U.S. patent application number 11/562149 was filed with the patent office on 2007-05-31 for piperazine derivatives.
This patent application is currently assigned to Fujisawa Pharmaceutical Co. Ltd.. Invention is credited to Hidenori Azami, Yoshiteru Eikyu, Junya Ishida, Natsuko Kayakiri, Nobukiyo Konishi, Masataka Morita, Kazuo Nakai, Shinji Shigenaga, Kazuhiko Take.
Application Number | 20070123532 11/562149 |
Document ID | / |
Family ID | 25645943 |
Filed Date | 2007-05-31 |
United States Patent
Application |
20070123532 |
Kind Code |
A1 |
Take; Kazuhiko ; et
al. |
May 31, 2007 |
PIPERAZINE DERIVATIVES
Abstract
This invention relates to piperazine derivatives of the formula:
##STR1## wherein each symbol is as defined in the description, and
its pharmaceutically acceptable salt, to processes for preparation
thereof, to pharmaceutical composition comprising the same, and to
a use of the same for treating or preventing Tachykinin-mediated
diseases in human being or animals.
Inventors: |
Take; Kazuhiko; (Osaka,
JP) ; Konishi; Nobukiyo; (Kyoto, JP) ;
Shigenaga; Shinji; (Hyogo, JP) ; Kayakiri;
Natsuko; (Osaka, JP) ; Azami; Hidenori;
(Hyogo, JP) ; Eikyu; Yoshiteru; (Nara, JP)
; Nakai; Kazuo; (Hyogo, JP) ; Ishida; Junya;
(Hyogo, JP) ; Morita; Masataka; (Hyogo,
JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Fujisawa Pharmaceutical Co.
Ltd.
Osaka
JP
541-8514
|
Family ID: |
25645943 |
Appl. No.: |
11/562149 |
Filed: |
November 21, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10968473 |
Oct 20, 2004 |
7166598 |
|
|
11562149 |
Nov 21, 2006 |
|
|
|
09857869 |
Jun 12, 2001 |
|
|
|
PCT/JP99/06943 |
Dec 10, 1999 |
|
|
|
10968473 |
Oct 20, 2004 |
|
|
|
Current U.S.
Class: |
514/235.5 ;
514/253.01; 514/254.01; 514/255.03; 544/120; 544/360; 544/373;
544/392 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 11/06 20180101; A61P 19/02 20180101; C07D 417/06 20130101;
A61P 11/04 20180101; A61P 25/04 20180101; C07D 401/06 20130101;
A61P 37/00 20180101; C07D 471/04 20130101; A61P 29/00 20180101;
A61P 11/10 20180101; A61P 1/02 20180101; A61P 43/00 20180101; C07D
498/08 20130101; C07D 491/08 20130101; A61P 3/00 20180101; C07D
401/14 20130101; A61P 37/08 20180101; C07D 241/04 20130101; A61P
11/14 20180101; A61P 27/00 20180101; A61P 17/00 20180101; C07D
403/06 20130101; A61P 11/00 20180101; C07D 495/04 20130101; A61P
25/06 20180101; C07D 498/04 20130101; C07D 413/14 20130101; C07D
413/06 20130101; A61P 11/02 20180101; C07D 403/14 20130101; C07F
7/1804 20130101 |
Class at
Publication: |
514/235.5 ;
514/253.01; 514/254.01; 514/255.03; 544/120; 544/360; 544/373;
544/392 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/496 20060101 A61K031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 14, 1998 |
AU |
PP7706 |
Oct 21, 1999 |
AU |
PQ3568 |
Claims
1. A compound of the formula ##STR7## wherein Y is bond or lower
alkylene, R.sup.1 is aryl which is substituted with 1 to 3 same or
different substituent(s) selected from the group consisting of
halogen, lower alkyl, lower alkoxy, mono(or di or
tri)halo(lower)alkyl, nitro, amino, lower alkylamino,
di(lower)alkylamino, lower alkylthio, lower alkylsulfonyl,
cyclo(lower)alkylsulfonyl, aminosulfonyl, lower alkylaminosulfonyl,
di(lower)alkylaminosulfonyl, pyrrolidinylsulfonyl,
morpholinylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, pyrrolyl
and pyridyl; R.sup.2 is aryl which is substituted with 1 to 3 same
or different substituent(s) selected from the group consisting of
lower alkyl, mono(or di or tri)halo(lower)alkyl, mono(or di or
tri)halo(lower)alkylsulfonyloxy, halogen, lower alkylenedioxy,
lower alkoxy, lower alkoxycarbonyl, lower
alkoxy(lower)alkoxy(lower)alkoxy, hydroxy,
diphenyl(lower)alkylsilyloxy, tri(lower)alkylsilyloxy,
hydroxy(lower)alkyl, cyano, amino, [mono(or di or
tri)halo(lower)alkylcarbonyl]amino, lower alkylamino, N-(lower
alkyl)-[mono(or di or tri)halo(lower)alkylcarbonyl]amino,
pyrrolidinyl and morpholinyl which may be substituted with lower
alkoxy(lower)alkyl or lower alkyl; R.sup.3 is hydrogen or lower
alkyl; and R.sup.4 is (3-pyridyl)methyl; (3-pyridyl)ethyl;
3-(3-pyridyl)propyl; 3-(3-pyridyl)propenyl; 3-(3-pyridyl)propynyl;
thiazolyl(lower)alkyl, 1,2,4-thiadiazolyl(lower)alkyl or
1,2,4-oxadiazolyl(lower)alkyl, each of which is substituted with
halogen, amino, lower alkylamino or di(lower)alkylamino;
pyrazolylmethyl which may be substituted with triphenyl(lower)alkyl
or hydroxy(lower)alkyl; pyrazolyl(lower)alkyl which is substituted
with lower alkyl, lower alkoxy(lower)alkylmorpholinyl(lower)alkyl
or lower alkoxy(lower)alkylmorpholinylcarbonyl-(lower)alkyl;
pyrrolidinyl(lower)alkyl which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisiting of
hydroxy, hydroxy(lower)alkyl, lower alkoxy and lower
alkoxy(lower)alkyl; piperidylmethyl; piperidyl(lower)alkyl which is
substituted with 1 or 2 same or different substituent(s) selected
from the group consisting of halogen, lower alkyl and lower
alkoxy(lower)alkyl;
[2,6-di[hydroxy(lower)alkyl]piperidyl](lower)alkyl;
(2,6-dimethylmorpholino)(lower)alkyl;
(2,2-dimethylmorpholino)(lower)alkyl;
(3,3-dimethylmorpholino)(lower)alkyl;
(cis-3,5-dimethylmorpholino)(lower)alkyl;
((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl;
((3S,5R)-3,5-dimethylmorpholino)(lower)alkyl;
(2-methoxymethylmorpholino)(lower)alkyl;
(3-methoxymethylmorpholino)(lower)alkyl;
(2-methoxymethyl-5-methylmorpholino)(lower)alkyl;
(2-methoxymethyl-5,5-dimethylmorpholino)(lower)-alkyl;
(3,5-dimethoxymethylmorpholino)(lower)alkyl;
(2,2-dimethoxymethylmorpholino)(lower)alkyl;
(2,3-dimethoxymethylmorpholino)(lower)alkyl;
(2,6-dimethoxymethylmorpholino)(lower)alkyl;
(2-methoxymethylmorpholino)(lower)alkenyl;
(3,3-dimethylmorpholino)(lower)alkynyl;
(2-methoxymethylmorpholino)(lower)alkynyl;
(2-methoxymethyl-5-methylmorpholino)(lower)alkynyl;
quinoly(lower)alkyl; [1H-pyrrolo[3,2-b]pyridinyl](lower)alkyl;
[4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl](lower)-alkyl;
[3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazinyl](lower)-alkyl;
(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)(lower)-alkyl; or lower
alkyl which is substituted with a saturated heterocyclic group of
the formula: ##STR8## (wherein r, s and t are each integer of 1 to
2, and q is integer of 0 to 2) which may be substituted with one or
two lower alkyl, provided that when R.sup.4 is 3-(3-pyridyl)propyl;
3-(3-pyridyl)propenyl; pyrazolylmethyl which may be substituted
with hydroxy(lower)alkyl; (2-methoxymethylmorpholino)(lower)alkyl;
(3-methoxymethylmorpholino)(lower)alkyl; or
(2-methoxymethylmorpholino)(lower)alkynyl, then R.sup.2 is not
di(lower)alkylphenyl, and a salt thereof.
2. The compound of claim 1, in which Y is lower alkylene; R.sup.1
is phenyl which is substituted with 1 or 2 same or different
substituent(s) selected from the group consisting of halogen, lower
alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl, nitro,
amino, lower alkylamino, di(lower)alkylamino, lower alkylthio,
lower alkylsulfonyl, cyclo(lower)alkylsulfonyl, aminosulfonyl,
lower alkylaminosulfonyl, di(lower)alkylaminosulfonyl,
pyrrolidinylsulfonyl, morpholinylsulfonyl, pyrrolylsulfonyl,
pyridylsulfonyl, pyrrolyl and pyridyl; R.sup.2 is phenyl which is
substituted with 1 or 2 same or different substituent(s) selected
from the group consisting of lower alkyl, mono(or di or
tri)halo(lower)alkyl, mono(or di or
tri)halo(lower)alkylsulfonyloxy, halogen, lower alkylenedioxy,
lower alkoxy, lower alkoxycarbonyl, lower
alkoxy(lower)alkoxy(lower)alkoxy, hydroxy,
diphenyl(lower)alkylsilyloxy, tri(lower)alkylsilyloxy,
hydroxy(lower)alkyl, cyano, amino, [mono(or di or
tri)halo(lower)alkylcarbonyl]amino, lower alkylamino, N-(lower
alkyl)-[mono(or di or tri)halo(lower)alkylcarbonyl]amino,
pyrrolidinyl and morpholinyl which may be substituted with lower
alkoxy(lower)alkyl or lower alkyl; R.sup.3 is hydrogen; and R.sup.4
is 3-(3-pyridyl)propyl; 3-(3-pyridyl)propynyl;
(2,6-dimethylmorpholino)(lower)alkyl;
(3,3-dimethylmorpholino)(lower)alkyl;
(cis-3,5-dimethylmorpholino)(lower)alkyl;
((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl;
((3S,5R)-3,5-dimethylmorpholino)(lower)alkyl;
(2-methoxymethylmorpholino)(lower)alkyl;
(3-methoxymethylmorpholino)(lower)alkyl;
(2-methoxymethyl-5-methylmorpholino)(lower)alkyl;
(2-methoxymethyl-5,5-dimethylmorpholino)(lower)-alkyl;
(3,5-dimethoxymethylmorpholino)(lower)alkyl;
(2,3-dimethoxymethylmorpholino)(lower)alkyl; or
(2-methoxymethylmorpholino)(lower)alkenyl, provided that when
R.sup.4 is 3-(3-pyridyl)propyl;
(2-methoxymethylmorpholino)(lower)alkyl; or
(3-methoxymethylmorpholino)(lower)alkyl, then R.sup.2 is not
di(lower)alkylphenyl.
3. The compound of claim 2, in which Y is C.sub.1-C.sub.4 alkylene;
R.sup.1 is bis[mono(or di or tri)halo(C.sub.1-C.sub.4)alkyl]phenyl;
R.sup.2 is phenyl which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisting of
C.sub.1-C.sub.4 alkyl, mono(or di or
tri)halo(C.sub.1-C.sub.4)alkyl, halogen, C.sub.1-C.sub.4 alkoxy and
hydroxy; R.sup.3 is hydrogen; and R.sup.4 is 3-(3-pyridyl)propyl;
3-(3-pyridyl)propynyl;
(2,6-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl;
(2-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl;
(3-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl; or
(2-methoxymethyl-5-methylmorpholino)(C.sub.1-C.sub.4)alkyl,
provided that when R.sup.4 is 3-(3-pyridyl)propyl;
(2-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl; or
(3-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, then R.sup.2 is
not di(C.sub.1-C.sub.4)alkylphenyl.
4. A compound of claim 3, which is selected from the group
consisting of (1)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[2-
-[(3R)-3-(methoxymethyl)morpholino]-ethyl]piperazine, (2)
1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino)ethy-
l]-2-(3-hydroxy-4-methylbenzyl)piperazine, (3)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[2-[(2-
S,5S)-2-methoxymethyl-5-methylmorpholino]ethyl]piperazine, (4)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3--
pyridyl)-2-propynyl]piperazine, (5)
1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholin-
o]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine, (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morp-
holino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine, (7)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3--
pyridyl)propyl]piperazine, (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine, (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine, and (10)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]-4--
[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine, or a
pharmaceutically acceptable salt thereof.
5. A process for the preparation of the compound of claim 1 or a
salt thereof, which comprises, (1) reacting a compound of the
formula (II): ##STR9## wherein R.sup.1, R.sup.2, R.sup.3 and Y are
each as defined in claim 1, or a salt thereof, with a compound of
the formula (III): W.sub.1--R.sup.4 (III) wherein R.sup.4 is as
defined in claim 1 and W.sub.1 is a leaving group, or a salt
thereof to give a compound of the formula (I): ##STR10## wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Y are each as defined in
claim 1, or a salt thereof, or (2) subjecting a compound of the
formula (Ia): ##STR11## wherein R.sup.1, R.sup.2, R.sup.3 and Y are
each as defined above, R.sup.5 is 3-pyridyl, and Z.sub.1 is lower
alkynylene, or a salt thereof to a reduction reaction to give a
compound of the formula (Ib): ##STR12## wherein R.sup.1, R.sup.2,
R.sup.3, Y and R.sup.5 are each as defined above, and X.sub.1 is
lower alkylene, or a salt thereof.
6. A pharmaceutical composition which comprises, as an active
ingredient, a compound of claim 1 or a pharmaceutically acceptable
salt thereof in admixture with pharmaceutically acceptable
carriers.
7. A compound of claim 1 for use as a medicament.
8. A method for treating or preventing Tachykinin-mediated diseases
which comprises administering an effective amount of a compound of
claim 1 or a pharmaceutically acceptable salt thereof to human
being or animals.
9. A compound of claim 1 for use as Tachykinin antagonist.
10. Use of a compound of claim 1 for manufacture of a medicament
for treating or preventing Tachykinin-mediated diseases.
Description
TECHNICAL FIELD
[0001] The present invention relates to new piperazine derivatives
and a salt thereof.
[0002] More particularly, it relates to new piperazine derivatives
and a salt thereof which have pharmacological activities such as
Tachykinin antagonism, especially Substance P antagonism,
Neurokinin A antagonism, Neurokinin B antagonism, and the like, to
a process for preparation thereof, to a pharmaceutical composition
comprising the same, and to a use of the same as a medicament.
[0003] Accordingly, one object of the present invention is to
provide new and useful piperazine derivatives and a salt thereof
which have pharmacological activities such as Tachykinin
antagonism, especially Substance P antagonism, Neurokinin A
antagonism, Neurokinin B antagonism, and the like.
[0004] Another object of the present invention is to provide a
process for the preparation of said piperazine derivatives and a
salt thereof.
[0005] A further object of the present invention is to provide a
pharmaceutical composition comprising, as an active ingredient,
said piperazine derivatives and a pharmaceutically acceptable salt
thereof.
[0006] Still further object of the present invention is to provide
a use of said piperazine derivatives or a pharmaceutically
acceptable salt thereof as Tachykinin antagonist, especially
Substance P antagonist, Neurokinin A antagonist or Neurokinin B
antagonist, useful for treating or preventing Tachykinin-mediated
diseases, for example, respiratory diseases such as asthma,
bronchitis, rhinitis, couph, expectoration, and the like;
ophthalmic diseases such as conjunctivitis, vernal conjunctivitis,
and the like; cutaneous diseases such as contact dermatitis, atopic
dermatitis, urticaria, and other eczematoid dermatitis, and the
like; inflammatory diseases such as rheumatoid arthritis,
osteoarthritis, and the like; pains or aches (e.g., migraine,
headache, toothache, cancerous pain, back pain, etc.); and the like
in human being or animals.
BACKGROUND ART
[0007] Some piperazine derivatives having pharmaceutical activities
such as Tachykinin antagonism have been known as described in WO
97/22597 A1 and WO 98/57954 A1.
DISCLOSURE OF INVENTION
[0008] The object compound of the present invention can be
represented by the following general formula (I): ##STR2## wherein
[0009] Y is bond or lower alkylene, [0010] R.sup.1 is aryl which is
substituted with 1 to 3 same or different substituent(s) selected
from the group consisting of halogen, lower alkyl, lower alkoxy,
mono(or di or tri)halo(lower)alkyl, nitro, amino, lower alkylamino,
di(lower)alkylamino, lower alkylthio, lower alkylsulfonyl,
cyclo(lower)alkylsulfonyl, aminosulfonyl, lower alkylaminosulfonyl,
di(lower)alkylaminosulfonyl, pyrrolidinylsulfonyl,
morpholinylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, pyrrolyl
and pyridyl; [0011] R.sup.2 is aryl which is substituted with 1 to
3 same or different substituent(s) selected from the group
consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl,
mono(or di or tri)halo(lower)alkylsulfonyloxy, halogen, lower
alkylenedioxy, lower alkoxy, lower alkoxycarbonyl, lower
alkoxy(lower)alkoxy(lower)alkoxy, hydroxy,
diphenyl(lower)alkylsilyloxy, tri(lower)alkylsilyloxy,
hydroxy(lower)alkyl, cyano, amino, [mono(or di or
tri)halo(lower)alkylcarbonyl]amino, lower alkylamino, N-(lower
alkyl)-[mono(or di or tri)halo(lower)alkylcarbonyl]amino,
pyrrolidinyl and morpholinyl which may be substituted with lower
alkoxy(lower)alkyl or lower alkyl; [0012] R.sup.3 is hydrogen or
lower alkyl; and [0013] R.sup.4 is (3-pyridyl)methyl; [0014]
(3-pyridyl)ethyl; [0015] 3-(3-pyridyl)propyl; [0016]
3-(3-pyridyl)propenyl; [0017] 3-(3-pyridyl)propynyl; [0018]
thiazolyl(lower)alkyl, 1,2,4-thiadiazolyl(lower)alkyl or
1,2,4-oxadiazolyl(lower)alkyl, each of which is substituted with
halogen, amino, lower alkylamino or di(lower)alkylamino; [0019]
pyrazolylmethyl which may be substituted with triphenyl(lower)alkyl
or hydroxy(lower)alkyl; [0020] pyrazolyl(lower)alkyl which is
substituted with lower alkyl, lower
alkoxy(lower)alkylmorpholinyl(lower)alkyl or lower
alkoxy(lower)alkylmorpholinylcarbonyl(lower)-alkyl; [0021]
pyrrolidinyl(lower)alkyl which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisiting of
hydroxy, hydroxy(lower)alkyl, lower alkoxy and lower
alkoxy(lower)alkyl; [0022] piperidylmethyl; [0023]
piperidyl(lower)alkyl which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisting of
halogen, lower alkyl and lower alkoxy-(lower)alkyl; [0024]
[2,6-di[hydroxy(lower)alkyl]piperidyl](lower)alkyl; [0025]
(2,6-dimethylmorpholino)(lower)alkyl; [0026]
(2,2-dimethylmorpholino)(lower)alkyl; [0027]
(3,3-dimethylmorpholino)(lower)alkyl; [0028]
(cis-3,5-dimethylmorpholino)(lower)alkyl; [0029]
((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl; [0030]
((3S,5R)-3,5-dimethylmorpholino)(lower)alkyl; [0031]
(2-methoxymethylmorpholino)(lower)alkyl; [0032]
(3-methoxymethylmorpholino)(lower)alkyl; [0033]
(2-methoxymethyl-5-methylmorpholino)(lower)alkyl; [0034]
(2-methoxymethyl-5,5-dimethylmorpholino)(lower)alkyl; [0035]
(3,5-dimethoxymethylmorpholino)(lower)alkyl; [0036]
(2,2-dimethoxymethylmorpholino)(lower)alkyl; [0037]
(2,3-dimethoxymethylmorpholino)(lower)alkyl; [0038]
(2,6-dimethoxymethylmorpholino)(lower)alkyl; [0039]
(2-methoxymethylmorpholino)(lower)alkenyl; [0040]
(3,3-dimethylmorpholino)(lower)alkynyl; [0041]
(2-methoxymethylmorpholino)(lower)alkynyl; [0042]
(2-methoxymethyl-5-methylmorpholino)(lower)alkynyl; [0043]
quinoly(lower)alkyl; [0044]
[1H-pyrrolo[3,2-b]pyridinyl](lower)alkyl; [0045]
[4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl](lower)alkyl; [0046]
[3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazinyl](lower)alkyl; [0047]
(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)(lower)-alkyl; or [0048]
lower alkyl which is substituted with a saturated heterocyclic
group of the formula: ##STR3## [0049] (wherein r, s and t are each
integer of 1 to 2, and q is integer of 0 to 2) which may be
substituted with one or two lower alkyl, provided that when [0050]
R.sup.4 is 3-(3-pyridyl)propyl [0051] 3-(3-pyridyl)propenyl; [0052]
pyrazolylmethyl which may be substituted with hydroxy(lower)alkyl;
[0053] (2-methoxymethylmorpholino)(lower)alkyl; [0054]
(3-methoxymethylmorpholino)(lower)alkyl; or [0055]
(2-methoxymethylmorpholino)(lower)alkynyl, then [0056] R.sup.2 is
not di(lower)alkylphenyl.
[0057] It is to be noted that the object compound (I) may include
one or more stereoisomers due to asymmetric carbon atom(s) and
double bond, and all of such isomers and a mixture thereof are
included within the scope of the present invention.
[0058] It is further to be noted that isomerization or
rearrangement of the object compound (I) may occur due to the
effect of the light, acid, base or the like, and the compound
obtained as the result of said isomerization or rearrangement is
also included within the scope of the present invention.
[0059] It is also to be noted that the solvating form of the
compound (I) (e.g. hydrate, etc.) and any form of the crystal of
the compound (I) are included within the scope of the present
invention.
[0060] According to the present invention, the object compound (I)
or a salt thereof can be prepared by processes which are
illustrated in the following schemes. Process 1 ##STR4## Process 2
##STR5## wherein [0061] Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each as defined above, [0062] X.sub.1 is lower alkylene, [0063]
Z.sub.1 is lower alkynylene, [0064] R.sup.5 is 3-pyridyl, and
[0065] W.sub.1 is a leaving group.
[0066] As to the starting compounds (II) and (III), some of them
are novel and can be prepared by the procedures described in the
Preparations and Examples mentioned later or similar manners
thereto.
[0067] Suitable salts of the starting and object compounds are
conventional non-toxic and pharmaceutically acceptable salt and
include an acid addition salt such as an organic acid salt (e.g.
acetate, trifluoroacetate, fumarate, maleate, tartrate,
methanesulfonate, benzenesulfonate, formate, toluenesulfonate,
etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide,
hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an
amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or
a metal salt such as an alkali metal salt (e.g. sodium salt,
potassium salt, etc.) and an alkaline earth metal salt (e.g.
calcium salt, magnesium salt, etc.), an ammonium salt, an organic
base salt (e.g. trimethylamine salt, triethylamine salt, pyridine
salt, picoline salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, etc.), or the like.
[0068] In the above and subsequent descriptions of the present
specification, suitable examples and illustrations of the various
definitions which the present invention intends to include within
the scope thereof are explained in detail as follows.
[0069] The term "lower" is intended to mean 1 to 6, preferably 1 to
4, carbon atom(s), unless otherwise indicated.
[0070] Suitable "lower alkylene" may include straight or branched
one having 1 to 6, preferably 1 to 4, carbon atom(s), such as
methylene, ethylene, trimethylene, propylene, tetramethylene,
methylmethylene, methyltrimethylene, hexamethylene, and the like,
in which the preferred one is methylene, ethylene, trimethylene or
methylmethylene.
[0071] Suitable "lower alkynylene" may include one having 2 to 6
carbon atoms, such as ethynylene, propynylene, butynylene, and the
like, in which the preferred one is propynylene or butynylene.
[0072] Suitable "halogen" and "halogen" moiety in the terms
"mono(or di or tri)halo(lower)alkyl", "mono(or di or
tri)halo(C.sub.1-C.sub.4)alkyl", etc. may include fluorine,
chlorine, bromine and iodine.
[0073] Suitable "lower alkyl" and "lower alkyl" moiety in the terms
"hydroxy(lower)alkyl", "pyrazolyl(lower)alkyl", etc. may include
straight or branched one having 1 to 6 carbon atom(s), such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl
and the like, in which the preferred one is C.sub.1-C.sub.4 alkyl
and the most preferred one is methyl, ethyl or propyl.
[0074] Suitable "lower alkenyl" moiety in the term
"(2-methoxymethylmorpholino)(lower)alkenyl" may include vinyl,
1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or
4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl
ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or
3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or
3-)butenyl, and the like, in which more preferable example may be
C.sub.2-C.sub.4 alkenyl.
[0075] Suitable "aryl" may include phenyl, naphthyl, and the like,
in which the preferred one is C.sub.6-C.sub.10 aryl and the most
preferred one is phenyl or naphthyl.
[0076] Suitable "lower alkoxy" and "lower alkoxy" moiety in the
terms "lower alkoxy(lower)alkylmorpholinyl(lower)alkyl", "lower
alkoxy(lower)alkylmorpholinylcarbonyl(lower)alkyl", etc. may
include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which
the preferred one is C.sub.1-C.sub.4 alkoxy and the most preferred
one is methoxy.
[0077] Suitable "leaving group" may include lower alkoxy (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
pentoxy, etc.), aryloxy (e.g., phenoxy, naphthoxy, etc.), an acid
residue or the like.
[0078] Suitable "acid residue" may be halogen (e.g., chlorine,
bromine, iodine, etc.), sulfonyloxy (e.g., methanesulfonyloxy,
phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.)
or the like.
[0079] Preferred embodiments of the object compound (I) are as
follows: [0080] Y is lower alkylene (more preferably
C.sub.1-C.sub.4 alkylene, most preferably methylene); [0081]
R.sup.1 is phenyl which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisting of
halogen (more preferably fluorine or chlorine), lower alkyl (more
preferably C.sub.1-C.sub.4 alkyl, most preferably methyl), lower
alkoxy (more preferably C.sub.1-C.sub.4 alkoxy, most preferably
methoxy), mono(or di or tri)halo(lower)alkyl (more preferably
trihalo(lower)alkyl, most preferably trifluoromethyl), nitro,
amino, lower alkylamino (more preferably C.sub.1-C.sub.4
alkylamino, most preferably methylamino), di(lower)alkylamino (more
preferably di(C.sub.1-C.sub.4)alkylamino, most preferably
dimethylamino), lower alkylthio (more preferably C.sub.1-C.sub.4
alkylthio, most preferably methylthio), lower alkylsulfonyl (more
preferably C.sub.1-C.sub.4 alkylsulfonyl, most preferably
methanesulfonyl), cyclo(lower)alkylsulfonyl (more preferably
cyclo(C.sub.1-C.sub.6)alkylsulfonyl, most preferably
cyclopentylsulfonyl), aminosulfonyl, lower alkylamino-sulfonyl
(more preferably C.sub.1-C.sub.4 alkylaminosulfonyl, most
preferably methylaminosulfonyl), di(lower)alkylamino-sulfonyl (more
preferably di(C.sub.1-C.sub.4)alkylaminosulfonyl, most preferably
dimethylaminosulfonyl), pyrrolidinylsulfonyl (more preferably
pyrrolidinosulfonyl), morpholinylsulfonyl (more preferably
morpholinosulfonyl), pyrrolylsulfonyl (more preferably
1-pyrrolylsulfonyl), pyridylsulfonyl (more preferably
4-pyridylsulfonyl), pyrrolyl (more preferably 1-pyrrolyl) and
pyridyl (more preferably 4-pyridyl); [0082] R.sup.2 is phenyl which
is substituted with 1 or 2 same or different substituent(s)
selected from the group consisting of lower alkyl (more preferably
C.sub.1-C.sub.4 alkyl, most preferably methyl or isopropyl),
mono(or di or tri)halo(lower)alkyl (more preferably mono(or di or
tri)halo (C.sub.1-C.sub.4)alkyl, most preferably trifluoromethyl),
mono(or di or tri)halo(lower)alkylsulfonyloxy (more preferably
mono(or di or tri)halo(C.sub.1-C.sub.4)alkylsulfonyl, most
preferably trifluoromethylsulfonyloxy), halogen (more preferably
chlorine or fluoride), lower alkylenedioxy (more preferably
C.sub.1-C.sub.4 alkylenedioxy, most preferably methylenedioxy or
ethylenedioxy), lower alkoxy (more preferably C.sub.1-C.sub.4
alkoxy, most preferably methoxy), lower alkoxycarbonyl (more
preferably C.sub.1-C.sub.4 alkoxycarbonyl, most preferably
methoxycarbonyl), lower alkoxy(lower)alkoxy(lower)alkoxy (more
preferably C.sub.1-C.sub.4
alkoxy(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkoxy, most
preferably (2-methoxyethoxy)methoxy), hydroxy,
diphenyl(lower)alkylsilyloxy (more preferably
diphenyl(C.sub.1-C.sub.4)alkylsilyloxy, most preferably
diphenyl(tert-butyl)silyloxy), tri(lower)alkylsilyloxy (more
preferably tri(C.sub.1-C.sub.4)alkylsilyloxy, most preferably
dimethyl(tert-butyl)silyloxy), hydroxy(lower)alkyl (more preferably
hydroxy(C.sub.1-C.sub.4)alkyl, most preferably hydroxymethyl or
1-hydroxy-1-methylethyl), cyano, amino, [mono(or di or
tri)halo(lower)alkylcarbonyl]amino (more preferably [mono(or di or
tri)halo(C.sub.1-C.sub.4)alkylcarbonyl]amino, most preferably
(trifluoromethylcarbonyl)amino), lower alkylamino (more preferably
C.sub.1-C.sub.4 alkylamino, methylamino), N-(lower alkyl)-[mono(or
di or tri)halo(lower)alkylcarbonyl]amino (more preferably
N-(C.sub.1-C.sub.4 alkyl)-[mono(or di or
tri)halo(C.sub.1-C.sub.4)alkyl-carbonyl]amino, most preferably
N-methyl-(trifluoro-methylcarbonyl)amino), pyrrolidinyl (more
preferably pyrrolidino) and morpholinyl (more preferably
morpholino) which may be substituted with lower alkoxy(lower)alkyl
(more preferably C.sub.1-C.sub.4 alkoxy(C.sub.1-C.sub.4)alkyl, most
preferably methoxymethyl) or lower alkyl (more preferably
C.sub.1-C.sub.4 alkyl, most preferably methyl); [0083] R.sup.3 is
hydrogen; and [0084] R.sup.4 is (3-pyridyl)methyl; [0085]
(3-pyridyl)ethyl (more preferably 2-(3-pyridyl) ethyl); [0086]
3-(3-pyridyl)propyl; [0087] 3-(3-pyridyl)propenyl (more preferably
3-(3-pyridyl)-2-propenyl); [0088] 3-(3-pyridyl)propynyl (more
preferably 3-(3-pyridyl)-2-propynyl); [0089] thiazolyl(lower)alkyl
(more preferably thiazolyl(C.sub.1-C.sub.4)alkyl, most preferably
4-thiazolymethyl), 1,2,4-thiadiazolyl(lower)alkyl (more preferably
1,2,4-thiadiazolyl(C.sub.1-C.sub.4)alkyl, most preferably
1,2,4-thiadiazolyl-3-ylmethyl) or 1,2,4-oxadiazolyl(lower)-alkyl
(more preferably 1,2,4-oxadiazolyl(C.sub.1-C.sub.4)alkyl, most
preferably 1,2,4-oxadiazolyl-5-ylmethyl), each of which is
substituted with halogen (more preferably bromine), amino, lower
alkylamino (more preferably C.sub.1-C.sub.4 alkylamino, most
preferably methylamino) or di(lower)alkylamino (more preferably
di(C.sub.1-C.sub.4)alkylamino, most preferably dimethylamino);
[0090] pyrazolylmethyl (more preferably (4-pyrazolyl)methyl or
(5-pyrazolyl)methyl) which may be substituted with
triphenyl(lower)alkyl (more preferably
triphenyl(C.sub.1-C.sub.4)alkyl, most preferably triphenylmethyl)
or hydroxy(lower)alkyl (more preferably
hydroxy(C.sub.1-C.sub.4)-alkyl, most preferably 2-hydroxyethyl);
[0091] pyrazolyl(lower)alkyl (more preferably
pyrazolyl-(C.sub.1-C.sub.4)alkyl, most preferably
(4-pyrazolyl)methyl, (5-pyrazolyl)methyl or 3-(4-pyrazolyl)propyl)
which is substituted with lower alkyl (more preferably
C.sub.1-C.sub.4 alkyl, most preferably methyl),
(lower)alkoxy(lower)-alkylmorpholinyl(lower)alkyl (more preferably
(C.sub.1-C.sub.4)-alkoxy(C.sub.1-C.sub.4)alkylmorpholinyl(C.sub.1-C.sub.4-
)alkyl, most preferably 2-(2-methoxymethylmorpholino)ethyl) or
(lower)alkoxy(lower)alkylmorpholinylcarbonyl(lower)alkyl (more
preferably
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)-alkylmorpholinylcarbonyl(C.sub.1-
-C.sub.4)alkyl, most preferably
(2-methoxymethylmorpholino)carbonylmethyl); [0092]
pyrrolidinyl(lower)alkyl (more preferably
pyrrolidinyl(C.sub.1-C.sub.4)alkyl, most preferably
2-pyrrolidinoethyl) which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisiting of
hydroxy, hydroxy(lower)alkyl (more preferably
hydroxy(C.sub.1-C.sub.4)alkyl, most preferably hydroxymethyl),
lower alkoxy (more preferably C.sub.1-C.sub.4 alkoxy, most
preferably methoxy) and lower alkoxy(lower)alkyl (more preferably
C.sub.1-C.sub.4 alkoxy(C.sub.1-C.sub.4)alkyl, most preferably
methoxymethyl); [0093] piperidylmethyl (more preferably
(4-piperidyl)methyl); piperidyl(lower)alkyl (more preferably
piperidyl(C.sub.1-C.sub.4)-alkyl, most preferably
2-piperidinoethyl) which is substituted with 1 or 2 same or
different substituent(s) selected from the group of halogen (more
preferably fluorine), lower alkyl (more preferably C.sub.1-C.sub.4
alkyl, most preferably methyl) and lower alkoxy(lower)alkyl (more
preferably C.sub.1-C.sub.4 alkoxy(C.sub.1-C.sub.4)alkyl, most
preferably methoxymethyl); [0094] [2,6-di
[hydroxy(lower)alkyl]piperidyl](lower)alkyl (more preferably
[2,6-di[hydroxy(C.sub.1-C.sub.4)alky]piperidyl](C.sub.1-C.sub.4)alkyl,
most preferably 2-[2,6-di(hydroxymethyl)piperidino]ethyl); [0095]
(2,6-dimethylmorpholino)(lower)alkyl (more preferably
(2,6-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(2,6-dimethylmorpholino)ethyl); [0096]
(2,2-dimethylmorpholino)(lower)alkyl (more preferably
(2,2-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(2,2-dimethylmorpholino)ethyl); [0097]
(3,3-dimethylmorpholino)(lower)alkyl (more preferably
(3,3-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(3,3-dimethylmorpholino)ethyl); [0098]
(cis-3,5-dimethylmorpholino)(lower)alkyl (more preferably
(cis-3,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(cis-3,5-dimethylmorpholino)ethyl); [0099]
((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl (more preferably
((3S,5S)-3,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-((3S,5S)-3,5-dimethylmorpholino)-ethyl); [0100]
((3S,5R)-3,5-dimethylmorpholino)(lower)alkyl (more preferably
((3S5,R)-3,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-((3S,5R)-3,5-dimethylmorpholino)-ethyl); [0101]
(2-methoxymethylmorpholino)(lower)alkyl (more preferably
(2-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
3-(2-methoxymethylmorpholino)propyl or
2-(2-methoxymethylmorpholino)ethyl); [0102]
(3-methoxymethylmorpholino)(lower)alkyl (more preferably
(3-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(3-methoxymethylmorpholino)ethyl); [0103]
(2-methoxymethyl-5-methylmorpholino)(lower)alkyl (more preferably
(2-methoxymethyl-5-methylmorpholino)-(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2-methoxymethyl-5-methylmorpholino)ethyl); [0104]
(2-methoxymethyl-5,5-dimethylmorpholino)(lower)alkyl (more
preferably
(2-methoxymethyl-5,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl,
most preferably 2-(2-methoxymethyl-5,5-dimethylmorpholino)ethyl);
[0105] (3,5-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(3,5-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(3,5-dimethoxymethylmorpholino)ethyl); [0106]
(2,2-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(2,2-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2,2-dimethoxymethylmorpholino)ethyl); [0107]
(2,3-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(2,3-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2,3-dimethoxymethylmorpholino)ethyl); [0108]
(2,6-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(2,6-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2,6-dimethoxymethylmorpholino)ethyl); [0109]
(2-methoxymethylmorpholino)(lower)alkenyl (more preferably
(2-methoxymethylmorpholino)(C.sub.2-C.sub.4)alkenyl, most
preferably 4-(2-methoxymethylmorpholino)-2-butenyl); [0110]
(3,3-dimethylmorpholino)(lower)alkynyl (more preferably
(3,3-dimethylmorpholino)(C.sub.2-C.sub.4)alkynyl, most preferably
4-(3,3-dimethylmorpholino)-2-butynyl); [0111]
(2-methoxymethylmorpholino)(lower)alkynyl (more preferably
(2-methoxymethylmorpholino)(C.sub.2-C.sub.4)alkynyl, most
preferably 4-(2-methoxymethylmorpholino)-2-butynyl); [0112]
(2-methoxymethyl-5-methylmorpholino)(lower)alkynyl (more preferably
(2-methoxymethyl-5-methylmorpholino)(C.sub.2-C.sub.4)alkynyl, most
preferably 4-(2-methoxymethyl-5-methylmorpholino)-2-butynyl);
[0113] quinolyl(lower)alkyl (more preferably
quinolyl(C.sub.1-C.sub.4)alkyl, most preferably
(6-quinolyl)methyl); [0114]
[1H-pyrrolo[3,2-b]pyridinyl](lower)alkyl (more preferably
[1H-pyrrolo[3,2-b]pyridinyl](C.sub.1-C.sub.4)alkyl, most preferably
[1H-pyrrolo[3,2-b]pyridin-3-yl]methyl); [0115]
[4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl](lower)alkyl (more
preferably
[4,5,6,7-tetrahydrothieno[3,2-c]-pyridinyl](C.sub.1-C.sub.4)alkyl,
most preferably
2-[4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl]ethyl); [0116]
[3,4-dihydro-2H-pyrido(3,2-b]-1,4-oxazinyl](lower)alkyl (more
preferably
[3,4-dihydro-2H-pyrido(3,2-b]-1,4-oxazinyl](C.sub.1-C.sub.4)alkyl,
most preferably
2-[3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-4-yl]ethyl); [0117]
(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)(lower)alkyl (more
preferably
(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)(C.sub.1-C.sub.4)alkyl,
most preferably 2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl);
or [0118] lower alkyl (more preferably C.sub.1-C.sub.4 alkyl, most
preferably ethyl) which is substituted with a saturated
heterocyclic group of the formula: ##STR6## [0119] (wherein r, s
and t are each integer of 1 to 2, and q is integer of 0 to 2) (more
preferably (1S,4S)-2-aza-5-oxabicyclo[2.2.1]-heptan-2-yl) which may
be substituted with one or two lower alkyl (more preferably
C.sub.1-C.sub.4 alkyl, most preferably methyl)).
[0120] More preferred embodiments of the object compound (I) are as
follows: [0121] Y is lower alkylene (more preferably
C.sub.1-C.sub.4 alkylene, most preferably methylene); [0122]
R.sup.1 is phenyl which is substituted with 1 or 2 same or
different substituent(s) selected from the group consisting of
halogen, lower alkyl, lower alkoxy, mono(or di or
tri)halo(lower)alkyl, nitro, amino, lower alkylamino,
di(lower)alkylamino, lower alkylthio, lower alkylsulfonyl,
cyclo(lower)alkylsulfonyl, aminosulfonyl, lower alkylaminosulfonyl,
di(lower alkyl)aminosulfonyl, pyrrolidinylsulfonyl,
morpholinylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, pyrrolyl
and pyridyl [more preferably dihalophenyl,
bis(trihalo(lower)alkyl)phenyl, (trihalo(lower)alkyl)(halo)phenyl,
(trihalo(lower)alkyl)((lower)alkyl)phenyl,
(trihalo(lower)alkyl)((lower)alkoxy)phenyl,
(trihalo(lower)alkyl)(nitro)phenyl, (trihalo(lower)alkyl)(lower
alkylamino)phenyl, (trihalo
(lower)alkyl)(di(lower)alkylamino)phenyl,
(trihalo(lower)alkyl)((lower)alkylthio)phenyl,
(trihalo(lower)alkyl)((lower)alkylsulfonyl)phenyl,
(trihalo(lower)alkyl)(cyclo(lower)alkylsulfonyl)phenyl,
(trihalo(lower)alkyl)(aminosulfonyl)phenyl,
(trihalo(lower)alkyl)(lower alkylaminosulfonyl)phenyl,
(trihalo(lower)alkyl)(di(lower)alkylaminosulfonyl)-phenyl,
(trihalo(lower)alkyl)(pyrrolidinylsulfonyl)-phenyl, (trihalo
(lower)alkyl)(morpholinylsufonyl)phenyl,
(trihalo(lower)alkyl)(pyridylsulfonyl)phenyl,
(trihalo(lower)alkyl)(pyrrolyl)phenyl or
(trihalo(lower)alkyl)(pyridyl)phenyl, most preferably
3,5-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl,
3-fluoro-5-trifluoromethylphenyl, 3-chloro-5-trifluoromethylphenyl,
3-methyl-5-trifluoromethylphenyl,
3-methoxy-5-trifluoromethylphenyl, 3-nitro-5-trifluoromethylphenyl,
3-methylamino-5-trifluoromethylphenyl,
3-dimethylamino-5-trifluoromethylphenyl,
3-methylthio-5-trifluoromethylphenyl,
3-methanesulfonyl-5-trifluoromethylphenyl,
3-cyclopentylsulfonyl-5-trifluoromethylphenyl,
3-aminosulfonyl-5-trifluoromethylphenyl,
3-methylaminosulfonyl-5-trifluoromethylphenyl,
3-dimethylaminosulfonyl-5-trifluoromethylphenyl,
3-pyrrolidinosulfonyl-5-trifluoromethylphenyl,
3-morpholinosulfonyl-5-trifluoromethylphenyl,
3-(4-pyridyl)sulfonyl-5-trifluoromethylphenyl,
3-(1-pyrrolyl)-5-trifluoromethylphenyl or
3-(4-pyridyl)-5-trifluoromethylphenyl]; [0123] R.sup.2 is phenyl
which is substituted with 1 or 2 same or different substituent(s)
selected from the group consisting of lower alkyl, mono(or di or
tri)halo(lower)alkyl, mono(or di or
tri)halo(lower)alkylsulfonyloxy, halogen, lower alkylenedioxy,
lower alkoxy, lower alkoxycarbonyl, lower
alkoxy(lower)alkoxy(lower)alkoxy, hydroxy, diphenyl
(lower)alkylsilyloxy, tri(lower)alkylsilyloxy, hydroxy(lower)alkyl,
cyano, amino, [mono(or di or tri)halo(lower)alkylcarbonyl]amino,
lower alkylamino, N-(lower alkyl)-[mono(or di or
tri)halo(lower)alkyl-carbonyl]amino, pyrrolidinyl and morpholinyl
which may be substituted with lower alkoxy(lower)alkyl or lower
alkyl [more preferably ((lower)alkylenedioxy)phenyl, (lower
alkoxy)phenyl, halophenyl, dihalophenyl,
(trihalo(lower)alkyl)phenyl, (trihalo(lower)alkyl)(lower
alkyl)phenyl, (halo)(lower alkyl)phenyl, (halo)(lower
alkoxy)phenyl, (halo)(hydroxy)phenyl,
(halo)(diphenyl(lower)alkylsilyloxy)phenyl,
(trihalo(lower)alkyl)(hydroxy)-phenyl,
(hydroxy(lower)alkyl)(hydroxy)phenyl, (cyano)(hydroxy)phenyl,
(dihalo(lower)alkyl)(hydroxy)-phenyl, (lower alkyl)(amino)phenyl,
(lower alkyl)(lower alkylamino)phenyl, (lower alkyl)(mono(or di or
tri)halo(lower)alkylsulfonyloxy)phenyl, (lower alkyl)[[mono(or di
or tri)halo(lower)alkylcarbonyl]-amino]phenyl, (lower alkyl)
[N-(lower alkyl)-[mono(or di or
tri)halo(lower)alkylcarbonyl]amino]phenyl, (lower
alkyl)(diphenyl(lower)alkylsilyloxy)phenyl, (lower alkyl)(lower
alkoxy(lower)alkoxy(lower)alkoxy)phenyl, (lower
alkyl)(tri(lower)alkylsilyloxy)phenyl, (lower
alkoxycarbonyl)(tri(lower)alkylsilyloxy)phenyl,
(hydroxy(lower)alkyl)(tri(lower)alkylsilyloxy)phenyl, (lower
alkyl)(hydroxy)phenyl, (lower alkyl)(pyrrolidinyl)phenyl, (lower
alkyl)(morpholinyl)phenyl, (lower alkyl)(lower
alkoxy-(lower)alkylmorpholinyl)phenyl or (lower alkyl)(lower
alkyl)morpholinyl)phenyl, most preferably 1,4-benzodioxan-6-yl,
4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,
3,4-difluorophenyl, 4-(trifluoromethyl)-phenyl,
3-methoxy-4-trifluoromethylphenyl, 4-fluoro-3-methylphenyl,
4-fluoro-3-methoxy-phenyl, 3-fluoro-4-methylphenyl,
4-fluoro-3-hydroxyphenyl, 4-chloro-3-methoxyphenyl,
4-chloro-3-(dimethyl(tert-butyl)silyloxy)phenyl,
4-chloro-3-hydroxy-phenyl, 3-hydroxy-4-(trifluoromethyl)phenyl,
3-hydroxy-4-(hydroxymethyl)phenyl, 3-hydroxy-4-methylphenyl,
3-hydroxy-4-(1-hydroxy-1-methylethyl)phenyl,
4-cyano-3-hydroxyphenyl, 3-hydroxy-4-(difluoromethyl)phenyl,
3-hydroxy-4-isopropylphenyl, 3-amino-4-methylphenyl,
4-methyl-3-methylaminophenyl,
4-methyl-3-(trifluoromethylsulfonyloxy)phenyl,
4-methyl-3-[(trifluoromethylcarbonyl) amino]phenyl,
4-methyl-3-[N-methyl-(trifluoromethylcarbonyl)amino]phenyl,
3-diphenyl (tert-butyl) silyloxy-4-methylphenyl,
4-methyl-3-[(2-methoxyethoxy)methoxy]phenyl,
3-dimethyl(tert-butyl)silyloxy-4-methylphenyl,
3-dimethyl(tert-butyl) silyloxy-4-methoxycarbonylphenyl, 3-dimethyl
(tert-butyl)silyloxy-4-(1-hydroxy-1-methylethyl)phenyl,
4-methyl-3-pyrrolidinophenyl or 4-methyl-3-morpholinophenyl];
[0124] R.sup.3 is hydrogen; and [0125] R.sup.4 is
(2,6-dimethylmorpholino)(lower)alkyl (more preferably
(2,6-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(2,6-dimethylmorpholino)ethyl); [0126]
(2,2-dimethylmorpholino)(lower)alkyl (more preferably
(2,2-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(2,2-dimethylmorpholino)ethyl); [0127]
(3,3-dimethylmorpholino)(lower)alkyl (more preferably
(3,3-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(3,3-dimethylmorpholino)ethyl); [0128]
(cis-3,5-dimethylmorpholino)(lower)alkyl (more preferably
(cis-3,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(cis-3,5-dimethylmorpholino)ethyl); [0129]
((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl (more preferably
((3S,5S)-3,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-((3S,5S)-3,5-dimethylmorpholino)-ethyl); [0130]
((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl (more preferably
((3S,5S)-3,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-((3S,5R)-3,5-dimethylmorpholino)-ethyl); [0131]
(2-methoxymethylmorpholino)(lower)alkyl (more preferably
(2-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
3-(2-methoxymethylmorpholino)propyl or
2-(2-methoxymethylmorpholino)ethyl); [0132]
(3-methoxymethylmorpholino)(lower)alkyl (more preferably
(3-methoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most preferably
2-(3-methoxymethylmorpholino)ethyl); [0133]
(2-methoxymethyl-5-methylmorpholino)(lower)alkyl (more preferably
(2-methoxymethyl-5-methylmorpholino)(C.sub.1-C.sub.4)-alkyl, most
preferably 2-(2-methoxymethyl-5-methylmorpholino)ethyl); [0134]
(2-methoxymethyl-5,5-dimethylmorpholino)(lower)alkyl (more
preferably
(2-methoxymethyl-5,5-dimethylmorpholino)(C.sub.1-C.sub.4)alkyl,
most preferably 2-(2-methoxymethyl-5,5-dimethylmorpholino)ethyl);
[0135] (3,5-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(3,5-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(3,5-dimethoxymethylmorpholino)ethyl); [0136]
(2,2-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(2,2-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2,2-dimethoxymethylmorpholino)ethyl); [0137]
(2,3-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(2,3-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2,3-dimethoxymethylmorpholino)ethyl); [0138]
(2,6-dimethoxymethylmorpholino)(lower)alkyl (more preferably
(2,6-dimethoxymethylmorpholino)(C.sub.1-C.sub.4)alkyl, most
preferably 2-(2,6-dimethoxymethylmorpholino)ethyl); [0139]
(2-methoxymethylmorpholino)(lower)alkenyl (more preferably
(2-methoxymethylmorpholino)(C.sub.2-C.sub.4)alkenyl, most
preferably 4-(2-methoxymethylmorpholino)-2-butenyl); [0140]
(3,3-dimethylmorpholino)(lower)alkynyl (more preferably
(3,3-dimethylmorpholino)(C.sub.2-C.sub.4)alkynyl, most preferably
4-(3,3-dimethylmorpholino)-2-butynyl); [0141]
(2-methoxymethylmorpholino)(lower)alkynyl (more preferably
(2-methoxymethylmorpholino)(C.sub.2-C.sub.4)alkynyl, most
preferably 4-(2-methoxymethylmorpholino)-2-butynyl); or [0142]
(2-methoxymethyl-5-methylmorpholino)(lower)alkynyl (more preferably
(2-methoxymethyl-5-methylmorpholino)(C.sub.2-C.sub.4)alkynyl, most
preferably 4-(2-methoxymethyl-5-methylmorpholino)-2-butynyl).
[0143] The Processes 1 and 2 for preparing the object compound (I)
of the present invention are explained in detail in the
following.
Process 1
[0144] The object compound (I) or a salt thereof can be prepared by
reacting the compound (II) or its reactive derivative at the imino
group or a salt thereof with the compound (III) or a salt
thereof.
[0145] Suitable reactive derivative at the imino group of the
compound (II) may include Schiff's base type imino or its
tautomeric enamine type isomer formed by the reaction of the
compound (II) with a carbonyl compound such as aldehyde, ketone or
the like; a silyl derivative formed by the reaction of the compound
(II) with a silyl compound such as bis(trimethylsilyl)acetamide,
mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like;
a derivative formed by reaction of the compound (II) with
phosphorus trichloride or phosgene and the like.
[0146] The reaction is usually carried out in a conventional
solvent such as water, alcohol [e.g. methanol, ethanol, etc.],
acetone, dioxane, acetonitrile, chloroform, methylene chloride,
ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine or any other organic solvent which
does not adversely influence the reaction. These conventional
solvents may also be used in a mixture with water.
[0147] The reaction may also be carried out in the presence of an
inorganic or organic base such as alkali metal carbonate (e.g.
potassium carbonate, etc.), alkali metal bicarbonate,
tri(lower)alkylamine, pyridine, N-(lower)alkyl-morpholine,
N,N-di(lower)alkylethylamine (e.g. N,N-diisopropylethylamine,
etc.), N,N-di(lower)alkylbenzylamine, or the like.
[0148] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to heating.
Process 2
[0149] The object compound (Ib) or a salt thereof can be prepared
by subjecting the compound (Ia) or a salt thereof to a reduction
reaction.
[0150] The reaction can be carried out in the manner disclosed in
Example 8 mentioned later or similar manners thereto.
[0151] The object compound (I) and a pharmaceutically acceptable
salt thereof have pharmacological activities such as Tachykinin
antagonism, especially Substance P antagonism, Neurokinin A
antagonism or Neurokinin B antagonism, and therefore are useful for
treating or preventing Tachykinin-mediated diseases, particularly
Substance P-mediated diseases, for example, respiratory diseases
such as asthma, bronchitis (e.g. chronic bronchitis, acute
bronchitis and diffuse panbronchiolitis, etc.), rhinitis, couph,
expectoration, and the like; ophthalmic diseases such as
conjunctivitis, vernal conjunctivitis, and the like; cutaneous
diseases such as contact dermatitis, atopic dermatitis, urticaria,
and other eczematoid dermatitis, and the like; inflammatory
diseases such as rheumatoid arthritis, osteoarthritis, and the
like; pains or aches (e.g. migraine, headache, cluster headache,
toothache, cancerous pain, back pain, neuralgia, etc.); and the
like.
[0152] Further, it is expected that the object compound (I) and a
pharmaceutically acceptable salt thereof of the present invention
are useful for treating or preventing ophthalmic diseases such as
glaucoma, uveitis, and the like; gastrointestinal diseases such as
ulcer, ulcerative colitis, irritable bowel syndrome, food allergy,
and the like; inflammatory diseases such as nephritis, and the
like; circulatory diseases such as hypertension, angina pectoris,
cardiac failure, thrombosis, Raynaud's disease, and the like;
epilepsy; spastic paralysis; pollakiuria; cystitis; bladder
detrusor hyperreflexia; urinary incontinence; Parkinson diseases;
dimentia; AIDS related dementia; Alzheimer's diseases; Down's
syndrome; Huntington's chorea; carcinoid syndrome; disorders
related to immune enhancement or suppression; disorders caused by
Helicobacter pylori or another spiral urease-positive gram-negative
bacterium; sunburn; angiogenesis or diseases caused by
angiogenesis; and the like.
[0153] It is furthermore expected that the object compound (I) and
a pharmaceutically acceptable salt thereof of the present invention
are useful for treating or preventing chronic obstructive pulmonary
diseases, particularly chronic pulmonary emphysema; iritis;
proliferative vitreoretinopathy; psoriasis; inflammatory intestinal
diseases, particularly Crohn's diseases; hepatitis; superficial
pain on congelation, burn, herpes zoster or diabetic neuropathy;
telalgia attended to hyperlipidemia; postoperative neuroma,
particularly of mastectomy; vulvar vestibulitis;
hemodialysis-associated itching; lichen planus; laryngopharyngitis;
bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis;
cystic fibrosis; emesis (e.g., nausea, retching, vomiting, acute
emesis, delayed emesis, anticipatory emesis, past operative nausea
and vomiting (PONV), acute and/or delayed emesis induced by drugs
such as cancer chemotherapeutic agents, etc.); mental diseases,
particularly anxiety disorders, stress-related disorders, affective
disorders, psychological development disorders and schizophrenia;
demyelinating diseases such as multiple sclerosis and amyotrophic
lateral sclerosis; attenuation of morphine withdrawal; oedema, such
as oedema caused by thermal injury; small cell carcinomas,
particularly small cell lung cancer (SCLC); hypersensitivity
disorders such as poison ivy; fibrosing and collagen diseases such
as scleroderma and eosinophilic fascioliasis; reflex sympathetic
dystrophy such as shoulder/hand syndrome; addiction disorders such
as alcoholism; stress related somatic disorders; rheumatic diseases
such as fibrositis; aggressive behaviour, optionally taking an
antipsychotic agent together; mania or hypomania, optionally taking
an antipsychotic agent together; symptoms associated with
Premenstrual Syndrome (PMS)(PMS is also now referred to as Late
Luteal Phase Syndrome (LLS); psychosomatic disoredrs;
psychoimmunologic disoredrs; attetion deficit disoredrs (ADD) with
or without hyperactivity; and the like.
[0154] Furthermore, the object compound (I) and a pharmaceutically
acceptable salt thereof of the present invention are Central
Nervous System (CNS) penetrant.
[0155] For therapeutic purpose, the compound (I) and a
pharmaceutically acceptable salt thereof of the present invention
can be used in a form of pharmaceutical preparation containing one
of said compound, as an active ingredient, in admixture with a
pharmaceutically acceptable carrier such as an organic or inorganic
solid or liquid excipient suitable for oral, parenteral, external
including topical, enternal, intravenous, intramuscular, inhalant,
nasal, intraarticular, intraspinal, transtracheal or transocular
administration. The pharmaceutical preparations may be solid,
semi-solid or solutions such as capsules, tablets, pellets,
dragees, powders, granules, suppositories, ointments, creams,
lotions, inhalants, injections, cataplasms, gels, tapes, eye drops,
solution, syrups, aerosols, suspension, emulsion, or the like. If
desired, there may be included in these preparations, auxiliary
substances, stabilizing agents, wetting or emulsifying agents,
buffers and other commonly used additives.
[0156] While the dosage of the compound (I) will vary depending
upon the age and condition of a patient, an average single dose of
about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000
mg of the compound (I) may be effective for treating
Tachykinin-mediated diseases such as asthma and the like. In
general, amounts between 0.1 mg/body and about 1,000 mg/body may be
administered per day.
[0157] In order to show the utility of the object compound (I) and
a pharmaceutically acceptable salt thereof, the pharmacological
test data of some representative compounds of the present invention
is shown in the following.
A. Evaluation of NK.sub.1 Antagonist Transport Efficiency to the
Central Nervous System Using a h-NK.sub.1 Receptor Binding
Assay
[1] Test Method
[0158] (1) Administration of test compound and extraction of the
compound from brain
[0159] Male SD rats were given an i.v. injection of a solution
containing a test compound (1 mg/kg). 5 Min later the animals were
anesthetized by ether, bled and perfused through the aorta
asscendens with 20 ml of saline. The brain was rapidly removed,
weighed and homogenized in 4 vol. ice-cold distilled water by using
Polytoron (KINEMATICA). To extract the test compound, 500 .mu.l of
the homogenate, 100 .mu.l of methanol, 500 .mu.l of 0.1 N NaCH and
4 ml of ethyl acetate were mixed by shaking for 10 min at room
temperature. The organic phase (2.5 ml) was recovered by
centrifugation at 3,000 rpm for 10 min, dried and dissolved in
dimethyl sulfoxide.
(2) h-NK.sub.1 Receptor Binding Assay
(a) Crude CHO Cell Membrane Preparation
[0160] CHO cells permanently expressing h-NK.sub.1 receptors were
harvested and homogenized with a Dounce homogenizer at 4.degree. C.
in a buffer (0.25 M sucrose, 25 mM Tris-HCl (pH 7.4), 10 mM
MgCl.sub.2, 1 mM EDTA, 5 .mu.g/ml p-APMSF). The homogenate was
centrifuged (500.times.g, 10 min), and the pellet was resuspended
in the same buffer, homogenized, and centrifuged. The two
supernatants were combined and centrifuged (100,000.times.g, 1
hour). The crude cell membranes thus isolated were resuspended in a
buffer (25 mM Tris-HCl (pH 7.4), 10 mM MgCl.sub.2, 1 mM EDTA, 5
.mu.g/ml p-APMSF) and stored at -80.degree. until use.
(b) .sup.125I-BH-Substance P Binding to the Prepared Membrane
[0161] Cell membranes (6 .mu.g/ml) were incubated with
.sup.125I-BH-Substance P (0.1 nM) with or without the extracted
compounds in 0.25 ml of a medium (50 mM Tris-HCl (ph 7.4), 5 mM
MnCl.sub.2, 20 .mu.g/ml chymostatin, 40 .mu.g/ml bacitracin, 4
.mu.g/ml leupeptin, 5 .mu.g/ml p-APMSF, 200 .mu.g/ml BSA) at
22.degree. C. for 90 min. At the end of the incubation period, the
contents were quickly filtered through a Blue Mat 11740 filter
(pretreated with 0.1% polyethylenimine for 3 hours prior to use) by
using SKATRON Cell Harvester. The filter was then washed with a
washing buffer (50 mM Tris-HCl (pH 7.4) 5 mM MnCl.sub.2). The
radioactivity was counted by using an auto gamma counter (Packard
RIASTAR 5420A). All data presented are specific binding defined as
that displaceable by 3 .mu.M unlabeled Substance P.
[II] Test Result
[0162] All of the following Test Compounds showed more than 80%
inhibition rate of .sup.125I-BH-Substance P binding to h-NK.sub.1
receptors at the dose of 1 mg/kg.
[0163] Test Compounds: The object compounds of the Examples 4-(1),
4-(2), 7 and 8
B. Emesis in the Dog
[I] Test Method
[0164] Individually housed adult female dogs (8 to 15 kg) were
given an i.v. injection of a solution containing a test compound. 5
Min later the emetic responses (retching and vomiting) were induced
by administration of subcutaneous apomorphine (0.1 mg/0.5 ml/kg)
and observed for the next 60 min. The timing and number of retches
and vomits observed were recorded for each animal. An individual
animal was tested with at least 10 days between experiments.
[II] Test Result
[0165] The following Test Compound showed 100% inhibition rate of
emesis in the dog at the dose of 0.32 mg/kg.
[0166] Test compound: The object compound of the Example 4-(1)
[0167] The following Preparations and Examples are given for the
purpose of illustrating this invention.
Preparation 1
[0168] (2-Methoxyethoxy)methyl chloride (4.87 ml) was added to a
solution of 3-hydroxy-4-methylbenzoic acid (2.16 g) and
N,N-diisopropylethylamine (9.2 ml) in 1,2-dichloroethane (40 ml) at
room temperature. The mixture was stirred under reflux for 24
hours. After removal of the solvent by evaporation, the residue was
partitioned between aqueous diluted hydrochloric acid solution and
ethyl acetate. The organic layer was separated and washed with
brine, dried over magnesium sulfate and evaporated under reduced
pressure. The crude oil was purified by column chromatography on
silica gel using mixed solvents of hexane and ethyl acetate (3:1).
The fractions containing the objective compound were collected and
evaporated under reduced pressure to give (2-methoxyethoxy)methyl
3-[(2-methoxyethoxy)methoxy]-4-methylbenzoate (4.82 g) as an oil.
[0169] IR (Neat): 1725, 1595 cm.sup.-1 [0170] NMR (CDCl.sub.3,
.delta.): 2.29 (3H, s), 3.37 (3H, s), 3.39 (3H, s), 3.54-3.90 (8H,
m), 5.35 (2H, s), 5.60 (2H, s), 7.21 (1H, d, J=8.0 Hz), 7.65 (1H,
dd, J=1.6 and 8.0 Hz), 7.74 (1H, d, J=1.4 Hz) [0171] MASS (API-ES):
351 (M+Na).sup.+ Preparation 2
[0172] Lithium aluminum hydride (0.35 g) was added by small
portions over 12 minutes to an ice-cooled solution of
(2-methoxyethoxy)methyl
3-[(2-methoxyethoxy)methoxy]-4-methylbenzoate (3.5 g) in
tetrahydrofuran (20 ml) below 5.degree. C. under nitrogen
atmosphere. After the mixture was stirred at the same temperature
for 30 minutes, 2N sodium hydroxide (0.5 ml) was added to the
mixture. After the mixture was stirred for 30 minutes, the
insoluble materials were removed by filtration and washed with
tetrahydrofuran. The filtrate and the washing were combined, and
evaporated under reduced pressure. The residue was dissolved into
ethyl acetate, and manganese(IV) oxide (3.5 g) was added to the
solution. After being stirred under reflux for 2 hours, the
reaction mixture was filtered through Celite.RTM. and the insoluble
mass was washed with ethyl acetate. The filtrate and the washing
were combined and evaporated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel using
mixed solvents of hexane and ethyl acetate (10:1). The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
3-[(2-methoxyethoxy)methoxy]-4-methylbenzaldehyde (1.7 g) as an
oil. [0173] IR (Neat): 1687, 1407 cm.sup.-1 [0174] NMR (CDCl.sub.3,
.delta.): 2.31 (3H, s), 3.38 (3H, s), 3.55-3.60 (2H, m), 3.82-3.87
(2H, m), 5.37 (2H, s), 7.30 (1H, d, J=7.7 Hz), 7.44 (1H, dd, J=1.4
and 7.7 Hz), 7.58 (1H, d, J=1.4 Hz), 9.92 (1H, s) [0175] MASS
(API-ES): 279 (M+Na+MeOH).sup.+, 247 (M+Na).sup.+ Preparation 3
[0176] To a stirred mixture of
3-[(2-methoxyethoxy)methoxy]-4-methylbenzaldehyde (1.70 g) and
1,4-diacetyl-2,5-piperazinedione (1.6 g) in a mixture of
N,N-dimethylformamide (17 ml) and tert-butanol (17 ml) was added
potassium tert-butoxide (900 mg) at 5.degree. C. The mixture was
stirred for 24 hours at room temperature and then poured into water
(300 ml). The aqueous mixture was adjusted to pH 4-5 with aqueous
diluted hydrochloric acid solution and extracted with ethyl
acetate. The extract was washed with brine, dried over sodium
sulfate and evaporated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel using
mixed solvents of toluene and ethyl acetate (3:1) The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
1-acetyl-3-[3-[(2-methoxyethoxy)methoxy]-4-methylphenyl]-methylene-2,5-pi-
perazinedione (2.05 g) as a powder. [0177] IR (KBr): 3208, 1700,
1627, 1598, 1455, 1375 cm.sup.-1 [0178] NMR (CDCl.sub.3, .delta.):
2.26 (3H, s), 2.65 (3H, s), 3.27 (3H, s), 3.58-3.62 (2H, m),
3.81-3.86 (2H, m), 4.49 (2H, s), 5.32 (2H, s), 6.94 (1H, dd, J=1.5
and 7.8 Hz), 7.15 (1H, d, J=7.8 Hz), 7.23 (1H, d, J=1.5 Hz), 7.27
(1H, s), 8.34 (1H, br s) [0179] MASS (API-ES): 417
(M+MeOH+Na).sup.+ Preparation 4
[0180] A solution of
1-acetyl-3-[[3-[(2-methoxyethoxy)methoxy]-4-methylphenyl]methylene]-2,5-p-
iperazinedione (2.0 g) in tetrahydrofuran (20 ml) was hydrogenated
over 10% palladium-carbon (50% wet, 0.2 g) at room temperature
under atmospheric pressure for 3 hours. After removal of the
catalyst by filtration, the filtrate was concentrated under reduced
pressure. The resulting residue was dissolved into tetrahydrofuran
(30 ml) and thereto was added hydrazine monohydride (1.5 ml). After
being stirred for 1 hour at room temperature, the mixture was
concentrated under reduced pressure. The residue was triturated
with isopropyl alcohol and the resulting solid was collected by
filtration to give
3-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-2,5-piperazinedione
(1.75 g). [0181] IR (KBr): 3183,3060, 1675, 1454 cm.sup.-1 [0182]
NMR (CDCl.sub.3, .delta.): 2.21 (3H, s), 2.95-4.00 (8H, m), 3.36
(3H, s), 4.20-4.27 (1H, m), 5.19 (1H, d, J=7.0 Hz), 5.38 (1H, d,
J=7.0 Hz), 6.50 (1H, br s), 6.72 (1H, br s), 6.75 (1H, dd, J=1.4
and 7.9 Hz), 6.97 (1H, d, J=1.4 Hz), 7.08 (1H, d, J=7.9 Hz) [0183]
MASS (APCI): 323 (M+H).sup.+, 247, 235 Preparation 5
[0184] Lithium aluminum hydride (0.62 mg) was added to an
ice-cooled solution of
3-[3-[(2-methoxyethoxy)methoxy]-4-methyl]-benzyl-2,5-piperazinedione
(1.7 g) in tetrahydrofuran (17 ml) below 5.degree. C. under
nitrogen atmosphere. The mixture was stirred under reflux for 3.5
hours. After the mixture was cooled below 5.degree. C., 2N sodium
hydroxide was added to the mixture. After the mixture was stirred
for 30 minutes at the same temperature, the insoluble materials
were removed by filtration and washed with tetrahydrofuran. The
filtrate and the washing were combined and evaporated under reduced
pressure. The residue was dissolved into ethyl acetate, and the
solution was dried over sodium sulfate and evaporated under reduced
pressure to give
2-[3-[(2-methoxyethoxy)-methoxy]-4-methylbenzyl]piperazine (1.27 g)
as an oil.
[0185] A solution of benzyloxycarbonyl chloride (0.75 g) in
dichloromethane (1 ml) was added dropwise over 5 minutes to an
ice-cooled solution of
2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (1.27 g)
obtained by above procedure and triethylamine (2.2 ml) in
dichloromethane (10 ml) below 5.degree. C. After the mixture was
stirred for 30 minutes at the same temperature, a solution of
3,5-bis(trifluoromethyl)-benzoyl chloride (0.93 ml) in
dichloromethane (1.0 ml) was added dropwise to the mixture over 10
minutes below 5.degree. C. After being stirred for 30 minutes at
the same temperature, the reaction mixture was washed with brine,
dried over magnesium sulfate and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
using mixed solvents of toluene and ethyl acetate (5:1). The
fractions containing the objective compound were collected and
evaporated under reduced pressure to give
1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-[3-[(2-methox-
yethoxy)methoxy]-4-methylbenzyl]piperazine (1.61 g) as an oil.
[0186] IR (Neat): 2879, 1700, 1645 cm.sup.-1 [0187] NMR
(CDCl.sub.3, .delta.): 2.19 (3H, s), 3.35 (3H, s), 2.40-5.40 (17H,
m), 6.40-8.10 (10H, m), 7.82 (1H, br s) [0188] MASS (APCI): 669
(M+H).sup.+ Preparation 6
[0189] A solution of
1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-[3-[(2-methox-
yethoxy)methoxy]-4-methylbenzyl]piperazine (1.6 g) in methanol (20
ml) was hydrogenated over 10% palladium-carbon (50% wet, 0.2 g) at
room temperature under atmospheric pressure for 4 hours. After
removal of the catalyst by filtration, the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel using mixed solvents of
dichloromethane and methanol (40:1). The fractions containing the
objective compound were collected and evaporated under reduced
pressure to give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]piperazine (0.89 g) as an oil. [0190] IR (Neat): 1732,
1714, 1705, 1647, 1431 cm.sup.-1 [0191] NMR (CDCl.sub.3, .delta.):
2.20 (3H, s), 2.50-5.20 (16H, m), 3.00 (3H, s), 6.40-7.40 (5H, m),
7.80 (1H, s) [0192] MASS (API-ES): 557 (M+Na).sup.+, 535
(M+H).sup.+ Preparation 7
[0193] To a mixed solution of (3R)-3-(methoxymethyl)morpholine
hydrochloride (4.71 g) and triethylamine (4.11 ml) in methanol (110
ml) was added 5.8M ethylene oxide (22 ml) in toluene solution at
room temperature. After the reaction mixture was stirred at the
same temperature for two days, it was evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel using mixed solvents of dichloromethane and methanol
(20:1). The fractions containing the objective compound were
collected and evaporated under reduced pressure to give
2-[(3R)-3-methoxymethylmorpholino]ethanol (4.67 g) as an oil.
[0194] IR (Neat): 3433, 2860, 1454, 1119, 1055 cm.sup.-1 [0195] NMR
(CDCl.sub.3, .delta.): 2.38-3.05 (5H, m), 3.33 (3H, s), 3.40-3.80
(8H, m) [0196] MASS (APCI): 176 (M+H).sup.+ Preparation 8
[0197] The following compounds were obtained according to a similar
manner to that of Preparation 8. [0198] (1)
2-[cis-2,6-Dimethylmorpholino]ethanol [0199] IR (Neat): 3431, 3402,
1456, 1373, 1325, 1146 cm.sup.-1 [0200] NMR (CDCl.sub.3, .delta.):
1.17 (6H, d, J=6.3 Hz), 1.84 (2H, dd, J=10.2 and 11.4 Hz), 2.5.2
(2H, t, J=5.5 Hz), 2.71-2.78 (2H, m), 3.65 (2H, t, J=5.6 Hz),
3.49-3.76 (2H, m) [0201] MASS (APCI): 160 (M+H).sup.+ [0202] (2)
2-[(2S,5S)-2-Methoxymethyl-5-methylmorpholino]ethanol [0203] IR
(Neat): 3433, 3400, 1456, 1379, 1327, 1086, 1051 cm.sup.-1 [0204]
NMR (CDCl.sub.3, .delta.): 1.19 (3H, d, J=6.3 Hz), 1.88 (1H, d,
J=10.8 Hz), 1.96 (1H, t, J=10.5 Hz), 2.54 (2H, t, J=5.5 Hz),
2.72-2.83 (2H, m), 3.38 (3H, s), 3.36-3.45 (2H, m), 3.63 (2H, t,
J=5.2 Hz), 3.60-3.90 (2H, m) [0205] MASS (APCI): 190 (M+H).sup.+
[0206] (3) 2-[(2S)-2-(Methoxymethyl)morpholino]ethanol [0207] IR
(Neat): 3435, 1456, 1354, 1302 cm.sup.-1 [0208] NMR (CDCl.sub.3,
.delta.): 2.06 (1H, t, J=10.7 Hz), 2.27 (1H, td, J=10.7 and 3.3
Hz), 2.53-2.58 (2H, m), 2.68-2.84 (2H, m), 3.38 (3H, s), 3.38-3.44
(2H, m), 3.61-3.75 (4H, m), 3.89-3.98 (1H, m) [0209] MASS (API-ES):
176 (M+H).sup.+, 198 (M+Na).sup.+ Preparation 9
[0210] To an ice-cooled solution of
2-[(3R)-3-methoxymethylmorpholino]ethanol (505 mg) in toluene (2.5
ml) was added dropwise a solution of thionyl chloride (429 mg) in
toluene (1.5 ml) below 5.degree. C. under nitrogen atmosphere. The
mixture was stirred at 70.degree. C. for 1.5 hours. After the
mixture was cooled at room temperature, ethyl acetate was added to
the mixture, and resulting suspension was evaporated under reduced
pressure. Diisopropyl ether was added to the residue, and after the
mixture was stirred at room temperature for 15 minutes, the
resulting precipitates were collected by filtration, washed with
diisopropyl ether and dried at 40.degree. C. under reduced pressure
to give (3R)-4-(2-chloroethyl)-3-(methoxymethyl)morpholine
hydrochloride (620 mg) as a light yellowish powder. [0211] mp:
162-163.degree. C. [0212] IR (KBr): 2945, 1140, 1109, 1084
cm.sup.-1 [0213] NMR (DMSO-d.sub.6, .delta.): 3.31 (3H, s),
3.10-4.10 (13H, m) [0214] MASS (APCI): 194 (M+H).sup.+ (free)
Preparation 10
[0215] The following compounds were obtained according to a similar
manner to that of Preparation 9. [0216] (1)
cis-2,6-Dimethyl-4-(2-chloroethyl)morpholine hydrochloride [0217]
IR (KBr): 1513, 1458, 1394, 1336, 1143 cm.sup.-1 [0218] NMR
(DMSO-d.sub.6, .delta.): 1.12 (6H, d, J=6.3 Hz), 2.60-2.80 (2H, m),
3.44-3.50 (4H, m), 3.95-4.10 (4H, m) [0219] MASS (APCI): 178
(M+H).sup.+ (free) [0220] (2)
(2S,5S)-4-(2-Chloroethyl)-2-methoxymethyl-5-methylmorpholine
hydrochloride [0221] IR (KBr): 2613, 1456, 1390, 1124, 1082
cm.sup.-1 [0222] NMR (DMSO-d.sub.6, .delta.): 1.13 (3H, d, J=6.3
Hz), 2.50-3.00 (3H, m), 3.27 (3H, s), 3.34-3.51 (7H, m), 4.03-4.10
(4H, m) [0223] MASS (APCI): 208 (M+H).sup.+ (free) [0224] (3)
(2S)-4-(2-Chloroethyl)-2-(methoxymethyl)morpholine hydrochloride
[0225] NMR (DMSO-d.sub.6, .delta.): 3.00 (2H, m), 3.27 (3H, s),
3.47 (4H, m), 3.75-4.12 (7H, m), 11.91 (1H, m) [0226] MASS (APCI):
194 (M+H).sup.+ (free) Preparation 11
[0227] Sodium triacetoxyborohydride (36.7 g) was added
portionwisely to a mixture of (2S)-2-amino-1-propanol (10.0 g) and
benzaldehyde (13.53 ml) in a mixture of dichloromethane (140 ml)
and acetic acid (8.38 ml) at 0.degree. C. and the whole was stirred
at room temperature overnight. The mixture was washed successively
with 2N sodium hydroxide and brine, and dried over sodium sulfate.
The solution was evaporated under reduced pressure and the
resulting residue was purified by column chromatography on silica
gel using a mixed solvent of dichloromethane and methanol (30:1).
The fractions containing the objective compound were collected and
evaporated under reduced pressure to give
(2S)-2-benzylamino-1-propanol (15.96 g). [0228] IR (KBr): 2843,
1496, 1454, 1377, 1340, 1065 cm.sup.-1 [0229] NMR (CDCl.sub.3,
.delta.): 1.10 (3H, d, J=6.4 Hz), 2.77-2.93 (1H, m), 3.28 (1H, dd,
J=10.6 and 6.9 Hz), 3.61 (1H, dd, J=10.6 and 4.0 Hz), 3.75, 3.87
(2H, ABq, J=13 Hz), 7.21-7.34 (5H, m) [0230] MASS (API-ES): 166
(M+H).sup.+ Preparation 12
[0231] (s)-(+)-Methyl glycidyl ether (8.25 ml) was added dropwise
to a solution of (2S)-2-benzylamino-1-propanol (7.6 g) in methanol
(7.6 ml) at room temperature. After being stirred at 40-50.degree.
for 24 hours, the solution was concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
using mixed solvents of dichloromethane and methanol (30:1). The
fractions containing the objective compound were collected and
evaporated under reduced pressure to give
(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-1-propa-
nol (10.4 g) as an oil. [0232] IR (Neat): 3400, 2929, 1452, 1414,
1373, 1329 cm.sup.-1 [0233] NMR (CDCl.sub.3, .delta.): 0.96 (3H, d,
J=6.7 Hz), 2.50-2.60 (1H, m), 2.57 (1H, dd, J=13.4 and 6.2 Hz),
2.67 (1H, dd, J=13.4 and 6.5 Hz), 2.95-3.10 (1H, m), 3.21-3.52 (4H,
m), 3.30 (3H, s), 3.49 (1H, d, J=13.6 Hz), 3.71-3.75 (1H, m), 3.83
(1H, d, J=13.6 Hz), 7.21-7.37 (5H, m) [0234] MASS (APCI): 254
(M+H).sup.+ Preparation 13
[0235] Triphenylphosphine (10.09 g) was added to a solution of
(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-1-propanol
(8.86 g) in tetrachloromethane (4.06 ml) at room temperature. After
being stirred at room temperature for 2 days, the solution was
concentrated under reduced pressure. The residue was triturated
with diisopropyl ether (200 ml) three times, and the soluble
portions were separated by decantation and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel using mixed solvents of dichloromethane and methanol
(40:1). The fractions containing the objective compound were
collected and evaporated under reduced pressure to give
(2S)-1-[N-benzyl-N-[(1S)-2-chloro-1-methylethyl]amino]-3-methoxy--
2-propanol (4.90 g) as an oil. [0236] IR (Neat): 3463, 1452, 1362
cm.sup.-1 [0237] NMR (CDCl.sub.3, .delta.): 1.43 (3H, d, J=6.6 Hz),
2.53-2.82 (4H, m), 3.30-3.39 (2H, m), 3.36 (3H, s), 3.59 (1H, d,
J=13.6 Hz), 3.83 (1H, d, J=13.6 Hz), 3.79-3.87 (1H, m), 4.01-4.09
(1H, m), 7.21-7.33 (5H, m) [0238] MASS (APCI): 272 (M+H).sup.+
Preparation 14
[0239] A solution of
(2S)-1-[N-benzyl-N-[(1S)-2-chloro-1-methylethyl]amino]-3-methoxy-2-propan-
ol (1.90 g) in N,N-dimethylformamide (10 ml) was added to an
ice-cooled suspension of sodium hydride (0.45 g, 60% in mineral
oil) in N,N-dimethylformamide (10 ml) at 0.degree. C. After being
stirred for 1 hour at the same temperature, the mixture was poured
into ice-water and extracted with ethyl acetate. The extract was
washed with brine, dried over magnesium sulfate and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel using mixed solvents of hexane and
ethyl acetate (10:1). The fractions containing the objective
compound were collected and evaporated under reduced pressure to
give (2S,5S)-4-benzyl-2-methoxymethyl-5-methylmorpholine (0.86 g)
as an oil. [0240] IR (Neat): 2875, 1452, 1362, 1325, 1130, 1082
cm.sup.-1 [0241] NMR (CDCl.sub.3, .delta.): 1.15 (3H, d, J=6.3 Hz),
1.73-1.93 (2H, m), 2.68-2.77 (2H, m), 3.35 (3H, s), 3.49 (2H, s),
3.31-3.49 (2H, m), 3.68-3.81 (2H, m), 7.25-7.32 (5H, m) [0242] MASS
(APCI): 236 (M+H).sup.+ Preparation 15
[0243] A solution of
(2S,5S)-4-benzyl-2-methoxymethyl-5-methylmorpholine (0.86 g) in a
mixture of concentrated hydrochloric acid (0.31 ml) and methanol
(8.6 ml) was hydrogenated over 10% palladium-carbon (50% wet, 0.2
g) at room temperature under atmospheric pressure for 3 hours.
After removal of the catalyst by filtration through Celite.RTM.,
the filtrate was concentrated under reduced pressure to give
(2S,5S)-2-methoxymethyl-5-methylmorpholine hydrochloride (0.71 g)
as an oil. [0244] IR (Neat): 3433,3402, 2939, 1597, 1456, 1392,
1331, 1107 cm.sup.-1 [0245] NMR (DMSO-d.sub.6, .delta.): 1.12 (3H,
d, J=6.3 Hz), 2.49-2.75 (2H, m), 3.13-3.19 (2H, m), 3.27 (3H, s),
3.38 (2H, d, J=4.8 Hz), 3.80-4.00 (2H, m) [0246] MASS (APCI): 146
(M+H).sup.+ (free) Preparation 16
[0247] N-Acetyl-3-methoxy-4-methyl-DL-phenylalanine (7.28 g) was
dissolved into a mixture of water (36.5 ml) and 1N sodium hydroxide
solution (29 ml). Cobalt(II) chloride hexahydrate (36.5 mg) and
acylase (Acylase Amano, 365 mg) were added to the solution and the
mixture was stirred at 37.degree. C. for 15.5 hours with
controlling the pH of the reaction mixture to 7.5 with 1N sodium
hydroxide solution. The insoluble material was removed by
filtration and the pH of the filtrate was made to 3 with 6N
hydrochloric acid, extracted with ethyl acetate, washed with water,
dried over sodium sulfate, and evaporated in vacuo to give crude
N-acetyl-3-methoxy-4-methyl-D-phenylalanine (3.17 g). The crude
product was again subjected to the acylase reaction (cobalt(II)
chloride hexahydrate 15.2 mg, acylase 152 mg, 37.degree. C., pH
7.5, 20 hours) to give pure
N-acetyl-3-methoxy-4-methyl-D-phenylalanine (2.70 g) as a viscous
oil. [0248] [.alpha.].sub.D.sup.26.8: -36.16.degree. (C=0.424,
MeOH) [0249] IR (Neat): 3350, 1740, 1725 cm.sup.-1 [0250] NMR
(CDCl.sub.3, .delta.): 1.99 (3H, s), 2.17 (3H, s), 3.00-3.30 (2H,
m), 3.78 (3H, s), 4.75-4.90 (1H, m), 6.00-7.10 (3H, m), 6.36 (2H,
br s) [0251] MASS (APCI): 252 (N+H).sup.+ Preparation 17
[0252] A mixture of N-acetyl-3-methoxy-4-methylphenyl-D-alanine
(2.55 g) in a mixture of 6N hydrochloric acid (25.5 ml) and toluene
(18 ml) was stirred under reflux for 4 hours. After being cooled to
room temperature, the aqueous layer was separated and the organic
layer was washed with water (10 ml) twice. The aqueous layer and
the washings were combined and evaporated under reduced pressure.
The resulting crystals were collected by filtration and washed with
ice-water to give 3-methoxy-4-methyl-D-phenylalanine hydrochloride
(1.35 g) as colorless crystals. The filtrate was evaporated under
reduced pressure to give crude 3-methoxy-4-methyl-D-phenylalanine
hydrochloride (0.6 g). [0253] mp: 207-211.degree. C. [0254]
[.alpha.].sub.D.sup.27.2: +20.2.degree. (C=0.5, H.sub.2O) [0255] IR
(KBr): 1735, 1610, 1508 cm.sup.-1 [0256] NMR (D.sub.2O, .delta.):
2.18 (3H, s), 3.17 (1H, dd, J=7.6 and 14.6 Hz), 3.32 (1H, dd, J=6.0
and 14.6 Hz), 3.85 (3H, s), 4.27 (1H, dd, J=6.0 and 7.0 Hz), 6.85
(1H, d, J=7.3 Hz), 6.91 (1H, s), 7.21 (1H, d, J=8.0 Hz) [0257] MASS
(APCI): 210 (M+H).sup.+ (free) Preparation 18
[0258] Thionyl chloride (0.7 ml) was added dropwise to a solution
of 3-methoxy-4-methyl-D-phenylalanine hydrochloride (1.75 g) in
methanol (8 ml) over 10 minutes at room temperature. The whole was
stirred at 40-50.degree. C. for 2 hours and then an additional
thionyl chloride (0.7 ml) was added to the mixture. The whole
mixture was stirred for further 1 hour and evaporated under reduced
pressure. The resulting solid was triturated with diisopropyl ether
and collected by filtration to give colorless crystals of
3-methoxy-4-methyl-D-phenylalanine methyl ester hydrochloride (1.70
g) [0259] mp: 196-197.degree. C. [0260] [.alpha.].sub.D.sup.30:
-4.60.degree. (C=0.5, MeOH) [0261] IR (Nujol): 3400, 1741, 1583,
1465, 1446, 1249 cm.sup.-1 [0262] NMR (D.sub.2O, .delta.): 2.19
(3H, s), 3.21 (1H, dd, J=7.4 and 14.5 Hz), 3.32 (1H, dd, J=6.0 and
14.5 Hz), 3.85 (6H, s), 4.43 (1H, dd, J=6.0 and 7.4 Hz), 6.82 (1H,
dd, J=1.4 and 7.6 Hz), 6.87 (1H, d, J=1.4 Hz), 7.22 (1H, d, J=7.6
Hz) [0263] MASS (APCI): 224 (M+H).sup.+ (free), 207, 164
Preparation 19
[0264] Potassium carbonate (1.70 g) was added by small portions
with ice-cooling to a mixture of 3-methoxy-4-methyl-D-phenylalanine
methyl ester hydrochloride (1.60 g) in mixed solvents of
dichloromethane (7 ml) and water (9 ml). Chloroacetyl chloride
(0.66 ml) was added to the mixture below 5.degree. C. over 15
minutes and then the whole was stirred for 30 minutes. The organic
layer was separated, washed with brine, dried over magnesium
sulfate and evaporated under reduced pressure to give an oil of
(2R)-2-[N-(chloroacetyl)-amino]-3-(3-methoxy-4-methylphenyl)propio-
nic acid methyl ester. [0265] IR (Neat): 3305, 1737, 1643, 1583
cm.sup.-1 Preparation 20
[0266] Benzylamine (1.65 g) and potassium carbonate (1.28 g) were
added successively to a solution of
(2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic
acid methyl ester (1.85 g) in N,N-dimethylformamide (15 ml) at
20.degree. C. After being stirred at 35.degree. C. for 1.5 hours,
the mixture was poured into a mixture of ice-water (20 ml) and
dichloromethane (20 ml). After the mixture was adjusted to pH 9
with diluted aqueous hydrochloric acid under stirring, the organic
layer was separated, washed with brine (20 ml), dried over
magnesium sulfate and evaporated under reduced pressure to give an
oil of
(2R)-2-[N-(benzylaminoacetyl)-amino]-3-(3-methoxy-4-methylphenyl)propioni-
c acid methyl ester. A solution of
(2R)-2-[N-(benzylaminoacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic
acid methyl ester obtained by above procedure and acetic acid (0.18
ml) in isopropyl alcohol (10 ml) was stirred for 12 hours under
reflux.
[0267] After the mixture was cooled to room temperature, isopropyl
ether was added to the mixture. The resulting precipitates were
collected by filtration and washed with isopropyl ether to give
colorless crystals of
(3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine-2,5-dione
(1.45 g) [0268] mp: 205-209.degree. C. [0269]
[.alpha.].sub.D.sup.30: +11.12.degree. (C=0.4, DMF) [0270] IR
(KBr): 3237, 1677, 1656, 1465, 1446, 1442 cm.sup.-1 [0271] NMR
(DMSO-d.sub.6, .delta.): 2.08 (3H, s), 2.76 (1H, d, J=17.2 Hz),
2.87 (1H, dd, J=4.8 and 13.4 Hz), 3.11 (1H, dd, J=4.8 and 13.4 Hz),
3.46 (1H, d, J=17.2 Hz), 3.69 (3H, s), 4.25 (1H, d, J=14.6 Hz),
4.20-4.30 (1H, m), 4.52 (1H, d, J=14.6 Hz), 6.54 (1H, dd, J=1.4 and
7.4 Hz), 6.69 (1H, d, J=1.4 Hz), 6.87 (1H, d, J=7.4 Hz), 7.04-7.11
(2H, m), 7.24-7.30 (3H, m), 8.33 (1H, d, J=2.2 Hz) [0272] MASS
(APCI): 339 (M+H).sup.+ Preparation 21
[0273] Lithium aluminum hydride (0.378 g) was added to an
ice-cooled suspension of
(3R)-1-benzyl-3-(3-methoxy-4-methylphenyl)-2,5-piperazinedione
(1.35 g) in tetrahydrofuran (22 ml) below 5.degree. C. under
nitrogen atmosphere. The mixture was stirred under reflux for 3
hours. After the mixture was cooled below 5.degree. C., 2N sodium
hydroxide was added to the mixture. After the mixture was stirred
for 30 minutes, the insoluble materials were removed by filtration
and washed with tetrahydrofuran. The filtrate and the washing were
combined and evaporated under reduced pressure to give
(3R)-1-benzyl-3-(3-methoxy-4-methylphenyl)piperazine as an oil. A
solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.80 ml) in
dichloromethane (1 ml) was added dropwise over 5 minutes to an
ice-cooled solution of
(3R)-1-benzyl-3-(3-methoxy-4-methylphenyl)piperazine obtained by
above procedure and triethylamine (0.84 ml) in dichloromethane (10
ml) below 5.degree. C. After being stirred for 30 minutes at the
same temperature, the reaction mixture was washed with brine, dried
over magnesium sulfate and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel using
mixed solvents of hexane and ethyl acetate (4:1). The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbe-
nzyl)piperazine (1.92 g) as an oil. [0274] IR (Neat): 2950, 2850,
1640, 1590, 1515 cm.sup.-1 [0275] NMR (CDCl.sub.3, .delta.): 2.16
(3H, s), 2.00-5.20 (14H, m), 6.25-6.32 (1H, m), 6.70-6.90 (2H, m),
7.20-7.44 (7H, m), 7.80 (1H, br s) [0276] MASS (APCI): 551
(M+H).sup.+, 573 (M+Na).sup.+ Preparation 22
[0277] A solution of boron tribromide in dichloromethane (1M
solution, 3.7 ml) was added dropwise over 20 minutes to an
ice-cooled solution of
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbe-
nzyl)-piperazine (0.68 g) in dichloromethane (5 ml) After being
stirred at the same temperature for 2 hours, followed by further
stirring at room temperature for 12 hours, the mixture was poured
into aqueous saturated sodium hydrogen carbonate solution. The
organic layer was separated, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using mixed solvents of hexane
and ethyl acetate (4:1). The fractions containing the objective
compound were collected and evaporated under reduced pressure to
give
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4--
methylbenzyl)piperazine (0.56 g) as a red foam. [0278] IR (Neat):
1630, 1430 cm.sup.-1 [0279] NMR (CDCl.sub.3, .delta.): 2.00-5.20
(14H, m), 5.61 (1H, br s), 6.20-6.25 (1H, m), 6.60-7.70 (2H, m),
7.20-7.60 (7H, m), 7.80-7.85 (1H, m) [0280] MASS (API-ES): 519
(M-H.sub.2O+H).sup.+, 537 (M+H).sup.+, 559 (M+Na).sup.+ Preparation
23
[0281] Sodium hydride (60% in mineral oil, 18 mg) was added by
small portions to an ice-cooled solution of
(2R)-4-benzyl-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine
(0.20 g) in N,N-dimethylformamide (2 ml) below 5.degree. C. under
nitrogen atmosphere. After the mixture was stirred for 5 minutes,
(2-methoxyethoxy)methyl chloride (0.064 ml) was added to the
mixture. The whole was stirred at room temperature for 2.5 hours,
and thereto water was added. The whole was extracted with ethyl
acetate. The extract was dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using mixed solvents of hexane
and ethyl acetate (7:3). The fractions containing the objective
compound were collected and evaporated under reduced pressure to
give
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methox-
yethoxy)methoxy]-4-methylbenzyl]piperazine (0.21 g) as an oil.
[0282] IR (Neat): 2950, 1645, 1435 cm.sup.-1 [0283] NMR
(CDCl.sub.3, .delta.): 2.19 (3H, s), 3.34 (3H, s), 2.00-5.20 (17H,
m), 6.60-7.40 (10H, m), 7.70-7.80 (1H, m) [0284] MASS (API-ES): 625
(M+H).sup.+, 647 (M+Na).sup.+ Preparation 24
[0285] A mixture of
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy-
)methoxy]-4-methylbenzyl]-piperazine (0.38 g) in methanol (6 ml)
was hydrogenated over 20% palladium hydroxide-carbon (0.06 g) at
room temperature under atmospheric pressure for 8 hours. After
removal of the catalyst by filtration through Celite.RTM., the
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using mixed
solvents of dichloromethane and methanol (30:1). The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]piperazine (0.32 g) as an oil. [0286] IR (KBr):
3000-2700, 1629, 1513, 1444 cm.sup.-1 [0287] NMR (CDCl.sub.3,
.delta.): 2.20 (3H, s), 2.50-5.30 (16H, m), 3.36 (3H, s), 6.40-7.50
(5H, m), 7.80 (1H, s) [0288] MASS (API-ES): 535 (M+H).sup.+, 557
(M+Na).sup.+
EXAMPLE 1
[0289] To a solution of
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]piperazine (440 mg) in N,N-dimethylformamide (2.2 ml)
were added (3R)-4-(2-chloroethyl)-3-(methoxymethyl)morpholine
hydrochloride (289 mg), potassium carbonate (434 mg) and potassium
iodide (149 mg) at room temperature. The whole was stirred at
73.degree. C. for 2 hours. After being cooled to room temperature,
the mixture was poured into ice-water and the aqueous mixture was
made alkaline with saturated aqueous sodium hydrogen carbonate
solution. The resulting mixture was extracted with ethyl acetate.
The extract was washed with brine, dried over sodium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using mixed solvents of
dichloromethane and methanol (40:1). The fractions containing the
objective compound were collected and evaporated under reduced
pressure to give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)-metho-
xy]-4-methylbenzyl]-4-[2-[(3R)-3-methoxymethyl-morpholino]ethyl]piperazine
(450 mg) as a light yellowish oil. [0290] IR (Neat): 2879, 1639,
1437, 1281, 1136, 1009 cm.sup.-1 [0291] NMR (CDCl.sub.3, .delta.):
2.20 (3H, s), 1.95-5.40 (34H, m), 6.40-8.10 (6H, m) [0292] MASS
(APCI): 692 (M+H).sup.+
EXAMPLE 2
[0293] The following compounds were obtained according to a similar
manner to that of Example 1. [0294] (1)
1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino)ethy-
l]-2-[3-[(2-methoxyethoxy)-methoxy]-4-methylbenzyl]piperazine
[0295] IR (Neat): 1680, 1643, 1508, 1435 cm.sup.-1 [0296] NMR
(CDCl.sub.3, .delta.): 1.17 (6H, d, J=6.3 Hz), 1.78 (2H, t, J=10.8
Hz), 2.20 (3H, br s), 2.20-5.30 (23H, m), 3.36 (3H, s), 6.42-8.02
(6H, m) [0297] MASS (APCI): 676 (M+H).sup.+ [0298] (2)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]-4-[2-[(2S,5S)-2-methoxymethyl-5-methylmorpholino]ethyl]piperazi-
ne [0299] IR (Neat): 2933, 2881, 1643, 1439, 1281, 1086, 1012
cm.sup.-1 [0300] NMR (CDCl.sub.3, .delta.): 1.18 (3H, d, J=6.2 Hz),
1.78-1.96 (2H, m), 2.20 (3H, br s), 2.20-5.30 (25H, m), 3.37 (3H,
s), 3.36 (3H, s), 6.66-7.80 (6H, m) [0301] MASS (API-ES): 706.3
(M+H).sup.+, 728.3 (M+Na).sup.+
EXAMPLE 3
[0302]
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy-
]-4-methylbenzyl]-4-[2-[(3R)-3-(methoxymethyl)morpholino]ethyl]piperazine
(430 mg) was dissolved in methanol (10 ml) at room temperature, and
methanesulfonic acid (0.215 ml) was added to the solution. After
being stirred at the same temperature for 18 hours, the reaction
mixture was concentrated until one third of original volume under
reduced pressure, and poured into iced water. The aqueous mixture
was made alkaline with 15% aqueous sodium hydroxide solution, and
the resulting mixture was extracted with ethyl acetate. The extract
was washed with brine, dried over sodium sulfate and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel using mixed solvents of
dichloromethane and methanol (30:1). The fractions containing the
objective compound were collected and evaporated under reduced
pressure, and the residue was treated with 4N hydrogen chloride in
ethyl acetate solution to give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-hydroxy-4-methylbenzyl]-4-[2-[(3-
R)-3-(methoxymethyl)-morpholino]ethyl]piperazine dihydrochloride
(280 mg) as a colorless powder. [0303] mp: 167-172.degree. C.
[0304] [.alpha.].sub.D.sup.28: -8.50.degree. (C=0.20, MeOH) [0305]
IR (KBr): 3400, 1645, 1429, 1282, 1184, 1138 cm.sup.-1 [0306] NMR
(DMSO-d.sub.6, .delta.): 2.08 (3H, s), 2.60-5.10 (25H, m),
6.18-7.10 (3H, m), 7.36-8.22 (3H, m), 9.25 (1H, br) [0307] MASS
(APCI): 604 (M+H).sup.+ (free)
EXAMPLE 4
[0308] The following compounds were obtained according to a similar
manner to that of Example 3. [0309] (1)
1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino)ethy-
l]-2-(3-hydroxy-4-methylbenzyl)piperazine dihydrochloride [0310]
mp: 188-200.degree. C. [0311] [.alpha.].sub.D.sup.29: +0.70.degree.
(C=0.25, MeOH) [0312] IR (KBr): 3402, 1643, 1516, 1429 cm.sup.-1
[0313] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H, d, J=6.0 Hz), 2.08
(3H, br s), 2.00-5.10 (19H, m), 6.19-8.21 (6H, m) [0314] MASS
(APCI): 588 (M+H).sup.+ (free) [0315] (2)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[2-[(2-
S,5S)-2-methoxymethyl-5-methylmorpholino]ethyl]piperazine
dihydrochloride [0316] mp: 214-218.degree. C. [0317]
[.alpha.].sub.D.sup.29: +0.80.degree. (C=0.25, MeOH) [0318] IR
(KBr): 3433,3398, 1645, 1516, 1429, 1371, 1281, 1182, 1140
cm.sup.-1 [0319] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, d, J=6.0
Hz), 2.08 (3H, br s), 2.50-5.10 (21H, m), 3.27 (3H, s), 6.20-8.20
(6H, m), 9.00-9.20 (1H, m) [0320] MASS (APCI): 618 (M+H).sup.+
(free) [0321] (3)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzoy)-4-[3-(3--
pyridyl)-2-propynyl]piperazine [0322] NMR (CDCl.sub.3, .delta.):
0.60-5.30 (14H, m), 5.77 (1H, br s), 6.20-8.90 (10H, m) [0323] MASS
(APCI): 562 (M+H).sup.+
EXAMPLE 5
[0324] The following compounds were obtained according to a similar
manner to that of Example 1 and then a similar manner to that of
Example 3. [0325] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morp-
holino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine
dihydrochloride [0326] mp: 207-210.degree. C. [0327]
[.alpha.].sub.D.sup.26.2: -6.40.degree. (C=0.4, MeOH) [0328] IR
(KBr): 3300, 3000, 2700, 1644, 1428 cm.sup.-1 [0329] NMR
(DMSO-d.sub.6, .delta.): 2.18 (3H, s), 2.20-5.20 (22H, m),
6.10-8.20 (6H, m), 9.00-9.40 (1H, br s), 11.00-12.00 (2H, m) [0330]
MASS (APCI): 604 (M+H).sup.+ (free) [0331] (2)
1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholin-
o]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine dihydrochloride
[0332] IR (KBr): 1645, 1516, 1458, 1425, 1369 cm.sup.-1 [0333] NMR
(DMSO-d.sub.6, .delta.): 2.08 (3H, br s), 3.28 (3H, br s),
2.40-5.10 (22H, m), 6.19-8.22 (6H, m) [0334] MASS (APCI): 604
(M+H).sup.+ (free)
EXAMPLE 6
[0335] A mixture of
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]piperazine (0.4 g), 1-chloro-3-(3-pyridyl)-2-propyne
hydrochloride (0.17 g), potassium carbonate (0.52 g) and a trace of
potassium iodide in N,N-dimethylformamide (7 ml) was stirred for 4
hours at 80.degree. C. After cooling, the solvent was removed by
evaporation, and ethyl acetate and aqueous sodium hydrogen
carbonate solution were added thereto. The organic layer was
separated, dried over magnesium sulfate, and evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel using ethyl acetate. The fractions containing the
objective compound were collected and evaporated under reduced
pressure to give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine (0.44 g) as an
oil. [0336] NMR (CDCl.sub.3, .delta.): 0.60-5.60 (23H, m),
6.30-8.90 (10H, m) [0337] MASS (APCI): 650 (M+H).sup.+
EXAMPLE 7
[0338] A solution of
1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3--
pyridyl)-2-propynyl]-piperazine (0.11 g) in methanol (10 ml) was
treated with 4N hydrogen chloride in ethyl acetate (1 ml) and the
mixture was evaporated under reduced pressure. The residue was
triturated with a mixture of dichloromethane and ethyl acetate and
the resulting powder was collected by filtration to give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3--
pyridyl)-2-propynyl]piperazine dihydrochloride (0.07 g). [0339] mp:
180-190.degree. C. [0340] IR (KBr): 1693, 1676, 1645, 1549, 1531,
1516, 1460, 1456, 1427, 1392, 1367, 1317, 1281, 1217, 1188, 1066
cm.sup.-1 [0341] NMR (DMSO-d.sub.6, .delta.): 1.60-5.20 (14H, m),
6.10-9.00 (10H, m) [0342] MASS (APCI): 562 (M+H).sup.+ (free)
EXAMPLE 8
[0343] A solution of
1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3--
pyridyl)-2-propynyl]-piperazine (0.16 g) in a mixed solvent of
methanol (10 ml) and tetrahydrofuran (10 ml) was hydrogenated over
10% palladium-charcoal (20 mg) at room temperature for 1.5 hours.
After removal of catalyst by filtration, the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel using ethyl acetate as an
eluent. The fractions containing the objective compound were
collected and evaporated under reduced pressure and the resulting
residue was treated with 4N hydrogen chloride in ethyl acetate to
give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3--
pyridyl)propyl]piperazine dihydrochloride (0.17 g) as a colorless
solid. [0344] mp: 60-70.degree. C. [0345] IR (KBr): 1707, 1693,
1676, 1645, 1628, 1558, 1550, 1541, 1516, 1466, 1456, 1427, 1387,
1365, 1329, 1319, 1281, 1182, 1136, 1039 cm.sup.-1 [0346] NMR
(DMSO-d.sub.6, .delta.): 1.80-5.20 (18H, m), 6.00-9.00 (10H, m)
[0347] MASS (APCI): 566 (M+H).sup.+ (free) Preparation 25
[0348] A solution of 3-methoxy-p-toluic acid (45.32 g) in
tetrahydrofuran (280 ml) was added to a suspension of sodium
borohydride (9.29 g) in tetrahydrofuran (45 ml) with ice bath
cooling under nitrogen atmosphere. After 10 minutes stirring, boron
trifuluoride diethyl etherate (41.5 ml) was added to the mixture at
3 to 150.degree. C. and the whole was stirred at room temperature
overnight. Water (210 ml) and diisopropyl ether (60 ml) were added
to the mixture. The organic layer was separated and the aqueous
layer was extracted with diisopropyl ether (100 ml). The combined
organic layer was washed successively with 1N sodium hydroxide
solution and brine, dried over sodium sulfate, and evaporated in
vacuo to give 3-methoxy-4-methylbenzylalcohol (41.63 g) as an oil.
[0349] IR (Neat): 3330, 1615, 1590, 1510, 1465, 1418, 1255
cm.sup.-1 [0350] NMR (CDCl.sub.3, .delta.): 1.70 (1H, br s), 2.21
(3H, s), 3.84 (3H, s), 4.65 (2H, s), 6.80-7.16 (3H, m) Preparation
26
[0351] A mixture of 3-methoxy-4-methylbenzylalcohol (41.61 g),
conc. hydrochloric acid (125 ml) and toluene (83 ml) was stirred at
90.degree. C. for 1 hour. After cooling, ice-water (125 ml) and
diisopropyl ether (80 ml) were added to the mixture, and the
organic layer was separated, and the aqueous layer was extracted
with diisopropyl ether (160 ml). The combined organic layer was
washed with saturated sodium hydrogen carbonate solution and brine,
dried over sodium sulfate, and evaporated in vacuo to give
3-methoxy-4-methylbenzyl chloride (46.35 g) as an oil. [0352] IR
(Neat): 1615, 1590, 1510, 1470, 1415, 1255 cm.sup.-1 [0353] NMR
(CDCl.sub.3, .delta.): 2.21 (3H, s), 3.85 (3H, s), 4.57 (2H, s),
6.82-7.15 (3H, m) Preparation 27
[0354] 3-Methoxy-4-methylbenzyl chloride (46.35 g) and ethyl
acetamidomalonate (71.16 g) were added successively into a solution
of sodium ethoxide (24.34 g) in ethanol (230 ml). The mixture was
stirred under reflux for 2 hours, poured into ice-water (690 ml)
and the pH of the mixture was adjusted to 7 with 6N hydrochloric
acid. The resulting precipitates were collected by filtration,
washed with aqueous ethanol (3:1, 100 ml) and dried to give crude
2-acetylamino-2-(3-methoxy-4-methylbenzyl)malonic acid diethyl
ester (85.03 g). A suspension of the crude product (80.66 g) in
heptane (400 ml) was stirred at 50.degree. C. for 1 hour and cooled
to room temperature. The resulting precipitates were collected by
filtration, washed with heptane, and dried to give pure product
(74.57 g) as a colorless crystals. [0355] mp: 123-125.degree. C.
[0356] IR (KBr): 3251, 1747, 1643, 1518, 1267, 1213, 1190, 1051
cm.sup.-1 [0357] NMR (CDCl.sub.3, .delta.): 1.30 (6H, t, J=7.1 Hz),
2.03 (3H, s), 2.16 (3H, s), 3.61 (2H, s), 3.76 (3H, s), 4.28 (4H,
q, J=7.1 Hz), 6.44-7.06 (4H, m) Preparation 28
[0358] A mixture of
2-acetylamino-2-(3-methoxy-4-methylbenzyl)-malonic acid diethyl
ester (10.0 g), potassium hydroxide solution (1.88 g) in water (25
ml) and ethanol (25 ml) were stirred under reflux for 1 hour.
Another potassium hydroxide solution (1.88 g) in water (10 ml) was
added to the mixture and the whole was stirred under reflux for 2
hours. After being cooled to room temperature, the reaction mixture
was concentrated under reduced pressure. Water (50 ml) and ethyl
acetate (50 ml) were added to the resulting aqueous solution. The
aqueous layer was separated and was adjusted to pH 1.5 with 6N
hydrochloric acid. The solution was extracted with ethyl acetate,
washed with brine, dried over sodium sulfate and evaporated under
reduced pressure to give
N-acetyl-3-methoxy-4-methyl-DL-phenylalanine (7.58 g) as a viscous
oil. [0359] IR (Neat): 3350, 1740, 1725 cm.sup.-1 [0360] NMR
(CDCl.sub.3, .delta.): 1.99 (3H, s), 2.17 (3H, s), 3.00-3.30 (2H,
m), 3.78 (3H, s), 4.75-4.90 (1H, m), 6.00-7.10 (3H, m), 6.37 (2H,
br s) Preparation 29
[0361] The following compounds were obtained according to a similar
manner to that of Preparation 27. [0362] (1)
2-Acetylamino-2-(4-chloro-3-methoxybenzyl)malonic acid diethyl
ester [0363] mp: 122-123.degree. C. [0364] IR (KBr): 3247, 2977,
1749, 1643, 1523, 1309, 1205 cm.sup.-1 [0365] NMR (CDCl.sub.3,
.delta.): 1.30 (6H, t, J=7.1 Hz), 2.03 (3H, s), 3.64 (2H, s), 3.83
(3H, s), 4.16-4.35 (4H, m), 6.53 (1H, dd, J=2.0 and 8.0 Hz), 6.56
(1H, d, J=2.0 Hz), 6.56 (1H, s), 7.23 (1H, d, J=8.0 Hz) [0366] MASS
(APCI): 372 (M+H).sup.+, 330, 282 [0367] (2)
2-Acetylamino-2-(4-fluoro-3-methoxybenzyl)malonic acid diethyl
ester [0368] mp: 128-131.degree. C. [0369] IR (KBr): 2981, 1747,
1641, 1520, 1269, 1211 cm.sup.-1 [0370] NMR (CDCl.sub.3, .delta.):
1.30 (6H, t, J=7.1 Hz), 2.04 (3H, s), 3.62 (2H, s), 3.82 (3H, s),
4.27 (4H, q, J=7.1 Hz), 6.48-7.09 (4H, m) [0371] MASS (APCI): 356
(M+H).sup.+ [0372] (3) 2-Acetylamino-2-(3,4-difluorobenzyl)malonic
acid diethyl ester [0373] IR (Nujol): 3259, 1749, 1645, 1518, 1317,
1277, 1205, 1051, 1016 cm.sup.-1 [0374] NMR (DMSO-d.sub.6,
.delta.): 1.16 (6H, t, J=7.1 Hz), 1.91 (3H, s), 3.42 (2H, s), 4.15
(4H, q, J=7.1 Hz), 6.76-7.45 (3H, m), 8.19 (1H, s) [0375] MASS
(APCI): 344 (M+H).sup.+, 302 [0376] (4)
2-Acetylamino-2-[3-methoxy-4-(trifluoromethyl)benzyl]-malonic acid
diethyl ester [0377] mp: 119-120.degree. C. [0378] IR (KBr):
3500-3150, 2700-2300, 1637, 1631, 1461, 1348, 1238, 1172 cm.sup.-1
[0379] NMR (CDCl.sub.3, .delta.): 1.31 (6H, t, J=7.2 Hz), 2.04 (3H,
s), 3.70 (2H, s), 3.84 (3H, s), 4.21-4.36 (4H, m), 6.57-6.64 (2H,
m), 7.44 (1H, d, J=8.2 Hz) [0380] MASS (APCI): 406 (M+H).sup.+, 316
[0381] (5) 2-Acetylamino-2-(4-fluoro-3-methylbenzyl)malonic acid
diethyl ester [0382] IR (Neat): 3250, 1740, 1640, 1510, 1460, 1370,
1270, 1210, 1185 cm.sup.-1 [0383] NMR (CDCl.sub.3, .delta.): 1.30
(6H, t, J=7.1 Hz), 2.03 (3H, s), 2.22 (3H, s), 3.58 (2H, s), 4.27
(4H, q, J=7.1 Hz), 6.53 (1H, s), 6.70-6.95 (3H, m) [0384] MASS
(APCI): 340 (M+H).sup.+ Preparation 30
[0385] The following compounds were obtained according to a similar
manner to that of Preparation 28. [0386] (1)
N-Acetyl-4-chloro-3-methoxy-DL-phenylalanine [0387] mp:
177-179.degree. C. [0388] IR (KBr): 3351, 3200-2500, 1735, 1629,
1548 cm.sup.-1 [0389] MASS (APCI): 272 (M+H).sup.+, 230 [0390] (2)
N-Acetyl-4-fluoro-3-methoxy-DL-phenylalanine [0391] mp:
150-152.degree. C. [0392] IR (KBr): 3340, 2947, 1718, 1603, 1514,
1259, 1215 cm.sup.-1 [0393] NMR (DMSO-d.sub.6, .delta.): 1.79 (3H,
s), 2.74-3.07 (2H, m), 3.81 (3H, s), 4.41 (1H, m), 6.77 (1H, m),
7.01-7.14 (2H, m), 8.17 (1H, d, J=8.1 Hz), 12.68 (1H, br) [0394]
MASS (APCI): 256 (M+H).sup.+ [0395] (3)
N-Acetyl-3,4-difluorophenyl-DL-alanine [0396] IR (KBr): 3360, 1710,
1615, 1550, 1530 cm.sup.-1 [0397] NMR (DMSO.sub.6, .delta.): 1.78
(3H, s), 2.50-2.88 (2H, m), 4.35-4.47 (1H, m), 7.07-7.41 (3H, m),
8.19 (1H, d, J=8.2 Hz) [0398] MASS (APCI): 244 (M+H).sup.+, 202
[0399] (4) N-Acetyl-3-methoxy-4-trifluoromethyl-DL-phenylalanine
[0400] mp: 156-160.degree. C. [0401] IR (KBr): 3326, 3200-2300,
1716, 1621, 1552, 1459 cm.sup.-1 [0402] NMR (DMSO-d.sub.6,
.delta.): 1.80 (3H, s), 2.85-3.50 (2H, m), 3.87 (3H, s), 4.23-4.54
(1H, m), 6.94 (1H, d, J=8.0 Hz), 7.13 (1H, s), 7.52 (1H, d, J=8.0
Hz), 8.23 (1H, d, J=8.1 Hz), 12.82 (1H, br s) [0403] MASS (APCI):
306 (M+H).sup.+ (free) [0404] (5)
N-Acetyl-4-fluoro-3-methyl-DL-phenylalanine [0405] IR (Neat): 3350,
1720, 1600, 1540, 1500, 1345 cm.sup.-1 [0406] NMR (DMSO-d.sub.6,
.delta.): 1.78 (3H, s), 2.20 (3H, s), 2.71-3.03 (2H, m), 4.31-4.42
(1H, m), 6.97-8.19 (3H, m), 12.68 (1H, br s) [0407] MASS (APCI):
240 (M+H).sup.+ [0408] (6)
N-Acetyl-3-fluoro-4-methyl-DL-phenylalanine [0409] IR (Neat): 3300,
1740, 1720, 1600, 1540 cm.sup.-1 Preparation 31
[0410] The following compounds were obtained according to a similar
manner to that of Preparation 16. [0411] (1)
N-Acetyl-4-chloro-3-methoxy-D-phenylalanine [0412] mp:
116-117.degree. C. [0413] [.alpha.].sub.D.sup.27: -36.6.degree.
(C=0.37, MeOH) [0414] IR (KBr): 3500-3150, 2700-2300, 1733, 1623
cm.sup.-1 [0415] MASS (APCI): 272 (M+H).sup.+, 230 [0416] (2)
N-Acetyl-4-fluoro-3-methoxy-D-phenylalanine [0417] IR (Neat): 3330,
2940, 1728, 1618, 1518, 1275, 1223 cm.sup.-1 [0418] NMR
(DMSO-d.sub.6, .delta.): 1.79 (3H, s), 2.70-3.10 (2H, m), 3.81 (3H,
s), 4.40 (1H, m), 6.78 (1H, m), 7.01-7.14 (2H, m), 8.18 (1H, d,
J=8.1 Hz), 12.63 (1H, br) [0419] MASS (APCI): 256 (M+H).sup.+
[0420] (3) N-Acetyl-3,4-difluoro-D-phenylalanine [0421] IR (KBr):
3395, 1720, 1615, 1545, 1515 cm.sup.-1 [0422] (4)
N-Acetyl-3-methoxy-4-trifluoromethyl-D-phenylalanine [0423] mp:
156-160.degree. C. [0424] IR (KBr): 3326, 3200-2300, 1716, 1621,
1552, 1459 cm.sup.-1 [0425] NMR (DMSO-d.sub.6, .delta.): 1.80 (3H,
s), 2.85-3.50 (2H, m), 3.87 (3H, s), 4.23-4.54 (1H, m), 6.94 (1H,
d, J=8.0 Hz), 7.13 (1H, s), 7.52 (1H, d, J=8.0 Hz), 8.23 (1H, d,
J=8.1 Hz), 12.82 (1H, br s) [0426] MASS (APCI): 306 (M+H).sup.+
(free) [0427] (5) N-Acetyl-4-fluoro-3-methyl-D-phenylalanine [0428]
[.alpha.].sub.D.sup.28: -34.60.degree. (C=0.5, MeOH) [0429] IR
(Nujol): 3400, 1715, 1605, 1530, 1500, 1450, 1240, 1200, 1120
cm.sup.-1 [0430] NMR (DMSO-d.sub.6, .delta.): 1.78 (3H, s), 2.20
(3H, s), 2.71-3.03 (2H, m), 4.31-4.42 (1H, m), 6.97-8.19 (3H, m),
12.68 (1H, br s) [0431] MASS (APCI): 240 (M+H).sup.+ [0432] (6)
N-Acetyl-3-fluoro-4-methyl-D-phenylalanine [0433]
[.alpha.].sub.D.sup.29: -46,10.degree. (C=0.5, MeOH) [0434] IR
(Nujol): 3300, 1705, 1600, 1560 cm.sup.-1 Preparation 32
[0435] The following compounds were obtained according to a similar
manner to that of Preparation 17. [0436] (1)
4-Chloro-3-methoxy-D-phenylalanine hydrochloride [0437] mp:
218-222.degree. C. [0438] [.alpha.].sub.D.sup.27: +3.17.degree.
(C=0.52, MeOH) [0439] IR (KBr): 3500-3150, 2700-2300, 1739, 1589,
1488 cm.sup.-1 [0440] NMR (D.sub.2O, .delta.): 3.19 (1H, dd, J=7.5
and 14.5 Hz), 3.33 (1H, dd, J=5.7 and 14.5 Hz), 3.91 (3H, s), 4.28
(1H, dd, J=5.7 and 7.5 Hz), 6.89 (1H, dd, J=1.8 and 8.1 Hz), 7.03
(1H, d, J=1.8 Hz), 7.42 (1H, d, J=8.1 Hz) [0441] MASS (APCI): 230
(M+H).sup.+ [0442] (2) 4-Fluoro-3-methoxy-D-phenylalanine
hydrochloride [0443] mp: 210-220.degree. C. (decomp.) [0444] IR
(KBr): 1738, 1606, 1520, 1487, 1462, 1417, 1274, 1223, 1209, 1157,
1128 cm.sup.-1 [0445] NMR (DMSO-d.sub.6, .delta.): 3.13 (2H, m),
3.83 (3H, s), 4.00-4.40 (1H, m), 6.70-6.90 (1H, m), 7.00-7.30 (2H,
m) [0446] MASS (APCI): 214 (M+H).sup.+ (free) [0447] (3)
3-Methoxy-4-trifluoromethyl-D-phenylalanine hydrochloride [0448]
mp: 156-160.degree. C. [0449] IR (KBr): 3326, 3200-2300, 1716,
1621, 1552, 1459 cm.sup.-1 [0450] NMR (D.sub.2O, .delta.): 3.19
(1H, dd, J=7.5 and 14.4 Hz), 3.33 (1H, dd, J=5.7 and 14.4 Hz), 3.86
(3H, s), 4.20-4.26 (1H, m), 6.97 (1H, d, J=8.0 Hz), 7.07 (1H, s),
7.58 (1H, d, J=8.0 Hz) [0451] MASS (APCI): 264 (M+H).sup.+ (free)
[0452] (4) 4-Fluoro-3-methyl-D-phenylalanine hydrochloride [0453]
IR (Nujol): 1735, 1485, 1460, 1375, 1210 cm.sup.-1 [0454] MASS
(APCI): 198 (M+H).sup.+ (free) [0455] (5)
3-Fluoro-4-methyl-D-phenylalanine hydrochloride [0456] IR (Nujol):
1730, 1480, 1555, 1250, 1220, 1200 cm.sup.-1 Preparation 33
[0457] The following compounds were obtained according to a similar
manner to that of Preparation 18. [0458] (1)
4-Chloro-3-methoxy-D-phenylalanine methyl ester hydrochloride
[0459] mp: 165-168.degree. C. [0460] IR (KBr): 3200-2500, 1745,
1583, 1494 cm.sup.-1 [0461] NMR (D.sub.2O, .delta.): 3.22 (1H, dd,
J=7.5 and 14.5 Hz), 3.35 (1H, dd, J=6.8 and 14.5 Hz), 3.85 (3H, s),
3.92 (3H, s), 4.44 (1H, dd, J=6.8 and 7.5 Hz), 6.89 (1H, dd, J=1.9
and 8.1 Hz), 7.02 (1H, d, J=1.9 Hz), 7.44 (1H, d, J=8.1 Hz) [0462]
MASS (APCI): 244 (M+H).sup.+ [0463] (2)
4-Fluoro-3-methoxy-D-phenylalanine methyl ester hydrochloride
[0464] mp: 172-173.degree. C. [0465] IR (KBr): 1745, 1610, 1581,
1518, 1452, 1398, 1294, 1273, 1242, 1215, 1163, 1120, 1061, 1028
cm.sup.-1 [0466] NMR (DMSO-d.sub.6, .delta.): 3.13 (2H, d, J=6.3
Hz), 3.71 (3H, s), 3.83 (3H, s), 4.31 (1H, t, J=6.3 Hz), 6.70-6.90
(1H, m), 7.00-7.30 (2H, m) [0467] MASS (APCI): 228 (M+H).sup.+
(free) [0468] (3) 3-Methoxy-4-trifluoromethyl-D-phenylalanine
methyl ester hydrochloride [0469] mp: 158-165.degree. C. [0470] IR
(KBr): 3326, 3200-2300, 1739, 1617, 1504, 1328 cm.sup.-1 [0471] NMR
(D.sub.2O, .delta.): 3.29 (1H, dd, J=7.5 and 14.4 Hz), 3.42 (1H,
dd, J=5.7 and 14.4 Hz), 3.85 (3H, s), 3.90 (3H, s), 4.46-4.55 (1H,
m), 7.00 (1H, d, J=8.0 Hz), 7.12 (1H, s), 7.65 (1H, d, J=8.0 Hz)
[0472] MASS (APCI): 277 (M+H).sup.+ (free) [0473] (4)
4-Fluoro-3-methyl-D-phenylalanine methyl ester hydrochloride [0474]
IR (Nujol): 3200, 1740, 1490, 1450, 1240 cm.sup.-1 [0475] NMR
(DMSO-d.sub.6, .delta.): 2.22 (3H, s), 3.00-3.17 (2H, m), 3.68 (3H,
s), 4.21-4.28 (1H, m), 7.07-7.18 (3H, m), 8.67 (3H, s) [0476] MASS
(APCI): 212 (M+H).sup.+ (free) [0477] (5)
3-Fluoro-4-methyl-D-phenylalanine methyl ester hydrochloride [0478]
IR (Nujol): 1740, 1580, 1510, 1450 cm.sup.-1 [0479] NMR
(DMSO-d.sub.6, .delta.): 2.21 (3H, s), 3.13 (2H, d, J=6.0 Hz), 3.69
(3H, s), 4.29 (1H, t, J=6.0 Hz), 6.95-7.28 (3H, m), 8.70 (3H, s)
[0480] MASS (APCI): 212 (M+H).sup.+ (free) [0481] (6)
4-Fluoro-D-phenylalanine methyl ester hydrochloride [0482] mp:
197.3-197.8.degree. C. [0483] IR (KBr): 2989, 2956, 2910, 1745,
1741, 1504, 1490, 1450, 1240, 825 cm.sup.-1 [0484] NMR
(DMSO-d.sub.6, .delta.): 3.10 (1H, dd, J=7.0 and 14.0 Hz), 3.18
(1H, dd, J=6.4 and 14.0 Hz), 3.67 (3H, s), 4.26 (1H, dd, J=6.4 and
7.0 Hz), 7.11-7.33 (4H, m), 8.67 (3H, br s) [0485] MASS: 198
(M+H).sup.+ (free) [0486] (7) 4-Chloro-D-phenylalanine methyl ester
hydrochloride [0487] mp: 210-211.degree. C. [0488] IR (KBr): 1743,
1707, 1693, 1645, 1547, 1541, 1514, 1495, 1454, 1240, 1186, 1147,
1126, 1099, 1061, 1024 cm.sup.-1 [0489] NMR (DMSO-d.sub.6,
.delta.): 3.00-3.30 (2H, m), 3.68 (3H, s), 4.28 (1H, t, J=6.5 Hz),
7.28 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz) [0490] MASS (APCI):
214 (M+H).sup.+ (free) [0491] (8) 4-Trifluoromethyl-D-phenylalanine
methyl ester hydrochloride [0492] mp: 198-199.degree. C. [0493] IR
(KBr): 3199, 2864, 1741 cm.sup.-1 [0494] NMR (DMSO-d.sub.6,
.delta.): 3.10-3.30 (2H, m), 3.69 (3H, s), 4.35 (1H, t, J=6. 4 Hz),
7.51 (2H, d, J=8.1 Hz), 7.71 (2H, d, J=8.1 Hz) [0495] MASS (APCI):
248 (M+H).sup.+ (free) Preparation 34
[0496] The following compounds were obtained according to a similar
manner to that of Preparation 19. [0497] (1)
(2R)-2-(2-Chloroacetylamino)-3-(4-chloro-3-methoxyphenyl)propionic
acid methyl ester [0498] mp: 68-69.degree. C. [0499] IR (KBr):
3303, 2954, 1739, 1654, 1538 cm.sup.-1 [0500] NMR (CDCl.sub.3,
.delta.): 3.13 (2H, d, J=6.0 Hz), 3.75 (3H, s), 3.88 (3H, s), 4.05
(2H, s), 4.84-4.93 (1H, m), 6.65 (1H, dd, J=1.8 and 8.1 Hz), 6.67
(1H, d, J=1.8 Hz), 7.28 (1H, d, J=8.1 Hz) [0501] MASS (APCI): 320
(M+H).sup.+, 288, 260 [0502] (2)
(2R)-2-(2-Chloroacetylamino)-3-(4-fluoro-3-methoxyphenyl)propionic
acid methyl ester [0503] mp: 86-87.degree. C. [0504] IR (KBr):
1726, 1687, 1649, 1614, 1550, 1518, 1454, 1423, 1419, 1362, 1331,
1273, 1227, 1213, 1186 cm.sup.-1 [0505] NMR (CDCl.sub.3, .delta.):
3.12 (2H, d, J=5.8 Hz), 3.75 (3H, s), 3.87 (3H, s), 4.05 (2H, s),
4.87 (1H, dt, J=8.0 and 5.8 Hz), 6.40-7.20 (3H, m) [0506] MASS
(APCI): 304 (M+H).sup.+ [0507] (3)
(2R)-2-(2-Chloroacetylamino)-3-(3,4-difluorophenyl)-propionic acid
methyl ester [0508] IR (Neat): 3305, 1470, 1675, 1660, 1515
cm.sup.-1 [0509] NMR (DMSO-d.sub.6, .delta.): 2.87-3.11 (2H, m),
3.63 (2H, s), 4.03 (3H, s), 4.48-4.57 (1H, m), 7.03-7.41 (3H, m),
8.68 (1H, d, J=7.8 Hz) [0510] MASS (APCI): 292 (M+H).sup.+ [0511]
(4)
(2R)-2-(2-Chloroacetylamino)-3-[3-methoxy-4-(trifluoromethyl)phenyl]propi-
onic acid methyl ester [0512] mp: 108-109.degree. C. [0513] IR
(KBr): 3315, 2965, 1751, 1648, 1536, 1459, 1421 cm.sup.-1 [0514]
NMR (CDCl.sub.3, .delta.): 3.10-3.29 (2H, m), 3.76 (3H, s), 3.89
(3H, s), 4.05 (2H, s), 4.87-4.97 (1H, m), 6.73-6.77 (2H, m),
7.00-7.05 (1H, m), 7.75 (1H, d, J=8.3 Hz) [0515] MASS (APCI): 354
(M+H).sup.+312 [0516] (5)
(2R)-2-(2-Chloroacetylamino)-3-(4-fluoro-3-methylphenyl)propionic
acid methyl ester [0517] IR (Nujol): 3300, 1730, 1540, 1500; 1450
cm.sup.-1 [0518] NMR (DMSO-d.sub.6, .delta.): 2.19 (3H, s),
2.82-3.06 (2H, m), 3,62 (3H, s), 4.06 (2H, s), 4.32-4.53 (1H, m),
6.97-7.13 (3H, m), 8.66 (1H, d, J=7.8 Hz) [0519] MASS (APCI): 288
(M+H).sup.+ [0520] (6)
(2R)-2-(2-Chloroacetylamino)-3-(3-fluoro-4-methylphenyl)propionic
acid methyl ester [0521] IR (Nujol): 3300, 1740, 1660, 1540, 1450,
1360 cm.sup.-1 [0522] NMR (DMSO-d.sub.6, .delta.): 2.19 (3H, s),
2.85-3.10 (2H, m), 3.63 (3H, s), 4.06 (2H, s), 4.45-4.56 (1H, m),
6.92-7.22 (3H, m), 8.68 (1H, d, J=7.8 Hz) [0523] MASS (APCI): 288
(M+H).sup.+ [0524] (7)
(2R)-2-(2-Chloroacetylamino)-3-(4-fluorophenyl)-propionic acid
methyl ester [0525] IR (KBr): 3330, 1735, 1646, 1538, 1509, 1448,
1367, 1226, 1151 cm.sup.-1 [0526] NMR (CDCl.sub.3, .delta.): 3.09
(1H, dd, J=5.8 and 14.0 Hz), 3.16 (1H, dd, J=5.8 and 14.0 Hz), 3.74
(3H, s), 4.03 (2H, s), 4.85 (1H, ddd, J=5.8, 5.8 and 7.9 Hz),
6.95-7.12 (5H, m) [0527] MASS: 274 (M+H).sup.+ [0528] (8)
(2R)-2-(2-Chloroacetylamino)-3-(4-chlorophenyl)-propionic acid
methyl ester [0529] mp: 87-88.degree. C. [0530] IR (KBr): 1738,
1662, 1537, 1495, 1491, 1446, 1408, 1363, 1265, 1209, 1119, 1090,
1036, 1016 cm.sup.-1 [0531] NMR (CDCl.sub.3, .delta.): 2.90-3.30
(3H, m), 3.75 (3H, s), 4.03 (2H, s), 4.70-5.00 (1H, m), 7.05 (2H,
d, J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz) [0532] MASS (APCI): 290
(M+H).sup.+ [0533] (9)
(2R)-2-(2-Chloroacetylamino)-3-[4-(trifluoromethyl)-phenyl]propionic
acid methyl ester [0534] mp: 83-84.degree. C. [0535] IR (KBr):
3294, 1741, 1655, 1547 cm.sup.-1 [0536] NMR (DMSO-d.sub.6,
.delta.): 3.12-3.32 (2H, m), 3.76 (3H, s), 4.04 (2H, s), 4.86-4.96
(1H, m), 7.25 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz) [0537] MASS
(APCI): 324 (M+H).sup.+ Preparation 35
[0538] The following compounds were obtained according to a similar
manner to that of Preparation 20. [0539] (1)
(3R)-1-Benzyl-3-(4-chloro-3-methoxybenzyl)piperazine-2,5-dione
[0540] mp: 149-150.degree. C. [0541] [.alpha.].sub.D.sup.27:
+6.38.degree. (C=0.47, MeOH) [0542] IR (KBr): 3253, 1658, 1461
cm.sup.-1 [0543] NMR (DMSO-d.sub.6, .delta.): 2.94 (1H, dd, J=4.7
and 13.4 Hz), 2.96 (1H, d, J=17.4 Hz), 3.14 (1H, dd, J=4.5 and 13.4
Hz), 3.56 (1H, d, J=17.4 Hz), 3.76 (3H, s), 4.21 (1H, d, J=14.6
Hz), 4.30-4.35 (1H, m), 4.61 (1H, d, J=14.6 Hz), 6.66 (1H, dd,
J=1.8 and 8.0 Hz), 6.91 (1H, d, J=1.8 Hz), 7.04-7.11 (2H, m), 7.17
(1H, d, J=8.0 Hz), 7.26-7.33 (3H, m), 8.38 (1H, br s) [0544] MASS
(APCI): 359 (M+H).sup.+ [0545] (2)
(3R)-1-Benzyl-3-(4-fluoro-3-methoxybenzyl)piperazine-2,5-dione
[0546] mp: 177-179.degree. C. [0547] IR (KBr): 3240, 1658, 1516,
1464 cm.sup.-1 [0548] NMR (CDCl.sub.3, .delta.): 3.00-3.30 (3H, m),
3.61 (1H, d, J=17.7 Hz), 3.84 (3H, s), 4.20-4.60 (3H, m), 6.29 (1H,
br s), 6.60-7.50 (8H, m) [0549] MASS (APCI): 343 (M+H).sup.+ [0550]
(3) (3R)-1-Benzyl-3-(3,4-difluorobenzyl)piperazine-2,5-dione [0551]
IR (KBr): 3313, 3255, 1650, 1515, 1465, 1275 cm.sup.-1 [0552] NMR
(DMSO-d.sub.6, .delta.): 2.90-4.70 (7H, m), 6.94-7.32 (8H, m), 8.35
(1H, s) [0553] MASS (APCI): 331 (M+H).sup.+ [0554] (4)
(3R)-1-Benzyl-3-[3-methoxy-4-(trifluoromethyl)benzyl]-piperazine-2,5-dion-
e [0555] IR (KBr): 3315, 1751, 1648, 1536, 1459, 1421 cm.sup.-1
[0556] NMR (DMSO-d.sub.6, .delta.): 2.89-3.25 (2H, m), 3.19 (1H, d,
J=17.5 Hz), 3.62 (1H, d, J=17.5 Hz), 3.77 (3H, s), 4.15 (1H, d,
J=14.5 Hz), 4.30-4.35 (1H, m), 4.68 (1H, d, J=14.5 Hz), 6.80 (1H,
d, J=8.0 Hz), 7.00-7.41 (7H, m), 8.41 (1H, br s) [0557] MASS
(APCI): 393 (M+H).sup.+, 351 [0558] (5)
(3R)-1-Benzyl-3-(4-fluoro-3-methylbenzyl)piperazine-2,5-dione
[0559] [.alpha.].sub.D.sup.28: -15.60.degree. (C=0.5, DMF) [0560]
IR (Nujol): 3250, 3225, 1650, 1430, 1320, 1250 cm.sup.-1 [0561] NMR
(DMSO-d.sub.6, .delta.): 2.13 (3H, s), 2.81-4.65 (7H, m), 6.83-7.34
(8H, m), 8.33 (1H, s) [0562] MASS (APCI): 327 (M+H).sup.+ [0563]
(6) (3R)-1-Benzyl-3-(3-fluoro-3-methylbenzyl)piperazine-2,5-dione
[0564] [.alpha.].sub.D.sup.27: -16.90.degree. (C=0.5, DMF) [0565]
IR (Nujol): 3250, 1680, 1640, 1460, 1320 cm.sup.-1 [0566] NMR
(DMSO-d.sub.6, .delta.): 2.17 (3H, s), 2.84-4.69 (7H, m), 6.80-7.34
(8H, m), 8.35 (1H, s) [0567] MASS (APCI): 327 (M+H).sup.+ [0568]
(7)
(2R)-2-[N-(Benzylaminoacetyl)amino]-3-(4-fluorophenyl)-propionic
acid methyl ester [0569] MASS: 345 (M+H).sup.+ [0570] (8)
(3R)-1-Benzyl-3-(4-fluorobenzyl)piperazine-2,5-dione [0571] mp:
190.1-190.8.degree. C. [0572] IR (KBr): 1671, 1656, 1509, 1448,
1334, 1162 cm.sup.-1 [0573] NMR (CDCl.sub.3, .delta.): 3.08 (1H, d,
J=4.4 and 14.0 Hz), 3.19 (1H, d, J=5.9 and 14.0 Hz), 3.05 (1H, d,
J=17.7 Hz), 3.56 (1H, d, J=17.7 Hz), 4.33 (1H, m), 4.41 (1H, d,
J=14.3 Hz), 4.54 (1H, d, J=14.3 Hz), 6.38-7.35 (10H, m) [0574]
MASS: 313 (M+H).sup.+ [0575] (9)
(3R)-1-Benzyl-3-(4-chlorobenzyl)piperazine-2,5-dione [0576] mp:
181-182.degree. C. [0577] IR (KBr): 1678, 1649, 1564, 1550, 1516,
1489, 1462, 1433, 1408, 1325, 1273, 1178, 1112, 1090, 1063
cm.sup.-1 [0578] NMR (CDCl.sub.3, .delta.): 2.80-3.30 (3H, m), 3.57
(1H, d, J=17.6 Hz), 4.20-4.40 (2H, m)), 4.60 (1H, d, J=14.3 Hz),
6.80-7.50 (9H, m) [0579] MASS (APCI): 329 (M+H).sup.+ [0580] (10)
(3R)-1-Benzyl-3-(4-(trifluoromethyl)benzyl]piperazine-2,5-dione
[0581] mp: 180-181.degree. C. [0582] IR (KBr): 3257, 1678, 1651
cm.sup.-1 [0583] NMR (DMSO-d.sub.6, .delta.): 2.86 (1H, d, J=17.3
Hz), 3.00 (1H, dd, J=4.8 and 13.5 Hz), 3.25 (1H, d, J=44.5 and 13.5
Hz), 3.59 (1H, d, J=17.3 Hz), 4.08 (1H, d, J=14.3 Hz), 4.30-4.40
(1H, m), 4.73 (1H, d, J=14.3 Hz), 7.05-7.32 (7H, m), 7.47 (2H, d,
J=8.2 Hz) [0584] MASS (APCI): 363 (M+H).sup.+ Preparation 36
[0585] The following compounds were obtained according to a similar
manner to that of Preparation 21. [0586] (1)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-methoxybe-
nzyl)piperazine [0587] IR (Neat): 1643, 1517 cm.sup.-1 [0588] NMR
(CDCl.sub.3, .delta.): 2.00-5.20 (14H, m), 6.20-8.00 (11H, m)
[0589] MASS (APCI): 571 (M+H).sup.+ [0590] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-benzylp-
iperazine [0591] IR (Neat): 1645, 1515, 1435, 1280, 1180, 1140
cm.sup.-1 [0592] NMR (DMSO-d.sub.6, .delta.): 2.06-4.82 (11H, m),
6.61-8.19 (11H, m) [0593] MASS (APCI): 543 (M+H).sup.+ Preparation
37
[0594] A solution of
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(4-chloro-3-methoxyb-
enzyl)piperazine (2.23 g) and 1-chloroethyl chloroformate (0.61 ml)
in 1,2-dichloroethane (10 ml) was stirred under reflux for 15
hours. After cooling, the reaction mixture was concentrated under
reduced pressure. The resulting syrup was dissolved into methanol
(10 ml) and the solution was stirred under reflux for 2 hours.
After cooling, the reaction mixture was concentrated under reduced
pressure and the resulting powder was collected by filtration to
give a yellow powder of
(2R)-1-[3,5-bis(tri-fluoromethyl)benzoyl]-2-(4-chloro-3-methoxybenzyl)pip-
erazine hydrochloride (2.00 g). [0595] mp: 70-71.degree. C. [0596]
MASS (APCI): 481 (M+H).sup.+ Preparation 38
[0597] A solution of boron tribromide in dichloromethane (1M
solution, 6.0 ml) was added dropwise over 20 minutes to an
ice-cooled solution of
(2R)-1-[3,5-bis(trifluoromethyl)-penzoyl]-2-(4-chloro-3-methoxybenzyl)pip-
erazine hydrochloride (0.98 g) in dichloromethane (5 ml). After
being stirred at the same temperature for 2 hours, followed by at
room temperature for 12 hours, an additional solution of boron
tribromide in dichloromethane (1M solution, 4.0 ml) was added, and
the whole was stirred at room temperature for further 4 hours. The
resulting mixture was poured into aqueous saturated sodium hydrogen
carbonate solution and the whole was stirred for 1 hour. The
organic layer was separated, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using a mixed solvent of
dichloromethane and methanol (20:1). The fractions containing the
objective compound were collected and evaporated under reduced
pressure to give
(2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybe-
nzyl)-piperazine (0.67 g) as a foam. [0598] IR (Neat): 3400-3000,
1635 cm.sup.-1 [0599] NMR (DMSO-d.sub.6, .delta.): 2.60-4.80 (10H,
m), 6.28-7.20 (3H, m), 7.41 (1H, s), 7.75 (1H, s), 8.14 (1H, d,
J=8.2 Hz), 10.00 (1H, br s) [0600] MASS (APCI): 467 (M+H).sup.+
Preparation 39
[0601] The following compounds were obtained according to a similar
manner to that of Preparation 38. [0602] (1)
(2R)-4-Benzyl-2-(4-chloro-3-hydroxybenzyl)piperazine [0603] mp:
65-68.degree. C. [0604] IR (KBr): 2939, 2813, 1444, 1429, 1294,
1236, 1136, 1047 cm.sup.-1 [0605] NMR (DMSO-d.sub.6, .delta.):
1.60-4.00 (11H, m), 6.60 (1H, dd, J=1.6 and 8.0 Hz), 6.78 (1H, d,
J=1.6 Hz), 7.16-7.40 (6H, m) [0606] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl)pipe-
razine [0607] mp: 82-86.degree. C. [0608] IR (KBr): 3282, 1637,
1282, 1182, 1136 cm.sup.-1 [0609] NMR (CDCl.sub.3, .delta.):
2.20-5.20 (10H, m), 6.10-8.10 (6H, m) [0610] MASS (APCI): 451
(M+H).sup.+ [0611] (3)
(3R)-1-Benzyl-3-(3-hydroxy-4-methylbenzyl)piperazine [0612] IR
(KBr): 1649, 1516 cm.sup.-1 [0613] NMR (CDCl.sub.3, .delta.):
1.95-2.20 (2H, m), 2.20 (3H, s), 2.57-3.06 (7H, m), 3.51 (1H, d,
J=13.1 Hz), 3.52 (1H, d, J=13.1 Hz), 6.60 (1H, d, J=7.4 Hz), 6.61
(1H, s), 7.03 (1H, d, J=7.4 Hz), 7.20-7.35 (5H, m) [0614] MASS
(APCI): 297 (M+H).sup.+ Preparation 40
[0615] To a solution of
(2R)-2-(4-chloro-3-hydroxybenzyl)-4-benzylpiperazine (3.78 g) and
triethylamine (5.71 ml) in dichloromethane was added
4-dimethylaminopyridine (0.29 g) and tert-butyldimethylsilyl
chloride (5.30 g) successively with ice bath cooling under nitrogen
atmosphere. After stirring overnight at room temperature, water (50
ml) was added to the mixture and the organic layer was separated,
washed with brine, dried over sodium sulfate, and evaporated in
vacuo. The residue was purified by column chromatography on silica
gel with a mixture of dichloromethane and methanol (10:1) as eluent
to give
(2R)-4-benzyl-2-[4-chloro-3-(tert-butyldimethylsilyloxy)benzyl]piperazine
(4.11 g) as an oil. [0616] IR (Neat): 1600, 1575, 1485, 1420, 1295,
1250, 1170, 1140 cm.sup.-1 [0617] NMR (CDCl.sub.3, .delta.): 0.15
(6H, s), 0.96 (9H, s), 1.80 (1H, t, J=10.0 Hz), 1.94-2.98 (8H, m),
3.40 (1H, d, J=13.0 Hz), 3.48 (1H, d, J=13.0 Hz), 6.60-7.34 (8H, m)
[0618] MASS (APCI): 431 (M+H).sup.+, 397 Preparation 41
[0619] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (1.93 g) was added to a mixture of
(2R)-4-benzyl-2-[4-chloro-3-(tert-butyldimethylsilyloxy)benzyl]-piperazin-
e (2.90 g) and 3-methoxy-5-(trifluoromethyl)benzoic acid (1.48 g),
1-hydroxybenzotriazole (1.14 g) in dichloromethane (18 ml) at room
temperature. After being stirred for 6 hours at the same
temperature, the reaction mixture was poured into a mixed solvent
of water (25 ml) and dichloromethane (15 ml). The aqueous layer was
adjusted to pH 9 with aqueous sodium hydrogen carbonate solution.
The organic layer was separated, washed with brine, dried over
sodium sulfate, and concentrated under reduced pressure. The
resulting residue was purified by column chromatography on silica
gel (52 g) using a mixed solvent of hexane and ethyl acetate (2:1).
The fractions containing the objective compound was collected and
evaporated under reduced pressure to give a syrup of
(2R)-1-[3-methoxy-5-(trifluoromethyl)-benzoyl]-2-[4-chloro-3-(tert-butyld-
imethylsilyloxy)benzyl]-4-benzylpeiperazine (3.3 g). [0620] IR
(Neat): 2937, 1639, 1603, 1421, 1250, 1173, 1132, 847 cm.sup.-1
[0621] NMR (CDCl.sub.3, .delta.): 0.13 (6H, s), 1.00 (9H, s),
1.60-5.10 (11H, m), 3.81 (3H, s), 6.30-8.20 (11H, m) [0622] MASS
(APCI): 633 (M).sup.+ Preparation 42
[0623] The following compounds were obtained according to a similar
manner to that of Preparation 37. [0624] (1)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)piperazine [0625] mp: 154-157.degree. C. [0626] IR (KBr): 3265,
2956, 1624, 1427, 1173, 1128 cm.sup.-1 [0627] NMR (DMSO-d.sub.6,
.delta.): 2.20-4.90 (10H, m), 3.82 (3H, s), 6.20-7.30 (6H, m),
10.02 (1H, br) [0628] MASS (APCI): 429 (M+H).sup.+ [0629] (2)
(2R)-1-[3-Trifluoromethyl-5-(methylthio)benzoyl]-2-[4-chloro-3-(tert-buty-
ldimethylsilyloxy)benzyl]piperazine [0630] IR (Neat): 1645, 1630,
1420, 1170, 1130 cm.sup.-1 [0631] NMR (CDCl.sub.3, .delta.): 0.18
(6H, s), 1.02 (9H, s), 2.48 (3H, s), 2.60-5.10 (10H, m), 6.28-8.26
(6H, m) [0632] MASS (APCI): 559 (M+H).sup.+ [0633] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-fluoro-3-methoxybenzyl]pipe-
razine hydrochloride [0634] mp: 127-134.degree. C. [0635] IR (KBr):
2970, 2947, 1645, 1520, 1281, 1184, 1136 cm.sup.-1 [0636] NMR
(DMSO-d.sub.6, .delta.): 2.60-5.20 (12H, m), 6.50-8.30 (6H, m),
9.60 (2H, br) [0637] MASS (APCI): 465 (M+H).sup.+ (free) [0638] (4)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl-
]piperazine hydrochloride [0639] IR (KBr): 1643, 1606, 1518, 1464,
1423, 1377, 1350, 1321, 1242, 1215, 1173, 1126, 1053, 1038
cm.sup.-1 [0640] NMR (DMSO-d.sub.6, .delta.): 2.30-5.30 (16H, m),
6.30-7.50 (6H, m) [0641] MASS (APCI): 427 (M+H).sup.+ (free) [0642]
(5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)piperazine
hydrochloride [0643] IR (KBr): 3435, 2940, 2800, 1645, 1520, 1435,
1365, 1280, 1185, 1135 cm.sup.-1 [0644] NMR (DMSO-d.sub.6,
.delta.): 2.50-5.17 (9H, m), 6.60-8.45 (6H, m), 9.63 (2H, br s)
[0645] MASS (APCI): 453 (M+H).sup.+ (free) [0646] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluoromethyl)-
benzyl]piperazine [0647] IR (Neat): 2952, 1639, 1623, 1461, 1423,
1124 cm.sup.-1 [0648] NMR (CDCl.sub.3, .delta.): 2.60-5.20 (13H,
m), 6.40-8.00 (6H, m) [0649] MASS (APCI): 515 (M+H).sup.+ [0650]
(7)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluorome-
thyl)benzyl]piperazine [0651] IR (Neat): 2950, 1637, 1461, 1423,
1317 cm.sup.-1 [0652] NMR (CDCl.sub.3, .delta.): 2.60-5.20 (15H,
m), 6.60-7.60 (6H, m) [0653] MASS (APCI): 477 (M+H).sup.+ [0654]
(8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methylbenzyl)piper-
azine [0655] IR (Neat): 3350, 1640, 1500, 1430, 1380, 1350, 1275
cm.sup.-1 [0656] NMR (DMSO-d.sub.6, .delta.): 2.00-4.84 (12H, m),
6.69-8.34 (7H, m) [0657] MASS (APCI): 449 (M+H).sup.+ [0658] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-4-methylbenzyl)piper-
azine [0659] IR (Neat): 3300, 1625, 1425, 1275, 1120 cm.sup.-1
[0660] NMR (DMSO-d.sub.6, .delta.): 2.18 (3H, s), 2.40-4.86 (9H, m)
6.62-8.20 (6H, m) [0661] MASS (APCI): 449 (M+H).sup.+ [0662] (10)
(2R)-2-(4-Fluorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazin-
e hydrochloride [0663] mp: 78.8-80.3.degree. C. [0664] IR (KBr):
1513, 1423, 1349, 1172, 1126, 1054 cm.sup.-1 [0665] NMR
(DMSO-d.sub.6, .delta.): 2.50-5.03 (9H, m), 3.82 (3H, s), 6.94-7.25
(8H, m), 9.56 (1H, br s) [0666] MASS (APCI): 397 (M+H).sup.+ (free)
[0667] (11)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)piperazine
hydrochloride [0668] mp: 240-260.degree. C. [0669] IR (Neat): 1658,
1496, 1437, 1387, 1362, 1331, 1282, 1186, 1132, 1101, 1059, 1018
cm.sup.-1 [0670] NMR (CDCl.sub.3, .delta.): 2.00-5.30 (9H, m),
6.70-8.50 (7H, m) [0671] MASS (APCI): 451 (M+H).sup.+ (free) [0672]
(12)
(2R)-2-(4-Chlorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]pipe-
razine hydrochloride [0673] IR (KBr): 1643, 1605, 1489, 1464, 1423,
1377, 1350, 1319, 1271, 1242, 1175, 1128, 1097, 1053 cm.sup.-1
[0674] NMR (DMSO-d.sub.6, .delta.): 2.00-5.40 (13H, m), 6.20-8.20
(7H, m) [0675] MASS (APCI): 413 (M+H).sup.+ (free) [0676] (13)
(2R)-1-(3,5-Bis(trifluoromethyl)benzoyl)-2-[4-(trifluoromethyl)benzyl]pip-
erazine [0677] NMR (CDCl.sub.3, .delta.): 2.30-5.30 (9H, m),
7.26-7.88 (7H, m) [0678] MASS (APCI): 485 (M+H).sup.+ [0679] (14)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzy-
l]piperazine [0680] IR (Neat): 2951, 1632, 1608 cm.sup.-1 [0681]
NMR (CDCl.sub.3, .delta.): 2.70-5.10 (9H, m), 3.80 (3H, s),
6.72-7.87 (7H, m) [0682] MASS (APCI): 447 (M+H).sup.+ [0683] (15)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperaz-
ine [0684] [.alpha.].sub.D.sup.28.8: -46.15.degree. (C=0.26, MeOH)
[0685] IR (Neat): 3740, 1630 cm.sup.-1 [0686] NMR (CDCl.sub.3,
.delta.): 2.5-5.4 (9H, m), 3.55 (3H, s), 6.51 (1H, br s), 6.87 (1H,
br s), 7.06 (1H, br s), 6.8-7.9 (7H, m) [0687] MASS (APCI): 429
(M+H).sup.+ [0688] (16)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]pi-
perazine [0689] IR (Neat): 3280, 1620, 1459, 1427 cm.sup.-1 [0690]
NMR (CDCl.sub.3, .delta.): 2.60-3.00 (10H, m), 3.74 (3H, s),
6.70-7.40 (8H, m), 8.25-8.52 (1H, m) [0691] MASS (APCI): 418
(M+H).sup.+ [0692] (17)
(2R)-1-tert-Butoxycarbonyl-2-(3-hydroxy-4-methylbenzyl)piperazine
[0693] IR (KBr): 1674 cm.sup.-1 [0694] NMR (CDCl.sub.3, .delta.):
1.37 (9H, s), 2.20 (3H, s), 2.72-3.15 (8H, m), 3.90-3.93 (1H, m),
4.16 (1H, br s), 6.62 (1H, s), 6.68 (1H, d, J=7.6 Hz), 7.02 (1H, d,
J=7.6 Hz) [0695] MASS (APCI): 207 (M+H-Boc).sup.+ [0696] (18)
(2R)-1-(tert-Butoxycarbonyl)-2-(4-chlorobenzyl)-piperazine [0697]
[.alpha.].sub.D.sup.27.2: +23.33.degree. (C=0.39, MeOH) [0698] IR
(Neat): 3340, 2980, 2870, 2830, 1690, 1410, 1370 cm.sup.-1 [0699]
NMR (CDCl.sub.3, .delta.): 1.36 (9H, s), 2.6-3.2 (7H, m), 3.90 (1H,
br), 4.18 (1H, br s), 7.15 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4
Hz) [0700] MASS (APCI): 311 (M+H).sup.+ Preparation 43
[0701] The following compounds were obtained according to a similar
manner to that of Preparation 41. [0702] (1)
(2R)-1-[3-Trifluoromethyl-5-(methylthio)benzoyl]-2-[4-chloro-3-(tert-buty-
ldimethylsilyloxy)benzyl]-4-benzylpiperazine [0703] IR (Neat):
1645, 1490, 1420, 1300, 1170, 1130 cm.sup.-1 [0704] NMR
(CDCl.sub.3, .delta.): 0.15 (6H, s), 1.00 (9H, s), 1.95-5.02 (11H,
m), 2.48 (3H, s), 6.20-8.25 (11H, m) [0705] MASS (APCI): 649
(M+H).sup.+, 615 [0706] (2)
(2R)-4-Benzyl-2-(4-fluoro-3-methoxybenzyl)-1-[3-methoxy-5-(trifluorom-
ethyl)benzoyl]piperazine [0707] IR (Neat): 1738, 1643, 1628, 1616,
1604, 1516, 1464, 1454, 1417, 1371, 1342, 1273, 1099, 1055
cm.sup.-1 [0708] NMR (CDCl.sub.3, .delta.): 0.60-5.20 (17H, m),
6.00-7.50 (11H, m) [0709] MASS (APCI): 517 (M+H).sup.+ [0710] (3)
(2R)-4-Benzyl-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(tr-
ifluoromethyl)benzyl]piperazine [0711] IR (Neat): 2811, 1643, 1280,
1180, 1137 cm.sup.-1 [0712] NMR (CDCl.sub.3, .delta.): 2.20-5.20
(17H, m), 6.40-7.50 (11H, m) [0713] MASS (APCI): 567 (M+H).sup.+
[0714] (4)
(2R)-4-Benzyl-2-(4-fluorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benz-
oyl]piperazine [0715] IR (Neat): 1639, 1509, 1460, 1423, 1344,
1128, 1010 cm.sup.-1 [0716] NMR (CDCl.sub.3, .delta.): 2.07 (1H,
br), 2.73-4.91 (8H, m), 6.57-7.53 (12H, m) [0717] MASS: 487
(M+H).sup.+ [0718] (5)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)piper-
azine [0719] IR (Neat): 1738, 1676, 1647, 1628, 1618, 1498, 1454,
1417, 1387, 1273, 1084, 1068 cm.sup.-1 [0720] NMR (CDCl.sub.3,
.delta.): 0.60-5.20 (11H, m), 6.40-8.70 (12H, m) [0721] MASS
(APCI): 541 (M+H).sup.+ [0722] (6)
(2R)-4-Benzyl-2-(4-chlorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-
piperazine [0723] IR (Neat): 1707, 1678, 1643, 1630, 1618, 1604,
1516, 1496, 1489, 1477, 1454, 1417, 1392, 1375, 1342, 1317
cm.sup.-1 [0724] NMR (CDCl.sub.3, .delta.): 0.60-5.20 (14H, m),
6.40-8.20 (12H, m) [0725] MASS (APCI): 503 (M+H).sup.+ [0726] (7)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-(trifluorcmethyl)b-
enzyl]piperazine [0727] IR (Neat): 2950, 2800, 1765, 1740, 1640
cm.sup.-1 [0728] NMR (DMSO-d.sub.6, .delta.): 1.70-4.30 (11H, m),
7.13 (1H, d, J=7.8 Hz), 7.20-7.70 (10H, m), 8.13 (1H, d, J=7.8 Hz)
[0729] MASS (APCI): 575 (M+H).sup.+ [0730] (8)
(2R)-4-Benzyl-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-2-[4-(trifluoromet-
hyl)benzyl]piperazine [0731] IR (Neat): 2945, 2812, 1643 cm.sup.-1
[0732] NMR (CDCl.sub.3, .delta.): 2.04-5.10 (11H, m), 3.81 (3H, s),
6.73-7.93 (12H, m) [0733] MASS (APCI): 537 (M+H).sup.+ [0734] (9)
(2R)-4-Benzyl-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-2-(2-naphthylmethy-
l)piperazine [0735] [.alpha.].sub.D.sup.28.8: -18.34.degree.
(C=0.35, MeOH) [0736] IR (Neat): 3740, 1640 cm.sup.-1 [0737] NMR
(CDCl.sub.3, .delta.): 1.9-2.4 (2H, m), 2.6-4.0 (11H, m), 4.4-5.2
(1H, m), 6.4-7.9 (15H, m) [0738] MASS (APCI): 519 (M+H).sup.+
[0739] (10)
(2R)-4-Benzyl-2-[(1H-indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)b-
enzoyl]piperazine [0740] IR (Neat): 3280, 1620, 1459 cm.sup.-1
[0741] NMR (CDCl.sub.3, .delta.): 2.00-5.20 (14H, m), 6.60-7.60
(13H, m), 7.90 (1H, br s) [0742] MASS (APCI): 508 (M+H).sup.+
Preparation 44
[0743] To a solution of 4-fluoro-3-methoxybenzaldehyde (5 g) in
methanol (25 ml) was added dropwise sodium borohydride (368 mg) in
0.1N sodium hydroxide aqueous solution (5 ml) in water bath and the
whole was stirred for 1 hour. After the mixture was evaporated
under reduced pressure, ethyl acetate and water were added thereto.
The organic layer was separated and the water layer was further
extracted with ethyl acetate. The combined organic layer was dried
over magnesium sulfate and concentrated in vacuo to give
4-fluoro-3-methoxybenzyl-alcohol (5.22 g) as an oil. [0744] IR
(Neat): 1610, 1516, 1462, 1417, 1315, 1277, 1149, 1115, 1032
cm.sup.-1 [0745] NMR (CDCl.sub.3, .delta.): 1.75 (1H, br s), 3.90
(3H, s), 4.64 (2H, s), 6.70-7.20 (3H, m) Preparation 45
[0746] The following compounds were obtained according to a similar
manner to that of Preparation 26. [0747] (1)
4-Fluoro-3-methoxybenzyl chloride [0748] IR (Neat): 1608, 1516,
1462, 1417, 1325, 1284, 1271, 1219, 1155, 1119, 1032 cm.sup.-1
[0749] NMR (CDCl.sub.3, .delta.): 3.91 (3H, s), 4.55 (2H, s),
6.70-7.20 (3H, m) [0750] (2) 3-Methoxy-4-(trifluoromethyl)benzyl
chloride [0751] IR (Neat): 1606, 1459, 1272, 1174 cm.sup.-1 [0752]
NMR (CDCl.sub.3, .delta.): 3.91 (3H, s), 4.73 (2H, s), 6.95 (1H,
dd, J=0.6 and 8.0 Hz), 7.04 (1H, d, J=0.6 Hz), 7.53 (1H, d, J=8.0
Hz) Preparation 46
[0753] The following compound was obtained according to a similar
manner to that of Preparation 24.
[0754]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenz-
yl)piperazine [0755] IR (Neat): 1641, 1633, 1626, 1514, 1475, 1462,
1452, 1446, 1435, 1423, 1417, 1385, 1340, 1336, 1273, 1095, 1063,
1045 cm.sup.-1 [0756] NMR (CDCl.sub.3, .delta.): 0.60-5.40 (12H,
m), 6.20-8.60 (6H, m) [0757] MASS (APCI): 465 (M+H).sup.+
Preparation 47
[0758] The following compound was obtained according to a similar
manner to that of Preparation 17 followed by a similar manner to
that of Preparation 18. [0759] 3,4-Difluorophenyl-D-alanine methyl
ester hydrochloride [0760] IR (KBr): 3400, 1735, 1610, 1235
cm.sup.-1 [0761] NMR (DMSO-d.sub.6, .delta.): 3.16 (2H, d, J=6.6
Hz), 3.70 (3H, s), 4.33 (1H, t, J=6.6 Hz), 7.05-7.52 (3H, m), 8.65
(3H, s) [0762] MASS (APCI): 216 (M+H).sup.+ (free) Preparation
48
[0763] 28% Sodium methoxide in methanol (50 ml) was added to a
solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (20.8 g) in
dimethylsulfoxide (200 ml). The mixture was stirred at 90.degree.
C. for 3.5 hours. After cooling at room temperature, the resulting
mixture was poured into ice-water (1.5 l) and made acidic with
diluted hydrochloric acid. After being stirred for 30 minutes, the
resulting precipitates were collected by filtration and air-dried
to give a colorless powder of 3-methoxy-4-(trifluoromethyl)benzoic
acid (22.95 g). [0764] mp: 203-204.degree. C. [0765] IR (KBr):
3500-3150, 2700-2300, 1637, 1606, 1459, 1272, 1174 cm.sup.-1 [0766]
NMR (DMSO-d.sub.6, .delta.): 3.95 (3H, s), 7.61-7.77 (3H, m), 13.45
(1H, s) Preparation 49
[0767] Lithium aluminum hydride (4.53 g) was added by small
portions to an ice-cooled solution of
3-methoxy-4-(trifluoromethyl)benzoic acid (23.3 g) in
tetrahydrofuran (400 ml) under nitrogen atmosphere, and the mixture
was stirred at room temperature for 2 hours. After being cooled
with ice, 2N sodium hydroxide (2 ml) was added to the mixture under
nitrogen atmosphere. The resulting precipitates were filtered off
and washed with tetrahydrofuran, and the filtrate and washings were
combined and evaporated under reduced pressure to give a crude oil.
The oil was purified by column chromatography on silica gel using a
mixture of dichloromethane and methanol (40:1) to give
3-methoxy-4-(trifluoromethyl)benzyl alcohol (20 g) as a colorless
oil. [0768] IR (Neat): 3500-3150, 2700-2300, 1637, 1606, 1459,
1272, 1174 cm.sup.-1 [0769] NMR (CDCl.sub.3, .delta.): 2.01 (1H, t,
J=4.6 Hz), 3.88 (3H, s), 4.72 (2H, d, J=4.6 Hz), 6.95 (1H, dd,
J=0.4 and 8.0 Hz), 7.04 (1H, d, J=0.4 Hz) 7.52 (1H, d, J=8.0 Hz)
Preparation 50
[0770] A solution of 5-bromo-2-fluorotoluene (6 g) in ethyl ether
(10 ml) and a catalytic amount of iodine were added to a suspension
of magnesium (960 mg) in ethyl ether (10 ml) under nitrogen
atmosphere and the whole was refluxed for 30 minutes. After
cooling, a solution of ethyl orthoformate (5.4 g) in ethyl ether
(20 ml) was added to the mixture and the whole was stirred
overnight. Sulfuric acid (10%, 20 ml) was added to the mixture and
the organic layer was separated, washed with brine, dried over
sodium sulfate, and evaporated. The residue was purified by column
chromatography on silica gel with a mixture of hexane and ethyl
acetate (10:1) as eluent to give 4-fluoro-3-methylbenzaldehyde as
an oil. [0771] IR (Neat): 1695, 1590, 1495, 1280, 1245, 1110
cm.sup.-1 [0772] NMR (CDCl.sub.3, .delta.): 2.36 (3H, s), 7.10-7.84
(3H, m), 9.93 (1H, s)
[0773] The obtained compound was dissolved in a mixture of methanol
and tetrahydrofuran and sodium borohydride was added to the
solution. After 1 hour of stirring, the solvent was removed and
water was added to the residue. The mixture was made acidic with
10% sulfuric acid, extracted with ethyl acetate, washed with brine,
dried over sodium sulfate, and evaporated in vacuo to give
4-fluoro-3-methylbenzylalcohol (1.33 g) as an oil. [0774] IR
(Neat): 3300, 1500, 1250 cm.sup.-1 [0775] NMR (CDCl.sub.3,
.delta.): 2.28 (3H, s), 4.62 (2H, s), 6.93-7.26 (3H, m) Preparation
51
[0776] Carbon tetrabromide (3.08 g) was added portionwisely to a
solution of 4-fluoro-3-methylbenzylalcohol (1.3 g) and
triphenylphosphine (2.9 g) in methylene chloride (50 ml) and the
mixture was stirred for 1 hour. The solution was washed
successively with saturated aqueous sodium hydrogen carbonate
solution and brine, dried over sodium sulfate, and evaporated in
vacuo. The residue was triturated with hexane and the resulting
precipitate was removed by filtration. The filtrate was evaporated
in vacuo and the residue was purified by column chromatography on
silica gel with hexane as eluent to give
4-fluoro-3-methylbenzylbromide (1.28 g) as an oil. [0777] IR
(Neat): 1500, 1250, 1200 cm.sup.-1 [0778] NMR (CDCl.sub.3,
.delta.). 2.26 (3H, s), 4.45 (2H, s), 6.91-7.26 (3H, m) Preparation
52
[0779] The following compound was obtained according to a similar
manner to that of Preparation 50. [0780]
3-Fluoro-4-methylbenzylalcohol [0781] IR (Neat): 3350, 1580, 1510,
1420, 1250 cm.sup.-1 Preparation 53
[0782] The following compound was obtained by a similar manner to
that of Preparation 51 followed by a similar manner to that of
Preparation 27.
[0783] 2-Acetylamino-2-(3-fluoro-4-methylbenzyl)malonic acid
diethyl ester [0784] IR (Nujol): 3250, 1740, 1630, 1510, 1360
cm.sup.-1 [0785] NMR (DMSO-d.sub.6, .delta.): 1.20 (6H, t, J=7.0
Hz), 1.94 (3H, s), 2.19 (3H, s), 3.40 (2H, s), 4.10 (4H, q, J=7.0
Hz), 6.67-7.23 (3H, m), 8.13 (1H, s) [0786] MASS (APCI): 340
(M+H).sup.+ Preparation 54
[0787] The following compounds were obtained according to a similar
manner to that of the first half of Preparation 21. [0788] (1)
(2R)-4-Benzyl-2-[4-chloro-3-methoxybenzyl]piperazine
dihydrochloride [0789] mp: 225-230.degree. C. (decomp.) [0790] IR
(KBr): 3398, 1460, 1419, 1246, 1030 cm.sup.-1 [0791] NMR
(DMSO-d.sub.6, .delta.): 2.80-4.60 (11H, m), 3.87 (3H, s), 6.86
(1H, d, J=8.1 Hz), 7.10 (1H, s), 7.30-7.60 (6H, m) 9.20-10.80 (3H,
br) [0792] MASS (APCI): 331 (M+H).sup.+ (free) [0793] (2)
(3R)-1-Benzyl-3-(4-fluoro-3-methoxybenzyl)piperazine [0794] IR
(Neat): 1666, 1608, 1516, 1456, 1419, 1321, 1275, 1217, 1151, 1126,
1034 cm.sup.-1 [0795] NMR (CDCl.sub.3, .delta.): 0.60-3.20 (9H, m),
3.58 (2H, s), 3.86 (3H, s), 6.50-7.10 (3H, m), 7.10-7.60 (5H, m)
[0796] MASS (APCI): 315 (M+H).sup.+ [0797] (3)
(2R)-4-Benzyl-2-[3-methoxy-4-(trifluoromethyl)benzoyl]-piperazine
[0798] IR (Neat): 2938, 2809, 1614, 1583, 1506, 1459, 1421
cm.sup.-1 [0799] NMR (CDCl.sub.3, .delta.): 1.84-2.16 (2H, m),
2.50-3.01 (7H, m), 3.51 (2H, s), 3.88 (3H, s), 6.83-6.85 (2H, m),
7.25-7.33 (6H, m), 7.47 (1H, d, J=8.2 Hz) [0800] MASS (APCI): 365
(M+H).sup.+ [0801] (4)
(2R)-4-Benzyl-2-(4-fluoro-3-methylbenzyl)piperazine [0802] IR
(Neat): 1500, 1450, 1320, 1245, 1205, 1120 cm.sup.-1 [0803] NMR
(DMSO-d.sub.6, .delta.): 1.60-3.52 (14H, m), 6.95-7.40 (8H, m)
[0804] MASS (APCI): 299 (M+H).sup.+ [0805] (5)
(2R)-4-Benzyl-2-(3-fluoro-4-methylbenzyl)piperazine [0806] IR
(Neat): 1575, 1510, 1450, 1320, 1250, 1130, 1110 cm.sup.-1 [0807]
(6) (2R)-4-Benzyl-2-(4-fluorobenzyl)piperazine [0808] IR (Neat):
2937, 2807, 1508, 1450, 1326, 1135, 827, 742 cm.sup.-1 [0809] NMR
(CDCl.sub.3, .delta.): 1.87 (1H, t, J=10.4 Hz), 2.14 (1H, dt, J=3.8
and 11.0 Hz), 2.35-2.94 (7H, m), 3.47 (1H, d, J=13.0 Hz), 3.53 (1H,
d, J=13.0 Hz), 6.92-7.32 (9H, m) [0810] MASS (APCI): 285
(M+H).sup.+ [0811] (7) (3R)-1-Benzyl-3-(4-chlorobenzyl)piperazine
[0812] IR (Neat): 1670, 1491, 1450, 1406, 1360, 1329, 1136, 1093,
1036, 1022 cm.sup.-1 [0813] NMR (CDCl.sub.3, .delta.): 1.70-3.80
(11H, m), 7.12 (2H, d, J=8.4 Hz), 7.20-7.60 (7H, m) [0814] MASS
(APCI): 301 (M+H).sup.+ [0815] (8)
(3R)-1-Benzyl-3-[4-(trifluoromethyl)benzyl]piperazine [0816] IR
(Neat): 2939, 2810, 1676, 1618 cm.sup.-1 [0817] NMR (CDCl.sub.3,
.delta.): 1.89 (1H, t, J=10.5 Hz), 2.09 (1H, dt, J=3.9 and 11.0
Hz), 2.55-3.04 (7H, m), 3.49 (1H, d, J=13.0 Hz), 3.52 (1H, d,
J=13.0 Hz), 7.25-7.32 (7H, m), 7.55 (2H, d, J=8.1 Hz) [0818] MASS
(APCI): 335 (M+H).sup.+ [0819] (9)
(3R)-1-Benzyl-3-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [0820] mp: 212-225.degree. C. [0821] IR (KBr):
3398, 2673, 1458, 1331 cm.sup.-1 [0822] NMR (DMSO-d.sub.6,
.delta.): 3.00-4.50 (11H, m), 7.43-7.76 (9H, m) [0823] MASS (APCI):
335 (M+H).sup.+ (free) Preparation 55
[0824] The following compounds were obtained according to a similar
manner to that of the latter half of Preparation 21. [0825] (1)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybe-
nzyl)piperazine [0826] IR (Neat): 1736, 1643, 1616, 1516, 1462,
1454, 1435, 1425, 1377, 1273, 1103, 1065, 1038 cm.sup.-1 [0827] NMR
(CDCl.sub.3, .delta.): 0.60-5.20 (14H, m), 6.20-8.60 (11H, m)
[0828] MASS (APCI): 555 (M+H).sup.+ [0829] (2)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluo-
romethyl)benzyl]piperazine [0830] IR (Neat): 1643, 1280, 1180, 1137
cm.sup.-1 [0831] NMR (CDCl.sub.3, .delta.): 2.20-5.20 (14H, m),
6.40-8.00 (11H, m) [0832] MASS (APCI): 605 (M+H).sup.+ [0833] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methylbenzyl)-4-be-
nzylpiperazine [0834] IR (Neat): 1640, 1500, 1430, 1380, 1350,
1275, 1130 cm.sup.-1 [0835] NMR (DMSO-d.sub.6, .delta.): 2.00-4.83
(14H, m), 6.60-8.21 (11H, m) [0836] MASS (APCI): 539 (M+H).sup.+
[0837] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-3-methylbenzyl)-4-be-
nzylpiperazine [0838] IR (Neat): 1640, 1430, 1280, 1170, 1130
cm.sup.-1 [0839] NMR (DMSO-d.sub.6, .delta.): 2.00-4.90 (11H, m),
2.16 (3H, s), 6.53-8.24 (11H, m) [0840] MASS (APCI): 539
(M+H).sup.+
EXAMPLE 9
[0841] The following compounds were obtained according to a similar
manner to that of Example 1 using N,N-diisopropyl-ethylamine
instead of potassium carbonate as a base. [0842] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [0843] mp: 160-169.degree. C. [0844]
[.alpha.].sub.D.sup.27: +10.0.degree. (C=0.52, MeOH) [0845] IR
(KBr): 3500-3150, 2700-2300, 1644, 1423, 1282 cm.sup.-1 [0846] NMR
(DMSO-d.sub.6, .delta.): 2.60-5.00 (25H, m), 6.30-7.25 (3H, m),
7.43 (1H, s), 7.79 (1H, s), 8.17-8.22 (1H, m), 10.13 (1H, br s),
11.00-12.00 (2H, m) [0847] MASS (APCI): 624 (M+H).sup.+ (free)
[0848] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [0849] mp: 180-190.degree. C. [0850]
[.alpha.].sub.D.sup.26.7: +13.90.degree. (C=0.5, MeOH) [0851] IR
(KBr): 1676, 1645, 1547, 1516, 1464, 1427, 1392, 1387, 1367, 1321,
1282, 1217, 1184, 1136, 1034 cm.sup.-1 [0852] NMR (DMSO-d.sub.6,
.delta.): 2.00-5.40 (28H, m), 6.30-8.30 (6H, m) [0853] MASS (APCI):
622 (M+H).sup.+ (free) [0854] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl-
]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [0855] mp: 146-159.degree. C. [0856]
[.alpha.].sub.D.sup.26.8: +10.67.degree. (C=0.239, MeOH) [0857] IR
(KBr): 3435, 2656, 2598, 2467, 1647, 1429, 1329, 1282, 1180, 1132,
1068 cm.sup.-1 [0858] NMR (DMSO-d.sub.6, .delta.): 2.66-5.32 (27H,
m), 7.10-8.30 (7H, m) [0859] MASS (APCI): 642 (M+H).sup.+ (free)
[0860] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piper-
azine [0861] IR (Neat): 1670, 1643, 1583, 1508, 1452, 1446, 1435,
1429, 1381, 1358, 1350, 1336, 1277 cm.sup.-1 [0862] NMR
(CDCl.sub.3, .delta.): 0.70-5.50 (31H, m), 6.20-8.60 (9H, m) [0863]
MASS (APCI): 695 (M+H).sup.+ [0864] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-chloro-3-hydroxybenzyl]-4-[-
4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride
[0865] mp: 181-186.degree. C. [0866] [.alpha.].sub.D.sup.27.1:
+0.571.degree. (C=0.175, MeOH) [0867] IR (KBr): 3431, 2586, 1647,
1431, 1281, 1180, 1134 cm.sup.-1 [0868] NMR (DMSO-d.sub.6,
.delta.): 1.32 (3H, s), 1.39 (3H, s), 2.60-5.20 (19H, m), 6.31-7.29
(3H, m), 7.54-8.21 (3H, m), 10.10 (1H, br) [0869] MASS (APCI): 632
(M).sup.+ (free) [0870] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-chloro-3-hydroxybenzyl]-4-[-
2-(cis-2,6-dimethylmorpholino)ethyl]-piperazine dihydrochloride
[0871] mp: 172-175.degree. C. [0872] [.alpha.].sub.D.sup.28.2:
-4.43.degree. (C=0.305, MeOH) [0873] IR (KBr): 3431, 2999, 1647,
1429, 1281, 1182, 1140 cm.sup.-1 [0874] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=6.1 Hz), 2.60-5.20 (19H, m), 6.32-7.28
(3H, m), 7.42-8.24 (3H, m), 10.12 (1H, br) [0875] MASS (APCI): 608
(M).sup.+ (free) [0876] (7)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-chloro-3-hydroxybenzyl]-4-[-
2-(4,4-difluoropiperidino)ethyl]-piperazine dihydrochloride [0877]
mp: 166-170.degree. C. [0878] [.alpha.].sub.D.sup.28.0:
-4.25.degree. (C=0.365, MeOH) [0879] IR (KBr): 3435, 1647, 1429,
1281, 1182, 1140 cm.sup.-1 [0880] NMR (DMSO-d.sub.6, .delta.):
2.20-5.20 (21H, m), 6.32-7.24 (3H, m), 7.42-8.18 (3H, m), 10.10
(1H, br) [0881] MASS (APCI): 614 (M+H).sup.+ (free) [0882] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-chloro-3-hydroxybenzyl]-4-[-
2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [0883] mp: 237-243.degree. C. (decomp.) [0884]
[.alpha.].sub.D.sup.26.1: -19.1.degree. (C=0.285, MeOH) [0885] IR
(KBr): 3433, 2561, 1645, 1427, 1281, 1185, 1136 cm.sup.-1 [0886]
NMR (DMSO-d.sub.6, .delta.): 2.60-6.10 (19H, m), 6.30-7.20 (3H, m),
7.40-8.20 (3H, m), 7.76 (1H, dd, J=4.5 and 8.1 Hz), 8.14 (1H, d,
J=8.1 Hz), 8.71 (1H, d, J=4.5 Hz), 10.20 (1H, br) [0887] MASS
(APCI): 627 (M).sup.+ (free) [0888] (9)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-[4-chloro-3-hydroxybenzyl-
]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [0889] mp: 160-168.degree. C. [0890]
[.alpha.].sub.D.sup.28.3: +14.83.degree. (C=0.30, MeOH) [0891] IR
(KBr): 3431, 2586, 1641, 1606, 1462, 1425, 1174, 1130 cm.sup.-1
[0892] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (25H, m), 3.82 (3H,
s), 6.32-7.31 (6H, m), 10.11 (1H, br) [0893] MASS (APCI): 586
(M).sup.+ (free) [0894] (10)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine
dihydrochloride [0895] mp: 187-195.degree. C. [0896]
[.alpha.].sub.D.sup.26.9: +9.19.degree. (C=0.37, MeOH) [0897] IR
(KBr): 3423, 1641, 1604, 1462, 1425, 1238, 1173, 1126 cm.sup.-1
[0898] NMR (DMSO-d.sub.6, .delta.): 1.33 (3H, s), 1.37 (3H, s),
2.80-5.20 (19H, m), 3.85 (3H, s), 6.30-7.30 (6H, m), 10.10 (1H, br)
[0899] MASS (APCI): 594 (M).sup.+ (free) [0900] (11)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine dihydrochloride
[0901] mp: 177-182.degree. C. [0902] [.alpha.].sub.D.sup.27.3:
+9.71.degree. (C=0.34, MeOH) [0903] IR (KBr): 3425, 2613, 1641,
1606, 1462, 1425, 1174, 1132 cm.sup.-1 [0904] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=5.8 Hz), 2.60-5.20 (19H, m), 3.82 (3H, s),
6.31-7.32 (6H, m), 9.90 (1H, br) [0905] MASS (APCI): 570 (M).sup.+
(free) [0906] (12)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxyb-
enzyl)-4-[2-(4,4-difluoropieridino)-ethyl]piperazine
dihydrochloride [0907] mp: 178-182.degree. C. [0908]
[.alpha.].sub.D.sup.27.1: +5.48.degree. (C=0.21, MeOH) [0909] IR
(KBr): 3435, 1641, 1606, 1464, 1425, 1173, 1134 cm.sup.-1 [0910]
NMR (DMSO-d.sub.6, .delta.): 2.20-5.20 (21H, m), 3.83 (3H, s),
6.32-7.40 (6H, m), 10.17 (1H, br) [0911] MASS (APCI): 576 (M).sup.+
(free) [0912] (13)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [0913] mp: 225-240.degree. C. (decomp.) [0914]
[.alpha.].sub.D.sup.28.3: -8.15.degree. (C=0.27, MeOH) [0915] IR
(KBr): 3435, 1641, 1626, 1464, 1425, 1238, 1173, 1130 cm.sup.-1
[0916] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (19H, m), 3.83 (3H,
s), 6.30-7.40 (6H, m), 7.71 (1H, dd, J=4.6 and 7.6 Hz), 8.12 (1H,
d, J=7.6 Hz), 8.71 (1H, d, J=4.6 Hz), 10.20 (1H, br) [0917] MASS
(APCI): 589 (M).sup.+ (free) [0918] (14)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-methoxybenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [0919] mp: 145-149.degree. C. [0920]
[.alpha.].sub.D.sup.27: +11.0.degree. (C=0.5, MeOH) [0921] IR
(KBr): 3500-3150, 2700-2300, 1644, 1423, 1282 cm.sup.-1 [0922] NMR
(DMSO-d.sub.6, .delta.): 2.60-5.00 (28H, m), 6.53-7.39 (3H, m),
7.45 (1H, s), 7.73 (1H, s), 8.19 (1H, m) [0923] MASS (APCI): 638
(M+H).sup.+ (free) [0924] (15)
(2R)-1-[3-Trifluoromethyl-5-methylthiobenzoyl)-2-(4-chloro-3-tert-butyldi-
methylsilyloxybenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine
[0925] IR (Neat): 1680, 1630, 1490, 1420, 1130, 1085 cm.sup.-1
[0926] NMR (CDCl.sub.3, .delta.): 0.18 (6H, s), 1.01 (9H, s), 1.15
(6H, d, J=6.3 Hz), 1.75 (2H, t, J=10.6 Hz), 2.08-5.10 (20H, m),
6.30-8.08 (6H, m) [0927] MASS (API-ES): 700 (M.sup.+) [0928] (16)
(2R)-1-(3-Trifluoromethyl-5-methylthiobenzoyl)-2-(4-chloro-3-tert-butyldi-
methylsilyloxybenzyl)-4-[2-(5,6,7,8-tetrahydro-1,6-naphthylidin-6-yl)ethyl-
]-piperazine [0929] IR (Neat): 1635, 1490, 1420, 1295, 1170, 1130,
1105 cm.sup.-1 [0930] NMR (CDCl.sub.3, .delta.): 0.18 (6H, s), 1.01
(9H, s), 2.08-5.10 (22H, m), 6.30-8.48 (9H, m) [0931] MASS
(API-ES): 719 (M.sup.+) [0932] (17)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine [0933] IR
(Neat): 1643, 1583, 1508, 1466, 1452, 1431, 1377, 1358, 1331, 1277,
1086, 1018 cm.sup.-1 [0934] NMR (CDCl.sub.3, .delta.): 0.70-5.60
(23H, m), 6.20-8.90 (10H, m) [0935] MASS (APCI): 650 (M+H).sup.+
[0936] (18)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride
[0937] mp: 125-130.degree. C. [0938] [.alpha.].sub.D.sup.26.8:
+11.77.degree. (C=0.31, MeOH) [0939] IR (KBr): 3425, 2586, 1647,
1518, 1281, 1182, 1132 cm.sup.-1 [0940] NMR (DMSO-d.sub.6,
.delta.): 1.33 (3H, s), 1.40 (3H, s), 2.70-5.20 (22H, m), 6.50-7.30
(3H, m), 7.50-8.21 (3H, m) [0941] MASS (APCI): 630 (M+H).sup.+
(free) [0942] (19)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-(cis-2,6-dimethylmorpholino)ethyl]-piperazine dihydrochloride
[0943] mp: 205.0-208.0.degree. C. [0944] [.alpha.].sub.D.sup.26.9:
+14.4.degree. (C=0.25, MeOH) [0945] IR (KBr): 3500-3150, 2700-2300,
1644, 1617, 1517, 1463, 1427, 1278, 1133 cm.sup.-1 [0946] NMR
(DMSO-d.sub.6, .delta.): 2.60-5.20 (28H, m), 6.60-8.40 (6H, m)
[0947] MASS (APCI): 606 (M+H).sup.+ (free) [0948] (20)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-(4,4-difluoropiperidino)ethyl]-piperazine dihydrochloride [0949]
mp: 240-243.degree. C. [0950] [.alpha.].sub.D.sup.28.3:
+2.86.degree. (C=0.315, MeOH) [0951] IR (KBr): 3384, 2941, 2418,
1649, 1518, 1282, 1184, 1138 cm.sup.-1 [0952] NMR (DMSO-d.sub.6,
.delta.): 2.20-5.20 (24H, m), 6.50-7.30 (3H, m), 7.43-8.20 (3H, m)
[0953] MASS (APCI): 612 (M+H).sup.+ (free) [0954] (21)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [0955] mp: 175-185.degree. C. [0956]
[.alpha.].sub.D.sup.27: -10.0.degree. (C=0.16, MeOH) [0957] IR
(KBr): 3500-3150, 2700-2300, 1641, 1562, 1459, 1432, 1282 cm.sup.-1
[0958] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (22H, m), 6.60-8.70
(9H, m) [0959] MASS (APCI): 625 (M+H).sup.+ (free) [0960] (22)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [0961] [.alpha.].sub.D.sup.26.7: +29.52.degree.
(C=0.31, MeOH) [0962] IR (KBr): 1643, 1635, 1618, 1606, 1518, 1462,
1419, 1273, 1169, 1132, 1103, 1041 cm.sup.-1 [0963] NMR
(DMSO-d.sub.6, .delta.): 0.70-5.40 (31H, m), 6.30-7.50 (6H, m)
[0964] MASS (APCI): 584 (M+H).sup.+ (free) [0965] (23)
(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-(4-fluoro-3-methoxybenzyl-
)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [0966] [.alpha.].sub.D.sup.28.0: +26.67.degree.
(C=0.24, MeOH) [0967] IR (KBr): 1676, 1645, 1635, 1628, 1616, 1516,
1464, 1423, 1346, 1273, 1171, 1126, 1101, 1049 cm.sup.-1 [0968] NMR
(DMSO-d.sub.6, .delta.): 1.10-5.30 (31H, m), 6.40-7.50 (6H, m)
[0969] MASS (APCI): 592 (M+H).sup.+ (free) [0970] (24)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-2-(4-fluoro-3-methoxybenzyl)-
-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride
[0971] [.alpha.].sub.D.sup.26.3: +23.54.degree. (C=0.24, MeOH)
[0972] IR (KBr): 1645, 1612, 1516, 1464, 1423, 1398, 1352, 1315,
1275, 1213, 1173, 1130, 1092, 1055, 1036 cm.sup.-1 [0973] NMR
(DMSO-d.sub.6, .delta.): 0.80-5.30 (31H, m), 6.30-7.50 (6H, m)
[0974] MASS (APCI): 568 (M+H).sup.+ (free) [0975] (25)
(2R)-4-[2-(4,4-Difluoropiperidino)ethyl]-2-(4-fluoro-3-methoxybenzyl)-1-[-
3-methoxy-5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride
[0976] [.alpha.].sub.D.sup.26.4: +24.63.degree. (C=0.27, MeOH)
[0977] IR (KBr): 2538, 2488, 1641, 1604, 1516, 1464, 1417, 1387,
1346, 1290, 1242, 1171, 1134, 1047, 1024 cm.sup.-1 [0978] NMR
(DMSO-d.sub.6, .delta.): 1.70-5.40 (27H, m), 6.30-7.50 (6H, m)
[0979] MASS (APCI): 574 (M+H).sup.+ (free) [0980] (26)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl-
]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [0981] [.alpha.].sub.D.sup.25.8: +5.22.degree.
(C=0.345, MeOH) [0982] IR (KBr): 1643, 1635, 1630, 1516, 1464,
1423, 1350, 1317, 1275, 1173, 1128, 1051, 1038 cm.sup.-1 [0983] NMR
(DMSO-d.sub.6, .delta.): 0.80-5.50 (25H, m), 6.20-8.70 (9H, m)
[0984] MASS (APCI): 587 (M+H).sup.+ (free) [0985] (27)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [0986] mp: 156-168.degree. C. [0987]
[.alpha.].sub.D.sup.27.6: +5.14.degree. (C=0.36, MeOH) [0988] IR
(KBr): 3458, 1647, 1518, 1433, 1282, 1184, 1140 cm.sup.-1 [0989]
NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (25H, m), 6.30-7.20 (3H, m),
7.43-8.23 (3H, m), 9.77 (1H, br) [0990] MASS (APCI): 608
(M+H).sup.+ (free) [0991] (28)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl)-4-[-
4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride
[0992] mp: 180-184.degree. C. [0993] [.alpha.].sub.D.sup.26.8:
+2,20.degree. (C=0.25, MeOH) [0994] IR (KBr): 3435, 2931, 2584,
1645, 1435, 1281, 1182, 1136 cm.sup.-1 [0995] NMR (DMSO-d.sub.6,
.delta.): 1.32 (3H, s), 1.39 (3H, s), 2.60-5.20 (19H, m), 6.30-7.20
(3H, m), 7.50-8.21 (3H, m), 9.76 (1H, br) [0996] MASS (APCI): 616
(M+H).sup.+ (free) [0997] (29)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl-
)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-piperazine
dihydrochloride [0998] mp: 170-195.degree. C. [0999]
[.alpha.].sub.D.sup.27: +6.77.degree. (C=0.27, MeOH) [1000] IR
(KBr): 3500-3150, 2700-2300, 1644, 1519, 1434, 1371, 1282, 1184
cm.sup.-1 [1001] NMR (DMSO-d.sub.6, .delta.): 0.80-5.20 (25H, m),
6.60-8.20 (7H, m), 11.40-11.80 (2H, br) [1002] MASS (APCI): 592
(M+H).sup.+ (free) [1003] (30)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl)-4-[-
2-(4,4-difluoropiperidino)ethyl]-piperazine dihydrochloride [1004]
mp: 190-200.degree. C. [1005] [.alpha.].sub.D.sup.27: +0.83.degree.
(C=0.3, MeOH) [1006] IR (KBr): 3500-3150, 2700-2300, 1646, 1517,
1432, 1373, 1282, 1139 cm.sup.-1 [1007] NMR (DMSO-d.sub.6,
.delta.): 2.60-5.20 (21H, m), 6.20-8.30 (7H, m), 9.00-10.40 (2H,
br) [1008] MASS (APCI): 598 (M+H).sup.+ (free) [1009] (31)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl)-4-[-
2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1010] mp: 240.0-241.0.degree. C. [1011]
[.alpha.].sub.D.sup.26: -11.66.degree. (C=0.57, MeOH) [1012] IR
(KBr): 3500-3150, 2700-2300, 1641, 1517, 1432, 1282, 1137 cm.sup.-1
[1013] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (19H, m), 6.20-8.80
(10H, m), 9.00-10.50 (2H, br) [1014] MASS (APCI): 611 (M+H).sup.+
(free) [1015] (32)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-[2-[(2S-
)-2-(methoxymethyl)morpholino]-ethyl]piperazine dihydrochloride
[1016] mp: 196-198.degree. C. [1017] [.alpha.].sub.D.sup.27:
+8.3.degree. (C=0.5, MeOH) [1018] IR (KBr): 3365, 2590, 2475, 1645,
1520, 1440, 1280 cm.sup.-1 [1019] NMR (DMSO-d.sub.6, .delta.):
2.73-5.07 (22H, m), 3.27 (3H, s), 6.88-8.21 (6H, m) [1020] MASS
(APCI): 610 (M+H).sup.+ (free) [1021] (33)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-[4-(3,3-
-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride [1022]
[.alpha.].sub.D.sup.27: +4.2.degree. (C=0.5, MeOH) [1023] IR (KBr):
2435, 1645, 1520, 1430, 1280 cm.sup.-1 [1024] NMR (DMSO-d.sub.6,
.delta.): 1.32 (3H, s), 1.38 (3H, s), 2.76-5.17 (19H, m), 6.79-8.26
(6H, m) [1025] MASS (APCI): 618 (M+H).sup.+ (free) [1026] (34)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-[2-(cis-
-2,6-dimethylmorpholino)ethyl]-piperazine dihydrochloride [1027]
mp: 223-280.degree. C. [1028] [.alpha.].sub.D.sup.27: +5.1.degree.
(C=0.5, MeOH) [1029] IR (KBr): 3435, 3390, 2600, 2495, 1650, 1520,
1435, 1280 cm.sup.-1 [1030] NMR (DMSO-d.sub.6, .delta.): 1.45 (6H,
d, J=6.0 Hz), 2.60-5.20 (19H, m), 6.80-8.28 (6H, m) [1031] MASS
(APCI): 594 (M+H).sup.+ (free) [1032] (35)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-[2-(4,4-
-difluoropiperidino)ethyl]-piperazine dihydrochloride [1033]
[.alpha.].sub.D.sup.27: +9.1.degree. (C=0.5, MeOH) [1034] IR (KBr):
2380, 1645, 1520, 1430, 1280 cm.sup.-1 [1035] NMR (DMSO-d.sub.6,
.delta.): 2.10-5.14 (21H, m), 6.78-8.26 (6H, m) [1036] MASS (APCI):
600 (M+H).sup.+ (free) [1037] (36)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-(1-meth-
yl-1H-pyrazol-4-yl)methyl)-piperazine hydrochloride [1038] mp:
230.degree. C. [1039] [.alpha.].sub.D.sup.27: -1.6.degree. (C=0.5,
MeOH) [1040] IR (KBr): 2520, 2470, 1645, 1525, 1440, 1365, 1275
cm.sup.-1 [1041] NMR (DMSO-d.sub.6, .delta.): 2.72-5.12 (11H, m),
3.86 (3H, s), 6.74-8.31 (8H, m) [1042] MASS (APCI): 547 (M+H).sup.+
(free) [1043] (37)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-(3-pyri-
dylmethyl)piperazine dihydrochloride [1044] mp: 203-208.degree. C.
[1045] [.alpha.].sub.D.sup.27: +5.3.degree. (C=0.5, MeOH) [1046] IR
(KBr): 2560, 1640, 1520, 1430, 1370, 1280 cm.sup.-1 [1047] NMR
(DMSO-d.sub.6, .delta.): 2.80-5.14 (11H, m), 6.72-9.10 (10H, m)
[1048] MASS (APCI): 544 (M+H).sup.+ (free) [1049] (38)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-[3-(3-p-
yridyl)propyl]piperazine dihydrochloride [1050] mp: 215-220.degree.
C. [1051] [.alpha.].sub.D.sup.27: +2.6.degree. (C=0.5, MeOH) [1052]
IR (KBr): 2650, 1645, 1550, 1520, 1430, 1280 cm.sup.-1 [1053] NMR
(DMSO-d.sub.6, .delta.): 2.13-5.15 (15H, m), 6.78-8.95 (10H, m)
[1054] MASS (APCI): 572 (M+H).sup.+ (free) [1055] (39)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-difluorobenzyl)-4-[2-(5,6-
,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1056] [.alpha.].sub.D.sup.27: -2.0.degree.
(C=0.5, MeOH) [1057] IR (KBr): 2620, 1645, 1515, 1430, 1280
cm.sup.-1 [1058] NMR (DMSO-d.sub.6, .delta.): 2.59-5.17 (19H, m),
6.76-8.69 (9H, m) [1059] MASS (APCI): 613 (M+H).sup.+ (free) [1060]
(40)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluoromethyl)-
benzyl]-4-[2-(cis-2,6-dimethyl-morpholino)ethyl]piperazine
dihydrochloride [1061] mp: 160.0-170.0.degree. C. [1062]
[.alpha.].sub.D.sup.27: +17.16.degree. (C=0.44, MeOH) [1063] IR
(KBr): 3500-3150, 2700-2300, 1648, 1623, 1587, 1511, 1463, 1280,
1132 cm.sup.-1 [1064] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (28H,
m), 6.40-8.20 (6H, m) [1065] MASS (APCI): 656 (M+H).sup.+ (free)
[1066] (41)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluoromethyl)-
benzyl]-[4-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1067] mp: 195-200.degree. C. [1068]
[.alpha.].sub.D.sup.27: +1.76.degree. (C=0.34, MeOH) [1069] IR
(KBr): 3500-3150, 2700-2300, 1646, 1625, 1511, 1465, 1427, 1369,
1280, 1130 cm.sup.-1 [1070] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20
(22H, m), 6.60-8.80 (9H, m) [1071] MASS (APCI): 675 (M+H).sup.+
(free) [1072] (42)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(triflu-
oromethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
dihydrochloride [1073] mp: 135-140.degree. C. [1074]
[.alpha.].sub.D.sup.27: +20.3.degree. (C=0.15, MeOH) [1075] IR
(KBr): 3500-3150, 2700-2300, 1644, 1623, 1463, 1423, 1321, 1128,
1045 cm.sup.-1 [1076] NMR (DMSO-d.sub.6, .delta.): 2.80-5.20 (31H,
m), 6.60-8.20 (6H, m), 10.60-12.20 (2H, br) [1077] MASS (APCI): 634
(M+H).sup.+ (free) [1078] (43)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluorome-
thyl)benzyl]-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine
dihydrochloride [1079] mp: 125-135.degree. C. [1080]
[.alpha.].sub.D.sup.27: +35.0.degree. (C=0.18, MeOH) [1081] IR
(KBr): 3500-3150, 2700-2300, 1644, 1623, 1511, 1463, 1423, 1351,
1274, 1128 cm.sup.-1 [1082] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20
(31H, m), 6.50-8.20 (6H, m), 11.20-11.80 (2H, br) [1083] MASS
(APCI): 618 (M+H).sup.+ (free) [1084] (44)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluorome-
thyl)benzyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazi-
ne trihydrochloride [1085] mp: 190-200.degree. C. [1086]
[.alpha.].sub.D.sup.27: +7.5.degree. (C=0.16, MeOH) [1087] IR
(KBr): 3500-3150, 2700-2300, 1623, 1614, 1511, 1463, 1321, 1126
cm.sup.-1 [1088] NMR (DMSO-d.sub.6, .delta.): 2.80-5.20 (25H, m),
6.60-8.80 (9H, m) [1089] MASS (APCI): 637 (M+H).sup.+ (free) [1090]
(45)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-4-methylbenzyl)-4-[2-
-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [1091] mp: 148-160.degree. C. [1092]
[.alpha.].sub.D.sup.26.5: -2.25.degree. (C=0.222, MeOH) [1093] IR
(KBr): 3435, 2661, 2593, 2465, 1645, 1514, 1429, 1363, 1324, 1282,
1184, 1140 cm.sup.-1 [1094] NMR (DMSO-d.sub.6, .delta.): 2.20 (3H,
s), 2.64-5.28 (25H, m), 6.62-8.28 (6H, m) [1095] MASS (APCI): 606
(M+H).sup.+ (free) [1096] (46)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methylbenzyl)-4-[2-
-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [1097] mp: 151-156.degree. C. [1098]
[.alpha.].sub.D.sup.27: +2.96.degree. (C=0.355, MeOH) [1099] IR
(KBr): 3435, 2941, 1647, 1510, 1281, 1184, 1138 cm.sup.-1 [1100]
NMR (DMSO-d.sub.6, .delta.): 2.10-2.21 (3H, m), 2.65-5.25 (25H, m),
6.70-8.30 (6H, m) [1101] MASS (APCI): 606 (M+H).sup.+ (free) [1102]
(47)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[4-[(2S)-2-(methoxymethyl)morpholino]-2-butynyl]piperazi-
ne [1103] IR (Neat): 1643, 1583, 1510, 1452, 1446, 1433, 1379,
1277, 1095, 1014 cm.sup.-1 [1104] NMR (CDCl.sub.3, .delta.):
0.60-5.40 (37H, m), 6.20-8.20 (6H, m) [1105] MASS (ESI): 716.3
(M+H).sup.+ [1106] (48)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholin-
o)-2-butynyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [1107] mp: 110-130.degree. C. [1108]
[.alpha.].sub.D.sup.24: +9.20.degree. (C=0.25, MeOH) [1109] IR
(KBr): 1647 cm.sup.-1 [1110] NMR (DMSO-d.sub.6, .delta.): 1.33-1.41
(6H, m), 2.80-5.30 (19H, m), 7.20-8.17 (7H, m) [1111] MASS (APCI):
650 (M+H).sup.+ (free) [1112] (49)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorph-
olino)ethyl]-2-[4-(trifluoromethyl)benzyl]-piperazine
dihydrochloride [1113] mp: 148-159.degree. C. [1114]
[.alpha.].sub.D.sup.27: +10.60.degree. (C=0.25, MeOH) [1115] IR
(KBr): 3437, 1645, 1516, 1427 cm.sup.-1 [1116] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=6.1 Hz), 6.60-5.30 (19H, m), 7.25-8.19
(7H, m) [1117] MASS (APCI): 626 (M+H).sup.+ (free) [1118] (50)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(4,4-difluoropiperidino)eth-
yl]-2-[4-(trifluoromethyl)benzyl]-piperazine dihydrochloride [1119]
mp: 209-253.degree. C. [1120] [.alpha.].sub.D.sup.26:
+15.60.degree. (C=0.25, MeOH) [1121] IR (KBr): 1647 cm.sup.-1
[1122] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (21H, m), 7.21-8.19
(7H, m) [1123] MASS (APCI): 632 (M+H).sup.+ (free) [1124] (51)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(1-methyl-1H-pyrazol-4-yl)met-
hyl]-2-[4-(trifluoromethyl)benzyl]-piperazine hydrochloride [1125]
mp: 200-229.degree. C. [1126] [.alpha.].sub.D.sup.24: +5.07.degree.
(C=0.25, MeOH) [1127] IR (KBr): 1647 cm.sup.-1 [1128] NMR
(DMSO-d.sub.6, .delta.): 2.84-5.20 (14H, m), 7.14-7.72 (7H, m),
7.94-7.96 (1H, m), 8.21 (1H, s) [1129] MASS (APCI): 579 (M+H).sup.+
(free) [1130] (52)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(3-pyridyl)-methyl]-2-[4-(tri-
fluoromethyl)benzyl]piperazine dihydrochloride [1131] mp:
198-223.degree. C. [1132] [.alpha.].sub.D.sup.27: +6.60.degree.
(C=0.25, MeOH) [1133] IR (KBr): 1645 cm.sup.-1 [1134] NMR
(DMSO-d.sub.6, .delta.): 2.80-5.20 (11H, m), 7.13-7.91 (7H, m),
8.34 (1H, s), 8.62 (1H, d, J=7.7 Hz), 8.87 (1H, d, J=5.2 Hz), 9.05
(1H, s) [1135] MASS (APCI): 576 (M+H).sup.+ (free) [1136] (53)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[3-(3-pyridyl)-2-propynyl]-2-[-
4-(trifluoromethyl)benzyl]-piperazine [1137] mp: 142-143.degree. C.
[1138] IR (KBr): 1643 cm.sup.-1 [1139] NMR (DMSO-d.sub.6, .delta.):
2.20-5.20 (11H, m), 7.19-7.64 (7H, m), 7.80-7.90 (1H, m), 8.16 (1H,
br s), 8.55-8.58 (1H, m), 8.66 (1H, br s) [1140] MASS (APCI): 600
(M+H).sup.+ [1141] (53)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[3-(3-pyridyl)-2-propynyl]-2-[-
4-(trifluoromethyl)benzyl]-piperazine [1142] mp: 142-143.degree. C.
[1143] IR (KBr): 1643 cm.sup.-1 [1144] NMR (DMSO-d.sub.6, .delta.):
2.20-5.20 (11H, m), 7.19-7.64 (7H, m) 7.80-7.90 (1H, m), 8.16 (1H,
br s), 8.35-8.58 (1H, m), 8.66 (1H, br s) [1145] MASS (APCI): 600
(M+H).sup.+ [1146] (54) (2R)-1-[3,5-Bis(trifluoromethyl)ben
zoyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]-2-[4-(trifluo-
romethyl)benzyl]piperazine trihydrochloride [1147] mp:
174-180.degree. C. [1148] [.alpha.].sub.D.sup.27: -2.80.degree.
(C=0.25, MeOH) [1149] IR (KBr): 3438, 1645, 1516 cm.sup.-1 [1150]
NMR (DMSO-d.sub.6, .delta.): 2.60-5.30 (19H, m), 7.20-8.67 (10H, m)
[1151] MASS (APCI): 645 (M+H).sup.+ (free) [1152] (55)
(2R)-4-[2-[(2S)-2-(Methoxymethyl)morpholino]ethyl]-1-[3-methoxy-5-(triflu-
oromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [1153] mp: 126-155.degree. C. [1154]
[.alpha.].sub.D.sup.26: +20.60.degree. (C=0.25, MeOH) [1155] IR
(KBr): 3460, 1645, 1464 cm.sup.-1 [1156] NMR (DMSO-d.sub.6,
.delta.): 2.80-5.30 (25H, m), 3.82 (3H, s), 6.31-7.80 (7H, m)
[1157] MASS (APCI): 604 (M+H).sup.+ (free) [1158] (56)
(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-1-[3-methoxy-5-(trifluorome-
thyl)benzyol]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [1159] mp: 158-165.degree. C. [1160]
[.alpha.].sub.D.sup.26: +19.93.degree. (C=0.25, MeOH) [1161] IR
(KBr): 3430, 1645, 1516, 1462, 1421 cm.sup.-1 [1162] NMR
(DMSO-d.sub.6, .delta.): 1.33 (3H, s), 1.38 (3H, s), 2.90-5.30
(19H, m), 3.83 (3H, s), 6.30-7.70 (7H, m) [1163] MASS (APCI): 612
(M+H).sup.+ (free) [1164] (57)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-1-[3-methoxy-5-(trifluoromet-
hyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [1165] mp: 139-151.degree. C. [1166]
[.alpha.].sub.D.sup.27: +19.00.degree. (C=0.25, MeOH) [1167] IR
(KBr): 3435, 1645, 1464, 1423 cm.sup.-1 [1168] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=6.1 Hz), 2.60-5.30 (19H, m), 3.82 (3H, s),
6.30-7.80 (7H, m) [1169] MASS (APCI): 588 (M+H).sup.+ (free) [1170]
(58)
(2R)-4-[2-(4,4-Difluoropiperidino)ethyl]-1-[3-methoxy-5-(trifluoromethyl)-
benzoyl]-2-[4-(trifluoromethyl)benzyl]-piperazine dihydrochloride
[1171] mp: 230.degree. C. [1172] [.alpha.].sub.D.sup.27:
+19.80.degree. (C=0.25, MeOH) [1173] IR (KBr): 1643, 1464, 1421
cm.sup.-1 [1174] NMR (DMSO-d.sub.6, .delta.): 2.30-5.30 (21H, m),
3.80 (3H, s), 6.30-7.80 (7H, m) [1175] MASS (APCI): 594 (M+H).sup.+
(free) [1176] (59)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-4-[3-(3-pyridyl)-2-propynyl-
]-2-[4-(trifluoromethyl)benzyl]-piperazine [1177] IR (Neat): 3585,
1637 cm.sup.-1 [1178] NMR (DMSO-d.sub.6, .delta.): 2.20-5.20 (11H,
m), 3.82 (3H, s), 6.81-7.70 (9H, m), 8.55 (1H, d, J=3.5 Hz), 8.66
(1H, s) [1179] MASS (APCI): 562 (M+H).sup.+ [1180] (60)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-4-[2-(5,6,7,8-tetrahydro-1,-
6-naphthyridin-6-yl)ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
trihydrochloride [1181] mp: 185-191.degree. C. [1182]
[.alpha.].sub.D.sup.27: +4,00.degree. (C=0.25, MeOH) [1183] IR
(KBr): 1645, 1423 cm.sup.-1 [1184] NMR (DMSO-d.sub.6, .delta.):
2.90-5.30 (19H, m), 3.83 (3H, s), 6.30-7.80 (8H, m), 8.11 (1H, d,
J=7.7 Hz), 8.70 (1H, d, J=4.7 Hz) [1185] MASS (APCI): 607
(M+H).sup.+ (free) [1186] (61)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-[2-[(2-
S)-2-(methoxymethyl)morpholino]-ethyl]piperazine dihydrochloride
[1187] mp: 90-120.degree. C. [1188] [.alpha.].sub.D.sup.27:
+5.18.degree. (C=0.28, MeOH) [1189] IR (KBr): 1707, 1693, 1676,
1645, 1547, 1539, 1516, 1498, 1489, 1477, 1464, 1454, 1427, 1392,
1387, 1367, 1281, 1182, 1138, 1101 cm.sup.-1 [1190] NMR
(DMSO-d.sub.6, .delta.): 2.00-5.40 (25H, m), 6.80-8.40 (7H, m)
[1191] MASS (APCI): 608 (M+H).sup.+ (free) [1192] (62)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-[4-(3,3-dim-
ethylmorpholino)-2-butynyl]-piperazine dihydrochloride [1193] mp:
120-150.degree. C. [1194] [.alpha.].sub.D.sup.27.6: -0.69.degree.
(C=0.29, MeOH) [1195] IR (KBr): 2578, 2515, 1645, 1496, 1489, 1431,
1362, 1319, 1281, 1217, 1182, 1136, 1099, 1066 cm.sup.-1 [1196] NMR
(DMSO-d.sub.6, .delta.): 1.10-1.50 (6H, m), 2.60-5.30 (19H, m),
6.80-8.40 (7H, m) [1197] MASS (APCI): 616 (M+H).sup.+ (free) [1198]
(63)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino-
)ethyl]-2-(4-chlorobenzyl)-piperazine dihydrochloride [1199] mp:
150-175.degree. C. (decomp.) [1200] [.alpha.].sub.D.sup.27.4:
-2.86.degree. (C=0.28, MeOH) [1201] IR (KBr): 1693, 1687, 1645,
1514, 1508, 1498, 1489, 1464, 1454, 1429, 1329, 1281, 1182, 1142,
1099, 1038 cm.sup.-1 [1202] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H,
d, J=6.1 Hz), 1.80-5.40 (19H, m), 6.80-8.30 (7H, m) [1203] MASS
(APCI): 592 (M+H).sup.+ (free) [1204] (64)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-[2-(4,4-dif-
luoropiperidino)ethyl]-piperazine dihydrochloride [1205] mp:
250-255.degree. C. [1206] [.alpha.].sub.D.sup.28.2: -3.52.degree.
(C=0.27, MeOH) [1207] IR (KBr): 1707, 1693, 1678, 1647, 1628, 1547,
1539, 1516, 1498, 1464, 1454, 1425, 1367, 1279, 1176, 1140, 1101,
1061, 974 cm.sup.-1 [1208] NMR (DMSO-d.sub.6, .delta.): 1.80-5.40
(21H, m), 6.80-8.40 (7H, m) [1209] MASS (APCI): 598 (M+H).sup.+
(free) [1210] (65)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-[2-(5,6,7,8-
-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine trihydrochloride
[1211] mp: 172-203.degree. C. (decomp.) [1212]
[.alpha.].sub.D.sup.27.4: -16.12.degree. (C=0.245, MeOH) [1213] IR
(KBr): 1674, 1645, 1630, 1558, 1550, 1539, 1516, 1498, 1489, 1464,
1427, 1392, 1387, 1367, 1281, 1182, 1136, 1101, 1043 cm.sup.-1
[1214] NMR (DMSO-d.sub.6, .delta.): 1.10-5.60 (19H, m), 6.80-8.80
(10H, m) [1215] MASS (APCI): 611 (M+H).sup.+ (free) [1216] (66)
(2R)-2-(4-Chlorobenzyl)-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]-1--
[3-methoxy-5-(trifluoromethyl)-benzoyl]piperazine dihydrochloride
[1217] mp: 70-90.degree. C. [1218] [.alpha.].sub.D.sup.28.2:
+13.00.degree. (C=0.227, MeOH) [1219] IR (KBr): 1643, 1606, 1514,
1508, 1496, 1423, 1387, 1350, 1315, 1271, 1242, 1174, 1130, 1097,
1051 cm.sup.-1 [1220] NMR (DMSO-d.sub.6, .delta.): 2.50-5.40 (28H,
m), 6.30-7.60 (7H, m) [1221] MASS (APCI): 570 (M+H).sup.+ (free)
[1222] (67)
(2R)-2-(4-Chlorobenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-1-[3-met-
hoxy-5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride [1223]
mp: 110-140.degree. C. [1224] [.alpha.].sub.D.sup.28.2:
+8.96.degree. (C=0.24, MeOH) [1225] IR (KBr): 1676, 1645, 1539,
1535, 1516, 1498, 1464, 1423, 1348, 1317, 1271, 1242, 1173, 1126,
1097, 1049 cm.sup.-1 [1226] NMR (DMSO-d.sub.6, .delta.): 1.10-1.60
(6H, m), 2.60-5.40 (22H, m), 6.40-7.60 (7H, m) [1227] MASS (APCI):
578 (M+H).sup.+ (free) [1228] (68)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-meth-
oxy-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride [1229]
mp: 90-120.degree. C. [1230] [.alpha.].sub.D.sup.27.9:
+10,.8.degree. (C=0.25, MeOH) [1231] IR (KBr): 1676, 1645, 1606,
1516, 1498, 1464, 1423, 1387, 1381, 1377, 1350, 1317, 1271, 1242,
1209, 1174, 1130, 1095, 1051 cm.sup.-1 [1232] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=6.1 Hz), 2.40-5.40 (22H, m), 6.30-7.60
(7H, m) [1233] MASS (APCI): 554 (M+H).sup.+ (free) [1234] (69)
(2R)-2-(4-Chlorobenzyl)-4-[2-(4,4-difluoropiperidino)-ethyl]-1-[3-methoxy-
-5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride [1235] mp:
220-250.degree. C. [1236] [.alpha.].sub.D.sup.28.3: +13.18.degree.
(C=0.425, MeOH) [1237] IR (KBr): 1641, 1635, 1604, 1539, 1516,
1498, 1464, 1417, 1344, 1292, 1269, 1242, 1174, 1138, 1097, 1047
cm.sup.-1 [1238] NMR (DMSO-d.sub.6, .delta.): 2.00-5.40 (24H, m),
6.30-7.60 (7H, m) [1239] MASS (APCI): 560 (M+H).sup.+ (free) [1240]
(70)
(2R)-2-(4-Chlorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-[2-(5,-
6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1241] mp: 140-170.degree. C. [1242]
[.alpha.].sub.D.sup.28.7: -6.11.degree. (C=0.36, MeOH) [1243] IR
(KBr): 1645, 1635, 1630, 1516, 1498, 1464, 1417, 1350, 1315, 1271,
1240, 1207, 1174, 1128, 1097, 1053 cm.sup.-1 [1244] NMR
(DMSO-d.sub.6, .delta.): 2.40-5.40 (22H, m), 6.30-8.90 (10H, m)
[1245] MASS (APCI): 573 (M+H).sup.+ (free) [1246] (71)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholi-
no)-2-butynyl]-2-(4-fluorobenzyl)piperazine dihydrochloride [1247]
mp: 76.5-130.6.degree. C. [1248] [.alpha.].sub.D.sup.26.3:
+7.53.degree. (C=0.25, MeOH) [1249] IR (KBr): 1644, 1513, 1430,
1282, 1182, 1133 cm.sup.-1 [1250] NMR (DMSO-d.sub.6, .delta.):
1.32, 1.39 (6H, 2 br s), 2.50-4.58 (19H, m), 6.99-8.20 (7H, m)
[1251] MASS: 600 (M+H).sup.+ (free) [1252] (72)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino-
)ethyl]-2-(4-fluorobenzyl)piperazine dihydrochloride [1253] mp:
89.0-110.2.degree. C. [1254] [.alpha.].sub.D.sup.28: +7.80.degree.
(C=0.25, MeOH) [1255] IR (KBr): 1644, 1513, 1282, 1182, 1137
cm.sup.-1 [1256] NMR (DMSO-d.sub.6, .delta.): 1.13 (6H, d, J=6.05
Hz), 2.73-4.55 (19H, m), 7.00-8.17 (7H, m) [1257] MASS: 576
(M+H).sup.+ (free) [1258] (73)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(4,4-difluoropiperidino)eth-
yl]-2-(4-fluorobenzyl)piperazine dihydrochloride [1259] mp:
264.0-270.6.degree. C. [1260] [.alpha.].sub.D.sup.26.6:
+5.07.degree. (C=0.25, MeOH) [1261] IR (KBr): 1644, 1513, 1427,
1278, 1187, 1141 cm.sup.-1 [1262] NMR (DMSO-d.sub.6, .delta.):
2.30-5.00 (21H, m), 6.99-8.17 (7H, m) [1263] MASS: 582 (M+H).sup.+
(free) [1264] (74)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)-4-[3-(3-pyrid-
yl)-2-propynyl]piperazine [1265] NMR (CDCl.sub.3, .delta.):
2.42-4.96 (11H, m), 6.95-8.66 (11H, m) [1266] MASS: 550 (M+H).sup.+
[1267] (75)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)-4-[2-(5,-
6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1268] mp: 155.5-170.1.degree. C. [1269]
[.alpha.].sub.D.sup.28: -81.20.degree. (C=0.50, MeOH) [1270] IR
(KBr): 1644, 1513, 1427, 1282, 1184, 1135 cm.sup.-1 [1271] NMR
(DMSO-d.sub.6, .delta.): 2.60-4.85 (19H, m), 7.03-8.69 (11H, m)
[1272] MASS: 595 (M+H).sup.+ (free) [1273] (76)
(2R)-2-(4-Fluorobenzyl)-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]-1--
[3-methoxy-5-(trifluoromethyl)-benzoyl]piperazine dihydrochloride
[1274] mp: 109.5-119.2.degree. C. [1275] [.alpha.].sub.D.sup.26.8:
+24.73.degree. (C=0.46, MeOH) [1276] IR (KBr): 1643, 1513, 1463,
1423, 1172, 1130, 1101 cm.sup.-1 [1277] NMR (DMSO-d.sub.6,
.delta.): 2.73-4.10 (24H, m), 3.26 (3H, s), 3.87 (3H, s), 6.45-7.41
(7H, m) [1278] MASS: 554 (M+H).sup.+ (free) [1279] (77)
(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-(4-fluorobenzyl)-1-[3-met-
hoxy-5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride [1280]
mp: 137.5-140.7.degree. C. [1281] [.alpha.].sub.D.sup.27.0:
+15.18.degree. (C=0.48, MeOH) [1282] IR (KBr): 1643, 1465, 1423,
1348, 1126 cm.sup.-1 [1283] NMR (DMSO-d.sub.6, .delta.): 1.32 and
1.37 (6H, s), 1.37 (6H, s x2), 3.10-5.00 (19H, m), 3.83 (3H, s),
6.99-12.0 (8H, m) [1284] MASS: 562 (M+H).sup.+ (free) [1285] (78)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-2-(4-fluorobenzyl)-1-[3-meth-
oxy-5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride [1286]
mp: 70.3-85.2.degree. C. [1287] [.alpha.].sub.D.sup.27.2:
+19.03.degree. (C=0.49, MeOH) [1288] IR (KBr): 1645, 1513, 1463,
1423, 1174, 1130 cm.sup.-1 [1289] NMR (DMSO-d.sub.6, .delta.): 1.03
and 1.14 (6H, d, J=6.1 Hz), 2.89-5.10 (19H, m), 3.83 (3H, s),
6.46-7.40 (7H, m) [1290] MASS: 538 (M+H).sup.+ (free) [1291] (79)
(2R)-4-[2-(4,4-Difluoropiperidino)ethyl]-2-(4-fluorobenzyl)-1-[3-methoxy--
5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride [1292] mp:
258.4-261.4.degree. C. [1293] [.alpha.].sub.D.sup.27.3:
+20.40.degree. (C=0.43, MeOH) [1294] IR (KBr): 1637, 1604, 1417,
1346, 1240, 1047, 970 cm.sup.-1 [1295] NMR (DMSO-d.sub.6, .delta.):
2.73-5.09 (21H, m), 3.82 (3H, s), 6.45-7.38 (7H, m) [1296] MASS:
544 (M+H).sup.+ (free) [1297] (80)
(2R)-4-(4-Fluorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-[3-(3--
pyridyl)-2-propynyl]-piperazine [1298] NMR (CDCl.sub.3, .delta.):
2.38-5.06 (11H, m), 3.82 (3H, s), 6.41-8.66 (11H, m) [1299] MASS:
512 (M+H).sup.+ [1300] (81)
(2R)-2-(4-Fluorobenzyl)-1-[3-methoxy-5-(trifluoro-methyl)benzoyl]-4-[2-(5-
,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1301] mp: 148.7-152.3.degree. C. [1302]
[.alpha.].sub.D.sup.27.1: -0.737.degree. (C=0.48, MeOH) [1303] IR
(KBr): 1643, 1635, 1514, 1464, 1421, 1350, 1173, 1128 cm.sup.-1
[1304] NMR (DMSO-d.sub.6, .delta.): 2.65-5.10 (19, m), 3.83 (3H,
s), 6.50-8.69 (10H, m) [1305] MASS: 557 (M+H).sup.+ (free) [1306]
(82)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholinc-
)ethyl]-2-(2-naphthylmethyl)-piperazine dihydrochloride [1307] mp:
168-195.degree. C. [1308] [.alpha.].sub.D.sup.26.4: -27.26.degree.
(C=0.31, MeOH) [1309] IR (KBr): 3410, 1640 cm.sup.-1 [1310] NMR
(DMSO-d.sub.6, .delta.): 1.16 (6H, d, J=6.0 Hz), 2.6-5.3 (19H, m),
7.0-8.2 (10H, m) [1311] MASS (APCI): 608 (M+H).sup.+ (free) [1312]
(83)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(4,4-difluoropiperidin-
o)ethyl]-2-(2-naphthylmethyl)piperazine dihydrochloride [1313] mp:
>250.degree. C. [1314] [.alpha.].sub.D.sup.27.3: -33.11.degree.
(C=0.37, MeOH) [1315] IR (KBr): 3740, 2400, 1650 cm.sup.-1 [1316]
NMR (DMSO-d.sub.6, .delta.): 2.9-5.4 (21H, m), 7.0-8.2 (10H, m)
[1317] MASS (APCI): 614 (M+H).sup.+ (free) [1318] (84)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[2-(5,6,7-
,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1319] mp: 189-194.degree. C. [1320]
[.alpha.].sub.D.sup.28.1: -34.93.degree. (C=0.28, MeOH) [1321] IR
(KBr): 3400, 1640 cm.sup.-1 [1322] NMR (DMSO-d.sub.6, .delta.):
2.9-5.4 (19H, m), 6.9-8.2 (12H, m), 8.66 (1H, d, J=4.4 Hz) [1323]
MASS (APCI): 627 (M+H).sup.+ (free) [1324] (85)
(2R)-4-[2-[(2S)-2-(Methoxymethyl)morpholino]ethyl]-1-[3-methoxy-5-(triflu-
oromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine dihydrochloride
[1325] mp: 134-140.degree. C. [1326] [.alpha.].sub.D.sup.28.5:
+0.78.degree. (C=0.35, MeOH) [1327] IR (KBr): 3750, 1640 cm.sup.-1
[1328] NMR (DMSO-d.sub.6, .delta.): 2.8-5.4 (28H, m), 6.3-8.0 (10H,
m) [1329] MASS (APCI): 586 (M+H).sup.+ (free) [1330] (86)
(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-1-[3-methoxy-5-(trifluorome-
thyl)benzoyl]-2-(2-naphthylmethyl)piperazine dihydrochloride [1331]
mp: 190-199.degree. C. [1332] [.alpha.].sub.D.sup.28.7:
-2.16.degree. (C=0.26, MeOH) [1333] IR (KBr): 3750, 3400, 1640
cm.sup.-1 [1334] NMR (DMSO-d.sub.6, .delta.): 1.32 (3H, s), 1.37
(3H, s), 3.0-5.4 (22H, m), 6.3-8.0 (1H, m) [1335] MASS (APCI): 594
(M+H).sup.+ (free) [1336] (87)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-1-[3-methoxy-5-(trifluo-
romethyl)benzoyl]-2-(2-naphthylmethyl)piperazine dihydrochloride
[1337] mp: 188-193.degree. C. [1338] [.alpha.].sub.D.sup.28.5:
-7.70.degree. (C=0.31, MeOH) [1339] IR (KBr): 3430, 3400, 1640
cm.sup.-1 [1340] NMR (DMSO-d.sub.6, .delta.): 1.16 (6H, d, J=6.0
Hz), 2.6-5.4 (22H, m), 6.3-8.0 (1H, m) [1341] MASS (APCI): 570
(M+H).sup.+ (free) [1342] (88)
(2R)-4-[2-(4,4-Difluoropiperidino)ethyl]-1-[3-methoxy-5-(trifluorome-
thyl)benzoyl]-2-(2-naphthylmethyl)piperazine dihydrochloride [1343]
mp: 243-260.degree. C. [1344] [.alpha.].sub.D.sup.28.7:
-10.36.degree. (C=0.28, MeOH) [1345] IR (KBr): 3400, 1640 cm.sup.-1
[1346] NMR (DMSO-d.sub.6, .delta.): 2.2-5.4 (24H, m), 6.3-8.0 (10H,
m) [1347] MASS (APCI): 576 (M+H).sup.+ (free) [1348] (89)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[3-(-
3-pyridyl)-2-propynyl]piperazine [1349] [.alpha.].sub.D.sup.28.7:
-5.37.degree. (C=0.27, MeOH) [1350] IR (KBr): 3740, 1640 cm.sup.-1
[1351] NMR (DMSO-d.sub.6, .delta.): 2.1-5.2 (14H, m), 6.5-8.0 (12H,
m), 8.57 (1H, m), 8.64 (1H, s) [1352] MASS (APCI): 544 (M+H).sup.+
[1353] (90)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)--
4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1354] mp: 173-183.degree. C. [1355]
[.alpha.].sub.D.sup.27.9: -20.91.degree. (C=0.26, MeOH) [1356] IR
(KBr): 3400, 1640 cm.sup.-1 [1357] NMR (DMSO-d.sub.6, .delta.):
2.8-5.4 (22H, m), 6.4-8.0 (11H, m), 8.03 (1H, d, J=8.5 Hz), 8.67
(1H, d, J=4.9 Hz) [1358] MASS (APCI): 589 (M+H).sup.+ (free) [1359]
(91)
(2R)-1-[3,5-Bis(trifluoromethyl)]-2-[(1H-indol-3-yl)-methyl]-4-[2-(5,6,7,-
8-tetrahydro-1,6-naphthyridin-6-yl)-ethyl]piperazine
trihydrochloride [1360] mp: 190-200.degree. C. [1361]
[.alpha.].sub.D.sup.27: -25.25.degree. (C=0.2, MeOH) [1362] IR
(KBr): 3500-3150, 2700-2300, 1646, 1519, 1434, 1371, 1272, 1236
cm.sup.-1 [1363] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (25H, m),
6.60-8.70 (11H, m), 11.17 (1H, s) [1364] MASS (APCI): 616
(M+H).sup.+ (free) [1365] (92)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-
-[2-[(2R)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [1366] mp: 200-210.degree. C. [1367]
[.alpha.].sub.D.sup.25.6: +34.4.degree. (C=0.27, MeOH) [1368] IR
(KBr): 3400-3000, 2900-2500, 1637, 1607, 1461, 1423 cm.sup.-1
[1369] NMR (DMSO-d.sub.6, .delta.): 2.81-5.20 (28H, m), 6.60-9.20
(8H, m), 10.98 (1H, s), 11.60-12.20 (2H, m) [1370] MASS (APCI): 575
(M+H).sup.+ (free) [1371] (93)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-
-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride
[1372] mp: 190-200.degree. C. [1373] [.alpha.].sub.D.sup.25.6:
+23.6.degree. (C=0.25, MeOH) [1374] IR (KBr): 3400-3000, 2900-2500,
1644, 1608, 1457, 1421 cm.sup.-1 [1375] NMR (DMSO-d.sub.6,
.delta.): 1.32-1.37 (6H, m), 3.20-5.20 (22H, m), 6.60-8.00 (8H, m),
10.96 (1H, s), 12.00-12.40 (2H, m) [1376] MASS (APCI): 583
(M+H).sup.+ (free) [1377] (94)
(2R)-2-[(1H-Indol-3-yl)methyl]-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1--
[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride
[1378] mp: 188-200.degree. C. [1379] [.alpha.].sub.D.sup.26:
+28.4.degree. (C=0.19, MeOH) [1380] IR (KBr): 3500-3150, 2700-2300,
1637, 1606, 1459, 1272, 1174 cm.sup.-1 [1381] NMR (DMSO-d.sub.6,
.delta.): 0.80-5.20 (28H, m), 6.60-8.20 (8H, m), 10.96 (1H, s),
11.40-11.80 (2H, br) [1382] MASS (APCI): 559 (M+H).sup.+ (free)
[1383] (95)
(2R)-4-[2-(4,4-Difluoropiperidino)ethyl]-2-[(1H-indol-3-yl)methyl]-1-[3-m-
ethoxy-5-(trifluoromethyl)benzoyl]-piperazine dihydrochloride
[1384] mp: 130-140.degree. C. [1385] [.alpha.].sub.D.sup.25.6:
+22.9.degree. (C=0.22, MeOH) [1386] IR (KBr): 3400-3000, 2900-2500,
1635, 1608, 1461, 1423 cm.sup.-1 [1387] NMR (DMSO-d.sub.6,
.delta.): 2.20-5.20 (24H, m), 6.60-8.80 (8H, m), 10.97 (1H, s),
11.20-12.20 (2H, m) [1388] MASS (APCI): 565 (M+H).sup.+ (free)
[1389] (96)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-
-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine hydrochloride [1390]
mp: 210-220.degree. C. [1391] [.alpha.].sub.D.sup.25.6:
+18.58.degree. (C=0.24, MeOH) [1392] IR (KBr): 3400-3000,
2900-2500, 1639, 1609, 1459, 1419, 1321 cm.sup.-1 [1393] NMR
(DMSO-d.sub.6, .delta.): 2.70-5.20 (17H, m), 6.50-8.80 (8H, m),
7.63 (1H, s), 7.94 (1H, s), 10.88-10.93 (1H, m), 11.59 (1H, br s)
[1394] MASS (APCI): 512 (M+H).sup.+ (free) [1395] (97)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-
-(3-pyridylmethyl)piperazine dihydrochloride [1396] mp:
190-200.degree. C. [1397] [.alpha.].sub.D.sup.25.6: +22.0.degree.
(C=0.34, MeOH) [1398] IR (KBr): 3400-3000, 2900-2500, 1637, 1606,
1463, 1421 cm.sup.-1 [1399] NMR (DMSO-d.sub.6, .delta.): 2.80-5.50
(14H, m), 6.50-8.00 (8H, m), 7.74-7.92 (1H, m), 8.67 (1H, d, J=8.0
Hz), 8.86 (1H, d, J=4.4 Hz), 9.07 (1H, s), 10.87 (1H, br s),
12.00-12.40 (2H, m) [1400] MASS (APCI): 509 (M+H).sup.+ (free)
[1401] (98)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-
-[3-(3-pyridyl)propyl]-piperazine dihydrochloride
[1402] mp: 135-145.degree. C. [1403] [.alpha.].sub.D.sup.26.3:
+21.2.degree. (C=0.29, MeOH) [1404] IR (KBr): 3400-3000, 2900-2500,
1635, 1607, 1463, 1421 cm.sup.-1 [1405] NMR (DMSO-d.sub.6,
.delta.): 2.20-5.20 (18H, m), 6.60-8.80 (11H, m), 11.80-12.00 (2H,
m) [1406] MASS (APCI): 537 (M+H).sup.+ (free) [1407] (99)
(2R)-2-[(1H-Indol-3-yl)methyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-
-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1408] mp: 180-190.degree. C. [1409]
[.alpha.].sub.D.sup.27: -8.3.degree. (C=0.15, MeOH) [1410] IR
(KBr): 3500-3150, 1700-2300, 1637, 1631, 1461, 1348, 1238, 1172
cm.sup.-1 [1411] NMR (DMSO-d.sub.6, .delta.): 3.20-5.20 (22H, m),
6.60-8.20 (11H, m), 10.98 (1H, s) [1412] MASS (APCI): 578
(M+H).sup.+ (free) [1413]
(100)1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
2-(4,4-difluoropiperidino)ethyl]-piperazine dihydrochloride [1414]
mp: 250-255.degree. C. [1415] IR (KBr): 3400-3000, 2900-2500, 1646,
1427, 1280 cm.sup.-1 [1416] NMR (DMSO-d.sub.6, .delta.): 2.08 (3H,
s), 2.35-5.20 (21H, m), 6.05-8.20 (7H, m), 8.90-9.50 (2H, m) [1417]
MASS (APCI): 594 (M+H).sup.+ (free) [1418] (101)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[2-[(2R)-2-(methoxymethyl)morpholino]ethyl]piperazine
[1419] IR (Neat): 1643, 1508, 1435, 1381, 1354, 1331, 1279, 1130,
1101, 1012 cm.sup.-1 [1420] NMR (CDCl.sub.3, .delta.): 1.90-5.60
(37H, m), 6.20-8.20 (6H, m) [1421] MASS (APCI): 692 (M+H).sup.+
[1422] (102)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(3S,5S)-3,5-dimethylmorpho-
lino]ethyl]-2-[3-[(2-methoxyethoxy)-methoxy]-4-methylbenzyl]piperazine
[1423] IR (Neat): 1643, 1583, 1508, 1435, 1379, 1356, 1329, 1279,
1132, 1099, 1012 cm.sup.-1 [1424] NMR (CDCl.sub.3, .delta.): 1.01
(6H, d, J=6.4 Hz), 1.90-5.50 (31H, m), 6.20-8.20 (6H, m) [1425]
MASS (APCI): 676 (M+H).sup.+ [1426] (103)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-3,5-dimethylmorpholino-
)ethyl]-2-[3-[(2-methoxyethoxy)-methoxy]-4-methylbenzyl]piperazine
[1427] IR (Neat): 1643, 1583, 1508, 1452, 1435, 1406, 1379, 1356,
1325, 1277, 1099, 1012 cm.sup.-1 [1428] NMR (CDCl.sub.3, .delta.):
0.51-5.70 (37H, m), 6.10-8.20 (6H, m) [1429] MASS (APCI): 676
(M+H).sup.+ [1430] (104)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[3-[(2S)-2-(methoxymethyl)morpholino]propyl]piperazine
[1431] IR (Neat): 1643, 1583, 1508, 1437, 1406, 1379, 1354, 1331,
1279, 1097, 1014 cm.sup.-1 [1432] NMR (CDCl.sub.3, .delta.):
1.60-5.40 (39H, m), 6.30-7.90 (6H, m) [1433] MASS (APCI): 706.3
(M+H).sup.+, 728.3 (M+Na).sup.+ [1434] (105)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(E)-4-[(2S)-2-(methoxymethyl)morpholino]-2-butenyl]pipe-
razine [1435] IR (Neat): 1643, 1510, 1454, 1435, 1406, 1379, 1352,
1331, 1281, 1134, 1101, 1012 cm.sup.-1 [1436] NMR (CDCl.sub.3,
.delta.): 0.70-5.40 (37H, m), 6.30-7.90 (8H, m) [1437] MASS (ESI):
718.3 (M+H).sup.+, 740.3 (M+Na).sup.+ [1438] (106)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[2-[4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl]ethyl]pi-
perazine [1439] IR (Neat): 1678, 1645, 1628, 1618, 1510, 1477,
1462, 1454, 1435, 1427, 1385, 1381, 1275 cm.sup.-1 [1440] NMR
(CDCl.sub.3, .delta.): 0.70-5.40 (31H, m), 6.20-8.20 (8H, m) [1441]
MASS (APCI): 700 (M+H).sup.+ [1442] (107)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(quinolin-6-yl)methyl]piperazine [1443] IR
(Neat): 1693, 1678, 1645, 1630, 1618, 1547, 1539, 1514, 1464, 1454,
1427, 1392, 1387, 1381, 1277 cm.sup.-1 [1444] NMR (CDCl.sub.3,
.delta.): 0.70-5.50 (23H, m), 6.20-9.00 (12H, m) [1445] MASS
(APCI): 676 (M+H).sup.+ [1446] (108)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(3-bromo-1,2,4-oxadiazol-5-yl)methyl]piperazine
[1447] NMR (CDCl.sub.3, .delta.): 2.19 (3H, s), 2.40-5.40 (15H, m),
3.38 (3H, s), 3.78 (2H, s), 6.30-8.00 (6H, m) [1448] MASS (APCI):
695 (M+H).sup.+, 621, 609
EXAMPLE 10
[1449] The following compounds were obtained according to a similar
manner to that of Example 1. [1450] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-fluorobenzyl]-4-[2-[(2S)-2--
(methoxymethyl)morpholino]-ethyl]piperazine dihydrochloride [1451]
mp: 129-133.degree. C. [1452] [.alpha.].sub.D.sup.28.0:
+6.96.degree. (C=0.28, MeOH) [1453] IR (KBr): 1645, 1516, 1281,
1182, 1138 cm.sup.-1 [1454] NMR (DMSO-d.sub.6, .delta.): 2.70-5.20
(25H, m), 7.00-8.22 (7H, m) [1455] MASS (APCI): 592 (M+H).sup.+
(free) [1456] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[2-[(2S)--
2-(methoxymethyl)morpholino]-ethyl]piperazine dihydrochloride
[1457] mp: 145-148.degree. C. [1458] [.alpha.].sub.D.sup.28.9:
-16.6.degree. (C=0.49, MeOH) [1459] IR (KBr): 1645, 1429, 1281,
1182, 1134 cm.sup.-1 [1460] NMR (DMSO-d.sub.6, .delta.): 2.80-5.40
(25H, m), 7.05-8.20 (10H, m) [1461] MASS (APCI): 624 (M+H).sup.+
(free) [1462] (3)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]-4-[4-[(2S,5S)-2-methoxymethyl-5-methylmorpholino]-2-butynyl]pip-
erazine [1463] IR (KBr): 1643 cm.sup.-1 [1464] NMR (CDCl.sub.3,
.delta.): 1.20 (3H, d, J=6.3 Hz), 2.19 (3H, br s), 1.92-2.12 (2H,
m), 2.60-5.40 (25H, m), 3.36 (6H, s), 6.67-7.81 (6H, m) [1465] MASS
(ESI+): 730.3 (M+H).sup.+, 752 (M+Na).sup.+ [1466] (4)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-met-
hylbenzyl]-4-(2-[(1R,4S)-3,3-dimethyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl-
]-ethyl]piperazine [1467] IR (Neat): 1643, 1437 cm.sup.-1 [1468]
NMR (CDCl.sub.3, .delta.): 1.10-1.12 (3H, m), 1.31 (3H, s),
1.60-1.75 (1H, m), 1.92 (1H, d, J=10.0 Hz), 2.20-(3H, s), 2.28 (1H,
d, J=10.0 Hz), 2.20-4.60 (19H, m), 3.36 (3H, s), 4.43 (1H, br s),
5.00-5.40 (2H, m), 6.30-7.79 (6H, m) [1469] MASS (APCI): 688
(M+H).sup.+
EXAMPLE 11
[1470] Sodium triacetoxyborohydride (0.3 g) was added in portions
to a mixture of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-
-4-methylbenzyl]-piperazine (0.5 g) and
1-methyl-1H-pyrazole-4-carboxaldehyde (0.12 g) in dichloromethane
(10 ml) and the whole was stirred at room temperature for 1 hour.
The mixture was washed with sodium hydrogen carbonate aqueous
solution, dried over magnesium sulfate and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel using ethyl acetate as an eluent. The fractions
containing the objective compound were collected and evaporated in
vacuo to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine
(0.54 g) as an oil. [1471] IR (Neat): 1641, 1579, 1508, 1435, 1381,
1352, 1329, 1277, 1097, 1088, 1014 cm.sup.-1 [1472] NMR
(CDCl.sub.3, .delta.): 1.75-5.40 (26H, m), 6.25-7.95 (8H, m) [1473]
MASS (APCI): 629 (M+H).sup.+
EXAMPLE 12
[1474] The following compounds were obtained according to a similar
manner to that of Example 11. [1475] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-(3-pyridylmethyl)piperazine [1476] IR (Neat):
1643, 1583, 1508, 1431, 1379, 1356, 1352, 1331, 1279, 1097
cm.sup.-1 [1477] NMR (CDCl.sub.3, .delta.): 0.70-5.60 (23H, m),
6.20-8.80 (10H, m) [1478] MASS (APCI): 626 (M+H).sup.+ [1479] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
(1-methyl-1H-pyrazol-4-yl)methyl]-piperazine hydrochloride [1480]
mp: 159-163.degree. C. [1481] [.alpha.].sub.D.sup.28: -5.25.degree.
(C=2.0, MeOH) [1482] IR (KBr): 3398, 1647, 1427, 1281, 1178, 1138
cm.sup.-1 [1483] NMR (DMSO-d.sub.6, .delta.): 2.60-5.10 (11H, m),
3.85 (3H, s), 6.26-7.21 (3H, m), 7.51-8.23 (5H, m), 10.20 (1H, br)
[1484] MASS (APCI): 561 (M+H).sup.+ (free) [1485] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-(-
3-pyridylmethyl)piperazine dihydrochloride [1486] mp:
187-192.degree. C. [1487] [.alpha.].sub.D.sup.27.3: -8.11.degree.
(C=0.185, MeOH) [1488] IR (KBr): 3435, 1645, 1429, 1281, 1182, 1136
cm.sup.-1 [1489] NMR (DMSO-d.sub.6, .delta.): 2.60-6.10 (11H, m),
6.29-7.20 (3H, m), 7.47-8.24 (4H, m), 8.61-9.03 (3H, m), 10.13 (1H,
br) [1490] MASS (APCI): 558 (M+H).sup.+ (free) [1491] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
3-(3-pyridyl)propyl]piperazine dihydrochloride [1492] mp:
65-70.degree. C. [1493] [.alpha.].sub.D.sup.27.9: -7.68.degree.
(C=0.28, MeOH) [1494] IR (KBr): 1647, 1427, 1279, 1180, 1136
cm.sup.-1 [1495] NMR (DMSO-d.sub.6, .delta.): 2.10-5.10 (15H, m),
6.30-7.29 (3H, m), 7.48 (1H, s), 7.84 (1H, s), 7.95-8.89 (5H, m),
10.20 (1H, br) [1496] MASS (APCI): 586 (M+H).sup.+ (free) [1497]
(5)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine hydrochloride
[1498] mp: 140-150.degree. C. [1499] [.alpha.].sub.D.sup.28.3:
+4.17.degree. (C=0.36, MeOH) [1500] IR (KBr): 3411, 2600, 1641,
1604, 1462, 1423, 1240, 1173, 1128 cm.sup.-1 [1501] NMR
(DMSO-d.sub.6, .delta.): 2.70-5.10 (11H, m), 3.85 (6H, s),
6.30-7.32 (6H, m), 7.60 (1H, s), 7.95 (1H, s), 10.18 (1H, br)
[1502] MASS (APCI): 523 (M+H).sup.+ (free) [1503] (6)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)-4-(3-pyridylmethyl)piperazine dihydrochloride [1504] mp:
215-224.degree. C. [1505] [.alpha.].sub.D.sup.28.3: +7.60.degree.
(C=0.25, MeOH) [1506] IR (KBr): 3400, 1639, 1606, 1464, 1425, 1173,
1128 cm.sup.-1 [1507] NMR (DMSO-d.sub.6, .delta.): 2.60-5.10 (11H,
m), 3.84 (3H, s), 6.26-7.33 (6H, m), 7.92 (1H, dd, J=4.8 and 7.9
Hz), 8.65 (1H, d, J=7.9 Hz), 8.88 (1H, d, J=4.8 Hz), 9.04 (1H, s),
10.13 (1H, br) [1508] MASS (APCI): 520 (M+H).sup.+ (free) [1509]
(7)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl-
)-4-[3-(3-pyridyl)propyl]-piperazine dihydrochloride [1510] mp:
90-110.degree. C. [1511] [.alpha.].sub.D.sup.28.3: +0.27.degree.
(C=0.185, MeOH) [1512] IR (KBr): 2952, 2600, 1645, 1606, 1464,
1425, 1238, 1171, 1126 cm.sup.-1 [1513] NMR (DMSO-d.sub.6,
.delta.): 2.10-5.20 (15H, m), 3.83 (3H, s), 6.30-7.33 (6H, m), 7.61
(1H, dd, J=4.2 and 8.0 Hz), 8.01 (1H, d, J=8.0 Hz), 8.58 (1H, d,
J=4.2 Hz), 8.65 (1H, s), 10.20 (1H, br) [1514] MASS (APCI): 548
(M).sup.+ (free) [1515] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-
-4-[(1-methyl-1H-pyrazol-4-yl)methyl]-piperazine hydrochloride
[1516] mp: 127-135.degree. C. [1517] [.alpha.].sub.D.sup.28.1:
+2.75.degree. (c=0.20, MeOH) [1518] IR (KBr): 3400, 1645, 1516,
1282, 1182, 1136 cm.sup.-1 [1519] NMR (DMSO-d.sub.6, .delta.):
2.80-5.20 (14H, m), 3.85 (3H, s), 6.40-7.30 (3H, m), 7.58-8.30 (5H,
m) [1520] MASS (APCI): 559 (M+H).sup.+ (free) [1521] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-(-
3-pyridylmethyl)piperazine dihydrochloride [1522] mp:
143-147.degree. C. [1523] [.alpha.].sub.D.sup.28.1: +0.889.degree.
(C=0.225, MeOH) [1524] IR (KBr): 3400, 1645, 1516, 1282, 1182, 1134
cm.sup.-1 [1525] NMR (DMSO-d.sub.6, .delta.): 2.80-5.20 (14H, m),
6.40-7.30 (3H, m), 7.50-8.30 (4H, m), 8.65 (1H, d, J=8.3 Hz), 8.88
(1H, d, J=5.0 Hz), 9.08 (1H, s) [1526] MASS (APCI): 556 (M+H).sup.+
(free) [1527] (10)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
3-(3-pyridyl)propyl]piperazine dihydrochloride [1528] mp:
125-130.degree. C. [1529] [.alpha.].sub.D.sup.27.7: +2.50.degree.
(C=0.18, MeOH) [1530] IR (KBr): 3400, 1645, 1516, 1281, 1182, 1134
cm.sup.-1 [1531] NMR (DMSO-d.sub.6, .delta.): 2.00-5.20 (18H, m),
6.40-7.40 (3H, m), 7.50-8.50 (5H, m), 8.70-9.00 (2H, m) [1532] MASS
(APCI): 584 (M+H).sup.+ (free) [1533] (11)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl-
]-4-[(1-methyl-1H-pyrazol-4-yl)-methyl]piperazine hydrochloride
[1534] [.alpha.].sub.D.sup.28: +23.27.degree. (C=0.245, MeOH)
[1535] IR (KBr): 1741, 1707, 1693, 1678, 1645, 1628, 1616, 1562,
1547, 1516, 1464, 1423, 1344, 1317, 1273, 1242, 1215, 1169, 1126,
1051 cm.sup.-1 [1536] NMR (DMSO-d.sub.6, .delta.): 2.00-5.20 (20H,
m), 6.30-8.00 (8H, m) [1537] MASS (APCI): 521 (M+H).sup.+ (free)
[1538] (12)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl-
]-4-(3-pyridylmethyl)piperazine dihydrochloride [1539]
[.alpha.].sub.D.sup.28: +24.20.degree. (C=0.345, MeOH) [1540] IR
(KBr): 1643, 1635, 1616, 1516, 1466, 1423, 1350, 1273, 1171, 1126,
1051 cm.sup.-1 [1541] NMR (DMSO-d.sub.6, .delta.): 0.80-5.30 (17H,
m), 6.00-9.00 (10H, m) [1542] MASS (APCI): 518 (M+H).sup.+ (free)
[1543] (13)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-methoxy-5-(trifluoromethyl)b-
enzoyl]-4-[3-(3-pyridyl)propyl]-piperazine dihydrochloride [1544]
[.alpha.].sub.D.sup.27.1: +25.77.degree. (C=0.26, MeOH) [1545] IR
(KBr): 1645, 1635, 1628, 1618, 1516, 1464, 1425, 1171, 1128, 1088,
1047 cm.sup.-1 [1546] NMR (DMSO-d.sub.6, .delta.): 1.60-5.30 (21H,
m), 6.00-9.00 (10H, m) [1547] MASS (APCI): 546 (M+H).sup.+ (free)
[1548] (14)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzy-
l)-4-[(1-methyl-1H-pyrazol-4-yl)methyl]-piperazine hydrochloride
[1549] mp: 160-170.degree. C. [1550] [.alpha.].sub.D.sup.27.6:
4.45.degree. (C=0.55, MeOH) [1551] IR (KBr): 1693, 1674, 1645,
1630, 1533, 1516, 1477, 1446, 1437, 1429, 1392, 1387, 1365, 1282,
1180, 1138, 1057 cm.sup.-1 [1552] NMR (DMSO-d.sub.6, .delta.):
0.80-5.20 (14H, m), 6.00-8.40 (8H, m) [1553] MASS (APCI): 545
(M+H).sup.+ (free) [1554] (15)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl-
)-4-(3-pyridylmethyl)piperazine dihydrochloride [1555] mp:
50-60.degree. C. [1556] [.alpha.].sub.D.sup.27.6: -0.95.degree.
(C=0.37, MeOH) [1557] IR (KBr): 1707, 1693, 1676, 1645, 1628, 1618,
1558, 1547, 1533, 1516, 1477, 1466, 1454, 1429, 1392, 1387, 1367,
1281, 1180, 1136 cm.sup.-1 [1558] NMR (DMSO-d.sub.6, .delta.):
0.80-5.20 (11H, m), 6.00-9.20 (10H, m) [1559] MASS (APCI): 542
(M+H).sup.+ (free) [1560] (16)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-hydroxybenzyl)-4-[-
3-(3-pyridyl)propyl]piperazine dihydrochloride [1561] mp:
80-95.degree. C. [1562] [.alpha.].sub.D.sup.26.5: -3.51.degree.
(C=0.285, MeOH) [1563] IR (KBr): 1647, 1518, 1281, 1180, 1136
cm.sup.-1 [1564] NMR (DMSO-d.sub.6, .delta.): 2.00-5.20 (15H, m),
6.30-7.20 (3H, m), 7.40-8.40 (5H, m), 8.60-8.80 (2H, m), 9.78 (1H,
br) [1565] MASS (APCI): 570 (M+H).sup.+ (free) [1566] (17)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-[(1-methyl--
1H-pyrazol-4-yl)methyl]-piperazine hydrochloride [1567] mp:
210-245.degree. C. (decomp.) [1568] [.alpha.].sub.D.sup.27.6:
-8.83.degree. (C=0.283, MeOH) [1569] IR (KBr): 1647, 1516, 1508,
1498, 1464, 1454, 1446, 1427, 1362, 1281, 1182, 1138, 1057, 1020
cm.sup.-1 [1570] NMR (DMSO-d.sub.6, .delta.): 2.00-5.40 (14H, m),
6.80-8.30 (9H, m) [1571] MASS (APCI): 545 (M+H).sup.+ (free) [1572]
(18)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-(3-pyridylm-
ethyl)piperazine dihydrochloride [1573] mp: 220-228.degree. C.
(decomp.) [1574] [.alpha.].sub.D.sup.27.7: -5.58.degree. (C=0.26,
MeOH) [1575] IR (KBr): 1643, 1495, 1489, 1468, 1429, 1363, 1319,
1284, 1279, 1186, 1136, 1053 cm.sup.-1 [1576] NMR (DMSO-d.sub.6,
.delta.): 2.00-5.80 (11H, m), 6.70-9.10 (11H, m) [1577] MASS
(APCI): 542 (M+H).sup.+ (free) [1578] (19)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-4-[3-(3-pyrid-
yl)propyl]piperazine dihydrochloride [1579] mp: 60-100.degree. C.
[1580] [.alpha.].sub.D.sup.28.3: 5.74.degree. (C=0.27, MeOH) [1581]
IR (KBr): 1645, 1551, 1514, 1498, 1468, 1429, 1363, 1319, 1281,
1184, 1136, 1103, 1039, 1024 cm.sup.-1 [1582] NMR (DMSO-d.sub.6,
.delta.): 2.00-5.40 (15H, m), 6.80-9.00 (11H, m) [1583] MASS
(APCI): 570 (M+H).sup.+ (free) [1584] (20)
(2R)-2-(4-Chlorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-[(1-me-
thyl-1H-pyrazol-4-yl)-methyl]piperazine hydrochloride [1585] mp:
70-100.degree. C. [1586] [.alpha.].sub.D.sup.27.8: +1.84.degree.
(C=0.435, MeOH) [1587] IR (KBr): 1693, 1641, 1635, 1628, 1604,
1550, 1547, 1539, 1516, 1498, 1466, 1437, 1414, 1352, 1269, 1169,
1128, 1092, 1051 cm.sup.-1 [1588] NMR (DMSO-d.sub.6, .delta.):
2.60-5.20 (17H, m), 6.50-8.10 (9H, m) [1589] MASS (APCI): 507
(M+H).sup.+ (free) [1590] (21)
(2R)-2-(4-Chlorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-(-
3-pyridylmethyl)piperazine dihydrochloride [1591] mp: 60-80.degree.
C. [1592] [.alpha.].sub.D.sup.27.8: +10.56.degree. (C=0.27, MeOH)
[1593] IR (KBr): 1643, 1610, 1496, 1466, 1421, 1373, 1350, 1315,
1271, 1242, 1174, 1130, 1097, 1049 cm.sup.-1 [1594] NMR
(DMSO-d.sub.6, .delta.): 2.60-5.20 (14H, m), 6.40-9.20 (11H, m)
[1595] MASS (APCI): 504 (M+H).sup.+ (free) [1596] (22)
(2R)-2-(4-Chlorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-[3-(3--
pyridyl)propyl]-piperazine dihydrochloride [1597] mp:
60-100.degree. C. [1598] [.alpha.].sub.D.sup.28.3: +4.08.degree.
(C=0.245, MeOH) [1599] IR (KBr): 1643, 1606, 1558, 1550, 1516,
1496, 1466, 1421, 1350, 1317, 1271, 1242, 1173, 1128, 1097, 1051
cm.sup.-1 [1600] NMR (DMSO-d.sub.6, .delta.): 1.80-5.40 (18H, m),
6.40-9.00 (11H, m) [1601] MASS (APCI): 532 (M+H).sup.+ (free)
[1602] (23)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)-4-[(1-methyl--
1H-pyrazol-4-yl)methyl]-piperazine hydrochloride [1603] mp:
143.3-146.4.degree. C. [1604] [.alpha.].sub.D.sup.26.6:
-5.60.degree. (C=0.25, MeOH) [1605] IR (KBr): 1647, 1513, 1427,
1282, 1182, 1135 cm.sup.-1 [1606] NMR (DMSO-d.sub.6, .delta.):
2.80-5.04 (14H, m), 6.96-8.23 (9H, m) [1607] MASS: 529 (M+H).sup.+
(free) [1608] (24)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)-4-(3-pyridylm-
ethyl)piperazine dihydrochloride [1609] mp: 130.0-137.3.degree. C.
[1610] [.alpha.].sub.D.sup.26: -13.03.degree. (C=0.33, MeOH) [1611]
IR (KBr): 1645, 1427, 1282, 1184, 1133 cm.sup.-1 [1612] NMR
(DMSO-d.sub.6, .delta.): 2.84-5.01 (11H, m), 6.94-9.05 (11H, m)
[1613] MASS: 526 (M+H).sup.+ (free) [1614] (25)
(2R)-2-(4-Fluorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-[(1-me-
thyl-1H-pyrazol-4-yl)-methyl]piperazine hydrochloride [1615] mp:
225.6-228.4.degree. C. [1616] [.alpha.].sub.D.sup.27.5:
+8.84.degree. (C=0.25, MeOH) [1617] IR (KBr): 1635, 1413, 1351,
1238, 1158, 1122, 1049 cm.sup.-1 [1618] NMR (DMSO-d.sub.6,
.delta.): 2.85-5.03 (17H, m), 6.59-8.45 (9H, m) [1619] MASS: 491
(M+H).sup.+ (free) [1620] (26)
(2R)-2-(4-Fluorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-(3-pyr-
idylmethyl)piperazine dihydrochloride [1621] mp: 81.4-84.3.degree.
C. [1622] [.alpha.].sub.D.sup.27.1: +15.58.degree. (C=0.50, MeOH)
[1623] IR (KBr): 1643, 1606, 1513, 1465, 1423, 1349, 1172, 1128
cm.sup.-1 [1624] NMR (DMSO-d.sub.6, .delta.): 2.95-5.00 (14H, m),
6.58-7.32 (7H, m), 7.80-9.03 (4H, m) [1625] MASS: 488 (M+H).sup.+
(free) [1626] (27)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(1-methyl-1H-pyrazol-4-y-
l)methyl]-2-(2-naphthylmethyl)piperazine hydrochloride [1627] mp:
>250.degree. C. [1628] [.alpha.].sub.D.sup.25.2: -19.62.degree.
(C=0.26, MeOH) [1629] IR (KBr): 3400, 1640 cm.sup.-1 [1630] NMR
(DMSO-d.sub.6, .delta.): 2.8-5.3 (11H, m), 3.78 (3H, s), 6.96 (1H,
d, J=8.1 Hz), 7.4-8.2 (11H, m) [1631] MASS (APCI): 561 (M+H).sup.+
(free) [1632] (28)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-pyridy-
lmethyl)piperazine dihydrochloride [1633] mp: 198-208.degree. C.
[1634] [.alpha.].sub.D.sup.24.8: -12.81.degree. (C=0.26, MeOH)
[1635] IR (KBr): 3430, 2590, 1640 cm.sup.-1 [1636] NMR
(DMSO-d.sub.6, .delta.): 3.0-5.2 (11H, m), 6.95 (1H, d, J=7.7 Hz),
7.4-8.0 (9H, m), 8.17 (1H, m), 8.54 (1H, d, J=8.0 Hz), 8.80 (1H, br
s), 9.00 (1H, s) [1637] MASS (APCI): 558 (M+H).sup.+ (free) [1638]
(29)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-4-[(1-methyl-1H-pyrazol-4-y-
l)methyl]-2-(2-naphthylmethyl)-piperazine hydrochloride [1639] mp:
226-228.degree. C. [1640] [.alpha.].sub.D.sup.27.2: -2.55.degree.
(C=0.28, MeOH) [1641] IR (KBr): 3400, 1640 cm.sup.-1 [1642] NMR
(DMSO-d.sub.6, .delta.): 2.9-5.3 (17H, m), 6.6-8.0 (12H, m) [1643]
MASS (APCI): 523 (M+H).sup.+ (free) [1644] (30)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-p-
yridylmethyl)piperazine dihydrochloride [1645] mp: 162-168.degree.
C. [1646] [.alpha.].sub.D.sup.27.6: -1.41.degree. (C=0.29, MeOH)
[1647] IR (KBr): 3400, 1640 cm.sup.-1 [1648] NMR (DMSO-d.sub.6,
.delta.): 2.8-5.3 (11H, m), 3.65 and 3.73 (3H, s), 6.5-8.0 (11H,
m), 8.51 (1H, d, J=8.7 Hz), 8.80 (1H, m), 8.98 (1H, s) [1649] MASS
(APCI): 520 (M+H).sup.+ (free) [1650] (31)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[2-(3-pyridyl)-ethyl]piperazine [1651] IR (Neat):
1674, 1643, 1581, 1547, 1510, 1429, 1381, 1356, 1350, 1333, 1279,
1132, 1097, 1012 cm.sup.-1 [1652] NMR (CDCl.sub.3, .delta.):
0.70-5.50 (25H, m), 6.20-8.80 (10H, m) [1653] MASS (APCI): 640
(M+H).sup.+ [1654] (32)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[3,4-dihydro-2H-pyrido-
[3,2-b]-1,4-oxazin-4-yl]ethyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylben-
zyl]piperazine [1655] IR (Neat): 1678, 1645, 1628, 1618, 1510,
1477, 1462, 1454, 1435, 1427, 1385, 1381, 1275 cm.sup.-1 [1656] NMR
(CDCl.sub.3, .delta.): 0.70-5.60 (29H, m), 6.20-8.00 (9H, m) [1657]
MASS (APCI): 697 (M+H).sup.+ [1658] (33)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(1-trityl-1H-pyrazol-4-yl)methyl]piperazine
[1659] [.alpha.].sub.D.sup.27.2: -26.15.degree. (C=0.260, MeOH)
[1660] IR (Neat): 1645, 1450, 1280, 1130, 1020 cm.sup.-1 [1661] NMR
(CDCl.sub.3, .delta.
): 1.86-5.40 (23H, m), 6.30-7.90 (23H, m) [1662] MASS (API-ES): 857
(M.sup.+) [1663] (34)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-4-[1-methyl-1H-pyrazol-4-yl-
methyl]-2-[4-(trifluoromethyl)-benzyl]piperazine hydrochloride
[1664] mp: 218-223.degree. C. [1665] [.alpha.].sub.D.sup.27:
+18.73.degree. (C=0.25, MeOH) [1666] IR (KBr): 3437, 3400, 1645
cm.sup.-1 [1667] NMR (DMSO-d.sub.6, .delta.): 2.80-5.30 (11H, m),
3.80 (3H, s), 3.85 (3H, s), 6.48-7.94 (9H, m) [1668] MASS (APCI):
541 (M+H).sup.+ (free) [1669] (35)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-4-(3-pyridylmethyl)-2--
[4-(trifluoromethyl)benzyl]piperazine dihydrochloride [1670] mp:
101-108.degree. C. [1671] [.alpha.].sub.D.sup.27: +15.60.degree. C.
(C=0.25, MeOH) [1672] IR (KBr): 3431, 1643, 1518 cm.sup.-1 [1673]
NMR (DMSO-d.sub.6, .delta.): 2.80-5.20 (11H, m), 3.83 (3H, s),
6.42-7.90 (8H, m), 8.56 (1H, d, J=7.6 Hz), 8.84 (1H, d, J=5.2 Hz),
9.01 (1H, s) [1674] MASS (APCI): 538 (M+H).sup.+ (free)
EXAMPLE 13
[1675] To a solution of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3-tert-butyldiphenylsilyloxy-
-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
(651.9 mg) in tetrahydrofuran (6.5 ml) was added tetrabutylammonium
fluoride (1M solution in tetrahydrofuran, 0.85 ml) at 5.degree. C.
After stirring at room temperature, the mixture was evaporated and
purified with column chromatography (silica gel, 65 ml,
methanol:dichloromethane=3:97) to give an oil (381.5 mg). The
solution of the oil in methanol (3 ml) was added 2.17M hydrogen
chloride in methanol (1.43 ml), and the mixture was concentrated to
give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
dihydrochloride as a solid. The solid was recrystallized with a
mixture of acetone (4.55 ml) and water (13.9 .mu.l) at room
temperature and then 0.degree. C. and dried under reduced pressure
at 45.degree. C. to give pure product (393.9 mg) as a powder.
[1676] mp: 206-224.5.degree. C. [1677] IR (KBr): 1635 cm.sup.-1
[1678] NMR (D.sub.2O, .delta.): 2.16 (3H, s), 2.60-5.30 (22H, m),
3.40 (3H, s), 6.30-8.10 (6H, m) [1679] MASS (APCI): 604 (M+H).sup.+
(free)
EXAMPLE 14
[1680] The following compounds were obtained according to a similar
manner to that of Example 13. [1681] (1)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-nitro-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1682] mp: 181-185.degree. C. [1683]
[.alpha.].sub.D.sup.23: +24.00.degree. (C=0.25, MeOH) [1684] IR
(KBr): 1641 cm.sup.-1 [1685] NMR (DMSO-d.sub.6, .delta.): 2.08 (3H,
s), 2.80-5.10 (25H, m), 6.18-8.55 (6H, m) [1686] MASS (APCI): 581
(M+H).sup.+ (free) [1687] (2)
(2R)-1-[3-Dimethylamino-5-(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methyl-
benzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
dihydrochloride [1688] mp: 182-186.degree. C. [1689]
[.alpha.].sub.D.sup.23: +27.00.degree. (C=0.25, MeOH) [1690] IR
(KBr): 1643 cm.sup.-1 [1691] NMR (DMSO-d.sub.6, .delta.): 2.06 (3H,
s), 2.94 (6H, br s), 2.70-5.20 (25H, m), 6.24-7.00 (6H, m) [1692]
MASS (APCI): 579 (M+H).sup.+ (free) [1693] (3)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methylamino-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1694] mp: 159-170.degree. C. [1695]
[.alpha.].sub.D.sup.22: +23.60.degree. (C=0.125, MeOH) [1696] IR
(KBr): 3433, 3400, 1643 cm.sup.-1 [1697] NMR (DMSO-d.sub.6,
.delta.): 2.06 (3H, s), 2.68 (3H, br s), 2.80-5.10 (25H, m),
6.10-7.00 (6H, m) [1698] MASS (APCI): 565.37 (M+H).sup.+ (free)
[1699] (4)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-(pyrrol-1-yl)-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1700] mp: 159-170.degree. C. [1701]
[.alpha.].sub.D.sup.24: +1.20.degree. (C=0.125, MeOH) [1702] IR
(KBr): 3433, 3400, 1636, 1494 cmn.sup.-1 [1703] NMR (DMSO-d.sub.6,
.delta.): 2.05 (3H, s), 2.80-5.10 (25H, m), 6.10-8.02 (10H, m)
[1704] MASS (APCI): 601.4 (M+H).sup.+ (free) [1705] (5)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1706] mp: 160-169.degree. C. [1707]
[.alpha.].sub.D.sup.24: +6.80.degree. (C=0.125, MeOH) [1708] IR
(KBr): 3430, 3400, 1643, 1461 cm.sup.-1 [1709] NMR (DMSO-d.sub.6,
.delta.): 2.07 (3H, s), 3.27 (3H, s), 3.93 (3H, br s), 2.40-4.10
(22H, m), 6.10-7.40 (6H, m) [1710] MASS (APCI): 566 (M+H).sup.+
(free) [1711] (6)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methylthio-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1712] mp: 154-168.degree. C. [1713]
[.alpha.].sub.D.sup.24: +5.87.degree. (C=0.125, MeOH) [1714] IR
(KBr): 3431, 3400, 1639 cm.sup.-1 [1715] NMR (DMSO-d.sub.6,
.delta.): 2.09 (3H, s), 3.27 (3H, s), 2.40-5.10 (25H, m), 6.17-7.60
(6H, m) [1716] MASS (APCI): 582 (M+H).sup.+ (free) [1717] (7)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methylsulfonyl-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1718] mp: 173.5-178.0.degree. C. [1719]
[.alpha.].sub.D.sup.25: -19.07.degree. (C=0.125, MeOH) [1720] IR
(KBr): 3437, 3402, 1645 cm.sup.-1 [1721] NMR (DMSO-d.sub.6,
.delta.): 2.08 (3H, s), 3.27 (3H, s), 3.37 (3H, s), 2.20-5.10 (22H,
m), 6.21-8.31 (6H, m) [1722] MASS (APCI): 614 (M+H).sup.+ (free)
[1723] (8)
(2R)-1-[3-Dimethylsulfamoyl-5-(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-me-
thylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
dihydrochloride [1724] mp: 153.5-160.degree. C. [1725]
[.alpha.].sub.D.sup.25: -15.60.degree. (C=0.125, MeOH) [1726] IR
(KBr): 3400, 1643, 1516 cm.sup.-1 [1727] NMR (DMSO-d.sub.6,
.delta.): 2.07 (3H, s), 2.66 (6H, s), 2.40-5.20 (25H, m), 6.18-8.01
(6H, m) [1728] MASS (APCI): 643.36 (M+H).sup.+ (free) [1729] (9)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methylsulfamoyl-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1730] mp: 120-187.degree. C. [1731]
[.alpha.].sub.D.sup.25: -15.07.degree. (C=0.125, MeOH) [1732] IR
(KBr): 1643 cm.sup.-1 [1733] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H,
s), 2.60-5.10 (28H, m), 6.17-8.10 (6H, m) [1734] MASS (APCI): 629
(M+H).sup.+ (free) [1735] (10)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-(1-pyrrolidinylsulfonyl)-5-(trifluoromethyl)benzoyl]-piperazin-
e dihydrochloride [1736] mp: 125-177.degree. C. [1737]
[.alpha.].sub.D.sup.24: -11.10.degree. (C=0.25, MeOH) [1738] IR
(KBr): 1645 cm.sup.-1 [1739] NMR (DMSO-d.sub.6, .delta.): 1.60-1.76
(4H, m), 2.07 (3H, s), 2.49-5.20 (29H, m), 6.20-8.02 (6H, m) [1740]
MASS (APCI): 669 (M+H).sup.+ (free) [1741] (11)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-(morpholinosulfonyl)-5-(trifluoromethyl)benzoyl]-piperazine
dihydrochloride [1742] mp: 130-175.degree. C. [1743]
[.alpha.].sub.D.sup.25: -8.60.degree. (C=0.25, MeOH) [1744] IR
(KBr): 1645 cm.sup.-1 [1745] NMR (DMSO-d.sub.6, .delta.): 2.08 (3H,
s), 2.60-5.10 (33H, m), 6.20-8.01 (6H, m) [1746] MASS (APCI): 685
(M+H).sup.+ (free) [1747] (12)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-(4-pyridyl)-5-(trifluoromethyl)benzoyl]piperazine
trihydrochloride [1748] mp: 169-173.degree. C. [1749]
[.alpha.].sub.D.sup.28: -1.60.degree. (C=0.125, MeOH) [1750] IR
(KBr): 1635 cm.sup.-1 [1751] NMR (DMSO-d.sub.6, .delta.): 1.91-2.04
(3H, m), 2.84-5.20 (25H, m), 6.17-8.37 (8H, m), 8.96 (2H, d, J=5.9
Hz) [1752] MASS (APCI): 613 (M+H).sup.+ (free) [1753] (13)
(2R)-1-[3-Trifluoromethyl-5-(methylthio)benzoyl]-2-(4-chloro-3-hydroxyben-
zyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine
dihydrochloride [1754] mp: 162-178.degree. C. [1755]
[.alpha.].sub.D.sup.26.2: +6.42.degree. (C=0.226, MeOH) [1756] IR
(KBr): 3400, 2665, 2600, 2488, 1643, 1425, 1331, 1311, 1174, 1130,
1043 cm.sup.-1 [1757] NMR (DMSO-d.sub.6-D.sub.2O, .delta.): 1.17
(6H, d, J=6.2 Hz), 2.40-5.20 (21H, m), 6.26-7.70 (6H, m) [1758]
MASS (APCI): 586 (M+H).sup.+ (free), 552 [1759] (14)
(2R)-1-[3-Trifluoromethyl-5-(methylthio)benzoyl]-2-(4-chloro-3-hydroxyben-
zyl)-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1760] mp: 169-178.degree. C. [1761]
[.alpha.].sub.D.sup.26.4: -7.99.degree. (C=0.263, MeOH) [1762] IR
(KBr): 3400, 2679, 2561, 1645, 1425, 1173, 1130, 1053 cm.sup.-1
[1763] NMR (DMSO-d.sub.6-D.sub.2O, .delta.): 2.40-5.40 (22H, m),
6.20-8.80 (9H, m) [1764] MASS (APCI): 605 (M+H).sup.+ (free), 571
[1765] (15)
(2R)-1-[3-(2,5-Dimethylpyrrol-1-ylsulfonyl)-5-(trifluoromethyl)benzoyl]-2-
-(3-hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]p-
iperazine [1766] IR (KBr): 1637 cm.sup.-1 [1767] NMR (DMSO-d.sub.6,
.delta.): 2.05 (3H, s), 2.30 (6H, s), 1.78-4.80 (25H, m), 6.05 (2H,
s), 6.00-9.17 (6H, m) [1768] MASS (APCI): 693 (M+H).sup.+ [1769]
(16)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-methyl]piperazine
hydrochloride [1770] mp: 140-156.degree. C. [1771]
[.alpha.].sub.D.sup.22.3: -15.68.degree. (C=0.204, MeOH) [1772] IR
(KBr): 3400, 1645, 1427, 1279, 1180, 1134 cm.sup.-1 [1773] NMR
(DMSO-d.sub.6-D.sub.2O, .delta.): 2.02-5.20 (18H, m), 6.14-8.26
(8H, m) [1774] MASS (APCI): 571 (M+H).sup.+ (free)
EXAMPLE 15
[1775] The following compounds were obtained according to a similar
manner to that of Example 3. [1776] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
(1-methyl-1H-pyrazol-4-yl)methyl]-piperazine hydrochloride [1777]
mp: 160-180.degree. C. [1778] [.alpha.].sub.D.sup.27.0:
-13.28.degree. (C=0.32, MeOH) [1779] IR (KBr): 2976, 1643, 1446,
1427, 1381, 1363, 1323, 1281, 1217, 1182, 1142, 1088, 1049
cm.sup.-1 [1780] NMR (DMSO-d.sub.6, .delta.): 1.60-5.20 (17H, m),
5.90-8.30 (8H, m) [1781] MASS (APCI): 541 (M+H).sup.+ (free) [1782]
(2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-(-
3-pyridylmethyl)piperazine dihydrochloride [1783] mp:
110-130.degree. C. [1784] [.alpha.].sub.D.sup.27.0: -7.75.degree.
(C=0.4, MeOH) [1785] IR (KBr): 1643, 1558, 1550, 1541, 1516, 1464,
1454, 1427, 1365, 1319, 1281, 1242, 1184, 1138, 1053 cm.sup.-1
[1786] NMR (DMSO-d.sub.6, .delta.): 1.70-5.80 (14H, m), 6.00-9.50
(1H, m) [1787] MASS (APCI): 538 (M+H).sup.+ (free) [1788] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1789] mp: 255-270.degree. C. [1790]
[.alpha.].sub.D.sup.25.1: -22.88.degree. (C=0.295, MeOH) [1791] IR
(KBr): 1643, 1635, 1562, 1550, 1516, 1462, 1427, 1365, 1327, 1282,
1244, 1184, 1138, 1041, 1003 cm.sup.-1 [1792] NMR (DMSO-d.sub.6,
.delta.): 0.80-5.40 (22H, m), 6.00-8.80 (9H, m) [1793] MASS (APCI):
607 (M+H).sup.+ (free) [1794] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
(Z)-3-(3-pyridyl)-2-propenyl]-piperazine dihydrochloride [1795] mp:
85-130.degree. C. [1796] [.alpha.].sub.D.sup.22.9: +2.86.degree.
(C=0.28, MeOH) [1797] IR (KBr): 1643, 1550, 1516, 1462, 1427, 1362,
1325, 1282, 1184, 1136, 1045, 1001 cm.sup.-1 [1798] NMR
(DMSO-d.sub.6, .delta.): 0.70-5.20 (14H, m), 6.00-10.00 (12H, m)
[1799] MASS (APCI): 564 (M+H).sup.+ (free) [1800] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
4-[(2S)-2-(methoxymethyl)-morpholino]-2-butynyl]piperazine [1801]
IR (KBr): 1741, 1707, 1693, 1678, 1645, 1562, 1558 1547, 1539,
1516, 1454, 1141, 1109 cm.sup.-1 [1802] NMR (DMSO-d.sub.6,
.delta.): 0.70-5.00 (28H, m), 6.00-8.20 (6H, m) [1803] MASS (APCI):
628 (M+H).sup.+ [1804] (6)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[4-[(2-
S,5S)-2-methoxymethyl-5-methylmorpholino]-2-butynyl]piperazine
dihydrochloride [1805] mp: 110-135.degree. C. [1806]
[.alpha.].sub.D.sup.29: +3.40.degree. (C=0.25, MeOH) [1807] IR
(KBr): 1645 cm.sup.-1 [1808] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H,
d, J=6.2 Hz), 2.08 (3H, br s), 3.25 (3H, s), 2.52-5.20 (21H, m),
6.17-8.20 (6H, m) [1809] MASS (APCI): 642 (M+H).sup.+ (free) [1810]
(7)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[2-[(1-
R,4S)-3,3-dimethyl-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethyl]piperazine
dihydrochloride [1811] mp: 173-185.degree. C. [1812]
[.alpha.].sub.D.sup.27: +14.20.degree. (C=0.25, MeOH) [1813] IR
(KBr): 3400, 2981, 1643 cm.sup.-1 [1814] NMR (DMSO-d.sub.6,
.delta.): 1.18 (3H, s), 1.49 (3H, s), 2.09 (3H, s), 2.20-5.10 (19H,
m), 6.20-8.25 (6H, m) [1815] MASS (APCI): 600 (M+H).sup.+ (free)
[1816] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
2-[(2R)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [1817] mp: 225-235.degree. C. [1818]
[.alpha.].sub.D.sup.26.6: -13.02.degree. (C=0.315, MeOH) [1819] IR
(KBr): 1645, 1516, 1454, 1425, 1365, 1321, 1281, 1190, 1134, 1001
cm.sup.-1 [1820] NMR (DMSO-d.sub.6, .delta.): 2.08 (3H, s),
2.50-5.20 (25H, m), 6.00-8.30 (6H, m) [1821] MASS (APCI): 604
(M+H).sup.+ (free) [1822] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(3S,5S)-3,5-dimethylmorpho-
lino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine dihydrochloride
[1823] mp: 240-250.degree. C. [1824] [.alpha.].sub.D.sup.26.7:
+10.24.degree. (C=0.21, MeOH) [1825] IR (KBr): 1645, 1516, 1454,
1427, 1387, 1365, 1327, 1281, 1184, 1136, 1041 cm.sup.-1 [1826] NMR
(DMSO-d.sub.6, .delta.): 1.00-1.60 (6H, m), 2.08 (3H, s), 2.30-5.20
(19H, m), 6.10-8.30 (6H, m) [1827] MASS (APCI): 588 (M+H).sup.+
(free) [1828] (10)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-3,5-dimethylmorpholino-
)ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine dihydrochloride
[1829] mp: 210-220.degree. C. [1830] [.alpha.].sub.D.sup.25.2:
-9.81.degree. (C=0.26, MeOH) [1831] IR (KBr): 1676, 1643, 1533,
1516, 1454, 1425, 1387, 1367, 1327, 1281, 1236, 1182, 1134, 1057
cm.sup.-1 [1832] NMR (DMSO-d.sub.6, .delta.): 0.80-5.30 (28H, m),
6.10-8.40 (6H, m) [1833] MASS (APCI): 588 (M+H).sup.+ (free) [1834]
(11)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
3-[(2S)-2-(methoxymethyl)-morpholino]propyl]piperazine
dihydrochloride [1835] mp: 150-170.degree. C. [1836]
[.alpha.].sub.D.sup.25: -10.50.degree. (C=0.30, MeOH) [1837] IR
(KBr): 1678, 1655, 1649, 1531, 1514, 1454, 1446, 1429, 1392, 1387,
1365, 1327, 1321, 1282, 1186, 1136 cm.sup.-1 [1838] NMR
(DMSO-d.sub.6, .delta.): 1.60-5.30 (30H, m), 5.90-8.50 (6H, m)
[1839] MASS (APCI): 618 (M+H).sup.+ (free) [1840] (12)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl-
)-4-[(E)-4-[(2S)-2-(methoxymethyl)-morpholino]-2-butenyl]piperazine
dihydrochloride [1841] mp: 50-70.degree. C. [1842]
[.alpha.].sub.D.sup.25: -4.79.degree. (C=0.24, MeOH) [1843] IR
(KBr): 1772, 1739, 1678, 1514, 1498, 1454, 1429, 1363, 1325, 1282,
1186, 1134 cm.sup.-1 [1844] NMR (DMSO-d.sub.6, .delta.): 1.80-5.20
(30H, m), 5.70-8.40 (6H, m) [1845] MASS (APCI): 630 (M+H).sup.+
(free) [1846] (13)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl-
)-4-[2-(3-pyridyl)ethyl]piperazine dihydrochloride [1847] mp:
90-120.degree. C. [1848] [.alpha.].sub.D.sup.26.9: -4.19.degree.
(C=0.215, MeOH) [1849] IR (KBr): 1643, 1550, 1516, 1466, 1454,
1427, 1365, 1327, 1281, 1184, 1138 cm.sup.-1 [1850] NMR
(DMSO-d.sub.6, .delta.): 0.70-5.20 (16H, m), 6.00-8.90 (10H, m)
[1851] MASS (APCI): 552 (M+H).sup.+ (free) [1852] (14)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
2-[4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-5-yl]ethyl]piperazine
dihydrochloride [1853] mp: 245-265.degree. C. [1854]
[.alpha.].sub.D.sup.27.9: -2.78.degree. (C=0.27, MeOH) [1855] IR
(KBr): 1693, 1674, 1645, 1547, 1533, 1516, 1454, 1427, 1365, 1329,
1281, 1182, 1138, 1041 cm.sup.-1 [1856] NMR (DMSO-d.sub.6,
.delta.): 1.60-5.50 (22H, m), 6.00-8.40 (8H, m) [1857] MASS (APCI):
612 (M+H).sup.+ (free) [1858] (15)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[3,4-dihydro-2H-pyrido[3,2--
b]-1,4-oxazin-4-yl]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine
dihydrochloride [1859] mp: 190-200.degree. C. [1860]
[.alpha.].sub.D.sup.26.9: +6.79.degree. (C=0.265, MeOH) [1861] IR
(KBr): 1641, 1618, 1566, 1454, 1427, 1281, 1184, 1132, 1066, 1032
cm.sup.-1 [1862] NMR (DMSO-d.sub.6, .delta.): 0.70-5.60 (20H, m),
6.00-8.40 (9H, m) [1863] MASS (APCI): 609 (M+H).sup.+ (free) [1864]
(16)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl-
)-4-[6-quinolylmethyl]piperazine dihydrochloride [1865] mp:
170-200.degree. C. [1866] [.alpha.].sub.D.sup.25.8: -28.54.degree.
(C=0.247, MeOH) [1867] IR (KBr): 1724, 1707, 1645, 1514, 1454,
1427, 1385, 1365, 1311, 1281, 1180, 1136 cm.sup.-1 [1868] NMR
(DMSO-d.sub.6, .delta.): 0.70-5.10 (15H, m), 6.00-9.40 (12H, m)
[1869] MASS (APCI): 588 (M+H).sup.+ (free)
EXAMPLE 16
[1870] The following compounds were obtained according to a similar
manner to that of Preparation 41. [1871] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-tert-butyldiphenylsilyloxy--
4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
[1872] NMR (CDCl.sub.3, .delta.): 1.09 (9H, s), 1.89-4.90 (22H, m),
2.35 (3H, s), 3.38 (3H, s), 6.10-7.92 (16H, m) [1873] MASS (ESO+):
842.4 (M+H).sup.+ [1874] (2)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-nitro-5-(trifluoromethyl)benzoyl]piperazine
[1875] IR (Neat): 1641 cm.sup.-1 [1876] NMR (CDCl.sub.3, .delta.):
1.09 (9H, s), 2.37 (3H, s), 1.89-4.80 (22H, m), 3.35 (3H, s),
6.00-8.40 (16H, m) [1877] MASS (ESI+): 819.3 (M+H).sup.+ [1878] (3)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-1-[3-dimethylamino-5-
-(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]pi-
perazine [1879] IR (KBr): 1641, 1608 cm.sup.-1 [1880] NMR
(CDCl.sub.3, .delta.): 1.50 (9H, s), 2.25 (3H, br s), 2.95 (6H, br
s), 3.35 (3H, s), 1.80-4.80 (22H, m), 6.05-7.80 (16H, m) [1881]
MASS (ESI+): 817.4 (M+H).sup.+ [1882] (4)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-methylamino-5-(trifluoromethyl)benzoyl]pipe-
razine [1883] IR (KBr): 1614 cm.sup.-1 [1884] NMR (DMSO-d.sub.6,
.delta.): 1.03 (9H, s), 1.70-4.80 (28H, m), 2.26 (3H, br s),
6.00-7.70 (16H, m) [1885] MASS (ESI+): 803.4 (M+H).sup.+, 825.3
(M+Na).sup.+ [1886] (5)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-(1-pyrrolyl)-5-(trifluoromethyl)benzoyl]pip-
erazine [1887] IR (KBr): 1643 cm.sup.-1 [1888] NMR (DMSO-d.sub.6,
.delta.): 1.00-1.04 (9H, m), 1.70-4.80 (28H, m), 6.00-8.00 (20H, m)
[1889] MASS (ESI+): 839.4 (M+H).sup.+, 861.4 (M+Na).sup.+ [1890]
(6)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazi-
ne [1891] IR (KBr): 2939, 1643, 1512, 1462, 1423 cm.sup.-1 [1892]
NMR (DMSO-d.sub.6, .delta.): 1.04 (9H, s), 2.22 (3H, s), 1.71-4.60
(28H, m), 5.99-7.75 (16H, m) [1893] MASS (ESI+): 804.4 (M+H).sup.+,
826.3 (M+Na).sup.+ [1894] (7)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-methylthio-5-(trifluoromethyl)benzoyl]piper-
azine [1895] IR (KBr): 2933, 1641, 1510, 1421 cm.sup.-1 [1896] NMR
(DMSO-d.sub.6, .delta.): 1.04 (9H, s), 2.29 (3H, s), 3.18 (3H, s),
1.70-4.70 (25H, m), 6.00-7.80 (16H, m) [1897] MASS (ESI+): 820.3
(M+H).sup.+, 842.3 (M+Na).sup.+ [1898] (8)
(2R)-2-(3-tert-Butyldlphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-methylsulfonyl-5-(trifluoromethyl)benzoyl]p-
iperazine [1899] IR (KBr): 1643 cm.sup.-1 [1900] NMR (CDCl.sub.300,
.delta.): 1.03 (9H, br s), 1.72-4.60 (28H, m), 2.28 (3H, br s),
6.02-8.28 (16H, m) [1901] MASS (ESI+): 852.3 (M+H).sup.+, 874.3
(M+Na).sup.+ [1902] (9)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-1-[3-dimethylsulfamo-
yl-5-(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethy-
l]piperazine [1903] IR (KBr): 1639 cm.sup.-1 [1904] NMR
(DMSO-d.sub.6, .delta.): 1.04 (9H, s), 1.71-4.70 (31H, m), 2.28
(3H, br s), 6.04-8.00 (16H, m) [1905] MASS (ESI+): 881.4
(M+H).sup.+, 904.3 (M+Na).sup.+ [1906] (10)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-methylsulfamoyl-5-(trifluoromethyl)benzoyl]-
piperazine [1907] IR (KBr): 1643 cm.sup.-1 [1908] NMR
(DMSO-d.sub.6, .delta.): 1.04-1.05 (9H, m), 1.70-4.60 (28H, m),
2.28 (3H, br s), 6.03-8.07 (16H, m) [1909] MASS (ESI+): 867.3
(M+H).sup.+ [1910] (11)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-(pyrrolidinosulfonyl)-5-(trifluoromethyl)be-
nzoyl]-piperazine [1911] IR (KBr): 1643 cm.sup.-1 [1912] NMR
(CDCl.sub.3, .delta.): 1.09 (9H, s), 1.75-1.82 (4H, m), 2.35 (3H,
s), 2.05-4.80 (29H, m), 6.00-8.65 (16H, m) [1913] MASS (ESI+): 907
(M+H).sup.+ [1914] (12)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-(morpholinosulfonyl)-5-(trifluoromethyl)ben-
zoyl]-piperazine [1915] IR (KBr): 1645 cm.sup.-1 [1916] NMR
(CDCl.sub.3, .delta.): 1.09 (9H, s), 2.35 (3H, s), 2.46-4.80 (33H,
m), 6.00-8.56 (16H, m) [1917] MASS (ESI+): 923.4 (M+H).sup.+ [1918]
(13)
(2R)-2-(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-1-[3-(4-pyridyl)-5-(trifluoromethyl)benzoyl]pipe-
razine [1919] IR (KBr): 1645 cm.sup.-1 [1920] NMR (CDCl.sub.3,
.delta.): 0.99-1.02 (9H, m), 1.80-4.80 (28H, m), 6.00-8.16 (18H,
m), 8.70 (2H, d, J=5.6 Hz) [1921] MASS (ESI+): 851.4 (M+H).sup.+,
873.3 (M+Na).sup.+ [1922] (14)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-nitr-
o-5-(trifluoro-methyl)benzoyl]piperazine dihydrochloride [1923] mp:
133.3-136.2.degree. C. [1924] [.alpha.].sub.D.sup.26: +5.62.degree.
(C=0.61, MeOH) [1925] IR (KBr): 1645, 1547, 1327, 1182, 1143
cm.sup.-1 [1926] NMR (DMSO-d.sub.6, .delta.): 1.02 and 1.14 (6H, d,
J=6.2 Hz), 2.71-4.53 (19H, m), 6.95-8.52 (7H, m) [1927] MASS: 569
(M.sup.+) (free) [1928] (15)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-meth-
ylamino-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride
[1929] mp: 245.6-248.7.degree. C. [1930] [.alpha.].sub.D.sup.26.4:
+21.44.degree. (C=0.26, MeOH) [1931] IR (KBr): 1612, 1494, 1427,
1182, 1143, 1095 cm.sup.-1 [1932] NMR (DMSO-d.sub.6, .delta.): 1.15
(6H, d, J=6.0 Hz), 2.68 (3H, s), 3.20-4.30 (19H, m), 6.14-7.47 (7H,
m) [1933] MASS: 553 (M.sup.+) (free) [1934] (16)
(2R)-2-(4-Chlorobenzyl)-1-[3-dimethylamino-5-(trifluoromethyl)benzoyl]-4--
[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine dihydrochloride
[1935] mp: 148.2-153.3.degree. C. [1936] [.alpha.].sub.D.sup.26.6:
+19.82.degree. (C=0.36, MeOH) [1937] IR (KBr): 1645, 1464, 1425,
1182, 1138 cm.sup.-1 [1938] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H,
d, J=6.0 Hz), 2.94 (6H, s), 3.40-4.20 (19H, m), 6.20-7.38 (7H, m)
[1939] MASS: 567 (M.sup.+) (free) [1940] (17)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-meth-
ylthio-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride [1941]
mp: 138.4-142.5.degree. C. [1942] [.alpha.].sub.D.sup.26.6:
+7.55.degree. (C=0.26, MeOH) [1943] IR (KBr): 1643, 1417, 1330,
1176, 1128, 1099 cm.sup.-1 [1944] NMR (DMSO-d.sub.6, .delta.): 1.02
and 1.15 (6H, d, J=6.2 Hz), 2.54 (3H, s), 2.71-3.99 (19H, m),
6.69-7.91 (7H, m) [1945] MASS: 570 (M.sup.+) (free) [1946] (18)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-meth-
anesulfonyl-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride
[1947] mp: 138.4-142.5.degree. C. [1948] [.alpha.].sub.D.sup.26.7:
+7.55.degree. (C=0.26, MeOH) [1949] IR (KBr): 1645, 1462, 1423,
1328, 1303, 1182, 1144 cm.sup.-1 [1950] NMR (DMSO-d.sub.6,
.delta.): 1.16 (6H, d, J=6.1 Hz), 2.55-4.05 (19H, m), 3.38 (3H, s),
6.98-8.32 (7H, m) [1951] MASS: 602 (M.sup.+) (free) [1952] (19)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-dime-
thylaminosulfonyl-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [1953] mp: 209.6-213.7.degree. C. [1954]
[.alpha.].sub.D.sup.26.5: +4.44.degree. (C=0.31, MeOH) [1955] IR
(KBr): 1645, 1461, 1423, 1344, 1173, 1146, 1103 cm.sup.-1 [1956]
NMR (DMSO-d.sub.6, .delta.): 1.17 (6H, d, J=6.0 Hz), 2.66 (6H, s),
3.00-4.46 (19H, m), 7.03-8.00 (7H, m) [1957] MASS: 631 (M.sup.+)
(free) [1958] (20)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-(1-p-
yrrolyl)-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride
[1959] mp: 152.7-157.9.degree. C. [1960] [.alpha.].sub.D.sup.26.2:
+5.96.degree. (C=0.55, MeOH) [1961] IR (KBr): 1345, 1496, 1178,
1130 cm.sup.-1 [1962] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H, d,
J=5.9 Hz), 2.70-4.20 (19H, m), 6.34 (2H, s), 6.96-7.91 (9H, m)
[1963] MASS: 589 (M.sup.+) (free) [1964] (21)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-(4-p-
yrrolyl)-5-(trifluoromethyl)benzoyl]piperazine trihydrochloride
[1965] mp: 287.7-289.1.degree. C. [1966] [.alpha.].sub.D.sup.26.9:
-3.00.degree. (C=0.36, MeOH) [1967] IR (KBr): 1641, 1635, 1427,
1270, 1178, 1130 cm.sup.-1 [1968] NMR (DMSO-d.sub.6, .delta.): 1.08
(6H, d, J=6.0 Hz), 2.73-5.15 (19H, m), 6.94-8.97 (11H, m) [1969]
MASS: 601 (M.sup.+) (free) [1970] (22)
(2R)-2-(4-Chlorobenzyl)-1-[3-chloro-5-(trifluoromethyl)benzoyl]-4-[2-(cis-
-2,6-dimethylmorpholino)ethyl]piperazine dihydrochloride [1971] mp:
136.4-141.0.degree. C. [1972] [.alpha.].sub.D.sup.26.8:
+1.06.degree. (C=0.45, MeOH) [1973] IR (KBr): 1644, 1417, 1326,
1178, 1135, 1095 cm.sup.-1 [1974] NMR (DMSO-d.sub.6, .delta.): 1.02
and 1.15 (6H, d, J=6.1 Hz), 2.60-4.12 (19H, m), 6.93-7.96 (7H, m)
[1975] MASS: 560 (M+H).sup.+ (free) [1976] (23)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-fluo-
ro-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride [1977] mp:
80.1-82.5.degree. C. [1978] [.alpha.].sub.D.sup.27.0: +3.54.degree.
(C=0.30, MeOH) [1979] IR (KBr): 1645, 1427, 1344, 1178, 1136, 1091
cm.sup.-1 [1980] NMR (DMSO-d.sub.6, .delta.): 1.16 (6H, d, J=6.1
Hz), 2.60-4.53 (19H, m), 6.78-7.78 (7H, m) [1981] MASS: 542
(M.sup.+) (free) [1982] (24)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-1-[3-meth-
yl-5-(trifluoromethyl)benzoyl]piperazine dihydrochloride [1983] mp:
82.3-88.2.degree. C. [1984] [.alpha.].sub.D.sup.26.5: +4.05.degree.
(C=0.315, MeOH) [1985] IR (KBr): 1643, 1635, 1425, 1174, 1128
cm.sup.-1 [1986] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H, d, J=6.1
Hz), 2.32-4.10 (22H, m), 6.68-7.57 (7H, m) [1987] MASS: 539
(M+H).sup.+ (free) [1988] (25)
(2R)-2-(4-Chlorobenzyl)-1-(3,5-dichlorobenzoyl)-4-[2-(cis-2,6-dimethylmor-
pholino)ethyl]piperazine dihydrochloride [1989] mp:
140.1-143.8.degree. C. [1990] [.alpha.].sub.D.sup.25.7:
+3.25.degree. (C=0.55, MeOH) [1991] IR (KBr): 1643, 1452, 1446,
1409, 1330, 1277, 1092, 1036 cm.sup.-1 [1992] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=6.2 Hz), 2.72-4.15 (19H, m), 6.56-7.64
(7H, m) [1993] MASS: 524 (M.sup.+) (free) [1994] (26)
(2R)-2-(4-Chlorobenzyl)-1-[3-nitro-5-(trifluoromethyl)-benzoyl]-4-[2-(5,6-
,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [1995] mp: 221-228.degree. C. [1996]
[.alpha.].sub.D.sup.7.2: -11.50.degree. (C=0.30, MeOH) [1997] IR
(KBr): 3430, 3400, 1640, 1550, 1470, 1420 cm.sup.-1 [1998] NMR
(DMSO-d.sub.6, .delta.): 2.6-5.2 (19H, m), 6.8-8.8 (10H, m) [1999]
MASS (APCI): 588 (M+H).sup.+ (free) [2000] (27)
(2R)-2-(4-Chlorobenzyl)-1-[3-methylamino-5-(trifluoromethyl)benzoyl]-4-[2-
-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2001] mp: 199-245.degree. C. [2002]
[.alpha.].sub.D.sup.27.1: +2.31.degree. (C=0.26, MeOH) [2003] IR
(KBr): 3430, 3400, 1630, 1510, 1460, 1430 cm.sup.-1 [2004] NMR
(DMSO-d.sub.6, .delta.): 2.69 (3H, s), 2.8-5.3 (19H, m), 6.41 (1H,
s), 6.83 (1H, s), 6.9-7.5 (5H, m), 7.71 (1H, dd, J=5, 8 Hz), 8.11
(1H, d, J=8 Hz), 8.70 (1H, d, J=5 Hz) [2005] MASS (APCI): 572
(M+H).sup.+ (free) [2006] (28)
(2R)-2-(4-Chlorobenzyl)-1-[3-methylthio-5-(trifluoromethyl)benzoyl]--
4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2007] mp: 182-195.degree. C. [2008]
[.alpha.].sub.D.sup.26.8: -9.58.degree. (C=0.24, MeOH) [2009] IR
(KBr): 3430, 3400, 1640, 1460, 1420 cm.sup.-1 [2010] NMR
(DMSO-d.sub.6, .delta.): 2.55 (3H, s), 2.6-5.2 (19H, m), 6.6-8.7
(10H, m) [2011] MASS (APCI): 589 (M+H).sup.+ (free) [2012] (29)
(2R)-2-(4-Chlorobenzyl)-1-[3-methanesulfonyl-5-(trifluoromethyl)benzoyl]--
4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2013] mp: 198-213.degree. C. [2014]
[.alpha.].sub.D.sup.26.8: -13.71.degree. (C=0.28, MeOH) [2015] IR
(KBr): 3430, 3400, 1640, 1460, 1420 cm.sup.-1 [2016] NMR
(DMSO-d.sub.6, .delta.): 2.6-5.2 (19H, m), 3.39 (3H, s), 6.9-8.2
(8H, m), 8.33 (1H, s), 8.67 (1H, d, J=5 Hz) [2017] MASS: 621
(M+H).sup.+ (free) [2018] (30)
(2R)-2-(4-Chlorobenzyl)-1-[3-dimethylsulfamoyl-5-(trifluoromethyl)be-
nzoyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2019] mp: 209-226.degree. C. [2020]
[.alpha.].sub.D.sup.26.8: -8.38.degree. (C=0.24, MeOH) [2021] IR
(KBr): 3740, 1680, 1640, 1520, 1460 cm.sup.-1 [2022] NMR
(DMSO-d.sub.6, .delta.): 2.67 (6H, s), 2.8-5.2 (19H, m), 6.9-8.7
(10H, m) [2023] MASS: 650 (M+H).sup.+ (free) [2024] (31)
(2R)-2-(4-Chlorobenzyl)-1-[3-(1-pyrrolyl)-5-(trifluoromethyl)benzoyl]-4-[-
2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2025] mp: 184-191.degree. C. [2026]
[.alpha.].sub.D.sup.26.7: -12.13.degree. (C=0.40, MeOH) [2027] IR
(KBr): 3400, 1640, 1500, 1430 cm.sup.-1 [2028] NMR (DMSO-d.sub.6,
.delta.): 2.8-5.3 (19H, m), 6.2-8.7 (14H, m) [2029] MASS: 608
(M+H).sup.+ (free) [2030] (32)
(2R)-2-(4-Chlorobenzyl)-1-[3-(4-pyridyl)-5-(trifluoromethyl)benzoyl]-4-[2-
-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
tetrahydrochloride [2031] mp: 206-217.degree. C. [2032]
[.alpha.].sub.D.sup.25.8: -20.08.degree. (C=0.27, MeOH) [2033] IR
(KBr): 3430, 3400, 1640, 1510, 1430 cm.sup.-1 [2034] NMR
(DMSO-d.sub.6, .delta.): 2.7-6.2 (19H, m), 6.8-8.1 (8H, m), 8.10
(1H, d, J=8.5 Hz), 8.41 (2H, d, J=6.5 Hz), 8.70 (1H, d, J=4.4 Hz),
9.04 (2H, d, J=6.5 Hz) [2035] MASS (API-ES): 620 (M+H).sup.+ (free)
[2036] (33)
(2R)-2-(4-Chlorobenzyl)-1-[3-chloro-5-(trifluoromethyl)benzoyl]-4-[2-(5,6-
,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2037] mp: 130.6-135.7.degree. C. [2038]
[.alpha.].sub.D.sup.26.6: -12.12.degree. (C=0.60, MeOH) [2039] IR
(KBr): 1643, 1635, 1417, 1326, 1321, 1178, 1135 cm.sup.-1 [2040]
NMR (DMSO-d.sub.6, .delta.): 2.79-4.78 (19H, m), 7.02-8.66 (10H, m)
[2041] MASS: 577 (M.sup.+) (free) [2042] (34)
(2R)-2-(4-Chlorobenzyl)-1-[3-fluoro-5-(trifluoromethyl)benzoyl]-4-[2-(5,6-
,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2043] mp: 127.3-130.9.degree. C. [2044]
[.alpha.].sub.D.sup.26.4: -10.20.degree. (C=0.51, MeOH) [2045] IR
(KBr): 1643, 1635, 1629, 1425, 1178, 1135 cm.sup.-1 [2046] NMR
(DMSO-d.sub.6, .delta.): 2.80-4.60 (19H, m), 6.80-8.63 (10H, m)
[2047] MASS: 561 (M.sup.+) (free) [2048] (35)
(2R)-2-(4-Chlorobenzyl)-1-[3-methyl-5-(trifluoromethyl)benzoyl]-4-[2-(5,6-
,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2049] mp: 102.5-110.4.degree. C. [2050]
[.alpha.].sub.D.sup.26.8: -13.35.degree. (C=0.310, MeOH) [2051] IR
(KBr): 1643, 1635, 1423, 1419, 1173, 1128 cm.sup.-1 [2052] NMR
(DMSO-d
.sub.6, .delta.): 2.35 (2H, m), 2.51-4.49 (20H, m), 7.03-8.69 (10H,
m) [2053] MASS: 557 (M.sup.+) (free) [2054] (36)
(2R)-2-(4-Chlorobenzyl)-1-[3-dimethylamino-5-(trifluoromethyl)benzoyl]-4--
[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2055] mp: 209-214.degree. C. [2056]
[.alpha.].sub.D.sup.27.1: +1.51.degree. (C=0.27, MeOH) [2057] IR
(KBr): 3430, 3400, 1640, 1500, 1460, 1420 cm.sup.-1 [2058] NMR
(DMSO-d.sub.6, .delta.): 2.8-5.3 (19H, m), 2.95 (6H, s), 6.1-7.5
(7H, m), 7.65 (1H, dd, J=5, 8 Hz), 8.05 (1H, d, J=8 Hz), 8.67 (1H,
d, J=5 Hz) [2059] MASS: 586 (M+H).sup.+ (free) [2060] (37)
(2R)-2(3-tert-Butyldiphenylsilyloxy-4-methylbenzyl)-1-[3-(2,
5-dimethylpyrrol-1-ylsulfonyl)-5-(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(-
methoxymethyl)-morpholino]ethyl]piperazine [2061] IR (KBr): 1643
cm.sup.-1 [2062] NMR (DMSO-d.sub.6, .delta.): 1.04 (9H, s), 2.30
(6H, br s), 2.30 (3H, br s), 1.91-4.60 (25H, m), 6.05 (2H, s),
6.60-7.98 (16H, m) [2063] MASS (ESI+): 931.3 (M+H).sup.+
EXAMPLE 17
[2064] The following compounds were obtained according to a similar
manner to that of Example 11 followed by a similar manner to that
of Example 3. [2065] (1)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[(E)-3-
-(3-pyridyl)-2-propenyl]-piperazine dihydrochloride [2066] mp:
60-80.degree. C. [2067] IR (KBr): 1707, 1693, 1676, 1645, 1628,
1550, 1539, 1516, 1477, 1464, 1454, 1427, 1392, 1365, 1281, 1182,
1136, 1049 cm.sup.-1 [2068] NMR (DMSO-d.sub.6, .delta.): 1.90-5.60
(16H, m), 6.10-9.10 (10H, m) [2069] MASS (APCI): 564 (M+H).sup.+
(free) [2070] (2)
1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
1-methyl-1H-pyrazol-4-yl)methyl]-piperazine hydrochloride [2071] IR
(KBr): 1707, 1693, 1676, 1645, 1562, 1550, 1547, 1533, 1516, 1454,
1427, 1392, 1363, 1319, 1281, 1182, 1138, 1057 cm.sup.-1 [2072] NMR
(DMSO-d.sub.6, .delta.): 1.60-5.20 (17H, m), 5.90-8.30 (8H, m)
[2073] MASS (APCI): 541 (M+H).sup.+ (free) [2074] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
(2-aminothiazol-4-yl)methyl]-piperazine dihydrochloride [2075] mp:
205-215.degree. C. [2076] [.alpha.].sub.D.sup.27: -12.13.degree.
(C=0.40, MeOH) [2077] IR (KBr): 3500-3000, 2700-2300, 1639, 1428,
1280 cm.sup.-1 [2078] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H, s),
2.60-5.20 (11H, m), 6.20-8.20(7H, m), 8.00-9.00 (2H, m) [2079] MASS
(APCI): 559 (M+H).sup.+ (free) [2080] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
(5-amino-1,2,4-thiadiazol-3-yl)-methyl]piperazine dihydrochloride
[2081] mp: 177-182.degree. C. [2082] [.alpha.].sub.D.sup.27:
-31.5.degree. (C=0.18, MeOH) [2083] IR (KBr): 3500-3000, 2700-2300,
1644, 1278 cm.sup.-1 [2084] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H,
s), 2.60-5.20 (11H, m), 6.20-8.20(8H, m), 8.00-9.00 (2H, m) [2085]
MASS (APCI): 560 (M+H).sup.+ (free), 447 [2086] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
[2-(dimethylamino)thiazol-4-yl]-methyl]piperazine dihydrochloride
[2087] mp: 162-165.degree. C. [2088] [.alpha.].sub.D.sup.27:
-17.6.degree. (C=0.5, MeOH) [2089] IR (KBr): 3500-3000, 2700-2300,
1639, 1427, 1365, 1280 cm.sup.-1 [2090] NMR (DMSO-d.sub.6,
.delta.): 1.80-1.90 (6H, m), 2.07 (3H s), 2.60-5.20 (11H, m),
4.50-5.80 (2H, m), 5.90-8.20 (7H, m) [2091] MASS (APCI): 587
(M+H).sup.+ (free) [2092] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
[3-(methylamino)-1,2,4-oxadiazol-5-yl]methyl]piperazine
dihydrochloride [2093] mp: 145-160.degree. C. [2094]
[.alpha.].sub.D.sup.26: -23.1.degree. (C=0.55, MeOH) [2095] IR
(KBr): 3500-3150, 2700-2300, 1644, 1428, 1363, 1280 cm.sup.-1
[2096] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H, s), 2.66-5.20 (14H,
m) 6.10-8.30 (7H, m) [2097] MASS (APCI): 558 (M+H).sup.+ (free)
EXAMPLE 18
[2098] The following compound was obtained according to a similar
manner to that of Example 1 followed by a similar manner to that of
Example 3.
[2099]
1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-5,5-dimethyl-2-(met-
hoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine
dihydrochloride [2100] mp: 150-180.degree. C. [2101] IR (KBr):
1707, 1693, 1678, 1645, 1628, 1562, 1547, 1539, 1533, 1516, 1477,
1464, 1454, 1427, 1392, 1367, 1281, 1182, 1138 cm.sup.-1 [2102] NMR
(DMSO-d.sub.6, .delta.): 1.10-1.60 (6H, m), 2.08 (3H, s), 2.30-5.20
(23H, m), 6.10-8.30 (6H, m), 9.15 (1H, br s) [2103] MASS (APCI):
632 (M+H).sup.+ (free)
EXAMPLE 19
[2104] A solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
4-[(2S)-2-(methoxymethyl)-morpholino]-2-butynyl]piperazine (0.33 g)
in methanol (10 ml) was hydrogenated over Lindlar catalyst (63 mg).
After removal of catalyst by filtration, the filtrate was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using methanol/dichloromethane
(1:9) as an eluent. The fractions containing the objective compound
were collected and evaporated in vacuo to give
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4--
[(Z)-4-[(2S)-2-(methoxymethyl)morpholino]-2-butenyl]piperazine
(0.22 g) as an oil. [2105] IR (Neat): 1707, 1693, 1678, 1645, 1635,
1547, 1539, 1535, 1516, 1464, 1454, 1423, 1417, 1405, 1387
cm.sup.-1 [2106] NMR (CDCl.sub.3, .delta.): 0.60-5.20 (28H, m),
5.40-5.90 (2H, m), 6.10-8.10 (6H, m) [2107] MASS (APCI): 630
(M+H).sup.+
EXAMPLE 20
[2108] The following compound was obtained according to a similar
manner to that of Example 19.
[2109]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)me-
thoxy]-4-methylbenzyl]-4-[(Z)-3-(3-pyridyl)-2-propenyl]piperazine
[2110] IR (Neat): 1670, 1641, 1585, 1550, 1510, 1431, 1379, 1350,
1329, 1279, 1130, 1101, 1012 cm.sup.-1 [2111] NMR (CDCl.sub.3,
.delta.): 0.70-5.50 (23H, m), 5.70-6.10 (1H, m), 6.10-8.80 (11H, m)
[2112] MASS (APCI): 652 (M+H).sup.+
EXAMPLE 21
[2113] The following compounds were obtained according to a similar
manner to that of Example 8. [2114] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[3-(3-pyridyl)propyl]-2-[4-(tr-
ifluoromethyl)benzyl]piperazine dihydrochloride [2115] mp:
64-74.degree. C. [2116] [.alpha.].sub.D.sup.27: +7.47.degree.
(C=0.5, MeOH) [2117] IR (KBr): 1645 cm.sup.-1 [2118] NMR
(DMSO-d.sub.6, .delta.): 2.10-2.40 (2H, m), 2.80-5.40 (13H, m),
7.19-7.69 (6H, m), 7.97-8.03 (1H, m), 8.19-8.22 (1H, m), 8.42-8.58
(1H, m), 8.81 (1H, d, J=5.5 Hz), 8.90-9.00 (1H, m) [2119] MASS
(APCI): 604 (M+H).sup.+ (free) [2120] (2)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-4-[3-(3-pyridyl)propyl]-2-[-
4-(trifluoromethyl)benzyl]piperazine dihydrochloride [2121] mp:
70-80.degree. C. [2122] [.alpha.].sub.D.sup.27: +19.49.degree.
(C=0.0065, MeOH) [2123] IR (KBr): 1643, 1466, 1423 cm.sup.-1 [2124]
NMR (DMSO-d.sub.6, .delta.): 2.10-2.40 (2H, m), 2.80-5.30 (13H, m),
3.82 (3H, s), 6.41-7.70 (7H, m), 7.97 (1H, dd, J=5.5 and 8.0 Hz),
8.45 (1H, d, J=8.0 Hz), 8.79 (1H, d, J=5.5 Hz), 8.88 (1H, s) [2125]
MASS (APCI): 566 (M+H).sup.+ (free) [2126] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-benzyl)-4-[3-(3-pyri-
dyl)propyl]piperazine dihydrochloride [2127] mp:
110.2-117.5.degree. C. [2128] [.alpha.].sub.D.sup.28:
+19.46.degree. (C=0.34, MeOH) [2129] IR (KBr): 1644, 1513, 1280,
1184, 1135 cm.sup.-1 [2130] NMR (DMSO-d.sub.6, .delta.): 1.03 (2H,
d, J=6.07 Hz), 2.23 (2H, m), 2.86-5.05 (11H, m), 6.99-8.85 (11H, m)
[2131] MASS: 554 (M+H).sup.+ (free) [2132] (4)
(2R)-2-(4-Fluorobenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]-4-[3-(3--
pyridyl)propyl]-piperazine dihydrochloride [2133] mp:
111.5-118.3.degree. C. [2134] [.alpha.].sub.D.sup.27.3:
+11.3.degree. (C=0.26, MeOH) [2135] IR (KBr): 1643, 1511, 1465,
1421, 1049 cm.sup.1 [2136] NMR (DMSO-d.sub.6, .delta.): 2.21 (1H,
br), 2.88-5.41 (18H, m), 6.56-8.86 (11H, m), 11.5 (1H, br) [2137]
MASS: 516 (M+H).sup.+ (free) [2138] (5)
(2R)-1-[3-Methoxy-5-(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[3-(-
3-pyridyl)propyl]piperazine dihydrochloride [2139]
[.alpha.].sub.D.sup.28.2: -9.96.degree. (C=0.24, MeOH) [2140] IR
(KBr): 3400, 1640 cm.sup.-1 [2141] NMR (DMSO-d.sub.6, .delta.):
2.1-2.4 (2H, m), 2.7-5.3 (13H, m), 3.61 and 3.71 (3H, s), 6.5-8.9
(14H, m) [2142] MASS: 548 (M+H).sup.+ (free)
EXAMPLE 22
[2143] To a solution of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-
-4-methylbenzyl]-4-[(1-trityl-1H-pyrazol-4-yl)methyl]piperazine
(1.184 g) in 1,4-dioxane (118 ml) was added 1N hydrochloric acid
(71 ml) and the resulting mixture was stirred at 40.degree. C. for
7 hours. After cooling, the pH of the mixture was adjusted to 7
with 4N sodium hydroxide solution and sodium chloride was added to
the mixture. The organic layer was separated, dried over magnesium
sulfate, and evaporated in vacuo. The residue was purified by
column chromatography on silica gel with a mixture of methylene
chloride and methanol (30:1) as eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(1H-pyrazol-4-yl)-methyl]piperazine (575 mg).
[2144] IR (Neat), 3250, 1645, 1280, 1130 cm.sup.-1 [2145] NMR
(CDCl.sub.3, .delta.): 1.95-5.22 (23H, m), 6.24-7.90 (8H, m) [2146]
MASS (APCI): 615 (M+H).sup.+ (free)
EXAMPLE 23
[2147] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]--
4-methylbenzyl]-4-[(1H-pyrazol-4-yl)methyl]piperazine (254 mg),
2-bromoethanol (259 mg), potassium carbonate (228 mg) and
tetrabutyl ammonium bromide (13 mg) in N,N-dimethylformamide (2.5
ml) was stirred at 100.degree. C. for 2 days. After cooling, the
mixture was evaporated in vacuo and water and ethyl acetate were
added to the residue. The organic layer was separated, washed with
brine, dried over magnesium sulfate and evaporated in vacuo. The
residue was purified by column chromatography on alumina with a
mixture of methylene chloride and methanol (100:1) as eluent to
give
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-
-4-methylbenzyl]-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine
(185 mg). [2148] IR (Neat): 3400, 1640, 1440, 1280, 1135 cm.sup.-1
[2149] NMR (CDCl.sub.3, .delta.): 1.84-5.38 (27H, m), 6.30-7.90
(8H, m) [2150] MASS (APCI): 659 (M+H).sup.+ (free)
EXAMPLE 24
[2151]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenz-
yl)-4-[4-[(2S)-2-(methoxymethyl)morpholino]-2-butynyl]piperazine
(0.05 g) in ethyl acetate (5 ml) was treated with 4N hydrogen
chloride in ethyl acetate (1 ml) and the mixture was concentrated
under reduced pressure. After the residue was triturated with a
mixture of dichloromethane and diisopropyl ether, the organic
solvents were removed under reduced pressure to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
4-[(2S)-2-(methoxymethyl)morpholino]-2-butynyl]piperazine
dihydrochloride (0.05 g) as a powder. [2152] mp: 110-130.degree. C.
[2153] [.alpha.].sub.D.sup.25.5: -7.89.degree. (C=0.40, MeOH)
[2154] IR (KBr): 1687, 1645, 1516, 1454, 1429, 1362, 1327, 1281,
1184, 1138 cm.sup.-1 [2155] NMR (DMSO-d.sub.6, .delta.): 1.70-5.30
(28H, m), 6.00-8.40 (6H, m) [2156] MASS (APCI): 628 (M+H).sup.+
(free)
EXAMPLE 25
[2157] The following compound was obtained according to a similar
manner to that of Example 24.
[2158]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenz-
yl)-4-[(Z)-4-[(2S)-2
(methoxymethyl)morpholino]-2-butenyl]piperazine dihydrochloride
[2159] mp: 180-200.degree. C. [2160] [.alpha.].sub.D.sup.25.6:
+049.degree. (C=0.205, MeOH) [2161] IR (KBr): 1693, 1687, 1645,
1531, 1516, 1454, 1427, 1363, 1321, 1281, 1184, 1140, 1003
cm.sup.-1 [2162] NMR (DMSO-d.sub.6, .delta.): 0.80-5.30 (30H, m),
5.80-8.40 (6H, m) [2163] MASS (APCI): 630 (M+H).sup.+ (free)
EXAMPLE 26
[2164] To a stirred suspension of
2-[3-methoxy-4-(trifluoromethyl)benzyl]piperazine dihydrobromide
(109 mg), potassium iodide (109 mg) and N,N-diisopropylethylamine
(0.26 ml) in N,N-dimethylformamide (4 ml) was added
(2R)-4-(2-chloroethyl)-2-(methoxymethyl)morpholine hydrochloride
(29 mg) at 5.degree. C. under nitrogen atmosphere and the mixture
was gradually warmed to room temperature overnight. To the above
stirred suspension was added 3,5-bis(trifluoromethyl)-benzoyl
chloride (118 mg) at 5.degree. C. and the mixture was stirred for 1
hour at the same temperature. The mixture was extracted with ethyl
acetate and the extract was washed with water, and dried over
magnesium sulfate. The usual work up followed by flash
chromatography on silica gel with a mixture of dichloromethane and
methanol (60:1) gave the product, which was dissolved in ethyl
acetate and treated with 4N hydrogen chloride in ethyl acetate to
give
1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-methoxy-4-(trifluoromethyl)benzy-
l]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride (22 mg) as a powder. [2165] NMR (DMSO-d.sub.6,
.delta.): 2.80-5.20 (28H, m), 6.60-8.50 (8H, m) [2166] MASS (APCI):
672 (M+H).sup.+ (free)
EXAMPLE 27
[2167]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)me-
thoxy]-4-methylbenzyl]-4-[(3-bromo-1,2,4-oxadiazol-5-yl)methyl]piperazine
(250 mg) was dissolved with 2M ammonia in tetrahydrofuran (10 ml).
After being stored at room temperature for one day, the solution
was evaporated under reduced pressure. The residue was partitioned
between ethyl acetate and brine. The organic layer was separated
and washed with brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel using a mixture of
dichloromethane and methanol (30:1). The fractions containing the
objective compound were collected and evaporated under reduced
pressure and treated with 4N hydrogen chloride in ethyl acetate to
give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[-
(3-amino-1,2,4-oxadiazol-5-yl)methyl]piperazine dihydrochloride (40
mg). [2168] mp: 160-170.degree. C. [2169] [.alpha.].sub.D.sup.26:
-20.1.degree. (C=0.38, MeOH) [2170] IR (KBr): 3500-3150, 2700-2300,
1635, 1428, 1280 cm.sup.-1 [2171] NMR (DMSO-d.sub.6, .delta.): 2.07
(3H, s), 2.60-5.20 (13H, m), 6.10-8.20 (7H, m), 8.60-9.40 (2H, m)
[2172] MASS (APCI): 544 (M+H).sup.+ (free)
EXAMPLE 28
[2173] The following compounds were obtained according to a similar
manner to that of Example 27.
[2174]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenz-
yl)-4-[[3-(dimethylamino)-1,2,4-oxadiazol-5-yl]-methyl]piperazine
dihydrochloride [2175] mp: 140-150.degree. C. [2176]
[.alpha.].sub.D.sup.27: -20.14.degree. (C=0.35, MeOH) [2177] IR
(KBr): 3500-3000, 2700-2300, 1635, 1606, 1430 cm.sup.-1 [2178] NMR
(DMSO-d.sub.6, .delta.): 2.07 (3H, s), 2.92 (3H, s), 2.94 (3H, s),
2.60-5.20 (11H, m), 6.10-8.20 (7H, m), 8.60-9.60 (2H, m) [2179]
MASS (APCI): 572 (M+H).sup.+ (free)
EXAMPLE 29
[2180]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenz-
yl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride (0.50 g) was partitioned between ethyl acetate and
saturated aqueous sodium hydrogen carbonate solution, and the
organic layer was separated, washed with brine, dried over
magnesium sulfate, and evaporated in vacuo to give
(2R)-1-[3,5-bis(trifluoro-methyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4--
[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (0.437 mg). A
solution of the obtained compound in methylene chloride was added
4-(dimethylamino)pyridine (9 mg) and trifuric anhydride (0.22 ml)
successively with ice-bath cooling under nitrogen atmosphere. After
stirring for 1 hour, saturated aqueous sodium hydrogen carbonate
solution was added to the mixture, and the organic layer was
separated and the aqueous layer was extracted with methylene
chloride. The combined organic layer was washed with brine, dried
over magnesium sulfate and silica gel (1.1 g), and evaporated in
vacuo to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(4-methyl-3-trifluoromethanesulfonyloxybenzyl-
)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (358 mg)
as an oil. [2181] IR (Neat): 1645, 1425, 1280, 1210, 1135 cm.sup.-1
[2182] NMR (CDCl.sub.30, .delta.): 1.90-5.14 (28H, m), 6.60-8.20
(6H, m) [2183] MASS (APCI): 736 (M+H).sup.+
EXAMPLE 30
[2184] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methyl-3-trifluoromethanesu-
lfonyloxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
(0.10 g), benzophenone imine (30.5 mg), cesium carbonate (62 mg),
palladium acetate (3 mg), and
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (12.7 mg) in toluene
was stirred at 80.degree. C. under nitrogen atmosphere for 22
hours. After cooling, water and ethyl acetate were added to the
mixture and the organic layer was separated, washed with brine,
dried over sodium sulfate, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel (NH-DM1020, Fuji
Silysia Chemical Ltd.) with a mixture of hexane and ethyl acetate
(3:1) as eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(diphenylmethyleneamino)-4--
methylbenzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
(75 mg) as an oil. [2185] [.alpha.].sub.D.sup.23.7: -63.51.degree.
(C=0.222, MeOH) [2186] IR (Neat): 2620, 1625, 1435 cm.sup.-1 [2187]
NMR (CDCl.sub.3, .delta.): 1.86-4.84 (28H, m), 6.00-7.95 (16H, m)
[2188] MASS (APCI): 767 (M+H).sup.+
EXAMPLE 31
[2189] A solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(diphenylmethyleneamino)-4--
methylbenzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
(65 mg) in methanol was subjected to hydrogenolysis (3 atm hydrogen
pressure) using 10% palladium on carbon (6 mg, 50% wet) at
50.degree. C. for 16 hours. After cooling, the mixture was filtered
and the filtrate was evaporated in vacuo. Ethyl acetate and water
were added to the residue and the organic layer was separated,
dried over magnesium sulfate, and evaporated in vacuo. The residue
was purified by column chromatography on silica gel (NH-DM1020,
Fuji Silysis Chemical Ltd.) with a mixture of hexane and ethyl
acetate (1:1) as eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2--
[(2S)-2-(methoxymethyl)morpholino]ethyl]-piperazine (18 mg). To a
solution of the obtained compound in methanol was added 4N hydrogen
chloride in ethyl acetate (0.05 ml) and the mixture was evaporated
in vacuo to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-piperazine trihydrochloride (20 mg)
[2190] mp: 180-186.degree. C. [2191] [.alpha.].sub.D.sup.24.4:
+9.41.degree. (C=0.085, MeOH) [2192] IR (KBr): 3435, 2600, 1645,
1514, 1454, 1429, 1365, 1282, 1182, 1105 cm.sup.-1 [2193] NMR
(D.sub.2O, .delta.): 2.20-5.35 (28H, m), 6.80-8.30 (6H, m) [2194]
MASS (APCI): 604 (M+H).sup.+ (free)
EXAMPLE 32
[2195] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2--
[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine (0.10 g),
succinimide (30 mg) and formalin (28 mg) in ethanol (0.5 ml) was
stirred at 100.degree. C. for 24 hours. After cooling, the mixture
was evaporated in vacuo and the residue of the following compound
was used to the next reaction without purification:
[2196]
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-[[(2,5-diox-
opyrrolidino)methyl]amino]benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]e-
thylpiperazine [2197] IR (Neat): 1705, 1640, 1280, 1130 cm.sup.-1
[2198] NMR (CDCl.sub.3, .delta.): 1.50-5.20 (34H, m), 6.02-7.90
(6H, m) [2199] MASS (API-ES): 714 (M.sup.+) (free)
EXAMPLE 33
[2200] A solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-[[(2,5-dioxopyrrol-
idino)methyl]amino]benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]pi-
perazine (0.14 g) in dimethylsulfoxide (0.42 ml) was added sodium
borohydride (10 mg) and the whole was stirred at 80.degree. C. for
15 hours. After cooling, water and ethyl acetate were added to the
mixture. The organic layer was separated, washed with brine, dried
over sodium sulfate and evaporated in vacuo. The residue was
purified by column chromatography on silica gel with a mixture of
methylene chloride and methanol (30:1 to 10:1) as eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[4-methyl-3-(methylamino)benz-
yl]-4-[2-[(2S)-2-(methoxymethyl)morpholinoethyl]piperazine (37 mg)
and
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-[[(5-hydroxy-2-oxo-
pyrrolidino)methyl]amino]benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]et-
hyl]piperazine (45 mg), respectively. Each compound was converted
to its trihydrochloride in a conventional manner.
[2201]
(2R)-1-(3,5-Bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-(methylamin-
o)benzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
trihydrochloride [2202] mp: 156-163.degree. C. [2203]
[.alpha.].sub.D.sup.25.9: -1.79.degree. (C=0.003, MeOH) [2204] IR
(KBr): 3425, 2669, 2605, 2451, 1647, 1516, 1462, 1429, 1281, 1134,
1105 cm.sup.-1 [2205] NMR (D.sub.2O, .delta.): 2.05-5.57 (31H, m),
6.74-8.25 (6H, m) [2206] MASS (APCI): 617 (M+H).sup.+ (free),
581
[2207]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-[[(5-hydrox-
y-2-oxopyrrolidino)methyl]aminolbenzyl]-4-[2-[(2S)-2-(methoxymethyl)morpho-
lino]ethyl]piperazine trihydrochloride [2208] mp: 163-176.degree.
C. [2209] IR (KBr): 3400, 2586, 2443, 1647, 1454, 1427, 1369, 1281,
1174, 1134, 1103 cm.sup.-1 [2210] NMR (D.sub.2O, .delta.):
1.70-6.50 (35H, m), 6.70-8.30 (6H, m) [2211] MASS (APCI): 716
(M+H).sup.+ (free)
EXAMPLE 34
[2212] The following compounds were obtained according to a similar
manner to that of Example 30. [2213] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methyl-3-pyrrolidinobenzyl)-
-4-[2-[(2S)-2--(methoxymethyl)-morpholino]ethyl]piperazine
trihydrochloride [2214] mp: 160-165.degree. C. [2215]
[.alpha.].sub.D.sup.24.6: +20.83.degree. (C=0.108, MeOH) [2216] IR
(KBr): 3438, 2665, 2586, 2482, 1645, 1516, 1454, 1429, 1282, 1182,
1138, 1105 cm.sup.-1 [2217] NMR (D.sub.2O, .delta.): 2.05-5.50
(36H, m), 6.74-8.30 (6H, m) [2218] MASS (APCI): 657 (M+H).sup.+
(free), 588 [2219] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methyl-3-morpholinobenzyl)--
4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
trihydrochloride [2220] mp: 150-170.degree. C. [2221]
[.alpha.].sub.D.sup.24.7: -4.48.degree. (C=0.067, MeOH) [2222] IR
(KBr): 3437, 2667, 2576, 2457, 1645, 1514, 1454, 1429, 1282, 1182,
1136 cm.sup.-1 [2223] NMR (D.sub.2O, .delta.): 2.15-5.50 (36H, m),
6.74-8.30 (6H, m) [2224] MASS (APCI): 673 (M+H).sup.+ (free),
588
EXAMPLE 35
[2225] To a solution of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2-
-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (132 mg) in
methylene chloride was added 4-(dimethylamino)pyridine (2 mg) and
trifluoroacetic anhydride (0.05 ml) successively and the mixture
was stirred at room temperature overnight. The mixture was
evaporated in vacuo and to the residue was added ethyl acetate and
water. The organic layer was separated, washed with brine, dried
over magnesium sulfate, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel with a mixture of
methylene chloride and methanol (25:1) as eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-(trifluoroacetylam-
ino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
(134 mg). [2226] MASS (APCI): 699 (M+H).sup.+
EXAMPLE 36
[2227] To a solution of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[4-methyl-3-(trifluoroacetyla-
mino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine
(131 mg) in tetrahydrofuran (2 ml) was added sodium hydride (10 mg)
and the resulting mixture was stirred for 20 minutes. Methyl iodide
(28 mg) was added to the mixture and the whole was stirred at room
temperature overnight. Brine was added to the mixture and the
organic layer was separated, dried over magnesium sulfate, and
evaporated in vacuo. The residue was purified by HPLC to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-(N-methyl-N-triflu-
oroacetylamino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piper-
azine (31 mg) as an oil. The obtained compound was converted to its
dihydrochloride in a conventional manner. [2228]
[.alpha.].sub.D.sup.27.3: -10.94.degree. (C=0.032, MeOH) [2229] IR
(KBr): 3425, 1695, 1647, 1282, 1207, 1180, 1140, 1101 cm.sup.-1
[2230] NMR (DMSO-d.sub.6, .delta.): 1.95-5.32 (31H, m), 6.75-8.34
(6H, m) [2231] MASS (APCI): 713 (M+H).sup.+ (free)
EXAMPLE 37
[2232] A suspension of
(2R)-1-[3-(2,5-dimethylpyrrol-1-ylsulfonyl)-5-(trifluoromethyl)benzoyl]-2-
-(3-hydroxy-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]--
piperazine (160.6 mg) in 6N hydrochloric acid (10 ml) was stirred
at 70.degree. C. for 2 hours. The mixture was poured into saturated
aqueous sodium hydrogen carbonate solution (150 ml) and extracted
with ethyl acetate (50 ml.times.3). The combined extracts were
washed with brine, dried over magnesium sulfate, and evaporated
under reduced pressure to give an oil (163.4 mg) The oil was
dissolved in ethyl acetate (1.6 ml) then 4N hydrogen chloride in
ethyl acetate (0.17 ml) and hexane (50 ml) was added successively
to the solution at room temperature. The resulting powder was
collected by filtration and dried under reduced pressure to give
(2R)-2-(3-hydroxy-4-methylbenzyl)-4-[2-(2S)-2-(methoxymethyl)-morpho-
lino]ethyl]-1-[3-sulfamoyl-5-(trifluoromethyl)benzoyl]-piperazine
dihydrochloride (149.3 g) as a powder. [2233] mp: 166-206.degree.
C. [2234] [.alpha.].sub.D.sup.25: -11.93.degree. (C=0.25, MeOH)
[2235] IR (KBr): 3431, 3402, 1641 cm.sup.-1 [2236] NMR
(DMSO-d.sub.6, .delta.) 2.08 (3H, s), 2.60-5.20 (25H, m), 6.18-9.20
(6H, m) [2237] MASS (APCI): 615 (M+H).sup.+ (free) Preparation
56
[2238] To a solution of
(3R)-1-benzyl-3-(3-hydroxy-4-methylbenzyl)piperazine (840 mg) in a
mixture of 1,4-dioxane (7.5 ml), water (5 ml), and 1N hydrochloric
acid (2.8 ml) was added successively a solution of di-tert-butyl
dicarbonate (740 mg) in 1,4-dioxane (2.5 ml) and 2N sodium
hydroxide solution (1.9 ml) at 0.degree. C. After stirring at
0.degree. C. for 1 hour, a solution of di-tert-butyl dicarbonate
(123 mg) in 1,4-dioxane was added to the solution, and stirred at
0.degree. C. for 2 hours. The mixture was adjusted to pH 7-8 by 1N
hydrochloric acid (0.99 ml) and extracted with dichloromethane (X
3). The combined extracts were washed with brine, dried over
magnesium sulfate, and evaporated under reduced pressure to give an
oil (1.74 g), which was purified with column chromatography (silica
gel, 50 ml, ethyl acetate:hexane (1:5-1:4)) to give
(2R)-4-benzyl-1-tert-butoxycarbonyl-2-(3-hydroxy-4-methylbenzyl)piperazin-
e (1.08 g) as a foam. [2239] IR (Neat): 1664 cm.sup.-1 [2240] NMR
(CDCl.sub.3, .delta.): 1.40 (9H, s), 1.92 (1H, dd, J=3.8 and 11.4
Hz), 2.15 (3H, s), 2.05-2.20 (1H, m), 2.64-3.10 (4H, m), 3.19 (1H,
dt, J=3.5 and 12.6 Hz), 3.25 (1H, d, J=12.8 Hz), 3.59 (1H, d,
J=12.8 Hz), 3.80-4.15 (2H, m), 4.77 (1H, br s), 6.15 (1H, br s),
6.55 (1H, d, J=7.5 Hz), 6.91 (1H, d, J=7.5 Hz), 7.26-7.37 (5H, m)
[2241] MASS (APCI): 397 (M+H).sup.+ Preparation 57
[2242] To a solution of
(2R)-1-tert-butoxycarbonyl-2-(3-hydroxy-4-methylbenzyl)piperazine
(7.73 g) and 4-dimethylaminopyridine (620 mg) in dichloromethane
(90 ml) was added successively triethylamine (15.82 ml) and
tert-butyldiphenylsilyl chloride (26.24 ml) at room temperature.
After stirring under reflux for 27.5 hours, water (200 ml) was
added to the mixture, and the mixture was extracted with
dichloromethane (100 ml, 50 ml.times.2). The combined organic
extracts were washed successively with water and brine, dried over
magnesium sulfate, and evaporated under reduced pressure to give
crude oil. The oil was purified with column chromatography (silica
gel, 500 ml, methanol:dichloromethane=5:95) to give
(2R)-1-tert-butoxycarbonyl-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl-
)piperazine (12.07 g) as a solid. [2243] mp: 64.5-65.5.degree. C.
[2244] IR (KBr): 2962, 2933, 1693 cm.sup.-1 [2245] NMR (CDCl.sub.3,
.delta.): 1.07-1.09 (9H, m), 1.26-1.50 (9H, m) 2.00-3.80 (9H, m),
2.36 (3H, s), 6.13-6.20 (1H, m), 6.67 (1H, d, J=7.6 Hz), 7.03 (1H,
d, J=7.6 Hz), 7.26-7.34 (6H, m), 7.65-7.73 (4H, m) [2246] MASS
(APCI): 545 (M+H).sup.+ Preparation 58
[2247] The following compounds were obtained by a similar manner to
that of Example 1 using N,N-diisopropylethylamine instead of
potassium carbonate as a base. [2248] (1)
(2R)-1-tert-Butoxycarbonyl-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl-
)-4-[2-((2S)-2-methoxymethylmorpholino)ethyl]piperazine [2249] IR
(Neat): 1695 cm.sup.-1 [2250] NMR (CDCl.sub.3, .delta.): 1.10 (9H,
s), 1.21 (9H, s), 1.60-3.00 (17H, m), 2.34 (3H, s), 3.37 (3H, s),
3.37-4.00 (5H, m), 6.23 (1H, s), 6.64 (1H, d, J=7.6 Hz), 7.38 (1H,
d, J=7.6 Hz), 7.34-7.42 (6H, m), 7.66-7.73 (4H, m) [2251] MASS
(ESI): 702.5 (M+H).sup.+ [2252] (2)
(2R)-1-(tert-Butoxycarbonyl)-2-(4-chlorobenzyl)-4-[2-(cis-2,6-dimethylmor-
pholino)ethyl]piperazine [2253] IR (Neat): 1693, 1410, 1367, 1087
cm.sup.-1 [2254] NMR (CDCl.sub.3, .delta.): 1.16 (6H, d, J=6.3 Hz),
1.38 (9H, s), 1.76 (1H, t, J=11.0 Hz), 2.03 (2H, m), 2.51 (4H, m),
2.60-3.20 (8H, m), 3.50-4.15 (4H, m), 7.12-7.27 (4H, m) [2255]
MASS: 452 (M.sup.+) [2256] (3)
(2R)-1-(tert-Butoxycarbonyl)-2-(4-chlorobenzyl)-4-[2-(5,6,7,8-tetrahydro--
1,6-naphthyridin-6-yl)ethyl]-piperazine [2257]
[.alpha.].sub.D.sup.27.2: +4.89.degree. (C=0.32, MeOH) [2258] IR
(Neat): 2970, 2930, 2810, 1690, 1580 cm.sup.-1 [2259] NMR
(CDCl.sub.3, .delta.): 1.39 (9H, s), 1.9-2.2 (2H, m), 2.4-3.3 (13H,
m), 3.67 (2H, s), 3.8-4.3 (2H, m), 7.07 (1H, dd, J=4.7 and 7.6 Hz),
7.13 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.33 (1H, d, J=7.6
Hz), 8.40 (1H, d, J=4.7 Hz) [2260] MASS (APCI): 471 (M+H).sup.+
Preparation 59
[2261] To a solution of
(2R)-1-tert-butoxycarbonyl-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl-
)-4-[2-[(2S)-2-methoxymethylmorpholino]ethyl]piperazine (13.43 g)
in dichloromethane (67.0 ml) was added trifluoroacetic acid (67.0
ml) at 0.degree. C. After stirring at room temperature for 30
minutes, the mixture was concentrated and was added dropwise
saturated aqueous sodium hydrogen carbonate solution. After
stirring at room temperature for 30 minutes, the mixture was
extracted with dichloromethane (100 ml.times.1, 50 ml.times.2). The
combined extracts were dried over magnesium sulfate and evaporated
under reduced pressure to give
(2R)-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-methoxy-
methylmorpholino]ethyl]piperazine (11.63 g) as a brown oil. [2262]
IR (Neat): 1676, 1614, 1579 cm.sup.-1 [2263] NMR (CDCl.sub.3,
.delta.): 1.10 (9H, s), 1.60-2.80 (17H, m), 2.36 (3H, s), 3.37 (3H,
s), 3.37-3.41 (2H, m), 3.60-3.95 (3H, m), 6.22 (1H, d, J=1.4 Hz),
6.60 (1H, dd, J=1.4 and 7.6 Hz), 7.06 (1H, d, J=7.6 Hz), 7.31-7.42
(6H, m), 7.68-7.73 (4H, m) [2264] MASS (APCI): 602 (M+H).sup.+
Preparation 60
[2265] To a solution of
(2R)-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]-piperazine (9.38 g) in ethyl acetate (40
ml) was added 4N hydrogen chloride in ethyl acetate (11.7 ml) at
0.degree. C. and then added dropwise hexane (200 ml). After
stirring at room temperature for 2 hours, the mixture was cooled at
0.degree. C. The resulting precipitates were collected by
filtration, washed with hexane, and dried under reduced pressure to
give
(2R)-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-(methox-
ymethyl)morpholino]ethyl]piperazine trihydrochloride (10.75 g) as a
powder. [2266] mp: 173-185.degree. C. [2267] IR (KBr): 3398, 2935,
1647, 1510 cm.sup.-1 [2268] NMR (DMSO-d.sub.6, .delta.): 1.07 (9H,
s), 2.31 (3H, s), 1.80-4.30 (25H, m), 6.15 (1H, br s), 6.70 (1H, d,
J=7.7 Hz), 7.17 (1H, d, J=7.7 Hz), 7.42-7.50 (6H, m), 7.65-7.70
(4H, m) [2269] NMR (D.sub.2O, .delta.): 1.03 (9H, s), 2.27 (3H, s),
2.90-4.20 (22H, m), 3.39 (3H, s), 6.32 (1H, s), 6.80-6.87 (1H, m),
7.19 (1H, d, J=7.8 Hz), 7.37-7.76 (10H, m) [2270] MASS (APCI): 602
(M+H).sup.+ (free) Preparation 61
[2271] N,O-Dimethylhydroxylamine hydrochloride (5.37 g) was added
to a mixture of 3-methoxy-4-(trifluoromethyl)benzoic acid (11.0 g),
1-hydroxybenzotriazole (6.76 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.59
g) and N,N-diisopropylethylamine (9.6 ml) in dichloromethane (200
ml), and the whole was stirred at room temperature for 18 hours.
Saturated aqueous sodium hydrogen carbonate solution was added to
the mixture and the organic layer was separated, dried over
magnesium sulfate, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel with 25% of ethyl
acetate in hexane as an eluent to give
3-methoxy-N-methoxy-N-methyl-4-(trifluoromethyl)-benzamide (12.0 g)
as a colorless oil. [2272] NMR (CDCl.sub.3, .delta.): 3.38 (3H, s),
3.56 (3H, s), 3.94 (3H, s), 7.28 (2H, m), 7.60 (1H, d, J=8.3 Hz)
[2273] MASS (APCI): 264 (M+H).sup.+ Preparation 62
[2274] To a stirred solution of
3-methoxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2.63 g)
in dry tetrahydrofuran (26 ml) was added lithium aluminum hydride
(380 mg) at -400.degree. C. under nitrogen atmosphere. After 1 hour
of stirring at 5.degree. C., 2N sodium hydroxide was added to the
mixture. The insoluble materials were removed by filtration through
Celite.RTM. and washed with ethyl acetate. The filtrate and washing
were combined and evaporated under reduced pressure to give crude
3-methoxy-4-(trifluoromethyl)benzaldehyde as a colorless oil. To a
stirred mixture of crude 3-methoxy-4-(trifluoromethyl)-benzaldehyde
and 1,4-diacetylpiperazine-2,5-dione (1.98 g) in a mixture of
N,N-dimethylformamide (10 ml) and tert-butanol (10 ml) was added
potassium tert-butoxide (1.12 g) at 5.degree. C. The mixture was
stirred for 18 hours at room temperature. Water (30 ml) and ethyl
acetate (100 ml) were added to the mixture and the organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate. The combined extract was washed with water, dried over
magnesium sulfate, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel with 50% of ethyl
acetate in hexane as an eluent to give
1-acetyl-3-[[3-methoxy-4-(trifluoromethyl)phenyl]methylene]piperazine-2,5-
-dione (2.11 g) as a powder. [2275] NMR (DMSO-d.sub.6, .delta.):
3.33 (3H, s), 3.90 (3H, s), 4.37 (2H, s), 6.98 (1H, s), 7.26 (1H,
d, J=8.1 Hz), 7.38 (1H, s), 7.63 (1H, d, J=8.1 Hz), 10.55 (1H, s)
[2276] MASS (APCI): 343 (M+H).sup.+ Preparation 63
[2277] A solution of
1-acetyl-3-[[3-methoxy-4-(trifluoromethyl)phenyl]methylene]piperazine-2,5-
-dione (1.8 g) in tetrahydrofuran (50 ml) was hydrogenated over 10%
palladium-carbon (50% wet, 180 mg) for 5 hours at atmospheric
pressure. After removal of the catalyst by filtration, the filtrate
was added hydrazine monohydrate (395 mg). The mixture was stirred
for 1.5 hours at room temperature and concentrated under reduced
pressure. The residue was triturated with isopropyl ether (12 ml)
and the precipitates were collected by filtration, and washed with
isopropyl ether to give
3-[3-methoxy-4-(trifluoromethyl)benzyl]piperazine-2,5-dione (1.29
g) as a powder. [2278] NMR (DMSO-d.sub.6, .delta.): 2.94-3.19 (3H,
m), 3.51 (1H, m), 3.84 (3H, s), 4.15 (1H, m), 6.90 (1H, d, J=7.9
Hz), 7.08 (1H, s), 7.52 (1H, d, J=7.9 Hz), 7.99 (1H, m), 8.20 (1H,
m) [2279] MASS (APCI): 303 (M+H).sup.+ Preparation 64
[2280] To a stirred suspension of
3-(3-methoxy-4-(trifluoromethyl)benzyl]piperazine-2,5-dione (1.2 g)
in tetrahydrofuran (100 ml) was added borane-tetrahydrofuran
complex (1M in tetrahydrofuran, 39.7 ml) by syringe under nitrogen
atmosphere at room temperature and the mixture was heated under
reflux for 18 hours. After cooling, the reaction mixture was
filtered, and the filtrate was slowly added 12% hydrogen bromide in
acetic acid (16 ml). To the mixture was added isopropyl ether (300
ml) and the whole was stirred for 1 hour at 5.degree. C. The
resulting precipitates were collected by filtration and dried under
reduced pressure to give
2-[3-methoxy-4-(trifluoromethyl)benzyl]piperazine dihydrobromide
(1.73 mg) as a powder. [2281] NMR (DMSO-d.sub.6, .delta.):
2.70-3.90 (9H, m), 3.92 (3H, s), 6.50 (1H, m), 7.03 (1H, d, J=7.9
Hz), 7.25 (1H, s), 7.62 (1H, d, J=7.9 Hz), 8.10 (1H, br s), 9.07
(2H, br s) [2282] MASS (APCI): 275 (M+H).sup.+ (free) Preparation
65
[2283] The following compound was obtained according to a similar
manner to that of Preparation 56.
[2284]
(2R)-4-Benzyl-1-(tert-butoxycarbonyl)-2-(4-chlorobenzyl)piperazine
[2285] mp: 139-140.degree. C. [2286] [.alpha.].sub.D.sup.26.8:
-2.96.degree. (C=0.27, MeOH) [2287] IR (KBr): 3740, 2970, 2810,
1700, 1650 cm.sup.-1 [2288] NMR (CDCl.sub.3, .delta.): 1.38 (9H,
s), 1.9-2.2 (2H, m), 2.58 (1H, d, J=11.5 Hz), 2.7-3.3 (4H, m), 3.32
(1H, d, J=12.9 Hz), 3.56 (1H, d, J=12.9 Hz), 3.7-4.3 (2H, m), 6.93
(2H, d, J=8.2 Hz), 7.12 (2H, d, J=8.2 Hz), 7.33 (5H, s) [2289] MASS
(APCI): 401 (M+H).sup.+ Preparation 66
[2290] The following compounds were obtained according to a similar
manner to that of Preparation 59. [2291] (1)
(2R)-2-(4-Chlorobenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine
trihydrochloride [2292] IR (KBr): 1645, 1454, 1425, 1120, 1086
cm.sup.-1 [2293] NMR (DMSO-d.sub.6, .delta.): 1.11 (6H, d, J=6.2
Hz), 2.59-4.60 (19H, m), 7.34 (2H, d, J=8.5 Hz), 7.44 (2H, d, J=8.5
Hz), 9.47-10.0 (1H, br), 9.50 (0.5H, br), 10.5 (0.5H, br) [2294]
MASS: 352 (M.sup.+) [2295] (2)
(2R)-2-(4-Chlorobenzyl)-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)et-
hyl]piperazine tetrahydrochloride [2296] [.alpha.].sub.D.sup.27.2:
+13.10.degree. (C=0.35, MeOH) [2297] IR (KBr): 3400, 1640, 1630,
1550, 1520 cm.sup.-1 [2298] NMR (DMSO-d.sub.6, .delta.): 2.8-6.2
(16H, m), 4.53 (2H, s), 7.34 (2H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz),
7.80 (1H, dd, J=5 and 8 Hz), 8.23 (1H, d, J=8 Hz), 8.75 (1H, d, J=5
Hz), 9.7-10.0 (1H, br), 10.1-10.3 (1H, br) [2299] MASS (APCI): 371
(M+H).sup.+ Preparation 67
[2300] To a 3-chlorosulfonyl-5-(trifluoromethyl)benzoic acid (0.4
g) was added 28% ammonia aqueous solution (5.0 ml) at 0.degree. C.
The mixture was stirred at 0.degree. C., and then allowed to stand
at room temperature overnight. The mixture was concentrated to
dryness, and then 1N hydrochloric acid (5 ml) was added to the
mixture, and stirred at 0.degree. C. for 30 minutes. The resulted
powder was collected by filtration and dried under reduced pressure
to give 3-sulfamoyl-5-(trifluoromethyl)benzoic acid (299.4 mg) as a
pale yellow powder. [2301] mp: 244-246.degree. C. [2302] IR (KBr):
1713 cm.sup.-1 [2303] NMR (DMSO-d.sub.6, .delta.): 7.73 (2H, s),
8.34 (1H, s), 8.37 (1H, s), 8.62 (1H, s) [2304] MASS (ESI-): 268.1
(M-H) Preparation 68
[2305] To a solution of 3-sulfamoyl-5-(trifluoromethyl)benzoic acid
(200 mg) and 2,5-hexanedione (0.26 ml) in toluene (1 ml) was added
p-toluenesulfonic acid monohydrate (28 mg), and the mixture was
stirred under reflux with Dean-Stark Trap for 24 hours. Then
2,5-hexanedione (0.26 ml) and p-toluenesulfonic acid monohydrate
(30 mg) was added to the mixture, and the mixture was stirred under
the same condition for 24 hours. The mixture was evaporated and
purified with column chromatography (silica gel, 50 ml,
methanol:dichloromethane (5:95-20:80)) to give
3-[(2,5-dimethylpyrrol-1-yl)-sulfonyl]-5-(trifluoromethyl)benzoic
acid (280 mg) as a crude solid. The solid was dissolved in a
mixture of lN sodium hydroxide aqueous solution (10 ml) and water
(20 ml), and then adjusted to pH 1-2 with 1N hydrochloric acid (20
ml) The resulting powder was collected by filtration and dried
under reduced pressure to give pure product (191.1 mg) [2306] mp:
150-153.degree. C. [2307] IR (KBr): 1701 cm.sup.-1 [2308] NMR
(DMSO-d.sub.6, .delta.): 2.33 (6H, s), 6.07 (2H, s), 8.13 (1H, s),
8.23 (1H, s), 8.46 (1H, s) [2309] MASS (APCI): 348 (M+H).sup.+
Preparation 69
[2310] A solution of a mixture of
3-chlorosulfonyl-5-trifluoromethylbenzoic acid (0.5 g) and
pyrrolidine (0.72 ml) in dichloromethane (5 ml) was stirred at room
temperature overnight. After evaporation to dryness, water (50 ml)
was added to the residue and adjusted to pH 1.0 by 1N hydrochloric
acid. The resulting precipitates were collected by filtration, and
dried under reduced pressure at 45.degree. C. to give
3-(pyrrolidinosulfonyl)-5-(trifluoromethyl)benzoic acid (0.514 g)
as a powder. [2311] mp: 198-199.degree. C. [2312] IR (KBr): 1697
cm.sup.-1 [2313] NMR (DMSO-d.sub.6, .delta.): 1.64-1.77 (4H, m),
3.18-3.29 (4H, m) 8.28 (1H, s), 8.45 (1H, s), 8.46 (1H, s) [2314]
MASS (APCI): 324 (M+H).sup.+ Preparation 70
[2315] The following compounds were obtained according to a similar
manner to that of Preparation 69. [2316] (1)
3-(Morpholinosulfonyl)-5-(trifluoromethyl)benzoic acid [2317] mp:
210-213.degree. C. [2318] IR (KBr): 1707 cm.sup.-1 [2319] NMR
(DMSO-d.sub.6, .delta.): 2.96-3.01 (4H, m), 3.62-3.67 (4H, m), 8.22
(1H, s), 8.41 (1H, s), 8.48 (1H, s) [2320] MASS (ESI-): 338.1 (M-H)
[2321] (2) 3-Methylsulfamoyl-5-(trifluoromethyl)benzoic acid [2322]
mp: 194-197.degree. C. [2323] IR (KBr): 1705 cm.sup.-1 [2324] NMR
(DMSO-d.sub.6, .delta.): 2.46 (3H, s), 7.84-7.94 (1H, m), 8.28 (1H,
s), 8.41 (1H, s), 8.55 (1H, s) [2325] NMR (CD.sub.3OD, .delta.):
2.57 (3H, s), 8.29 (1H, s), 8.48 (1H, s), 8.65 (1H, s) [2326] MASS
(ESI-): 282 (M-H) [2327] (3)
3-Dimethylsulfamoyl-5-(trifluromethyl)benzoic acid [2328] mp:
145-155.degree. C. [2329] IR (KBr): 1705 cm.sup.-1 [2330] NMR
(DMSO-d.sub.6, .delta.): 2.70 (6H, s), 8.24 (1H, s), 8.42 (1H, s),
8.46 (1H, s) [2331] MASS (APCI): 298 (M+H).sup.+ Preparation 71
[2332] A solution of 3-amino-5-(trifluoromethyl)benzoic acid (2.0
g) and 2,5-dimethoxytetrahydrofuran (1.52 ml) in a mixture of
acetic acid (10 ml) and 1,4-dioxane (10 ml) was stirred at
100.degree. C. for 2 hours. After cooling to room temperature, the
mixture was concentrated and purified with column chromatography
(silica gel, 50 ml, methanol:dichloromethane=10:90) to give crude
solid. The solid was recrystallized from ethyl acetate (5.0 ml) and
hexane (200 ml) to give 3-(pyrrol-1-yl)-5-(trifluoromethyl)-benzoic
acid (1.72 g) as a powder. [2333] mp: 191-192.5.degree. C. [2334]
IR (KBr): 1705, 1614, 1496 cm.sup.-1 [2335] NMR (CDCl.sub.3,
.delta.): 6.43 (2H, s), 7.19 (2H, s), 7.87 (1H, s), 8.22 (1H, s),
8.31 (1H, s) [2336] MASS (ESI-): 254 (M-H), 509.1 (2M-1)
Preparation 72
[2337] To a solution of 3-iodo-5-(trifluoromethyl)benzoic acid
(2.32 g) and triethylamine (1.13 ml) in dichloromethane (20 ml) was
added dropwise a solution of ethyl chloroformate (1.4 ml) in
dichloromethane (2.0 ml) over 10 minutes at -300.degree. C., and
the mixture was stirred at -300.degree. C. for 1 hour.
2-Amino-2-methyl-1-propanol was added dropwise to the mixture over
5 minutes at -30.degree. C., and the mixture was stirred at
-30.degree. C. for 30 minutes and then at room temperature for 1
hour. The mixture was quenched with aqueous ammonium chloride
solution at 0.degree. C., and extracted with dichloromethane
(.times.2). The combined organic extracts were washed successively
with saturated aqueous sodium hydrogen carbonate solution, 1N
hydrochloric acid and brine, and then dried over magnesium sulfate,
evaporated, and purified with column chromatography (silica gel,
ethyl acetate:hexane=20:80) to give
N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluoromethyl)benzamide
(2.10 g) as an oil. [2338] IR (Neat): 3400, 1640, 1550 cm.sup.-1
[2339] NMR (CDCl.sub.3, .delta.): 1.44 (6H, s), 3.69 (2H, d, J=5.9
Hz), 4.02 (1H, t, J=5.9 Hz), 7.93 (1H, d, J=0.6 Hz), 8.05 (1H, d,
J=0.6 Hz), 8.22 (1H, s) [2340] NMR (DMSO-d.sub.6, .delta.): 3.33
(6H, s), 3.53 (2H, d, J=5.7 Hz), 4.81 (1H, t, J=5.7 Hz), 8.12 (1H,
s), 8.22 (1H, s), 8.45 (1H, s) [2341] MASS (ESI+): 410.1
(M+Na).sup.+ Preparation 73
[2342] To
N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluromethyl)benzam-
ide (2.11 g) was added thionyl chloride (1.29 ml), and the mixture
was stirred at room temperature for 4 hours. The mixture was
concentrated under reduced pressure, quenched with saturated
aqueous sodium hydrogen carbonate solution, and extracted with
ethyl acetate (.times.2). The combined extracts were dried over
magnesium sulfate, evaporated, and purified with column
chromatography (silica gel, ethyl acetate:hexane=2.5:97.5) to give
2-[3-iodo-5-(trifluoromethyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole
(1.66 g) as a solid. [2343] mp: 73-74.5.degree. C. [2344] IR (KBr):
2968, 1645, 1566 cm.sup.-1 [2345] NMR (CDCl.sub.3, .delta.): 1.39
(6H, s), 4.14 (2H, s), 8.03 (1H, d, J=0.7 Hz), 8.16 (1H, d, J=0.7
Hz), 8.48 (1H, s) [2346] MASS (APCI): 370 (M+H).sup.+ Preparation
74
[2347] To a solution of
2-[3-iodo-5-(trifluromethyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole
(2.11 g) and triisopropyl borate (1.26 g) in tetrahydrofuran (21
ml) was added dropwise butyllithium (1.6 M in hexane) at
-70.degree. C. After stirring for 4 hours, the mixture was quenched
with 2N hydrochloric acid and extracted with ethyl acetate. The
combined extracts were washed with brine, dried over magnesium
sulfate, and evaporated in vacuo to give
3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenylboroic
acid (1.65 g) as a yellow oil. This oil was used immediately in the
next reaction without further purification because of its
instability.
Preparation 75
[2348] To a suspension of
3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenylboroic
acid (0.58 g) and 4-bromopyridine hydrochloride (0.39 g) in a
mixture of sodium carbonate aqueous solution (2M, 6 ml) and
1,2-dimethoxyethane (4 ml) was added
tetrakis(triphenylphosphine)palladium (0.116 g) under nitrogen
atmosphere. After stirring at 80.degree. C. for 12 hours, the
mixture was quenched with water and extracted with ethyl acetate
twice. The combined extracts were dried over magnesium sulfate,
evaporated, and purified with column chromatography (silica gel,
ethyl acetate:hexane=1:3-2:1-1:2) to give
4-[3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenyl]pyri-
dine (0.61 g) as a syrup. [2349] IR (KBr): 2972, 1651, 1597, 1446
cm.sup.-1 [2350] NMR (CDCl.sub.3, .delta.): 1.42 (6H, s), 4.14 (2H,
s), 7.57 (2H, d, J=6.2 Hz), 7.96 (1H, s), 8.28 (1H, s), 8.40 (1H,
s), 8.72 (2H, d, J=6.2 Hz) [2351] MASS (ESI+): 321.1 (M+H).sup.+
Preparation 76
[2352] A mixture of
4-[3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenyl]pyri-
dine (0.60 g) and 6N hydrochloric acid (6 ml) was stirred at
90.degree. C. for 5 hours. After cooling to room temperature, the
mixture was concentrated. Small amount of water was added to the
residue and the appeared crystals were gathered by filtration and
dried under reduced pressure to give
5-(4-pyridinyl)-3-(trifluoromethyl)benzoic acid hydrochloride (0.33
g) as a powder. The second crystals were obtained from mother
liquid similarly (0.1 g). [2353] mp: .about.230.degree. C. [2354]
IR (KBr): 2534, 1703, 1641, 1608, 1514 cm.sup.-1 [2355] NMR
(DMSO-d.sub.6, .delta.): 8.36 (1H, s), 8.50 (2H, d, J=6.7 Hz), 8.60
(1H, s), 8.69 (1H, s), 9.01 (2H, d, J=6.7 Hz) [2356] MASS (ESI+):
268.2 (M+H).sup.+ Preparation 77
[2357] The following compound was obtained according to a similar
manner to that of Preparation 11. [2358]
2-Benzylamino-2-methyl-1-propanol [2359] NMR (CDCl.sub.3, .delta.):
1.14 (6H, s), 3.34 (2H, s), 3.67 (2H, s), 7.20-7.34 (5H, m) [2360]
MASS (APCI): 180 (M+H).sup.+ Preparation 78
[2361] The following compound was obtained according to a similar
manner to that of Preparation 12.
[2362]
2-Methyl-[2-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-1-p-
ropanol [2363] IR (Neat): 3400, 2973, 2881, 1643, 1454 cm.sup.-1
[2364] NMR (CDCl.sub.3, .delta.): 1.03 (3H, s), 1.13 (3H, s), 2.49
(1H, dd, J=3.5 and 14.0 Hz), 2.79 (1H, dd, J=9.2 and 14.0 Hz), 3.28
(3H, s), 2.92-3.32 (3H, m), 3.38-3.48 (1H, m), 3.48-3.61 (2H, m),
4.02 (1H, d, J=15.3 Hz), 7.17-7.41 (5H, m) [2365] MASS (APCI): 268
(M+H).sup.+ Preparation 79
[2366] The following compounds were obtained according to a similar
manner to that of Preparation 13. [2367] (1)
(2S)-1-[N-Benzyl-N-(2-chloro-1,1-dimethylethyl)amino]-3-methoxy-2-propano-
l [2368] IR (Neat): 2933, 1645, 1456 cm.sup.-1 [2369] NMR
(CDCl.sub.3, .delta.): 1.08-1.53 (6H, m), 2.46-4.10 (9H, m), 3.34
(3H, s), 7.23-7.40 (5H, m) [2370] MASS (APCI): 286 (M+H).sup.+
[2371] (2)
(1R,4S)-3,3-Dimethyl-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane
hydrochloride [2372] IR (KBr): 294S, 2603, 1514, 1462 cm.sup.-1
[2373] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, s), 1.45 (3H, s),
2.20-2.40 (2H, m), 3.21 (1H, d, J=11.9 Hz), 3.40-3.80 (3H, m),
3.90-4.15 (2H, m), 4.31 (1H, s), 4.56 (1H, s) [2374] MASS (APCI):
190 (M+H).sup.+ (free) Preparation 80
[2375] The following compound was obtained according to a similar
manner to that of Preparation 14.
[2376] (2S)-4-Benzyl-5,5-dimethyl-2-(methoxymethyl)morpholine
[2377] NMR (CDCl.sub.3, .delta.): 1.10 (3H, s), 1.12 (3H, s), 2.21
(1H, dd, J=10.5 and 11.7 Hz), 2.37 (1H, dd, J=3.0 and 11.7 Hz),
3.00 (1H, d, J=13.8 Hz), 3.32 (3H, s), 3.24-3.56 (4H, m), 3.61-3.71
(1H, m), 4.02 (1H, d, J=13.8 Hz), 7.20-7.36 (5H, m) [2378] MASS
(APCI): 250 (M+H).sup.+ Preparation 81
[2379] The following compounds were obtained according to a similar
manner to that of Preparation 15. [2380] (1) (2S)-5,
5-Dimethyl-2-(methoxymethyl)morpholine hydrochloride [2381] IR
(Neat): 3398, 2947, 1458, 1390 cm.sup.-1 [2382] NMR (CDCl.sub.3,
.delta.): 1.26 (3H, s), 1.33 (3H, s), 2.90-3.00 (2H, m), 3.27 (3H,
s), 3.35-3.50 (2H, m), 3.49-3.64 (2H, m), 3.82-3.94 (1H, m) [2383]
MASS (APCI): 1.60 (M+H).sup.+ (free) [2384] (2)
(1R,4S)-3,3-Dimethyl-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride
[2385] mp: 237-238.degree. C. [2386] IR (KBr): 2895, 2727, 1587,
1464 cm.sup.-1 [2387] NMR (DMSO-d.sub.6, .delta.): 1.11 (3H, s),
1.31 (3H, s), 1.92 (1H, d, J=11.3 Hz), 2.28 (1H, d, J=11.3 Hz),
3.00-3.15 (2H, m), 4.08 (1H, s), 4.53 (1H, s) [2388] MASS (APCI):
128 (M+H).sup.+ (free) Preparation 82
[2389] The following compounds were obtained according to a similar
manner to that of Preparation 7. [2390] (1)
(2S)-S,5-Dimethyl-4-(2-hydroxyethyl)-2-(methoxymethyl)-morpholine
[2391] IR (KBr): 3433, 2970, 2875, 1458, 1365 cm.sup.-1 [2392] NMR
(CDCl.sub.3, .delta.): 0.98 (3H, s), 1.06 (3H, s), 2.12 (1H, ddd,
J=2.2, 3.2 and 12.9 Hz), 2.31 (1H, dd, J=10.8 and 11.8 Hz), 2.63
(1H, dd, J=2.8 and 11.8 Hz), 2.96 (1H, ddd, J=5.3, 10.7 and 12.9
Hz), 3.39 (3H, s), 3.33-3.60 (6H, m), 3.60-3.80 (1H, m) [2393] MASS
(APCI): 204 (M+H).sup.+ [2394] (2)
(1R,4S)-3,3-Dimethyl-5-(2-hydroxyethyl)-2-oxa-5-azabicyclo[2.2.1]heptane
[2395] IR (KBr): 3433, 2978, 1460 cm.sup.-1 [2396] NMR (CDCl.sub.3,
.delta.): 1.13 (3H, s), 1.34 (3H, s), 1.63 (1H, dd, J=11.7 and 10.2
Hz), 1.99 (1H, ddd, J=1.1, 1.1 and 10.2 Hz), 2.32 (1H, dd, J=1.7
and 10.4 Hz), 2.52 (1H, ddd, J=4.1, 5.4 and 12.3 Hz), 2.85 (1H,
ddd, J=4.8, 6.8 and 12.3 Hz), 2.98 (1H, br s), 3.00 (1H, d, J=10.4
Hz), 3.40-3.75 (2H, m), 4.38 (1H, br s) [2397] MASS (APCI): 172
(M+H).sup.+ [2398] (3) 4,4-Difluoro-1-(2-hydroxyethyl)piperidine
[2399] NMR (CDCl.sub.3, .delta.): 1.85-2.05 (5H, m), 2.55-2.65 (6H,
m), 3.62 (2H, t, J=5.3 Hz) [2400] MASS (APCI): 166 (M+H).sup.+
Preparation 83
[2401] Methylmagnesium bromide (0.93 M in tetrahydrofuran, 120 ml)
was added to a solution of N-benzyl-trans-4-hydroxy-L-proline
methyl ester (5.0 g) in tetrahydrofuran (50 ml) with dry ice
acetone bath cooling under nitrogen atmosphere and the whole was
stirred for 30 minutes. Saturated ammonium chloride aqueous
solution was added to the mixture and the organic layer was
separated, washed with brine, dried over sodium sulfate, and
evaporated in vacuo to give
(2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-hydroxypyrrolidine
(5.0 g) as an oil. [2402] IR (Neat): 3400, 1455, 1370, 1120
cm.sup.-1 [2403] NMR (CDCl.sub.3-D.sub.2O, .delta.): 1.15 (3H, s),
1.30 (3H, s), 1.80-2.02 (2H, m), 2.52-2.66 (1H, m), 3.02 (1H, dd,
J=11.9 and 3.8 Hz), 3.15 (1H, d, J=8.0 Hz), 3.92 (1H, d, J=13.6
Hz), 4.17 (1H, d, J=13.6 Hz), 4.32-4.45 (1H, m), 7.15-7.44 (5H, m)
[2404] MASS (APCI): 236 (M+H).sup.+ Preparation 84
[2405] To a solution of triethylamine (4.32 ml) and
(2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-hydroxypyrrolidine
(4.87 g) in dichloromethane (50 ml) was added methanesulfonyl
chloride (2.4 ml) at 0.degree. C. After stirring at room
temperature for 4 hours, the mixture was quenched with water and
extracted with ethyl acetate (.times.2). The combined extracts were
washed with brine, dried over magnesium sulfate, evaporated under
reduced pressure, and purified with column chromatography (silica
gel, 500 ml, methanol:dichloromethane=4:96) to give
(2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-(methanesulfonylox-
y)pyrrolidine (3.34 g) as a pale yellow solid. [2406] IR (Neat):
3431, 3402, 1647, 1458 cm.sup.-1 [2407] NMR (CDCl.sub.3, .delta.):
1.15 (3H, s), 1.32 (3H, s), 2.04-2.35 (2H, m), 2.93-3.21 (3H, m),
3.02 (3H, s), 3.89 (1H, d, J=13.9 Hz), 4.13 (1H, d, J=13.9 Hz),
5.14 (1H, br s), 7.23-7.35 (5H, m) [2408] MASS (APCI): 314
(M+H).sup.+ Preparation 85
[2409] To a solution of
(2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-(methanesulfonyloxy)pyrrol-
idine (3.65 g) in N,N-dimethylformamide (36 ml) was added sodium
hydride (1.12 g, 60% in mineral oil) at 0.degree. C. The mixture
was stirred at room temperature for 2.5 hours and allowed to stand
overnight. The mixture was quenched with methanol (20 ml), then
stirred for 30 minutes, and evaporated. The residue was added water
(300 ml) and extracted with ethyl acetate (100 ml.times.3). The
combined extracts were washed successively with water and brine.
The organic layer was dried over magnesium sulfate, evaporated, and
purified with column chromatography (silica gel, 125 ml, ethyl
acetate:hexane=5:95-20:80) to give
(1R,4S)-2-benzyl-3,3-dimethyl-2-oxa-5-azabicyclo[2.2.1]-heptane
(2.32 g) as a colorless oil. [2410] IR (Neat): 2978, 1676, 1647
cm.sup.-1 [2411] NMR (CDCl.sub.3, .delta.): 1.08 (3H, s), 1.40 (3H,
s), 1.73 (1H, dd, J=1.9 and 10.1 Hz), 1.92 (1H, ddd, J=1.1, 1.1 and
10.1 Hz), 2.30 (1H, dd, J=1.6 and 10.5 Hz), 2.92 (1H, br s), 2.98
(1H, d, J=10.5 Hz), 3.62 (1H, d, J=13.6 Hz), 3.77 (1H, d, J=13.6
Hz), 4.36 (1H, br s) 7.19-7.42 (5H, m) [2412] MASS (APCI): 218
(M+H).sup.+ Preparation 86
[2413] The following compound was obtained according to a similar
manner to that of Example 1.
[2414]
(2S,5S)-4-(4-Chloro-2-butynyl)-2-methoxymethyl-5-methylmorpholine
[2415] IR (Neat): 2877, 1454, 1381, 1327 cm.sup.-1 [2416] NMR
(CDCl.sub.3, .delta.): 1.20 (3H, d, J=6.3 Hz), 1.94-2.14 (2H, m),
2.69-2.79 (2H, m), 3.35 (2H, t, J=2.0 Hz), 3.38 (3H, s), 3.38-3.51
(2H, m), 3.68-3.81 (2H, m), 4.17 (2H, t, J=2.0 Hz) [2417] MASS
(APCI): 232 (M+H).sup.+ Preparation 87
[2418] To a solution of 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine
(0.4 g) in N,N-dimethylformamide (5 ml) was added sodium hydride
(60% oil suspension; 0.24 g) in portions. After a few minutes, a
solution of 2-chloromethyl-1,3-dioxolane (0.43 g) in
N,N-dimethylformamide (2 ml) was added dropwise to the mixture.
After stirring for 2 hours, the mixture was poured into a mixed
solvent of water and ethyl acetate. The organic layer was
separated, washed with water twice, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel using a mixed solvent of
ethyl acetate and hexane (1:1) as an eluent to give
3,4-dihydro-4-[(1,3-dioxolan-2-yl)methyl]-2H-pyrido[3,2-b]-1,4-oxazine
(0.28 g) as an oil. [2419] NMR (CDCl.sub.3, .delta.): 3.30-4.40
(10H, m), 5.10 (1H, t, J=4.4 Hz), 6.49 (1H, dd, J=4.9 and 7.6 Hz),
6.91 (1H, dd, J=1.5 and 7.6 Hz), 7.73 (1H, dd, J=1.5 and 4.9 Hz)
[2420] MASS (APCI): 223 (M+H).sup.+ Preparation 88
[2421] A solution of
3,4-dihydro-4-[(1,3-dioxolan-2-yl)methyl]-2H-pyrido[3,2-b]-1,4-oxazine
(0.13 g) in acetone (10 ml) and water (1 ml) was heated under
reflux in the presence of p-toluenesulfonic acid (2.24 g) for 3
days. The mixture was concentrated in vacuo and the residue was
poured into aqueous saturated sodium hydrogen carbonate solution.
The water layer was extracted with ethyl acetate three times and
the combined organic layers were dried over magnesium sulfate and
concentrated in vacuc. The residue was purified by column
chromatography on silica gel using a mixed solvent of methanol and
dichloromethane (1:10) as an eluent. The fractions containing the
objective compound were collected and evaporated under reduced
pressure to give
2-[3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-4-yl]acetaldehyde (0.09
g) as an oil. [2422] NMR (CDCl.sub.3, .delta.): 3.56 (2H, t, J=4.5
Hz), 4.00-4.40 (4H, m), 6.57 (1H, dd, J=5.5 and 8 Hz), 6.97 (1H,
dd, J=1.4 and 8.0 Hz), 7.69 (1H, dd, J=1.4 and 5.5 Hz), 9.73 (1H,
s) [2423] MASS (APCI): 179 (M+H).sup.+ Preparation 89
[2424] A mixture of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.86
g), 2-bromoethanol (0.66 g), potassium carbonate (2.58 g) and
potassium iodide (3.10 g) in N,N-dimethylformamide (20 ml) was
stirred at 70.degree. C. for 2 hours. After cooling, ethyl acetate
and water were added thereto. The organic layer was separated,
washed with water twice, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using a mixed solvent of
methanol and dichloromethane (1:10) as an eluent. The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.53 g)
as an oil. [2425] IR (Neat): 1664, 1456, 1441, 1406, 1360, 1327,
1111, 1065, 1043 cm.sup.-1 [2426] NMR (DMSO-d.sub.6, .delta.)
2.60-3.10 (6H, m), 3.50-3.90 (4H, m), 6.74 (1H, d, J=5.1 Hz), 7.10
(1H, d, J=5.1 Hz) [2427] MASS (APCI): 184 (M+H).sup.+ Preparation
90
[2428] To a solution of
5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.49 g)
in dichloromethane (20 ml) was added dropwise thionyl chloride
(0.39 ml). The mixture was stirred at 40.degree. C. for 1.5 hours.
After the mixture was evaporated under reduced pressure, the
residue was triturated with diisopropyl ether. The resulting powder
was collected by filtration, washed with diisopropyl ether and
dried in vacuo to give
5-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
hydrochloride (0.44 g). [2429] mp: 205-215.degree. C. [2430] IR
(KBr): 2667, 2576, 2544, 2467, 2397, 1693, 1645, 1547, 1539, 1516,
1452, 1437, 1184, 1155, 1086, 1066 cm.sup.-1 [2431] NMR
(DMSO-d.sub.6, .delta.): 2.80-4.80 (10H, m), 6.91 (1H, d, J=5.2
Hz), 7.49 (1H, d, J=5.2 Hz) [2432] MASS (ESI): 202.2 (M+H).sup.+
(free) Preparation 91
[2433] The following compounds were obtained according to a similar
manner to that of Preparation 90. [2434] (1)
1-(2-Chloroethyl)-4,4-difluoropiperidine hydrochloride [2435] mp:
158-159.degree. C. [2436] IR (KBr): 2700-2300, 1477, 1388 cm.sup.-1
[2437] NMR (DMSO-d.sub.6, .delta.): 2.20-2.60 (4H, m), 3.00 (4H,
m), 3.55 (2H, t, J=7.0 Hz), 4.07 (2H, t, J=7.0 Hz) [2438] (2)
(2S)-4-(2-Chloroethyl)-5,5-dimethyl-2-(methoxymethyl)-morpholine
hydrochloride [2439] IR (KBr): 1562, 1558, 1547, 1539, 1516, 1498,
1464, 1456, 1198, 1180, 1126, 1105, 1041 cm.sup.-1 [2440] NMR
(DMSO-d.sub.6, .delta.): 1.41 (3H, s), 1.54 (3H, s), 2.60-4.70
(14H, m) [2441] MASS (APCI): 222 (M+H).sup.+ (free) Preparation
92
[2442] The following compounds were obtained by a similar manner to
that of Preparation 7 followed by a similar manner to that of
Preparation 90. [2443] (1)
(3S,5S)-4-(2-Chloroethyl)-3,5-dimethylmorpholine hydrochloride
[2444] mp: 190-195.degree. C. (decomp.) [2445] IR (KBr): 1516,
1454, 1398, 1371, 1342, 1250, 1205, 1153, 1132, 1103, 1074, 1024
cm.sup.-1 [2446] NMR (DMSO-d.sub.6, .delta.): 0.90-1.50 (6H, m),
3.00-4.50 (10H, m) [2447] MASS (APCI): 178 (M+H).sup.+ (free)
[2448] (2) cis-4-(2-Chloroethyl)-3,5-dimethylmorpholine
hydrochloride [2449] mp: 70-80.degree. C. (decomp.) [2450] IR
(KBr): 2559, 2478, 2407, 1477, 1466, 1454, 1429, 1390, 1146, 1120,
1074, 1030 cm.sup.-1 [2451] NMR (DMSO-d.sub.6, .delta.): 1.27 (6H,
d, J=6.1 Hz), 3.20-4.40 (10H, m), 11.58 (1H, br s) [2452] MASS
(APCI): 178 (M+H).sup.+ (free) [2453] (3)
(2R)-4-(2-Chloroethyl)-2-(methoxymethyl)morpholine hydrochloride
[2454] mp: 150-155.degree. C. (decomp.) [2455]
[.alpha.].sub.D.sup.27.5: -9.69.degree. (C=0.485, MeOH) [2456] IR
(KBr): 2673, 2590, 2476, 1516, 1477, 1454, 1400, 1201, 1132, 1107,
1084 cm.sup.-1 [2457] NMR (DMSO-d.sub.6, .delta.): 2.80-3.20 (2H,
m), 3.28 (3H, s), 3.30-4.40 (11H, m) [2458] MASS (APCI): 194
(M+H).sup.+ (free) Preparation 93
[2459] A mixture of (2S)-2-(methoxymethyl)morpholine hydrochloride
(0.5 g), 1-bromo-3-chloropropane (1.47 ml) and potassium carbonate
(2.06 g) in N,N-dimethylformamide (6 ml) was stirred at room
temperature for 1 hour. After ethyl acetate and water were added to
the mixture, the organic layer was separated, washed with water
twice, dried over magnesium sulfate and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel using ethyl acetate as an eluent. The fractions
containing the objective compound were collected and evaporated
under reduced pressure. The resulting oil was treated with 4N
hydrogen chloride in ethyl acetate to give
(2S)-4-(3-chloropropyl)-2-(methoxymethyl)morpholine hydrochloride
(0.44 g). [2460] mp: 165-170.degree. C. (decomp.) [2461] IR (KBr):
1547, 1539, 1516, 1454, 1192, 1142, 1111, 1092, 1066 cm.sup.-1
[2462] NMR (DMSO-d.sub.6, .delta.): 2.10-2.40 (2H, m), 2.70-4.20
(16H, m), 11.53 (1H, br s) [2463] MASS (APCI): 208 (M+H).sup.+
(free) Preparation 94
[2464] The following compounds were obtained according to a similar
manner to that of Preparation 93. [2465] (1)
(2S)-4-[(E)-4-Chloro-2-butynyl]-2-(methoxymethyl)-morpholine
hydrochloride [2466] IR (Neat): 1722, 1450, 1400, 1360, 1286, 1255,
1201, 1136, 1090, 1030 cm.sup.-1 [2467] NMR (DMSO-d.sub.6,
.delta.): 2.60-3.60 (10H, m), 3.60-4.20 (4H, m), 4.28 (2H, d,
J=S5.9 Hz), 5.80-6.30 (2H, m), 11.87 (1H, br s) [2468] MASS (APCI):
220 (M+H).sup.+ (free) [2469] (2)
(2S)-4-[4-Chloro-2-butynyl]-2-(methoxymethyl)-morpholine
hydrochloride [2470] mp: 70-75.degree. C. (decomp.) [2471] IR
(KBr): 1516, 1464, 1454, 1427, 1398, 1273, 1194, 1136, 1086, 1032
cm.sup.-1 [2472] NMR (DMSO-d.sub.6, .delta.): 2.60-4.80 (16H, m)
[2473] MASS (APCI): 218 (M+H).sup.+ (free) Preparation 95
[2474] The following compound was obtained according to a similar
manner to that of Preparation 27.
[2475] 2-Acetylamino-2-(4-benzyloxy-3-methoxybenzyl)malonic acid
diethyl ester [2476] mp: 105-106.degree. C. [2477] IR (KBr): 3224,
2977, 1752, 1635, 1519, 1301, 1236 cm.sup.-1 [2478] NMR
(CDCl.sub.3, .delta.): 1.29 (6H, t, J=7.2 Hz), 2.02 (3H, s), 3.58
(2H, s), 3.82 (3H, s), 4.12-4.32 (4H, m), 5.11 (2H, 5), 6.48 (1H,
dd, J=2.0 and 8.1 Hz), 6.55 (1H, d, J=2.0 Hz), 6.56 (1H, s), 6.76
(1H, d, J=8.1 Hz), 7.29-7.40 (5H, m) [2479] MASS (APCI): 444
(M+H).sup.+, 402, 354 Preparation 96
[2480] The following compound was obtained according to a similar
manner to that of Preparation 28.
[2481] (D,L)-N-Acetyl-4-benzyloxy-3-methoxy-DL-phenylalanine [2482]
mp: 125.0-130.0.degree. C. [2483] IR (KBr): 3316, 3200-2500, 1714,
1652, 1544 cm.sup.-1 [2484] NMR (DMSO-d.sub.6, .delta.): 1.79 (3H,
s), 2.76 (1H, dd, J=9. 6 and 13.7 Hz), 2.96 (1H, dd, J=4.8 and 13.7
Hz), 3.74 (3H, S s), 4.35-4.37 (1H, m), 5.02 (2H, s), 6.71 (1H, dd,
J=1.8 and 8.2 Hz), 6.86 (1H, d, J=1.8 Hz), 6.92 (1H, d, J=8.2 Hz),
7.31-7.45 (5H, m), 8.15 (1H, d, J=8.0 Hz), 12.63 (1H, br s) [2485]
MASS (APCI): 344 (M+H).sup.+, 302 Preparation 97 [2486]
(D)-N-Acetyl-4-benzyloxy-3-methoxy-D-phenylalanine [2487]
[.alpha.].sub.D.sup.26: -14.3.degree. (C=0.5, DMF) [2488] mp:
148.0-149.0.degree. C. [2489] IR (KBr): 3324, 3200-2700, 1741,
1616, 1550, 1513, 1398 cm.sup.-1 [2490] NMR (DMSO-d.sub.6,
.delta.): 1.79 (3H, s), 2.76 (1H, dd, J=9.2 and 13.9 Hz), 2.97 (1H,
dd, J=4.8 and 13.9 Hz), 3.74 (3H, s), 4.31-4.42 (1H, m), 5.02 (2H,
s), 6.71 (1H, dd, J=1.8 and 8.2 Hz), 6.86 (1H, d, J=1.8 Hz), 6.92
(1H, d, J=8.2 Hz), 7.28-7.45 (5H, m), 8.14 (1H, d, J=8.2 Hz), 12.85
(1H, br s) [2491] MASS (APCI): 344 (M+H).sup.+, 372 Preparation
98
[2492] The following compound was obtained according to a similar
manner to that of Preparation 17. [2493]
4-Hydroxy-3-methoxy-D-phenylalanine hydrochloride [2494] mp:
188-200.degree. C. [2495] IR (KBr): 3500-3150, 2700-2300, 1739,
1589, 1488 cm.sup.-1 [2496] NMR (D.sub.2O, .delta.): 3.13 (1H, dd,
J=7.6 and 14.6 Hz), 3.28 (1H, dd, J=5.8 and 14.6 Hz), 3.85 (3H, s),
4.28 (1H, dd, J=5.8 and 7.6 Hz), 6.77-6.95 (3H, m) [2497] MASS
(APCI): 212 (M+H).sup.+, (free) Preparation 99
[2498] Di-tert-butyl dicarbonate (2.55 g) was added to a solution
of 4-hydroxy-3-methoxy-D-phenylalanine hydrochloride (2.2 g) and
triethylamine (2.9 ml) in a mixture of acetone (25 ml) and water
(25 ml). After being stirred at room temperature for 5 hours, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was separated, dried over magnesium
sulfate and evaporated under reduced pressure to give
N-tert-butyloxycarbonyl-4-hydroxy-3-methoxy-D-phenylalanine (2.6 g)
as an oil. [2499] NMR (CDCl.sub.3, .delta.): 1.42 (9H, s),
2.82-3.20 (2H, m), 3.83 (3H, s), 4.20-5.50 (2H, m), 6.56-6.68 (2H,
m), 6.83 (1H, d, J=8.5 Hz), 7.23 (1H, s) [2500] MASS (APCI): 212
(M+H-Boc).sup.+, 195 Preparation 100
[2501] Benzyl bromide (2.34 ml, 19.8 ml) was added to a solution of
N-tert-butyloxycarbonyl-4-hydroxy-3-methoxy-D-phenylalanine (3.44
g) and N,N-diisopropylethylamine (3.85 ml) in N,N-dimethylformamide
(20 ml). After being stirred at room temperature for 6 hours, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was separated, dried over magnesium
sulfate and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel using a mixture of
hexane and ethyl acetate (4:1) to give
(2R)-2-(tert-butyloxycarbonylamino)-3-(4-hydroxy-3-methoxyphenyl)propioni-
c acid benzyl ester (2.98 g) as colorless powders. [2502] IR (KBr):
3438, 3378, 2700-2300, 1725, 1683, 1521, 1488 cm.sup.-1 [2503] NMR
(CDCl.sub.3, .delta.): 1.41 (9H, s), 3.03 (2H, d, J=5.8 Hz), 3.76
(3H, s), 4.45-4.55 (1H, m), 4.95-5.05 (1H, m), 5.09 (1H, d, J=12.5
Hz), 5.18 (1H, d, J=12.5 Hz), 5.53 (1H, s), 6.56-6.68 (2H, m), 6.76
(1H, d, J=8.0 Hz), 7.25-7.36 (5H, m) [2504] MASS (APCI): 302
(M+H-Boc).sup.+ Preparation 101
[2505] 4N Hydrogen chloride in 1,4-dioxane solution (9 ml) was
added to an ice-cooled solution of
(2R)-2-(tert-butyloxycarbonylamino)-3-(4-hydroxy-3-methoxyphenyl)propioni-
c acid benzyl ester (2.90 g) in dichloromethane (29 ml). After
being stirred at the same temperature for 2 hours, the mixture was
concentrated under reduced pressure to give
(2R)-2-amino-3-(4-hydroxy-3-methoxyphenyl)propionic acid benzyl
ester hydrochloride (2.8 g) as an oil. [2506] NMR (DMSO-d.sub.6,
.delta.): 3.00-3.10 (2H, m), 3.70 (3H, s), 4.31 (1H, t, J=6.2 Hz),
5.18 (2H, s), 6.54 (1H, dd, J=1.7 and 8.0 Hz), 6.68 (1H, d, J=8.0
Hz), 6.81 (1H, d, J=1.7 Hz), 7.29-7.39 (5H, m), 8.57 (3H, br s),
8.97 (1H, s) [2507] MASS (APCI): 301 (M+H).sup.+ (free) Preparation
102
[2508] The following compound was obtained according to a similar
manner to that of Preparation 19.
[2509]
(2R)-2-[N-(Chloroacetyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propio-
nic acid benzyl ester
Preparation 103
[2510] The following compound was obtained according to a similar
manner to that of the first half of Preparation 20.
[2511]
(2R)-2-[N-[(Benzylamino)acetyl]amino]-3-(4-hydroxy-3-methoxyphenyl-
)propionic acid benzyl ester
Preparation 104
[2512] The following compound was obtained according to a similar
manner to that of the second half of Preparation 20.
[2513]
(3R)-1-Benzyl-3-(4-hydroxy-3-methoxybenzyl)piperazine-2,5-dione
[2514] [.alpha.].sub.D.sup.26: -5.2.degree. (C=0.5, DMF) [2515] mp:
225.0-226.0.degree. C. [2516] IR (KBr): 3335, 1677, 1515, 1463,
1276, 1185 cm.sup.-1 [2517] NMR (DMSO-d.sub.6, .delta.): 2.73 (1H,
d, J=17.2 Hz), 2.78 (1H, dd, J=4.6 and 13.6 Hz), 3.04 (1H, dd,
J=4.6 and 13.6 Hz), 3.42 (1H, d, J=17.2 Hz), 3.66 (3H, s), 4.28
(1H, m), 4.27 (1H, d, J=14.6 Hz), 4.47 (1H, d, J=14.6 Hz), 6.43
(1H, dd, J=1.8 and 8.0 Hz), 6.54 (1H, d, J=8.0 Hz), 6.67 (1H, d,
J=1.8 Hz), 7.05-7.31 (5H m), 8.31 (1H, br s), 8.84 (1H, s) [2518]
MASS (APCI): 341 (M+H).sup.+ Preparation 105
[2519] Lithium aluminum hydride (614 mg) was added to a suspension
of (3R)-1-benzyl-3-(4-hydroxy-3-methoxybenzyl)piperazine-2,5-dione
(1.1 g) in tetrahydrofuran (40 ml) at room temperature. After being
stirred under reflux for 5 hours, the reaction mixture was treated
with 2N sodium hydroxide (5 ml) under nitrogen atmosphere. The
whole mixture was diluted with water (40 ml) and thereto
3,5-bis(trifluoromethyl)benzoyl chloride (1.6 ml) was added
dropwise under ice-cooling. After being stirred for 30 minutes, the
resulting mixture was extracted with ethyl acetate. The organic
layer was separated, dried over magnesium sulfate and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel using a mixture of hexane and ethyl
acetate (4:1) to give the objective
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-hydroxy-3-methoxyb-
enzyl)piperazine and its 3,5-bis(trifluoromethyl)benzoate, which
was converted to the objective compound by treatment with a mixture
of 1N sodium hydroxide and methanol. [2520] NMR (CDCl.sub.3,
.delta.): 2.20-4.55 (14H, m), 6.20-7.90 (12H, m) [2521] MASS
(APCI): 553 (M+H).sup.+ Preparation 106
[2522] Trifluoromethane sulfonic acid anhydride (5.25 ml) was added
dropwise over 30 minutes to an ice-cooled solution of
(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-hydroxy-3-methoxyb-
enzyl)piperazine (14.3 g) and 4-(dimethylamino)pyridine (0.47 g)
and 2,6-lutidine (3.6 ml) in dichloromethane (150 ml) below
10.degree. C. After being stirred at the same temperature for 2
hours, the reaction mixture was poured into water. The pH of the
whole mixture was adjusted to 7 with diluted hydrochloric acid and
the organic layer was separated, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using a mixture of toluene and
ethyl acetate (100:1-5:1) to give the objective
trifluoromethanesulfonic acid
4-[[(2R)-1-[3,5-bis(trifluoro-methyl)benzoyl]-4-benzylpiperazin-2-yl]meth-
yl]-2-methoxyphenyl ester as an oil.
Preparation 107
[2523] Carbon monoxide was introduced by bubbling to a mixture of
trifluoromethanesulfonic acid
4-([(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-benzylpiperazin-2-yl]methy-
l-2-methoxyphenyl ester (15.0 g), palladium acetate (150 mg),
1,3-bis(diphenylphosphino)propane (275 mg) and triethylamine (4.28
ml) in a mixed solvent of methanol (30 ml) and
N,N-dimethylformamide (75 ml) at room temperature for 1 hour. The
mixture was warmed to 70.degree. C. and stirred under carbon
monoxide atmosphere for 3 hours. The resulting mixture was filtered
through Celite.RTM. and the residue was washed with ethyl acetate.
The filtrate and washings were combined and evaporated under
reduced pressure. The residue was dissolved into ethyl acetate and
the solution was washed with water and brine successively, dried
over magnesium sulfate, and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel using a
mixed solvent of toluene and hexane as eluent. The fractions
containing the objective compound was collected and evaporated
under reduced pressure to give a syrup, which was treated with 4N
hydrogen chloride in ethyl acetate to give a powder of
4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-benzylpiperazin-2-yl]methy-
l]-2-methoxybenzoic acid methyl ester hydrochloride (7.71 g).
[2524] mp: 100-102.degree. C. [2525] IR (KBr): 3335, 1720, 1648,
1614, 1459, 1427, 1185 cm.sup.-1 [2526] NMR (DMSO-d.sub.6,
.delta.): 2.95-5.20 (11H, m), 3.41 (3H, s), 3.75 (3H, s), 6.40-8.25
(11H, m), 11.50-11.80 (1H, m) [2527] MASS (API-ES): 617 (M+Na,
free).sup.+, 595 (M+H, free).sup.+ Preparation 108
[2528] The following compound was obtained according to a similar
manner to that of Preparation 22.
[2529]
4-[[(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-benzylpiperazin-2-y-
l]methyl]-2-hydroxybenzoic acid methyl ester [2530] IR (Neat):
1677, 1643, 1438, 1280 cm.sup.-1 [2531] NMR (CDCl.sub.3, .delta.):
2.00-5.10 (11H, m), 3.93 (3H, s), 6.20-7.90 (11H, m), 10.71 (1H, br
s) [2532] MASS (API-ES): 603 (M+Na).sup.+, 581 (M+H).sup.+
Preparation 109
[2533] tert-Butyldimethylsilyl chloride (2.34 g) was added to a
solution of
4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-piperazin-2-yl]methyl]-2--
hydroxybenzoic acid methyl ester (2.56 g),
4-(dimethylamino)pyridine (126 mg) and triethylamine (2.51 ml) in
dichloromethane (50 ml) at room temperature. After stirring at room
temperature for 15 hours, additional triethylamine (2.51 ml) and
tert-butyldimethylsilyl chloride (2.34 g) were added and the whole
mixture was stirred for further 1 day. Water (200 ml) was added to
the mixture, and the resulting mixture was extracted with
dichloromethane. The organic extracts were washed with water and
brine successively, dried over magnesium sulfate, and evaporated
under reduced pressure to give crude oil. The oil was purified by
column chromatography on silica gel using a mixed solvent of
dichloromethane and methanol to give
4-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]piperazin-2-yl]-methyl]-2-(ter-
t-butyldimethylsilyloxy)benzoic acid methyl ester (1.72 g). [2534]
IR (Neat): 2955, 1727, 1639, 1436, 1280 cm.sup.-1 [2535] NMR
(CDCl.sub.3, .delta.): 0.10-0.30 (6H, m), 1.00 (9H, s), 2.80-5.10
(9H, m), 3.85 (3H, s), 6.30-7.90 (6H, m) [2536] MASS (APCI): 605
(M+H).sup.+, 573, 491 Preparation 110
[2537] To a solution of
(2R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid
(5.14 g) in dichloromethane (50 ml) was added triethylamine (8.49
ml), N-benzylglycine benzyl ester hydrochloride (5.08 g), and
2-chloro-1-methylpyridinium iodide (4.89 g) under ice-bath cooling.
After being stirred at room temperature 90 minutes, the reaction
mixture was concentrated under reduced pressure, and ethyl acetate
(50 ml) and water (50 ml) were added to the residue with stirring,
adjusted pH 1 with diluted hydrochloric acid. The organic layer was
separated, washed with brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel (100 g) using a
mixed solvent of toluene and ethyl acetate (10:1). The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
N-benzyl-N-(benzyloxycarbonylmethyl)-(2R)-2-(tert-butoxycarbonylamino)-3--
(4-methoxyphenyl)propionamide (8.57 g) as a syrup. [2538]
[.alpha.].sub.D.sup.24.0: +6.60.degree. (C=0.50, MeOH) [2539] IR
(Neat): 3300, 1740, 1700, 1650, 1240 cm.sup.-1 [2540] NMR
(DMSO-d.sub.6, .delta.): 1.27 and 1.31 (9H, s, s), 2.76 (2H, m),
3.69 and 3.70 (3H, s, s), 3.95-4.90 (5H, m), 5.13 (2H, m),
6.70-7.36 (15H, m) [2541] MASS (APCI): 533 (M+H).sup.+ Preparation
111
[2542] 4N Hydrogen chloride in 1,4-dioxane solution (48 ml) was
added dropwise to a solution of
N-benzyl-N-benzyloxycarbonylmethyl-(2R)-2-(tert-butoxycarbonylamino)-3-(4-
-methoxyphenyl)propionamide (8.48 g) in dichloromethane (48 ml)
under ice-bath cooling. After being stirred for 2 hours at the same
temperature, the reaction mixture was concentrated under reduced
pressure. The residue was added to aqueous sodium bicarbonate
solution (50 ml) and dichloromethane (50 ml), and the organic layer
was separated, washed with brine, dried over sodium sulfate, and
evaporated under reduced pressure to give a powder of
(3R)-1-benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione (3.65 g).
[2543] [.alpha.].sub.D.sup.27.9: -38.6.degree. (C=0.50, MeOH)
[2544] IR (Nujol): 3250, 1680, 1640, 1245 cm.sup.-1 [2545] NMR
(DMSO-d.sub.6, .delta.): 2.60 (1H, d, J=17 Hz), 2.80 (!H, dd, J=4.7
and 14 Hz), 3.09 (1H, dd, J=3.8 and 14 Hz), 3.46 (1H, d, J=17 Hz),
3.67 (3H, s), 4.11 (1H, d, J=14 Hz), 4.22 (1H, br), 4.65 (1H, d,
J=14 Hz), 6.63 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.7 Hz), 7.10-7.40
(5H, m), 8.30 (1H, br) [2546] MASS (APCI): 325 (M+H).sup.+
Preparation 112
[2547] Under nitrogen atmosphere, to a suspension of lithium
aluminum hydride (0.85 g) in tetrahydrofuran (65 ml) was added
(3R)-1-benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione (3.65 g)
portionwise under ice-bath cooling. The reaction mixture was
refluxed with stirring for one hour. After cooling, it was quenched
by sequential addition of water (0.85 ml), 15% aqueous sodium
hydroxide (0.85 ml), and water (2.5 ml) and the whole was stirred
at room temperature for 30 minutes. The resulting insoluble
material was removed by filtration, and the filtrate was added to a
mixture of ethyl acetate (50 ml) and brine (70 ml). The organic
layer was separated, dried over magnesium sulfate, and concentrated
under reduced pressure to give
(2R)-2-(4-methoxybenzyl)-4-benzylpiperazine (3.51 g) as a syrup.
[2548] IR (Neat): 3250, 1240 cm.sup.-1 [2549] NMR (DMSO-d.sub.6,
.delta.): 1.60-2.00 (4H, m), 2.40-2.90 (5H, m), 3.30-3.50 (2H, m),
3.70 (3H, s), 6.81 (2H, d, J=8.6 Hz), 7.07 (2H, d, J=8.6 Hz),
7.15-7.40 (6H, m) [2550] MASS (APCI): 297 (M+H).sup.+ Preparation
113
[2551] To a solution of 3,5-bis(trifluoromethyl)benzoic acid (3.04
g) and pyridine (0.030 ml) in tetrahydrofuran (9 ml) was added
dropwise oxalyl chloride (1.80 g) over 5 minutes, and the reaction
mixture was heated at 55.degree. C. with stirring for one hour.
After cooling, the solution was added dropwise to a solution of
(2R)-2-(4-methoxybenzyl)-4-benzylpiperazine (3.47 g) and
triethylamine (3.55 g) in dichloromethane (35 ml) below 5.degree.
C. over 30 minutes under nitrogen atmosphere. The reaction mixture
was stirred at room temperature for one hour, and concentrated
under reduced pressure. To the residue were added ethyl acetate (40
ml) and water (20 ml) with stirring. The organic layer was
separated, washed with brine, and dried over magnesium sulfate.
After removal of the solvent by evaporation, the resulting residue
was purified by column chromatography on silica gel (70 g) using a
mixed solvent of toluene and ethyl acetate (5:1). The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-benzylpipe-
razine (5.03 g) as syrup. [2552] [.alpha.].sub.D.sup.28.0:
-21.4.degree. (C=0.50, MeOH) [2553] IR (Neat): 1740, 1640, 1270
cm.sup.-1 [2554] NMR (DMSO-d.sub.6, .delta.): 1.70-2.40 (3H, m),
2.60-3.80 (11H, m), 6.60-7.60 (10H, m), 7.65-8.55 (2H, m) [2555]
MASS (APCI): 537 (M+H).sup.+ Preparation 114
[2556] To a solution of
(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(4-methoxybenzyl)-4-benzylpip-
erazine (4.90 g) in ethanol (50 ml) were added water (5 ml),
ammonium formate (1.44 g), and 10% palladium on activated carbon
[50% wet] (0.49 g) under nitrogen atmosphere. The reaction mixture
was heated at 60.degree. C. with stirring for 2 hours. Insoluble
material was removed by filtration, and the filtrate was
concentrated under reduced pressure. Ethyl acetate (40 ml) and
water (40 ml) were added to the residue, and the organic layer was
separated, washed with brine, and dried over magnesium sulfate.
After removal of the solvent by evaporation, the resulting residue
was purified by column chromatography on silica gel (70 g) using a
mixed solvent of ethyl acetate and methanol (10:1). The fractions
containing the objective compound were collected and evaporated
under reduced pressure to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)piperazine
(3.18 g) as syrup. [2557] [.alpha.].sub.D.sup.28.1: -32.6.degree.
(C=0.50, MeOH) [2558] IR (Neat): 3300, 1630, 1280 cm.sup.-1 [2559]
NMR (DMSO-d.sub.6, .delta.): 2.40-3.55 (9H, m), 3.72 (3H, s),
6.70-8.45 (7H, m) [2560] MASS (APCI): 447 (M+H).sup.+ Preparation
115
[2561] The following compounds were obtained according to a similar
manner to that of Preparation 56. [2562] (1)
(2R)-4-Benzyl-1-(tert-butoxycarbonyl)-2-[4-(trifluoromethyl)benzyl]pipera-
zine [2563] NMR (CDCl.sub.3, .delta.): 1.36 (9H, s), 1.98 (1H, dd,
J=11.5 and 3.7 Hz), 2.10 (1H, td, J=12.0 and 3.4 Hz), 2.58 (1H, d,
J=11.5 Hz), 2.83-3.13 (3H, m), 3.20 (1H, td, J=12.8 and 3.4 Hz),
3.26 (1H, d, J=12.8 Hz), 3.58 (1H, d, J=12.8 Hz), 3.80-4.30 (2H,
m), 7.12 (2H, d, J=7.7 Hz), 7.26-7.42 (7H, m) [2564] MASS (APCI):
435 (M+H).sup.+ [2565] (2)
(2R)-4-Benzyl-2-(4-fluoro-3-methoxybenzyl)-1-(tert-butoxycarbonyl)piperaz-
ine [2566] IR (Neat): 1516, 1458, 1400, 1327, 1275, 1217, 1169
cm.sup.-1 [2567] NMR (CDCl.sub.3, .delta.): 1.39 (9H, s), 1.95-2.13
(2H, m), 2.60-3.24 (5H, m), 3.32-3.57 (2H, m), 3.79 (3H, s),
3.90-4.14 (2H, m), 6.52-7.35 (8H, m) [2568] MASS (APCI): 415
(M+H).sup.+ [2569] (3)
(2R)-4-Benzyl-1-(tert-butoxycarbonyl)-2-[4-chloro-3-(tert-butyldimet-
hylsilyloxy)benzyl]piperazine [2570] IR (Neat): 1695, 1480, 1415,
1250, 1170 cm.sup.-1 [2571] (4)
(3S,4S)-1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diol [2572] mp:
156-158.degree. C. [2573] IR (KBr): 3398, 3334, 1662, 1431, 1174,
1122, 1082, 985 cm.sup.-1 [2574] NMR (DMSO-d.sub.6, .delta.): 1.42
(9H, s), 3.10 (2H, br d, J=11.3 Hz), 3.25-3.44 (2H, m), 3.86 (2H,
br s), 5.05 (2H, d, J=3.2 Hz) [2575] MASS (ES+): 429,3
(2M+Na).sup.+, 226.2 (M+Na).sup.+ (free) Preparation 116
[2576] The following compounds were obtained according to a similar
manner to that of Preparation 37. [2577] (1)
4-[(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]piperazin-2-l]methyl]-2-hydrox-
ybenzoic acid methyl ester [2578] IR (Neat): 3083, 1677, 1639,
1438, 1280 cm.sup.-1 [2579] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-(tert-butyldimethylsilyloxy-
)-4-chlorobenzyl]piperazine [2580] mp: 95-97.degree. C. [2581] IR
(KBr): 1954, 1628, 1481, 1437 cm.sup.-1 [2582] NMR (CDCl.sub.3,
.delta.): 0.17 (3H, s), 0.20 (3H, s), 1.01 (9H, s), 2.50-5.10 (9H,
m), 6.30-7.70 (5H, m), 7.87 (1H, s) [2583] MASS (APCI): 581
(M+H).sup.+ [2584] (3)
(2R)-2-[3-(tert-Butyldimethylsilyloxy)-4-chlorobenzyl]-1-[3-chloro-5-(tri-
fluoromethyl)benzoyl]piperazine [2585] IR (Neat): 2954, 2933, 1635,
1483, 1419 cm.sup.-1 [2586] NMR (CDCl.sub.3, .delta.): 0.18 (3H,
s), 0.21 (3H, s), 1.02 (9H, s), 2.50-5.20 (9H, m), 6.20-7.70 (6H,
m) [2587] MASS (APCI): 547 (M+H).sup.+ [2588] (4)
(2R)-1-(tert-Butoxycarbonyl)-2-[4-chloro-3-(tert-butyldimethylsilyloxy)be-
nzyl]piperazine [2589] NMR (DMSO-d.sub.6, .delta.): 0.99 (9H, s),
1.24 (9H, s), 2.15 (6H, s), 2.20-4.10 (9H, m), 6.78-7.33 (3H, m)
[2590] MASS (APCI): 441 (M+H).sup.+ Preparation 117
[2591] The following compounds were obtained according to a similar
manner to that of Preparation 24. [2592] (1)
(2R)-1-(tert-Butoxycarbonyl)-2-[4-(trifluoromethyl)-benzyl]piperazine
[2593] mp: 61-62.degree. C. [2594] IR (KBr): 2981, 2952, 1682,
1417, 1330 cm.sup.-1 [2595] NMR (CDCl.sub.3, .delta.): 1.33 (9H,
s), 2.67-4.40 (9H, m), 7.35 (2H, d, J=8.0 Hz), 7.54 (2H, d, J=8.0
Hz) [2596] MASS (ESI): 345.3 (M+H).sup.+, 289.2 (M-Bu).sup.+ [2597]
(2)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-(tert-butoxycarbonyl)piperazine
[2598] IR (Neat): 1689, 1515, 1414, 1273, 1165, 1115 cm.sup.-1
[2599] NMR (CDCl.sub.3, .delta.): 1.38 (9H, s), 2.70-3.14 (8H, m),
3.87 (3H, s), 3.88-4.18 (2H, m), 6.74-7.26 (3H, m) [2600] MASS
(APCI): 225 (M-Boc+1).sup.+, 269 (M-tBu+1).sup.+ [2601] (3)
(2R)-1-[3-(Dimethylsulfamoyl)-5-(trifluoromethyl)-benzoyl]-2-[4-(trifluor-
omethyl)benzyl]piperazine [2602] IR (KBr): 2956, 1639, 1462, 1423,
1329 cm.sup.-1 [2603] NMR (CDCl.sub.3, .delta.): 2.60-5.20 (9H, m),
2.72 (6H, s), 7.00-7.60 (5H, m), 7.67 (1H, s), 8.00 (1H, s) [2604]
MASS (APCI): 524 (M+H).sup.+ [2605] (4)
(2R)-1-[3-Methylsulfonyl-5-(trifluoromethyl)benzoyl]-2-[4-(trifluoromethy-
l)benzyl]piperazine hydrochloride [2606] mp: 94.5-101.degree. C.
[2607] IR (KBr): 3433, 1645 cm.sup.-1 [2608] NMR (DMSO-d.sub.6,
.delta.): 2.80-5.30 (12H, m), 7.00-8.31 (7H, m) [2609] MASS (APCI):
495 (M+H).sup.+ (free) [2610] (5)
(2R)-2-(3-tert-Butyldimethylsilyloxy-4-methylbenzyl)-1-[3-methoxy-5-(trif-
luoromethyl)benzoyl]piperazine [2611] IR (KBr): 2956, 2935, 1641,
1606 cm.sup.-1 [2612] NMR (CDCl.sub.3, .delta.): 0.14, 0.17 (6H,
s), 0.99 (9H, s), 2.15 (3H, s), 2.50-5.20 (9H, m), 3.81 (3H, s),
6.75-7.13 (6H, m) [2613] MASS (APCI): 523 (M+H).sup.+ Preparation
118
[2614] The following compounds were obtained according to a similar
manner to that of Example 1 using N,N-diisopropylethylamine instead
of potassium carbonate as a base. [2615] (1)
(2R)-1-(tert-Butoxycarbonyl)-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6--
yl)ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine [2616] IR (KBr):
2974, 2935, 2814, 1693 cm.sup.-1 [2617] NMR (CDCl.sub.3, .delta.):
1.35 (9H, s), 2.04-2.17 (2H, m), 2.50-4.30 (17H, m), 7.07 (1H, dd,
J=4.8 and 7.6 Hz), 7.27-7.34 (3H, m), 7.50 (2H, d, J=8.0 Hz), 8.40
(1H, d, J=4.8 Hz) [2618] MASS (APCI): 505 (M+H).sup.+ [2619] (2)
(2R)-1-(tert-Butoxycarbonyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-2-[4-
-(trifluoromethyl)benzyl]-piperazine [2620] IR (Neat): 2974, 1693,
1680 cm.sup.-1 [2621] NMR (CDCl.sub.3, .delta.): 1.19, 1.20 (6H, d,
J=6.2 Hz), 1.32 (9H, s), 2.02-2.21 (4H, m), 2.71-3.31 (11H, m),
3.90-4.50 (4H, m), 7.34 (2H, d, J=7.9 Hz), 7.54 (2H, d, J=7.9 Hz)
[2622] MASS (APCI): 486 (M+H).sup.+ [2623] (3)
(2R)-1-(tert-Butoxycarbonyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl-
]-2-[4-(trifluoromethyl)-benzyl]piperazine [2624] IR (Neat): 3438,
2816, 1691 cm.sup.-1 [2625] NMR (CDCl.sub.3, .delta.): 1.33 (9H,
s), 2.02-4.30 (22H, m), 3.37 (3H, s), 7.35 (2H, d, J=8.0 Hz), 7.54
(2H, d, J=8.0 Hz) [2626] MASS (APCI): 502 (M+H).sup.+ [2627] (4)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-(tert-butoxycarbonyl)-4-[2-(cis-2,
6-dimethylmorpholino) ethyl]-piperazine [2628] IR (Neat): 1515,
1458, 1414, 1367, 1323, 1115, 1086 cm.sup.-1 [2629] NMR
(CDCl.sub.3, .delta.): 1.14 (6H, d, J=1.2 Hz), 1.40 (9H, s),
1.70-2.10 (4H, m), 2.36-3.20 (12H, m), 3.61-4.18 (3H, m), 3.88 (3H,
s), 6.74-7.02 (3H, m) [2630] MASS (APCI): 466 (M+H).sup.+ [2631]
(5)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-(tert-butoxycarbonyl)-4-[2-[(2S)-2-(m-
ethoxymethyl)morpholino]-ethyl]piperazine [2632] IR (Neat): 1516,
1456, 1414, 1273, 1165, 1111, 1036 cm.sup.-1 [2633] NMR
(CDCl.sub.3, .delta.): 1.40 (9H, s), 1.90-4.25 (22H, m), 3.38 (3H,
s), 3.87 (3H, s), 6.69-7.27 (3H, m) [2634] MASS: 482 (M+H).sup.+
[2635] (6)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-(tert-butoxycarbonyl)-4-[2-(5,6,7,8-t-
etrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine [2636] NMR
(DMSO-d.sub.6, .delta.): 1.40 (9H, s), 1.99-2.15 (2H, m), 2.51-3.18
(14H, m), 3.67-4.18 (3H, m), 3.86 (3H, s), 6.73-8.40 (6H, m) [2637]
MASS: 485 (M+H).sup.+ [2638] (7)
(2R)-1-(tert-Butoxycarbonyl)-2-(4-chloro-3-hydroxybenzyl)-4-[2-[(2S)-2-(m-
ethoxymethyl)morpholino]-ethyl]piperazine Preparation 119
[2639] The following compounds were obtained according to a similar
manner to that of Preparation 41. [2640] (1)
(2R)-4-Benzyl-1-[3-(dimethylsulfamoyl)-5-(trifluoro-methyl)benzoyl]-2-[4--
(trifluoromethyl)ben zyl]piperazine [2641] IR (Neat): 1645, 1456,
1419, 1319 cm.sup.-1 [2642] NMR (CDCl.sub.3, .delta.): 2.00-2.40
(2H, m), 2.70-5.10 (9H, m), 2.73 (6H, s), 6.90-7.60 (10H, m), 7.73
(1H, s), 8.01 (1H, s) [2643] MASS (APCI): 614 (M+H).sup.+ [2644]
(2)
(2R)-4-Benzyl-1-[3-methylsulfonyl-5-(trifluoro-methyl)benzoyl]-2-[4-(trif-
luaromethyl)benzyl]piperazine [2645] NMR (CDCl.sub.3, .delta.):
2.00-2.40 (2H, m), 2.70-3.71 (8H, m), 3.06 (3H, s), 4.50-5.10 (1H,
m), 6.80-7.60 (10H, m), 7.86 (1H, s), 8.19 (1H, s) [2646] MASS
(APCI): 585 (M+H).sup.+ [2647] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-benzyl-2-[3-(tert-butyldimethy-
lsilyloxy)-4-chlorobenzyl]piperazine [2648] IR (Neat): 2935, 2860,
2812, 1645, 1483, 1423 cm.sup.-1 [2649] NMR (CDCl.sub.3, .delta.):
0.10-0.30 (6H, br), 1.00 (9H, s), 1.80-5.10 (11H, m), 6.20-8.00
(10H, m), 7.87 (1H, s) [2650] MASS (APCI): 671 (M+H).sup.+ [2651]
(4)
(2R)-4-Benzyl-2-[3-(tert-butyldimethylsilyloxy)-4-chlorobenzyl]-1-[3-chlo-
ro-5-(trifluoromethyl)benzoyl]-piperazine [2652] IR (Neat): 2935,
1641, 1483, 1417 cm.sup.-1 [2653] NMR (CDCl.sub.3, .delta.):
0.10-0.30 (6H, br), 1.01 (9H, s), 1.80-5.00 (11H, m), 6.20-7.70
(10H, m), 7.59 (1H, s) [2654] MASS (APCI): 637 (M+H).sup.+ [2655]
(5)
(2R)-4-Benzyl-2-[3-(tert-butyldimethylsilyloxy)-4-methylbenzyl]-1-[3-meth-
oxy-5-(trifluoromethyl)benzoyl]-piperazine [2656] IR (KBr): 1643,
1464, 1421, 1267 cm.sup.-1 [2657] NMR (CDCi.sub.3, .delta.): 0.09
(6H, br s), 0.98 (9H, s), 2.04-2.21 (2H, m), 2.14 (3H, s),
2.60-5.10 (12H, m), 6.24-7.36 (11H, m) [2658] MASS (APCI). 613
(M+H).sup.+ Preparation 120
[2659] The following compounds were obtained according to a similar
manner to that of Preparation 59. [2660] (1)
(2R)-4-[2-(5,6,7,8-Tetrahydro-1,6-naphthyridin-6-yl)-ethyl]-2-[4-(trifluo-
romethyl)benzyl]piperazine tetrahydrochloride [2661] NMR
(DMSO-d.sub.6, .delta.): 3.03-4.00 (19H, m), 7.57 (2H, d, J=8.1
Hz), 7.75 (2H, d, J=8.1 Hz), 7.85 (1H, dd, J=7.7 and 5.6 Hz), 8.29
(1H, d, J=7.7 Hz), 8.78 (1H, d, J=5.6 Hz) [2662] MASS (APCI): 405
(M+H).sup.+ (free) [2663] (2)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-2-[4-(trifluoromethyl)benzyl-
]piperazine trihydrochloride [2664] mp: >250.degree. C. [2665]
IR (KBr): 2563, 2426, 1456, 1327 cm.sup.-1 [2666] NMR (CDCl.sub.3,
.delta.): 1.11 (6H, d, J=6.2 Hz), 2.59-4.50 (19H, m), 7.56 (2H, d,
J=8.1 Hz), 7.75 (2H, d, J=8.1 Hz) [2667] MASS (APCI): 386
(M+H).sup.+ (free) [2668] (3)
(2R)-4-[2-[(2S)-2-(Methoxymethyl)morpholino]ethyl]-2-[4-(trifluoromethyl)-
benzyl]piperazine trihydrochloride [2669] mp: 80-95.degree. C.
[2670] IR (KBr): 1695, 1516 cm.sup.-1 [2671] NMR (DMSO-d.sub.6,
.delta.): 2.80-4.60 (25H, m), 7.56 (2H, d, J=8.1 Hz), 7.75 (2H, d,
J=8.1 Hz) [2672] MASS (APCI): 402 (M+H).sup.+ (free) [2673] (4)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-
piperazine trihydrochloride [2674] IR (KBr): 1610, 1517, 1452,
1425, 1367, 1326, 1274 cm.sup.-1 [2675] NMR (DMSO-d.sub.6,
.delta.): 1.11 (6H, d, J=6.0 Hz), 2.49-4.40 (21H, m), 3.86 (3H, s),
6.87-7.24 (3H, m), 9.55-10.06 (2H, m) [2676] MASS: 366 (M+H).sup.+
(free) [2677] (5)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-[(2S)-2-(methoxy-methyl)morpholino-
]ethyl]piperazine trihydrochloride [2678] IR (KBr): 3465, 3435,
3400, 1615, 1515, 1455, 1270, 1235 cm.sup.-1 [2679] NMR
(DMSO-d.sub.6, .delta.): 2.65-4.20 (22H, m), 3.27 (3H, s), 3.86
(3H, s), 6.82-7.23 (3H, m) [2680] MASS (APCI): 382 (M+H).sup.+
(free) [2681] (6)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyrid-
in-6-yl)ethyl]piperazine tetrahydrochloride [2682] IR (KBr): 1515,
1464, 1269, 1153, 1095 cm.sup.-1 [2683] NMR (CDCl.sub.3, .delta.):
2.60-4.50 (22H, m), 3.84 (3H, s), 6.85-10.0 (8H, m) [2684] MASS:
385 (M+H).sup.+ (free) [2685] (7)
(2R)-2-(4-Chloro-3-hydroxybenzyl)-4-[2-[(2S)-2-(methoxy-methyl)morpholino-
]ethyl]piperazine trihydrochloride [2686] IR (KBr): 1645, 1450,
1425, 1370, 1236, 1140 cm.sup.-1 [2687] NMR (DMSO-d.sub.6,
.delta.): 2.64-4.50 (22H, m), 3.27 (3H, s), 6.71-7.32 (3H, s)
[2688] MASS (APCI): 384 (M+H).sup.+ (free) [2689] (8)
(3S,4S)-3,4-Dimethoxypyrrolidine hydrochloride [2690] mp:
168.degree. C. [2691] IR (KBr): 3464, 2900-2350, 1198, 1109, 1065,
1024 cm.sup.-1 [2692] NMR (DMSO-d.sub.6, .delta.): 3.05-3.35 (4H,
m), 3.31 (6H, s), 4.00 (2H, d, J=3.5 Hz), 9.67 (2H, br s) [2693]
MASS (APCI): 132 (M+H).sup.+ (free) Preparation 121
[2694] 2-Bromoethanol (310 mg) was added to a solution of
(2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
(1 g) in acetonitrile (10 ml). The reaction mixture was stirred at
70.degree. C. for 19 hours. The mixture was filtered, and the
residue on filter was washed with dichloromethane twice. The
filtrate and combined washings were concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted
with methanol in dichloromethane (2% then 5%) to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-hydroxyethyl)-2-[4-(tr-
ifluoromethyl)benzyl]piperazine (927 mg) as an amorphous powder.
[2695] IR (Neat): 3462, 3435, 2949, 2817, 1637, 1439 cm.sup.-1
[2696] NMR (CDCl.sub.3, .delta.): 2.1-5.2 (14H, m), 6.9-8.0 (7H, m)
[2697] MASS (APCI): 529 (M+H).sup.+ Preparation 122
[2698] The following compound was obtained according to a similar
manner to that of Preparation 121.
[2699]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenz-
yl)-4-(2-hydroxyethyl)piperazine [2700] IR (Neat): 2945, 2817,
1639, 1518, 1442 cm.sup.-1 [2701] NMR (CDCl.sub.3,
.delta.):-2.20-5.10 (13H, m), 4.52 (3H, s), 6.30-7.89 (6H, m)
[2702] MASS (APCI): 509 (M+H).sup.+ Preparation 123
[2703] The following compounds were obtained according to a similar
manner to that of Preparation 9. [2704] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(2-chloroethyl)-2-[4-(trifluor-
omethyl)benzyl]piperazine hydrochloride [2705] IR (KBr): 3437,
3429, 2561, 1649, 1427 cm.sup.-1 [2706] NMR (DMSO-d.sub.6,
.delta.): 2.20-5.40 (13H, m), 7.10-8.30 (7H, m) [2707] MASS (APCI):
547 (M+H).sup.+ (free) [2708] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(2-chloroethyl)-2-(4-fluoro-3--
methoxybenzyl)piperazine hydrochloride [2709] mp: 75-79.degree. C.
[2710] IR (KBr): 1647, 1518, 1427 cm.sup.-1 [2711] NMR
(DMSO-d.sub.6, .delta.): 2.75-5.20 (13H, m), 4.49 (3H, s),
6.50-8.23 (6H, m) [2712] MASS (APCI): 527 (M+H).sup.+ (free)
Preparation 124
[2713] The following compound was obtained according to a similar
manner to that of Preparation 57.
[2714]
(2R)-4-Benzyl-2-[3-(tert-butyldimethylsilyloxy)-4-methylbenzyl]pip-
erazine [2715] IR (Neat): 2952, 2933, 2856, 1504 cm.sup.-1 [2716]
NMR (DMSO-d.sub.6, .delta.): 0.21 (6H, s), 1.02 (9H, s), 1.66-2.00
(2H, m), 2.13 (3H, s), 2.49-2.85 (4H, m), 3.37-3.41 (5H, m), 6.63
(1H, s), 6.69 (1H, d, J=7.6 Hz), 7.05 (1H, d, J=7.6 Hz), 7.25-7.40
(5H, m) [2717] MASS (ESI+): 411.4 (M+H).sup.+ Preparation 125
[2718] A solution of (2S,
4R)-1-benzyl-4-hydroxy-2-(hydroxymethyl)pyrrolidine (1.49 g) in
N,N-dimethylformamide (10 ml) was added to a suspension of sodium
hydride (60% dispersion in mineral oil, 689 mg) in
N,N-dimethylformamide (5 ml) dropwise at ambient temperature. The
reaction mixture was stirred at the same temperature for 1 hour. To
the reaction mixture was added methyl iodide (2.55 g) in
N,N-dimethylformamide (3 ml) dropwise. After stirring at ambient
temperature for 2 hours, the reaction mixture was poured into ice
water, and the whole was extracted with ethyl acetate twice. The
combined organic layer was washed successively with a mixture of
saturated aqueous sodium bicarbonate solution and 5% aqueous sodium
thiosulfate solution, and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with methanol in dichloromethane 1% then 2% to give (2S,
4R)-1-benzyl-4-methoxy-2-(methoxymethyl)pyrrolidine (1.07 g) as an
oil. [2719] IR (Neat): 2877, 2817, 1452 cm.sup.-1 [2720] NMR
(CDCl.sub.3, .delta.): 1.79-2.02 (2H, m), 2.26 (1H, dd, J=9.9 and
5.6 Hz), 2.88-3.01 (1H, m), 3.19-3.49 (4H, m), 3.25 (3H, s), 3.35
(3H, s), 3.86 (1H, m), 4.10 (1H, d, J=13.1 Hz), 7.20-7.33 (5H, m)
[2721] MASS (APCI): 236 (M+H).sup.+ Preparation 126
[2722] The following compounds were obtained according to a similar
manner to that of Preparation 15. [2723] (1)
(2S,4R)-4-Methoxy-2-(methoxymethyl)pyrrolidine [2724] IR (Neat):
3342, 2881, 1668, 1444 cm.sup.-1 [2725] NMR (CDCl.sub.3, .delta.):
1.55 (1H, m), 1.93 (1H, dd, J=13.6 and 7.1 Hz), 2.88-3.09 (2H, m),
3.24-3.52 (3H, m), 3.29 (3H, s), 3.36 (3H, s), 3.89 (1H, m) [2726]
MASS (APCI): 146 (M+H).sup.+ [2727] (2)
(3S,4S)-Pyrrolidine-3,4-diol hydrochloride [2728] mp: 69-73.degree.
C. [2729] IR (KBr): 3400, 1622, 1442, 1238, 1109, 1030, 989
cm.sup.-1 [2730] NMR (DMSO-d.sub.6-D.sub.2O, .delta.): 3.05 (2H, d,
J=12.1 Hz), 3.28 (2H, dd, J=12.1 and 3.2 Hz), 4.10 (2H, d, J=3.2
Hz) [2731] MASS (APCI): 104 (M+H).sup.+ (free) [2732] (3)
cis-2,6-Dimethoxymethylpiperidine hydrochloride [2733] mp:
200-202.degree. C. [2734] IR (KBr): 3402, 2941, 2821, 2735, 1645,
1516, 1456 cm.sup.-1 [2735] NMR (DMSO-d.sub.6, .delta.): 1.30-1.90
(6H, m), 3.10-3.40 (2H, m), 3.30 (6H, s), 3.54 (4H, d, J=5.3 Hz)
[2736] MASS (APCI): 1.74 (M+H).sup.+ (free) [2737] (4)
cis-3,5-Dimethoxymethylpiperidine hydrochloride [2738] mp:
220-222.degree. C. [2739] IR (KBr): 2939, 2806, 2783, 1460, 1392
cm.sup.-1 [2740] NMR (DMSO-d.sub.6, .delta.): 0.99 (1H, q, J=12.4
Hz), 1.69 (1H, m), 1.90-2.25 (2H, m), 2.50 (2H, t, J=12.3 Hz),
3.10-3.40 (6H, m), 3.23 (6H, s) [2741] MASS (APCI): 174 (M+H).sup.+
(free) [2742] (5) cis-2,6-Dimethoxymethylmorpholine hydrochloride
[2743] IR (Neat): 2935, 2819, 1595, 1513, 1456 cm.sup.-1 [2744] NMR
(CDCl.sub.3, .delta.): 2.73 (2H, t, J=12.0 Hz), 3.18 (2H, d, J=12.0
Hz), 3.35 (6H, s), 3.35-3.46 (4H, m), 3.92-4.05 (2H, m) [2745] MASS
(APCI): 176 (M+H).sup.+ (free) [2746] (6)
2,2-Dimethoxymethylmorpholine hydrochloride [2747] IR (Neat): 2935,
2522, 1594, 1454 cm.sup.-1 [2748] NMR (CDCl.sub.3, .delta.):
2.92-3.00 (4H, m), 3.29 (6H, s), 3.46 (2H, d, J=10.2 Hz), 3.51 (2H,
d, J=10.2 Hz), 3.81-3.86 (2H, m) [2749] MASS (APCI): 176
(M+H).sup.+ (free) [2750] (7) 8-Oxa-3-azabicyclo[3.2.1]octane
hydrochloride [2751] mp: 205-207.5.degree. C. [2752] IR (KBr):
2920, 2792, 1591, 1442 cm.sup.-1 [2753] NMR (DMSO-d.sub.6,
.delta.): 1.85-2.18 (4H, m), 2.97-3.08 (4H, m), 4.39-4.40 (2H, m)
[2754] MASS (APCI): 114 (M+H).sup.+ (free) Preparation 127
[2755] The following compounds were obtained according to a similar
manner to that of Preparation 89. [2756] (1)
(2S,4R)-1-(2-Hydroxyethyl)-4-methoxy-2-(methoxymethyl)-pyrrolidine
[2757] IR (Neat): 3400, 2881, 1660, 1458, 1379 cm.sup.-1 [2758] NMR
(CDCl.sub.3, .delta.): 1.77 (1H, m), 2.00 (1H, m), 2.45 (1H, dd,
J=110.4, 4.5 Hz), 2.62 (1H, dt, J=12.7, 3.7 Hz), 2.95-3.11 (2H, m),
3.29-3.45 (3H, m), 3.30 (3H, s), 3.36 (3H, s), 3.50-3.70 (2H, m),
3.90 (1H, m) [2759] MASS (APCI): 190 (M+H).sup.+ [2760] (2)
2,2-Dimethyl-4-(2-hydroxyethyl)morpholine [2761] IR (Neat): 2972,
2941, 1458, 1387 cm.sup.-1 [2762] NMR (CDCl.sub.3, .delta.): 1.26
(6H, s), 2.31 (2H, s), 2.45-2.54 (4H, m), 3.63 (2H, t, J=5.1 Hz),
3.77 (2H, t, J=5.1 Hz) [2763] MASS (APCI): 160 (M+H).sup.+ [2764]
(3) (3S,4S)-1-(2-Bromoethyl)-3,4-dimethoxypyrrolidine hydrochloride
Preparation 128
[2765] The following compounds were obtained according to a similar
manner to that of Preparation 90. [2766] (1)
(2S,4R)-1-(2-Chloroethyl)-4-methoxy-2-(methoxymethyl)-pyrrolidine
hydrochloride [2767] IR (Neat): 3400, 2939, 1645, 1450 cm.sup.-1
[2768] NMR (DMSO-d.sub.6, .delta.): 1.80 (1H, m), 2.23 (1H, m),
3.26 (3H, s), 3.32 (3H, s), 3.20-4.20 (10H, m) [2769] MASS (APCI):
208 (M+H).sup.+ (free) [2770] (2)
2,2-Dimethyl-4-(2-chloroethyl)morpholine hydrochloride [2771] mp:
180-185.degree. C. [2772] IR (KBr): 2978, 2677, 2630, 2584, 1456
cm.sup.-1 [2773] NMR (DMSO-d.sub.6, .delta.): 1.18 (3H, s), 1.44
(3H, s), 2.80-3.10 (2H, m), 3.30-3.91 (6H, m), 4.10 (2H, t, J=6.9
Hz) [2774] MASS (APCI): 178 (M+H).sup.+ (free) [2775] (3)
(3S,4S)-1-(2-Chloroethyl)-3,4-dimethoxypyrrolidine hydrochloride
[2776] IR (Neat): 3400, 2563, 2440, 1637, 1460, 1113 cm.sup.-1
[2777] NMR (DMSO-d.sub.6, .delta.): 3.20-3.86 (6H, m), 3.32 (6H,
s), 3.92-4.16 (4H, m), 11.44 (1H, s) [2778] MASS (APCI): 194
(M+H).sup.+ (free) Preparation 129
[2779] A solution of 3-dimethylamino-1H-pyrrolo[3,2-b]pyridine
(1.53 g) and hexamethylenetetramine (1.22 g) in 6.68 g of 66%
propionic acid was added dropwise to a refluxing solution of 2.44 g
of hexamethylenetetramine in 8.92 g of the same solvent. The
addition was carried out over a period of one hour and the solution
was refluxed 3.5 hours more. The solution was concentrated in vacuo
and thereto water (30 ml), ethyl acetate (25 ml), and
tetrahydrofuran (20 ml) were added. The organic layer was
separated, dried over sodium sulfate, and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel (12 g) using a mixed solvent of
dichloromethane and methanol (15:1). The fractions containing the
objective compound were collected and evaporated under reduced
pressure to give a powder of 3-formyl-1H-pyrrolo[3,2-b]pyridine
(0.45 g). [2780] mp: 230.degree. C. (decomp.) [2781] IR (KBr):
2744, 1658, 1466, 1408, 1142, 1113, 777 cm.sup.-1 [2782] NMR
(DMSO-d.sub.6, .delta.): 7.27 (1H, dd, J=4.6 and 8.3 Hz), 7.92 (1H,
d, J=8.3 Hz), 8.44 (1H, s), 8.50 (1H, d, J=4.6 Hz), 10.19 (1H, s),
12.38 (1H, s) [2783] MASS (APCI): 147 (M+H).sup.+ Preparation
130
[2784] The following compounds were obtained according to a similar
manner to that of Preparation 125. [2785] (1)
(3S,4S)-1-(tert-Butoxycarbonyl)-3,4-dimethoxypyrrolidine [2786] IR
(Neat): 1690, 1410, 1365, 1165, 1100 cm.sup.-1 [2787] NMR
(CDCl.sub.3, .delta.): 1.45 (9H, s), 3.37 (6H, s), 3.30-3.56 (4H,
m), 3.72-3.85 (2H, m) [2788] MASS (APCI): 132 (M-Boc+H).sup.+
[2789] (2) cis-2,6-Dimethoxymethyl-1-benzylpiperidine [2790] IR
(Neat): 2924, 2883, 1489, 1450 cm.sup.-1 [2791] NMR (CDCl.sub.3,
.delta.): 1.30-1.85 (6H, m), 2.68-2.78 (2H, m), 3.13 (6H, s), 3.18
(2H, dd, J=9.6, 6.2 Hz), 3.35 (2H, dd, J=9.6, 4.4 Hz), 3.84 (2H,
s), 7.17-7.42 (5H, m) [2792] MASS (APCI): 264 (M+H).sup.+ [2793]
(3) cis-3,5-Dimethoxymethyl-1-benzylpiperidine [2794] IR (Neat):
2920, 2829, 1454, 1389 cm.sup.-1 [2795] NMR (CDCl.sub.3, .delta.):
0.68 (1H, q, J=12.2 Hz), 1.61 (2H, t, J=11.1 Hz), 1.78 (1H, m),
1.85-2.20 (2H, m), 2.90-3.05 (2H, m), 3.19 (4H, d, J=6.2 Hz), 3.29
(6H, s), 3.52 (2H, s), 7.20-7.32 (5H, m) [2796] MASS (APCI): 264
(M+H).sup.+ Preparation 131
[2797] A solution of (S)-methyl glycidyl ether (10 g) and
benzylamine (3.62 g) in methanol (50 ml) was stirred at 55.degree.
C. for 2 hours. To the mixture was added (S)-methyl glycidyl ether
(1 g), and the mixture was stirred at 55.degree. C. for 2 hours,
and then evaporated under reduced pressure. Toluene was added to
the residue and evaporated under reduced pressure to give
(2S)-1-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-3-methoxypropan-
-2-ol (8.84 g) as a pale yellow oil. [2798] IR (Neat): 3430, 3402,
2889, 1454 cm.sup.-1 [2799] NMR (CDCl.sub.3, .delta.): 2.52-2.70
(4H, m), 3.34 (6H, s), 3.26-3.44 (4H, m), 3.61 (1H, d, J=13.7 Hz),
3.81-3.92 (2H, m), 3.84 (1H, d, J=13.7 Hz), 7.20-7.33 (5H, m)
[2800] MASS (APCI): 284 (M+H).sup.+ Preparation 132
[2801] A mixture of triphenylphosphine (10.2 g), diethyl
azodicarboxylate (6.12 ml), and
(2S)-1-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-3-methoxypropan-
-2-ol (7.34 g) in tetrahydrofuran (70 ml) was stirred at 0.degree.
C. for 5 hours. To the mixture was added successively
triphenylphosphine (2.04 g) and diethyl azodicarboxylate (1.2 ml),
and the mixture was stirred at 0.degree. C. for 3 hours. The
mixture was poured into water and extracted with dichloromethane
(.times.3). The combined extracts were washed with brine, dried
over sodium sulfate, and evaporated. Isopropyl ether (50 ml) was
added to the residue and stirred at room temperature for 30
minutes. The insoluble precipitate was filtered off, and the
solution was evaporated and purified twice with column
chromatography (1st: silica gel 800 ml, ethyl acetate:isopropyl
ether=2:8-3:7) (2nd: silica gel 300 ml, ethyl acetate:isopropyl
ether 3:97-10.90) to give
4-benzyl-cis-2,6-dimethoxymethylmorpholine (2.65 g) as an oil.
[2802] IR (Neat): 2883, 1514, 1458, 1099 cm.sup.-1 [2803] NMR
(CDCl.sub.3, .delta.): 1.93 (2H, t, J=11.0 Hz), 2.77 (2H, d, J=11.0
Hz), 3.34 (6H, s), 3.36-3.50 (4H, m), 3.51 (2H, s), 3.75-3.87 (2H,
m), 7.25-7.32 (5H, m) [2804] MASS (APCI): 266 (M+H).sup.+
Preparation 133
[2805] To a solution of N-benzylethanolamine (302 g) in a mixture
of water (8.92 ml) and toluene (1510 ml) and diglyme (151 ml) was
added dropwise sulfuric acid (128 ml) over 30 minutes, and the
mixture was stirred under reflux for 6 hours. After cooled to room
temperature, to the mixture was added methanol (300 ml), and then
the mixture was stirred for 1 hour. The precipitate was filtered
and washed with methanol (300 ml.times.4), and dried to give
2-(N-benzylamino)ethyl hydrogen sulfate (352.6 g) as a white
powder. [2806] MASS (APCI): 232 (M+H).sup.+ [2807] Elemental
Analysis Calcd. for C.sub.9H.sub.13N.sub.1O.sub.4S: Calcd. C,
46.74%; H, 5.67%; N, 6.06%. Found. C, 46.42%; H, 5.63%; N, 5.93%.
Preparation 134
[2808] To a solution of 2-(N-benzylamino)ethyl hydrogen sulfate (28
g) in a mixture of water (36.3 ml) and 40% sodium hydroxide aqueous
solution (12.1 ml) was added 2,2-bis(methoxymethyl)oxirane (16.0 g)
at room temperature over 30 minutes. After stirring at room
temperature for 87 hours, 40% sodium hydroxide aqueous solution (73
ml) was added dropwise to the mixture over 20 minutes. The mixture
was stirred at room temperature for 1 hour and at 40.degree. C. for
20 hours, and extracted with ethyl acetate (100 ml.times.3). The
organic layer was extracted with 1N hydrochloric acid (.times.6).
The combined extracts were neutralized with sodium hydroxide, and
then added sodium chloride, and extracted with ethyl acetate (100
ml.times.3). The combined extracts were washed with brine, dried
over magnesium sulfate, and evaporated under reduced pressure to
give 4-benzyl-2,2-dimethoxymethylmorpholine (31.79 g) as an orange
oil. [2809] IR (Neat): 2922, 2877, 2812, 1454 cm.sup.-1 [2810] NMR
(CDCl.sub.3, .delta.): 2.38-2.44 (4H, m), 3.27-3.45 (4H, m) 3.37
(6H, s), 3.65 (2H, d, J=9.6 Hz), 3.77-3.84 (2H, m), 7.20-7.34 (5H,
m) [2811] MASS (APCI): 266 (M+H).sup.+ Preparation 135
[2812] A mixture of 2,5-bis(hydroxymethyl)tetrahydrofuran
bis(p-toluenesulfonate) (10 g) and benzylamine (9.7 g) was stirred
at 70.degree. C. for 24 hours. To the mixture was added a solution
of sodium hydroxide (1.85 g) in methanol (30 ml). After stirring at
room temperature for 30 minutes, the mixture was filtered. The
filtrate was evaporated, added dichloromethane, and filtered. The
filtrate was evaporated under reduced pressure, and purified with
column chromatography (silica gel, 250 ml, ethyl acetate:hexane
1:4) to give 3-benzyl-8-oxa-3-azabicyclo[3.2.1]octane (4.05 g) as
an oil. [2813] IR (Neat): 2951, 2800, 1452 cm.sup.-1 [2814] NMR
(CDCl.sub.3, .delta.): 1.78-2.07 (4H, m), 2.33 (2H, dd, J=11.1 and
1.8 Hz), 2.54 (2H, br d, J=11.1 Hz), 3.45 (2H, s), 4.25-4.28 (2H,
m), 7.18-7.34 (5H, m) [2815] MASS (APCI): 204 (M+H).sup.+
EXAMPLE 38
[2815] [2816] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(2,2-dimethylmorpholino)eth-
yl]-2-[4-(trifluoromethyl)benzyl]-piperazine dihydrochloride [2817]
[.alpha.].sub.D.sup.26: +11.00.degree. (C=0.25, MeOH) [2818] mp:
215-231.degree. C. [2819] IR (KBr): 3438, 1645, 1329, 1281
cm.sup.-1 [2820] NMR (DMSO-d.sub.6, .delta.): 1.25, 1.33 (6H, s),
2.60-5.30 (19H, m), 7.21-8.19 (7H, m) [2821] MASS (APCI): 626
(M+H).sup.+ (free) [2822] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S,5S)-2-methoxymethyl-5--
methylmorpholino]ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [2823] [.alpha.].sub.D.sup.26: +12.33 .degree.
(C=0.25, MeOH) [2824] mp: 142-182.degree. C. [2825] IR (KBr): 1647,
1281 cm.sup.-1 [2826] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, d,
J=6.2 Hz), 2.70-5.30 (24H, m), 7.21-8.19 (7H, m) [2827] MASS
(APCI): 656 (M+H).sup.+ (free) [2828] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethoxymethylmor-
pholino)ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2829] [.alpha.].sub.D.sup.24: +9.00.degree.
(C=0.25, MeOH) [2830] mp: 130-138.degree. C. [2831] IR (KBr): 3437,
1647, 1427, 1329, 1282 cm.sup.-1 [2832] NMR (DMSO-d.sub.6,
.delta.): 2.80-5.30 (29H, m), 7.21-8.18 (7H, m) [2833] MASS (APCI):
686 (M+H).sup.+ (free) [2834] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(2,2-dimethoxymethylmor-
pholino)ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2835] [.alpha.].sub.D.sup.26: +5.27.degree.
(C=0.25, MeOH) [2836] mp: 123-149.degree. C. [2837] IR (KBr): 3435,
1647 cm.sup.-1 [2838] NMR (DMSO-d.sub.6, .delta.): 2.70-5.30 (29H,
in), 7.21-8.19 (7H, m) [2839] MASS (APCI): 686 (M+H).sup.+ (free)
[2840] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(8-oxa-3-azabicyclo[3.2.1]o-
ctan-3-yl)ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [2841] [.alpha.].sub.D.sup.25: +11.67.degree.
(C=0.25, MeOH) [2842] mp: 232-250.degree. C. [2843] IR (KBr): 3438,
1645, 1281 cm.sup.-1 [2844] NMR (DMSO-d.sub.6, .delta.): 1.91-2.27
(4H, m), 2.80-5.40 (19H, m), 7.21-8.19 (7H, m) [2845] MASS (APCI):
624 (M+H).sup.+ (free) [2846] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(2,2-dimethylmorpholino)eth-
yl]-2-(4-fluoro-3-methoxybenzyl)piperazine dihydrochloride [2847]
[.alpha.].sub.D.sup.26: +9-73.degree. (C=0.25, MeOH) [2848] mp:
152-162.degree. C. [2849] IR (KBr): 3438, 1645, 1516, 1282
cm.sup.-1 [2850] NMR (DMSO-d.sub.6, .delta.): 1.30 (6H, br s),
2.60-5.30 (22H, m), 6.40-8.20 (6H, m) [2851] MASS (APCI): 606
(M+H).sup.+ (free) [2852] (7)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S,5S)-2-methoxymethy-
l-5-methylmorpholino]ethyl]-2-(4-fluoro-3-methoxybenzyl)piperazine
dihydrochloride [2853] [.alpha.].sub.D.sup.24: +12.33.degree.
(C=0.25, MeOH) [2854] mp: 140-164.degree. C. [2855] IR (KBr): 3437,
1645, 1282 cm.sup.-1 [2856] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H,
d, J=6.1 Hz), 2.70-5.30 (27H, m), 6.50-8.20 (6H, m) [2857] MASS
(APCI): 636 (M+H).sup.+ (free) [2858] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]]-4-[2-(cis-2,6-dimethoxymethylmo-
rpholino)ethyl]-2-(4-fluoro-3-methoxybenzyl)piperazine
dihydrochloride [2859] [.alpha.].sub.D.sup.26: +10.60.degree.
(C=0.25, MeOH) [2860] mp: 148-156.degree. C. [2861] IR (KBr): 1645,
1516, 1281 cm.sup.-1 [2862] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20
(32H, m), 6.40-8.20 (6H, m) [2863] MASS (APCI): 666 (M+H).sup.+
(free) [2864] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(2,2-dimethoxymethylmorphol-
ino)ethyl]-2-(4-fluoro-3-methoxybenzyl)pipeazine dihydrochloride
[2865] [.alpha.].sub.D.sup.23: +6.60.degree. (C=0.25, MeOH) [2866]
mp: 132-150.degree. C. [2867] IR (KBr): 3437, 1645, 1516, 1282
cm.sup.-1 [2868] NMR (DMSO-d.sub.6, .delta.): 2.60-5.30 (32H, m),
6.45-8.20 (6H, m) [2869] MASS (APCI): 666 (M+H).sup.+ (free) [2870]
(10)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(8-oxa-3-azabicyclo[3.2.1]o-
ctan-3-yl)ethyl]-2-(4-fluoro-3-methoxybenzyl)piperazine
dihydrochloride [2871] [.alpha.].sub.D.sup.23: +13.20.degree.
(C=0.25, MeOH) [2872] mp: 163-178.degree. C. [2873] IR (KBr): 3431,
1645, 1518, 1427, 1282 cm.sup.-1 [2874] NMR (DMSO-d.sub.6,
.delta.): 1.91-2.30 (4H, m), 2.70-5.30 (22H, m), 6.45-8.25 (6H, m)
[2875] MASS (APCI): 604 (M+H).sup.+ (free)
EXAMPLE 39
[2876] The following compounds were obtained according to a similar
manner to that of Example 1 using N,N-diisopropylethylamine instead
of potassium carbonate as a base. [2877] (1)
4-[[(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)-
morpholino]ethyl]piperazin-2-yl]-methyl]-2-(tert-butyldimethylsilyloxy)ben-
zoic acid methyl ester [2878] IR (Neat): 1677, 1643, 1438, 1280
cm.sup.-1 [2879] NMR (CDCl.sub.3, .delta.): 0.10-0.30 (6H, m), 0.99
(9H, s), 2.00-5.10 (22H, m), 3.38 (3H, s), 3.87 (3H, s), 6.30-7.90
(6H, m) [2880] MASS (APCI): 784 (M+Na).sup.+, 763 (M+H).sup.+
[2881] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-[2-[(2S)-2-
-(methoxymethyl)morpholino]-ethyl]piperazine dihydrochloride [2882]
[.alpha.].sub.D.sup.25: -5.16.degree. (C=0.32, MeOH) [2883] mp:
146-149.degree. C. [2884] IR (KBr): 1645, 1282, 1182, 1136
cm.sup.-1 [2885] NMR (DMSO-d.sub.6, .delta.): 2,60-5.20 (28H, m),
6.75-6.90 (4H, m), 7.29-8.21 (3H, m) [2886] MASS (APCI): 604
(M+H).sup.+ (free) [2887] (3)
(2R)-2-[3-(tert-Butyldimethylsilyloxy)-4-methylbenzyl]-1-[3-methoxy-5-(tr-
ifluoromethyl)benzoyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethy-
l]piperazine [2888] IR (Neat): 2935, 1641, 1464, 1421 cm.sup.-1
[2889] NMR (CDCl.sub.3, .delta.): 0.13 (6H, br s), 0.99 (9H, s),
2.15 (3H, s), 2.10-5.10 (19H, m), 3.81 (3H, s), 6.20-7.10 (7H, m),
7.32 (1H, d, J=6.7 Hz), 8.40 (1H, d, J=3.8 Hz) [2890] MASS (APCI):
683 (M+H).sup.+ [2891] (4)
(2R)-2-[3-(tert-Butyldimethylsilyloxy)-4-methylbenzyl]-4-[4-(3,3-dimethyl-
morpholino)-2-butynyl]-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine
[2892] IR (Neat): 2952, 1645, 1510 cm.sup.-1 [2893] NMR
(CDCl.sub.3, .delta.): 0.14 (6H, br s), 0.99 (9H, s), 1.05 (6H, s),
2.15 (3H, s), 2.20-5.20 (19H, m), 3.81 (3H, s), 6.20-7.58 (6H, m)
[2894] MASS (APCI): 688 (M+H).sup.+ [2895] (5)
(2R)-1-[3-(Dimethylsulfamoyl)-5-(trifluoromethyl)-benzoyl]-4-[2-(5,6,7,8--
tetrahydro-1,6-naphthyridin-6-yl)ethyl]-2-[4-(trifluoromethyl)benzyl]piper-
azine trihydrochloride [2896] [.alpha.].sub.D.sup.26: +1.33.degree.
(C=0.25, MeOH) [2897] mp: 190-194.degree. C. [2898] IR (KBr): 3398,
1647 cm.sup.-1 [2899] NMR (DMSO-d.sub.6, .delta.): 2.66 (6H, s),
2.80-5.30 (19H, m), 6.90-8.71 (10H, m) [2900] MASS (APCI): 684
(M+H).sup.+ (free) [2901] (6)
(2R)-1-[3-Methylsulfonyl-5-(trifluoromethyl)benzoyl]-2-[4-(trifluoromethy-
l)benzyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [2902] [.alpha.].sub.D.sup.26: -2.33.degree.
(C=0.25, MeOH) [2903] mp: 192-197.degree. C. [2904] IR (KBr):
3433,3400, 1647 cm.sup.-1 [2905] NMR (DMSO-d.sub.6, .delta.):
2.70-5.30 (22H, m), 7.0S-8.68 (10H, m) [2906] MASS (APCI): 655
(M+H).sup.+ (free) [2907] (7)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2R)-2-(methoxymethyl-
)morpholino]ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2908] [.alpha.].sub.D.sup.26.5: +5.18.degree.
(C=0.28, MeOH) [2909] mp: 188-194.degree. C. [2910] IR (KBr): 3438,
1645, 1516, 1464, 1456 cm.sup.-1 [2911] NMR (DMSO-d.sub.6,
.delta.): 2.50-5.30 (22H, m), 3.27 (3H, s), 7.10-8.30 (7H, m)
[2912] MASS (API-ES positive): 642 (M+H).sup.+ (free) [2913] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S,4R)-4-methoxy-2-(metho-
xymethyl)pyrrolidino]ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [2914] [.alpha.].sub.D.sup.26.7: -17.43.degree.
(C=0.23, MeOH) [2915] mp: 56.59.degree. C. [2916] IR (KBr): 3438,
1647, 1427 cm.sup.-1 [2917] NMR (DMSO-d.sub.6, .delta.): 1.70-5.40
(21H, m), 3.29 (3H, s), 3.35 (3H, s), 7.10-7.80 (6H, m), 8.19 (1H,
br s) [2918] MASS (APCI): 656 (M+H).sup.+ (free) [2919] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(3S,4S)-3,4-dimethoxypyrro-
lidino]ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2920] [.alpha.].sub.D.sup.23.1: +5.94.degree.
(C=0.202, MeOH) [2921] mp: 203-208.degree. C. [2922] IR (KBr):
3437, 2565, 2440, 1647, 1429, 1331, 1282, 1178, 1128, 1066
cm.sup.-1 [2923] NMR (DMSO-d.sub.6, .delta.): 2.76-5.32 (25H, m),
7.10-8.26 (7H, m) [2924] MASS (APCI): 642 (M+H).sup.+ (free) [2925]
(10)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-[(2S,4R)-4-methoxy-2-(methoxy-methyl)pyrrolidino]ethyl]piperazine
dihydrochloride [2926] [.alpha.].sub.D.sup.26.6: -12.27.degree.
(C=0.30, MeOH) [2927] mp: 128-134.degree. C. [2928] IR (KBr): 3437,
3400, 1645, 1516 cm.sup.-1 [2929] NMR (DMSO-d.sub.6, .delta.):
1.70-5.30 (21H, m), 3.29 (3H, s), 3.35 (3H, s), 3.57 (3H, s),
6.40-8.30 (6H, m) [2930] MASS (APCI): 636 (M+H).sup.+ (free) [2931]
(11)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[-
2-[(2R)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [2932] [.alpha.].sub.D.sup.26.8: +6.249 .degree.
(C=0.33, MeOH) [2933] mp: 139-148.degree. C. [2934] IR (KBr): 3438,
1644, 1516, 1464, 1427 cm.sup.-1 [2935] NMR (DMSO-d.sub.6,
.delta.): 2.60-5.30 (25H, m), 3.27 (3H, s), 6.40-8.30 (6H, m)
[2936] MASS (APCI): 622 (M+H).sup.+ (free) [2937] (12)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(3S,4S)-3,4-dimethoxypyrro-
lidino]ethyl]-2-(4-fluoro-3-methoxybenzyl)piperazine
dihydrochloride [2938] [.alpha.].sub.D.sup.23.5: +8.05.degree.
(C=0.205, MeOH) [2939] mp: 112-120.degree. C. [2940] IR (KBr):
3431, 2561, 2436, 1645, 1516, 1464, 1427, 1282, 1182, 1134, 1034
cm.sup.-1 [2941] NMR (DMSO-d.sub.6, .delta.): 2.65-5.24 (28H, m),
6.44-8.30 (6H, m) [2942] MASS (APCI): 622 (M+H).sup.+ (free) [2943]
(13)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
2-[(2R)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride [2944] [.alpha.].sub.D.sup.26.5: -11.28.degree.
(C=0.27, MeOH) [2945] mp: 204-214.degree. C. [2946] IR (KBr): 1645,
1539, 1516 cm.sup.-1 [2947] NMR (DMSO-d.sub.6, .delta.): 2.50-5.20
(22H, m), 3.27 (3H, s), 6.30-8.30 (6H, m), 9.90-10.30 (1H, br)
[2948] MASS (API-ES positive): 624 (M+H).sup.+ (free) [2949] (14)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
2-[(25,4R)-4-methoxy-2-(methoxy-methyl)pyrrolidino]ethyl]piperazine
dihydrochloride [2950] [.alpha.].sub.D.sup.26.4: -25.54.degree.
(C=0.33, MeOH) [2951] mp: 95-105.degree. C. [2952] IR (KBr): 3400,
1645, 1516, 1429 cm.sup.-1 [2953] NMR (DMSO-d.sub.6, .delta.):
1.70-5.30 (21H, m), 3.28 (3H, s), 3.35 (3H, s), 6.20-8.30 (6H, m),
10.07-11.26 (1H, br) [2954] MASS (APCI): 638 (M+H).sup.+ (free)
[2955] (15)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
2-[(3S,4S)-3,4-dimethoxypyrrolidino]-ethyl]piperazine
dihydrochloride [2956] [.alpha.].sub.D.sup.23.8: -6.49.degree.
(C=0.23, MeOH) [2957] mp: 150-155.degree. C. [2958] IR (KBr): 3398,
2600, 2436, 1645, 1429, 1281, 1180, 1136, 1107, 1047 cm.sup.-1
[2959] NMR (DMSO-d.sub.6, .delta.): 2.55-5.15 (25H, m), 6.24-8.30
(6H, m) [2960] MASS (APCI): 624 (M+H).sup.+ (free) [2961] (16)
(2R)-2-[3-(tert-Butyldimethylsilyloxy)-4-chlorobenzyl]-1-[3-chloro-5-(tri-
fluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine
[2962] IR (Neat): 2935, 1641, 1417 cm.sup.-1 [2963] NMR
(CDCl.sub.3, .delta.): 0.18 (6H, br s), 1.02 (9H, s), 1.16 (6H, d,
J=6.3 Hz), 1.76 (2H, t, J=10.7 Hz), 2.00-5.10 (17H, m), 6.30-7.50
(5H, m), 7.61 (1H, s) [2964] MASS (APCI): 688 (M+H).sup.+ [2965]
(17)
(2R)-2-[3-(tert-Butyldimethylsilyloxy)-4-chlorobenzyl]-1-[3-chloro-5-(tri-
fluoromethyl)benzoyl]-4-[2-(5,6,7,
8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine [2966] IR
(KBr): 2954, 2935, 1643, 1419 cm.sup.-1 [2967] NMR (DMSO-d.sub.6,
.delta.): 0.00-0.07 (6H, br), 0.83 (9H, s), 1.70-5.00 (19H, m),
6.20-8.10 (8H, m), 8.18 (1H, d, J=4.7 Hz) [2968] MASS (API-ES
positive): 707 (M+H).sup.+
EXAMPLE 40
[2969] The following compound was obtained by reacting
(2R)-4-(2-chloroethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-(trifluor-
omethyl)benzyl]piperazine hydrochloride with
(2S)-2-(hydroxymethyl)pyrrolidine with a reaction condition similar
to that of Example 1 using N,N-diisopropylethylamine instead of
potassium carbonate as a base.
[2970]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(hydroxymeth-
yl)pyrrolidino]ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2971] [.alpha.].sub.D.sup.24.0: +6.43.degree.
(C=0.28, MeOH) [2972] mp: 221-224.degree. C. [2973] IR (KEr): 1643,
1516, 1427 cm.sup.-1 [2974] NMR (DMSO-d.sub.6, .delta.): 1.65-2.30
(4H, m), 2.60-5.40 (19H, m), 7.10-8.30 (7H, m) [2975] MASS (APCI):
612 (M+H).sup.+ (free)
EXAMPLE 41
[2976] The following compounds were obtained according to a similar
manner to that of Example 40. [2977] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dihydroxymethylpip-
eridino)ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2978] [.alpha.].sub.D.sup.24.2: +10.36.degree.
(C=0.14, MeOH) [2979] mp: 164-167.degree. C. [2980] IR (KBr): 3396,
3369, 1645, 1516, 1427 cm.sup.-1 [2981] NMR (DMSO-d.sub.6,
.delta.): 1.30-2.10 (6H, m), 2.40-5.60 (21H, m) 7.00-8.30 (7H, m)
[2982] MASS (APCI): 656 (M+H).sup.+ (free) [2983] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoylI-4-[2-(cis-2,6-dimethoxymethylpip-
eridino)ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2984] [.alpha.].sub.D.sup.23.1: +5.12.degree.
(C=0.21, MeOH) [2985] mp: 147-151.degree. C. [2986] IR (KBr): 1645,
1516, 1454, 1427 cm.sup.-1 [2987] NMR (DMSO-d.sub.6, .delta.):
1.40-2.00 (6H, m), 2.80-5.30 (25H, m)), 7.10-8.40 (7H, m) [2988]
MASS (APCI): 684 (M+H).sup.+ (free) [2989] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-3,5-dimethoxymethylpip-
eridino)ethyl]-2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2990] [.alpha.].sub.D.sup.23.4: +8.28.degree.
(C=0.32, MeOH) [2991] mp: 157-160.degree. C. [2992] IR (KBr): 3438,
1647, 1464, 1427 cm.sup.-1 [2993] NMR (DMSO-d.sub.6, .delta.): 1.05
(1H, q, J=12.4 Hz), 1.70 (1H, m), 2.10-5.40 (23H, m), 3.24 (6H, s),
7.10-8.30 (7H, m) [2994] MASS (APCI): 684 (M+H).sup.+ (free) [2995]
(4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(3S,4S)-3,4-dihydroxypyrro-
lidino]ethyl].degree. 2-[4-(trifluoromethyl)-benzyl]piperazine
dihydrochloride [2996] [.alpha.].sub.D.sup.23.9: +7.37-(C=0.29,
MeOH) [2997] mp: 154-159.degree. C. [2998] IR (KBr): 3398, 3369,
1645, 1427 cm.sup.-1 [2999] NMR (DMSO-d.sub.6, .delta.): 2.20-5.40
(21H, m), 7.1-8.3 (7H, m) [3000] MASS (APCI): 614 (M+H).sup.+
(free) [3001] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-
-4-[2-[(2S)-2-(hydroxymethyl)pyrrolidino]-ethyl]piperazine
dihydrochloride [3002] [.alpha.].sub.D.sup.24.1: +4.76.degree.
(C=0.25, MeOH) [3003] mp: 198-201.degree. C. [3004] IR (KBr): 1645,
1516, 1464, 1425 cm.sup.-1 [3005] NMR (DMSO-d.sub.6, .delta.):
160-5.40 (23H, m), 3.59 (3H, s), 6.40-8.30 (6H, m) [3006] MASS
(APCI): 592 (M+H).sup.+ (free) [3007] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dihydroxymethylpip-
eridino)ethyl]-2-(4-fluoro-3-methoxybenzyl)piperazine
dihydrochloride [3008] [.alpha.].sub.D.sup.24.3: +11.33.degree.
(C=0.27, MeOH) [3009] mp: 159-161.degree. C. [3010] IR (KBr): 3367,
1645, 1516, 1464, 1427 cm.sup.-1 [3011] NMR (DMSO-d.sub.6,
.delta.): 1.40-2.00 (6H, m), 2.60-5.30 (24H, m), 6.40-8.30 (6H, m)
[3012] MASS (APCI): 636 (M+H).sup.+ (free) [3013] (7)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-3,5-dimethoxymethylpip-
eridino)ethyl]-2-(4-fluoro-3-methoxybenzyl)piperazine
dihydrochloride [3014] [.alpha.].sub.D.sup.23.7: +9.45.degree.
(C=0.28, MeOH) [3015] mp: 150-156.degree. C. [3016] IR (KBr): 3438,
2939, 1645, 1518, 1464, 1427 cm.sup.-1 [3017] NMR (DMSO-d.sub.6,
.delta.): 1.05 (1H, q, J=12.3 Hz), 1.70 (1H, m), 2.10-5.30 (26H,
m), 3.24 (6H, s), 6.40-8.30 (6H, m) [3018] MASS (APCI): 664
(M+H).sup.+ (free)
EXAMPLE 42
[3019] The following compounds were obtained according to a similar
manner to that of Example 13. [3020] (1)
(2R)-2-(3-Hydroxy-4-methylbenzyl)-1-[3-methoxy-5-(trifluoromethyl)benzoyl-
]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [3021] [.alpha.].sub.D.sup.2.7: -17.11.degree.
(C=0.15, MeOH) [3022] mp: 192-208.degree. C. [3023] IR (KBr): 1643,
1628, 1464 cm.sup.-1 [3024] NMR (DMSO-d.sub.6, .delta.): 2.06 (3H,
s), 2.60-5.10 (22H, m), 6.20-7.30 (6H, m), 7.62-7.69 (1H, m), 8.05
(1H, d, J=7.8 Hz), 8.67 (1H, d, J=4.0 Hz) [3025] MASS (APCI): 569
(M+H).sup.+ (free) [3026] (2)
(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-(3-hydroxy-4-methylbenzyl-
)-1-[3-methoxy-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [3027] [.alpha.].sub.D.sup.27: +13.87.degree.
(C=0.25, MeOH) [3028] mp: 181-188.degree. C. [3029] IR (KBr): 1645,
1464, 1425 cm.sup.-1 [3030] NMR (DMSO-d.sub.6, .delta.): 1.25-1.32
(6H, m), 2.07 (3H, s), 2.70-5.20 (22H, m), 6.20-7.29 (6H, m) [3031]
MASS (APCI): 574 (M+H).sup.+ (free) [3032] (3)
(2R)-2-(4-Chloro-3-hydroxybenzyl)-1-[3-chloro-5-(trifluoromethyl)benzoyl]-
-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine dihydrochloride
[3033] [.alpha.].sub.D.sup.26.5: -12.04.degree. (C=0.25, MeOH)
[3034] mp: 196-199.degree. C. [3035] IR (Kr): 3398, 1643, 1514,
1456, 1425 cm.sup.-1 [3036] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H,
d, J=6.1 Hz), 2.60-5.20 (19H, m), 6.30-8.10 (6H, m), 10.08 (1H, br
s) [3037] MASS (APCI): 574 (M+H).sup.+ (free) [3038] (4)
(2R)-2-(4-Chloro-3-hydroxybenzyl)-1-[3-chloro-5-(trifluoromethyl)benzoyl]-
-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [3039] [.alpha.].sub.D.sup.26.5: -20.57.degree.
(C=0.28, MeOH) [3040] mp: 200-204.degree. C. [3041] IR (KBr): 3430,
3400, 1645, 1514, 1464, 1425 cm.sup.-1 [3042] NMR (DMSO-d.sub.6,
.delta.): 2.60-5.20 (19H, m), 6.30-8.10 (8H, m), 8.63 (1H, d, J=4.6
Hz), 10.09 (1H, br) [3043] MASS (APCI): 593 (M+H).sup.+ (free)
EXAMPLE 43
[3044] The following compounds were obtained according to a similar
manner to that of Example 41. [3045] (1)
(2R)-2-(4-Chlorobenzyl)-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]-1--
[3-(4-pyridyl)-5-(trifluoromethyl)-benzoyl]piperazine
trihydrochloride [3046] [.alpha.].sub.D.sup.27: +1.5.degree.
(C=0.5, MeOH) [3047] IR (KBr): 1645, 1510, 1460, 1425, 1270, 1240,
1175, 1135 cm.sup.-1 [3048] NMR (DMSO-d.sub.6, .delta.): 2.62-5.15
(22H, m), 3.28 (3H, s), 6.16-9.01 (11H, m) [3049] MASS (APCI): 617
(M).sup.+ (free) [3050] (2)
(2R)-2-(4-Chlorobenzyl)-4-[2-[(2-5)-2-(methoxymethyl)-morpholino]ethyl]-1-
-[3-methyl-S-(trifluoromethyl)-benzoyl]piperazine dihydrochloride
[3051] [.alpha.].sub.D.sup.27: +10.9.degree. (C=0.5, MeOH) [3052]
mp: 148-151.degree. C. [3053] IR (KBr): 1645, 1510, 1465, 1425,
1270, 1230 cm.sup.-1 [3054] NMR (DMSO-d.sub.6, .delta.): 2.33 (3H,
s), 3.28 (3H, s), 2.66-5.24 (22H, m), 6.16-7.70 (7H, m) [3055] MASS
(APCI): 554 (M).sup.+ (free) [3056] (3)
(2R)-2-(4-Chlorobenzyl)-1-[3-cyclopentylsulfonyl-5-(trifluoromethyl)benzo-
yl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3057] [.alpha.].sub.D.sup.27: +12.1.degree.
(C=0.5, DMF) [3058] mp: >230.degree. C. [3059] IR (KBr): 1650,
1465, 1425, 1335, 1305, 1235, 1135 cm.sup.-1 [3060] NMR
(DMSO-d.sub.6, .delta.): 1.45-1.93 (9H, m), 2.80-5.20 (22H, m) 3.27
(3H, s), 6.14-8.30 (7H, m) [3061] MASS (APCI): 672 (M).sup.+ (free)
[3062] (4)
(2R)-2-(4-Chlorobenzyl)-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]-1--
[3-methylthio-5-(trifluoromethyl)-benzoyl]piperazine
dihydrochloride [3063] [.alpha.].sub.D.sup.27: +13.3.degree.
(C=0.5, MeOH) [3064] mp: 140-146.degree. C. [3065] IR (KBr): 1625,
1415, 1320, 1270, 1225, 1175 ci .sup.1 [3066] NMR (DMSO-d.sub.6,
.delta.): 2.54 (3H, s), 2.66-5.20 (22H, m), 3.27 (3H, s), 6.66-7.64
(7H, m) [3067] MASS (APCI): 586 (M).sup.+ (free) [3068] (5)
(2R)-2-(4-Chlorobenzyl)-1-[3-chloro-5-(trifluoromethyl)-benzoyl]-4-[2-[(2-
S)-2-(methoxymethyl)morpholino]ethyl]-piperazine dihydrochloride
[3069] [.alpha.].sub.D.sup.27: +7.0.degree. (C=0.5, MeOH) [3070]
mp: 148-153.degree. C. [3071] IR (KBr): 1645, 1460, 1420, 1315,
1270, 1230, 1175 cm.sup.-1 [3072] NMR (DMSO-d.sub.6, .delta.):
2.66-5.20 (22H, m), 3.28 (3H, s) 6.02-8.00 (7H, m) [3073] MASS
(APCI): 574 (M).sup.+ (free) [3074] (6)
(2R)-2-(4-Chlorobenzyl)-1-[3-fluoro-5-(trifluoromethyl)-benzoyl]-4-[2-[(2-
S)-2-(methoxymethyl)morpholino]ethyl]-piperazine dihydrochloride
[3075] [.alpha.].sub.D.sup.27: +10.0.degree. (C=0.5, MeOH) [3076]
mp: 199-204.degree. C. [3077] IR (KBr): 1645, 1425, 1235, 1175,
1135 cm.sup.-1 [3078] NMR (DMSO-d.sub.6, .delta.): 2.70-5.16 (22H,
m), 3.28 (3H, s), 6.16-7.90 (7H, m) [3079] MASS (APCI): 558
(M).sup.+ (free) [3080] (7)
(2R)-1-[3-Methylthio-5-(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)be-
nzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3081] [.alpha.].sub.D.sup.22: +21.93.degree.
(C=0.25, MeOH) [3082] mp: 153-170.degree. C. [3083] IR (KBr): 3433,
1645 cm.sup.-1 [3084] NMR (DMSO-d.sub.6, .delta.): 2.54 (3H, s),
2.70-5.30 (25H, m), 6.50-7.80 (7H, m) [3085] MASS (APCI): 620
(M+H).sup.+ (free) [3086] (8)
(2R)-1-[3-Chloro-5-(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl-
]-4-[2-[(2S)-2-(mnethoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3087] [.alpha.].sub.D.sup.22: +29.60.degree.
(C=0.21, MeOH) [3088] mp: 168-173.degree. C. [3089] IR (KBr): 3433,
1647 cm.sup.-1 [3090] NMR (DMSO-d.sub.6, .delta.): 2.80-5.30 (25H,
m), 6.87-8.00 (7H, m) [3091] MASS (APCI): 608 (M+H).sup.+ (free)
[3092] (9)
(2R)-1-[3-Fluoro-5-(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymet-
hyl)morpholino]ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [3093] [.alpha.].sub.D.sup.27: +17.47.degree.
(C=0.25, MeOH) [3094] mp: 173-176.degree. C. [3095] IR (KBr): 1647
cm.sup.-1 [3096] NMR (DMSO-d.sub.6, .delta.): 2.80-5.30 (25H, m),
6.70-7.90 (7H, m) [3097] MASS (APCI): 592 (M+H).sup.+ (free) [3098]
(10)
(2R)-4-[2-[(2S)-2-(Methoxymethyl)morpholino]ethyl]-1-[3-(4-pyridyl)-5-(tr-
ifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]piperazine
trihydrochloride [3099] [.alpha.].sub.D.sup.26: +13.60.degree.
(C=0.25, MeOH) [3100] mp: 81-91.degree. C. [3101] IR (KBr): 3435,
1643 cm.sup.-1 [3102] NMR (DMSO-d.sub.6, .delta.): 2.80-5.30 (25H,
m), 6.88-8.98 (11H, m) [3103] MASS (APCI): 651 (M+H).sup.+ (free)
[3104] (11)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-1-[3-methylthio-5-(tri-
fluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [3105] [.alpha.].sub.D.sup.27: +19.00.degree.
(C=0.25, MeOH) [3106] mp: 154-156.degree. C. [3107] IR (KBr): 3435,
1647 cm.sup.-1 [3108] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H, d,
J=6.1 Hz), 2.54 (3H, s), 2.60-5.30 (19H, m), 6.50-7.70 (7H, m)
[3109] MASS (APCI): 604 (M+H).sup.+ (free) [3110] (12)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-1-[3-methylsulfonyl-5-(trifl-
uoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [3111] [.alpha.].sub.D.sup.25: +12.60.degree.
(C=0.25, MeOH) [3112] mp: 188-195.degree. C. [3113] IR (KBr): 1647
cm.sup.-1 [3114] NMR (DMSO-d.sub.6, .delta.): 1.15 (6H, d, J=6.1
Hz), 2.60-5.30 (22H, m), 7.00-8.32 (7H, m) [3115] MASS (APCI): 636
(M+H).sup.+ (free) [3116] (13)
(2R)-4-[2-(cis-2,6-Dimethylmorpholino)ethyl]-1-[3-(4-pyridyl)-5-(trifluor-
omethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]piperazine
trihydrochloride [3117] [.alpha.].sub.D.sup.26: +8.40.degree.
(C=0.25, MeOH) [3118] mp: 135-145.degree. C. [3119] IR (KBr):
3433,3402, 1641 cm.sup.-1 [3120] NMR (DMSO-d.sub.6, .delta.): 1.15
(6H, d, J=6.2 Hz), 2.60-5.30 (19H, m), 6.80-9.02 (11H, m) [3121]
MASS (APCI): 635 (M+H).sup.+ (free) [3122] (14)
(2R)-1-[3-Methylthio-5-(trifluoromethyl)benzoyl]-4-[2-(5,6,7,8-tetrahydro-
-1,6-naphthyridin-6-yl)ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
dihydrochloride [3123] [.alpha.].sub.D.sup.27: +1.53.degree.
(C=0.25, MeOH) [3124] mp: 190-210.degree. C. [3125] IR (KBr): 3431,
1643 cm.sup.-1 [3126] NMR (DMSO-d.sub.6, .delta.): 2.54 (3H, s),
2.80-5.30 (19H, m), 6.50-8.71 (10H, m) [3127] MASS (APCI): 623
(M+H).sup.+ (free) [3128] (15)
(2R)-1-[3-(4-Pyridyl)-5-(trifluoromethyl)benzoyl]-4-[2-(5,6,7,8-tetrahydr-
o-1,6-naphthyridin-6-yl)ethyl]-2-[4-(trifluoromethyl)benzyl]piperazine
tetrahydrochloride [3129] [.alpha.].sub.D.sup.26: -5.73 .degree.
(C=0.25, MeOH) [3130] mp: 205-218.degree. C. [3131] IR (KBr): 3400,
1641 cm.sup.-1 [3132] NMR (DMSO-d.sub.6, .delta.): 2.60-5.30 (19H,
m), 6.85-9.02 (14H, m) [3133] MASS (APCI): 654 (M+H).sup.+ (free)
[3134] (16)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-(cis-2,6-dimethylmorpholino)-
ethyl]-1-[3-methylthio-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [3135] [.alpha.].sub.D.sup.27.3: +23.47.degree.
(C=0.36, MeOH) [3136] mp: 62.5-82.4.degree. C. [3137] IR (KBr):
1645, 1518, 1421, 1176, 1126 cm.sup.-1 [3138] NMR (DMSO-d.sub.6,
.delta.): 1.15 (6H, d, J=6.1 Hz), 2.60-4.20 (27H, m), 6.50-7.56
(6H, m) [3139] MASS: 584 (M+H).sup.+ (free) [3140] (17)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-
-1-[3-(4-pyridyl)-5-(trifluoromethyl)benzoyl]piperazine
trihydrochloride [3141] [.alpha.].sub.D.sup.27.4: +14.30.degree.
(C=0.37, MeOH) [3142] mp: 137.6-142.5.degree. C. [3143] IR (KBr):
1641, 1515, 1425, 1270, 1176, 1145, 1132 cm.sup.-1 [3144] NMR
(DMSO-d.sub.6, .delta.): 1.14 (6H, d, J=6.0 Hz), 2.60-4.20 (25H,
m), 6.52-8.90 (10H, m) [3145] MASS (APCI): 615 (M+H).sup.+ (free)
[3146] (18)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-methylthio-5-(trifluoromethyl)benz-
oyl]-4-[2-(5,6,7,
8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
trihydrochloride [3147] [.alpha.].sub.D.sup.27.4: -3.51.degree.
(C=0.39, MeOH) [3148] mp: 143.3-147.5.degree. C. [3149] IR (KBr):
1645, 1516, 1417, 1173, 1126 cm.sup.-1 [3150] NMR (DMSO-d.sub.6,
.delta.): 3.80-5.20 (28H, m), 6.53-8.68 (9H, m) [3151] MASS (APCI):
603 (M+H).sup.+ (free) [3152] (19)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-(4-pyridyl)-5-(trifluoromethyl)ben-
zoyl]-4-[2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]piperazine
tetrahydrochloride [3153] [.alpha.].sub.D.sup.27.9: -9.07 .degree.
(C=0.46, MeOH) [3154] mp: 236.8-248.5.degree. C. [3155] IR (KBr):
1641, 1635, 1516, 1423, 1273, 1130 cm.sup.-1 [3156] NMR
(DMSO-d.sub.6, .delta.): 2.65-5.10 (26H, m), 6.51-9.00 (13H, m)
[3157] MASS: 634 (M+H).sup.+ (free) [3158] (20)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-(4-pyridyl)-5-(trifluoromethyl)benzoyl]piperazine
trihydrochloride [3159] [.alpha.].sub.D.sup.28: +32.5.degree.
(C=0.5, MeOH) [3160] IR (KBr): 1645, 1515, 1425, 1270, 1235
cm.sup.1 [3161] NMR (DMSO-d.sub.6, .delta.): 2.66-5.24 (25H, m),
3.27 (3H, s), 6.45-8.93 (10H, m) [3162] MASS (APCI): 631
(M+H).sup.+ (free) [3163] (21)
(2R)-1-[3-Chloro-5-(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-
-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3164] [.alpha.].sub.D.sup.28: +25.4.degree.
(C=0.5, MeOH) [3165] mp: 139-142.degree. C. [3166] IR (KBr): 1645,
1515, 1460, 1420, 1315, 1270, 1230 cm.sup.-1 [3167] NMR
(DMSO-d.sub.6, .delta.): 2.72-5.21 (22H, m), 3.29 (3H, s), 3.44
(3H, s), 6.17-8.00 (6H, m) [3168] MASS (APCI): 588 (M).sup.+ (free)
[3169] (22)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methylthio-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [3170] [.alpha.].sub.D.sup.28: +28.1.degree.
(C=0.5, MeOH) [3171] mp: 132-135.degree. C. [3172] IR (KBr): 1645,
1515, 1460, 1420, 1315, 1270, 1230, 1130 cm.sup.-1 [3173] NMR
(DMSO-d.sub.6, .delta.): 2.54 (3H, s), 2.73-5.27 (22H, m), 3.28
(3H, s), 3.41 (3H, s), 6.15-7.83 (6H, m) [3174] MASS (APCI): 600
(M+H).sup.+ (free) [3175] (23)
(2R)-2-(4-Fluoro-3-methoxybenzyl)-1-[3-fluoro-5-(trifluoromethyl)ben-
zoyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3176] [.alpha.].sub.D.sup.27: +21.4.degree.
(C=0.5, MeOH) [3177] IR (KBr): 1640, 1515, 1465, 1425, 1345, 1275,
1230, 1135 cm.sup.-1 [3178] NMR (DMSO-d.sub.6, .delta.): 2.76-5.20
(22H, m), 3.29 (3H, s), 3.42 (3H, s), 6.16-7.86 (6H, m) [3179] MASS
(APCI): 572 (M+H).sup.+ (free)
EXAMPLE 44
[3180] The following compounds were obtained according to a similar
manner to that of the second half of Preparation 21. [3181] (1)
(2R)-2-(4-Chloro-3-hydroxybenzyl)-1-[3-chloro-5-(trifluoromethyl)benzoyl]-
-4-[2-[(2S)-2-((methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3182] [.alpha.].sub.D.sup.28: +6.1.degree. (C=0.5,
MeOH) [3183] IR (KBr): 1645, 1510, 1425, 1235, 1175 cm.sup.-1
[3184] NMR (DMSO-d.sub.6, .delta.): 2.55-5.10 (22H, m), 3.27 (3H,
s), 6.31-8.03 (6H, m), 10.07 (1H, br s) [3185] MASS (APCI): 590
(M).sup.+ (free) [3186] (2)
(2R)-2-(4-Chloro-3-hydroxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-
ethyl]-1-[3-methylthio-5-(trifluoromethyl)benzoyl]piperazine
dihydrochloride [3187] [.alpha.].sub.D.sup.28: +15.0.degree.
(C=0.5, MeOH) [3188] mp: 169-174.degree. C. [3189] IR (KBr): 3475,
3420, 1640, 1425, 1320, 1270, 1230, 1135 cm.sup.-1 [3190] NMR
(DMSO-d.sub.6, .delta.): 2.54 (3H, s), 2.56-5.10 (22H, m), 3.27
(3H, s), 6.29-7.69 (6H, m), 10.10 (1H, br s) [3191] MASS (APCI):
602 (M).sup.+ (free) [3192] (3)
(2R)-2-(4-Chloro-3-hydroxybenzyl)-1-[3-fluoro-5-(trifluoromethyl)ben-
zoyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine
dihydrochloride [3193] [.alpha.].sub.D.sup.27: +7.6.degree. (C=0.5,
MeOH) [3194] mp: 176-178.degree. C. [3195] IR (KBr): 1645, 1510,
1460, 1425, 1235, 1175 cm.sup.-1 [3196] NMR (DMSO-d.sub.6,
.delta.): 2.52-4.98 (22H, m), 3.28 (3H, s), 6.34-7.77 (7H, m)
[3197] MASS (APCI) 574 (M).sup.+ (free)
EXAMPLE 45
[3198] The following compounds were obtained according to a similar
manner to that of Example 11. [3199] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
(1H-pyrrolo[3,2-b]pyridin-3-yl)-methyl]piperazine dihydrochloride
[3200] [.alpha.].sub.D.sup.25.0: +5.42.degree. (C=0.60, MeOH)
[3201] mp: 208-211.degree. C. [3202] IR (KBr): 1647, 1281, 1180,
1138 cm.sup.-1 [3203] NMR (DMSO-d.sub.6, .delta.): 2.60-5.10 (11H,
m), 6.26-7.20 (3H, m), 7.43-7.82 (3H, m), 8.18-8.72 (4H, m), 10.08
(1H, br), 13.11 (1H, s) [3204] MASS (APCI): 597 (M+H).sup.+ (free)
[3205] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[-
(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]piperazine dihydrochloride
[3206] [.alpha.].sub.D.sup.24.9: -0.90.degree. (C=0.50, MeOH)
[3207] mp: 197-200.degree. C. [3208] IR (KBr): 1647, 1281, 1180,
1136 cm.sup.-1 [3209] NMR (DMSO-d.sub.6, .delta.): 2.60-5.20 (1H,
m), 6.24-7.40 (4H, m), 7.45 (1H, s), 7.76 (1H, s), 7.95-8.55 (4H,
m), 11.60 (1H, br), 12.45 (1H, s) [3210] MASS (APCI): 597
(M+H).sup.+ (free)
EXAMPLE 46
[3211] 1M Methylmagnesium iodide in diethyl ether solution (3.15
ml) was added to a solution of
4-[[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)-
-morpholino]ethyl]piperazin-2-yl]methyl]-2-(tert-butyldimethylsilyloxy)ben-
zoic acid methyl ester (0.8 g) in toluene (8 ml). After being
stirred at 45.degree. C. for 4 hours, the mixture was quenched with
saturated aqueous ammonium chloride solution and the whole was
extracted with ethyl acetate. The organic layer was separated,
washed with water and brine successively, dried over magnesium
sulfate, and evaporated under reduced pressure to give crude oil.
The oil was purified by column chromatography on silica gel using a
mixed solvent of dichloromethane and methanol (40:1) to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(tert-butyldimethyl-silylox-
y)-4-(1-hydroxy-1-methylethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholi-
no]ethyl]piperazine (0.333 g) [3212] IR (Neat): 1643, 1438, 1280
cm.sup.-1 [3213] NMR (CDCl.sub.3, .delta.): 0.10-0.50 (6H, m), 1.03
(9H, s), 1.58 (6H, s), 2.00-5.10 (22H, m), 3.38 (3H, s), 6.30-7.90
(6H, m) [3214] MASS (API-ES): 784 (M+Na).sup.+, 763 (M+H).sup.+
EXAMPLE 47
[3215] Methanesulfonyl chloride (0.115 ml) was added to an
ice-cooled solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(tert-butyldimethylsilyloxy-
)-4-(1-hydroxy-1-methylethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholin-
o]-ethyl]piperazine (0.76 g) and triethylamine (0.35 ml) in
dichloromethane (9 ml) After being stirred at the same temperature
for 2 hours, the mixture was washed with water. The organic layer
was separated, washed with brine, dried over magnesium sulfate and
evaporated under reduced pressure to give a mixture of the
mesylated and unmesylated compound. The mixture was dissolved into
methanol without further purification and the solution was
hydrogenated over 20% palladium hydroxide-charcoal (0.1 g) at room
temperature at 3 atmosphere for 5 hours. The reaction mixture was
filtered through Celite.RTM. and washed with methanol. The filtrate
and washing were combined and evaporated under reduced pressure.
The resulting syrup was dissolved in tetrahydrofuran (6.5 ml) and
thereto tetrabutylammonium fluoride (1M solution of
tetrahydrofuran, 0.1 ml) was added below 10.degree. C. After
stirring at room temperature, the mixture was evaporated under
reduced pressure and the residue was purified by column
chromatography using a mixed solvent of dichloromethane and
methanol (40:1) to give an oil. The oil was treated with 4N
hydrogen chloride in ethyl acetate to give a powder of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-hydroxy-4-(1-meth-
ylethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine
dihydrochloride (150 mg). [3216] [.alpha.].sub.D.sup.26:
-1.25.degree. (C=0.2, MeOH) [3217] mp: 218-228.degree. C. [3218] IR
(KBr): 3500-3150, 2700-2300, 1644, 1498, 1461, 1282, 1174 cm.sup.-1
[3219] NMR (DMSO-d.sub.6, .delta.): 1.00-1.30 (6H m), 2.60-5.10
(26H, m), 6.20-8.20 (6H, m), 9.22 (1H, br s) [3220] MASS (APCI):
632 (M+H).sup.+ (free)
* * * * *