-[1-(S)-(3-methoxymethoxyphenyl)-2-(3-(S-
)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N-propylbenzamide
in 97% yield according to a procedure similar to that described in
Example 2.
[0561] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3-DMSO-d6)
.delta. 8.85 (1H, br. s), 7 69 (2H, d, J=9.2 Hz), 7.11 (1H, t,
J=7.7 Hz), 6.98-6.90 (1H, m), 6.82-6.68 (5H, m), 5.06 (1H, dd,
J=6.2, 8.4 Hz), 4.30-4.18 (1H, m), 3 67 (1H, br. s), 3.40-3.30 (2H,
m), 3.15-2 95 (2H, m), 2.86 (3H, s), 2.85-2.67 (2H, m), 2.63-2.56
(1H, m), 2.55-2.43 (1H, m), 2.15-1 98 (1H, m), 1.70-1.52 (3H, m),
0.96 (3H, t, J=7 3 Hz).
[0562]
[0563] HCl salt: amorphous solid.
[0564] IR(KBr): 3350, 1610 cm.sup.-1.
[0565] MS m/z: 397(M+).
[0566] Anal. Calcd for
C.sub.21H.sub.31N.sub.3O.sub.3.multidot.HCl.multido- t.2.3H.sub.2O
C, 58 11 H, 7.76; N, 8.84
[0567] Found: C,57.82; H,8.06; N, 9.24.
EXAMPLE 35
[0568] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-(3-meth-
oxyphenyl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0569] To a solution of
4-{N-[1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrr-
olidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide (100 mg, 0
252 mmol) in MEOH (0 1 ml)--CH.sub.3CN (0.9 ml) was added
N,N-diisopropylethylamine (0 0641 ml, 0 353 mmol) and
10%-trinethylsilyl-diazomethane in CH.sub.2Cl.sub.2 (0.6 ml) at
room temperature After stirring for 22h at room temperature,
25%-NH.sub.4OH was added to the mixture and extracted with
CH.sub.2Cl.sub.2. The extract was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated to give brown oil, which was
purified by column chromato-Rraphy (silica gel 5 g,
CH.sub.2Cl.sub.2/MeOH: 30/1-10/1) to afford 55.2 mg (53%) of white
amorphous
[0570] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.65
(2H d, J=8 8 Hz), 7 24 (1H, t, J=7 7 Hz), 6.90-6.77 (5H, m),
6.05-5.90 (1H, m), 5.10 (1H, dd, J=5.9, 8.8 Hz), 4 25-4 18 (1H, m),
3.77 (3H, s), 3.45-3.35 (2H, m), 3.11 (1H, dd, J=9.2, 12 8 Hz), 3
01 (1H, dd, J=5 9, 12 8 Hz), 2.95-2.80 (1H, m), 2.84 (3H, s), 2.72
(1H, d, J=9 5 Hz), 2.56 (1H, dd, J=4 8, 9 5 Hz), 2.38-2.25 (1H, m),
2.16-2.00 (1H, m), 1 85-155 (4H, m), 0.97 (3H, t, J=7 7 Hz).
[0571] HCl salt: amorphous solid.
[0572] IR(neat, free amine): 3350, 1610 cm.sup.-1.
[0573] MS m/z: 412(M+H).sup.+.
[0574] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.3.multidot.HCl.multido- t.0 5H.sub.2O.
C, 63 08 H, 7.72, N, 9 19
[0575] Found. C, 62.89; H, 7.77; N, 9.25.
EXAMPLE 36
[0576] Preparation of
4-{N-[1-(S)-(3-t-Butoxycarbonylmethoxyphenyl)-2-(3-(-
S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino
}-N'-propylbenzamide
[0577] A mixture of
4-{N-[1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolid-
in-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide (100 mg, 0.252
mmol), t-butyl bromoacetate (0.0409 ml, 0 277 mmol) and
K.sub.2CO.sub.3 (38 3 mg, 0 277 mmol in DMF (1 5 ml) was stirred at
room temperature for 2h. H.sub.2O was added to the mixture and
extracted with AcOEtL/toluene=2/1. The extract was washed with
water, brine, dried (Na.sub.2SO.sub.4) and concentrated to give
pale brown amorphous, which was purified by column chromato-graphy
(silica gel 6 g. CH.sub.2Cl.sub.2/MeOH: 30/1-10/1) to afford 80 1
mg (62%) of white amorphous.
[0578] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.65 (2H, d, J=9.2
Hz), 7.23 (1H, t, J=7.7 Hz), 6.94-6.86 (2H, m), 6.82-6.72 (3H, m),
6.05-5.90 (1H, m), 5.09 (1H, dd, J=6 2, 8.8 Hz), 4 48 (2H, s),
4.25-4.18 (1H, m), 3.45-3.35 (2H, m), 3.09 (1H, dd, J=9.2, 12.8
Hz), 3.00 (1H, dd, J=5.9, 12.8 Hz), 2.95-2.80 (1H, m), 2.83 (3H,
s), 2.71 (1H, d, J=9.5 Hz), 2.54 (1H, dd, J=4.8, 9.5 Hz), 2.38-2.25
(1H, m), 2.16-2.00 (1H, m), 1 85-1.50 (4H, m), 1.46 (9H, s) 0.98
(3H, t, J=7.3 Hz).
EXAMPLE 37
[0579] Preparation of 4-{N-[1-
(S)-(3-Carboxymethoxyphenyl)-2-(3-(S)-hydro-
xypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0580] A solution of
4-{N-[1-(S)-(3-t-butoxycarbonylmethoxyphenyl)-2-(3-(S-
)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
(80.1 mg, 0.157 mmol) in trifluoroacetic acid (1 ml) and
CH.sub.2Cl.sub.2 (0.5 ml) was stirred at room temperature for 1.5h.
The solvent was evaporated. The residue was dissolved in
CH.sub.2Cl.sub.2 and 1.0M hydrogen chloride solution in diethyl
ether (1 ml) was added. The white powder was collected and washed
with Et.sub.2O and dried under reduced pressure for 6.5h at
45.degree. C. to afford 86.2 mg (quant) of white powder.
[0581] HCl salt: white powder.
[0582] .sup.1H NMR (270 MHz, CDCl.sub.3-DMSO-d6) .delta. 12.49 (1H,
br. s), 7.79 (2H, d, J=8.4 Hz), 7.42 (1H, br. s), 7.23 (1H, t,
J=7.7 Hz), 7.07 (2H, d, J=8.4 Hz), 6.85-6.76 (3H, m), 5 95-5 80
(1H, m), 4.53 (2H, s), 4.50-4.40 (1H, m), 4.00-3.70 (4H, m),
3.50-2.50 (3H, m), 2 80 (3H, s), 2.50-2.00 (2H, m), 1.75-1.55 (4H,
m), 0.96 (31H, t, J=7.3 Hz).
[0583] IR(KBr): 3400, 1730, 1610 cm.sup.-1.
[0584] MS m/z: 456(M+H).sup.+.
[0585] mp. 108-[110.degree. C.
[0586] Anal. Calcd for
C.sub.25H.sub.33N.sub.3O.sub.5.multidot.HCl.multido- t.3.5H.sub.2O
C, 54.10; H, 7.45; N, 7.57
[0587] Found: C, 54.07; H, 7.49; N, 7.39
EXAMPLE 38
[0588] Preparation of 4-{N
[1-(S)-Phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methy-
lamino}-N'-propylbenzamide
[0589] (i) Methyl 4-{N-[1
(S)-phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylami- no}benzoate
[0590] This was prepared from the mixture of
2-(R)-phenyl-2-(pyrrolidin-1-- yl)ethanol and
1-(S)-phenyl-2-(pyrrolidin-1-yl)ethanol and methyl
4-methylaminobelzoate in 52% yield according to a procedure simllar
to that described in Example 1 (i).
[0591] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 88 (2H, d, J=9.2
Hz), 7.38-7 20 (5H, m), 6 78 (2H, d, J=9.2 Hz), 5.17 (1, t, J=7.3
Hz), 3.84 (3H, s), 3.04 (2H, d, J=7.3 Hz), 2.86 (3H, s), 2 65-2.45
(4H, m), 1.80-1.65 (4H, m)
[0592] (ii)
4-{N-[1-(S)-Phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}ben-
zoic acid
[0593] This was prepared from methyl
4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl-
)ethyl]-N-methylamnino}benzoate in 100% yield according to a
procedure similar to that described in Example 1 (ii).
[0594] .sup.1H NMR (270 MHz, CDCl.sub.3-DMSO-d6) .delta. 7 92 (2H
d, J=8 8 Hz), 7 38-7.20 (5H, m), 7 02 (2H, d, J=8.8 Hz), 5 80 (1H,
br s), 4.00-3.00 (7H, m), 2.85 (3H, s), 2.20-1 90 (4H, m)
[0595] (iii)
4-{N-[1-(S)-Phenyl-2-(pvrrolidin-1-yl)ethyl]-N-methylamino}-N-
'-propylbenzamide
[0596] This was prepared from
4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl)ethyl]-
-N-methylamino}benzoic acid and n-propylamine in 56% yield
according to a procedure similar to that described in Example 1
(iii).
[0597] .sup.1H NMR (270 MHz, free amine CDCl.sub.3) .delta. 7.65
(2H, d, J=8 8 Hz), 7 36-7 20 (5H, m), 679 (2H, d, J=8.8 Hz);
6.05-5.90 (1H, m), 5.14 (1H, t, J=7 0 Hz), 3 45-3 35 (2H, m), 3.04
(2H, d, J=7.0 Hz), 2.84 (3H, s), 2.65-2.45 (4H, m), 1.75-1.50 (6H,
m), 0 97 (3H, t, J=7 3 Hz).
[0598] HCl salt: amorphous solid.
[0599] IR(KBr): 1610 cm.sup.-1.
[0600] MS m/z: 366(M+H).sup.+.
[0601] Anal. Calcd for
C.sub.23H.sub.31N.sub.3O.multidot.HCl.multidot.0.5H- .sub.2O. C, 67
22, H, 8.09; N, 10.22
[0602] Found: C, 67.48; H, 8.37; N, 10.32.
EXAMPLE 39
[0603] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propylphthalimide
[0604] This was prepared from
2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-ylox-
ypyrrolidin-1-yl)ethanol and
1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxy-
pyrrolidin-1-yl)ethanol and 4-methylamino-N'-propylphthalimide in
16% over all yield according to a procedure similar to that
described in Example 1 (i) and 2.
[0605] .sup.1H NMR (270 MHZ, free aniine, CDCl.sub.3) .delta. 7.63
(1H, d, J=8.4 Hz), 7.38-7.22 (6H, m), 6.94 (1H, dd, J=2.6, 8.4 Hz),
5.19 (1H, dd, J=5.9, 9.5 Hz), 4.30-4.20 (1H, m), 3.59 (2H, t, J=7.3
Hz), 3.18 (1H, dd, J=9.5, 13.2 Hz), 3.03 (1H, dd, J=5.5, 12.8 Hz),
2.95 (3H, s), 2.95-2.85 (1H, m), 2.71 (1H, d, J=9.2 Hz), 2.61 (1H,
dd, J=4.8, 9.5 Hz), 2.37 (1H, ddd, J=5.9, 8.8, 8.8 Hz), 2.20-2.05
(1H, m), 1.75-1.60 (4H, m), 0.93 (3H, t, J=7 3 Hz)
[0606] HCl salt: amorphous solid.
[0607] IR(KBr): 3400, 1760, 1700, 1620 cm.sup.31 1.
[0608] Anal. Calcd for
C.sub.24H.sub.29N.sub.3O.sub.3.multidot.HCl.multido- t.0.5H.sub.2O:
C, 63.64; H,6.90; N, 9.28
[0609] Found: C,63.99; H, 7.18; N, 9.00.
EXAMPLE 40
[0610] Preparation of
5-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-propyl-2-thiophenecarboxamide
[0611] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
5-methylamino-N'-propyl-2-thiophenecarboxamide in 49% yield
according to a procedure similar to that described in Example 1
(i).
[0612] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.35-7.25 (5H, m),
7.18 (1H, d, J=4.4 Hz), 5 83 (1H, d, J=4.0 Hz), 5.68-5.60 (1H, m),
4.86 (1H, dd, J=7.0, 7.7 Hz), 4.62 (1H, d, J=7.0 Hz), 4 58 (1H, d,
J=7.0 Hz), 4.25-4.15 (1H, m), 3.40-3.30 (2H, m), 3.32 (3H, s),
3.1,-3 00 (2H, m), 2.94 (1H, dd, J=6.2, 9.9 Hz), 2.83 (3H, s),
2.80-2.70 (1H, m), 2.67-2.55 (2H, m), 2.15-2.00 (1H, m), 1.87-1.73
(1H, m), 1.70-1.50 (2H, m), 0.95 (3H, t, J=7.7 Hz)
EXAMPLE 41
[0613] Preparation of 5-{N
-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-l(S)-phenv-
lethyl]-N-methylamino}-N'-propyl-2-thiophenecarboxamide
[0614] This was prepared from
5-{N-[2-(3-(S)-methoxymethoxypyrroldin-1-yl)-
-1-(S)-phenylethyl]-N-methylamino}-N'-propyl-2-thiophenecarboxamide
in 78% yield according to a procedure similar to that described in
Example 2.
[0615] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.38-7
24 (5H, m), 7 18 (1H d, J=4 0 Hz). 5.84 (1H, d, J=4.4 Hz),
5.70-5.60 (1H, m), 4.88 (1H, dd, J=6.0, 9.0 Hz), 4.30-4 22 (1H, m),
3.40-3.30 (2H, m), 3.15 (1H, dd, J=9.2, 12.8 Hz), 3.07-2.95 (2H,
m), 2.81 (3H, s), 2.75 (1H, d, J=9.5 Hz), 2.63 (1H, dd, J=4.8, 9.5
Hz), 2.42-2.30 (1H, m), 2 22-2 05 (1H, m), 1.80-1.50 (4H, m), 0.96
(3H, t, J=7.7 Hz).
[0616] Fumaric acid salt: amorphous solid.
[0617] IR(KBr): 3300, 1610 cm.sup.-1.
[0618] MS m/z=388(M+H).sup.+
[0619] Anal. Calcd for
C.sub.21H.sub.29N.sub.3O.sub.2S.multidot.C.sub.4H.s-
ub.4O.sub.4.multidot.0.5H.sub.2O.multidot.CH.sub.4O: C, 57.34; H
7.03, N, 7.71
[0620] Found C, 57.37; H, 7.31; N, 7.79.
EXAMPLE 42
[0621] Preparation of
4-{N-[2(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-p-
henylethyl]aminol}-N'-propylbenzamide
[0622] (i) Methyl
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phen-
ylethyl]amino}benzoate
[0623] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
methyl 4aminobenzoate in 69% yield according to a procedure similar
to that described in Example 1 (i).
[0624] .sup.1H NNM (270 MHZ, CDCl.sub.3) .delta. 7.75 (2H, d, J=8 8
Hz), 7.37-7.27 (5H, m), 6.47 (2H, d, J=8.8 Hz), 5.56 (1H, br. s),
4.65 (1H, d, J=6.6 Hz), 4.61 (1H, d, J=7 0 Hz), 4 35-4 28 (1H, m),
4.26-4.23 (1H, m), 3.80 (3H, s), 3 36 (3H, s), 2.90-2.76 (3H, m),
2.62-2 51 (2H, m), 2.48-2.42 (1H, m), 2.18-2.10 (1H, m), 1.84-1.82
(1H, m)
[0625] (ii)
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethy-
l]amino}benzoic acid
[0626] This was prepared from methyl
4-{N-[2-(3-(S)-methoxymethoxypyrroiid-
in-1-yl)-1-(S)-phenylethyl]amino}benzoate in 100% yield according
to a procedure similar to that described in Example 1 (ii).
[0627] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.72 (2H, d, J=8 4
Hz), 7.36-7.23 (5H, m), 6.42 (2H, d, J=8.4 Hz), 5.80 (1H, br. s),
4.69-4.65 (1H, m), 4.63 (1H, d, J=7.0 Hz), 4.60 (1H, d, J=7.0 Hz),
4.39-4.37 (1H, m), 4.32-4.22 (1H, m), 3.34 (3H, s), 3.00-2.82 (3H,
m), 2.66-2.48 (3H, m), 2.17-2.10 (1H, m), 1.95-1.78 (1H, m)
[0628] (iii) 4-
{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylet-
hyl]amino}-N'-propylbenzamide
[0629] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]amino}benzoic acid and n-propylarnine in 62%
yield according to a procedure sirular to that described in Example
1 (iii).
[0630] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.49 (2H, d, J=8.5
Hz), 7.38-7.24 (5H, m), 6.48 (2H, d, J=8.8 Hz), 5.95-5.80 (1H, m),
5.46 (1H, br. s), 4.65 (1H, d, J=7.0 Hz), 4.61 (1H, d, J=7.0 Hz),
4.32-4.23 (2H, m), 3.36 (3H, s), 3.38-3.31 (2H, m), 2.90-2.76 (3H,
m), 2.59 (1H, dd, J=3.9, 10.8 Hz), 2.53-2.42 (2H, m), 2.18-2.11
(1H, m), 1.83-1.82 (1H, m), 1.60-1.50 (2H, m), 0.93 (3H, t, J=7.3
Hz).
EXAMPLE 43
[0631] Preparation of 4-{N-[2-(3-(
S)-Hydroxypyrrolidin-1-yl-1-(S)-phenyle-
thyl]amino}-N'-propylbenzamide
[0632] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]amino}-N'-propylbenzamide in 67% yield
according to a procedure similar to that described in Example
2.
[0633] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.50
(2H, d, J=8.8 Hz), 7.38-7.22 (5H, m), 6.48 (2H, d, J=8.8 Hz), 5
95-5.80 (1H, m), 5 39 (1H, br. s), 4.39-4.29 (2H, m), 3 40-3 28
(2H, m), 2.99-2.84 (2H, m), 2.73-2.53 (3H, m), 2.40-2.31 (1H, m), 2
26-2 13 (1H, m), 1.90-1.67 (2H, m), 1.65-1.50 (2H, m), 0.94 (3H, t,
J=7.3 Hz).
[0634] HCl salt: amorphous solid.
[0635] IR(KBr):3350, 1610 cm.sup.-1.
[0636] Anal. Calcd for
C.sub.22H.sub.29N.sub.3O.sub.2.multidot.HCl.multido- t.1 1H.sub.2O:
C, 62.44; H 8.05; N, 9.72
[0637] Found: C,62.36; H,7.66; N, 9 92.
EXAMPLE 44
[0638] Preparation of
4-{N-[1-(S)-3-Chlorophenyl)2-(3-(S)-methoxymethoxypy-
rrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0639] (i) Methyl
4{N-[1-(S)-(3-chloraphenyl)-2-(3-(S)-methoxymethoxypyrro-
lidin-1-yl)-ethyl]-N-methylamino}benzoate
[0640] This was prepared from the mixture of
2-(R)-(3-chlorophenyl)-2-(3-(- S)-methoxymethoxypyrrolidin-1
-yl)ethanol and 1-(S)-(3-chlorophenyl)-2-(3--
(S)-methoxymethoxypyrrolidin-1-yl)ethanol and methyl
4-methylaminobenzoate in 66% yield according to a procedure similar
to that described in Example 1 (i).
[0641] .sup.1H NMR (270 Mz, CDCl.sub.3) .delta. 7.90 (2H, d, J=8.8
Hz), 7 30-7.14 (4H, m), 6.77 (2H, d, J=9 2 Hz), 5.11 (1H, dd,
J=7.0, 7.7 Hz), 4.60 (1H, d, J=7.0 Hz), 4.55 (1H, d, J=10 Hz),
4.22-4.13 (1H, m), 3.86 (3H, s), 3.30 (3H s), 3.12-2.94 (2H, m),
2.90-2 78 (1H, m), 2.87 (3H, s), 2.76-2.52 (3H, m), 2.15-1.98 (1H,
m), 1.85-1.70 (1H, m).
[0642] (iii)
4-{N-[1-(S-(3-Chlorophenyl)-2-(3-(S)-methoxvmethoxypyrrolidin-
-1-yl)-ethyl]-N-methylamino}benzoic acid
[0643] This was prepared from methyl
4-{N-[1-(S)-(3-chlorophenyl)-2-(3-(S)-
-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoate in
96% yield according to a procedure similar to that described in
Fxampie 1 (ii).
[0644] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.93 (2H, d, J=9 2
Hz), 7.32-7 10 (4H, m), 6.82 (2H, d, J=9.2 Hz), 5.40-5.25 (1H, m),
4.62 (1H, d, J=7 0 Hz), 4 58 (1H, d, J=7.0 Hz), 4 30-4.18 (1H, m),
3.40-3.00 (3H, m), 3.31 (3H s), 2.95-2.65(3H, m), 2.88 (3H, s),
2.20-2 00 (1H, m), 1.95-1.80 (1H, m).
[0645] (iii)
4-{N-[1-(S)-(3-Chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidi-
n-1-yl)-ethyl]-N-methylamino}-N-propylbenzamide
[0646] This was prepared from
4-{N-[1-(S)-(3-chlorophenyl)-2-(3-(S)-methox-
ymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoic acid and
n-propylamine in 77% yield according to a procedure similar to that
described in Example 1 (iii).
[0647] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.66(2H, d, J=9.2
Hz), 7.30-7.13 (4H, m), 6.78 (2H, d, J=9.2 Hz), 6.02-5.92 (1H, m),
5.07 (1H, dd, J=6.6, 7.7 Hz), 4.60 (1H, d, J=7.0 Hz), 4.55 (1H, d,
J=7.0 Hz), 4.25-4.12 (1H, m), 3.45-3.35 (2H, m), 3.30 (3H, s),
3.12-2.93 (2H, m), 2.90-2.78 (1H, m), 2.85 (3H s), 2.75-2.52 (3H,
m), 2.13-1.97 (1H, m), 1.85-1 70 (1H, m), 1.69-1.54 (2H, m),
0.98(3H, t, J=7.3 Hz).
EXAMPLE 45
[0648] Preparation of
4-{N-[1-(S)-(3-Chlorophenyl)-2-(3-(S)-hydroxypyrroli-
din-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0649] This was prepared from 4-{N-[1-(S)-(3chlorophenyl)-2-(3
-(S-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzami-
de in 83% yield according to a procedure similar to that described
in Example 2.
[0650] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.67
(2H, d, J=9.2 Hz), 7.30-7.14 (4H, m), 6.79 (2H, d, J=8.8 Hz),
6.03-5.94 (1H, m), 5.09 (1H, dd, J=6.2, 8.8 Hz), 4.27-4 18 (1H, m),
3.45-3.35 (2H, m), 3.09 (1H, dd, J=8.8, 12.8 Hz), 3.01 (1H, dd,
J=6.2, 12 8 Hz), 2.93-2.80 (1H, m), 2.84 (3H, s), 2.72 (1H, d,
J=9.9 Hz), 2.57 (1H, dd, J=5.0, 9.7 Hz), 2.38-2.27 (1H, m),
2.11-2.02 (1H, m), 1.80-1.55 (4H, m), 0.98 (3H, t, J=7.3 Hz).
[0651] Fumaric acid salt: amorphous solid.
[0652] IR(KBr): 3350, 1610 cm.sup.-1.
[0653] MS m/z: 416(M+H).sup.+
EXAMPLE 46
[0654] Preparation of
4-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylet-
hyl]-N-methylamino}-N'-propylbenzamide
[0655] (i) Methyl 4-{N-[2-(3
-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-
]-N-methylamino}benzoate
[0656] This was prepared from
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and
2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and methyl
4-methylaminobenzoate in 54% yield according to a procedure similar
to that described in Example 1 (i).
[0657] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.89 (2H, d, J=9.2
Hz), 7.38-7.22 (5H, m), 6.78 (2H, d, J=9.2 Hz), 5.25-4.95 (1H, m),
5.14 (1H, dd, J=6 6, 8.8 Hz), 3.84 (3H, s), 3.18-3 00 (2H, m),
2.95-2.75 (3H, m), 2.89 (3H, s), 2.60-2.50 (1H, m), 2.15-1.85 (2H,
m).
[0658] (ii)
4-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-met-
hylamino}benzoic acid
[0659] This was prepared from methyl
4{N-[2-(3-(S)-fluoropyrrolidin-1-yl)--
1-(S)-phenylethyl]-N-methylamino} benzoate in 100% yield according
to a procedure similar to that described in Example 1 (ii).
[0660] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.92 (2H d, J=8.8
Hz), 7.40-7.10 (5H, m), 6.83 (2H, d, J=8 8 Hz), 5.40-5.00 (2H, m),
3.40-3.15 (2H, m), 3.10-2.70 (4H, m), 2.90 (3H, s), 2.30-1.90 (2H,
m).
[0661] (iii) 4-
{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-m-
ethylamino}-N'-propylbenzamide
[0662] This was prepared from
4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}benzoic acid and n-propylamiLse in 73%
yield according to a procedure similar to that described in Example
1 (ii).
[0663] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.65
(2H, d, J=8.8 Hz), 7.37-7 22 (5H, m), 6.79 (2H, d, J=8.8 Hz),
6.03-5.92 (1H, m), 5.25-4.95 (1H, m), 5.11 (1H, dd, J=6 2, 8.4 Hz),
3.45-3.35 (2H, m), 3.18-3.02 (2H, m), 2.95-2.72 (3H, m), 2.87 (3H,
s), 2.63-2.50 (1H, m), 2.18-1.85 (2H, m), 1.72-1.54 (2H, m), 0.97
(3H, t, J=7.3 Hz)
[0664] HCl salt: amorphous solid.
[0665] IR(KBr): 1605 cm.sup.-1.
[0666] MS m/z 384(M+H).sup.+
[0667] Anal. Calcd for
C.sub.23H.sub.30N.sub.3OF.multidot.HCl.multidot.0
3H.sub.2O.multidot.CH.sub.4O C, 63.02; H, 7 84; N, 9 19
[0668] Found: C, 62.69; H, 8.17; N, 9.57.
EXAMPLE 47
[0669] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)--
phenylethyl]-N-methylamino}-N'-propylbenzamide
[0670] (i) Methyl
4-{N-[2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1-(R)-pheny-
lethyl]-N-methylamino}benzoate
[0671] This was prepared from
2-(3-S)-methoxymethoxypyrrolidin-1-yl)-1-(R)- -phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(S)-phenyleth- anol and
methyl 4-methylaninobenzoate in 49% yield according to a procedure
similar to that described in Example 1 (i).
[0672] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.88 (2H, d, J=8.8
Hz), 7.34-7.23 (5H, m), 6.73 (2H, d, J=9.2 Hz), 5.17 (1H, dd,
J=7.0, 7.7 Hz), 4.58 (1H d, J=7.0 Hz), 4.53 (1H, d, J=6.6 Hz),
4.22-4.15 (1H, m), 3.85 (3H, s), 3 68-3 52 (1H, m), 3.28 (3H, s), 3
08-3 04 (2H, m), 2.86 (3H, s), 2.76-2.67 (1H, m), 2.62-2.51 (2H,
m), 2.08-1.97 (1H, m), 1.83-1.72 (1H, m).
[0673] (ii)
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethy-
l]-N-methylamino}benzoic acid
[0674] This was prepared from methyi
4-{N-[2-(3-(S)-methoxymethoxypyrrolid-
in-1-yl)-1-(R)-phenylethyl]-N-methyiamino}benzoase in 100% yield
according to a procedure similar to that described in Example 1
(ii).
[0675] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.89 (2H, d, J=9.2
Hz), 7 33-7.18 (5H, m), 6.75 (2H, d, J=9.2 Hz), 5.15 (1H, dd,
J=7.0, 7.3 Hz), 4.57 (1H, d, J=7.0 Hz), 4.52 (1H, d, J=7.0 Hz),
4.25-4.15 (1H, m), 33 3 (3H, s), 3 05 (1H, d, J=6.6 Hz), 2.88-2.84
(1H, m), 2.85(3H, s), 2.76-2.62 (1H, m), 2.50-2.61 (3H, m),
2.07-2.02 (1H, m), 1.78-1 73 (1H, m).
[0676] (iii)
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenyleth-
yl]-N-methylamino}-N'-propylbenzamide
[0677] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(R)-phenylethyl]-N-methylamino}benzoic acid and n-propylamine
in 60% yield according to a procedure similar to that described in
Example 1 (iii).
[0678] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 63 (2H, d, J=9.2
Hz), 7 34-7.24 (5H, m), 6 79 (2H, d, J=9.2 Hz), 5.98-5.82 (1H, m),
5.13 (1H, t, J=7.3Hz), 4 58 (1H, d, J=6.6 Hz), 4 54 (1H, d, J=7.0
Hz), 4.26-4.13 (1H, m), 3.43-3.34 (2H, m), 3.29 (3H, s), 3.06 (2H,
d, J=7.3 Hz), 2.91-2.88 (1H, m), 2.85 (3H, s), 2.73-2.67 (1H, m),
2.61-2.54 (2H, m), 2.11-1.98 (1H, m), 1.84-1.72 (1H, m), 1.65-1.57
(2H, m), 0.97 (3H, t, J=7.3 Hz).
EXAMPLE 48
[0679] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(R)-2phenyl-
ethyl]-N-methylamino}-N'-propylbenzamide
[0680] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(R)-phenylethyl]-N-methylamino}-N'-propylbenzamide in 15% yield
according to a procedure similar to that described in Example
2.
[0681] .sup.1H NMR (270 Mz, free amine, CDCl.sub.3) .delta. 7.59
(2H, d, J=9 2 Hz), 7.28-7.16 (5H, m), 6.75 (2H, d, J=8.8 Hz),
6.07-5.94 (1H, m), 5.12 (1H, t, J=7.3 Hz), 4.18-4.13 (1H, m),
3.35-3.27 (2H, m), 3.03 (2H, d, J=7.8 Hz), 2.92-2.86 (1H, m), 2.73
(3H, s), 2.66 (1H, d, J=9.9 Hz), 2.50 (1H, dd, J=4.8, 9.7 Hz),
2.38-2.33 (1H, m), 2.09-1.96 (2H, m), 1 67-1.46 (3H, m), 0.90 (3H,
t, J=7.3 Hz)
[0682] IR(neat): 3350, 1610 cm.sup.-1.
[0683] HCl salt: amorphous solid.
[0684] Anal. Calcd for C.sub.23H.sub.31N.sub.3O.sub.2.multidot.HCl
1.9H.sub.2O: C 61.52; H, 8.37; N. 9.20.
[0685] Found: C, 61.33; H, 7.97; N, 9.33.
EXAMPLE 49
[0686] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-pyrrolidinebenzamide
[0687] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and pyrrolidine in
77% yield according to a procedure similar to that described in
Example 1 (iii).
[0688] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.47 (2H, d, J=8.8
Hz), 7.33-7.21 (5H, m), 6.77 (2H, d, J=8 8 Hz), 5.11 (1H, dd,
J=6.6, 7.3 Hz), 4 60 (1H, d, J=7 0 Hz), 4.56 (1H, dd, J=7 0 Hz),
4.21-4.15 (1H, m), 3.62-3.52 (4H, m), 3.30 (3H, s), 3.12-2.97 (2H,
m),-2.82 (3H, s), 2.75-2.54 (4H, m), 2.09-1.74 (6H, m)
EXAMPLE 50
[0689] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-pyrrolidinebenzamide
[0690] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-pyrrolidinebenzamide in 51%
yield according to a procedure similar to that described in Example
2.
[0691] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7.49
(2H, d, J=9.2 Hz), 7.46-7 23 (5H, m), 6.79 (2H, d, J=8.8 Hz), 5.14
(1H, dd, J=6.2, 8.8 Hz), 4.24-4.20 (1H, m), 3.68-3.52 (4H, m), 3.12
(1H, dd, J=8.8, 12.6 Hz), 3.03 (1H, dd, J=6.2, 12.8 Hz), 2.95-2.87
(1H, m), 2.81 (3H, s), 2.75 (1H, d, J=10.3 Hz), 2.55 (1H, dd,
J=4.8, 9.5 Hz), 2.35-2.27 (1H, m), 2.17-2.03 (1H, m), 1.98-1.82
(6H, m)
[0692] IR(neat): 3400, 1610 cm.sup.-1.
[0693] HCl salt: amorphous solid.
[0694] Anal. Calcd for
C.sub.24H.sub.31N.sub.3O.sub.2.multidot.HCl.multido- t.2H.sub.2O:
C, 61.65; H, 8.08; N, 8.83
[0695] Found: C, 61.86; H, 7.79; N, 9.02.
EXAMPLE 51
[0696] Preparation of
4-{N-[2-(3-(S)-tert-Butyldimethylsilyloxypyrrolidin--
1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-ethoxybenzamide
[0697] (i) Methyl
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-
]-N-methylamino}benzoate
[0698] This was prepared from methyl
4-{N-[2-(3-(S)-methoxymethoxypyrrolid-
in-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate in 100% yield
according to the procedures similar to those described in Example
2.
[0699] .sup.1NMR (270 MHz, CDCl.sub.3) .delta. 7.90(2H, d, J=9 2
Hz), 7 36-7 23(5H, m), 6 80(2H, d, J=9 2 Hz), 5.18(1H, dd, J=5.9,
90 Hz), 424-4 20(1H, m), 3 85(3H, s), 3 13(1H, dd, J=5.9, 12 8 Hz),
2.94-2.88 (2H, m), 2 85(3H, s), 2.73(1H, d, J=9.9 Hz). 2 56(1H, dd,
J=4 8, 9 5 Hz), 2 36-2.30(1H, m), 2 27-2 05(1H, m), 1 80-1 50(2H,
m).
[0700] (ii) Methyl
4-{N-[2-(3-(S)-tert-butyldimethylsilyloxypyrrolidin-1-y-
l)-1-(S)-phenylethyl]-N-methylamino}benzoate
[0701] To a stirred solution of methyl
4-{N-[2-(3-(S)hydroypyrrolidin-1-yl-
)-(S)-phenylethyl]-N-methylamino}benzoate (865 mg, 2.44 mmol) in
DMF (10 ml) was added imidazole(1.54 g, 24.4 mmol) and
tert-butyldimethylsilylchl- oride(1.83 g, 12.2 mmol) at 0.degree.
C. After 3hr stining, saturated NaCO.sub.3 aqueous solution was
added to the reaction mixture and extracted with CH.sub.2Cl.sub.2.
The extract was washed with water and brine,
dried(Na.sub.2SO.sub.4), and concentrated to give brown oil, which
was purified by columnn chromatography (silica gel; 40 g,
CH.sub.2Cl.sub.2/MeOH: 100/1-50/1) to give 760 mg(66%) of title
compound.
[0702] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 79(2H, d, J=9 2
Hz), 7 24-7.14(5H, m), 6 68(2H, d, J=9.2 Hz), 5.05(1H, dd, J=6.2,
7.3 Hz), 4.21-4.12(1H, m), 3.75(3H, s), 2.97-2.92(2H, m), 2 82-2
76(1H, m), 2.75(3H, s), 2.58-2 53(2H, m), 2 27(1H, dd, J=4 4, 9 2
Hz), 1 93-1.86(1H, m), 1.58-1.47(1H, m), 0.74(9H, s), 0 01(6H,
s)
[0703] (iii)
4-{N-[2-(3-(S)-tert-Butyldimethylsilyloxpyrrolidin-1-yl)-1-(S-
)-phenylethyl]-N-methylamino}benzoic acid
[0704] This was prepared from methyl
4-{N-[2-(3-(S)-tert-butyldimethylsily-
loxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate in
32% yield according to the procedures similar to those described in
Example 1 (ii)
[0705] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.90(2H, d, J=9.2
Hz), 7 32-7 23(5H, m), 6.80(2H, d, J=9 2 Hz), 5 29-5 26(1H, m), 4
32-4 25(1H, m), 3 26-3.12(2H, m), 3 12-3 06(1H, m), 2.85(3H, s),
2.73-2.65(2H, m), 2.46-2.41(1H, m), 2.07-2 00(1H, m), 1.71-1 62(1H,
m), 0 84(9H, s), 0 01(6H, s).
[0706] (iv)
4-{N-[2-(3-(S)-tert-Butyldimethylsilyloxvpyrrolidin-1-yl)-1-(S-
)-phenylethyl]-N-methylamino}-N'-ethoxybenzamide
methylamino}-N'-ethoxyben- zamide
[0707] This was prepared from
4-{N-[2-(3-(S)-tert-butyldimethylsilyloxypyr-
rolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
O-ethythydroxyiamine in 41% yield according to the procedures
similar to those described in Example 1 (iii)
[0708] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 8.39(1H, br.s),
7.62(2H, d, J=8.8 Hz), 7.34-7.24(5H, m), 6.78(2H, d, J=9.2 Hz),
5.11-5.09(1H, m), 4.32-4 23(1H, m), 4.07(2H, q, J=7 0 Hz),
3.06-3.02(1H, m), 2.92-2.86(1H, m), 2.84(3H, s), 2.68-2.63(2H, m),
2.38(1H, dd, J=4.4, 9.2 Hz), 2.03-1.96(1H, m), l.68-1.62(2H, m),
1.32(3H, t, J=7 0 Hz), 0 84(9H, s), 0.01(6H, s).
EXAMPLE 52
[0709] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-ethoxybenzamide
[0710] To a stirred solution of
4-{N-[2-(3-(S)-tert-butyldimethylsilyloxyp-
yrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-ethoxybenzamide
(44.7 mg, 0.0901 mmol) in THF(1 ml) was added 10M solution of
tetrabutylammonium fluoride in THF(0 273 ml. 0.273 mmol) at room
temperature. After 18hr stirring, saturated NaHCO.sub.3 aqueous
solution was added to the reaction mixture and extracted with
CH.sub.2Cl.sub.2 The extract was washed with water and brine,
dried(Na.sub.2SO.sub.4), and concentrated to give brown oil, which
was purified by column chromatography (silica gel; 20 g,
CH.sub.2Cl.sub.2/MeOH: 25/1-10/1) to give 28.4 mg(82%) of title
compound.
[0711] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 8
60(1H, br s), 7 64(2H, d, J=9 2 Hz), 7 36-7.24(5H, m), 6.80(2H, d,
J=9.2 Hz), 5.16(1H, dd, J=5.9, 9.2 Hz), 4.24-4.20(1H, m), 4.06(2H,
q, J=7.0 Hz), 3.14(1H, dd, J=9 2, 13.2 Hz), 3.04(1H, dd, J=5.9,
12.0 Hz), 2 89-2.83(1H, m), 2.83(3H, s), 2.76(1H. d, J=9 5 Hz),
2.57(1H, dd, J=4 3, 9.9 Hz), 2 38-2.29(1H, m), 2.16-2.03(1H, m),
1.90-1.56(2H, m), 1.32(3H, t, J=7.0 Hz).
[0712] HCl salt: amorphous solid.
[0713] Anal. Calcd for
C.sub.22H.sub.29N.sub.3O.sub.3.multidot.HCl.multido- t.0 7H.sub.2O
C, 58 04, H, 8.00, N,8.46
[0714] Found: C, 58.26; H, 8.40; N,8.58.
EXAMPLE 53
[0715] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}morpholinebenzamide
[0716] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
-)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and morpholine in
54% yield according to the procedures similar to those described in
Example 1 (iii)
[0717] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.32(2H, d, J=8 8
Hz), 7 29-7 28(5H, m), 6 78(2H, d J=8 8 Hz), 5.10(1H, dd, J=7.0, 7
7 Hz), 4 60(1H, d, J=7 0 Hz), 4.55(1H, d, J=6 6Hz), 4 22-4.13(1H,
m), 3.68-3.67(8H, m), 3.30(3H, s), 3.07-3.02(2H, m), 2 90(1H, m), 2
84(3H, s), 2.75-2.57(3H, m), 2.07-2.02(1H, m), 1.81-1 72(1H, m)
EXAMPLE 54
[0718] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-morpholinebenzamide
[0719] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-morpholinebenzamide in 76%
vield according to the procedures sirilar to those described in
Example 2.
[0720] .sup.1H NMR (270 MHz, free arine, CDCl.sub.3) .delta. 7
34(2H d, J=9 2 Hz), 7 30-7 24(5H, m), 6 80(2H, d, J=8.8 Hz),
5.13(1H, dd, J=6 6, 8 8 Hz), 4 27-4.21(1H, m), 3 81-3 53(8H, m), 3
16-2.96(2H, m), 2.92-2.87(1H, m), 2 82(3H, s), 2.75(1H, d, J=9 2
Hz), 2 55(1H, dd, J=4 4, 9.5 Hz), 2.36-2.27(1H, m), 2.12-2 09(1H,
m), 1.75-1.60(2H, m)
[0721] IR(neat) 3400, 1610 cm.sup.-1.
[0722] HCl salt: amorphous solid.
[0723] MS m/z:410(M+H).sup.+
EXAMPLE 55
[0724] Preparation of
4-{N-[2-(3-(S)-Methoxymethoypyrrolidin-1-yl)-1-(S)-p-
henylethyl]-N-methylamino}-N'-(3-hydroxypropyl)benzamide
[0725] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl-]-N-methylamino}benzoic acid and
3-amino-1-propanol in 48% yield according to the procedures similar
to those described in Example 1 (iii).
[0726] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 66(2H, d, J=9.2
Hz), 7 40-7 20(5H, m), 6 80(2H, d, J=8.8 Hz), 6.40-6.30(1H, m),
5.14(1H, dd, J=7.0, 7.7 Hz), 4.60(1H, d, J=6 6 Hz), 4.55(1H, d,
J=6.6 Hz), 4.25-4.13(1H, m), 3.73-3.55(4H, m), 3.30(3H, s), 3.13-3
00(2H, m), 2.90-2.80(1H, m), 2.86(3H, s), 2.78-2.52(3H, m), 2
13-1.98(1H, m), 1.81-1.45(4H, m)
EXAMPLE 56
[0727] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-(3-hydroxypropyl)benzamide
[0728] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-(3-hydroxypropyl)benzamnide
in 82% yield according to the procedures similar to those described
in Example 2.
[0729] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.66(2H, d, J=9.2 Hz), 7.35-7.26(5H, m), 6.81(2H, d, J=9.2 Hz),
6.42-6.33(1H, m), 5.15(1H, dd, J=5.9, 8.8 Hz), 4.27-4.17(1H, m), 3
66(2H, t, J=5.5 Hz), 3.59(2H, t, J=5.9 Hz), 3.13(1H, dd, J=9.2,
12.8 Hz), 3.03(1H, dd, J=5.9, 12.8 Hz), 2.94-2.86(1H, m), 2.84(3H,
s), 2.72(1H, d, J=9.5 Hz), 2.56(1H, dd, J=4.8, 9.9 Hz),
2.36-2.28(1H, m), 2.13-2.03(1H, m), 1.79-1.61(5H, m)
[0730] IR(neat) : 3350, 1610 cm.sup.-1.
[0731] HCl salt: amorphous solid.
[0732] MS m/z:398(M+H).sup.+
EXAMPLE 57
[0733] Peparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-p-
henylethyl]-N-methylamino}-N'-(2-(R)-hydroxypropyl)benzamide
[0734] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
(R)-(-)-1-amino-2-propanol in 83% yield according to the procedures
similar to those described in Example 1 (iii)
[0735] .sup.1H NMR (270 MHZ, CDCl.sub.3) .delta. 7 67(2H, d, J=8 3
Hz), 7 40-7 20(5H, m), 6 80(2H, d, J=88 Hz), 6.50-6.40(1H, m),
5.14(1H, dd, J=70, 7.7 Hz), 4.59(1H, d, J=7 0 Hz), 4 55(1H, d, J=7
0 Hz), 4 23-4 13(1H, m), 4 07-3 95(1H, m), 3 66-3 55(1H, m), 3 40-3
20(1H, m), 3.30(3H, s), 3.13-3 00(2H, m), 2.90-2.80(1H, m), 2
85(3H, s), 2 76-2.52(3H, m), 2.13-1.98(1H, m), 1.85-1.45(2H, m), 1
23(3H, d, J=6 2 Hz)
EXAMPLE 58
[0736] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-(2-(R)-hydroxypropyl)benzamide
[0737] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-(2-(R)-hydroxypropyl)benzamide
in 84% yield according to the procedures similar to those described
in Example 2.
[0738] .sup.1H NMR (270 Mz, free amine, CDCl.sub.3) .delta. 7
68(2H, d, J=8 8 Hz), 7 40-7 20(5H, m), 6 82(2H, d, J=8.8 Hz),
6.50-6.38(1H, m), 5.16(1H, dd, J=5.9, 8 8 Hz), 4 28-4 18(1H, m),
4.10-3 95(1H, m), 3.66-3.55(1H, m), 3 40-3 35(1H, m), 3 16-3 00(2H,
m), 2 95-2.80(1H, m), 2.84(3H, s), 2.74(1 H, d, J=9.2 Hz), 2.56(1H,
dd, J=4.4, 9 5 Hz), 2.40-2 25(1H, m), 2.17-2.00(1H, m), 1.90-1
40(3H, m), 1 24(3H, d, J=6 6 Hz).
[0739] IR(neat) 3350, 1610 cm.sup.-1.
[0740] HCl salt: amorphous solid.
[0741] MS m/z:398(M+H).sup.+
[0742] Anal Calcd for
C.sub.23H.sub.31N.sub.3O.sub.3.multidot.HCl.multidot- .0
85CH.sub.2O C, 62.11, H, 774, N, 9 11
[0743] Found: C, 62.50; H 8.13; N, 9 37
EXAMPLE 59
[0744] Preparation of
4-{N-[2-(3-(S)-Mylethoxymethoxypyrrolidin-1-yl)-1-(S-
)-phenylethyl]-N-methylamino}-N'-isobutylbenzamide
[0745] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and isobutylamine
in 72% yield according to the procedures similar to those described
in Example 1 (iii).
[0746] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.65(2,H d, J=8.8
Hz), 7 34-7 24(5H, m), 6.80(2H, d, J=8.8 Hz), 6 04-5.92(1H, m), 5
18-5 08(1H, m), 4 59(1H, d, J=7.0 Hz), 4 55(1H, d, J=6.6 Hz),
4.22-4.13(1H, m), 3.29(3 H, s), 3.28-3.23(2H, m), 3.10-3.02(2H, m),
2 84-2.80(1H. m), 2.84(3H, s), 2.72-2.57(3H, m), 2.12-1.98(1H, m),
1.89-1.79(1H, m), 1.78-1.69(1H, m), 0.96(6H, d, J=6.6 Hz).
EXAMPLE 60
[0747] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-isobutylbenzamide
[0748] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-isobutylbenzamide in 86%
yield according to the procedures similar to those described in
Example 2.
[0749] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.66(2H, d, J=8.8 Hz), 7.35-7.26(5H, m), 6.81(2H, d, J=8.8 Hz),
6.06-5.96(1H, m), 5.15(1H, dd, J=5.9, 8.8 Hz), 4.26-4.18(1H, m),
3.26(2H, t, J=6.2 Hz), 3.13(1H, dd, J=8.8, 12.8 Hz), 3.03(1H, dd,
J=5.9, 12.8 Hz), 2.92-2.85(1H, m), 2.84(3H, s), 2.73(1H, d, J=9.5
Hz), 2.56(1H, dd, J=4.6, 9 7 Hz), 2.36-2.28(1H, m), 2.16-2.04(1H,
m), 1.96-1 58(3H, m), 0 97(6H, d, J=7.0 Hz)
[0750] IR(neat) : 3350, 1610 cm.sup.-1.
[0751] HCl salt: amorphous solid.
[0752] MS m/z:396(M+H).sup.+
[0753] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.2.multidot.HCl.multido- t.0 5H.sub.2O
C, 65 36, H, 8 00, N, 9 53
[0754] Found : C, 65.58; H, 8.17; N,9.48.
EXAMPLE 61
[0755] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-allylbenzamide
[0756] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and allylamine in
33% yield according to the procedures sitilar to those described in
Example 1 (iii).
[0757] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 67(2H, d, J=8 8
Hz), 7 3 1-7 26(5H, m), 6 79(2H, d, J=9 2 Hz), 6.01-5.88(2H, m),
5.28-5 27(1H, m), 5.21-5 11(2H, m), 4 59(1H, d, J=7.0 Hz), 4 55(1H,
d, J=6.6 Hz), 4 25-4 13(1H, m), 4.09-4 04(2H, m), 3 29(3H, s), 3
07-3.03(2H, m), 2.95-2 80(1H, m), 2.85(3H, s), 2.75-2 67(1H, m),
2.64-2 56(1H, m), 2.06-2.01(1H, m), 1.76-1.60(1H, m), 1.60-1.52(1H,
m).
EXAMPLE 62
[0758] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-allylbenzamide
[0759] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-allylbenzamide in 52% yield
according to the procedures similar to those described in Example
2.
[0760] .sup.1H NMR (270 MHz, free amirne, CDCl.sub.3) .delta. 7
68(2H, d, J=8 8 Hz), 7 35-7 26(5H, m), 6.81(2H d, J=8.8 Hz),
6.01-5.89(2H, m), 5.28-5.12(3H, m), 4.27-4.19(1H, m), 4 09-4.05(2H,
m), 3.13(1H, dd, J=9.2, 12 8 Hz), 3.03(1H, dd, J=5.9, 12 8 Hz), 2
92-2 86(1H, m), 2.84(3H, s), 2.73(1H, d, J=9.2 Hz), 2.56(1H, dd,
J=4 8, 9 5 Hz), 2.33-2 30(1H, m), 2.27-2.08(1H, m), 1.67-1.48(2H,
m).
[0761] IR(neat) 3350, 1610 cm.sup.-1.
[0762] HCl salt: amorphous solid.
[0763] MS m/z:380(M+H).sup.+
[0764] Anal. Calcd for
C.sub.23H.sub.21N.sub.3O.sub.2.multidot.HCl.multido- t.0
1H.sub.2O.multidot.CH.sub.2O C, 64 09, H, 7 66; N, 9 34
[0765] Found: C, 63.86; H, 7.85; N, 9 32.
EXAMPLE 63
[0766] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-cyclopropylbenzamide
[0767] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
cyclopropylamine in 48% yield according to the procedures similar
to those described in Example 1 (iii).
[0768] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.61(2H, d, J=8.8
Hz), 7.33-7.22(5H, m), 6 78(2H, d, J=8.8 Hz), 6.11-6.02(1H, m),
5.15-5.11(1H, m), 4.59(1H, d, J=6.6 Hz), 4 55(1H, d, J=6.6 Hz),
4.19-4.14(1H, m), 3.29(3H, s), 3.07-3.03(2H, m), 2.90-2 80(1H, m),
2.84(3H, s), 2.72-2.66(1H, m), 2.64-2.56(2H, m), 2.08-2.01(1H, m),
1.79-1.73(1H, m), 1.37-1.25(1H, m), 0.94-0 80(2H, m), 0 60-0.54(2H,
m).
EXAMPLE 64
[0769] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-cyclopropylbenzamide
[0770] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-cyclopropylbenzamide in 76%
yield according to the procedures similar to those described in
Example 2.
[0771] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.63(2H, d, J=9.2 Hz,), 735-7.23(5H, m), 6.79(2H, d, J=8.8 Hz),
6.12-6.04(1H, m), 5.15(1H, d, J=5.9, 8.8 Hz), 4.24-4.19(1H, m),
3.13(1H, dd, J=9.2, 12.8 Hz), 3.03(1H, dd, J=5.9, 10.3 Hz),
2.94-2.84(2H, m), 2 83(3H, s), 2.78(1H, d, J=9.5 Hz), 2.58-2.53(1H,
m), 2.33-2.31(1H, m), 2.11-2.08 (1H, m), 1.68-1.61(2H, m),
0.87-0.80(2H, m), 0.60-0.54(2H, m).
[0772] IR(neat): 3350, 1610 cm.sup.-1.
[0773] HCl salt: amorphous solid.
[0774] MS m/z:380(M+H).sup.+
[0775] Anal. Calcd for
C.sub.23H.sub.29N.sub.3O.sub.2.multidot.HCl.multido- t.0.8H.sub.2O.
C, 64.19 H, 7.40 N, 9 76
[0776] Found: C, 64.04; H, 7.50; N, 9.83
EXAMPLE 65
[0777] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-(S)-sec-butylbenzamide
[0778] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
(S)-sec-butylamine in 18% yield according to the procedures similar
to those described in Example 1 (iii)
[0779] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 65(2H, d, J=8 8
Hz), 7.40-7 20(5H, m), 6 79(2H, d, J=8 8 Hz), 5.74(1H, d, J=8.4
Hz), 5.13(1H, dd, J=6.6, 8.1 Hz), 4.59(1H, d, J=7 0 Hz), 4 55(1H,
d, J=7 0 Hz), 4 25-4 05(2H, m), 3 30(3H, s), 3 15-2 95(2H, m), 2
90-2 90(1H, m), 2.85(3H, s), 2.76-2.55(3H, m), 2.13-1.98(1H, m),
1.85-1.70(1H, m), 1.65-1 50(2H, m), 1.20(3H, d, J=6.6 Hz), 0.95(3H,
t, J=7.7 Hz).
EXAMPLE 66
[0780] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}- N'-(S)-sec-butylbenzamide
[0781] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrroidin-1-yl)-
-1-(S)-phenylethyl]-N-methylamino}-N'-(S)-sec-butylbenzamide in
100% yield aeccrding to the procedures similar to those described
in Example 2.
[0782] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
65(2H, d, J=9 2 Hz), 7.40-7 20(5H, m), 6.80(2H, d, J=9 2 Hz),
5.76(1H, d, J=8 4 Hz), 5 14(1H, dd, J=6 2, 8 8 Hz), 4 25-4 05(2H,
m), 3.17-2.98(2H, m), 2.95-2.78(1H, m), 2.83(3H, s), 2.72(1H, d,
J=9 5 Hz), 2 57(1H, dd, J=4.8, 9.5 Hz), 2.40-2.28(1H, m), 2.20-1
95(2H, m), 1.70-1.50(3H, m), 1 20(3H, d, J=6 6 Hz), 0 95(3H, t, J=7
3 Hz)
[0783] HCl salt: amorphous solid.
[0784] MS m/z:396(M+H).sup.+
[0785] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.2.multidot.HCl.multido- t.0
3H.sub.2O.multidot.CH.sub.2O C, 63.96, H, 8 29, N, 8 95
[0786] Found: C, 64 14; H, 8 01; N, 8.70
EXAMPLE 67
[0787] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-(R)-sec-butylbenzamide
[0788] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
(R)-sec-butylamine in 18% yield according to the procedures similar
to those described in Example 1 (iii).
[0789] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.65(2H, d, J=8.8
Hz), 7.33-7.23(5H, m), 6.79(2H, d J=9.2 Hz), 5.74(1H, d, J=8.1 Hz),
5.13(1H, dd, J=6.6, 7.7 Hz), 4.59(1H, d, J=6.6 Hz), 4.55(1H, d,
J=6.6 Hz), 4.19-4.08(2H, m), 3.29(3H, s), 3.09-2.98(2H, m),
2.90-2.80(1H, m), 2.84(3H, s), 2.72-2.57(3H, m), 2.13-1.98(1H, m),
1.78-1.75(1H, m), 1 60-1 49(2H, m), 1.20(3H, d, J=6.6 Hz), 0.94(3H,
t, J=7.7 Hz).
EXAMPLE 68
[0790] Preparation of 4-{N-[2-(3
-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyl- ethyl]-N-methylamino}-
N'-(R)-sec-butylbenzamide
[0791] This was prepared from
4{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-
-1-(S)-phenylethyl]-N-methylamino}-N'-(R)-sec-butylbenzamide in 95%
yield according to the procedures similar to those described in
Example 2.
[0792] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
65(2H, d, J=8.8 Hz), 7.40-7.20(5H, m), 6.80(2H, d, J=8.8 Hz),
5.78(1H, d, J=8.3 Hz), 5.14(1H, dd, J=5.9, 8.8 Hz), 4.25-4.03(2H,
m), 3.17-2.98(2H, m), 2.95-2.78(1H, m), 2.83(3H, s), 2.71(1H, d,
J=9.5 Hz), 2.58(1H, dd, J=4.8, 9.5 Hz), 2.42-2.30(1H, m), 2.23(1H,
br s), 2.15-2.00(1H, m), 1.70-l.50(3H, m), 1.20(3H, d, J=6.6 Hz),
0.95(3H, t, J=7.3 Hz).
[0793] HCl salt: amorphous solid.
[0794] MS m/z:396(M+H).sup.+
[0795] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.2.multidot.HCl.multido- t.0
4H.sub.2O.multidot.CH.sub.4O. C, 63 72; H, 8.30, N, 8.92
[0796] Found: C, 63.96; H, 8.08; N, 9.08
EXAMPLE 69
[0797] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrroidin-1-yl)-1-(S)-p-
henylethyl]-N-methylamino}-N'-propargylbenzamide
[0798] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and propargylamine
in 18% yield according to the procedures similar to those described
in Example 1 (iii)
[0799] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 65(2H, d, J=8.8
Hz), 7 34-7 24(5H, m), 6 80(2H, d, J=9 2 Hz), 6.12-6 03(1H, m),
5.14(1H, dd, J=6 6, 73 Hz), 4 59(1H, d, J=7 0 Hz), 4 55(1H, d, J=7
0 Hz), 4.23(2H, q, J=2.6 Hz), 4 19-4 14(1H, m), 3 29(3H, s), 3
07-3.03(2H, m), 2.85-2.80(1H, m), 2.85(3H, s), 2.75-2.70(1H, m),
2.67-2.56(2H, m), 2.25(H, t, J=2 6 Hz), 2.08-2.01(1H, m), 1 87-1
70(1H, m)
EXAMPLE 70
[0800] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propargylbenzamide
[0801] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-propargylbenzamide in 77%
yield according to the procedures sirilar to those described in
Example 2.
[0802] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.67(2H d, J=8 8 Hz), 7 35-7.24(5H, m), 6.81(2H, d, J=8 8 Hz),
6.13-6.03(1H, m), 5 16(1H, dd, J=5 9, 9.0 Hz), 4 24-4 21(3H, m),
3.13(1H, dd, J=9.5, 12.8 Hz), 3 03(1H, dd, J=5 9, 12 8 Hz), 2.93-2
86(1H, m), 2 84-(3H, s), 2.73(1H, d, J=8.3 Hz), 2 58-2.53(1H, m),
2.32-2.24(2H, m), -2 11-205(1H, m), 1.76-1 58(2H, m).
[0803] IR(neat) 3300, 1610 cm.sup.-1
[0804] HCl salt: amorphous solid.
[0805] MS m/z 378(M+H).sup.+
[0806] Anal calcd for
C.sub.23H.sub.27N.sub.3O.sub.2.multidot.HCl.multidot- .0
8H.sub.2O.multidot.CH.sub.4O C. 62 61 H 7 36, N 9 13
[0807] Found: C, 62 23; H, 7 26; N, 9 50.
EXAMPLE 71
[0808] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-(3,3,3,-trifluoropropyl)benzamide
[0809] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
3,3,3,-trifluoropropylamine in 39.degree. yield according to the
procedures similar to those described in Example 1 (iii)
[0810] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.63(2H, d, J=8.8
Hz), 7.31-7.24(5H, m), 6 80(2H, d, J=9.2 Hz), 6.21-6.12 (1H, m),
5.14(1H, dd, J=7.0, 8.1 Hz), 4.59(1H, d, J=7 0 Hz), 4.55(1H, d,
J=7.0 Hz), 4.21-4.12(1H, m), 3.69(2H, q, J=6.2 Hz), 3.29(3H, s),
3.07-3 03(2H, m), 2.85(3H, s), 2.84-2.80(1H, m), 2.72-2.67(1H, m),
2.64-2.56(2H, m), 2.50-2.38(2H, m), 2.08-2.01(1H, m), 1.77-1.76(1H,
m).
EXAMPLE 72
[0811] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-(3,3,3,-trifluoropropyl)benzamide
[0812] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-(3,3,3,-trifluoropropyl)benzamide
in 69% yield according to the procedures similar to those described
in Example 2.
[0813] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.66(2H, d, J=8.8 Hz), 7 36-7 26(5H, m), 6.81(2H, d, J=9.2 Hz),
6.26-6.20 (1H, m), 5.16(1H, dd, J=5.9, 9.2 Hz), 425-4 19(1H, m), 3
69(2H, q, J=6.2 Hz), 3.17-3.02(2H, m), 2 99-2.88(1H, m), 2 84(3H,
s), 2 80-2.72(1H, m), 2.59-2.53(1H, m), 2.52-2.38(2H, m),
2.37-2.28(1H, m), 2.16-2.05(1H, m), 1.80-1.75(2H, m).
[0814] IR(neat): 3350, 1610 cm.sup.-1.
[0815] HCl salt: amorphous solid.
[0816] MS m/z:436(M+H).sup.+
[0817] Anal. Calcd for
C.sub.23H.sub.28N.sub.3O.sub.2F.sub.3.multidot.HCl.- multidot.0
4H.sub.2O C, 57 65 H, 6.27, N, 8 77
[0818] Found: C, 57 60; H, 6.26; N, 8 50
EXAMPLE 73
[0819] Preparation of
4-{-N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-
-phenylethyl]-N-methylamino}-N'-(2-(S)-hydroxypropyl)benzamide
[0820] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and
(S)-(-)-1-amino-2-propanol in 55% yield according to the procedures
similar to those described in Example 1 (iii)
[0821] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 67(2H, d, J=9 2
Hz), 7 40-7 20(5H, m), 6 80(2H, m), J=8 8 Hz), 6.50-6.40(1H, m), 5
14(1H, dd, J=7 0, 7 7 Hz), 4 60(1H, d, J=6 6 Hz), 4 55(1H, d, J=7 0
Hz), 4 23-4 13(1H, m), 4 07-3 95(]H, m), 3 66-3 55(1H, m), 3 40-3
25(1H, m), 3.30(3H, s), 3.13-3 00(2H, m), 2.90-2 80(1H, m),
2.86(3H, s), 2 76-2 52(3H, m), 2.13-1 98(1H, m), 1 85-1 45(2H, m),
1 23(,H, d, J=6 2 Hz)
EXAMPLE 74
[0822] Preparation of
4-{N-[2-(3-(S)-Hvdroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-(2-(S)-hydroxypropyl)benzamide
[0823] This was prepared from,
4-({N-[2-(3-(S)-methoxymethoxypyrrolidin-1--
yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(2-(S)-hydroxypropyl)berzamide
in 81% yield according to the procedures similar to those described
in Example 2.
[0824] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
68(2H, d, J=8 8 Hz), 7 40-7 20(5H, m), 6 80(2H, d, J=8 8 Hz),
6.60-6.50(1H, m), 5 15(1H, dd, J=5 9, 9 2 Hz), 4 28-4 18(1H, m), 4
07-3 93(1H, m), 3 66-3.55(1H, m), 3 35-3 23(1H, m), 3.13(1H, dd,
J=9 2. 12 8 Hz), 3 03(1H, dd, J=5.9, 12.8 Hz), 2.95-2 80(1H, m), 2
83(3H, s), 2 72(1H, d, J=9 5 Hz), 2 56(1H, dd, J=4 8, 9 9 Hz), 2
40-2 25(1H, m), 2 20-1 75(3H, m), 1 70-1 55(1H, m), 1 22(3H, d,
J=6.2 Hz).
[0825] IR(neat) 3350, 1610 cm.sup.-1
[0826] Maleic acid salt: amorphous solid
[0827] MS m/z 396(M-H).sup.-
[0828] Anal Calcd for
C.sub.23H.sub.31N.sub.3O.sub.3.multidot.C.sub.4H.sub-
.4O.sub.4.multidot.0 3H.sub.2O C, 62.49, H, 6.91 N, 8 10
[0829] Found: C, 62 65; H, 7 24; N, 7 90
EXAMPLE 75
[0830] Preparation of
4-{N-[1-(R)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methox-
ymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0831] (i) Methyl
4-{N-[1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymet-
hoxypyrrolidin-1-yl)-ethyyl]-N-methylamino}benzoate
[0832]
2-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1--
yl)ethanol and
1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrro-
lin-1-yl)ethanol were prepared from
(R)-1-(3-methoxymethoxyphenyl)-1,2-eth- anediol-2-tosylate in 58%
yield as a mixture according to the procedures similar to those
described in Preparation 3. Title compound was prepared by reacting
the mixture of 2-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methox-
ymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3
methoxymethoxyphenyl)-2-(3-(S-
)-methoxymethoxypyrrolidin-1-yl)ethanol with methyl
4-methylaminobenzoate in 54% yield according to the procedures
similar to those described in Example 1 (i).
[0833] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.88 (2H, d, J=8.8
Hz), 7.23-7.19 (1H, m), 6.95-6.90(3H, m), 6.77(2H, d, J=8.8 Hz), 5
13(2H, s), 5.12-5,08(1H m), 4 58 (1H, d, J=6 6 Hz), 4 53 (1H, d,
J=6.6 Hz), 4.22-4.15 (1H, m), 3.84 (3H, s), 3.45(3H, s), 3.28 (3H,
s), 3 13-2.92(2H, m), 2.88 (3H, s), 2.90-2.84(1H, m), 2.75-2.66(1H,
m), 2.61-2 50(2H, m), 2.06-1.99(1H, m), 1.83-1.74(I1H, m).
[0834] (ii)
4-{N-[1-(R)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypy-
rroidin-1-yl)-ethyl]-N-methylamino}benzoic acid
[0835] This was prepared from methyl
4-{N-[1-(R)-(3-methoxymethoxyphenyl)--
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoate
in 91% yield according to the procedures similar to those described
in Example 1 (ii)
[0836] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 91 (2H, d, J=8.8
Hz), 7 30-7 12(1H, m), 6 98-6 84(3H, m), 6 82(2H, d, J=9.2 Hz),
5.35-5 25(1H, m), 5 14(2H, s), 4.60(1H, d, J=7 0 Hz), 4,55(1H, d,
J=7. 0 Hz), 4.30-4.20(1H, m), 3.45(3H, s), 3.30(3H, s), 3.25-3
05)2H, m), 2.90(3H, s), 2.90-2.60(4H, m), 2.20-2.00(1H, m),
1.90-1.80(1H, m).
[0837] (iii)
4-{N-[1-(R)-(3-Mettoxymethoxyphenyl)-2-(3-(S)-methoxymethoxyp-
yrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0838] This was prepared from
4-{N-[1-(R)-(3-methoxymethoxyphenl)-2-(3-(S)-
-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoic acid
and n-propylamine in 71% yield according to the procedures similar
to those described in Example 1 (iii)
[0839] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.64(2H, d, J=8,8
Hz), 7.28-7 18(1H, m), 6 98-6 88(3H, m), 6 78(2H, d, J=9 2 Hz),
6.00-5 90(1H, m), 5 14(2H, s), 5 09(1H, :, J=7 7 Hz), 4 58(1H, d,
J=7.0 Hz), 4.54(1H, d, J=7 0 Hz), 4.25-4.12(1H, m), 3.46(3H, s), 3
45-3 35(2H, m), 3.29(3H, s), 3.08-2.96(2H, m), 2.92-2.80(1H, m),
2.86(3H, s), 2 75-2 50(3H, m), 2 12-1.95(1H, m), 1.85-1.52(3H, m),
0.97(3H, t, J=7 3 Hz)
EXAMPLE 76
[0840] Preparation of
4-{N-[1-(R)-(3-t-Butoxycarbonylmethoxyphenyl)-2-(3-(-
S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0841] This was prepared from
4-{N-[1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S-
)-methoxymethoxypyrroidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
in 11% over all yield accprding to the procedures similar to those
described in Example 2 and Example 36.
[0842] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.65(2H, d, J=8.8
Hz), 7.26-7 20(1H, m), 6 92-6 89 (2H, m), 679(2H, d, J=9.2 Hz),
6.79-6.75(1H, m), 6.01-5.92(1H, m), 5 11(1H, dd, J=,7 0, 7 2 Hz),
4.47(2H, s), 4 26-4 17(1H, m), 3 45-3 35(2H, m), 3 04(2H, d, J=7 3
Hz), 2 98-2 91 (1H, m), 2.81(3H, s), 2.69(1H, d, J=9 2 Hz),
2.49(1H, dd, J=4 8, 9 9 Hz), 2 40-2.25(1H, m), 2.17-2.06(1H, m),
1.75-1.52(4H, m), 1.45(9H, s), 0.98(3H, t, J=7 3 Hz)
EXAMPLE 77
[0843] Preparation of
4-{N-[1-(R)-(3-Carboxymethoxyphenyl)-2-(3-(S)-hydrox-
ypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide
[0844] This was prepared from
4-{N-[1-(R)-(3-t-butoxycarbonylmethoxyphenyl-
)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamid-
e in 86% yield according to the procedures similar to those
described in Example 3
[0845] HCl salt: ligt brown solid.
[0846] .sup.1H NMR (270 MHz, DMSO-d6) .delta. 10.55-10.15(1H, m),
8.32-8.24(1H, m), 791-7 80(2H, m), 7.34(1H, t, J=7.7 Hz), 7
21-7.09(2H, m), 6.98-6.84(3H, m), 5 95- 5 80(1H, m), 4.72(2H, s),
4.60-4.40(1H, m), 440-3.20(7H, m), 2.82(1.2H, s), 2 81(1H, s),
2.50-2.30(2H, m), 2.15-1.85(2H m), 1.70-1.50(2H, m), 0.96(3H, t,
J=7 3 Hz)
[0847] IR(KBr): 3400, 1730, 1610 cm.sup.-1.
[0848] MS m/z: 456(M+H).sup.+.
[0849] Anal. Calcd for
C.sub.25H.sub.33N.sub.3O.sub.5.multidot.HCl.multido- t.3.5H.sub.2O:
C, 54.10,; H, 7.45, N, 7.57
[0850] Found: C, 54.49; H, 7.85; N, 7.76
EXAMPLE 78
[0851] Preparation of
3-Fluoro-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-y-
l)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide
[0852] (i) Methyl
3-fluoro4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1--
(S)-phenylethyl]-N-methylamino}benzoate
[0853] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
methyl 3-fluoro4-methylamninobenzoate in 52% yield according to the
procedures similar to those described in Example 29 (i).
[0854] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.72-7.62(2H, m),
7.39-7.22 (5H, m), 6.81(1H, t, J=8.8 Hz), 5.12-5.02(1H, m), 4.58
(1H, d, J=7.0 Hz), 4 55(1H d, J=7.0 Hz), 4 15-4 03(1H, m), 3.88(3H,
s), 3.30(3H, s), 3 18-2 95(2H, m), 2.88-2.78(1H, m), 2 71(3H, d,
J=0.7 Hz), 2.67-2.45(3H, m), 2.05-1.90(1H, m), 1.75-1.60(1H m)
[0855] (ii)
3-Fluoro-4-{N-[2-(3-(S)-methoxyrmethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}benzoic acid
[0856] This was prepared from methyl
3-fluoro-4-{N-[2-(3-(S)-methoxymethox-
ypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate in 100%
yield according to the procedures similar to those described in
Example 1 (ii)
[0857] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 763-7 54(2H, m), 7
38-7 22 (5H, m), 6 76(1H, t, J=8 4 Hz), 5 27-5 17(1H, m), 4 61 (1H,
d, J=7 0 Hz), 4 58(1H, d, J=7 0 Hz), 4 30-4 20(1H, m), 3 55-3
43(1H, m), 3 40-3 15(3H, m), 3 31(3H, s), 2 95-2 73(2H, m), 2
74(3H, s), 2 22-2.05(1H, m), 1 95-1 80(1H, m)
[0858] (iii)
3-Fluoro-4-{N-[2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1-(S)-p-
henylethyl]-N-methylamino}-N'-propylbenzamide
[0859] This was prepared from
3-fluoro-4-{N-[2-(3-(S)-methoxymethoxypyrrol-
din-1-yl)-1-(S)-phenylethyl]-N'-methylaminoberzoic acid and
n-propylamine in 80% yield according to the procedures similar to
those described in Example 1 (iii)
[0860] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 48 (1H, dd, J=1
8, 14 3 Hz), 7 41-7 20(6H, m), 6 80(1H, t, J=8 8 Hz), 6 08-6 00(1H,
m), 5 03-4 92(1H, m), 4 58 (1H, d, J=7 0 Hz), 4 54(1H, d, J=6 6
Hz), 4.13-4 03(1H, m), 3 45-3 35(2H, m), 3 30(3H, s), 3 18-3 07(1H,
m), 3 02(1H, dd, J=6.6, 12 8 Hz), 2 83(1H, dd, J=6 2, 9 9 Hz), 2
68(3H, m), 2 65-2.45((3H, m), 2.07-1.93 (1H, m), 1.75-1.55(3H, m),
0.99(3H, t, J=7 3 Hz)
EXAMPLE 79
[0861] Preparation of
3-Fluoro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S-
)-phenylethyl-N-methylamino}-N'-propylbenzamide
[0862] This was prepared from
3-Fluoro-4-{N-[2-(3-(S)-methoxymethoxypyrrol-
idin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide in
40% yield according to the procedures similar to those described in
Example 2
[0863] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7 53 (
1H, dd, J=2 2. 14 3 Hz), 7 41-7 24(6H, m), 6.83(1H, t, J=8.8 Hz),
6.11-6 02(1H, m), 5.12-5 02(1H, m), 4 22-4 13(1H, m), 3 45-3.35(2H,
m), 335-3.23(1H, m), 3 00(1H, dd, J=5 5, 12 5 Hz), 2 92-2 73(2H,
m), 2 68(3H, s), 2.60-2.50(1H, m), 2 33-2 13(1H, m), 2 13-1.95(1H,
m), 1 90 (1H, br s), 1 70-1 48(3H, m), 0.99(3,H, t, J=7 3 Hz)
[0864] Malec acid salt, amorphous solid
[0865] IR(KBr) 3350, 1620 cm.sup.-1.
[0866] MS 400(M+H).sup.+
[0867] Anal. Calcd for
C.sub.23H.sub.30N.sub.3O.sub.2F.multidot.C.sub.4H.s-
ub.4O.multidot.0 5H.sub.2O: C, 61.82; H, 6.72; N, 8.01
[0868] Found: C, 61.52; H, 6.70; N, 8.02.
EXAMPLE 80
[0869] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-(2,2,3,3,3,-pentafluoropropyl)benzamide
[0870] This was prepared from 2-(3
-(S)-methoxymethoxypyrrolidin-1-yl)-1-(- S)-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenyle- thanol and
4-methylamino-N'-2,2,3,3,3,-pentafluoropropyl)benzamide in 32%
yield according to the procedures similar to those described in
Example 1 (i).
[0871] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.67(2H, d, J=8 8
Hz), 7 34-7.25 (5H, m), 6.81(2H, d, J=9.2 Hz), 6.30-6.13(1H, m),
5.15(1H, t, J=7.7 Hz), 4.59 (1H, d, J=6.6 Hz), 4.55(1H, d, J=6.6
Hz), 423-4.10(3H, m), 3 30(3H, s), 3.07-3.04(2H, m), 2.87(3H, s), 2
84-2 80(1H, m), 2.76-2.67(1H, m), 2.64-2.53(2H, m), 2.09-2.01(1H,
m), 1 77-1 70(1H, m)
EXAMPLE 81
[0872] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-ethylaminol-N'-(2,2,3,3,3,-pentafluoropropyl)benzamide
[0873] This was prepared from 4{N-[2-(3-(S)
methoxymethoxypyrrolidin-1-yl)-
-1-(S)-phenylethyl]-N-methylamino}-N'-(2,2,3,3,3,-pentafluoropropyl)benzam-
ide in 97% yield according to the procedures similar to those
described in Example 2.
[0874] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.69(2H, d, J=8.8 Hz), 7.36-7 26 (5H, m), 6 82(2H, d, J=8.8 Hz), 6
20-616(1H, m), 5 16(1H, dd, J=5.5, 8 8 Hz), 4.25-4 21(1H, m), 4
14(2H, dd, J=6.2, 14.7 Hz), 3.14(1H, dd, J=9.2, 12.8 Hz), 3.04(1H,
dd, J=5 9, 12 8 Hz), 2.95-2.88(1H, m), 2.86(3H, s), 2.73(1H, d,
J=9.5 Hz), 2.57(1H, dd, J=4.8, 9 5 Hz), 2.37-2.29(1H, m),
2.16-2.05(1H, m), 1.80-1.60(2H, m)
[0875] IR(neat). 3350, 1610 cm.sup.-1
[0876] HCl salt arnorphous solid.
[0877] MS m/z 470(M-H).sup.-
[0878] Anal. Calcd for
C.sub.23H.sub.26N.sub.3O.sub.2F.sub.3.multidot.HCl.-
multidot.0.4CH.sub.4O: C, 53 63 H, 5 44 N, 8 16
[0879] Found: C, 53.90; H, 5.33; N, 7.79.
EXAMPLE 82
[0880] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}-N'-tert-amylbenzamide
[0881] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- anol and
4-methylamino-N'-tert-amylbenzamide in 36% yield according to the
procedures similar to those described in Example 1 (i).
[0882] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 60(2H, d, J=8 8
Hz), 7 34-7 23 (5H, m), 6 78(2H, d, J=8 8 Hz), 5.73-5.62(1H, m), 5
13(1H, dd, J=6 2, 8.4 Hz), 4 60 (1H, d, J=7 0 Hz), 4 55(1H, d,
J=7.0 Hz), 4 17-4.15(1H, m), 3 30(3H, s), 3 07-3 02(2H, m), 2
83(3H, s), 2.96-2.90(1H, m), 2.72-2.64(1H, m), 2.63-2 57(2H, m),
2.09-2.01(1H, m), 1 87-1 79(1H, m), 1.83(2H, q, J=7 3 Hz), 1 39(6H,
s), 0.88(3H, t, J=7 3 Hz)
EXAMPLE 83
[0883] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-tert-amylbenzamide
[0884] This was prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidn-1-yl)-
-1-(S)-phenylethyl]-N-methylatino}-N'-tert-amylbenzamide in 88%
yield according to the procedures similar to those described in
Example 2
[0885] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
62(2H d, J=8 8 Hz), 7 35-7 22 (5H, m), 6 79(2H, d, J=8.8 Hz),
5.73-5.63(1H, m), 5 14(1H, dd, J=5 9, 9 2 Hz), 424-4 20(1H, m),
3.12(1H, dd, J=8.8, 12.8 Hz), 3.03(1H, dd, J=5.9, 12.8 Hz),
2.93-2.86(1H, m), 2.83(3H, s) 2 73(1H, d, J=9.9 Hz), 2 56(1H, dd,
J=4.8, 9.5 Hz), 2.36-2.27(1H, m), 2 14-2 04(1H, m), 1.83(2H, q,
J=7.3 Hz), 1.80-1.60(2H, m), 1.40(6H, s), 0.88(3H, t, J=7.3 Hz)
[0886] IR(neat) 3350, 1610 cm.sup.-1
[0887] HCl salt: amorphous solid.
[0888] MS m/z:410(M+H).sup.+
[0889] Anal. Calcd for
C.sub.25H.sub.35N.sub.3O.sub.2.multidot.HCl.multido-
t.0.2CH.sub.4O: C, 66.78, H, 8.16; N, 9.35
[0890] Found: C, 66.67; H, 8.43; N, 9.33.
EXAMPLE 84
[0891] Preparation of
4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl-1-(S)-p-
henylethyl]-N-methylamino}-N'-tert-butylbenzamide
[0892] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hanol and
4-methylamino-N'-tert-butylbenzamide in 66% yield according to the
procedures similar to those described in Example 1 (i).
[0893] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7.61(2H, d, J=8.8
Hz), 7.40-7 20 (5H, m), 6.78(2H, d, J=9.2 Hz), 5.90-5.65(1H, m),
5.18-5.10(1H, m), 4.60 (1H, d, J=6.6 Hz), 4 56(1H, d, J=7 0 Hz), 4
24-4 14(1H, m), 8 30(3H, s), 3 10-2.98(2H, m), 2.90-2.78(1H, m), 2
84(3H, s), 2.76-2.54(3H, m), 2.15-1.95(1H, m), 1.80-1.60(1H, m),
1.45(9H, s).
EXAMPLE 85
[0894] Preparation of
4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-tert-butylbenzamide
[0895] This was prepared from 4-{N-[2-(3
-(S)-Methoxymethoxypyrrolidn-1-yl-
)-1-(S)-phenylethyl]-N-methylamino}-N'-tert-butylbenzamide in 52%
yield according to the procedures similar to those described in
Example 2.
[0896] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
62(2H, d, J=8 8 Hz), 7 35-7 24 (5H, m), 6 79(2H, d, J=9 2 Hz), 5
83-5 77(1H, m), 5 14(1H, dd, J=5 5, 8 8 Hz), 4 26-4 18(1H, m), 3
13(1H, dd, J=9 2, 12.8 Hz), 3 03(1H, dd, J=5 9, 12.8 Hz), 2 92-2
86(1H, m), 283(3H, s), 2 74(1H, d, J=9 9 Hz), 2 55(1H, dd, J=4 8, 9
9 Hz), 2 36-2 27(1H, m), 2 11-2 08(1H, m), 1.72-1 54(2H, m), 1
45(9H, s).
[0897] IR(neat) 3350, 1610 cm.sup.-1
[0898] HCl salt amorphous solid.
[0899] MS m/z:396(M+H).sup.+
[0900] Anal. Calcd for
C.sub.24H.sub.33N.sub.3O.sub.2.multidot.HCl.multido- t.1 2H.sub.2O
C, 63 55, H, 8 09 , N, 9 26
[0901] Found: C, 63.34; H, 7 93; N, 9 01
EXAMPLE 86
[0902] Preparation of
5-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propylpicolinamide
[0903] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylet- hethanol
and 5-methylamino-N'-propylpicolinamide in 24% over all yield
according to the procedures similar to those described in Example 1
(i) and Example 2.
[0904] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 8
12(1H, d, J=3 3 Hz), 8 02(1H, d, J=8 8 Hz), 7 82-7 74(1H, m),
7.38-7 24 (5H, m), 7 13(1H, dd, J=3.3, 8 8 Hz), 5 10(1H, dd, J=5 5,
9.5 Hz), 4 30-4 20(1H, m), 3 45-3 35(2H, m), 3 17(1H, dd, J=9 5, 12
8 Hz), 3 01 (1H, dd, J=5 5, 12 8 Hz), 2.95-2.84(1H, m), 2 91(3H,
s), 2 70(1H, d, J=9 2 Hz), 2.61(1H, dd, J=4 8, 9.5 Hz),
2.42-2.30(1H, m), 2.18-2 02(1H, m), 1 80-1 55(4H, m), 0 98(3H, t,
J=7 3 Hz).
[0905] Fumaric acid salt amorphous solid.
[0906] IR(KBr) 3400, 1650 cm.sup.-1.
[0907] MS m/z.383(M+H).sup.+
[0908] Anal Calcd for
C.sub.22H.sub.30N.sub.4O.sub.2.multidot.C.sub.4H.sub-
.4O.sub.4.multidot.0.5H.sub.2O C, 61. 52; H, 6 95, N, 11 04
[0909] Found: C, 61 75; H, 7.09; N, 10.95
EXAMPLE 87
[0910] Preparation of
4-{N-Hydroxy-N-[2-(3-(S)-methoxymethoxypyrrolidin-1--
yl)-1-(S)-phenylethyl]amino}-N'-propylbenzamide
[0911] This was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S- )-phenylethanol and 2
-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenyle- thanol and
methyl 4-hydroxyaminobenzoate in 33% over all yield according to
the procedures similar to those described in Example 1 (i), (ii)
and (iii).
[0912] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. 7 55(2H, d, J=8.8
Hz), 7.43-7.18 (5H, m), 6.90(2H, d, J=8.8 Hz), 6.05-5.95(1H, m),
4.87(1H, dd, J=5.1, 10.3 Hz), 4.63 (1H, d, J=7.0 Hz), 4.60(1H, d,
J=7.0 Hz), 4.30-4.20(1H, m), 3.58-3 46(2H, m), 3.43-3 25(2H, m),
3.35(3H, s), 2.95-2.50(4H, m), 2.20-1.80(2H, m), 1.70-1.50(2H,, m),
0 96(3H, t, J=7.3 Hz)
EXAMPLE 88
[0913] Preparation of
4-{N-Hydroxy-N-[2-(3-(S)-hydroxpyrrolidin-1-yl)-1-(S-
)-phenylethyl]amino}-N'-propylbenzamide
[0914] This was prepared from
4-{N-hydroxy-N-[2-(3-(S)-methoxymethoxypyrro-
lidin-1-yl)-1-(S)-phenylethyl]amino}-N'-propylbenzamide in 63%
yield according to the procedures similar to those described in
Example 2.
[0915] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 8
86(1H, s), 8.18-8.08(1H ,m), 7 64(2H, d, J=8.8 Hz), 7.42(2H, d,
J=6.6 Hz). 7 27-7 12 (3H, m), 7.07(2H, d, J=8 8 Hz), 4.96(1H, dd,
J=6.6, 7.3 Hz), 4.62 (1H, d, J=4 8 Hz), 4 15-4.05(1H, m), 3
20-3.10(2H, m), 3 07-2.92(2H, m), 2 74(1H, dd, J=6 2, 9 5 Hz) 2
55(2H, t, J=7 3 Hz), 2 36(1H, dd, J=4 0, 9 5 Hz), 2.00-1 80(1H, m),
1 55-1 40(3H, m), 0 86(3H, t, J=7 3 Hz).
[0916] Fumaric acid salt: amorphous solid.
[0917] IR(KBr): 3300, 1630 cm.sup.-1.
[0918] MS m/z:384(M+H).sup.+
[0919] Anal. Calcd for
C.sub.22H.sub.29:N.sub.3O.sub.3.multidot.C.sub.4H.s-
ub.4O.sub.4.multidot.0.5H.sub.2O: C, 61.40, H, 6 74, N, 8 26
[0920] Found: C, 61.40; H,6.78; N, 8 08.
EXAMPLE 89
[0921] Preparation of
4-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylet-
hyl]-N-methylamino}-N'-(2-(S)-hydroxcypropyl)benzamide
[0922] This was prepared from
4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)--
phenylethyl]-N-methylamino}benzoic acid and
(S)-(+)-1-amino-2-propanol in 38% yield according to the procedures
similar to those described in Example 1 (iii)
[0923] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
67(2H, d, J=8 8 Hz), 7 35-7 23(5H, m), 6 78(2H, d, J=8 8 Hz),
647-6.42 (1H, m), 5.21-4 94(1H, m), 5 11(1H, dd, J=6 0, 8 4 Hz), 4
03-3 97(1H, m), 3.64-3 56(1H, m), 3 35-3 25(1H, m), 3 16-3 01 (2H,
m 2.89-2.76(3H, m), 2.87(3H, s), 2.58-2.50(1H, m), 2.11-1.90(1H,
m), 1.76-1 55(2H, m), 1 22(3H, d, J=6 6 Hz)
[0924] Fumaric acid salt: amorphous solid.
[0925] MS m/z. 400(M+H).sup.+
[0926] Anal. Calcd for
C.sub.23H.sub.30N.sub.3O.sub.2F.multidot.C.sub.4H.s-
ub.4O.multidot.0 8CH.sub.4O. C, 61 70, H, 6 93, N, 7 76
[0927] Found: C, 61.52; H, 6.59; N, 7 64
EXAMPLE 90
[0928] Preparation of
2-Chloro4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)--
phenyethyl]-N-methylamino}-N'-propylbenzamide
[0929] This was prepared from
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and
2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and
2-chloro4-methylamino-N'-propylbenzamide in 13% yield according to
the procedures similar to those described in Example 1 (i).
[0930] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.75(1H, d, J=8 4 Hz), 7 38-7 20 (5H, m), 6.78-6 70(2H, m),
6.58-6.50 (1H, m), 5.25-4.95(1H, m), 5.04(1H, dd, J=6 2, 8 4 Hz),
3.50-3.37(2H, m), 3.12(1H, dd, J=9.2, 12.8 Hz), 3.03(1H, dd, J=5 9,
12 8 Hz), 2.90-2.75(2H, m), 2.85(3H, s), 2.60-2.50(1H, m),
2.17-1.85 (2H, m), 1 70-1 55(3H, m), 0.99(3H, t, J=7.3 Hz).
[0931] Fumaric acid salt: amorphous solid.
[0932] MS m/z: 418(M+H).sup.+
[0933] Anal. Calcd for
C.sub.23H.sub.29N.sub.3OFCl.multidot.C.sub.4H.sub.4-
O.sub.4.multidot.0.1H.sub.2O: C, 60.52 H, 6.25; N, 7 84.
[0934] Found: C, 60.16; H, 6.61; N, 7.64.
EXAMPLE 91
[0935] Preparation of
4-{N-[2-3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenyleth-
yl]-N-hydroxyamino}-N'-propylbenzamide
[0936] This was prepared from
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and 2-(3
-(S)-fluoropyrrolidin-1-yl)-2 -(R)-phenylethanol and
4-hydroxyamino-N'-propylbenzamide in 56% yield according to the
procedures similar to those described in Example 1 (i).
[0937] HCl salt:.
[0938] mp: 195-200.degree. C.
[0939] .sup.1H NMR (270 MHz, DMSO) .delta. 10 67(1H, br s),
9.35-9.20(1H, m), 8.30-8.20(1H, m), 7.70(2H, d, J=8.4 Hz),
7.50-7.15 (7H, m), 5 70-5 35(2H, m), 4.25-3.30(6H, m),
3.25-3.10(2H, m), 2 70-2.10(2H, m), 1 60-1.40(2H, m), 0.86(3H, t,
J=7.3 Hz)
[0940] IR(KBr): 1600 cm.sup.-1
[0941] MS m/z: 384(M-H).sup.-
[0942] Anal. Calcd for C.sub.12H.sub.28N.sub.3O.sub.2F.multidot.HCl
C, 62 63, H, 6 93, N, 9 96
[0943] Found: C, 62 23; H, 7 10; N, 9 79
EXAMPLE 92
[0944] Preparation of
5-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenyeth-
yl]-N-methylamino}-N'-propylpicolinamide
[0945] This was prepared from
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and
2-(3-(S)-fluoropyrolidin-1-yl)-2-(R)-phenylethanol and
5-methylamino-N'-propylpicolinamide in 26% yield according to the
procedures similar to those described in Example 1 (i)
[0946] .sup.1H NMR (270 MHz, free anine, CDCl.sub.3) .delta. 8
10(1H, d, J=2.9 Hz), 8 01(1H, d, J=8 8 Hz), 7 82-7 74(1H, m), 7
38-7 24 (5H, m), 7 11(1H, dd, J=2 9, 8 8 Hz), 5 23-4 95(1H, m), 5
07(1H, dd, J=5.9, 9 5 Hz), 3 45-3 35(2H, m), 3 18(1H, dd, J=9 5, 12
8 Hz), 3 03(1H, dd, J=5.9, 12.8 Hz), 2.95-2.75(2H, m), 2.93(3H, s),
2.60-2.50(1H, m), 2.18-1.90(2H, m), 1 70-1 55(3H, m), 0.98(3H, t,
J=7 3 Hz).
[0947] Fumanc acid salt: amorphous solid.
[0948] IR(KBr): 1650 cm.sup.-1.
[0949] MS m/z 385(M+H).sup.+
[0950] Anal. Calcd for
C.sub.22H.sub.29N.sub.4OF.multidot.C.sub.4H.sub.4O.-
sub.4.multidot.0 6H.sub.2O C, 61 07, H, 6 74 N, 10 96
[0951] Found: C, 60 87; H, 6.35; N, 10 89
EXAMPLE 93
[0952] Preparation of
4-{N-Methylamino-N-[2-(3-pyrroilin-1-yl)-1-(S)-pheny-
lethyl]-N'-propylbenzamide
[0953] This was prepared from
2-(R)-phenyl-2-(3-pyrrolin-1-yl)ethanol and
4-methylamino-N'-propylbenzamide in 12% yield according to the
procedures similar to those described in Example 1 (i).
[0954] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
65(2H, d, J=9.2 Hz), 7.35-7.24 (5H, m), 6.80(2H, d, J=9.2 Hz), 5.97
(1H, br s), 5 72(2H, s), 5.12(1H, dd, J=7 0, 7 7 Hz), 3 58-3 49(4H,
m), 3.38(2H, dd, J=5 9, 7 3 Hz), 3.25-3.21(2H, m), 2 86(3H, s), 1
61(2H, dd, J=7.3, 14.7 Hz), 0.97(3H, t, J=7.3 Hz)
[0955] IR(neat): 2950, 1650 cm.sup.-1.
[0956] HCl salt: amorphous solid.
[0957] MS m/z: 363(M.sup.+)
[0958] Anal. Calcd for
C.sub.23H.sub.29N.sub.3O.multidot.HCl.multidot.0
1CH.sub.4O.multidot.0.9H.sub.2O: C, 66.16 H, 7.74; N, 10 02.
[0959] Found: C, 66.56; H, 7.64; N, 9.65
EXAMPLE 94
[0960] Preparation of
4-{N-[2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylet-
hyl]-N-methylamino}-N'-propylbenzamide
[0961] This was prepared from
2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and
2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and
4-methylamino-N'-propylbenzamide in 47% yield according to the
procedures similar to those described in Example 1 (i).
[0962] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
67(2H, d, J=8.8 Hz), 7.34-7.24 (5H, m), 6.79(2H, d, J=8.8 Hz), 6.13
(1H, br. s), 5.25-4.95(1H, m), 5.13(1H, dd, J=6 2, 8 4 Hz), 3.41-3
34(2H, m), 3.17-3.05(2H, m), 3.02-2.77(3H, m), 2.82(3H, s),
2.59-2.51(1H, m), 2.09-1.91(2H, m), 1.72-1.54(2H, m), 0 95(3H, t,
J=7 3 Hz)
[0963] HCl salt: amorphous solid.
[0964] MS m/z: 383(M.sup.+)
[0965] Anal Calcd for
C.sub.23H.sub.30N.sub.3OF.multidot.HCl.multidot.0 5H.sub.2O C, 64
40, H, 7 52, N, 9 80.
[0966] Found: C, 64 51; H, 7.74; N, 9 46
EXAMPLE 95
[0967] Preparation of
4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylet-
hyl]-N-methylamino}-N'-propylbenzamide
[0968] This was prepared from
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenyl- ethanol and
2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol and
4-methylamino-N'-propylbenzamide in 28% yield according to the
procedures similar to those described in Example 1 (i).
[0969] .sup.1H NMR (270 MHz, free arrine, CDCl.sub.3) .delta.
7.65(2H, d, J=8.4 Hz), 7 30-7 24 (5H, m), 6 80(2H, d, J=8.4 Hz),
6.00 (1H, br. s), 5 25-4 95(2H, m), 3 43-3 36(2H, m), 3 13-3.07(2H,
m), 3.01-2.89(2H, m), 2.83(3H, s), 2.58-2.55(1H, m), 2.10-2 00(1H,
m), 2.00-1 92(1H, m), 1.73-1 55(3H, m), 0.97(3H, t, J=7 3 Hz)
[0970] HCl salt: amorphous solid.
[0971] MS m/z: 383(M.sup.+)
[0972] Anal. Calcd for
C.sub.23H.sub.30N.sub.3OF.multidot.HCl.multidot.2H.- sub.2O C,
60.58; H, 7 74, N, 9 21
[0973] Found: C, 60.59; H, 7.36; N, 9.23.
EXAMPLE 96
[0974] Preparation of
4-{N-[2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylet-
hyl]-N-methylamino}-N'-propylbenzamide
[0975] This was prepared from
2-(3-(S)-chloropyrroiidin-1-yl)-1-(S)-phenyl- ethanol and
2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol and
4-methylamino-N'-propylbenzamide in 40% yield according to the
procedures similar to those described in Example 1 (i)
[0976] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
68(2H, d, J=8 8 Hz), 7 33-7 27 (5H, m), 6 78(2H, d, J=8 8 Hz), 6.23
(1H, br. s), 5 08(1H, dd, J=7 3, 7 7 Hz), 4 30-4 25(1H, m), 3.40-3
33(2H, m), 3 13-3.08(3H, m), 2.84(3H, s), 2.81-2.65(3H, m), 2.36-2
22(1H, m), 2.02-1 95(1H, m), 1 63-1.53(2H, m), 0 94(3H, t, J=7.3
Hz).
[0977] HCl salt amorphous solid.
[0978] MS m/z: 399(M.sup.+)
[0979] Anal. Calcd for
C.sub.23H.sub.30N.sub.3OCl.multidot.HCl.multidot.2.- 5H.sub.2O: C,
57.38; H, 7.54, N, 8.73.
[0980] Found: C, 57.10; H, 7.42; N, 8.48
EXAMPLE 97
[0981] Preparation of
4-{N-[2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylet-
hyl]-N-methylamino}-N'-(2-(S)-hydroxypropyl)benzamide
[0982] This was prepared from
2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and
2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol and
4-methylamino-N'-(2-(S)-hydroxypropyl)benzamide in 45% yield
according to the procedures similar to those described in Example 1
(i).
[0983] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta.
7.68(2H, d, J=9.2 Hz), 7 35-7.28 (1H, m), 6 79(2H, d, J=8 8 Hz),
6.52 (1H, br. s), 5 10(1H, t, J=7 3 Hz), 4 32-4.27(1H, m), 4 02-3
97(1H, m), 3.64-3.56(1H, m), 3.35-3 24(1H, m), 3.14-3.10(3H, m),
2.86(3H, s) 2 82-2.76(2H, m), 2.74-2.69(1H, m), 2.38-2.27(1H, m),
2.05-1.80(2H, m), 1.22(3H, d, J-=6.2 Hz)
[0984] HCl salt: amorphous solid.
[0985] MS m/z: 415(M.sup.+)
EXAMPLE 98
[0986] Preparation of
4-{N-[2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylet- hyl]-N-
methylamino}-N'-(2-(R)-hydroxypropyl)benzamide
[0987] This was prepared from
2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenyl- ethanol and 2-(3
-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol and
4-methylamino-N'-(2-(R )-hydroxypropyl)benzamide in 44% yield
according to the procedures similar to those described in Example 1
(i)
[0988] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
58(2H, d, J=9 2 Hz), 7 35-7 23 (5H, m 6 79(2H, d, J=9 2 Hz), 6 53
(1H, br s), 5 11(1H, t, J=7 3 Hz), 4 33-4 27(1H, m), 4 03-3 98(1H,
m), 3 64-3 56(1H, m), 3 35-3 25(1H, m), 3 16-311(1H, m), 3 12(2H,
d, J=7 3 Hz), 2 85(3H, s), 2 83-2 71(3H, m), 2 36-2.27(1H, m), 2
04-1 98(1H, m), 1.22(3H, d, J=6.2 Hz)
[0989] HCl salt: amorphous solid.
[0990] MS m/z: 416(M+H).sup.+
[0991] Anal. Calcd for
C.sub.23H.sub.30N.sub.3O.sub.3Cl.multidot.HCl.multi- dot.H.sub.2O
C, 58 72 H, 7.07; N, 8 93
[0992] Found: C, 58.56; H, 7 00; N, 8.76
EXAMPLE 99
[0993] Preparation of
4-{N-[2-(3-Oxopyrrolidin-1-yl)-1-(S)-phenylethyl]-N--
methylamino}-N'-propylbenzamide
[0994] To a stirred solution of oxaiylchlonide(0 26 ml, 3 0 mmol)
in CH.sub.2Cl.sub.2(15 ml) was added a solution of DMSO(0 29 ml, 4
0 mmol) in CH.sub.2Cl.sub.2(1 ml) at -78 C. The reaction mixture
was stirred for 10 min and a solution of
4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phe-
nylethyl]-N-methylamino}-N'-propylbenzamide(5 73 mg, 15 mmol) in
CH.sub.2Cl.sub.2(5 ml) was added and stirring was continued for an
additional 15 min at -78.degree. C. 60 min at -45.degree. C.
Triethylamine(1 6ml, 11 0 mmol) was added and then the reaction
mixture was allowed to warm to room temperature Saturated
NH.sub.4Cl aqueous solution was added and extracted wizh AcOEt The
extract was washed with water and brine, dried(Na.sub.2SO.sub.4),
and concentrated to give brown oil, which was purified by column
chromatography (silica gel. 70 g. CH.sub.2Cl.sub.2/MeOH. 50/1-40/1)
to give 195 mg(34% ) of pale yellow oil
[0995] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
66(2H, d, J=9.2 Hz), 7 36-7 25 (5H, m), 6 80(2H, d, J=9 2 Hz), 6 01
(1H, br s), 5 17(1H, t, J=7 3 Hz), 3 43-3 36(2H, m), 3 17-3.13(2H,
m), 3.07-2.92(4H, m), 2.85(3H, s), 2.35(2H, t, J=7.0 Hz), 1.6-1
53(2H, m), 0.97(3H, t, J=7 7 Hz).
[0996] HCl salt. amorphous solid.
[0997] MS m/z: 379(M.sup.+)
EXAMPLE 100
[0998] Preparation of
4-{N-[2-(3-(S)-Hydroxvpyrrolidin-1-yl)-1-(S)-phenyle-
thyl]-N-methylamino}-N'-propylbenzamide
[0999] 4- {N-[2-(3
-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]--
N-methylamino}-N'-propylbenzamide was prepared from
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and
2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and
4-methylamino-N'-propylbenzamide according to the procedures
similar to those described in Example 1 (i). Title compound was
prepared from
4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyl-
amino}-N'-propylbenzamide in 65% over all yield according to the
procedures similar to those described in Example 2. The title
compound was the same as one obtained in Example 2.
[1000] .sup.1H NMR (270 MHz, free amine, CDCl.sub.3) .delta. 7
66(2H, d, J=8.8 Hz), 7.40-7.20(5H, m), 6 80(2H d, J=9.2 Hz),
6.05-5.90(1H, m), 5.14(1H, dd, J=5.9, 9.2 Hz), 4.28-4 16(1H, m),
3.46-3.32(2H, m), 3.12(1H, dd, J=9 2, 12.9 Hz), 3 03(1H, dd, J=5.9,
12.8 Hz), 2 95-2.80(1H, m), 2.83(3H, s), 2.72(1H, d, J=9.5 Hz),
2.56(1H, dd, J=4.8, 9.9 Hz), 2 33(1H, ddd, J=6.2, 8.8, 8.8 Hz),
2.18-2.00(1H, m), 1.89(1H, br. s), 1.70-1.50(3H, m), 0 97(3H, t,
J=7.3 Hz)
[1001] HCl salt: amorphous solid.
[1002] MS m/z: 382(M+H).sup.+
[1003] Anal. Calcd for
C.sub.23H.sub.31O.sub.2.multidot.HCl.multidot.1
5H.sub.2O.multidot.CH.sub.4O C, 60.43; H, 8.24, N, 8 81
[1004] Found: C, 60.23; H, 8.62; N, 9.03.
[1005] The chemical structures of the compounds prepared in
Examples 1 to 100 are summarized in the following tables. In the
tables, H-- represents hydrogen, Me--, Et--, Pr--, Bu--, Pe-- and
Am-- represent methyl, ethyl, propyl, buzyl, pertyl and amyl
respectively; F-- and Cl-- represent fluorine and chlorine
respectively. All-- and Prp-- represent allyl and propargyl
respectively; MeO-- and EtO-- represent methoxy and ethoxy
respectively; HO-- represents hydroxy; Car-- represents carboxy;
Ph--, Py--, Th-- and Bn-- represent phenyl, pyridyl, thienyl and
benzyl respectively; MOM--, t--Boc--, 2-THP-- and TBDMS-- represent
methoxymethyl, t-butoxycarbonyl, tetrahydropyran-2-yl and
t-butyldimethylsilyl respectively; tri--F--Pr--, penta-F--Pr-- and
2-HO--Pr-- represent 3,3,3-trifluoropropyl,
2,2,3,3,3-pentafluoropropyl and 2-hydroxypropyl respectively,
O=represents oxo; and cyc represents cyclic.
1TABLE 1 (I) 12 Ex. -# A Ar.sup.1 Ar.sup.2 R.sup.1 R.sup.2 R.sup.3
1 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- Pr-- H-- 2 (S)--HO--
(S)--Ph-- 1,4-Ph-- Me-- Pr-- H-- 3 (S)--MOM-O-- (S)--Ph-- 1,4-Ph--
Me-- Me-- H-- 4 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- Me-- H-- 5
(S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- Et-- H-- 6 (S)--HO-- (S)--Ph--
1,4-Ph-- Me-- Et-- H-- 7 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- Bu--
H-- 8 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- Bu-- H-- 9 (S)-2-THP-O--
(S)--Ph-- 1,4-Ph-- Me-- Pe-- H-- 10 (S)--HO-- (S)--Ph-- 1,4-Ph--
Me-- Pe-- H-- 11 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- i-Pr-- H-- 12
(S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- i-Pr-- H-- 13 (S)--MOM-O--
(S)--Ph-- 1,4-Ph-- Me-- Ph-- H-- 14 (S)--HO-- (S)--Ph-- 1,4-Ph--
Me-- Ph-- H-- 15 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- 2-Cl--Bn--
H-- 16 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- 2-Cl--Bn-- H-- 17
(S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- Me-- Me-- 18 (S)--HO--
(S)--Ph-- 1,4-Ph-- Me-- Me-- Me-- 19 (S)-2-THP-O-- (S)--Ph--
1,4-Ph-- Me-- Pr-- Me-- 20 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- Pr--
Me-- 21 (S)--MOM-O-- (S)--Ph-- 1,3-Ph-- Me-- Pr-- H-- 22 (S)--HO--
(S)--Ph-- 1,3-Ph-- Me-- Pr-- H-- 33 (S)--MOM-O-- (S)-3-MOM-O--Ph--
1,4-Ph-- Me-- Pr-- H-- 34 (S)--HO-- (S)-3-HO--Ph-- 1,4-Ph-- Me--
Pr-- H-- 35 (S)--HO-- (S)-3-MeO--Ph-- 1,4-Ph-- Me-- Pr-- H-- 36
(S)--HO-- (S)-3-t-Boc-MeO-- 1,4-Ph-- Me-- Pr-- H-- 37 (S)--HO--
(S)-3-Car-MeO--Ph-- 1,4-Ph-- Me-- Pr-- H-- 38 H-- (S)--Ph--
1,4-Ph-- Me-- Pr-- H-- 40 (S)--MOM-O-- (S)--Ph-- 2,5-Th-- Me-- Pr--
H-- 41 (S)--HO-- (S)--Ph-- 2,5-Th-- Me-- Pr-- H-- 42 (S)--MOM-O--
(S)--Ph-- 1,4-Ph-- H-- Pr-- H-- 43 (S)--HO-- (S)--Ph-- 1,4-Ph-- H--
Pr-- H-- 44 (S)--MOM-O-- (S)-3-Cl--Ph-- 1,4-Ph-- Me-- Pr-- H-- 45
(S)--HO-- (S)-3-Cl--Ph-- 1,4-Ph-- Me-- Pr-- H-- 46 (S)--F--
(S)--Ph-- 1,4-Ph-- Me-- Pr-- H-- 47 (S)--MOM-O-- (R)--Ph-- 1,4-Ph--
Me-- Pr-- H-- 48 (S)--HO-- (R)--Ph-- 1,4-Ph-- Me-- Pr-- H-- 51
(S)--TBDMS-O-- (S)--Ph-- 1,4-Ph-- Me-- EtO-- H-- 52 (S)--HO--
(S)--Ph-- 1,4-Ph-- Me-- EtO-- H-- 55 (S)--MOM-O-- (S)--Ph--
1,4-Ph-- Me-- 3-HO--Pr-- H-- 56 (S)--HO-- (S)--Ph 1,4-Ph-- Me--
3-HO--Pr-- H-- 57 (S)--MOM-O-- (S)--Ph 1,4-Ph-- Me--
2-(R)--HO--Pr-- H-- 58 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me--
2-(R)--HO--Pr-- H-- 59 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- i-Bu--
H-- 60 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- i-Bu-- H-- 61 (S)--MOM-O--
(S)--Ph-- 1,4-Ph-- Me-- All- H-- 62 (S)--HO-- (S)--Ph-- 1,4-Ph--
Me-- All- H-- 63 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- cyc-Pr-- H--
64 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- cyc-Pr-- H-- 65 (S)--MOM-O--
(S)--Ph-- 1,4-Ph-- Me-- (S)-sec-Bu-- H-- 66 (S)--HO-- (S)--Ph--
1,4-Ph-- Me-- (S)-sec-Bu-- H-- 67 (S)--MOM-O-- (S)--Ph-- 1,4-Ph--
Me-- (R)-sec-Bu-- H-- 68 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me--
(R)-sec-Bu-- H-- 69 (S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- Prp- H--
70 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- Prp- H-- 71 (S)--MOM-O--
(S)--Ph-- 1,4-Ph-- Me-- tri-F--Pr-- H-- 72 (S)--HO-- (S)--Ph--
1,4-Ph-- Me-- tri-F--Pr-- H-- 73 (S)--MOM-O-- (S)--Ph 1,4-Ph Me
2-(S)--HO--Pr H 74 (S)--OH (S)--Ph-- 1,4-Ph-- Me-- 2-(S)--HO--Pr--
H-- 75 (S)--MOM-O-- (R)-3-MOM-O--Ph-- 1,4-Ph-- Me-- Pr-- H-- 76
(S)--HO-- (R)-3-t-Boc-MeO--Ph-- 1,4-Ph-- Me-- Pr-- H-- 77 (S)--HO--
(R)-3-Car-MeO--Ph-- 1,4-Ph-- Me-- Pr-- H-- 80 (S)--MOM-O--
(S)--Ph-- 1,4-Ph-- Me-- penta-F--Pr-- H-- 81 (S)--HO-- (S)--Ph--
1,4-Ph-- Me-- penta-F--Pr-- H-- 82 (S)--MOM-O-- (S)--Ph-- 1,4-Ph--
Me-- t-Am-- H-- 83 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- t-Am-- H-- 84
(S)--MOM-O-- (S)--Ph-- 1,4-Ph-- Me-- t-Bu-- H-- 85 (S)--HO--
(S)--Ph-- 1,4-Ph-- Me-- t-Bu-- H-- 87 (S)--MOM-O-- (S)--Ph--
1,4-Ph-- HO-- Pr-- H-- 88 (S)--HO-- (S)--Ph-- 1,4-Ph-- HO-- Pr--
H-- 89 (S)--F-- (S)--Ph-- 1,4-Ph-- Me-- 2-(S)--HO--Pr-- H-- 91
(S)--F-- (S)--Ph-- 1,4-Ph-- HO-- Pr-- H-- 94 (R)--F-- (S)--Ph--
1,4-Ph-- Me-- Pr-- H-- 95 (S)--F-- (R)--Ph-- 1,4-Ph-- Me-- Pr-- H--
96 (S)--Cl-- (S)--Ph-- 1,4-Ph-- Me-- Pr-- H-- 97 (S)--Cl--
(S)--Ph-- 1,4-Ph-- Me-- 2-(S)--HO--Pr-- H-- 98 (S)--Cl-- (S)--Ph--
1,4-Ph-- Me-- 2-(R)--HO--Pr-- H-- 99 O.dbd. (S)--Ph-- 1,4-Ph-- Me--
Pr-- H-- 100 (S)--HO-- (S)--Ph-- 1,4-Ph-- Me-- Pr-- H--
[1006]
2TABLE 2 Example 23 13 Example 24 14 Example 25 15 Example 26 16
Example 27 17 Example 28 18 Example 29 19 Example 30 20 Example 31
21 Example 32 22 Example 39 23 Example 49 24 Example 50 25 Example
53 26 Example 54 27 Example 78 28 Example 79 29 Example 86 30
Example 90 31 Example 92 32 Example 93 33
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