U.S. patent application number 11/298980 was filed with the patent office on 2006-07-27 for piperazine compounds and medicinal use thereof.
This patent application is currently assigned to MITSUBISHI PHARMA CORPORATION. Invention is credited to Kunitomo Adachi, Yoshiyuki Aoki, Tokushi Hanano, Masao Hisadome, Hiroshi Morimoto.
Application Number | 20060167014 11/298980 |
Document ID | / |
Family ID | 26544906 |
Filed Date | 2006-07-27 |
United States Patent
Application |
20060167014 |
Kind Code |
A1 |
Adachi; Kunitomo ; et
al. |
July 27, 2006 |
Piperazine compounds and medicinal use thereof
Abstract
The present invention relates to a piperazine compound of the
formula ##STR1## wherein R.sup.1 and R.sup.2 are each hydrogen,
halogen, lower alkyl, lower alkoxy, amino, substituted amino,
nitro, hydroxy or cyano, R.sup.3, R.sup.4 and R.sup.5 are each
hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino,
substituted amino or hydroxy, R.sup.6 and R.sup.7 are each
hydrogen, lower alkyl, lower alkyl substituted by halogen, aralkyl,
acyl or lower acyl substituted by halogen, R.sup.8 and R.sup.9 are
each hydrogen or lower alkyl, Y is lower alkylene and the like, and
ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or
imidazolyl, a pharmaceutically acceptable salt thereof and
pharmaceutical agents containing these compounds. The compound of
the present invention has superior TNF-.alpha. production
inhibitory effect and/or IL-10 production promoting effect, and,
since it is free of or shows only strikingly reduced expression of
an effect on the central nervous system, the compound is useful as
a highly safe and superior TNF-.alpha. production inhibitor an/or
IL-10 production promoter and is useful as an agent for the
prophylaxis or treatment of various diseases caused by abnormal
TNF-.alpha. production, diseases curable with IL-10, such as
chronic inflammatory diseases, acute inflammatory diseases,
inflammatory diseases due to infection, autoimmune diseases,
allergic diseases, and TNF-.alpha. mediated diseases.
Inventors: |
Adachi; Kunitomo;
(Chikujo-gun, JP) ; Aoki; Yoshiyuki;
(Hirakata-shi, JP) ; Hanano; Tokushi; (Iruma-shi,
JP) ; Morimoto; Hiroshi; (Chikujo-gun, JP) ;
Hisadome; Masao; (Chikujo-gun, JP) |
Correspondence
Address: |
CROWELL & MORING LLP;INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
MITSUBISHI PHARMA
CORPORATION
|
Family ID: |
26544906 |
Appl. No.: |
11/298980 |
Filed: |
December 12, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10187286 |
Jul 2, 2002 |
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11298980 |
Dec 12, 2005 |
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09529491 |
Apr 14, 2000 |
6455528 |
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PCT/JP98/04613 |
Oct 13, 1998 |
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10187286 |
Jul 2, 2002 |
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Current U.S.
Class: |
514/255.03 ;
544/394 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 19/02 20180101; C07D 239/50 20130101; C07D 277/42 20130101;
C07C 2601/02 20170501; C07D 239/52 20130101; C07D 233/88 20130101;
C07D 239/42 20130101; A61P 37/08 20180101; A61P 37/06 20180101;
C07D 239/48 20130101; C07D 239/47 20130101; A61P 29/00 20180101;
C07D 213/74 20130101; C07D 295/135 20130101; C07D 239/545
20130101 |
Class at
Publication: |
514/255.03 ;
544/394 |
International
Class: |
A61K 31/495 20060101
A61K031/495; C07D 241/04 20060101 C07D241/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 14, 1997 |
JP |
280880/1997 |
Sep 16, 1998 |
JP |
261100/1998 |
Claims
1. A piperazine compound of the formula ##STR364## wherein R.sup.1
and R.sup.2 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, amino, amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, nitro, hydroxy or cyano; R.sup.3,
R.sup.4 and R.sup.5 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino
mono- or di-substituted by a group selected from the group
consisting of lower alkyl and lower acyl; R.sup.6 and R.sup.7 are
the same or different and each is hydrogen, lower alkyl, lower
alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); R.sup.8 and R.sup.9 are the same
or different and each is hydrogen or lower alkyl; Y is a group of
the formula ##STR365## wherein R.sup.10 and R.sup.11 are the same
or different and each is hydrogen or lower alkyl, R.sup.12 and
R.sup.13 are the same or different and each is hydrogen or lower
alkyl, or R.sup.12 and R.sup.13 in combination form alkylene,
R.sup.14 and R.sup.15 are the same or different and each is
hydrogen or lower alkyl, m is an integer of 0-2, n is an integer of
0-2, and 0.ltoreq.m+n.ltoreq.2; and ring A is phenyl, provided that
when one of R.sup.6 and R.sup.7 is hydrogen and the other is butyl,
in Y, both R.sup.12 and R.sup.13 are hydrogen, m and n are 0,
R.sup.1, R.sup.2, R.sup.8 and R.sup.9 are hydrogen, and ring A is
phenyl, then one of R.sup.3, R.sup.4 and R.sup.5 should not be
2-isopropoxy and the remaining two should not be hydrogen, or a
pharmaceutically acceptable salt thereof.
2. The piperazine compound of claim 1, which has the following
formula ##STR366## wherein R.sup.1 and R.sup.2 are the same or
different and each is hydrogen, halogen, lower alkyl, lower alkoxy,
amino, amino mono- or di-substituted by a group selected from the
group consisting of lower alkyl and lower acyl, nitro, hydroxy or
cyano; R.sup.3, R.sup.4 and R.sup.5 are the same or different and
each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino,
hydroxy or amino mono- or di-substituted by a group selected from
the group consisting of lower alkyl and lower acyl; R.sup.6 and
R.sup.7 are the same or different and each is hydrogen, lower
alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl
or lower acyl substituted by 1 to 3 halogen(s); and Y.sup.1 is a
group of the formula ##STR367## wherein R.sup.12 and R.sup.13 are
the same or different and each is hydrogen or lower alkyl, or
R.sup.12 and R.sup.13 in combination form alkylene, or a
pharmaceutically acceptable salt thereof.
3. The piperazine compound of claim 1, which has the following
formula ##STR368## wherein R.sup.1 and R.sup.2 are the same or
different and each is hydrogen, halogen, lower alkyl, lower alkoxy,
amino, amino mono- or di-substituted by a group selected from the
group consisting of lower alkyl and lower acyl, nitro, hydroxy or
cyano; R.sup.3, R.sup.4 and R.sup.5 are the same or different and
each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino,
hydroxy or amino mono-or di-substituted by a group selected from
the group consisting of lower alkyl and lower acyl; R.sup.6 and
R.sup.7 are the same or different and each is hydrogen, lower
alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl
or lower acyl substituted by 1 to 3 halogen(s); R.sup.8a is lower
alkyl; and Y.sup.1 is a group of the formula ##STR369## wherein
R.sup.12 and R.sup.13 are the same or different and each is
hydrogen or lower alkyl, or R.sup.12 and R.sup.13 in combination
form alkylene, or a pharmaceutically acceptable salt thereof.
4. The piperazine compound of claim 3, wherein R.sup.8a is methyl,
or a pharmaceutically acceptable salt thereof.
5. The piperazine compound of claim 1, which has the following
formula ##STR370## wherein R.sup.1 and R.sup.2 are the same or
different and each is hydrogen, halogen, lower alkyl, lower alkoxy,
amino, amino mono-or di-substituted by a group selected from the
group consisting of lower alkyl and lower acyl, nitro, hydroxy or
cyano; R.sup.3, R.sup.4 and R.sup.5 are the same or different and
each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino,
hydroxy or amino mono-or di-substituted by a group selected from
the group consisting of lower alkyl and lower acyl; R.sup.6 and
R.sup.7 are the same or different and each is hydrogen, lower alkyl
or lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or
lower acyl substituted by 1 to 3 halogen(s); R.sup.8a and R.sup.9a
are the same or different and each is lower alkyl; and Y.sup.1 is a
group of the formula ##STR371## wherein R.sup.12 and R.sup.13 are
the same or different and each is hydrogen or lower alkyl, or
R.sup.12 and R.sup.13 in combination form alkylene, or a
pharmaceutically acceptable salt thereof.
6. The piperazine compound of claim 5, wherein R.sup.8a and
R.sup.9a are both methyl, or a pharmaceutically acceptable salt
thereof.
7. The piperazine compound of claim 1, wherein R.sup.3, R.sup.4 and
R.sup.5 are the same or different and each is hydrogen, halogen or
lower alkoxy, or a pharmaceutically acceptable salt thereof.
8. The piperazine compound of claim 1, which has the following
formula ##STR372## wherein R.sup.1 and R.sup.2 are the same or
different and each is hydrogen, halogen, lower alkyl, lower alkoxy,
amino, amino mono-or di-substituted by a group selected from the
group consisting of lower alkyl and lower acyl, nitro, hydroxy or
cyano; ring A' is a group of the formula ##STR373## wherein
R.sup.16 and R.sup.17 are the same or different and each is
hydrogen, halogen, lower alkyl, lower alkoxy or amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, and R.sup.18 is hydrogen or lower
alkyl; R.sup.6 and R.sup.7 are the same or different and each is
hydrogen, lower alkyl, lower alkyl substituted by 1 to 3
halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3
halogen(s); and Y.sup.1 is a group of the formula ##STR374##
wherein R.sup.12 and R.sup.13 are the same or different and each is
hydrogen or lower alkyl, or R.sup.12 and R.sup.13 in combination
form alkylene, or a pharmaceutically acceptable salt thereof.
9. The piperazine compound of claim 1, which has the following
formula ##STR375## wherein R.sup.1 and R.sup.2 are the same or
different and each is hydrogen, halogen, lower alkyl, lower alkoxy,
amino, amino mono- or di-substituted by a group selected from the
group consisting of lower alkyl and lower acyl, nitro, hydroxy or
cyano; ring A' is a group of the formula ##STR376## wherein
R.sup.16 and R.sup.17 are the same or different and each is
hydrogen, halogen, lower alkyl, lower alkoxy, amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, and R.sup.18 is hydrogen or lower
alkyl; R.sup.6 and R.sup.7 are the same or different and each is
hydrogen, lower alkyl, lower alkyl substituted by 1 to 3
halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3
halogen(s); R.sup.8a is lower alkyl; and Y.sup.1 is a group of the
formula ##STR377## wherein R.sup.12 and R.sup.13 are the same or
different and each is hydrogen or lower alkyl, or R.sup.12 and
R.sup.13 in combination form alkylene, or a pharmaceutically
acceptable salt thereof.
10. The piperazine compound of claim 9, wherein R.sup.8a is methyl,
or a pharmaceutically acceptable salt thereof.
11. The piperazine compound of claim 1, which has the following
formula ##STR378## wherein R.sup.1 and R.sup.2 are the same or
different and each is hydrogen, halogen, lower alkyl, lower alkoxy,
amino, amino mono- or di-substituted by a group selected from the
group consisting of lower alkyl and lower acyl, nitro, hydroxy or
cyano; ring A' is a group of the formula ##STR379## wherein
R.sup.16 and R.sup.17 are the same or different and each is
hydrogen, halogen, lower alkyl, lower alkoxy or amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, and R.sup.18 is hydrogen or lower
alkyl; R.sup.6 and R.sup.7 are the same or different and each is
hydrogen, lower alkyl, lower alkyl substituted by 1 to 3
halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3
halogen(s); R.sup.8a and R.sup.9a are the same or different and
each is lower alkyl; and Y.sup.1 is a group of the formula
##STR380## wherein R.sup.12 and R.sup.13 are the same or different
and each is hydrogen or lower alkyl, or R.sup.12 and R.sup.13 in
combination form alkylene, or a pharmaceutically acceptable salt
thereof.
12. The piperazine compound of claim 11, wherein R.sup.8a and
R.sup.9a are both methyl, or a pharmaceutically acceptable salt
thereof.
13. The piperazine compound of claim 1, wherein one of R.sup.6 and
R.sup.7 is hydrogen and the other is acyl, or a pharmaceutically
acceptable salt thereof.
14. The piperazine compound of claim 1, wherein R.sup.12 and
R.sup.13 are the same or different and each is hydrogen or methyl,
or R.sup.12 and R.sup.13 in combination form ethylene, or a
pharmaceutically acceptable salt thereof.
15. The piperazine compound of claim 1, which is a member selected
from the group consisting of
N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide,
N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,
N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,
N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamid-
e, N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,
N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide-
, N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide-
,
N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-ethyl)ace-
tamide,
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-1-methy-
lethyl)acetamide,
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)-acetamide
and
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)ac-
etamide, or a pharmaceutically acceptable salt thereof.
16. The piperazine compound of claim 1, which is a member selected
from the group consisting of
N-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamide,
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamide
and
N-(4-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-ac-
etamide, or a pharmaceutically acceptable salt thereof.
17. The piperazine compound of claim 1, which is
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)ace-
tamide, or a pharmaceutically acceptable salt thereof.
18. The piperazine compound of claim 1, which is
N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
or a pharmaceutically acceptable salt thereof.
19. (canceled)
20. A pharmaceutical composition containing the piperazine compound
of claim 1, or a pharmaceutically acceptable salt thereof, as an
active ingredient.
21.-26. (canceled)
27. The piperazine compound of claim 7, wherein one of R.sup.6 and
R.sup.7 is hydrogen and the other is acyl, or a pharmaceutically
acceptable salt thereof.
28. The piperazine compound of claim 7, wherein R.sup.12 and
R.sup.13 are the same or different and each is hydrogen or methyl,
or R.sup.12 and R.sup.13 in combination form ethylene, or a
pharmaceutically acceptable salt thereof.
29. The piperazine compound of claim 13, wherein R.sup.12 and
R.sup.13 are the same or different and each is hydrogen or methyl,
or R.sup.12 and R.sup.13 in combination form ethylene, or a
pharmaceutically acceptable salt thereof.
30. A piperazine compound of the formula ##STR381## wherein R.sup.1
and R.sup.2 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, amino, amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, nitro, hydroxy or cyano; R.sup.3,
R.sup.4 and R.sup.5 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino
mono- or di-substituted by a group selected from the group
consisting of lower alkyl and lower acyl; R.sup.6 and R.sup.7 are
the same or different and each is hydrogen, lower alkyl, lower
alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); R.sup.8 and R.sup.9 are the same
or different and each is hydrogen or lower alkyl; Y is a group of
the formula ##STR382## wherein R.sup.10 and R.sup.11 are the same
or different and each is hydrogen or lower alkyl, R.sup.12 and
R.sup.13 are the same or different and each is hydrogen or lower
alkyl, or R.sup.12 and R.sup.13 in combination form alkylene,
R.sup.14 and R.sup.15 are the same or different and each is
hydrogen or lower alkyl, m is an integer of 0-2, n is an integer of
0-2, and 0.ltoreq.m+n.ltoreq.2; and ring A is thiazolyl or
imidazolyl, provided that when one of R.sup.6 and R.sup.7 is
hydrogen and the other is butyl, in Y, both R.sup.12 and R.sup.13
are hydrogen, m and n are 0, R.sup.1, R.sup.2, R.sup.8 and R.sup.9
are hydrogen, and ring A is phenyl, then one of R.sup.3, R.sup.4
and R.sup.5 should not be 2-isopropoxy and the remaining two should
not be hydrogen, or a pharmaceutically acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a pharmaceutical agent,
particularly, a piperazine compound useful as a TNF-.alpha.
production inhibitor and/or an IL-10 production promoter, and use
thereof as a pharmaceutical agent.
BACKGROUND ART
[0002] There are a number of cytokines that have been found as
proteins involved in the expression of biological functions, such
as biological immune responses, inflammatory reactions and the
like. Of such cytokines, tumor necrosis factor alpha (hereinafter
to be referred to as TNF-.alpha.) was first found as a cytokine
having an anti-tumor effect. Subsequent studies have characterized
it as a cytokine involved in inflammations. In recent years,
TNF-.alpha. has been recognized as a cytokine broadly involved in
biophylaxis through inflammation and immune responses.
[0003] For example, TNF-.alpha. has been reported to show a
promoting effect on the production of interleukin-1 (hereinafter to
be referred to as IL-1), which is an inflammatory cytokine, and the
like, an endotoxin shock induction effect, a fibroblast
proliferation effect, a bone resorption effect, and an action to
cause arthritis, such as cartilage destruction effect and the like
[Beutler, B., et al., Nature, 316, 552-554 (1985):Peetre, C., et
al., J. Clin. Invest., 78, 1694-1700 (1986):Bevilacqua, M. P., et
al., Science, 241, 1160-1165 (1989)].
[0004] In rheumatoid arthritis, TNF-.alpha. activity has been found
in synovial fluid and sera [Macnaul, K. L., et al., J. Immunol.,
145, 4154-4166 (1990):Brennan, F. M., et al., J. Immunol., 22,
1907-1912 (1992)]. Since an anti-TNF-.alpha. chimera antibody has
been recently reported to be effective against rheumatoid arthritis
and Crohn's disease, the importance of TNF-.alpha. in these
diseases has been recognized [Elliott, M. J, et al., Arthritis
Rheum., 36, 1681-1690 (1993):VanDullemen, H. M. et al.,
Gastroenterology 109, 129-135(1995)].
[0005] Increased TNF-.alpha. concentrations have been reported in
the expectoration of patients with adult respiratory distress
syndrome (ARDS), which is a serious respiratory disease, and
TNF-.alpha. is considered to be involved in ARDS [Marks, J. D. et
al., Am. Rev. Respir. Dis. 141, 94-97 (1990), Millar, A. B. et al.,
Nature, 324, 73 (1986)]. TNF-.alpha. is also considered to be
involved in viral hepatitis and fulminant viral hepatitis [Sheron,
N. et al., Lancet 336, 321-322 (1990), Muto, Y. et al., Lancet, ii,
72-74 (1986)].
[0006] In the case of myocardial ischemia, such as acute myocardial
infarction, the TNF-.alpha. concentration in blood has been
reported to increase [Latini, R., et al., J. Cardiovasc.
Pharmacol., 23, 1-6(1990), thereby suggesting the involvement of
TNF-.alpha. in such disease state [Squadrito, F. et al.,
Inflammation Res., 45, 14-19 (1996), Lefer, A. M. et al., Science,
249, 61-64 (1990)]. More recently, TNF-.alpha. has been reported to
inhibit myocardial contraction [Finkel, M. S., et al., Science,
257, 387-389 (199.2); Pagani, D. F., et al., J. Clin. Invest., 90,
389-398 (1992)].
[0007] In addition, TNF-.alpha. has been found to be equivalent to
cachectin which is a cachexia inducer that hypercatabolizes the
systemic metabolism in cancer and infectious diseases and causes
utmost exhaustion [B. Beutler, D. Greenwald, J. D. Hulmes et al.,
Nature, 316, 552-554 (1985)].
[0008] TNF-.alpha. is listed as one of the causes of sepsis
[Starnes, H. F. Jr. et al., J. Immunol., 145, 4185-4191 (1990),
Lechner, A. J. et al., Am. J. Physiol., 263, 526-535 (1992)], and
an inhibitory effect on septic shock has been acknowledged in an
experiment using a TNF-.alpha. antibody [Starnes, H. F. Jr., et
al., J. Immunol., 145, 4185-4191 (1990); Beutler, B., et al.,
Science, 229, 869-871 (1985)].
[0009] Other than the above-mentioned, possible involvement of
TNF-.alpha. has been suggested in osteoarthritis [Lewis, A. J. et
al., Immunopharm. Immunotoxicol., 17, 607-613 (1995), Venn, G., et
al., Arthritis Rheum., 36(6), 819-826 (1993)],multiple sclerosis
(Sharief, M. K., et al., Engl. J. Med., 325(7), 467-472 (1991),
Beck, J. et al., Acta. Neurol. Scand., 78, 318-323 (1988),
Franciotta, D. M. et al., Ann. Neurol., 26, 787-789 (1989),
Hofmann, F. M. et al., J. Exp. Med., 170, 607-612 (1989), Gallo, P.
et al., J. Neuroimmunol., 23, 41-44 (1989)], Kawasaki disease
[Matsubara, T., et al., Clin. Immunol., Immunopathol., 56,29-36
(1990)], inflammatory bowel diseases such as ulcerative colitis,
Crohn's disease and the like [Murch, S. et al., Arch. Dis. Child,
66, 561 (1991), Van Dullemen et al., Gastroenterology, 109, 129-135
(1995)], Behcet's disease [Akoglu, T., et al., J. Rheumatol., 17,
1107-1108(1990)], systemic lupus erythematosus (SLE) [Maury, C. P.
J., et al., Arthritis Rheum., 32, 146-150(1989)], graft versus host
disease (GvHD) [Piruet et al., J. Exp. Med., 170, 655-663 (1987),
Holler et al., Blood, 75, 1011-1016 (1990), Irle et al., Bone
Marrow Transplant., 3, 127 (1988), Symington et al.,
Transplantation, 50, 518-521 (1990), Herve et al., Blood, 79,
3362-3368 (1992), Herve et al., Immunol. Rev., 129, 31-55 (1992),
Nestel, F. P., et al., J. Exp. Med., 175, 405-413 (1992)],
allograft rejection [Imagawa et al., Transplantation, 50, 189-193
(1990)], malaria [Grau, G. E., et al., Science, 237, 1210-1212
(1987), Grau et al., N. Engl. J. Med., 320, 1586-1591 (1989),
Kwiatkowski et al., Q. J. Med., 86, 91-98 (1993)], acquired
immunodeficiency syndrome (AIDS) [Lahdevirt et al., Am. J. Med.,
85, 289-291 (1988), Tracy, Cancer. Cell, 1, 62-63 (1989), Odeh, J.
Intern. Med., 228, 549-556 (1990), Bromberg et al., J. Immunol.,
148, 3412-3417 (1992), Wllaurie et al., AIDS, 6, 1265-1268 (1992),
Ayehunie et al., Clin. Exp. Immunol., 91, 37-42 (1993)], meningitis
[Waage, A., et al., Lancet I, 355-357(1987)], diabetes [Held, W. et
al., Proc. Natl. Acad. Sci. USA, 87, 2239-2243 (1990),
Hotamisligil, G. S., et al., Science, 259, 87-91(1993)], thermal
burn [Marano, M. A. et al., Surg. Gynecol. Obstet., 170, 32-38
(1990)], ischemia-reperfusion injury [Squadrito, F. et al., J.
Lipid Mediators 8, 53-65 (1993)], chronic heart failure [Levine, B.
et al., New Engl. J. Med., 323, 236-241 (1990)], infection [Chang
et al., Immunol. Infect. Dis., 2, 61-68 (1992), Harvell, J.
Immunol., 143, 2894-2899 (1989), Kindler et al., Cell, 56,731-740
(1989), Liew et al., Immunology, 69, 570-573 (1990), Nakane et al.,
Infect. Immun., 57, 3331-3337 (1989), Nakano et al., J. Immunol.,
144, 1935-1941 (1990), Opal et al., J. Infect. Dis., 161, 1148-1152
(1990)], contact dermatitis [Piguet et al., J. Exp. Med., 173,
673-679 (1991)], bacterial shock [Exley et al., Lancet, 335,
1275-1277 (1990)], endotoxemia [Beutler et al., Science, 229,
860-871 (1985)], demyelinating disease [Probert et al., Proc. Natl.
Acad. Sic. U.S.A., 92, 11294-11298 (1995)], fibroid lung [Piguet et
al., J. Exp. Med., 170, 655-663 (1989), Piguet et al., Nature, 344,
245-247 (1990)], osteoporosis [Ishimi et al., J. Immunol., 145,
3297-3303 (1990), MacDonald et al., Br. J. Rheumatol., 31, 149-155
(1992)], thrombus due to disseminated intravascular coagulation
(DIC) and the like [Tracy et al., Surg. Gen. Obstet., 164, 415-422
(1987), Van et al., N. Engl. J. Med., 322, 1622-1629 (1990)] and
the like.
[0010] Interleukin-10 (hereinafter to be referred to as IL-10) is a
cytokine mainly produced by type 2 helper T cells. IL-10
potentiates activity of B cells and mast cells, but for
macrophages, it is one of the inhibitory cytokines that strongly
inhibit the function of type 1 helper T cell involved in cellular
immunity, because they inhibit antigen presenting ability or
cytokine (TNF-.alpha., IL-1 and the like) production capability of
macrophages. Thus, IL-10 plays an important role in the immune
response system. For example, IL-10 has been reported to inhibit
TNF-.alpha. production by joint synovial cells in rheumatoid
arthritis [Isomaki, P, et al., Arthritis Rheum., 39, 386-395
(1996)]. It has been also reported that, when IL-10 is
intravenously injected to a healthy subject and hemocytes of the
subject are stimulated by endotoxin, TNF-.alpha. production is
inhibited [Chernoff, A. E, et al., J. Immunol., 154, 5492-5499
(1995)]. Moreover, a report has been documented that, in IL-10 gene
knockout mice, chronic colitis spontaneously occurs and, when
compared to normal mice, inflammatory cytokine (TNF-.alpha., IL-1
and the like) concentration in colon tissue significantly
increases, but that administration of IL-10 inhibits incidence of
colitis and progress of the disease [Breg D. J. et al., J. Clin.
Invest., 98, 1010 (1996)]. In the tumor cells, into which IL-10
gene has been transferred, the tumor growth can be inhibited and
metastasis of the tumor can be also inhibited [Kundu N. et al.,
Int. J. Cancer, 76, 713 (1998)]. At present, a gene recombinant
human IL-10 has been under development as a therapeutic drug of
septic shock, Crohn's disease, rheumatoid arthritis and malignant
tumor.
[0011] JP-A-52-156879 discloses a piperazine derivative useful as
an analgesic and antiphlogistic agent, psychotropic, antianxiety
drug and hypotensive agent, and JP-A-9-208570 discloses a
benzylpiperazine derivative useful as an anti-allergic agent and
anti-inflammatory agent. U.S. Pat. No. 5,569,659 discloses a
4-arylpiperazine compound and a 4-arylpiperidine compound useful as
an antipsychotic drug, and J. Med. Chem., vol. 38, pp. 4211-4222
(1995) discloses an N-aryl-N'-benzylpiperazine compound which is
useful as an antipsychotic drug. Moreover, WO92/12154 discloses an
imidazotriazine compound, and WO94/19350 discloses a
pyrazolotriazine compound, respectively as an IL-1 and TNF-.alpha.
production inhibitor.
[0012] As mentioned above, it has become clear that hyperproduction
of TNF-.alpha. causes intense effect on normal cells and various
disease states. Thus, a TNF-.alpha. production inhibitor that can
cure such disease states has been desired. However, the
anti-TNF-.alpha. antibody currently under development is associated
with therapeutic problems such as availability only as an
injection, easy generation of antibody and the like, and therefore,
it is not entirely satisfactory as a TNF-.alpha. production
inhibitor.
[0013] A pharmaceutical agent that promotes the production of IL-10
is expected to be a therapeutic agent of the diseases in which
TNF-.alpha. is involved, because IL-10 inhibits production of
TNF-.alpha.. However, such pharmaceutical agent is not commercially
available at the moment. A gene recombinant human IL-10 now being
developed is a biological preparation, which is subject to
therapeutic problems such as availability only as an injection,
easy generation of antibody and the like, as in the case of
anti-TNF-.alpha. antibody, and therefore, it is insufficient.
[0014] The compound disclosed in the above-mentioned JP-A-52-156879
has lower alkylene between phenyl and piperazine ring wherein the
lower alkylene may be methylene, ethylene, propylene, trimethylene
or ethylidene. Specific examples include only the compounds wherein
lower alkylene is ethylene or propylene. These disclosed compounds
have an analgesic and antiphlogistic effect but simultaneously have
an effect on the central nervous system. Because of the side
effects due to the effect on the central nervous system, the
development of the compound as an analgesic or antiphlogistic agent
is difficult. In addition, the compounds disclosed in WO92/12154
and WO94/19350 do not show sufficient TNF-.alpha. production
inhibitory effect, and are not satisfactory.
[0015] It is therefore an object of the present invention to
provide a compound which has a superior TNF-.alpha. production
inhibitory effect and/or IL-10 production promoting effect, has no
effect on the central nervous system, and which is useful for the
prophylaxis or treatment of autoimmune diseases, inflammatory
diseases and the like.
[0016] The present inventors have conducted intensive studies with
the purpose of solving the above-mentioned problems and found that,
of the compounds described in JP-A-52-156879, a compound wherein
lower alkylene between phenyl and piperazine ring is methylene or
methylene substituted by lower alkyl, which compound is not
concretely disclosed therein, has superior TNF-.alpha. production
inhibitory effect and/or IL-10 production promoting effect and is
free of or shows only strikingly reduced expression of an effect on
the central nervous system, which resulted in the completion of the
present invention.
DISCLOSURE OF THE INVENTION
[0017] Accordingly, the present invention provides the
following.
[0018] (1) A piperazine compound of the formula ##STR2## wherein
[0019] R.sup.1 and R.sup.2 are the same or different and each is
hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, nitro, hydroxy or cyano; [0020]
R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is
hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy
or amino mono- or di-substituted by a group selected from the group
consisting of lower alkyl and lower acyl; [0021] R.sup.6 and
R.sup.7 are the same or different and each is hydrogen, lower
alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl
or lower acyl substituted by 1 to 3 halogen(s); [0022] R.sup.8 and
R.sup.9 are the same or different and each is hydrogen or lower
alkyl; [0023] Y is a group of the formula ##STR3## wherein R.sup.10
and R.sup.11 are the same or different and each is hydrogen or
lower alkyl, R.sup.12 and R.sup.13 are the same or different and
each is hydrogen or lower alkyl, or R.sup.12 and R.sup.13 in
combination form alkylene, R.sup.14 and R.sup.15 are the same or
different and each is hydrogen or lower alkyl, m is an integer of
0-2, n is an integer of 0-2, and 0.ltoreq.m+n=.ltoreq.2; and [0024]
ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or
imidazolyl, [0025] provided that when one of R.sup.6 and R.sup.7 is
hydrogen and the other is butyl, in Y, both R.sup.12 and R.sup.13
are hydrogen, m and n are 0, R.sup.1, R.sup.2, R.sup.8 and R.sup.9
are hydrogen, and ring A is phenyl, one of R.sup.3, R.sup.4 and
R.sup.5 should not be 2-isopropoxy and the remaining two should not
be hydrogen, and a pharmaceutically acceptable salt thereof.
[0026] (2) The piperazine compound of the above-mentioned (1),
which has the following formula ##STR4## wherein [0027] R.sup.1 and
R.sup.2 are the same or different and each is hydrogen, halogen,
lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by
a group selected from the group consisting of lower alkyl and lower
acyl, nitro, hydroxy or cyano; [0028] R.sup.3, R.sup.4 and R.sup.5
are the same or different and each is hydrogen, halogen, lower
alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl; [0029] R.sup.6 and R.sup.7 are the same
or different and each is hydrogen, lower alkyl, lower alkyl
substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); and [0030] Y.sup.1 is a group of
the formula ##STR5## wherein R.sup.12 and R.sup.13 are the same or
different and each is hydrogen or lower alkyl, or R.sup.12 and
R.sup.13 in combination form alkylene, [0031] provided that when
one of R.sup.6 and R7 is hydrogen and the other is butyl, in
Y.sup.1, both R.sup.12 and R.sup.13 are hydrogen and R.sup.1 and
R.sup.2 are hydrogen, one of R.sup.3, R.sup.4 and R.sup.5 should
not be 2-isopropoxy and the remaining two should not be hydrogen,
and a pharmaceutically acceptable salt thereof.
[0032] (3) The piperazine compound of the above-mentioned (1),
which has the following formula ##STR6## wherein [0033] R.sup.1 and
R.sup.2 are the same or different and each is hydrogen, halogen,
lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by
a group selected from the group consisting of lower alkyl and lower
acyl, nitro, hydroxy or cyano; [0034] R.sup.3, R.sup.4 and R.sup.5
are the same or different and each is hydrogen, halogen, lower
alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono-or
di-substituted by a group selected from the group consisting of
lower alkyl, and lower acyl; [0035] R.sup.6 and R.sup.7 are the
same or different and each is hydrogen, lower alkyl, lower alkyl
substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); [0036] R.sup.8a is lower alkyl;
and [0037] Y.sup.1 is a group of the formula ##STR7## wherein
R.sup.12 and R.sup.13 are the same or different and each is
hydrogen or lower alkyl, or R.sup.12 and R.sup.13 in combination
form alkylene, and a pharmaceutically acceptable salt thereof.
[0038] (4) The piperazine compound of the above-mentioned (3),
wherein R.sup.8a is methyl and a pharmaceutically acceptable salt
thereof.
[0039] (5) The piperazine compound of the above-mentioned (1),
which has the following formula ##STR8## wherein [0040] R.sup.1 and
R.sup.2 are the same or different and each is hydrogen, halogen,
lower alkyl, lower alkoxy, amino, amino mono-or di-substituted by a
group selected from the group consisting of lower alkyl and lower
acyl, nitro, hydroxy or cyano; [0041] R.sup.3 R.sup.4 and R.sup.5
are the same or different and each is hydrogen, halogen, lower
alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono-or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl; [0042] R.sup.6 and R7 are the same or
different and each is hydrogen, lower alkyl, lower alkyl
substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); [0043] R.sup.8a and R.sup.9a are
the same or different and each is lower alkyl; and [0044] Y.sup.1
is a group of the formula ##STR9## wherein R.sup.12 and R.sup.13
are the same or different and each is hydrogen or lower alkyl, or
R.sup.12 and R.sup.13 in combination form alkylene, and a
pharmaceutically acceptable salt thereof.
[0045] (6) The piperazine compound of the above-mentioned (5),
wherein R.sup.8a and R.sup.9a are both methyl, and a
pharmaceutically acceptable salt thereof.
[0046] (7) The piperazine compound of any of the above-mentioned
(1) to (6), wherein R.sup.3, R.sup.4 and R.sup.5 are the same or
different and each is hydrogen, halogen or lower alkoxy, and a
pharmaceutically acceptable salt thereof.
[0047] (8) The piperazine compound of the above-mentioned (1),
which has the following formula ##STR10## wherein [0048] R.sup.1
and R.sup.2 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, amino, amino mono-or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, nitro, hydroxy or cyano; [0049] ring A'
is a group of the formula ##STR11## wherein R.sup.16 and R.sup.17
are the same or different and each is hydrogen, halogen, lower
alkyl, lower alkoxy or amino mono- or di-substituted by a group
selected from the group consisting of lower alkyl and lower acyl,
and R.sup.18 is hydrogen or lower alkyl; [0050] R.sup.6 and R.sup.7
are the same or different and each is hydrogen, lower alkyl, lower
alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); and [0051] Y.sup.1 is a group of
the formula ##STR12## wherein R.sup.12 and R.sup.13 are the same or
different and each is hydrogen or lower alkyl, or R.sup.12 and
R.sup.13 in combination form alkylene, and a pharmaceutically
acceptable salt thereof.
[0052] (9) The piperazine compound of the above-mentioned (1),
which has the following formula ##STR13## wherein [0053] R.sup.1
and R.sup.2 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, amino, amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, nitro, hydroxy or cyano; [0054] ring A'
is a group of the formula ##STR14## wherein R.sup.16 and R.sup.17
are the same or different and each is hydrogen, halogen, lower
alkyl, lower alkoxy, amino mono- or di-substituted by a group
selected from the group consisting of lower alkyl and lower acyl,
and R.sup.18 is hydrogen or lower alkyl; [0055] R.sup.6 and R.sup.7
are the same or different and each is hydrogen, lower alkyl, lower
alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); [0056] R.sup.8a is lower alkyl;
and [0057] Y.sup.1 is a group of the formula ##STR15## wherein
R.sup.12 and R.sup.13 are the same or different and each is
hydrogen or lower alkyl, or R.sup.12 and R.sup.13 in combination
form alkylene, and a pharmaceutically acceptable salt thereof.
[0058] (10) The piperazine compound of the above-mentioned (9),
wherein R.sup.8a is methyl, and a pharmaceutically acceptable salt
thereof.
[0059] (11) The piperazine compound of the above-mentioned (1),
which has the following formula ##STR16## wherein [0060] R.sup.1
and R.sup.2 are the same or different and each is hydrogen,
halogen, lower alkyl, lower alkoxy, amino, amino mono- or
di-substituted by a group selected from the group consisting of
lower alkyl and lower acyl, nitro, hydroxy or cyano; [0061] ring A'
is a group of the formula ##STR17## wherein R.sup.16 and R.sup.17
are the same or different and each is hydrogen, halogen, lower
alkyl, lower alkoxy or amino mono- or di-substituted by a group
selected from the group consisting of lower alkyl and lower acyl,
and R.sup.18 is hydrogen or lower alkyl; [0062] R.sup.6 and R.sup.7
are the same or different and each is hydrogen, lower alkyl, lower
alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl
substituted by 1 to 3 halogen(s); [0063] R.sup.8a and R.sup.9a are
the same or different and each is lower alkyl; and [0064] Y.sup.1
is a group of the formula ##STR18## wherein R.sup.12 and R.sup.13
are the same or different and each is hydrogen or lower alkyl, or
R.sup.12 and R.sup.13 in combination form alkylene, and a
pharmaceutically acceptable salt thereof.
[0065] (12) The piperazine compound of the above-mentioned (11),
wherein R.sup.8a and R.sup.9a are both methyl, and a
pharmaceutically acceptable salt thereof.
[0066] (13) The piperazine compound of any of the above-mentioned
(1) to (12), wherein one of R.sup.6 and R.sup.7 is hydrogen and the
other is acyl, and a pharmaceutically acceptable salt thereof.
[0067] (14) The piperazine compound of any of the above-mentioned
(1) to (13), wherein R.sup.12 and R.sup.13 are the same or
different and each is hydrogen or methyl, R.sup.12 and R.sup.13 in
combination form ethylene, and a pharmaceutically acceptable salt
thereof.
[0068] (15) The piperazine compound of the above-mentioned (1),
(2), (7), (13) or (14), which is a member selected from the group
consisting of [0069]
N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide, [0070]
N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acet-
amide, [0071]
N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,
[0072]
N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)--
acetamide, [0073]
N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,
[0074]
N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide-
, [0075]
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,
[0076]
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)--
acetamide, [0077]
N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-ethyl)aceta-
mide, [0078]
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)a-
cetamide, [0079]
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)-acetamide
and [0080]
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclop-
ropyl)acetamide, and a pharmaceutically acceptable salt
thereof.
[0081] (16) The piperazine compound of the above-mentioned (1),
(3), (4), (7), (13) or (14), which is a member selected from the
group consisting of [0082]
N-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamide,
[0083]
N-(4-(l-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-ac-
etamide and [0084]
N-(4-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetami-
de, and a pharmaceutically acceptable salt thereof.
[0085] (17) The piperazine compound of the above-mentioned (1),
(5)-(7), (13) or (14), which is
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)
acetamide, and a pharmaceutically acceptable salt thereof.
[0086] (18) The piperazine compound of the above-mentioned (1),
(7), (8), (13) or (14), which is a member selected from the group
consisting of [0087]
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acet-
amide, [0088]
N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide-
, [0089]
N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-cyclo-
propyl)acetamide, [0090]
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-formamide,
[0091]
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-prop-
ionamide, [0092]
N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
and [0093]
N-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetami-
de, and a pharmaceutically acceptable salt thereof.
[0094] (19) The piperazine compound of the above-mentioned (1),
(7), (9), (10), (13) or (14), which is
N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)ace-
tamide, and a pharmaceutically acceptable salt thereof.
[0095] (20) A pharmaceutical composition containing the piperazine
compound of any of the above-mentioned (1) to (19) or a
pharmaceutically acceptable salt thereof as an active
ingredient.
[0096] (21) A TNF-.alpha. production inhibitor and/or IL-10
production promoter containing the piperazine compound of any of
the above-mentioned (1) to (19) or a pharmaceutically acceptable
salt thereof as an active ingredient.
[0097] (22) An agent for the prophylaxis or treatment of diseases
caused by abnormal TNF-.alpha. production, TNF-.alpha. mediated
diseases or diseases curable with IL-10, which contains the
piperazine compound of any of the above-mentioned (1) to (19) or a
pharmaceutically acceptable salt thereof as an active
ingredient.
[0098] (23) An agent for the prophylaxis or treatment of an
inflammatory disease, which contains the piperazine compound of any
of the above-mentioned (1) to (19) or a pharmaceutically acceptable
salt thereof as an active ingredient.
[0099] (24) An agent for the prophylaxis or treatment of an
autoimmune disease, which contains the piperazine compound of any
of the above-mentioned (1) to (19) or a pharmaceutically acceptable
salt thereof as an active ingredient.
[0100] (25) An agent for the prophylaxis or treatment of rheumatoid
arthritis, which contains the piperazine compound of any of the
above-mentioned (1) to (19) or a pharmaceutically acceptable salt
thereof as an active ingredient.
[0101] (26) An agent for the prophylaxis or treatment of an
allergic disease, which contains the piperazine compound of any of
the above-mentioned (1) to (19) or a pharmaceutically acceptable
salt thereof as an active ingredient.
[0102] The groups shown by respective symbols in the specification
are explained in the following.
[0103] Halogen at R.sup.1 and R.sup.2 is fluorine, chlorine,
bromine or iodine.
[0104] Lower alkyl at R.sup.1 and R.sup.2 is alkyl having 1 to 4
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl and the like.
[0105] Lower alkoxy at R.sup.1 and R.sup.2 is alkoxy having 1 to 4
carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
tert-butoxy and the like.
[0106] With regard to the amino mono- or di-substituted by a group
selected from lower alkyl and lower acyl at R.sup.1 and R.sup.2,
lower alkyl as a substituent means alkyl having 1 to 4 carbon
atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl and the like. Lower acyl as a substituent means lower
alkanoyl having 1 to 4 carbon atoms, lower alkoxycarbonyl having 1
to 4 carbon atoms or C.sub.1-C.sub.4 lower alkanoyl substituted by
phenyl. Examples thereof include formyl, acetyl, propionyl,
butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl.
Amino mono- or di-substituted by these substituents means
methylamino, dimethylamino, ethylamino, diethylamino, propylamino,
butylamino, acetylamino, diacetylamino, propionylamino,
dipropionylamino, butyrylamino, N-methyl-N-acetylamino,
N-ethyl-N-acetylamino, N-methyl-N-propionylamino,
methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,
tert-butoxycarbonylamino, benzoylamino, phenylacetylamino and the
like.
[0107] Halogen at R.sup.3, R.sup.4 and R.sup.5 is fluorine,
chlorine, bromine or iodine.
[0108] Lower alkyl at R.sup.3, R.sup.4 and R.sup.5 means alkyl
having 1 to 4 carbon atoms, such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl and the like.
[0109] Lower alkoxy at R.sup.3, R.sup.4 and R.sup.5 means alkoxy
having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, tert-butoxy and the like.
[0110] With regard to the amino mono- or di-substituted by a group
selected from lower alkyl and lower acyl at R.sup.3, R.sup.4 and
R.sup.5, lower alkyl as a substituent means alkyl having 1 to 4
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl and the like. Lower acyl as a substituent
means lower alkanoyl having 1 to 4 carbon atoms, lower
alkoxycarbonyl having 1 to 4 carbon atoms or C.sub.1-C.sub.4 lower
alkanoyl substituted by phenyl. Examples thereof include formyl,
acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, phenylacetyl and
phenylpropionyl. The amino mono- or di-substituted by these
substituents may be methylamino, dimethylamino, ethylamino,
diethylamino, propylamino, butylamino, acetylamino, diacetylamino,
propionylamino, dipropionylamino, butyrylamino,
N-methyl-N-acetylamino, N-ethyl-N-acetylamino,
N-methyl-N-propionylamino, methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino,
tert-butoxycarbonylamino, benzoylamino, phenylacetylamino and the
like.
[0111] Lower alkyl at R.sup.6 and R.sup.7 means alkyl having 1 to 4
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl and the like.
[0112] The lower alkyl substituted by 1 to 3 halogen(s) at R.sup.6
and R.sup.7 is C.sub.1-C.sub.4 lower alkyl substituted by halogen
(e.g., fluorine, chlorine, bromine and the like). Examples thereof
include fluoromethyl, trifluoromethyl, chloromethyl, bromomethyl,
2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl,
3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl and
the like.
[0113] Aralkyl at R.sup.6 and R.sup.7 means benzyl, 2-phenylethyl,
3-phenylpropyl and the like,
[0114] Acyl at R.sup.6 and R.sup.7 means alkanoyl having 1 to 5
carbon atoms, lower alkoxycarbonyl having 1 to 4 carbon atoms,
C.sub.1-C.sub.4 lower alkanoyl substituted by phenyl or pyridyl, or
C.sub.1-C.sub.4 lower alkylsulfonyl. Examples thereof include
formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl,
trimethylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, benzoyl, nicotinoyl, isonicotinoyl,
picolinoyl, phenylacetyl, phenylpropionyl, methanesulfonyl and the
like.
[0115] Lower acyl substituted by 1 to 3 halogen(s) at R.sup.6 and
R.sup.7 is C.sub.1-C.sub.4 lower acyl substituted by halogen (e.g.,
fluorine, chlorine, bromine and the like). Examples thereof include
fluoroacetyl, trifluoroacetyl, chloroacetyl, bromoacetyl,
3-chloropropionyl, 3-bromopropionyl, 4-chlorobutyryl,
4-bromobutyryl and the like.
[0116] Lower alkyl at R.sup.8 and R.sup.9 means alkyl having 1 to 4
carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl and the like.
[0117] Lower alkyl at R.sup.10 and R.sup.11 means alkyl having 1 to
4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and
the like.
[0118] Lower alkyl at R.sup.12 and R.sup.13 means alkyl having 1 to
4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and
the like.
[0119] The alkylene formed by R.sup.12 and R.sup.13 in combination
means methylene, ethylene, trimethylene, tetramethylene,
pentamethylene and the like.
[0120] Lower alkyl at R.sup.14 and R.sup.15 means alkyl having 1 to
4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and
the like.
[0121] Halogen at R.sup.16 and R.sup.17 means fluorine, chlorine,
bromine or iodine.
[0122] Lower alkyl at R.sup.16 and R.sup.17 means alkyl having 1 to
4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl and the like.
[0123] Lower alkoxy at R16 and R.sup.17 means alkoxy having 1 to 4
carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
tert-butoxy and the like.
[0124] With regard to the amino mono- or di-substituted by a group
selected from lower alkyl and lower acyl at R.sup.16 and R .sup.17,
lower alkyl as a substituent means alkyl having 1 to 4 carbon
atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl and the like. Lower acyl as a substituent means lower
alkanoyl having 1 to 4 carbon atoms, lower alkoxycarbonyl having 1
to 4 carbon atoms or C.sub.1-C.sub.4 lower alkanoyl substituted by
phenyl. Examples thereof include formyl, acetyl, propionyl,
butyryl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, benzoyl, phenylacetyl and phenylpropionyl. The
amino mono- or di-substituted by these substituents is exemplified
by methylamino, dimethylamino, ethylamino, diethylamino,
propylamino, butylamino, acetylamino, diacetylamino,
propionylamino, dipropionylamino, butyrylamino,
N-methyl-N-acetylamino, N-ethyl-N-acetylamino,
N-methyl-N-propionylamino, methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino,
tert-butoxycarbonylamino, benzoylamino, phenylacetylamino and the
like.
[0125] Lower alkyl at R.sup.18 means alkyl having 1 to 4 carbon
atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl and the like.
[0126] Ring A is ##STR19## wherein each symbol is as defined in the
above. Ring A' is 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrazyl or 2-imidazolyl, mentioned above, with
preference given to the above-mentioned 2-pyrimidyl, 2-thiazolyl,
2-pyridyl or 2-imidazolyl.
[0127] The pharmaceutically acceptable salt of the compound (I) of
the present invention is, for example, a salt with inorganic acid
such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, a salt
with organic acid such as acetic acid, maleic acid, fumaric acid,
benzoic acid, citric acid, succinic acid, tartaric acid, malic
acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, 10-camphorsulfonic acid and the like. The
compound of the present invention can be converted to a quaternary
ammonium salt. The compound of the present invention (I) and a
pharmaceutically acceptable salt thereof may be a hydrate
(monohydrate, 1/2 hydrate, 1/4 hydrate, 1/5 hydrate, dihydrate, 3/2
hydrate, 3/4 hydrate and the like) or a solvate. When the inventive
compound (I) has an asymmetric carbon, at least two optical isomers
exist. The present invention encompasses these optical isomers and
racemates thereof.
[0128] The compound of the present invention can be produced by,
for example, the following methods. Method A ##STR20## wherein Lv
is a leaving group widely used in the organic synthetic chemistry,
such as halogen (e.g, fluorine, chlorine, bromine or iodine),
methanesulfonyloxy, p-toluenesulfonyloxy and
trifluoromethane-sulfonyloxy, P.sup.1 and P.sup.2 encompass R.sup.6
and R.sup.7 defined earlier, and further mean an amino-protecting
group widely used in the organic synthetic chemistry, such as
benzyloxycarbonyl, P.sup.1 and P.sup.2 may form an imido group,
such as phthalimide, together with the adjacent nitrogen atom and
other symbols are as defined above. When R.sup.3, R.sup.4 and
R.sup.5 have a functional group such as amino, hydroxy and the
like, they may be protected as necessary.
[0129] The base to be used for the condensation of compound (II)
and compound (III) may be, for example, potassium carbonate,
potassium hydrogencarbonate, sodium carbonate, sodium
hydrogencarbonate, sodium hydroxide, sodium methoxide, sodium
ethoxide, sodium hydride, potassium hydride, lithium
diisopropylamide, butyl lithium, lithium hexamethyldisilazane,
triethylamine, diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undeca-7-ene, pyridine and
4-dimethylaminopyridine.
[0130] The solvent to be used for the condensation may be, for
example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, benzene, dichloromethane, dichloroethane,
chloroform, toluene, xylene, hexane, dimethylformamide, dimethyl
sulfoxide, water and a mixture thereof.
[0131] The reaction temperature of condensation is generally from
-80.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0132] The reaction time of condensation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0133] After condensation under the above-mentioned reaction
conditions, a protecting group(s) is/are removed as necessary,
after which compound (I) can be purified by a method known in the
field of organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0134] The compound (III) may be a commercially available one or
may be synthesized from bis(2-chloro or bromoethyl)amine and
substituted aromatic amine according to the method disclosed in
Journal of Medicinal Chemistry (J. Med. Chem.), vol. 29, pp.
630-634 (1986) or Tetrahedron Letters, vol. 37, pp. 319-322 (1996).
Alternatively, it can be synthesized by treating
bis(2-hydroxyethyl)amine and substituted aromatic amine in an
aqueous hydrochloric acid solution.
Method B
[0135] Compound (I) wherein one of R.sup.6 and R.sup.7 is acyl and
the other is hydrogen is hydrolyzed to give compound (I-1) wherein
R.sup.6 and R.sup.7 of compound (I) are hydrogen ##STR21## wherein
each symbol is as defined above.
[0136] Hydrolysis can be performed under both acidic conditions and
basic conditions. When acidic conditions are employed, mineral acid
(e.g., hydrochloric acid, sulfuric acid and the like), preferably a
concentrated or diluted aqueous hydrochloric acid solution, is used
and, as an organic co-solvent, for example, methanol, ethanol,
tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl
ether, dimethylformamide, dimethyl sulfoxide, acetonitrile or a
mixture thereof is used. When basic conditions are employed, the
base to be used may be, for example, sodium hydroxide, potassium
hydroxide, lithium hydroxide or barium hydroxide. The solvent used
may be, for example, water, methanol, ethanol, tert-butyl alcohol,
tetrahydrofuran, dimethylformamide, dimethyl sulfoxide,
acetonitrile or a mixture thereof.
[0137] The reaction temperature of hydrolysis is generally from
-20.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0138] The reaction time of hydrolysis is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0139] After hydrolysis under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-1) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0140] The methods (Method B1 to Method B8) for modifying the amino
group of compound (I-1) are explained in the following. Method B1
##STR22## wherein R.sup.a is C.sub.1-C.sub.4 alkyl optionally
substituted by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine
and the like), Hal is halogen (e.g., chlorine, bromine, iodine and
the like), R.sup.b is C.sub.1-C.sub.4 alkyl optionally substituted
by 1 to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the
like), R.sup.c is C.sub.1-C.sub.4 alkyl optionally substituted by 1
to 3 halogen(s) (e.g., fluorine, chlorine, bromine and the like),
and the other symbols are as defined above.
[0141] The base to be used for condensation of compound (I-1) may
be, for example, triethylamine, diisopropylethylamine, potassium
carbonate, potassium hydrogencarbonate, sodium carbonate, sodium
hydrogencarbonate, sodium hydroxide, sodium methoxide, sodium
ethoxide, pyridine and 4-dimethylaminopyridine.
[0142] The solvent to be used for condensation may be, for example,
water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, benzene, dichloromethane, dichloroethane,
chloroform, ethyl acetate, toluene, xylene, hexane,
dimethylformamide, dimethyl sulfoxide and a mixture thereof.
[0143] The reaction temperature of condensation is generally from
-20.degree. C. to 80.degree. C., and a temperature above or under
this range can be employed as necessary.
[0144] The reaction time of condensation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0145] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-2) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin. Method B2 ##STR23## wherein each symbol is as
defined above.
[0146] The reducing agent to be used for reduction of amide group
in compound (I-2) may be, for example, metallic reducing reagent
such as aluminum lithium hydride, sodium borohydride, lithium
borohydride and the like, or diborane.
[0147] The solvent to be used for reduction of amide group may be,
for example, tetrahydrofuran, dioxane, diethyl ether, methanol,
ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene
glycol dimethyl ether, a mixture thereof and the like.
[0148] The reaction temperature of reduction of amino group is
generally from -20.degree. C. to 80.degree. C., and a temperature
above or under this range can be employed as necessary.
[0149] The reaction time of reduction of amide group is generally
from 30 minutes to 10 hours, and a time longer or shorter than this
range can be employed as necessary.
[0150] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-3) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method B3
[0151] Compound (I-3) can be also produced by the following method.
##STR24## wherein each symbol is as defined above.
[0152] The reducing agent to be used for reductive amination of
compound (I-1) may be, for example, sodium borohydride or sodium
cyanoborohydride, and catalytic reduction using transition metal
(e.g., palladium-carbon, platinum oxide, Raney nickel, rhodium,
ruthenium) is also effective.
[0153] The solvent to be used for reductive amination may be, for
example, water, methanol, ethanol, 1-propanol, 2-propanol,
tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether,
ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic
acid, benzene, toluene, xylene, dimethylformamide, dimethyl
sulfoxide or a mixture thereof.
[0154] The reaction temperature of reductive amination is generally
from -20.degree. C. to 150.degree. C., and a temperature above or
under this range can be employed as necessary.
[0155] The reaction time of reductive amination is generally from
30 minutes to 2 days, and a time longer or shorter than this range
can be employed as necessary.
[0156] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-3) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin. Method B4 ##STR25## wherein R.sup.d is hydrogen or
C.sub.1-C.sub.4 alkyl optionally substituted by 1 to 3 halogen(s)
(e.g., fluorine, chlorine, bromine and the like), and the other
symbols are as defined above.
[0157] The reaction conditions (reagent, reaction solvent, reaction
time) of acylation are the same as in Method B1.
[0158] After acylation under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-4) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin. Method B5 ##STR26## wherein each symbol is as
defined above.
[0159] The reaction conditions (reagent, reaction solvent, reaction
time) of reduction are the same as in Method B2.
[0160] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-5) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin. Method B6 ##STR27## wherein R.sup.e is
C.sub.1-C.sub.4 alkyl optionally substituted by 1 to 3 halogen(s)
(e.g., fluorine, chlorine, bromine and the like), and the other
symbols are as defined above.
[0161] In this reaction, the acyl moiety (R.sup.c--C.dbd.O) is
preferably electron-withdrawing group such as trifluoroacetyl and
the like.
[0162] The base to be used for condensation of compound (I-2) may
be, for example, sodium hydroxide, sodium methoxide, sodium
ethoxide, sodium hydride, potassium hydride, lithium
diisopropylamide, butyl lithium, phenyl lithium, lithium
hexamethyldisilazane, triethylamine, diisopropylethylamine or
1,8-diazabicyclo[5.4.0]undeca-7-ene.
[0163] The solvent to be used for condensation may be, for example,
methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,
tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl
ether, dichloromethane, dichloroethane, chloroform, benzene,
toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide or a
mixture thereof.
[0164] The reaction temperature of condensation is generally from
-80.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0165] The reaction time of condensation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0166] After condensation under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-6) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin. Method B7 ##STR28## wherein each symbol is as
defined above.
[0167] Hydrolysis is performed under the same reaction conditions
as in Method B.
[0168] After hydrolysis under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-7) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin. Method B8 ##STR29## wherein each symbol is as
defined above.
[0169] The reduction is performed under the same reaction
conditions as in Method B2.
[0170] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-5a) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method C
[0171] Compound (I) can be also produced by the following method.
##STR30## wherein each symbol is as defined above.
[0172] The reaction conditions (reagent, reaction solvent, reaction
time) of condensation are the same as in the condensation in Method
A.
[0173] After condensation under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method D
[0174] Compound (I-1) can be also produced by the following method.
##STR31## wherein each symbol is as defined above.
[0175] The metal azide compound to be used for the azidation of
compound (VIII) is exemplified by sodium azide, lithium azide and
the like.
[0176] The solvent to be used for azidation may be, for example,
water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, acetone, ethyl acetate, acetic acid, benzene,
toluene, xylene, dimethylformamide, dimethyl sulfoxide or a mixture
thereof.
[0177] The reaction temperature of azidation is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0178] The reaction time of azidation is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0179] The reducing agent to be used for reduction of the azide
group in compound (X) may be, for example, a metallic reducing
reagent such as aluminum lithium hydride, sodium borohydride,
lithium borohydride, sodium cyanoborohydride and the like, diborane
or triphenylphosphine, and catalytic reduction using transition
metal (e.g., palladium-carbon, platinum oxide, Raney nickel,
rhodium, ruthenium) is also effective.
[0180] The solvent to be used for reduction of the azide group may
be, for example, water, methanol, ethanol, 1-propanol, 2-propanol,
tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether,
ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic
acid, benzene, toluene, xylene, dimethylformamide, dimethyl
sulfoxide or a mixture thereof.
[0181] The reaction temperature of reduction of the azide group is
generally from -20.degree. C. to 150.degree. C., and a temperature
above or under this range can be employed as necessary.
[0182] The reaction time of reduction of the azide group is
generally from 30 minutes to 2 days, and a time longer or shorter
than this range can be employed as necessary.
[0183] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method E
[0184] Compound (I-1) can be also produced by the following method.
##STR32## wherein each symbol is as defined above.
[0185] The solvent to be used for condensation of compound (VIII)
may be, for example, water, methanol, ethanol, 1-propanol,
2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl
ether, ethylene glycol dimethyl ether, acetone, ethyl acetate,
acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl
sulfoxide or a mixture thereof.
[0186] The reaction temperature of condensation is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0187] The reaction time of condensation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0188] The base to be used for cleavage of compound (XI) may be,
for example, hydrazine hydrate, methyl hydrazine, phenyl hydrazine,
sodium hydroxide, potassium hydroxide, barium hydroxide or lithium
hydroxide.
[0189] The solvent to be used for cleavage may be, for example,
water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, acetone, dimethylformamide, dimethyl sulfoxide or a
mixture thereof.
[0190] The reaction temperature of cleavage is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0191] The reaction time of cleavage is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0192] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method F
[0193] Compound (XI) can be also produced by the following method.
##STR33## wherein each symbol is as defined above.
[0194] The reagent to be used for Mitsunobu reaction may be, for
example, dialkyl azodicarboxylate (wherein alkyl means lower alkyl
such as ethyl, propyl, isopropyl, butyl, isobutyl and the like) and
triphenylphosphine.
[0195] The solvent to be used for Mitsunobu reaction may be, for
example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, acetone, dimethylformamide, dimethyl sulfoxide or a
mixture thereof.
[0196] The reaction temperature of Mitsunobu reaction is generally
from -80.degree. C to 100.degree. C., and a temperature above or
under this range can be employed as necessary.
[0197] The reaction time of Mitsunobu reaction is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0198] After Mitsunobu reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (XI) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method G
[0199] Compound (I) can be also produced by the following method.
##STR34## wherein Q is the aforementioned leaving group, Lv and its
precursor hydroxyl group with or without protection with a suitable
protecting group, which can be easily converted to Lv by a method
known in the field of organic synthetic chemistry, and other
symbols are as defined above.
[0200] The reaction conditions of the condensation of compound
(XIII) and compound (IX) are the same as in the conditions for
Method C, Method D and Method E. The group Q of the obtained
compound (XIV) is converted to a leaving group Lv as necessary by a
method known in the field of organic synthetic chemistry, and
condensed with compound (III) in the same manner as in Method A,
which is followed by, where necessary, removal of protecting
group(s) to produce compound (I).
[0201] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method H
[0202] Compound (I) can be also produced by the following method.
##STR35## wherein each symbol is as defined above.
[0203] The reaction conditions of the condensation of compound (XV)
and compound (III) are the same as in the conditions for Method A.
The group Q of the obtained compound (XVI) is converted to a
leaving group Lv by a method known in the field of organic
synthetic chemistry. Then, in the same manner as in Method C,
Method D and Method E, it is condensed with compound (IX) and,
where necessary, the protecting group(s) is/are removed to produce
compound (I).
[0204] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method I
[0205] Compound (I) can be also produced by the following method.
##STR36## wherein each symbol is as defined above.
[0206] The reaction conditions (reagent, reaction solvent, reaction
time) of condensation of compound (II) and compound (XVII) are the
same as in Method A.
[0207] The group Q of the obtained compound (XVIII) is converted to
a leaving group Lv as necessary by a method known in the field of
organic synthetic chemistry. In the same manner as in Method A, it
is condensed with compound (XIX) and, where necessary, the
protecting group(s) is/are removed to produce compound (I).
[0208] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method J
[0209] Compound (I) can be also produced by the following method.
##STR37## wherein each symbol is as defined above.
[0210] The reaction conditions (reagent, reaction solvent, reaction
time) of condensation in this method are the same as in Method
A.
[0211] After condensation under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0212] The compound (XXI) can be produced by condensing compound
(XIX) with compound (XXIIa) ##STR38## wherein Q, Hal and R are as
defined above, in the same manner as in Method A to give compound
(XXIIb) (wherein each symbol is as defined above), and converting
the group Q of compound (XXIIb) to a leaving group Lv as necessary
by a method known in the field of organic synthetic chemistry. The
compound (XXIIb) can be produced by condensing compound (XIX) with
compound (XXIIc) (wherein R is lower alkyl having 1 to 4 carbon
atoms and Hal is as defined above) in the same manner as in Method
A to give compound (XXIId) (wherein each symbol is as defined
above), and converting the resulting compound by a method known in
the field of organic synthetic chemistry.
[0213] The reaction conditions (reagent, reaction solvent, reaction
time) of condensation are the same as in Method A.
[0214] The reducing agent to be used for reduction of the ester
group in compound (XXIId) may be, for example, a metallic reducing
reagent such as aluminum lithium hydride, sodium borohydride,
lithium borohydride and the like, or diborane.
[0215] The solvent to be used for reduction of the ester group may
be, for example, tetrahydrofuran, dioxane, diethyl ether, methanol,
ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethylene
glycol dimethyl ether or a mixture thereof.
[0216] The reaction temperature of reduction of the ester group is
generally from -20.degree. C. to 80.degree. C., and a temperature
above or under this range can be employed as necessary.
[0217] The reaction time of reduction of the ester group is
generally from 30 minutes to 10 hours, and a time longer or shorter
than this range can be employed as necessary.
[0218] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (XXIIb) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method K
[0219] Compound (I) can be also produced by the following method.
##STR39## wherein L.sub.v1 is a leaving group widely used in
aromatic nucleophilic substitution reaction, such as halogen (e.g.,
fluorine, chlorine, bromine or iodine), nitro,
p-toluenesulfonyloxy, methanesulfonyloxy,
trifluoromethanesulfonyloxy, benzenesulfenyl, benzenesulfonyl,
azido, aryloxy, alkoxy, alkylthio or amino, and the other symbols
are as defined above.
[0220] The solvent to be used for aromatic nucleophilic
substitution reaction of compound (XXIII) may be, for example,
methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,
tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl
ether, benzene, dichloromethane, dichloroethane, chloroform,
toluene, xylene, hexane, dimethylformamide, dimethyl sulfoxide,
acetonitrile or a mixture thereof.
[0221] For aromatic nucleophilic substitution reaction, a catalyst
such as copper powder, copper oxide and the like can be added as
necessary.
[0222] The reaction temperature of aromatic nucleophilic
substitution reaction is generally from 0.degree. C. to 150.degree.
C., and a temperature above or under this range can be employed as
necessary.
[0223] The reaction time of aromatic nucleophilic substitution
reaction is generally from 30 minutes to 2 days, and a time longer
or shorter than this range can be employed as necessary.
[0224] After aromatic nucleophilic substitution reaction under the
above-mentioned reaction conditions and, where necessary, removal
of protecting group(s), compound (I) can be purified by a method
known in the field of organic synthetic chemistry, such as solvent
extraction, recrystallization, chromatography, and a method using
an ion exchange resin.
Method L
[0225] Compound (II) wherein R.sup.8 and R.sup.9 are both hydrogen
can be produced by the following method. ##STR40## wherein W is
carboxylic acid derivative that can be easily converted to each
other by a method basic and widely used in the field of organic
synthetic chemistry, such as carboxylic acid, carboxylic acid ester
(COOR; wherein R is lower alkyl having 1 to 4 carbon atoms),
carboxamide or carbonitrile, and the other symbols are as defined
above.
[0226] The compound (XXV) is converted to an ester group as
necessary by a method known in the field of organic synthetic
chemistry and subjected to reduction.
[0227] The reducing agent to be used for reduction of the ester
group may be, for example, a metallic reducing reagent (e.g.,
aluminum lithium hydride, sodium borohydride, lithium borohydride
and the like) or diborane.
[0228] The solvent to be used for reduction of the ester group may
be, for example, water, tetrahydrofuran, dioxane, diethyl ether,
methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,
ethylene glycol dimethyl ether, a mixture thereof, and the
like.
[0229] The reaction temperature of reduction of the ester group is
generally from -20.degree. C. to 80.degree. C., and a temperature
above or under this range can be employed as necessary.
[0230] The reaction time of reduction of the ester group is
generally from 30 minutes to 10 hours, and a time longer or shorter
than this range can be employed as necessary.
[0231] After reduction under the above-mentioned reaction
conditions, the hydroxyl group of compound (XXVI) is converted to a
group Lv by a method known in the field of organic synthetic
chemistry, and where necessary, the protecting group(s) is/are
removed. The compound (II-a) can be purified by a method known in
the field of organic synthetic chemistry, such as solvent
extraction, recrystallization, chromatography, and a method using
an ion exchange resin.
[0232] The compound (II-a) and compound (III) are condensed in the
same manner as in Method A, and, where necessary, the protecting
group(s) is/are removed to give compound (I) wherein R.sup.8 and
R.sup.9 are both hydrogen, namely, compound (I-8) ##STR41## wherein
each symbol is as defined above. Method M
[0233] Compound (XIV) wherein R.sup.8 is lower alkyl and R.sup.9 is
hydrogen can be produced by the following method. ##STR42## wherein
R.sup.8a is lower alkyl, and the other symbols are as defined
above.
[0234] The acid catalyst used for Friedel-Crafts reaction of
compound (XXVII) is, for example, aluminum chloride, aluminum
bromide, titanium chloride, sulfuric acid, zinc chloride, iron
chloride or hydrogen fluoride, phosphoric acid.
[0235] The solvent to be used for the Friedel-Crafts reaction may
be, for example, tetrahydrofuran, dioxane, diethyl ether,
dichloromethane, dichloroethane, chloroform, ethylene glycol
dimethyl ether, acetonitrile, nitromethane, carbon disulfide or a
mixture thereof. Where necessary, the solvent may not be used.
[0236] The reaction temperature of the Friedel-Crafts reaction is
generally from -20.degree. C. to 100.degree. C., and a temperature
above or under this range can be employed as necessary.
[0237] The reaction time of reduction of the Friedel-Crafts
reaction is generally from 30 minutes to 24 hours, and a time
longer or shorter than this range can be employed as necessary.
[0238] The reducing agent to be used for reduction of the carbonyl
group in compound (XXIX) may be, for example, a metallic reducing
reagent such as aluminum lithium hydride, sodium borohydride,
lithium borohydride and the like, or diborane.
[0239] The solvent to be used for reduction of the carbonyl group
may be, for example, water, tetrahydrofuran, dioxane, diethyl
ether, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, ethylene glycol dimethyl ether, a mixture thereof, and the
like.
[0240] The reaction temperature of reduction of the carbonyl group
is generally from -20.degree. C. to 80.degree. C., and a
temperature above or under this range can be employed as
necessary.
[0241] The reaction time of reduction of the carbonyl group is
generally from 30 minutes to 10 hours, and a time longer or shorter
than this range can be employed as necessary.
[0242] The obtained compound (XXX) is converted to a group Q by a
method known in the field of organic synthetic chemistry to produce
compound (XIV-a).
[0243] The group Q of compound (XIV-a) is converted to a group Lv
as necessary by a method known in the field of organic synthetic
chemistry and condensed with compound (III) in the same manner as
in Method A. Where necessary, the protecting group(s) is/are
removed to produce compound (I) wherein R.sup.9 is hydrogen,
namely, compound (I-9) ##STR43## wherein each symbol is as defined
above.
[0244] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method N
[0245] Compound (II) wherein R.sup.8 and R.sup.9 are both hydrogen
and Lv is particularly halogen can be produced by the following
method. ##STR44## wherein each symbol is as defined above.
[0246] The reagent to be used for halomethylation of compound
(XXVII) is exemplified by formaldehyde and hydrogen chloride,
formaldehyde and hydrogen bromide, formaldehyde and hydrogen
iodide, chloromethyl methyl ether, bis(chloromethyl) ether,
methoxyacetyl chloride and 1-chloro-4-(chloromethoxy)butane.
[0247] The catalyst to be used for halomethylation is, for example,
zinc chloride, aluminum chloride, aluminum bromide, titanium
chloride or iron chloride.
[0248] The solvent to be used for halomethylation may be, for
example, tetrahydrofuran, dioxane, diethyl ether, dichloromethane,
dichloroethane, chloroform, ethylene glycol dimethyl ether,
acetonitrile, nitromethane, carbon disulfide or a mixture
thereof.
[0249] The reaction temperature of halomethylation is generally
from -20.degree. C. to 100.degree. C., and a temperature above or
under this range can be employed as necessary.
[0250] The reaction time of halomethylation is generally from 30
minutes to 24 hours, and a time longer or shorter than this range
can be employed as necessary.
[0251] After halomethylation under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (II-b) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0252] Moreover, compound (II-b) and compound (III) are condensed
in the same manner as in Method A to produce compound (I-8).
Method O
[0253] Compound (XXVI) can be also produced by the following
method. ##STR45## wherein each symbol is as defined above.
[0254] The Lewis acid to be used for the reaction with
dichloromethyl methyl ether may be, for example, aluminum chloride,
titanium tetrachloride, tin tetrachloride, antimony(V)chloride,
iron(III) chloride, boron trifluoride, bismuth(III) chloride, zinc
chloride, mercury(II) chloride and the like.
[0255] The organic solvent to be used for the reaction with
dichloromethyl methyl ether may be, for example, tetrahydrofuran,
diethyl ether, ethylene glycol dimethyl ether, dimethylformamide,
dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane,
acetonitrile, nitromethane, carbon disulfide and the like. Where
necessary, a solvent may not be used.
[0256] The temperature of reaction with dichloromethyl methyl ether
is generally from -50.degree. C. to 50.degree. C., and a
temperature above or under this range can be employed as
necessary.
[0257] The time of reaction with dichloromethyl methyl ether is
generally from 30 minutes to 24 hours, and a time longer or shorter
than this range can be employed as necessary.
[0258] The reducing agent to be used for reduction of the formyl
group in compound (XXXI) may be, for example, a metallic reducing
reagent such as aluminum lithium hydride, sodium borohydride,
lithium borohydride and the like, or diborane.
[0259] The solvent to be used for reduction of the formyl group may
be, for example, water, tetrahydrofuran, dioxane, diethyl ether,
methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,
ethylene glycol dimethyl ether, a mixture thereof, and the
like.
[0260] The reaction temperature of reduction of the formyl group is
generally from -20.degree. C. to 80.degree. C., and a temperature
above or under this range can be employed as necessary.
[0261] The reaction time of reduction of the formyl group is
generally from 30 minutes to 10 hours, and a time longer or shorter
than this range can be employed as necessary.
[0262] The compound (XXVI) can be produced using a haloform
reaction as the key reaction.
[0263] The acylation of compound (XXVII) with acetyl chloride is
performed under the same reaction conditions as in Method M.
[0264] The reagent to be used for the haloform reaction of compound
(XXIXa) may be, for example, base (e.g., sodium hydroxide,
potassium hydroxide and the like), and a halogenating agent (e.g.,
bromine, chlorine, sodium (potassium) hypochlorite, sodium
(potassium) hypobromite and the like).
[0265] The solvent to be used for haloform reaction may be, for
example, water, methanol, ethanol, 1-propanol, 2-propanol,
tert-butyl alcohol, tetrahydrofuran, dioxane, a mixture thereof,
and the like.
[0266] The temperature of haloform reaction is generally from
-20.degree. C. to 100.degree. C., and a temperature above or under
this range can be employed as necessary.
[0267] The reaction time of haloform reaction is generally from 30
minutes to 24 hours, and a time longer or shorter than this range
can be employed as necessary.
[0268] Conversion of compound (XXVa) via compound (XXVb) to
compound (XXVI) is performed under the reaction conditions
described for Method L.
[0269] The compound (XXVa) can be also produced by directly from
compound (XXVII) by Friedel-Crafts reaction using oxalyl chloride.
The Friedel-Crafts reaction using oxalyl chloride is performed
under the reaction conditions described for Method M.
[0270] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
[0271] The compound (XXXI) can be also produced from compound
(XXVII) using known Friedel-Crafts type reaction widely used in the
field of organic synthetic chemistry, such as Gattermann-Koch
method, Gattermann method, Vilsmeier method, Duff method.
Method P
[0272] The compound (XIV), compound (II-a), compound (XV) can be
converted to compound (XX) by introducing an amino group described
in, for example, Method D, Method E and Method F.
Method Q
[0273] Compound (I-1) and compound (XII) wherein R.sup.8 and
R.sup.9 are both hydrogen can be also produced by the following
method. ##STR46## wherein Y.sup.a is single bond or alkyl having
one less carbon atoms than Y defined above, A is hydroxy or amino,
and the other symbols are as defined above.
[0274] For condensation of compound (XXXII) and compound (III), for
example, 1) acid chloride method and 2) mixed acid anhydride method
widely used in the field of organic synthetic chemistry are
particularly effective.
[0275] The reagent used for the acid chloride method may be, for
example, thionyl chloride and oxazolyl chloride.
[0276] The solvent to be used for acid chloride method may be, for
example, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, benzene, dichloromethane, dichloroethane,
chloroform, toluene, xylene and hexane.
[0277] The reaction temperature of acid chloride method is
generally from 0.degree. C. to 80.degree. C., and a temperature
above or under this range can be employed as necessary.
[0278] The reaction time of acid chloride method is generally from
30 minutes to 2 days, and a time longer or shorter than this range
can be employed as necessary.
[0279] The reagent used for the mixed acid anhydride method may be,
for example, methyl chlorocarbonate, ethyl chlorocarbonate,
isopropyl chlorocarbonate, isobutyl chlorocarbonate or phenyl
chlorocarbonate.
[0280] The base to be used for mixed acid anhydride method may be,
for example, triethylamine, diisopropylethylamine, potassium
carbonate, potassium hydrogencarbonate, sodium carbonate, sodium
hydrogencarbonate, sodium hydroxide, sodium methoxide or sodium
ethoxide.
[0281] The solvent to be used for acid anhydride method may be, for
example, tetrahydrofuran, dioxane, acetone, diethyl ether, ethylene
glycol dimethyl ether, benzene, dichloromethane, dichloroethane,
chloroform, toluene, xylene or hexane.
[0282] The reaction temperature of mixed acid anhydride method is
generally from -80.degree. C. to 20.degree. C., and a temperature
above or under this range can be employed as necessary.
[0283] The reaction time of acid anhydride method is generally from
30 minutes to 2 days, and a time longer or shorter than this range
can be employed as necessary.
[0284] The reducing agent to be used for compound (XXXIII) may be,
for example, a metallic reducing reagent (e.g., aluminum lithium
hydide, sodium borohydride, lithium borohydride and the like), or
diborane.
[0285] The solvent to be used for reduction may be, for example,
water, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol,
1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycol
dimethyl ether, a mixture thereof, and the like.
[0286] The reaction temperature of reduction is generally from
-20.degree. C. to 80.degree. C., and a temperature above or under
this range can be employed as necessary.
[0287] The reaction time of reduction is generally from 30 minutes
to 10 hours, and a time longer or shorter than this range can be
employed as necessary.
[0288] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method R
[0289] Compound (I-1) can be also produced by the following method.
##STR47## wherein each symbol is as defined above.
[0290] The compound (XXXV) and compound (III) are condensed under
the same reaction conditions as in Method A.
[0291] The group Q of compound (XXXVI) is converted to a leaving
group Lv as necessary by a method known in the field of organic
synthetic chemistry and then subjected to cyanation.
[0292] The reagent to be used for cyanation may be, for example,
sodium cyanide or potassium cyanide.
[0293] The solvent to be used for cyanation may be, for example,
methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,
tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or a mixture
thereof.
[0294] The reaction temperature of cyanation is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0295] The reaction time of cyanation is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0296] The reducing agent to be used for reduction of the cyano
group in compound (XXXVII) may be, for example, a metallic reducing
reagent such as aluminum lithium hydide, sodium borohydride and
lithium borohydride, or diborane.
[0297] The solvent to be used for cyanation may be, for example,
tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol,
1-propanol, 2-propanol, tert-butyl alcohol, ethylene glycoldimethyl
ether, a mixture thereof, and the like.
[0298] The reaction temperature of reduction of the cyano group is
generally from -20C. to 80.degree. C., and a temperature above or
under this range can be employed as necessary.
[0299] The reaction time of reduction of the cyano group is
generally from 30 minutes to 10 hours, and a time longer or shorter
than this range can be employed as necessary.
[0300] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method S
[0301] Compound (XXXVII) can be also produced by the following
method. ##STR48## wherein each symbol is as defined above.
[0302] In this method, the conditions of cyanation are the same as
in Method R and those of condensation are the same as in Method
A.
[0303] After cyanation and condensation under the above-mentioned
reaction conditions and, where necessary, removal of protecting
group(s), the synthetic intermediate in each step and the objective
compound can be purified by a method known in the field of organic
synthetic chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method T
[0304] Compound (XXV) wherein R.sup.1 is hydrogen and R.sup.2 is
nitro can be produced by the following method. ##STR49## wherein
each symbol is as defined above.
[0305] By this nitration, compound (XXV-b) is mainly produced.
[0306] The reagent to be used for nitration may be, for example,
nitric acid, mixed acid, acetyl nitrate, dinitrogen pentaoxide or
nitronium salt.
[0307] The solvent to be used for nitration may be, for example,
water, acetic acid, acetic anhydride, con. sulfuric acid,
chloroform, dichloromethane, carbon disulfide, dichloroethane or a
mixture thereof, or the solvent may not be used.
[0308] The reaction temperature of nitration is generally from
-20.degree. C. to 80.degree. C., and a temperature above or under
this range can be employed as necessary.
[0309] The reaction time of nitration is generally from 30 minutes
to 10 hours, and a time longer or shorter than this range can be
employed as necessary.
[0310] After nitration under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (XXV-b), compound (XXV-c) can be purified by a method
known in the field of organic synthetic chemistry, such as solvent
extraction, recrystallization, chromatography, and a method using
an ion exchange resin.
[0311] Further, compound (XXV-b) and compound (XXV-c) are reacted
in the same manner as in Method L to produce compound (I-8a)
##STR50## wherein each symbol is as defined above. Method U
[0312] Compound (I-8) wherein R.sup.1 is hydrogen and R.sup.2 is
amino can be produced by the following method. ##STR51## wherein
each symbol is as defined above.
[0313] The reducing agent to be used for reduction of the nitro
group may be, for example, a metallic reducing reagent (e.g.,
sodium borohydride, lithium borohydride, aluminum lithium hydide
and the like), reduction using metal (e.g., iron, zinc, tin and the
like), and catalytic reduction using transition metal (e.g.,
palladium-carbon, platinum oxide, Raney-nickel, rhodium, ruthenium
and the like). When catalytic reduction is applied, ammonium
formate, sodium dihydrogenphosphate, hydrazine and the like can be
used as the hydrogen source.
[0314] The solvent to be used for reduction of the nitro group may
be, for example, water, methanol, ethanol, tert-butyl alcohol,
tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate,
acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl
sulfoxide or a mixture thereof.
[0315] The reaction temperature of reduction of nitro is generally
from -20.degree. C. to 150.degree. C., and a temperature above or
under this range can be employed as necessary.
[0316] The reaction time of reduction of nitro is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0317] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-8b) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0318] In compound (I-8b), when R.sup.6 and R.sup.7 are not
hydrogen and R.sup.3, R.sup.4 and R.sup.5 are not amino, the
functional group (hydroxy and the like) are protected as necessary,
and the compound is subjected to the reactions as described in
Method B1 to Method B8 to produce a compound wherein the amino
group on the corresponding phenylene ring has been alkylated and/or
acylated.
Method V
[0319] Compound (I-8) wherein R.sup.1 is hydrogen, R.sup.2 is
hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine),
hydroxy or cyano can be produced by the following method. ##STR52##
wherein Rg is hydrogen, halogen (e.g., fluorine, chlorine, bromine
or iodine), hydroxy or cyano, and the other symbols are as defined
above.
[0320] As the Sandmeyer type reaction, Sandmeyer reaction,
Gattermann reaction, Schiemann reaction and the like are
exemplified. The Sandmeyer type reaction comprises processes of
diazotization of amine and nucleophilic substitution of the
resulting diazonium salt using various nucleophiles.
[0321] For diazotization, an aqueous sodium nitrite solution,
nitrous acid and organic nitrite ester (e.g., isopentyl nitrite)
are generally used.
[0322] The solvent to be used for diazotization may be, for
example, water, hydrochloric acid, hydrobromic acid, nitric acid,
dilute sulfuric acid, benzene, toluene or a mixture thereof.
[0323] The reaction temperature of diazotization is generally from
-20.degree. C. to 100.degree. C., and a temperature above or under
this range can be employed as necessary.
[0324] The reaction time of diazotization is generally from 10
minutes to 5 hours, and a time longer or shorter than this range
can be employed as necessary.
[0325] The reagent to be used for nucleophilic substitution may be,
for example, hypophosphorous acid, fluoroboric acid, hydrochloric
acid--copper (I) chloride, hydrochloric acid--Gattermann copper,
hydrobromic acid--copper(I) bromide, hydrobromic acid--Gattermann
copper, iodine, potassium iodide, sodium iodide, trimethylsilyl
iodide, water, copper(I) cyanide, sodium cyanide, potassium cyanide
and the like.
[0326] The solvent to be used for nucleophilic substitution may be,
for example, water, hydrochloric acid, hydrobromic acid, nitric
acid, dilute sulfuric acid, benzene, toluene, chloroform,
dichloromethane, acetonitrile or a mixture thereof.
[0327] The reaction temperature of nucleophilic substitution is
generally from -20.degree. C. to 100.degree. C., and a temperature
above or under this range can be employed as necessary.
[0328] The reaction time of nucleophilic substitution is generally
from 30 minutes to 5 hours, and a time longer or shorter than this
range can be employed as necessary.
[0329] After nucleophilic substitution under the above-mentioned
reaction conditions and, where necessary, removal of protecting
group(s), compound (I-8c) can be purified by a method known in the
field of organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method W
[0330] Compound (XXV) wherein R.sup.1 is hydrogen and R.sup.2 is
amino can be produced by the following method. ##STR53## wherein
each symbol is as defined above.
[0331] The reaction conditions of reduction of nitro are the same
as in Method U.
[0332] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (XXV-d) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0333] Further, the amino group of compound (XXV-d) is protected
and reacted in the same manner as in Method L to produce compound
(I-8b).
Method X
[0334] Compound (XXV) wherein R.sup.1 is hydrogen, R.sup.2 is
hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine),
hydroxy or cyano can be produced by the following method. ##STR54##
wherein each symbol is as defined above.
[0335] The reaction conditions of Sandmeyer type reaction are the
same as in Method V.
[0336] After Sandmeyer type reaction under the above-mentioned
reaction conditions and, where necessary, removal of protecting
group(s), compound (XXV-e) can be purified by a method known in the
field of organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0337] Further, compound (XXV-e) is reacted in the same manner as
in Method L to produce compound (I-8c).
Method Y
[0338] Compound (XXIX) wherein R.sup.1 is hydrogen and R.sup.2 is
nitro can be produced by the following method. ##STR55## wherein
each symbol is as defined above.
[0339] The reaction conditions of nitration are the same as in
Method T.
[0340] After nitration under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (XXIX-b) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0341] Further, compound (XXIX-b) is reacted in the same manner as
in Method M, Method G or Method I to produce compound (I-9a)
##STR56## wherein each symbol is as defined above. Method Z
[0342] Compound (I-9) wherein R.sup.1 is hydrogen and R.sup.2 is
amino can be produced by the following method. ##STR57## wherein
each symbol is as defined above.
[0343] The reaction conditions of reduction are the same as in
Method U.
[0344] After reduction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (I-9b) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
[0345] In compound (I-9b), when R.sup.6 and R.sup.7 are not
hydrogen and R.sup.3, R.sup.4 and R.sup.5 are not amino, the
functional group (hydroxy and the like) are protected as necessary,
and the compound is subjected to the reactions as described in
Method B1 to Method B8 to produce a compound wherein the amino
group on the corresponding phenylene ring has been alkylated and/or
acylated.
Method AA
[0346] Compound (I-9) wherein R.sup.1 is hydrogen and R.sup.2 is
hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine),
hydroxy or cyano can be produced by the following method. ##STR58##
wherein each symbol is as defined above.
[0347] The reaction conditions of Sandmeyer type reaction are the
same as in Method V.
[0348] After Sandmeyer type reaction under the above-mentioned
reaction conditions and, where necessary, removal of protecting
group(s), compound (I-9c) can be purified by a method known in the
field of organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method BB
[0349] The compound (X) can be produced by subjecting compound
(XII) to Mitsunobu reaction in the same manner as in Method F using
hydrogen azide.
[0350] The reaction conditions (reagent, solvent, reaction
temperature, reaction time) of Mitsunobu reaction are the same as
in Method F.
[0351] After Mitsunobu reaction under the above-mentioned reaction
conditions, the protecting group(s) is/are removed as necessary,
and compound (X) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method CC
[0352] Compound (I) wherein Y is methylene and R.sup.8 and R.sup.9
are both hydrogen can be produced by the following method.
##STR59## wherein Hal is halogen such as chlorine, bromine, iodine
and the like, and the other symbols are as defined above.
[0353] The halogenizing agent to be used for the halogenation of
compound (XL) may be, for example, halogen (e.g., chlorine,
bromine, iodine and the like), N-bromosuccinimide,
N-chlorosuccinimide, sulfuryl chloride, hypohalite tert-butyl and
the like. For acceleration of the reaction, a radical initiator
such as dibenzoyl peroxide, azobisisobutyronitrile and the like can
be used. In addition, the reaction may be carried out under heat or
light for acceleration of the reaction.
[0354] The solvent to be used for halogenation is preferably carbon
tetrachloride.
[0355] The reaction temperature of halogenization is generally from
0.degree. C. to 100.degree. C., and a temperature above or under
this range can be employed as necessary.
[0356] The reaction time of halogenization is generally 1 to 12
hours, and a time longer or shorter than this range can be employed
as necessary.
[0357] The reducing agent to be used for reduction of compound
(XLI) may be, for example, those used in catalytic reduction such
as diisobutylaluminum hydride, sodium borohydride--cobalt(II)
chloride, aluminum lithium hydride--aluminum chloride, lithium
trimethoxyaluminum hydride, borane--methyl sulfide and transition
metal (e.g., palladium-carbon, platinum oxide, Raney-nickel,
rhodium, ruthenium and the like).
[0358] The solvent to be used for reduction may be, for example,
methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl
ether, dioxane, ethyl acetate, benzene, toluene, xylene,
dimethylformamide, dimethyl sulfoxide and the like.
[0359] The reaction temperature of reduction is generally from
-20.degree. C. to 80.degree. C., and a temperature above or under
this range can be employed as necessary.
[0360] The reaction time of reduction is generally from 30 minutes
to 24 hours, and a time longer or shorter than this range can be
employed as necessary.
[0361] The compound resulting from reduction is alkylated,
aralkylated, acylated or protected by a protecting group as
necessary by a method known in the field of organic synthetic
chemistry to give compound (II-c).
[0362] Further, compound (II-c) and compound (III) are condensed in
the same manner as in Method A to produce compound (I-10).
[0363] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method DD
[0364] Compound (III) can be produced by the following method.
##STR60## wherein Ac is acetyl, and the other symbols are as
defined above.
[0365] The compound (XLII) and 1-acetylpiperazine are condensed
under the same reaction conditions as in Method K.
[0366] The reagent used for hydrolysis of compound (III-a) may be,
for example, hydrochloric acid, sulfuric acid, acetic acid,
trifluoroacetic acid, sodium hydroxide, potassium hydroxide, barium
hydroxide, lithium hydroxide and the like.
[0367] The solvent to be used for hydrolysis may be, for example,
water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol,
acetone, tetrahydrofuran, ethylene glycol dimethyl ether,
dimethylformamide, dimethyl sulfoxide or a mixture thereof.
[0368] The reaction temperature of hydrolysis is generally from
-20.degree. C. to 100.degree. C., and a temperature above or under
this range can be employed as necessary.
[0369] The reaction time of hydrolysis is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0370] The solvent to be used for condensation to directly obtain
compound (III) from compound (XLII) and piperazine may be, for
example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol
dimethyl ether, benzene, dichloromethane, dichloroethane,
chloroform, toluene, xylene, hexane, dimethylformamide, dimethyl
sulfoxide, acetonitrile or a mixture thereof, or the solvent may
not be used.
[0371] The reaction temperature of condensation is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0372] The reaction time of condensation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0373] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method EE
[0374] Compound (III) can be also produced by the following method.
##STR61## wherein each symbol is as defined above.
[0375] The reducing agent to be used for reduction of the nitro
group in compound (XLIII) may be, for example, a metallic reducing
reagent such as sodium borohydride, lithium borohydride, aluminum
lithium hydide and the like, reduction with metal (e.g., iron,
zinc, tin and the like), and catalytic reduction using transition
metal (e.g., palladium-carbon, platinum oxide, Raney nickel,
rhodium, ruthenium and the like). When catalytic reduction is
applied, ammonium formate, sodium dihydrogenphosphate, hydrazine
and the like can be used as the hydrogen source.
[0376] The solvent to be used for reduction of the nitro group may
be, for example, water, methanol, ethanol, tert-butyl alcohol,
tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate,
acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl
sulfoxide or a mixture thereof.
[0377] The reaction temperature of reduction of nitro is generally
from -20.degree. C. to 80.degree. C., and a temperature above or
under this range can be employed as necessary.
[0378] The reaction time of reduction is generally 1 to 24 hours,
and a time longer or shorter than this range can be employed as
necessary.
[0379] The compound (XIX) and compound (XVII-a) are condensed under
the same reaction conditions as in Method A to produce compound
(III).
[0380] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method FF
[0381] The compound (I) wherein Y is a group of the formula
##STR62## wherein each symbol is as defined above,and R.sup.9 is
hydrogen, can be produced by the following method. ##STR63##
wherein G is a hydroxyl group or lower alkoxy, and the other
symbols are as defined above.
[0382] The organic solvent to be used for addition reaction of
compound (XLIV) may be, for example, tetrahydrofuran, diethyl
ether, ethylene glycoldimethyl ether, dimethylformamide, dimethyl
sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride,
chloroform, dichloroethane and the like.
[0383] The reaction temperature of addition is generally from
-20.degree. C. to 100.degree. C., and a temperature above or under
this range can be employed as necessary.
[0384] The reaction time of addition is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0385] The reducing agent to be used for reduction of compound
(XLV) may be, for example, sodium borohydride, lithium borohydride,
aluminum lithium hydride, diisobutylaluminum hydride, lithium
trimethoxyaluminum hydride, lithium tri-tert-butoxyaluminum
hydride, diborane and the like.
[0386] The organic solvent to be used for reduction may be, for
example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran,
diethyl ether, ethylene glycol dimethyl ether, acetone and methyl
ethyl ketone.
[0387] The reaction temperature of reduction is generally from
-100.degree. C. to 80.degree. C., and a temperature above or under
this range can be employed as necessary.
[0388] The reaction time of reduction is generally from 30 minutes
to 10 hours, and a time longer or shorter than this range can be
employed as necessary.
[0389] The organic solvent to be used for Ritter reaction of
compound (XLVI) may be, for example, hydrogen cyanide,
acetonitrile, benzonitrile and the like.
[0390] The organic solvent to be used for Ritter reaction may be,
for example, acetic acid, tetrahydrofuran, diethyl ether, ethylene
glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide,
benzene, toluene, xylene, dioxane, methylene chloride, chloroform,
dichloroethane and the like.
[0391] The acid catalyst to be used for Ritter reaction may be, for
example, strong acid such as sulfuric acid, trifluoroacetic acid
and the like.
[0392] The reaction temperature of Ritter reaction is generally
from -20.degree. C. to 80.degree. C., and a temperature above or
under this range can be employed as necessary.
[0393] The reaction time of Ritter reaction is generally from 30
minutes to 24 hours, and a time longer or shorter than this range
can be employed as necessary.
[0394] The compound obtained by Ritter reaction is hydrolyzed,
alkylated, aralkylated, acylated or protected by a protecting group
as necessary by a method known in the field of organic synthetic
chemistry to produce compound (XLVII).
[0395] The compound (XLVII) and compound (III) are condensed under
the same reaction conditions as in Method A to produce compound
(I-11).
[0396] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method GG
[0397] The compound (I) wherein Y is a group of the formula
##STR64## wherein each symbol is as defined above, and R.sup.9 is
hydrogen, can be produced by the following method. ##STR65##
wherein each symbol is as defined above.
[0398] The addition reaction of compound (XLV) and Ritter reaction
of compound (XLVIII) can be carried out under the same reaction
conditions as in Method FF.
[0399] The compound (XLIX) and compound (III) are condensed under
the same reaction conditions as in Method A.
[0400] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method HH
[0401] Compound (XXIX) and compound (XXX) can be also produced by
the following method. ##STR66## wherein each symbol is as defined
above.
[0402] The azidating agent to be used for azidation of compound (L)
is exemplified by metal azide (e.g., sodium azide, lithium azide
and the like) and the like.
[0403] The reaction temperature of azidation is generally from
0.degree. C. to 100.degree. C., and a temperature above or under
this range can be employed as necessary.
[0404] The reaction time of azidation is generally 1 to 24 hours,
and a time longer or shorter than this range can be employed as
necessary.
[0405] The reducing agent to be-used for reduction of compound (LI)
may be, for example, a metallic reducing reagent such as sodium
borohydride, lithium borohydride, aluminum lithium hydride and the
like, triphenylphosphine, and catalytic reduction using transition
metal (Lindlar catalyst (palladium, calcium carbonate),
palladium-carbon, Raney nickel, platinum oxide, rhodium, ruthenium
and the like). For the selective reduction of the azide group alone
of compound (LI), catalytic reduction using triphenylphosphine or
transition metal is particularly effective.
[0406] The organic solvent to be used for reduction may be, for
example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran,
diethyl ether, dioxane, acetone, ethyl acetate, acetic acid,
benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide and
the like.
[0407] The reaction temperature of reduction is generally from
-20.degree. C. to 80.degree. C., and a temperature above or under
this range can be employed as necessary.
[0408] The reaction time of reduction is generally 1 to 24 hours,
and a time longer or shorter than this range can be employed as
necessary.
[0409] The compound obtained by reduction is alkylated,
aralkylated, acylated or protected by a protecting group as
necessary by a method known in the field of organic synthetic
chemistry to produce compound (XXIX).
[0410] After reaction under the above-mentioned reaction conditions
and, where necessary, removal of protecting group(s), the synthetic
intermediate in each step and the objective compound can be
purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method II
[0411] Compound (I) wherein Y is methylene and R.sup.8 and R.sup.9
are the same or different and each is lower alkyl can be produced
by the following method. ##STR67## wherein R.sup.9a is lower alkyl,
and the other symbols are as defined above.
[0412] The base to be used for condensation of compound (LII) may
be, for example, sodium methoxide, sodium ethoxide, sodium hydride,
potassium hydride, lithium diisopropylamide, lithium
hexamethyldisilazane, diisopropylethylamine,
1,8-diazabicyclo[4.3.0]undeca-5-ene, sodium amide and the like.
[0413] The organic solvent to be used for condensation may be, for
example, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran,
diethyl ether, ethylene glycol dimethyl ether, dimethylformamide,
dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene
chloride, chloroform, dichloroethane, acetonitrile and the
like.
[0414] The reaction temperature of condensation is generally from
-20.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0415] The reaction time of condensation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0416] The base to be used for hydrolysis of compound (LIII) may
be, for example, acid such as hydrochloric acid, sulfuric acid,
formic acid, acetic acid and the like, or alkali such as sodium
hydroxide, potassium hydroxide and the like.
[0417] The solvent to be used for hydrolysis may be, for example,
water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol,
ethylene glycol, diethylene glycol, a mixture thereof, and the
like.
[0418] The reaction temperature of hydrolysis is generally from
-20.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0419] The reaction time of hydrolysis is generally from 30 minutes
to 2 days, and a time longer or shorter than this range can be
employed as necessary.
[0420] After halogenation of compound (LIV), the compound is
subjected to azidation to produce compound (LIX). The halogenation
of compound (LIV) can be performed under the same reaction
conditions as in Method CC. The obtained halogenated compound is
subjected to azidation under the same reaction conditions as in
Method HH.
[0421] The compound (LV) is reduced under the same reaction
conditions as in Method HH.
[0422] The base to be used for Curtius rearrangement of compound
(LVI) may be, for example, Hunig base such as triethylamine,
diisopropylethylamine and the like. When the substrate of this
reaction, carboxylic acid, is a salt, a base is not necessary.
[0423] The activator to be used for Curtius rearrangement is
exemplified by methyl chlorocarbonate, ethyl chlorocarbonate,
isopropyl chlorocarbonate, isobutyl chlorocarbonate, phenyl
chlorocarbonate and the like.
[0424] The azidating agent to be used for Curtius rearrangement is
exemplified by sodium azide, diphenylphosphoryl azide (when this
reagent is used, base or activator is not necessary) and the
like.
[0425] The solvent to be used for Curtius rearrangement may be, for
example, aprotic solvent in the former half of the reaction, such
as tetrahydrofuran, acetone, diethyl ether, ethylene glycol
dimethyl ether, dimethylformamide, dimethyl sulfoxide, dioxane,
methylene chloride, chloroform, dichloroethane, acetonitrile and
the like, and in the latter half of the reaction, for example,
methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl
ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl
sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride,
chloroform, dichloroethane, acetonitrile or benzyl alcohol is
used.
[0426] The reaction temperature of Curtius rearrangement is
generally from -20.degree. C. to 150.degree. C., and a temperature
above or under this range can be employed as necessary.
[0427] The reaction time of Curtius rearrangement is generally from
30 minutes to 10 hours, and a time longer or shorter than this
range can be employed as necessary.
[0428] The carbamic acid compound obtained by Curtius rearrangement
is treated with benzyl alcohol and subjected to catalytic reduction
to produce compound (LVII). When carbamic acid compound is treated
with an alcohol solution of acid (e.g., hydrochloric acid, sulfuric
acid and the like) or alkali (e.g., sodium hydroxide, potassium
hydroxide and the like), or trimethylsilyl iodide, compound (LVII)
can be produced.
[0429] The compound (LVII) and compound (XXI) are condensed under
the same reaction conditions as in Method J.
[0430] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method JJ
[0431] Compound (XVIII) can be produced by the following method.
##STR68## wherein each symbol is as defined above.
[0432] The compound (XX) and compound (XXIIa) are condensed under
the same reaction conditions as in Method J.
[0433] The compound (XX) and compound (XXIIc) are condensed under
the same reaction conditions as in Method J. The compound (XXb) is
reduced under the same reaction conditions as in Method J.
[0434] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method KK
[0435] Compound (I) wherein m=n=0, R.sup.12 and R.sup.13 in
combination form ethylene and R.sup.8 and R.sup.9 are both hydrogen
can be produced by the following method. ##STR69## wherein each
symbol is as defined above.
[0436] The compound (LXI) is halomethylated under the same reaction
conditions as in Method N.
[0437] The compound (LXII) and compound (III) are condensed under
the same reaction conditions as in Method A.
[0438] The compound (LXIII) is subjected to Curtius rearrangement
under the same reaction conditions as in Method II. The carbamic
acid compound obtained by Curtius rearrangement is reacted with a
Grignard reagent to produce compound (I-13) wherein R.sup.6 or
R.sup.7 is acylated. The amine compound obtained by Curtius
rearrangement is alkylated, aralkylated or acylated by a method
known in the field of organic synthetic chemistry to produce
compound (I-13).
[0439] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method LL
[0440] Compound (I) wherein m=n=0, R.sup.12 and R.sup.13 in
combination form ethylene and R.sup.9 is hydrogen can be produced
by the following method. ##STR70## wherein each symbol is as
defined above.
[0441] The compound (LXIV) is subjected to Curtius rearrangement
under the same reaction conditions as in Method KK.
[0442] The Friedel-Crafts reaction of compound (LXV) and reduction
of compound (LXVI) can be carried our under the same reaction
conditions as in Method M. The hydroxyl group of compound (LXVII)
is converted to a leaving group Lv by a method known in the field
of organic synthetic chemistry to give compound (LXVIII), which is
then condensed with compound (III) in the same manner as in Method
A to produce compound (I-14).
[0443] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
Method MM
[0444] Compound (XXIV) wherein Lv.sub.1 is chlorine or bromine can
be produced by the following method. ##STR71## wherein each symbol
is as defined above.
[0445] The compound (XIX) is subjected to Sandmeyer type reaction
under the same reaction conditions as in Method V.
[0446] After Sandmeyer type reaction under the above-mentioned
reaction conditions and, where necessary, removal of protecting
group(s), compound (XXIV) can be purified by a method known in the
field of organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method NN
[0447] Compound (XXIV) wherein Lv.sub.1 is chlorine can be produced
by the following method. ##STR72## wherein each symbol is as
defined above.
[0448] This method is particularly effective for converting the
hydroxyl group of hetero ring derivative, such as
2-hydroxypyrimidine, 2-hydroxypyridine and the like, to
chloride.
[0449] The reagent to be used for chlorination of compound (LXIX)
may be, for example, phosphorous oxychloride.
[0450] The solvent to be used for chlorination may be, for example,
dichloromethane, dichloroethane, chloroform, carbon tetrachloride
or a mixture thereof, or the reaction proceeds without solvent.
[0451] The reaction temperature of chlorination is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0452] The reaction time of chlorination is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0453] After chlorination under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
compound (XXIV) can be purified by a method known in the field of
organic synthetic chemistry, such as solvent extraction,
recrystallization, chromatography, and a method using an ion
exchange resin.
Method OO
[0454] Compound (XXVII) wherein m=n=0 at Y can be produced by the
following method. ##STR73## wherein each symbol is as defined
above.
[0455] The reagent to be used for halogenation of compound (LXX)
may be, for example, N-bromosuccimide and N-chlorosuccimide.
[0456] For the halogenation, a radical initiator such as
2,2'-azobisisobutyronitrile (AIBN),benzoylperoxide and the like can
be used as necessary.
[0457] The solvent to be used for halogenation may be, for example,
carbon tetrachloride, chloroform, dichloromethane or benzene.
[0458] The reaction temperature of halogenation is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0459] The reaction time of halogenation is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0460] The reagent to be used for ammonolysis of compound (LXXI)
may be, for example, liquid ammonia.
[0461] The solvent to be used for ammonolysis may be, for example,
water, methanol, ethanol, 1-propanol, tetrahydrofuran, dioxane or a
mixture thereof.
[0462] The reaction temperature of ammonolysis is generally from
0.degree. C. to 150.degree. C., and a temperature above or under
this range can be employed as necessary.
[0463] The reaction time of ammonolysis is generally from 30
minutes to 2 days, and a time longer or shorter than this range can
be employed as necessary.
[0464] The compound (LXXII) can be converted to compound (XXVII)
according to Methods B1 to B8.
[0465] After each reaction under the above-mentioned reaction
conditions and, where necessary, removal of protecting group(s),
the synthetic intermediate in each step and the objective compound
can be purified by a method known in the field of organic synthetic
chemistry, such as solvent extraction, recrystallization,
chromatography, and a method using an ion exchange resin.
[0466] The compound (I) of the present invention can be treated
with an acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic
acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid,
maleic acid, fumaric acid, benzoic acid, citric acid, succinic
acid, tartaric acid, malic acid, mandelic acid, methanesulfonic
acid, benzenesulfonic acid, p-toluenesulfonic acid,
10-camphorsulfonic acid and the like), as necessary, in a suitable
solvent (e.g., water, methanol, ethanol, diethyl ether,
tetrahydrofuran, dioxane and the like) to convert to a
pharmaceutically acceptable salt. The compound (I) of the present
invention can be converted to a quaternary ammonium salt by
treating with lower alkyl halide (e.g., methyl iodide, methyl
bromide, ethyl iodide, ethyl bromide and the like) in the presence
of a base. When the obtained crystals of the compound of the
present invention are anhydride, the compound of the present
invention is treated with water, a water-containing solvent or a
different solvent to give a hydrate (e.g., monohydrate, 1/2
hydrate, 1/4 hydrate, 1/5 hydrate, dihydrate, 3/2 hydrate, 3/4
hydrate and the like) or solvate.
[0467] The compound of the present invention thus obtained can be
isolated and purified by a conventional method such as
recrystallization, column chromatography and the like. When the
resulting product is a racemate, for example, a desired optically
active compound can be resolved by fractional recrystallization of
a salt with an optically active acid or by passing the racemate
through a column packed with an optically active carrier.
Individual diastereomers can be separated by fractional
crystallization, chromatography and the like. These can be also
obtained by using an optically active starting compound.
[0468] The compound of the present invention has a TNF-.alpha.
production inhibitory effect and/or IL-10 production promoting
effect, and is useful for the prophylaxis and treatment of various
diseases caused by abnormal TNF-.alpha. production, diseases
treatable with IL-10, such as chronic inflammatory disease, acute
inflammatory disease, inflammatory disease due to infection,
autoimmune diseases, allergic diseases, and other TNF-.alpha.
mediated diseases.
[0469] The chronic inflammatory diseases include osteoarthritis,
psoriatic arthritis, inflammatory dermal disease (psoriasis,
eczematoid dermatitis, seborrheic dermatitis, lichen planus,
pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,
vascular edema, angiitis, erythema, dermal eosinophilia, acne,
alopecia areata, eosinophilic fasciitis, atherosclerosis and the
like), inflammatory bowel disease (ulcerative colitis, Crohn's
disease and the like) and the like.
[0470] The acute inflammatory diseases include contact dermatitis,
adult respiratory distress syndrome (ARDS), sepsis (inclusive of
organ disorders etc. caused by sepsis), septic shock, and the
like.
[0471] The inflammatory diseases due to infection include endotoxin
shock, acquired immunodeficiency syndrome (AIDS), meningitis,
cachexia, viral hepatitis, fulminant hepatitis, other inflammatory
responses due to infection with bacteria, virus, mycoplasma and the
like (inclusive of fever, pain, organ disorders caused by
influenzal or non-influenzal cold and the like) and the like.
[0472] The autoimmune diseases include rheumatoid arthritis,
ankylosing spondylitis, systemic lupus erythematosus, glomerular
nephritis (nephrotic syndrome (idiopathic nephrotic syndrome,
minimal-change nephropathy and the like) and the like), multiple
sclerosis, polychondritis, scleroderma, dermatomyositis, Wegener's
granulomatosis, active chronic hepatitis I, primary biliary
cirrhosis, myasthenia gravis, idiopathic sprue, Graves' disease,
sarcoidosis, Reiter's syndrome, juvenile diabetes (type I diabetes
mellitus), autoimmune ophthalmic disease (endocrine ophthalmopathy,
uveitis, keratitis (keratoconjunctivitis sicca, vernal
keratoconjunctivitis and the like) and the like), Behget's disease,
autoimmune hemopathy (hemolytic anemia, aplastic anemia, idiopathic
thrombocytopenia and the like), various malignant tumors
(adenocarcinoma and the like), matastatic carcinoma and the
like.
[0473] The allergic diseases include atopic dermatitis, asthmatic
diseases (bronchial asthma, infantile asthma, allergic asthma,
intrinsic asthma, extrinsic asthma, dust asthma, late-onset asthma,
bronchial hypersensitivity, bronchitis and the like), allergic
rhinitis, allergic conjunctivitis and the like.
[0474] Other TNF-.alpha. mediated diseases include resistant
responses in organ or tissue transplantation (e.g., allograft or
xenograft of heart, kidney, liver, lung, bone marrow, cornea,
pancreas, pancreatic cell, small intestine, duodenum, limbs,
muscle, nerve, fatty marrow, skin and the like) in mammals such as
human, dog, cat, cow, horse, swine, monkey, mice and the like,
i.e., rejection and graft versus host disease (GvHD), osteoporosis,
cancer cachexia, thermal burn, trauma, scald, inflammatory response
(inclusive of shock)and the like against plant and animal
components (inclusive of snake venom and the like) and
administration of drug and the like, myocardial infarction, chronic
heart failure, congestive heart failure, ischemia-reperfusion
injury, Kawasaki disease, pneumonia, malaria, meningitis,
peritonitis, fibroid lung and disseminated intravascular
coagulation (DIC). In addition to these, the inventive compound is
useful for the prophylaxis and treatment of hepatopathy.
[0475] The compound of the present invention is characteristically
void of effect on the central nervous system, because it has no or
extremely weak affinity for the receptors distributed in the
central nervous system. Moreover, the compound of the present
invention having a TNF-.alpha. production inhibitory effect and an
IL-10 production promoting effect is expected to show superior
prophylactic and therapeutic effects on the above-mentioned
diseases, particularly chronic diseases such as rheumatoid
arthritis, chronic inflammatory diseases and the like, by the
synergistic action of these two effects. In the present invention,
a compound having these two effects is preferable.
[0476] When the compound (I) of the present invention is used as a
TNF-.alpha. production inhibitor and/or an IL-10 production
promoter, it is prepared into a typical pharmaceutical preparation.
For example, the compound of the present invention (I) is prepared
into a dosage form suitable for oral or parenteral administration
upon admixing with a pharmaceutically acceptable carrier
(excipient, binder, disintegrant, corrigent, flavor, emulsifier,
diluent, solubilizer and the like) to give a pharmaceutical
composition or preparation, such as tablet, pill, powder, granule,
capsule, troche, syrup, liquid, emulsion, suspension, injection
(liquid, suspension and the like), suppository, inhalent,
transdermal absorber, eye drop, nose drop, eye ointment and the
like.
[0477] When a solid preparation is produced, an additive is used,
such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol,
dextran, starches, agar, arginates, chitins, chitosans, pectins,
tragacanth, acacia, gelatins, collagens, casein, albumin, calcium
phosphate, sorbitol, glycine, carboxymethylcellulose,
polyvinylpyrrolidone, hydroxypropylcellulose,
hydroxypropylmethylcellulose, glycerol, polyethylene glycol, sodium
hydrogencarbonate, magnesium stearate, talc and the like. The
tablets can be made into those having typical tablet film, as
necessary, such as sugar-coated tablet, enteric coated tablet, film
coating tablet, or two-layer tablet, or multi-laye tablet.
[0478] When a semi-solid preparation is produced, plant and animal
fats and oils (olive oil, corn oil, castor oil and the like),
mineral oils (petrolatum, white petrolatum, solid paraffin and the
like), wax (jojoba oil, carnauba wax, bee wax and the like),
partially synthesized or completely synthesized glycerol fatty acid
ester (lauric acid, myristic acid, palmitic acid and the like), and
the like are used. Commercially available products of these are,
for example, Witepsol (manufactured by Dynamitnovel Ltd.),
pharmasol (manufactured by Japan Oil & Fat Co. Ltd.) and the
like.
[0479] When a liquid preparation is produced, an additive is used,
such as sodium chloride, glucose, sorbitol, glycerol, olive oil,
propylene glycol, ethyl alcohol and the like. In particular, when
an injection is prepared, sterile aqueous solution, such as
physiological saline, isotonic liquid and oily liquid (e.g., sesami
oil and soybean oi) are used. Where necessary, a suitable
suspending agent, such as sodium carboxymethylcellulose, nonionic
surfactant and solubilizer (e.g., benzyl benzoate, benzyl alcohol
and the like) may be used concurrently. Further, when an eye drop
or nasal drop is given, an aqueous liquid or aqueous solution is
used, particularly, sterile aqueous solution for injection. The
liquid for eye drop or nasal drop may contain various additives as
appropriate, such as buffer (borate buffer, acetate buffer,
carbonate buffer and the like are preferable for reducing
irritation), isotonicity agent, solubilizer, preservative, viscous
agent, chelating agent, pH adjusting agent (pH is preferably
adjusted generally to about 6-8.5) and aromatic.
[0480] The amount of the active ingredient in these preparations is
0.1-100 wt %, suitably 1-50 wt %, of the preparation. The dose
varies depending on the condition, body weight, age and the like of
patients. In the case of oral administration, it is generally about
0.01-50 mg per day for an adult, which is administered once or in
several doses.
EXAMPLES
[0481] The present invention is explained in detail in the
following by way of Examples which do not limit the present
invention of the symbols used in the chemical structures, Ac means
acetyl, Me means methyl and Et means ethyl.
Example 1
Synthesis of
N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
(1) 4-acetamidomethylbenzoic acid
[0482] ##STR74##
[0483] To a solution of 4-(aminomethyl)benzoic acid (20.46 g) in
ethyl acetate (100 ml) was added an aqueous sodium hydroxide (12 g)
solution (100 ml) and acetic anhydride (14 ml) was further added at
5-7.degree. C. This reaction mixture was stirred at room
temperature for 1 hr and made acidic with 10% hydrochloric acid and
extracted with ethyl acetate:ethanol (10:1) (100 ml.times.5). The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a pale-yellow
solid (27.2 g). The obtained solid was crystallized from ethyl
acetate:ethanol (1:1,500 ml) to give the objective compound (16.7
g) as white crystals, m.p. 200-202.degree. C.
[0484] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
4.32(2H,d,J=5.9 Hz), 7.36(2H,d,J=7.9 Hz), 7.89(2H,d,J=8.6 Hz),
8.41(1H,m), 12.84(1H,br.s)
[0485] IR(KBr): 3298, 1691, 1646, 1539 cm.sup.-1
[0486] MS(EI): 193(M.sup.+)
[0487] Elemental analysis:
[0488] Calculated: C;62.17, H;5.74, N;7.25
[0489] Found: C;62.01, H;5.71, N;7.21
(2) methyl 4-acetamidomethylbenzoate
[0490] ##STR75##
[0491] 4-Acetamidomethylbenzoic acid(4.0 g) was dissolved in 0.5%
hydrochloric acid-methanolsolution(100 ml). The mixture was stirred
at 40.degree. C. for 3.5 hr, and poured into ice water (300 ml) and
extracted with ethyl acetate (100 ml.times.4). The extract was
washed with saturated sodium hydrogencarbonate solution and
saturated brine, and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a pale-yellow solid (4.3 g). The
obtained solid was crystallized from ethyl acetate (50 ml) to give
the title compound (3.2 g) as pale-yellow white crystals,
m.p.=110-111.degree. C.
[0492] .sup.1H-NM(DMSO-d.sub.6).delta.: 1.90(3H,s), 3.84(3H,s),
4.33(2H,d,J=5.9 Hz), 7.39(2H,d,J=8.6 Hz), 7.92(2H,d,J=7.9 Hz),
8.43(1H,m)
[0493] IR(KBr): 3277, 1727, 1643, 1556 cm.sup.-1
[0494] MS(EI): 207 (M.sup.+)
[0495] Elemental analysis:
[0496] Calculated: C;63.76, H;6.32, N;6.76
[0497] Found: C;63.76, H;6.38, N;6.76
(3) N-(4-hydroxymethylphenylmethyl)acetamide
[0498] ##STR76##
[0499] To a suspension of aluminum lithium hydride (570 mg) in
tetrahydrofuran (80 ml) was added a solution of methyl
4-acetamidomethylbenzoate (3.1 g) in tetrahydrofuran (20 ml) under
ice-cooling. The mixture was stirred at room temperature for 1.5 hr
and a saturated aqueous sodium sulfate solution (7 ml) was added at
10.degree. C. The mixture was stirred at room temperature for 1 hr.
The sediment was filtrated and the solvent was evaporated to give
the title substance (2.8 g) as a white solid.
[0500] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.86(3H,s),
4.22(2H,d,J=5.9 Hz), 4.46(2H,s), 5.13(1H,br.s), 7.19(2H,d,J=7.9
Hz), 7.25(2H,d,J=8.6 Hz), 8.30(1H,m)
[0501] MS(EI): 179(M.sup.+)
(4) N-(4-chloromethylphenylmethyl)acetamide
[0502] ##STR77##
[0503] To a solution of N-(4-hydroxymethylphenylmethyl)acetamide
(1.5 g) in chloroform (50 ml) was added thionyl chloride (0.73 ml)
and the mixture was refluxed under heating for 1 hr. The solvent
was evaporated and the obtained residue was crystallized from ethyl
acetate to give the title compound (1.8 g) as pale-yellow
crystals.
[0504] m.p.=116-118.degree. C.
[0505] .sup.1H-NMR(CDCl.sub.3).delta.: 2.01(3H,s), 4.40(2H,d,J=5.9
Hz), 4.56(2H,s), 6.20(1H,br.s), 7.26(2H,d,J=8.6 Hz),
7.34(2H,d,J=7.9 Hz)
[0506] MS(EI): 197(M.sup.+)
(5) N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
[0507] ##STR78##
[0508] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.65
g), 1-phenylpiperazine (1.3 ml) and potassium carbonate (1.2 g) in
dimethylformamide (50 ml) was stirred at 60.degree. C. for 1 hr.
The reaction mixture was poured into water (200 ml) and extracted
with ethyl acetate (100 ml.times.3). The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a brown solid (4.4 g). The obtained
solid was purified by silica gel column chromatography (developing
solvent; chloroform:methanol=10:1) to give a pale-brown solid (3.45
g). The obtained solid was crystallized from ethyl acetate and the
crystals were recrystallized from a mixture of ethyl acetate,
ethanol and hexane to give the title compound (1.4 g) as white
crystals, m.p.=135-136.degree. C.
[0509] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s), 2.50(4H,m),
3.11(4H,m), 3.49(2H,s), 4.23(2H,d,J=5.9 Hz), 6.76(1H,t,J=7.3 Hz),
6.90(2H,d,J=7.9 Hz), 7.15-7.29(6H,m), 8.30(1H,t,J=5.9 Hz)
[0510] IR(KBr): 3318, 2813, 1645, 1538 cm.sup.-1
[0511] MS(EI): 323(M.sup.+)
[0512] Elemental analysis:
[0513] Calculated: C;74.27, H;7.79, N;12.99
[0514] Found: C;74.01, H;7.88, N;12.77
Example 2
Synthesis of
4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine
[0515] ##STR79##
[0516] N-(4-((4-Phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
(2.6 g) was dissolved in 10% hydrochloric acid (50 ml) and the
mixture was refluxed under heating for 6 hr. To the mixture was
added 10% aqueous sodium hydroxide solution to make it alkaline and
the mixture was extracted with ethyl acetate (100 ml.times.3). The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated and the obtained residue
was crystallized from water-ethanol to give the title compound
(1.34 g) as white crystals, m.p.=68-70.degree. C.
[0517] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.40-2.50(4H,m),
3.05-3.15(4H,m), 3.10-3.45(2H,br.s), 3.48(2H,s), 3.69(2H,s),
6.76(1H,t,J=7.3 Hz), 6.90(2H,d,J=7.9 Hz), 7.15-7.30(6H,m)
[0518] IR(KBr): 3359, 2805, 1602, 1506 cm.sup.-1
[0519] MS(EI): 281(M.sup.+)
[0520] Elemental analysis:
[0521] Calculated: C;76.83, H;8.24, N;14.93
[0522] Found: C;76.60, H;8.21, N;14.59
Example 3
Synthesis of
N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)formamide
[0523] ##STR80##
[0524] A mixture of acetic anhydride (0.36 ml) and formic acid
(0.15 ml) was stirred at 50-60.degree. C. for 2 hr, and to the
obtained acetic acid and formic acid anhydride was added a solution
of 4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine (0.5 g) in
methylene chloride (10 ml) under ice-cooling. This reaction mixture
was stirred at 5-10.degree. C. for 2.5 hr and left standing at room
temperature for 14 hr. To this reaction mixture were added ethanol
(20 ml) and ethyl acetate (150 ml) and the mixture was washed with
saturated sodium hydrogencarbonate solution and saturated brine,
and dried over anhydrous sodium sulfate. The solvent was evaporated
to give a brown solid (0.56 g). The obtained solid was purified by
silica gel column chromatography (developing solvent;
chloroform:methanol=9:1) to give a pale-brown solid (0.55 g). The
obtained solid was crystallized from ethyl acetate-hexane (2:1) to
give the title compound (0.41 g) as pale-yellow white crystals,
m.p.=108-109.degree. C.
[0525] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.45-2.53(4H,m),
3.05-3.15(4H,m), 3.49(2H,s), 4.29(2H,d,J=5.9 Hz), 6.76(1H,t,J=7.3
Hz), 6.90(2H,d,J=8.6 Hz), 7.15-7.30(6H,m), 8.13(1H,d,J=1.3 Hz),
8.47(1H,m)
[0526] IR(KBr): 3315, 2846, 2821, 1658, 1522 cm.sup.-1
[0527] MS(EI): 309(M.sup.+)
[0528] Elemental analysis:
[0529] Calculated: C;73.76, H;7.49, N;13.58
[0530] Found: C;73.36, H;7.53, N;13.47
Example 4
Synthesis of
N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)propionamide
[0531] ##STR81##
[0532] A solution of
4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine 0.62 g),
propionyl chloride (0.23 ml) and triethylamine (0.37 ml) in
methylene chloride (20 ml) was stirred at room temperature for 4
hr. To this reaction mixture was added chloroform (100 ml), and the
mixture was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a pale-brown
solid (0.9 g). The obtained solid was crystallized from ethyl
acetate (50 ml) to give the title compound (0.5 g) as pale-yellow
white crystals, m.p.=140-141.degree. C.
[0533] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.03(3H,t,J=7.9 Hz),
2.14(2H,q,J=7.9 Hz), 2.45-2.55(4H,m), 3.05-3.15(4H,m), 3.49(2H,s),
4.24(2H,d,J=5.9 Hz), 6.76(1H,t,J=7.3 Hz), 6.90(2H,d,J=7.9 Hz),
7.15-7.30(6H,m), 8.24(2H,t,J=5.9 Hz)
[0534] IR(KBr): 3318, 2940, 2819, 1645, 1535 cm.sup.-1
[0535] MS(EI): 337(M.sup.+)
[0536] Elemental analysis:
[0537] Calculated: C;74.74, H;8.06, N;12.45
[0538] Found: C;74.66, H;8.11, N;12.16
Example 5
Synthesis of
N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0539] ##STR82##
[0540] By similar reaction and treatment to that in Example 1(5)
using (4-fluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=164-166.degree. C.
[0541] .sup.1H-NMR(DMSO-d.sub.6)6: 1.87(3H,s), 2.45-2.55(4H,m),
3.00-3.10(4H,m), 3.49(2H,s), 4.23(2H,d,J=5.9 Hz), 6.89-6.95(2H,m),
6.95-7.06(2H,m), 7.19-7.39(4H,m), 8.30(1H,t,J=5.9 Hz)
[0542] IR(KBr): 3317, 2920, 2832, 1643, 1513 cm.sup.-1
[0543] MS(EI): 341(M.sup.+)
[0544] Elemental analysis:
[0545] Calculated: C;70.36, H;7.09, N;12.31
[0546] Found: C;70.08, H;7.06, N;12.13
Example 6
Synthesis of
N-(4-((4-(2-chlorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide-dih-
ydrochloride
[0547] ##STR83##
[0548] By similar reaction using (2-chlorophenyl)piperazine instead
of phenylpiperazine to that in Example 1(5) and treatment with 4M
hydrochloric acid-dioxane in ethanol, the title compound was
obtained as pale-brown crystals.
[0549] m.p.=235-238.degree. C. (decomposition).
[0550] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.10-3.40(8H,m), 4.28(2H,d,J=5.9 Hz), 4.37(2H,m), 7.05-7.20(1H,m),
7.30-7.35(3H,m), 7.44(1H,dd,J=1.3,7.9 Hz), 7.63(2H,d,J=7.9 Hz),
8.45(1H,t,J=5.9 Hz), 11.43(1H,br.s)
[0551] IR(KBr): 3282, 2591, 1664, 1543 cm.sup.-1
[0552] MS(EI): 357(M.sup.+)
[0553] Elemental analysis:
[0554] Calculated: C;60.76, H;6.23, N;10.63
[0555] Found: C;60.49, H;6.34, N;10.63
Example 7
Synthesis of
N-(4-((4-(2,3-dimethylphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide-
-hydrochloride
[0556] ##STR84##
[0557] By similar reaction using (2,3-dimethylphenyl)piperazine
hydrochloride instead of phenylpiperazine to that in Example 1(5)
and treatment with 4M hydrochloric acid-dioxane in ethanol, the
title compound was obtained as white crystals.
[0558] m.p.=253-255.degree. C. (decomposition)
[0559] .sup.1H-NMR(DMSO-d.sub.6).delta.:
1.89(3H,s),2.15(3H,s),2.21(3H,s),3.00-3.35(8H,m), 4.28(2H,d,J=5.9
Hz), 4.35(2H,s), 6.88(1H,d,J=7.9 Hz), 6.92(1H,d,J=7.3 Hz),
7.06(1H,dd,J=7.3,7.9 Hz), 7.33(2H,d,J=8.6 Hz), 7.63(2H,d,J=8.6 Hz),
8.45(1H,m), 11.33(1H,br.s)
[0560] IR(KBr): 3253, 2465, 1649, 1556 c.sup.-1
[0561] MS(EI): 351(M.sup.+)
[0562] Elemental analysis:
[0563] Calculated: C;68.11, H;7.79, N;10.83
[0564] Found: C;67.74, H;7.94, N;10.67
Example 8
Synthesis of
N-(4-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide-di-
hydrochloride
[0565] ##STR85##
[0566] In Example 1(5), (2-methoxyphenyl)piperazine was used for
reaction instead of phenylpiperazine, which was followed by
treatment with hydrochloric acid--ether and recrystallization from
methanol-ethyl acetate to give the title compound as white
crystals.
[0567] m.p.=221-223.degree. C.
[0568] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.06-3.27(4H,m), 3.31-3.35(2H,m), 3.44-3.57(2H,m), 3.78(3H,s),
4.28(2H,d,J=5.9 Hz), 4.34(2H,br.s), 6.86-7.05(4H,m),
7.33(2H,d,J=8.4 Hz), 7.61(2H,d,J=8.5 Hz), 8.45(1H,t,J=5.9 Hz),
11.33(1H,br.s)
[0569] IR(KBr): 3263, 2487, 1666, 1535 cm.sup.-1
[0570] MS(EI): 353(M.sup.+)
[0571] Elemental analysis:
[0572] Calculated: C;58.88, H;7.29, N;9.81
[0573] Found: C;58.45, H;6.91, N;9.75
Example 9
Synthesis of
N-(4-((4-(3-methylphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0574] ##STR86##
[0575] By similar reaction and treatment to that in Example 1(5)
using (3-methylphenyl)piperazine instead of phenylpiperazine, the
title compound was obtained as pale-yellow crystals,
m.p.=80-81.degree. C.
[0576] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.31(3H,s),
2.58(4H,dt,J=5.3,4.7 Hz), 3.18(4H,dd,J=5.3,4.7 Hz), 3.55(2H,s),
4.42(2H,d,J=5.3 Hz), 5.72(1H,br.s), 6.67(1H,d,J=7.3 Hz),
6.72(1H,d,J=7.3 Hz), 6.74(1H,s), 7.13(1H,t,J=7.3 Hz),
7.24(2H,d,J=7.9 Hz), 7.33(2H,d,J=7.9 Hz)
[0577] IR(KBr): 3317, 2815, 1633, 1537 cm.sup.-1
[0578] MS(EI): 337(M.sup.+)
[0579] Elemental analysis:
[0580] Calculated: C;74.74, H;8.06, N;12.54
[0581] Found: C;74.60, H;8.04, N;12.47
Example 10
Synthesis of
N-(4-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
hydrochloride 3/4 hydrate
[0582] ##STR87##
[0583] In Example 1(5), (.sup.3-methoxyphenyl)piperazine was used
for reaction instead of phenylpiperazine, which was followed by
treatment with hydrochloric acid--ether and recrystallization from
methanol-ethyl acetate to give the title compound as white
crystals, m.p.=201.5-202.5.degree. C.
[0584] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.07-3.29(4H,m), 3.33-3.39(2H,m), 3.72(3H,s), 3.77-3.81(2H,m),
4.28(2H,d,J=5.9 Hz), 4.34(2H,d,J=3.3 Hz), 6.45(1H,ddd,J=8.6,7.9,2.0
Hz), 6.49(1H,s), 6.52(1H,ddd,J=8.6,7.9,2.0 Hz),
7.14(1H,ddd,J=8.6,7.9 Hz), 7.33(2H,d,J=7.9 Hz), 7.70(2H,d,J=7.9
Hz), 8.44(1H,t,J=5.9 Hz), 11.33(1H,br.s)
[0585] IR(KBr): 3280, 2464, 1643, 1556 cm.sup.-1
[0586] MS(EI): 353(M.sup.+)
[0587] Elemental analysis:
[0588] Calculated: C;62.52, H;7.37, N;10.42
[0589] Found: C;62.64, H;7.34, N;10.44
Example 11
Synthesis of
N-(4-((4-(4-chlorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0590] ##STR88##
[0591] By similar reaction and treatment to that in Example 1(5)
using (4-chlorophenyl)piperazine instead of phenylpiperazine, the
title compound was obtained as pale-yellow crystals,
m.p.=180.5-182.degree. C.
[0592] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s),
2.58(4H,dd,J=5.3,4.6 Hz), 3.15(4H,dd,J=5.3,4.6 Hz ), 3.54(2H,s),
4.42(2H,d,J=5.9 Hz), 5.74(1H,br.s), 6.82(2H,ddd,J=9.2,3.3,2.0 Hz),
7.19(2H,ddd,J=9.2,3.3,2.0 Hz), 7.24(2H,d,J=7.9 Hz), 7.32(2H,d,J=7.9
Hz)
[0593] IR(KBr): 3315, 2890, 1645, 1542 cm.sup.-1
[0594] MS(EI): 357(M.sup.+)
[0595] Elemental analysis:
[0596] Calculated: C;67.12, H;6.76, N;11.45
[0597] Found: C;67.08, H;6.73, N;11.75
Example 12
Synthesis of
N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
hydrochloride 1/4 hydrate
[0598] ##STR89##
[0599] In Example 1(5), (2-fluorophenyl)piperazine was used for
reaction instead of phenylpiperazine, which was followed by
treatment with hydrochloric acid--ether and recrystallization from
a mixture of ethanol-ethyl acetate-hexane to give the title
compound as pale-brown crystals, m.p.=250-252.degree. C.
(decomposition).
[0600] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.15-3.60(8H,m), 4.28(2H,d,J=5.9 Hz), 4.35(2H,br.s), 7.15(4H,m),
7.33(2H,d,J=7.9 Hz), 7.62(2H,d,J=7.9 Hz), 8.46(1H,t,J=5.9 Hz),
11.43(1H,br.s)
[0601] IR(KBr): 3265, 2679, 1664, 1504 cm.sup.-1
[0602] MS(EI): 341(M.sup.+)
[0603] Elemental analysis:
[0604] Calculated: C;62.82, H;6.72, N;10.99
[0605] Found: C;62.60, H;6.56, N;11.00
Example 13
Synthesis of
N-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0606] ##STR90##
[0607] By similar reaction and treatment to that in Example 1(5)
using (4-methoxyphenyl)piperazine instead of phenylpiperazine, the
title compound was obtained as white crystals, m.p.=137-138.degree.
C.
[0608] .sup.1H-NMR(CDCl.sub.3).delta.: 1.87(3H,s), 2.50(4H,m),
2.99(4H,m), 3.48(2H,s), 3.67(3H,s), 4.23(2H,d,J=5.9 Hz),
6.79(2H,d,J=9.2 Hz), 6.86(2H,d,J=9.2 Hz), 7.21(2H,d,J=8.6 Hz),
7.27(2H,d,J=7.9 Hz), 8.30(1H,t,J=5.6 Hz)
[0609] IR(KBr): 3325, 1649, 1514 cm.sup.-1
[0610] MS(EI): 353(M.sup.+)
[0611] Elemental analysis:
[0612] Calculated: C;71.36, H;7.70, N;11.89
[0613] Found: C;71.19, H;7.70, N;11.77
Example 14
Synthesis of
N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide
(1) N-(2-(4-chloromethylphenyl)ethyl)acetamide
[0614] ##STR91##
[0615] To a solution of N-(2-phenylethyl)acetamide (5.0 g) in
dichloromethane (31 ml) was added titanium tetrachloride (17 ml) at
0-5.degree. C. over 30 min. Thereto was added dichloromethyl methyl
ether (8.4 ml) at 0-5.degree. C. over 30 min. This reaction mixture
was stirred at room temperature for 3 hr and was poured into
icewater (1000 ml). The mixture was extracted with ethyl acetate
(200 ml.times.2). The ethyl acetate layer was washed with aqueous
sodium hydroxide and saturated brine, and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a mixture (1.4
g) containing N-(2-(4-formylphenyl)ethyl)acetamide and
N-(2-(2-formylphenyl)ethyl)acetamide at about 8:1 as a pale-brown
oil.
[0616] To a solution of this mixture (1.4 g) in ethanol (7.3 ml)
was added sodium borohydride (0.56 g) and the mixture was stirred
at 50.degree. C. for 3 hr. Thereto was added 2N hydrochloric acid
(ca. 20 ml) at below 10.degree. C. This mixture was poured into
water (300 ml) and extracted with ethyl acetate (250 ml.times.2).
The ethyl acetate layer was washed with aqueous sodium hydroxide
(200 ml) and saturated brine (200 ml), and dried over anhydrous
sodium sulfate. The solvent was evaporated and the obtained residue
was purified by silica gel column chromatography (developing
solvent; ethyl acetate:methanol:chloroform=3:1:12) to give a
mixture (0.58 g) containing
N-(2-(4-hydroxymethylphenyl)ethyl)-acetamide and
N-(2-(2-hydroxymethylphenyl)ethyl)acetamide at about 8:1 as a
yellow oil.
[0617] A solution of this mixture (0.58 g) and thionyl chloride
(0.30 ml) in dichloromethane (15 ml) was refluxed under heating for
2 hr. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography (developing solvent;
ethyl acetate) to give a mixture (0.40 g) containing the title
compound and N-(2-(2-chloromethylphenyl)ethyl)acetamide at about
8:1 as white crystals.
[0618] In the same manner as in the above, white crystals (0.70 g)
containing the title compound and
N-(2-(2-chloromethylphenyl)-ethyl)acetamide at about 8:1 was
obtained. The crystals were combined with the crystals (0.40 g)
obtained earlier and recrystallized from a mixture of ethyl
acetate-isopropyl ether-hexane to give the title compound (0.58 g)
as white crystals, m.p.=86-88.degree. C.
[0619] .sup.1H-NMR(CDCl.sub.3).delta.: 1.94(3H,s),
2.82(2H,dd,J=7.3,6.6 Hz), 3.50(2H,dd,J=7.3,6.6 Hz), 4.57(2H,s),
5.49(1H,br.s), 7.19(2H,d,J=8.6 Hz), 7.34(2H,d,J=7.9 Hz)
[0620] IR(KBr): 3297, 1633, 1543 cm.sup.-1
[0621] MS(EI): 211((M+1)+)
[0622] Elemental analysis:
[0623] Calculated: C;62.41, H;6.67, N;6.62
[0624] Found: C;62.34, H;6.80, N;6.70
(2)
N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide
[0625] ##STR92##
[0626] By similar reaction and treatment to that in Example 1(5)
using N-(2-(4-chloromethylphenyl)ethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals, m.p.=117-118.degree. C.
[0627] .sup.1H-NMR(CDCl.sub.3).delta.: 1.94(3H,s), 2.61(4H,t,J=5.3
Hz), 3.15(2H,dd,J=7.3,6.6 Hz ), 3.20(2H,t,J=5.3 Hz ),
3.15(2H,dd,J=6.6,5.9 Hz ), 3.55(2H,s), 5.46(1H,br.s),
6.84(1H,t,J=7.3 Hz), 6.92(2H,d,J=7.9 Hz), 7.16(1H,d,J=7.9 Hz ),
7.23(2H,d,J=7.9 Hz), 7.30(2H,d,J=7.9 Hz)
[0628] IR(KBr): 3352, 3302, 1647, 1535 cm.sup.-1
[0629] MS(EI): 337((M-1)+)
[0630] Elemental analysis:
[0631] Calculated: C;74.74, H;8.06, N;12.45
[0632] Found: C;74.49, H;8.05, N;12.40
Example 15
Synthesis of
N-(3-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide 1/4
hydrate
(1) N-(3-(4-chloromethylphenyl)propyl)acetamide
[0633] ##STR93##
[0634] To a solution of N-(3-phenylpropyl)acetamide (10.14 g) in
dichloromethane (130 ml) was added titanium tetrachloride (28 ml)
at 5-7.degree. C. over30 min. Thereto was added a solution of
dichloromethyl methyl ether (18 ml) in dichloromethane (20 ml) at
5-8.degree. C. over 30 min. This reaction mixture was stirred at
room temperature for 3 hr, and poured into ice water (1000 ml). The
mixture was extracted with chloroform (500 ml.times.2). The
chloroform layer was washed with saturated aqueous sodium
hydrogencarbonate, and dried over anhydrous sodium sulfate. The
solvent was evaporated and the obtained residue was purified by
silica gel column chromatography (developing solvent; hexane:ethyl
acetate=2:1.fwdarw.methanol:chloroform=3:97) to give a mixture
(10.85 g) containing N-(3-(4-formylphenyl)propyl)acetamide and
N-(3-(2-formylphenyl)-propyl)acetamide at about 6:1 as a yellow
oil.
[0635] To a solution of this mixture (10.85 g) in ethanol (100 ml)
was added sodium borohydride (2.0 g) at 5.degree. C. over 15 min.
This mixture was stirred at room temperature for 1 hr and 2N
hydrochloric acid (ca.20 ml) was added at below 10.degree. C. This
mixture was poured into water (300 ml) and extracted with ethyl
acetate (250 ml.times.2). The ethyl acetate layer was washed with
saturated sodium hydrogencarbonate solution (200 ml) and saturated
brine (200 ml), and dried over anhydrous sodium sulfate. The
solvent was evaporated and the obtained residue was purified by
silica gel column chromatography (developing solvent;
methanol:chloroform=4:96) to give a mixture (4.36 g) containing
N-(3-(4-hydroxymethylphenyl)propyl)acetamide and
N-(3-(2-hydroxymethylphenyl)propyl)acetamide at about 6:1 as white
crystals.
[0636] A solution of this mixture (1.428 g) and thionyl chloride
(0.60 ml) in chloroform (50 ml) was refluxed under heating for 2
hr. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography (developing solvent;
methanol:chloroform=3:97) to give a mixture (1.26 g) containing the
title compound and N-(3-(2-chloromethylphenyl)propyl)acetamide at
about 6:1 as white crystals. The crystals (0.98 g) were
recrystallized from ethyl acetate-hexane to give the title compound
(0.23 g) as white crystals.
[0637] m.p.=89-90.degree. C.
[0638] .sup.1H-NMR(CDCl.sub.3).delta.: 1.82(2H,tt,J=7.4,7.4 Hz),
1.94(3H,s), 2.65(2H,t,J=7.6 Hz), 3.27(2H,dt,J=6.8 Hz), 4.56(2H,s),
5.55(1H,br.s), 7.17(2H,d,J=8.6 Hz), 7.29(2H,d,J=7.9 Hz)
[0639] IR(KBr): 3298, 1639, 1551 cm.sup.-1
[0640] MS(EI): 226((M+1)+)
[0641] Elemental analysis:
[0642] Calculated: C;63.85, H;7.14, N;6.21
[0643] Found: C;63.69, H;7.17, N;6.20
(2) N-(3-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide
1/4 hydrate
[0644] ##STR94##
[0645] By similar reaction and treatment to that in Example 1(5)
using N-(3-(4-chloromethylphenyl)propyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals, m.p.=117-118.degree. C.
[0646] .sup.1H-NMR(CDCl.sub.3).delta.: 1.83(2H,tt,J=7.4,7.4 Hz),
1.94(3H,s), 2.62(6H,m), 3.19(4H,t,J=4.9 Hz), 3.27(2H,dt,J=6.8,6.8
Hz), 3.53(2H,s), 5.48(1H,br.s), 6.84(1H,t,J=7.2 Hz),
6.91(2H,d,J=7.1 Hz), 7.14(2H,d,J=7.9 Hz), 7.25(4H,m)
[0647] IR(KBr): 3323, 2941, 1641, 1601, 1537 cm.sup.-1
[0648] MS(EI): 351((M+1)+)
[0649] Elemental analysis:
[0650] Calculated: C;74.23, H;8.35, N;11.80
[0651] Found: C;74.27, H;8.26, N;11.89
Example 16
Synthesis of
N-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamide
dihydrochloride
(1) N-phenylmethylacetamide
[0652] ##STR95##
[0653] To a solution of benzylamine (98.1 g) in methylene chloride
(100 ml) was added an aqueous solution (200 ml) of sodium hydroxide
(44 g). While further stirring the mixture, acetyl chloride (78 ml)
was added at 15-20.degree. C. over 1 hr. This reaction mixture was
stirred at room temperature for 30 min and extracted with
chloroform (100 ml.times.2). The chloroform layer was washed with
water and dried over anhydrous magnesium sulfate. The solvent was
evaporated to give a white solid (160 g). The obtained solid was
crystallized from hexane: ethyl acetate (2:1, 750 ml) to give the
title compound (125.7 g) as white crystals, m.p.=61-62.degree.
C.
[0654] .sup.1H-NMR(CDCl.sub.3).delta.: 2.00(3H,s), 4.41(2H,d,J=5.3
Hz), 5.95(1H,br.s), 7.20-7.35(5H,m)
[0655] IR(KBr): 3298, 1645, 1552 cm.sup.-1
[0656] MS(EI): 149(M.sup.+)
[0657] Elemental analysis:
[0658] Calculated: C;72.46, H;7.43, N;9.39
[0659] Found: C;72.40, H;7.32, N;9.35
(2) N-[(4-acetylphenyl)methyl]acetamide
[0660] ##STR96##
[0661] To a suspension of aluminum chloride (22.3 g) in
dichloroethane (40 ml)was added acetyl chloride (7.1 ml). Thereto
was added a solution of N-phenylmethylacetamide (10 g) in
dichloroethane (20 ml) at 10-15.degree. C. over 20 min. This
reaction mixture was stirred at room temperature for 6 hr and
poured into ice water (100 ml). The mixture was extracted with
chloroform (100 ml.times.3). The chloroform layer was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a black brown oil (15.5 g). The
obtained residue was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=20:1) to give the title
compound (6.48 g) as a black brown solid.
[0662] .sup.1H-NMR(CDCl.sub.3).delta.: 2.04(3H,s), 2.57(3H,s),
4.46(2H,d,J=5.9 Hz), 6.30(1H,br.s), 7.34(2H,d,J=7.9 Hz),
7.88(2H,d,J=7.9 Hz)
[0663] MS(EI): 191(M.sup.+)
(3) N-{[4-(1-hydroxyethyl)phenyl]methyl}acetamide
[0664] ##STR97##
[0665] To a solution of N-[(4-acetylphenyl)methyl]acetamide (6.1 g)
in methanol (50 ml) was added sodium borohydride (1.2 g) under
ice-cooling. This reaction mixture was stirred at 5-7.degree. C.
for 2 hr. Thereto was added 2% hydrochloric acid and extracted with
ethyl acetate (100 ml.times.3). The ethyl acetate layer was washed
with saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a brown oil (6.3 g). The obtained
brown oil was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=9:1) to give the title
compound (5.98 g) as a pale-brown oil, m.p.=61-62.degree. C.
[0666] .sup.1H-NMR(CDCl.sub.3).delta.: 1.46(3H,d,J=6.6 Hz),
1.97(3H,s), 2.55(1H,br.s), 4.35(2H,d,J=5.9 Hz), 4.85(1H,q,J=6.6
Hz), 6.15(1H,br.s), 7.21(2H,d,J=7.9 Hz), 7.31(2H,d,J=7.9 Hz)
[0667] IR(neat): 3302, 2971, 1651, 1556 cm.sup.-1
[0668] MS(EI): 193(M.sup.+)
(4) N-{[4-(1-chloroethyl)phenyl]methyl}acetamide
[0669] ##STR98##
[0670] A solution of N-{[4-(1-hydroxyethyl)phenyl]methyl}acetamide
(5.7 g) and thionyl chloride (2.6 ml) in chloroform (50 ml) was
refluxed under heating for 1.5 hr. The solvent was evaporated to
give a brown oil (6.7 g). The obtained brown oil was purified by
silica gel column chromatography (developing solvent;
chloroform:methanol=20:1) to give the title compound (5.5 g) as a
pale-brown oil.
[0671] .sup.1H-NMR(CDCl.sub.3).delta.: 1.83(3H,d,J=7.3 Hz),
2.01(3H,s), 4.40(2H,d,J=4.6 Hz), 5.07(1H,q,J=7.3 Hz),
6.12(1H,br.s), 7.26(2H,d,J=8.6 Hz), 7.38(2H,d,J=8.6 Hz)
[0672] MS(EI): 211(M.sup.+)
(5) N-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamide
dihydrochloride
[0673] ##STR99##
[0674] In Example 1(5),
N-{[4-(1-chloroethyl)phenyl]methyl}acetamide was used for reaction
instead of N-(4-chloromethylphenylmethyl)-acetamide, which was
followed by treatment with 4M hydrochloric acid-dioxane in ethanol
to give the title compound as white crystals.
[0675] m.p.=233-235.degree. C. (decomposition)
[0676] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.74(3H,d,J=6.6 Hz),
1.89(3H,s), 2.80-3.20(4H,m), 3.38(1H,m), 3.65-3.85(3H,m),
4.27(2H,d,J=5.9 Hz), 4.51(1H,m), 6.86(1H,t,J=7.3 Hz),
6.96(2H,d,J=7.9 Hz), 7.25(2H,dd,J=7.3,8.6 Hz), 7.34(2H,d,J=7.9 Hz),
7.65(2H,d,J=7.9 Hz), 8.47(1H,m), 11.71(1H,br.s)
[0677] IR(KBr): 3296, 3061, 2397, 1668, 1542 cm.sup.-1
[0678] MS(EI): 337(M.sup.+)
[0679] Elemental analysis:
[0680] Calculated: C;61.46, H;7.12, N;10.24
[0681] Found: C;61.41, H;7.20, N;10.32
Example 17
Synthesis of
N-((2,6-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)phenyl)methyl)acetamid-
e 1/5 hydrate
(1) 4-nitromesitylenecarboxylic acid
[0682] ##STR100##
[0683] To a solution of chromic anhydride (40 g) in acetic acid
(450 ml) was added a solution of nitromesitylene (20 g) in acetic
acid (50 ml) at 65-70.degree. C. over 20 min. This reaction mixture
was stirred at 65-70.degree. C. for 30 min and isopropyl alcohol
(45 ml) was added. This reaction mixture was further stirred at
50.degree. C. for 30 min. Water was added to the reaction mixture
to make the total amount 500 ml and the mixture was ice-cooled. The
precipitated crystals were collected by filtration to give the
title compound (13 g) as pale-green crystals.
[0684] .sup.1H-NMR(CDCl.sub.3).delta.: 2.37(6H,s), 7.89(2H,s)
[0685] IR(KBr): 2968, 2930, 1696, 1602, 1535 cm.sup.-1
[0686] MS(EI): 195(M.sup.+)
(2) ethyl 4-nitromesitylenecarboxylate
[0687] ##STR101##
[0688] To a solution of 4-nitromesitylenecarboxylic acid (13 g) in
ethanol (50 ml) was added a solution of 28% hydrochloric
acid-ethanol (50 ml) and the mixture was refluxed under heating for
2 hr. The reaction mixture was concentrated and ethyl acetate was
added. The mixture was washed with water and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated
and the obtained residue was purified by silica gel column
chromatography (developing solvent; hexane:ethyl acetate=9:1) to
give the title compound (7.7 g) as pale-brown crystals.
[0689] .sup.1H-NMR(CDCl.sub.3).delta.: 1.41(3H,t,J=4 Hz),
2.35(6H,s), 4.40(2H,q,J=4 Hz), 7.81(2H,s)
[0690] IR(KBr): 3077, 2998, 1725, 1606, 1524 cm.sup.-1
[0691] MS(EI): 223(M.sup.+)
(3) ethyl 4-aminomesitylenecarboxylate
[0692] ##STR102##
[0693] To a solution of ethyl 4-nitromesitylenecarboxylate (7.7 g)
in ethyl acetate (300 ml) was added 10% palladium-carbon (3 g) and
the mixture was stirred for 3.5 hr under a hydrogen atmosphere. The
catalyst was filtered off from the reaction mixture and the
filtrate was washed with water and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was evaporated to give the
title compound (6.6 g) as pale-brown crystals.
[0694] .sup.1H-NMR(CDCl.sub.3).delta.: 1.37(3H,t,J=4 Hz),
2.20(6H,s), 3.96(2H,br.s), 4.32(2H,q,J=4 Hz), 7.66(2H,s)
[0695] IR(KBr): 3506, 3398, 1692, 1627 cm.sup.-1
[0696] MS(EI): 193(M.sup.+)
(4) ethyl 4-cyanomesitylenecarboxylate
[0697] ##STR103##
[0698] To a solution of ethyl 4-aminomesitylenecarboxylate (6.6 g)
in conc. hydrochloric acid (50 ml) was added a solution of sodium
sulfite (2.6 g) in water (15 ml) at 0-5.degree. C. over 30 min.
This reaction mixture was stirred at 0.degree. C. for 1 hr. To this
reaction mixture was neutralized by adding sodium carbonate and
then ethyl acetate (100 ml) was added. To a solution of copper
cyanide (6.8 g) in water (100 ml) was added potassium cyanide (18
g) and the mixture was stirred at 0.degree. C. for 30 min. The
above-mentioned reaction mixture was added at 0-5.degree. C. and
the mixture was stirred at 0.degree. C. for 1 hr. The reaction
mixture was extracted with ethyl acetate, washed with aqueous
sodium hydrogencarbonate and saturated brine, and dried over
anhydrous magnesium sulfate. The solvent was evaporated and the
obtained residue was recrystallized from ethyl acetate-hexane to
give the title compound (5.5 g) as pale-brown crystals.
[0699] .sup.1H-NMR(CDCl.sub.3).delta.: 1.39(3H,t,J=4 Hz),
2.57(6H,s), 4.37(2H,q,J=4 Hz), 7.76(2H,s)
[0700] IR(KBr): 3056, 2222, 1716, 1585 cm.sup.-1
[0701] MS(EI): 203(M.sup.+)
(5) 4-aminomethyl-3,5-dimethylbenzyl alcohol
[0702] ##STR104##
[0703] To a solution of aluminum lithium hydride (2.1 g) in
tetrahydrofuran (20 ml) was added a solution of ethyl
4-cyanomesitylenecarboxylate (2.9 g) in tetrahydrofuran (30 ml) at
0.degree. C. and the mixture was refluxed under heating for 6 hr.
To this reaction mixture was added 50% (v/v) tetrahydrofuran in
water under ice-cooling. This mixture was stirred at room
temperature for 30 min and the catalyst was filtered off using
Celite. The solvent was evaporated and the obtained residue was
recrystallized from methanol-isopropyl ether to give the title
compound (5.5 g) as white crystals.
[0704] .sup.1H-NMR(CDCl.sub.3).delta.: 1.52(3H,br.s), 2.39(6H,s),
3.85(2H,s), 4.59(2H,s), 7.03(2H,s)
[0705] IR(KBr): 3294, 2927, 2858, 1647, 1554 cm.sup.-1
[0706] MS(EI): 164(M.sup.+)
(6) N-((4-hydroxymethyl-2,6-dimethylphenyl)methyl)acetamide
[0707] ##STR105##
[0708] To a solution of 4-aminomethyl-3,5-dimethylbenzyl alcohol
(2.3 g) in ethyl acetate (70 ml) was added a solution of potassium
carbonate (2.0 g) in water (35 ml). To this solution was added
acetyl chloride (0.95 ml) under ice-cooling. This mixture was
stirred at room temperature for 1 hr. The reaction mixture was
extracted with ethyl acetate, washed with saturated brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated and
the obtained residue was recrystallized from methanol-ethyl acetate
to give the title compound (2.0 g) as white crystals,
m.p.=193.5-194.5.degree. C.
[0709] .sup.1H-NMR(CDCl.sub.3).delta.: 1.97(3H,s), 2.36(6H,s),
4.44(2H,d,J=4.6 Hz), 4.62(2H,s), 5.27(1H,br.s), 7.06(2H,s)
[0710] IR(KBr): 3286, 2951, 1632, 1537 cm.sup.-1
[0711] MS(EI): 207(M.sup.+)
(7) N-((4-chloromethyl-2,6-dimethylphenyl)methyl)acetamide
[0712] ##STR106##
[0713] To a solution of
N-((4-hydroxymethyl-2,6-dimethylphenyl)-methyl)acetamide (1.0 g) in
dichloromethane (12 ml) was added thionyl chloride (0.88 ml). This
mixture was stirred at room temperature for 3 hr. The reaction
mixture was poured into water and extracted with ethyl acetate. The
extract was washed with aqueous sodium hydrogencarbonate and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated and the obtained residue was recrystallized
from ethyl acetate-isopropyl ether to give the title compound (1.0
g) as white crystals.
[0714] m.p.=193-194.5.degree. C.
[0715] .sup.1H-NMR(CDCl.sub.3).delta.: 1.97(3H,s), 2.36(6H,s),
4.44(2H,d,J=4.6 Hz), 4.50(2H,s), 5.26(1H,br.s), 7.06(2H,s)
[0716] IR(KBr): 3284, 1633, 1538 cm.sup.-1
[0717] MS(EI): 225(M.sup.+)
(8)
N-(4-(4-phenylpiperazin-1-ylmethyl)-2,6-dimethylphenylmethyl)-acetamid-
e 1/5 hydrate
[0718] ##STR107##
[0719] By similar reaction and treatment to that in Example 1(5)
using N-((4-chloromethyl-2,6-dimethylphenyl)methyl)acetamide
instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound was obtained as white crystals, m.p.=159-160.5.degree.
C.
[0720] .sup.1H-NMR(CDCl.sub.3).delta.: 1.97(3H,s), 2.36(6H,s),
2.60(4H,dd,J=5.3,4.6 Hz), 3.20(4H,dd,J=5.3,4.6 Hz), 3.48(2H,s),
4.46(2H,d,J=4.6 Hz), 5.27(1H,br.s), 6.86(1H,dt,J=7.3,1.3 Hz),
6.92(2H,dd,J=7.3,1.3 Hz), 7.04(2H,s), 7.21-7.29(2H,m)
[0721] IR(KBr): 3269, 2952, 1600, 1546 cm.sup.-1
[0722] MS(EI): 351(M.sup.+)
[0723] Elemental analysis:
[0724] Calculated: C;74.41, H;8.35, N;11.83
[0725] Found: C;74.63, H;8.32, N;11.79
Example 18
Synthesis of
N-(4-(4-(4-fluorophenyl)piperazin-1-ylmethyl)-2,6-dimethylphenylmethyl)ac-
etamide
[0726] ##STR108##
[0727] By similar reaction and treatment to that in Example 17(8)
using 1-(4-fluorophenyl)piperazine instead of 1-phenylpiperazine,
the title compound was obtained as white crystals,
m.p.=163-164.degree. C.
[0728] .sup.1H-NMR(CDCl.sub.3).delta.: 1.98(3H,s), 2.36(6H,s),
2.60(4H,dd,J=5.3,4.6 Hz), 3.12(4H,dd,J=5.3,4.6 Hz), 3.48(2H,s),
4.45(2H,d,J=4.6 Hz), 5.25(1H,br.s), 6.83-6.98(4H,m), 7.03(2H,s)
[0729] IR(KBr): 3323, 2947, 1645, 1531 cm.sup.-1
[0730] MS(EI): 369(M.sup.+)
[0731] Elemental analysis:
[0732] Calculated: C;71.52, H;7.64, N;11.37
[0733] Found: C;71.22, H;7.71, N;11.28
Example 19
Synthesis of
N-(4-(1-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide
dihydrochloride
[0734] ##STR109##
[0735] In Example 1(5),
N-((4-(1-chloroethyl)phenyl)methyl)acetamide was used for reaction
instead of N-(4-chloromethylphenylmethyl)-acetamide and
1-(2-methoxyphenyl)piperazine instead of 1-phenylpiperazine, which
was followed by treatment with 4M hydrochloric acid--dioxane in
ethanol to give the title compound as white crystals.
[0736] m.p.=220-223.degree. C. (decomposition)
[0737] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.75(3H,d,J=6.6 Hz),
1.90(3H,s), 2.90-3.25(4H,m), 3.40-3.60(3H,m), 3.77(3H,s),
3.82(1H,m), 4.28(1H,d,J=5.3 Hz), 4.53(1H,m), 6.85-7.10(4H,m),
7.35(2H,d,J=7.9 Hz), 7.68(2H,d,J=8.6 Hz), 8.53(1H,t,J=5.3 Hz),
11.81(1H,br.s)
[0738] IR(KBr): 3286, 3253, 2983, 2404, 1668 cm.sup.-1
[0739] MS(EI): 367(M.sup.+)
[0740] Elemental analysis:
[0741] Calculated: C;60.00, H;7.09, N;9.54
[0742] Found: C;60.07, H;7.19, N;9.61
Example 20
Synthesis of
N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0743] ##STR110##
[0744] By similar reaction and treatment to that in Example 1(5)
using (2,4-difluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as pale-brown
crystals, m.p.=94-95.degree. C.
[0745] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s),
2.61(4H,dd,J=5.28,4.62 Hz), 3.04(4H,dd,J=5.3,4.6 Hz), 3.56(2H,s),
4.42(2H,d,J=5.9 Hz), 5.71(1H,br.s), 6.73-6.93(3H,m),
7.24(2H,d,J=7.9 Hz), 7.32(2H,d,J=7.9 Hz)
[0746] IR(KBr): 3307, 2939, 2821, 1645, 1556 cm.sup.-1
[0747] MS(EI): 359(M.sup.+)
[0748] Elemental analysis:
[0749] Calculated: C;66.84, H;6.45, N;11.69
[0750] Found: C;66.84, H;6.43, N;11.66
Example 21
Synthesis of
N-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
(1) methyl 4-acetamidomethyl-3-nitrobenzoate
[0751] ##STR111##
[0752] To a mixture (mixed acid) of fuming nitric acid (70 ml) and
conc. sulfuric-acid (70 ml) was added methyl
4-acetamidomethylbenzoate (54 g) at 7-15.degree. C. for 1.5 hr.
This reaction mixture was stirred at room temperature for 1 hr and
poured into ice water (600 ml). The mixture was extracted with
chloroform (300 ml.times.3). The extract was washed with water,
saturated sodium hydrogencarbonate solution and saturated brine,
and dried over anhydrous sodium sulfate. The solvent was evaporated
to give a yellow oil (75 g). The obtained yellow oil was
crystallized from ethyl acetate (50 ml) and recrystallized from
hexane/ethyl acetate (1:1, 600 ml) to give the title compound (45.5
g) as pale-yellow crystals.
[0753] m.p.=100-102.degree. C.
[0754] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 3.97(3H,s),
4.71(2H,d,J=6.6 Hz), 6.38(1H,m), 7.76(1H,d,J=7.9 Hz),
8.24(1H,dd,J=1.3,7.9 Hz), 8.67(1H,d,J=1.3 Hz)
[0755] IR(KBr): 3280, 1735, 1648, 1533, 1434 cm.sup.-1
[0756] MS(EI): 253((M+1)+)
[0757] Elemental analysis:
[0758] Calculated: C;52.38, H;4.80, N;11.11
[0759] Found: C;52.33, H;4.79, N;11.11
(2) N-(4-hydroxymethyl-2-nitrophenylmethyl)acetamide
[0760] ##STR112##
[0761] A solution of methyl 4-acetamidomethyl-3-nitrobenzoate (20
g) and lithium borohydride (1.7 g) in tetrahydrofuran (200 ml) was
stirred at 40-50.degree. C. for 2.5 hr. The reaction mixture was
poured into water (150 ml) and extracted with ethylacetate (100
ml.times.3). The extract was washed with saturated brine and dried
over anhydrous sodium sulfate. The solvent was evaporated to give a
yellow oil (15.5 g). The obtained yellow oil was purified by silica
gel column chromatography (developing solvent;
chloroform:methanol=9:1) to give a pale-brown solid (13.5 g). The
obtained solid was crystallized from ethyl acetate/ethanol/hexane
(30:2:5) to give the title compound (12 g) as yellow white
crystals.
[0762] m.p.=133-135.degree. C.
[0763] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.90(3H,s),4.51(2H,d,J=5.9
Hz),4.58(2H,d,J=5.3 Hz), 5.47(1H,t,J=5.3 Hz), 7.49(1H,d,J=7.9 Hz),
7.64(1H,d,J=7.9 Hz), 7.96(1H,s), 8.39(1H,m)
[0764] IR(KBr): 3290, 1656, 1558, 1529 cm.sup.-1
[0765] MS(EI): 225((M+1)+)
(3) N-(4-chloromethyl-2-nitrophenylmethyl)acetamide
[0766] ##STR113##
[0767] To a solution of
N-(4-hydroxymethyl-2-nitrophenylmethyl)-acetamide (9.1 g),
triethylamine (6.2 ml) and dimethylaminopyridine (0.99 g) in
dichloromethane (150 ml)-tetrahydrofuran (50 ml) was added
p-toluenesulfonyl chloride (8.5 g) under ice-cooling. This mixture
was stirred at room temperature for 3 hr. The reaction mixture was
washed with water and saturated brine, and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a yellow oil
(15.5 g). The obtained yellow oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=20:1) to
give the title compound (12 g) as a pale-brown solid (7.8 g).
[0768] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.90(3H,s),
4.52(2H,d,J=5.9 Hz), 4.87(2H,s), 7.54(1H,d,J=8.6 Hz),
7.79(1H,dd,J=1.3,8.6 Hz), 8.12(1H,d,J=1.3 Hz), 8.43(1H,m)
[0769] MS(EI): 243(M.sup.+)
(4)
N-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)-acetamide
[0770] ##STR114##
[0771] A solution of
N-(4-chloromethyl-2-nitrophenylmethyl)acetamide (1.4 g),
phenylpiperazine (0.8 ml) and potassium carbonate (0.6 g) in
dimethylformamide (20 ml) was stirred at 60.degree. C. for 4 hr.
The reaction mixture was poured into water (150 ml) and extracted
with ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated to
give a pale-yellow solid. The obtained pale-yellow solid was
crystallized from ethyl acetate to give the title compound (1.3 g)
as pale-yellow white crystals, m.p.=135-136.degree. C.
[0772] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.90(3H,s),
2.50-2.60(4H,m), 3.10-3.15(4H,m), 3.62(2H,s), 4.51(2H,d,J=5.9 Hz),
6.77(1H,m), 6.91(2H,d,J=7.9 Hz), 7.20(2H,m), 7.50(1H,d,J=7.9 Hz),
7.68(1H,dd,J=1.3,7.9 Hz), 7.97(1H,d,J=1.3 Hz), 8.40(1H,t,J=5.9
Hz)
[0773] IR(KBr): 3251, 3080, 2823, 1641, 1599 cm.sup.-1
[0774] MS(EI): 368(M.sup.+)
[0775] Elemental analysis:
[0776] Calculated: C;65.20, H;6.57, N;15.21
[0777] Found: C;65.17, H;6.58, N;15.12
Example 22
Synthesis of
N-(2-amino-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
[0778] ##STR115##
[0779] To a solution of
N-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
(0.5 g) and water-containing Raney-nickel (0.5 g) in ethanol(8 ml)
was added dropwise hydrazine monohydrate (0.7 ml) and the mixture
was refluxed under heating at room temperature for 1 hr.
Raney-nickel was removed by passing the mixture through Celite and
the solvent was evaporated to give a white solid (0.48 g). The
obtained white solid was crystallized from hexane/ethyl acetate
(1:1, 100 ml) to give the title compound (45.5 g) as white
crystals, m.p.=148-149.degree. C.
[0780] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.85(3H,s),
2.40-2.55(4H,m), 3.05-3.15(4H,m), 3.35(2H,s), 4.08(2H,d,J=5.9 Hz),
5.05(2H,s), 6.46(1H,dd,J=1.3,5.9 Hz), 6.62(1H,d,J=1.3 Hz),
6.76(1H,t,J=7.3 Hz), 6.89-6.93(3H,m), 7.15-7.25(2H,m),
8.21(1H,t,J=5.9 Hz)
[0781] IR(KBr): 3336, 3239, 2809, 1623, 1523 cm.sup.-1
[0782] MS(EI): 338(M.sup.+)
[0783] Elemental analysis:
[0784] Calculated: C;70.98, H;7.74, N;16.55
[0785] Found: C;70.85, H;7.77, N;16.33
Example 23
Synthesis of
N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-2-nitrophenylmethyl)aceta-
mide
[0786] ##STR116##
[0787] In Example 21(4), (4-fluorophenyl)piperazine dihydrochloride
was used instead of phenylpiperazine to give the title compound as
yellow crystals, m.p.=112-114.degree. C.
[0788] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.91(3H,s),
2.45-2.55(4H,m), 3.05-3.15(4H,m), 3.62(2H,s), 4.52(2H,d,J=5.9 Hz),
6.90-7.00(2H,m), 7.00-7.07(2H,m), 7.51(1H,d,.J=7.9 Hz),
7.68(1H,dd,J=1.3,7.9 Hz), 7.97(1H,d,J=1.3 Hz), 8.40(1H,t,J=5.9
Hz)
[0789] IR(KBr): 3253, 2831, 1639, 1562 cm.sup.-1
[0790] MS(EI): 386(M.sup.+)
[0791] Elemental analysis:
[0792] Calculated: C;62.16, H;6.00, N;14.50
[0793] Found: C;61.80, H;5.97, N;14.13
Example 24
Synthesis of
N-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide
[0794] ##STR117##
[0795] In Example 22,
N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-2-nitrophenylmethyl)aceta-
mide was used instead of
N-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
to give the title compound as yellow white crystals,
m.p.=163-164.degree. C.
[0796] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.85(3H,s),
2.45-2.55(4H,m), 3.00-3.10(4H,m), 3.33(2H,s), 4.08(2H,d,J=6.6 Hz),
5.05(2H,s), 6.46(1H,dd,J=1.3,7.3 Hz), 6.61(1H,d,J=1.3 Hz),
6.89-6.95(3H,m), 6.99-7.06(2H,m), 8.21(1H,t,J=5.9 Hz)
[0797] IR(KBr): 3311, 3241, 2836, 1626, 1510 cm.sup.-1
[0798] MS(EI): 356(M.sup.+)
[0799] Elemental analysis:
[0800] Calculated: C;67.39, H;7.07, N;15.72
[0801] Found: C;67.56, H;7.14, N;15.59
Example 25
Synthesis of
N-(2-acetamide-4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)-
acetamide
[0802] ##STR118##
[0803] A solution of
N-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (1.65 g), acetic anhydride (0.52 ml) and triethylamine (0.77
ml) in methylene chloride (20 ml) was refluxed under heating for 3
hr. The reaction mixture was poured into water (150 ml) and
extracted with chloroform. The extract was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a brown oil. The obtained brown oil was purified
by silica gel column chromatography (developing solvent;
chloroform:methanol=20:1) to give a pale-brown solid (1.5 g). This
pale-brown solid was crystallized from ethyl acetate to give the
title compound (1.1 g) as pale-yellow crystals,
m.p.=145-146.degree. C.
[0804] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s), 2.07(3H,s),
2.45-2.55(4H,m), 3.00-3.10(4H,m), 3.47(2H,s), 4.20(2H,d,J=5.9 Hz),
6.88-6.98(2H,m), 6.99-7.07(3H,m), 7.20(1H,d,J=7.9 Hz), 7.66(1H,s),
8.48(1H,t,J=5.9 Hz), 9.82(1H,s)
[0805] IR(KBr): 3288, 2819, 1673, 1626, 1587 cm.sup.-1
[0806] MS(EI): 398(M.sup.+)
[0807] Elemental analysis:
[0808] Calculated: C;66.31, H;6.83, N;14.06
[0809] Found: C;66.06, H;6.78, N;13.94
Example 26
Synthesis of
N-(2-chloro-4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)ace-
tamide
[0810] ##STR119##
[0811] To an aqueous solution (2 ml) of sodium nitrite (213 mg) was
added a solution of
N-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (1.1 g) in conc. hydrochloric acid (5 ml) under ice-cooling.
This mixture was stirred at the same temperature -for 40 min. The
reaction mixture was added to a solution of copper(I) chloride (183
mg) in conc. hydrochloric acid (2 ml) over 10 min. The mixture was
stirred at room temperature for 2 hr. The reaction mixture was
poured into aqueous sodium hydroxide solution and extracted with
ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated to
give a green oil (1.4 g). The obtained green oil was purified by
silica gel column chromatography (developing solvent ;
chloroform:methanol=20:1) to give a pale-brown solid (0.9 g). This
pale-brown solid was crystallized from ethyl acetate/hexane to give
the title compound (0.75 g) as yellow crystals.
[0812] m.p.=141-142.degree. C.
[0813] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.90(3H,s),
2.45-2.55(4H,m), 3.00-3.10(4H,m), 3.51(2H,s), 4.30(2H,d,J=5.9 Hz),
6.85-6.95(2H,m), 6.95-7.05(2H,m), 7.22-7.32(2H,m), 7.38(1H,s),
8.32(1H,t,J=5.9 Hz)
[0814] IR(KBr): 3267, 2827, 1653, 1554, 1512 cm.sup.-1
[0815] MS(EI): 375(M.sup.+)
[0816] Elemental analysis:
[0817] Calculated: C;63.91, H;6.17, N;11.18
[0818] Found: C;63.85, H;6.16, N;11.23
Example 27
Synthesis of
N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide
(1)
4-((4-chloromethylphenyl)methyl)-1-(4-fluorophenyl)piperazine
[0819] ##STR120##
[0820] To an aqueous solution (100 ml) of
1-(4-fluorophenyl)piperazine dihydrochloride was added an aqueous
solution (50 ml) of sodium hydroxide (10 g) and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a white solid (ca. 20 g). A solution
of this solid (1-(4-fluorophenyl)piperazine),
.alpha.,.alpha.'-dichloro-p-xylene (20.0 g) and potassium carbonate
in dimethylformamide (150 ml) was stirred at 75.degree. C. for 2 hr
and poured into ice water (500 ml). The mixture was extracted with
ethyl acetate (400 ml.times.2). The ethyl acetate layer was washed
with saturated brine and dried over anhydrous sodium sulfate. The
obtained residue was purified by silica gel column chromatography
(developing solvent; ethyl acetate:hexane=1:3) and recrystallized
from ethyl acetate-hexane to give the title compound (10.66 g) as
white crystals.
[0821] m.p.=81-83.degree. C.
[0822] .sup.1H-NMR(CDCl.sub.3).delta.: 2.60(4H,t,J=5.3 Hz),
3.11(4H,t,J=4.9 Hz), 3.56(2H,s), 4.58(2H,s), 6.90(4H,m),
7.35(4H,s)
[0823] IR(KBr): 2947, 2839, 2773, 1514 cm.sup.-1
[0824] MS(EI): 318(M.sup.+)
[0825] Elemental analysis:
[0826] Calculated: C;67.81, H;6.32, N;8.79
[0827] Found: C;67.80, H;6.34, N;8.75
(2)
2-(4-(4-(4-fluorophenyl)piperazin-1-ylmethyl)phenyl)acetonitrile
[0828] ##STR121##
[0829] A solution of
4-((4-chloromethylphenyl)methyl)-1-(4-fluorophenyl)piperazine (10.0
g), sodium cyanide (1.72 g) and a catalytic amount of sodium iodide
in dimethylformamide (50 ml) was stirred at 70.degree. C. for 3 hr,
and poured into ice water (200 ml) and extracted with ethyl acetate
(300 ml.times.2). The ethyl acetate layer was washed with saturated
brine and dried over anhydrous sodium sulfate. The obtained residue
was purified by silica gel column chromatography (developing
solvent; ethyl acetate:hexane=1:2) and recrystallized from ethyl
acetate-hexane to give the title compound (6.50 g) as pale-yellow
crystals.
[0830] m.p.=111-113.degree. C.
[0831] .sup.1H-NMR(CDCl.sub.3).delta.: 2.60(4H,t,J=5.0 Hz),
3.11(4H,t,J=4.9 Hz), 3.56(2H,s), 3.73(2H,s), 6.89(4H,m),
7.29(2H,d,J=7.9 Hz), 7.37(2H,d,J=7.9 Hz)
[0832] IR(KBr): 2946, 2816, 2775, 2248, 1514 cm.sup.-1
[0833] MS(EI): 291((M-F)+)
[0834] Elemental analysis:
[0835] Calculated: C;73.76, H;6.52, N;13.58
[0836] Found: C;73.98, H;6.52, N;13.52
(3)
N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetami-
de
[0837] ##STR122##
[0838] To a solution of aluminum lithium hydride (0.74 g) in
tetrahydrofuran (30 ml) was added
2-(4-(4-(4-fluorophenyl)-piperazin-1-ylmethyl)phenyl)acetonitrile
(2.0 g) in tetrahydrofuran (30 ml) at 5-10.degree. C., and the
mixture was refluxed under heating for 4 hr. To this reaction
mixture was added saturated aqueous sodium sulfate solution (10 ml)
under ice-cooling. The insoluble matter was filtered off and the
solvent was evaporated to give the obtained residue as purified by
silica gel column chromatography (developing solvent; ethyl
acetate:hexane=3:1; methanol:chloroform=1:9, later 1:6) to give
4-(4-(2-aminoethyl)phenyl)-1-(4-fluorophenyl)piperazine (0.59 g) To
this compound in a dichloromethane solution (20 ml) were added
triethylamine (0.24 ml) and acetic anhydride (0.21 ml) and the
mixture was left standing at room temperature for 10 min and poured
into ice water (100 ml) and extracted with ethyl acetate (100
ml.times.2). The ethyl acetate layer was washed with saturated
brine (100 ml) and dried over anhydrous sodium sulfate. The
obtained crude crystals were recrystallized from ethyl
acetate/hexane to give the title compound (416 mg) as pale-brown
crystals, m.p.=121-123.degree. C.
[0839] .sup.1H-NMR(CDCl.sub.3).delta.: 1.94(3H,s), 2.61(4H,t,J=5.0
Hz), 2.81(2H,t,J=6.9 Hz), 3.12(4H,t,J=4.9 Hz), 3.51(2H,q,J=6.4 Hz),
3.54(2H,s), 5.50(1H,br.s), 6.89(4H,m), 7.16(2H,d,J=7.9 Hz),
7.29(2H,d,J=7.9 Hz)
[0840] IR(KBr): 3292, 2819, 1647, 1514 cm.sup.-1
[0841] MS(EI): 355(M.sup.+)
[0842] Elemental analysis:
[0843] Calculated: C;70.96, H;7.37, N;11.82
[0844] Found: C;70.81, H;7.41, N;11.68
Example 28
Synthesis of
N-(2-bromo-4-(((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)ace-
tamide
[0845] ##STR123##
[0846] To an aqueous solution (4 ml) of sodium nitrite (387 mg) was
added a solution of
N-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (2.0 g) in 48% hydrobromic acid (10 ml) under ice-cooling.
This reaction mixture was stirred at the same temperature for 45
min and added to a solution of copper(I) bromide (483 mg) in 48%
hydrobromic acid (6 ml) over 15 min. This reaction mixture was
stirred at room temperature for 5 hr and poured into aqueous sodium
hydroxide solution. The mixture was passed through Celite and
extracted with ethyl acetate. The extract was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a brown oil (1.7 g). The obtained brown oil was
purified by silica gel column chromatography (developing solvent;
chloroform:methanol=20:1) to give a brown oil (1.4 g). This brown
oil was crystallized from ethyl acetate-hexane and recrystallized
from ethyl acetate-hexane to give the title compound (0.9 g) as
yellow white crystals, m.p.=149-150.degree. C.
H-NMR(DMSO-d.sub.6).delta.: 1.91(3H,s), 2.45-2.55(4H,m),
3.00-3.10(4H,m), 3.50(2H,s), 4.27(2H,d,J=5.9 Hz), 6.85-6.95(2H,m),
6.95-7.05(2H,m), 7.22-7.35(2H,m), 7.55(1H,s), 8.33(1H,t,J=5.9
Hz)
[0847] IR(KBr): 3269, 2827, 1653, 1550, 1512 cm.sup.-1
[0848] MS(EI): 420(M.sup.+)
[0849] Elemental analysis:
[0850] Calculated: C;57.15, H;5.52, N;10.00
[0851] Found: C;56.92, H;5.39, N;9.92
Example 29
Synthesis of
N-(3-nitro-4-(((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)ace-
tamide dihydrochloride 1/2 hydrate
(1) 4-methyl-3-nitrobenzonitrile
[0852] ##STR124##
[0853] To conc. sulfuric acid (50 ml) was added p-tolunitrile (50
g) under ice-cooling and fuming nitric acid (38 ml) was added at
the same temperature over 1 hr. The reaction mixture was poured
into ice water (700 g) and the precipitated crystals were collected
by filtration. The obtained crystals were washed with water to give
yellow white crystals (90 g). The yellow white crystals were
recrystallized from ethanol:water (9:1) to give the title compound
(61 g) as white crystals.
[0854] m.p.=102-103.degree. C.
[0855] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.58(3H,s),
7.73(1H,d,J=7.9 Hz), 8.09(1H,dd,J=1.3,7.9 Hz), 8.50(1H,d,J=1.3
Hz)
[0856] IR(KBr): 3088, 2235, 1616, 1525 cm.sup.-1
[0857] MS(EI): 163(M.sup.+)
[0858] Elemental analysis:
[0859] Calculated: C;59.26, H;3.73, N;17.28
[0860] Found: C;59.05, H;3.53, N;16.86
(2) 4-bromomethyl-3-nitrobenzonitrile
[0861] ##STR125##
[0862] A solution of 4-methyl-3-nitrobenzonitrile (30 g),
N-bromosuccinimide (37 g) and azobisisobutyronitrile (3.1 g) in
carbon tetrachloride (300 ml) was refluxed under heating for 8 hr.
To the reaction mixture was added water (100 ml) and the mixture
was extracted with chloroform. The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(developing solvent; ethyl acetate:hexane=1:4) and recrystallized
from ethyl acetate-hexane to give the title compound (23.7 g) as
pale-yellow crystals, m.p.=85-89.degree. C.
[0863] .sup.1H-NMR(DMSO-d.sub.6).delta.: 4.96(2H,s),
7.97(1H,d,J=7.9 Hz), 8.22(1H,dd,J=1.3,7.9 Hz), 8.61(1H,d,J=1.3
Hz)
[0864] IR(KBr): 3082, 2235, 1614, 1530 cm.sup.-1
[0865] MS(EI): 241(M.sup.+)
[0866] Elemental analysis:
[0867] Calculated: C;39.86, H;2.09, N;11.62
[0868] Found: C;40.64, H;2.15, N;11.85
(3) N-(4-bromomethyl-3-nitrophenylmethyl)acetamide
[0869] ##STR126##
[0870] To a solution of 4-bromomethyl-3-nitrobenzonitrile (25.7 g)
in tetrahydrofuran (250 ml) was added a 2.0 M tetrahydrofuran
solution (59 ml) of a borane-methylsulfide complex and the mixture
was refluxed under heating for 4.5 hr. To the reaction mixture was
added hydrochloric acid-methanol and the mixture was refluxed under
heating for 1.5 hr. The solvent was evaporated under reduced
pressure to give a brown oil. The obtained brown oil was
crystallized from ethyl acetate to give yellow white crystals. To a
mixed solution of the obtained yellow white crystals, acetic
anhydride (12.1 ml), water (50 ml) and ethyl acetate (100 ml) was
added an aqueous solution (50 ml) of sodium hydroxide (12.8 g)
under ice-cooling. This reaction mixture was stirred at room
temperature for 2.5 hr and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=20:1) to
give the title compound (21.4 g) as a brown oil.
[0871] 1H-NMR(CD3OD).delta.: 2.03(3H,s), 4.45(2H,s),
4.94(2H,d,J=2.0 Hz), 7.55-7.65(2H,m), 7.96(1H,s)
[0872] MS(EI): 287(M.sup.+)
(4)
N-(3-nitro-4-(((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide dihydrochloride 1/2 hydrate
[0873] ##STR127##
[0874] A solution of N-(4-bromomethyl-3-nitrophenylmethyl)acetamide
(21 g), 1-(4-fluorophenyl)piperazine dihydrochloride (20.4 g) and
potassium carbonate (40.4 g) in dimethylformamide (200 ml) was
stirred at 85.degree. C. for 8.5 hr. The reaction mixture was
poured into water (300 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a brown oil (37
g). The obtained residue was purified by silica gel column
chromatography (developing solvent; ethyl acetate:hexane=1:1) to
give a brown oil (15.5 g). To a solution of this brown oil (1.0 g)
in ethanol (20 ml) was added 1M hydrochloric acid--ether (6.5 ml).
The solvent was evaporated under reduced pressure. The residue was
crystallized from ethanol-ethyl acetate to give the title compound
(1.1 g) as pale-brown crystals.
[0875] m.p.=202-204.degree. C. (decomposition)
[0876] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.92(3H,s),
3.20-3.50(8H,m), 4.39(2H,d,J=5.9 Hz), 4.70(2H,s),
4.70-4.90(2H,brs), 6.95-7.15(4H,m), 7.75(1H,m), 8.05-8.10(2H,m),
8.72(1H,t,5.9 Hz)
[0877] IR(KBr): 3255, 2337, 2157, 1627, 1537 cm.sup.-1
[0878] MS(EI): 241(M.sup.+)
[0879] Elemental analysis:
[0880] Calculated: C;51.29, H;5.60, N;11.96
[0881] Found: C;51.56, H;5.58, N;11.91
Example 30
Synthesis of
N-(3-amino-4-(((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)ace-
tamide
[0882] ##STR128##
[0883] To a solution of
N-(3-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide
(14.5 g) and water-containing Raney-nickel (5.0 g) in ethanol (150
ml) was added dropwise hydrazine monohydrate (18.2 ml) at room
temperature and the mixture was refluxed under heating for 4 hr.
Raney-nickel was removed by passing the mixture through Celite and
the solvent was evaporated to give a brown oil (18.0 g). The
obtained brown oil was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=20:1) to give a brown oil
(11.6 g). The obtained brown oil was crystallized from hexane:ethyl
acetate (2:1) to give the title compound (7.4 g) as yellow white
crystals.
[0884] m.p.=131-132.degree. C.
[0885] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.86(3H,s),
2.45-2.55(4H,m), 3.05-3.10(4H,m), 3.40(2H,s), 4.11(2H,d,J=5.9 Hz),
5.25(2H,s), 6.41(1H,dd,J=1.3,5.9 Hz), 6.53(1H,d,J=1.3 Hz),
6.88-6.95(3H,m), 7.00-7.06(2H,m), 8.20(1H,t,J=5.3 Hz)
[0886] IR(KBr): 3305, 2819, 1625,. 1512 cm.sup.-1
[0887] MS(EI): 356(M.sup.+)
[0888] Elemental analysis:
[0889] Calculated: C;67.39, H;7.07, N;15.72
[0890] Found: C;67.06, H;7.19, N;15.40
Example 31
Synthesis of
N-(3-chloro-4-(((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)ace-
tamide dihydrochloride 1/2 hydrate
[0891] ##STR129##
[0892] To an aqueous solution (2 ml) of sodium nitrite (213 mg) was
added a solution of
N-(3-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (1.0 g) in conc. hydrochloric acid (5 ml) under ice-cooling.
This reaction mixture was stirred at the same temperature for 1 hr
and added to a solution of copper(I) chloride (167 mg) in conc.
hydrochloric acid (3 ml). The reaction mixture was stirred at room
temperature for 3 hr, poured into an aqueous sodium hydroxide
solution and extracted with ethyl acetate. The extract was washed
with saturated brine and dried over anhydrous sodium sulfate and
the solvent was evaporated to give a brown oil (1.4 g). The
obtained brown oil was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=10:1) to give a brown oil
(1.2 g). The brown oil was treated with 1M hydrochloric acid--ether
(10 ml) in ethanol and concentrated under reduced pressure to give
a brown solid. The obtained brown solid was crystallized from ethyl
acetate-ethanol to give the title compound (0.7 g) as pale-yellow
crystals, m.p.=200-205.degree. C. (decomposition).
[0893] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.91(3H,s),
3.10-3.50(6H,m), 3.60-3.70(2H,m), 4.29(2H,d,J=5.9 Hz), 4.51(2H,s),
4.90-5.10(2H,m), 6.95-7.15(4H,m), 7.33(1H,d,J=7.3 Hz), 7.45(1H,s),
8.00(1H,d,J=7.9 Hz), 8.60(1H,t,J=5.9 Hz), 11.69(1H,brs)
[0894] IR(KBr): 3282, 2493, 2443, 2418, 2063, 1676, 1542
cm.sup.-1
[0895] MS(EI): 376(M.sup.+)
[0896] Elemental analysis:
[0897] Calculated: C;52.47, H;5.72, N;9.18
[0898] Found: C;52.76, H;5.57, N;9.58
Example 32
Synthesis of
N-(3-bromo-4-(((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
[0899] ##STR130##
[0900] To an aqueous solution (3 ml) of sodium nitrite (290 mg) was
added a solution of
N-(3-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (1.5 g) in 48% hydrobromic acid (8 ml) under ice-cooling. This
reaction mixture was stirred at the same temperature for 45 min and
added to a solution of copper(I) bromide (362 mg) in 48%
hydrobromic acid (4 ml) over 15 min. The reaction mixture was
stirred at room temperature for 4.5 hr and poured into an aqueous
sodium hydroxide solution. After passing through Celite, the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine and dried over anhydrous sodium sulfate and
the solvent was evaporated to give a brown solid (1.8 g). The
obtained brown solid was crystallized from ethyl acetate to give
the title compound (1.3 g) as yellow crystals, m.p.=125-127.degree.
C.
[0901] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.88(3H,s),
2.50-2.60(4H,m), 3.05-3.10(4H,m), 3.57(2H,s), 4.23(2H,d,J=5.9 Hz),
6.85-6.95(2H,m), 6.95-7.05(2H,m), 7.25(1H,dd,J=1.3,7.9 Hz),
7.44(1H,d,J=7.9 Hz), 7.48(1H,d,J=1.3 Hz), 8.36(1H,t,J=5.9 Hz)
[0902] IR(KBr): 3304, 2823, 1649, 1508 cm.sup.-1
[0903] MS(EI): 420(M.sup.+)
[0904] Elemental analysis:
[0905] Calculated: C;57.15, H;5.52, N;10.00
[0906] Found: C;57.15, H;5.54, N;10.05
Example 33
Synthesis of
N-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0907] ##STR131##
[0908] By similar reaction and treatment to that in Example 1(5)
using (4-nitrophenyl)piperazine instead of phenylpiperazine, the
title compound was obtained as yellow crystals,
m.p.=151.5-153.5.degree. C.
[0909] .sup.1H-NMR(CDCl.sub.3).delta.: 2.03(3H,s),
2.58(4H,dd,J=5.3,4.6 Hz), 15 3.42(4H,dd,J=5.3,4.6 Hz), 3.55(2H,s),
4.42(2H,d,J=5.9 Hz), 5.77(1H,br.s), 6.80(2H,d,J=9.9 Hz),
7.25(2H,d,J=7.9 Hz), 7.31(2H,d,J=7.9 Hz), 8.16(2H,d,J=9.2 Hz).
[0910] IR(KBr): 3307, 2922, 2848, 1641, 1540 cm.sup.-1
[0911] MS(EI): 368(M.sup.+)
[0912] Elemental analysis:
[0913] Calculated: C;65.20, H;6.57, N;15.21
[0914] Found: C;65.06, H;6.58, N;15.19
Example 34
Synthesis of
N-(4-((4-(4-aminophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
3 hydrochloride 3/2 hydrate
[0915] ##STR132##
[0916] To a solution of
N-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(6.1 g) and Raney-nickel (0.6 g) in ethanol (166 ml) was added
dropwise hydrazine monohydrate (4 ml) at 2.degree. C. -3.degree. C.
over 30 min. This reaction mixture was stirred at room temperature
for 1 hr, then at 35.degree. C. for 30 min, and subsequently
refluxed under heating at 50.degree. C. for 6 hr and 40 min. To
this solution was again added hydrazine monohydrate (4 ml) and the
mixture was refluxed under stirring at 50.degree. C. for 8 hr. The
reaction mixture was passed through Celite and the filtrate was
concentrated under reduced pressure and the residue was poured into
water, which was followed by extraction with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate and the solvent was evaporated to give a purple
solid (5.0 g). To the obtained solid were added methanol and
hydrochloric acid, and the mixture was concentrated to dryness
under reduced pressure. The obtained solid was recrystallized from
methanol-ethyl acetate to give the title compound (1.3 g) as purple
crystals.
[0917] m.p.=198-200.degree. C.
[0918] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.05-3.40(6H,m), 3.75-3.85(2H,m), 4.28(2H,d,J=5.9 Hz), 4.34(2H,s),
7.06(2H,d,J=8.6 Hz), 7.29(2H,d,J=7.9 Hz), 7.33(2H,d,J=8.6 Hz),
7.62(2H,d,J=7.9 Hz), 8.47(1H,t,J=5.9 Hz), 10.30(3H,br.s),
11.61(1H,br.s).
[0919] IR(KBr): 3437, 3278, 2985, 2846, 1626, 1560 cm.sup.-1
[0920] MS(EI): 338(M.sup.+)
[0921] Elemental analysis:
[0922] Calculated: C;50.59, H;6.86, N;11.80
[0923] Found: C;50.62, H;6.69, N;11.79
Example 35
Synthesis of
N-(4-((4-(4-acetamidophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[0924] ##STR133##
[0925] To a solution of
N-(4-((4-(4-aminophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(1.8 g) and potassium carbonate (3.1 g) in a mixed solvent of water
(50 ml) and ethyl acetate (50 ml) was added dropwise acetyl
chloride (0.43 ml) at room temperature over 10 min. This reaction
mixture was stirred at room temperature for 4 hr and poured into
saturated brine, which was followed by extraction with chloroform.
The extract was washed with saturated brine and dried over
anhydrous magnesium sulfate and the solvent was evaporated to give
a purple solid (5.0 g). The obtained solid was subjected to column
chromatography (elution solvent;chloroform:methanol=9:1) to give a
pale-brown solid. The solid was recrystallized from methanol-water
to give the title compound (0.75 g) as pale-red crystals,
m.p.=225-226.degree. C.
[0926] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s), 1.98(3H,s),
2.46-2.51(4H,m), 3.03-3.06(4H,m), 3.48(2H,s), 4.23(2H,d,J=5.9 Hz),
6.84(2H,d,J=8.6 Hz), 7.20(2H,d,J=8.6 Hz), 7.27(2H,d,J=7.9 Hz),
7.39(2H,d,J=9.2 Hz), 8.29(1H,t,J=5.9 Hz), 9.66(1H,s).
[0927] IR(KBr): 3311, 2933, 2819, 1655, 1516 cm.sup.-1
[0928] MS(EI): 380(M.sup.+)
[0929] Elemental analysis:
[0930] Calculated: C;69.45, H;7.42, N;14.73
[0931] Found: C;69.19, H;7.48, N;14.68
Example 36
Synthesis of
N-(4-((4-(4-hydroxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
dihydrochloride
[0932] ##STR134##
[0933] To a solution of
N-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(2.0 g) in methylene chloride (27 ml) was added dropwise a solution
of boron tribromide (2.2 ml) in methylene chloride (10 ml) at
-70.degree. C. over 15 min. The temperature of this solution was
gradually raised and the mixture was left standing overnight at
room temperature. The reaction mixture was poured into ice water
and stirred at 40.degree. C. for 30 min. After the reaction, the
reaction mixture was neutralized by adding an aqueous sodium
hydroxide solution and extracted with chloroform. The extract was
dried over anhydrous sodium sulfate and the solvent was evaporated
to give a brown solid (1.6 g). The obtained solid was subjected to
column chromatography (elution solvent;chloroform:methanol=8:1) to
give a pale-brown solid (1.4 g). This solid was dissolved in
methanol and converted to hydrochloride with 1 M hydrochloric
acid--ether solution. The solvent was evaporated and the residue
was recrystallized from methanol-ether to give the title compound
(0.81 g) as white crystals, m.p.=218-220.degree. C.
[0934] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.15-3.80(8H,.m), 4.28(2H,d,J=5.9 Hz), 4.35(2H,s), 6.72(2H,d,J=9.2
Hz), 6.93(2H,d,J=8.5 Hz), 7.33(2H,d,J=7.9 Hz), 7.60(2H,d,J=9.2 Hz),
8.44(1H,t,J=5.9 Hz), 11.30(1H,br.s).
[0935] IR(KBr): 3367, 2987, 2628, 1637, 1552, 1517 cm.sup.-1
[0936] MS(EI): 339(M.sup.+)
[0937] Elemental analysis:
[0938] Calculated: C;58.25, H;6.60, N;10.19
[0939] Found: C;57.88, H;6.71, N;9.90
Example 37
Synthesis of
N-(4-((4-(4-fluoro-2-nitrophenyl)-piperazin-1-yl)methyl)phenylmethyl)acet-
amide
(1) Synthesis of 1-acetyl-4-(4-fluoro-2-nitrophenyl)piperazine
[0940] ##STR135##
[0941] To a solution of 1-acetylpiperazine (48 g) in acetonitrile
(100 ml) were added 2,5-difluoronitrobenzene (50 g) and potassium
carbonate (44 g) and the mixture was refluxed under heating for 5
hr. The reaction mixture was poured into water and extracted with
ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate and the solvent was
evaporated to give the title compound (88 g) as a red solid.
[0942] .sup.1H-NMR(CDCl.sub.3).delta.: 2.13(3H,s), 2.98-3.03(4H,m),
3.61(2H,dd,J=5.28,4.62 Hz), 3.76(2H,dd,J=5.28,4.62 Hz),
7.17-7.31(2H,m), 7.53(1H,dd,J=7.91,3.30 Hz).
[0943] IR(KBr): 3087, 2918, 2835, 1633, 1583 cm.sup.-1
[0944] MS(EI): 267(M.sup.+)
(2) Synthesis of 1-(4-fluoro-2-nitrophenyl)piperazine
[0945] ##STR136##
[0946] To 1-acetyl-4-(4-fluoro-2-nitrophenyl)piperazine (10 g) was
added 1. 2N hydrochloric acid (190 ml) and the mixture was refluxed
under heating for 17 hr. The reaction mixture was made alkaline (pH
12) with an aqueous sodium hydroxide solution and extracted with
ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give a red oil. The oil was crystallized from ethyl
acetate-isopropyl ether-hexane to give the title compound (5.6 q)
as a red solid.
[0947] m.p.=85-87.degree. C.
[0948] .sup.1H-NMR(CDCl.sub.3).delta.: 2.96-3.04(8H,m),
7.15-7.29(2H,m), 7.49(1H,dd,J=7.9,3.3 Hz).
[0949] IR(KBr): 3325, 2954, 2815, 1520, 1456 cm.sup.-1
[0950] MS(EI): 225(M.sup.+)
[0951] Elemental analysis:
[0952] Calculated: C;53.33, H;5.37, N;18.66
[0953] Found: C;53.44, H;5.40, N;18.47
(3) Synthesis of
N-(4-((4-(4-fluoro-2-nitrophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide
[0954] ##STR137##
[0955] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluoro-2-nitrophenyl)piperazine instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=94.5-96.degree. C.
[0956] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.58(4H,t,J=4.6
Hz), 3.02(4H,t,J=4.6 Hz), 3.55(2H,s), 4.42(2H,d,J=5.3 Hz),
5.76(1H,br.s), 7.14-7.22(2H,m), 7.24(2H,d,J=7.9 Hz),
7.30(2H,d,J=9.2 Hz), 7.48(1H,dd,J=7.9,2.6 Hz).
[0957] IR(KBr): 3277, 2943, 2821, 1645, 1529 cm.sup.-1
[0958] MS(EI): 386(M.sup.+)
[0959] Elemental analysis:
[0960] Calculated: C;62.16, H;6.00, N;14.50
[0961] Found: C;62.15, H;5.90, N;14.40
Example 38
Synthesis of
N-(4-((4-(2-amino-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide
[0962] ##STR138##
[0963] By similar reaction and treatment to that in Example 34
using
N-(4-((4-(4-fluoro-2-nitrophenyl)piperazin-1-yl)methyl)-phenylmethyl)acet-
amide instead of
N-(4-((4-(4-nitrophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide,
the title compound was obtained as pale-brown crystals,
m.p.=139-140.degree. C.
[0964] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.58(2H,br.s),
5.87(4H,t,J=4.6 Hz), 3.56(2H,s), 4.11(2H,br.s), 5.73(1H,br.s),
6.36-6.44(2H,m), 6.93(2H,dd,J=7.9,5.9 Hz), 7.24(2H,d,J=7.9 Hz),
7.32(2H,d,J=7.9 Hz).
[0965] IR(KBr): 3444, 3302, 2829, 1662, 1560 cm.sup.-1
[0966] MS(EI): 356(M.sup.+)
[0967] Elemental analysis:
[0968] Calculated: C;67.39, H;7.07, N;15.72
[0969] Found: C;67.34, H;7.08, N;15.64
Example 39
Synthesis of
N-(4-((4-(2-acetylamino-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl-
)acetamide
[0970] ##STR139##
[0971] By similar reaction and treatment to that in Example 35
using
N-(4-((4-(2-amino-4-fluorophenyl)piperazin-1-yl)methyl)-phenylmethyl)acet-
amide instead of
N-(4-((4-(4-aminophenyl)-piperazin-1-yl)methyl)phenylmethyl)acetamide,
the title compound was obtained as white crystals,
m.p.=148-149.5.degree. C.
[0972] .sup.1H-NMR(CDCl.sub.3).delta.: 2.03(3H,s), 2.20(3H,s),
2.61(4H,br.s), 2.84(4H,t,J=4.6 Hz), 3.57(2H,s), 4.43(2H,d,J=5.9
Hz), 5.77(1H,br.s), 6.72(1H,dt,J=8.6,2.6 Hz), 7.11(1H,dd,J=8.6,5.9
Hz), 7.25(2H,d,J=7.9 Hz), 7.32(2H,d,J=7.9 Hz), 8.16(1H,dd,J=11,2.6
Hz), 8.62(1H,br.s).
[0973] IR(KBr): 3348, 2935, 2829, 1660, 1603, 1552 cm.sup.-1
[0974] MS(EI): 398(M.sup.+)
[0975] Elemental analysis:
[0976] Calculated: C;66.31, H;6.83, N;14.16
[0977] Found: C;66.31, H;6.92, N;13.87
Example 40
Synthesis of
N-(4-((4-(4-fluoro-2-methoxyphenyl)-piperazin-1-yl)methyl)phenylmethyl)ac-
etamide dihydrochloride 1/4 hydrate
(1) Synthesis of 4-fluoro-2-methoxynitrobenzene
[0978] ##STR140##
[0979] To a suspension of sodium hydride (1.3 g) in
dimethylformamide (10 ml) was added a solution of
5-fluoro-2-nitrophenol (5.0 g) in dimethylformamide(20 ml)under
ice-cooling. This reaction mixture was stirred at room temperature
for 1 hr. To this solution was added methyl iodide (2.0 ml) and the
mixture was left standing overnight. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with an aqueous sodium hydroxide solution and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated to give a red solid. This solid was subjected to silica
gel column chromatography (developing solvent; hexane:ethyl
acetate=4:1) to give the title compound (4.3 g) as a yellow
solid.
[0980] .sup.1H-NMR(CDCl.sub.3).delta.: 3.97(3H,s), 6.69-6.82(2H,m),
7.96(1H,dt,J=3.3,2.6 Hz).
[0981] IR(KBr): 3124, 3086, 2994, 1624, 1587 cm.sup.-1
[0982] MS(EI): 171(M.sup.+)
(2) Synthesis of 4-fluoro-2-methoxyaniline
[0983] ##STR141##
[0984] To a solution of 4-fluoro-2-methoxynitrobenzene (4.2 g) in
ethanol (50 ml) was added Raney-nickel (0.4 g) at room temperature.
To this solution was added dropwise hydrazine monohydrate (6 ml)
under ice-cooling. This reaction mixture was stirred at room
temperature for 1 hr and passed through Celite. The solvent was
evaporated to give an oil. The oil was poured into water and
extracted with ethyl acetate. The extract was washed with saturated
brine and dried over anhydrous magnesium sulfate and the solvent
was evaporated to give a brown oil. The oil was subjected to silica
gel column chromatography (developing solvent; hexane:ethyl
acetate=1:1) to give the title compound (3.1 g) as a brown oil.
[0985] .sup.1H-NMR(CDCl.sub.3).delta.: 3.51(2H,br.s), 3.82(3H,s),
6.45-6.64(3H,m).
[0986] IR(KBr): 3452, 3369, 2964, 1612, 1514 cm.sup.-1
[0987] MS(EI): 141(M.sup.+)
(3) Synthesis of 1-(4-fluoro-2-methoxyphenyl)piperazine
dihydrochloride
[0988] ##STR142##
[0989] To a solution of 4-fluoro-2-methoxyaniline (3.0 g) in
orthoxylene (50 ml) was added bis (2-chloroethyl)amine
hydrochloride (3.8 g) and the mixture was refluxed under heating
for 13 hr. The reaction mixture was poured into water and washed
with isopropyl ether. To the aqueous layer was added an aqueous
sodium hydroxide solution to make it alkaline (pH 12) and the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine and dried over anhydrous magnesium sulfate and
the solvent was evaporated to give a black oil. The oil was
dissolved in methanol and conc. hydrochloric acid was added and the
mixture was concentrated. To this concentrated solution added
tetrahydrofuran to give the title compound (3.1 g) as pale-purple
crystals.
[0990] .sup.1H-NMR(DMSO-d.sub.6).delta.:
3.20(8H,br.s),3.82(3H,s),6.72(1H,dt,J=8.6,3.3 Hz),
6.92(1H,dd,J=11,3.3 Hz), 7.01(1H,dd,J=8.6,5.9 Hz),
9.51(2H,br.s).
[0991] IR(KBr): 3352, 2997, 2808, 1625, 1510 cm.sup.-1
[0992] MS(EI): 210(M.sup.+)
(4) Synthesis of
N-(4-((4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)ace-
tamide dihydrochloride 1/4 hydrate
[0993] ##STR143##
[0994] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluoro-2-methoxyphenyl)piperazine dihydrochloride
instead of phenylpiperazine, the title compound was obtained as
white crystals, m.p.=228-229.5.degree. C.
[0995] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.06-3.20(4H,m), 3.26-3.43(4H,m), 3.79(3H,s), 4.28(2H,d,J=5.9 Hz),
4.33(2H,d,J=2.6 Hz), 6.70(1H,dt,J=8.6,2.6 Hz), 6.87-6.95(2H,m),
7.33(2H,d,J=7.9 Hz), 7.62(2H,d,J=7.9 Hz), 7.45(1H,t,J=5.9 Hz),
11.5(1H,br.s).
[0996] IR(KBr): 3286, 2368, 1664, 1624, 1539 cm.sup.-1
[0997] MS(EI): 371(M.sup.+)
[0998] Elemental analysis:
[0999] Calculated: C;56.19, H;6.40, N;9.36
[1000] Found: C;56.04, H;6.66, N;9.35
Example 41
Synthesis of
N-(4-((4-(2-ethoxy-4-fluorophenyl)-piperazin-1-yl)methyl)phenylmethyl)ace-
tamide
(1) Synthesis of 2-ethoxy-4-fluoronitrobenzene
[1001] ##STR144##
[1002] To a solution of ethanol (4.2 ml) in tetrahydrofuran (65 ml)
was added a solution of triphenylphosphine (13 g) and
5-fluoro-2-nitrophenol (10 g) in tetrahydrofuran (65 ml). To this
solution was added diethyl azodicarboxylate (10 ml) under
ice-cooling and the mixture was stirred at room temperature for 4
hr. The reaction mixture was concentrated under reduced pressure
and diisopropyl ether was added. The precipitated crystals were
collected by filtration and concentrated under reduced pressure.
The concentrate was subjected to silica gel column chromatography
(developing solvent; hexane: ethyl acetate=4:1) to give a yellow
oil. To this oil was added ethyl acetate, washed with an aqueous
sodium hydroxide solution, dried over magnesium sulfate and
concentrated under reduced pressure to give the title compound (9.6
g) as a yellow oil.
[1003] .sup.1H-NMR(CDCl.sub.3).delta.: 1.50(3H,t,J=7.3 Hz),
4.17(2H,q,J=7.3 Hz), 6.67-6.79(2H,m), 7.92(1H,dt,J=3.3,2.6 Hz).
[1004] MS(EI): 185(M.sup.+)
(2) Synthesis of 2-ethoxy-4-fluoroaniline
[1005] ##STR145##
[1006] By similar reaction and treatment to that in Example 40(2)
using 2-ethoxy-4-fluoronitrobenzene instead of
4-fluoro-2-methoxynitrobenzene, the title compound was obtained as
a black oil.
[1007] .sup.1H-NMR(CDCl.sub.3).delta.: 1.44(3H,t,J=7.3
Hz),3.50(2H,br.s),4.00(2H,q,J=7.3 Hz), 6.27-6.64(3H,m).
[1008] IR(KBr): 3548, 3369, 2981, 1618, 1512 cm.sup.-1
[1009] MS(EI): 155(M.sup.+)
(3) Synthesis of
1-(2-ethoxy-4-fluorophenyl)piperazine-dihydrochloride
[1010] ##STR146##
[1011] By similar reaction and treatment to that in Example 40(3)
using 2-ethoxy-4-fluoroaniline instead of
4-fluoro-2-methoxyaniline, the title compound was obtained as
purple crystals.
[1012] 1H-NMR(DMSO-d.sub.6).delta.: 1.37(3H,t,J=7.4 Hz),
3.20(8H,br.s), 4.05(2H,q,J=7.4 Hz), 6.71(1H,dt,J=8.6,2.6 Hz),
6.89(1H,dd,J=8.6,2.6 Hz), 7.00(1H,dd,J=3.3,2.6 Hz),
9.51(2H,br.s).
[1013] IR(KBr): 3439, 2997, 2841, 1624, 1521 cm.sup.-1
[1014] MS(EI): 224(M.sup.+)
(4) Synthesis of
N-(4-((4-(2-ethoxy-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
[1015] ##STR147##
[1016] By similar reaction and treatment to that in Example 1(5)
using 1-(2-ethoxy-4-fluorophenyl)piperazine dihydrochloride instead
of phenylpiperazine, the title compound was obtained as pale-brown
crystals.
[1017] m.p.=108-109.degree. C.
[1018] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(3H,t,J=6.6 Hz),
2.02(3H,s), 2.62-2.64(4H,m), 3.04(4H,br.s), 3.56(2H,s),
4.02(2H,q,J=6.6 Hz), 4.42(2H,d,J=5.3 Hz), 5.76(1H,br.s),
6.54-6.60(2H,m), 6.81(1H,dd,J=9.2,5.9 Hz), 7.24(2H,d,J=7.9 Hz),
7.33(2H,d,J=7.9 Hz).
[1019] IR(KBr): 3423, 3261, 2929, 1637, 1602, 1560 cm.sup.-1
[1020] MS(EI): 385(M.sup.+)
[1021] Elemental analysis:
[1022] Calculated: C;68.55, H;7.32, N;10.90
[1023] Found: C;68.24, H;7.35, N;10.70
Example 42
Synthesis of
N-(4-((4-(4-fluoro-2-isopropoxyphenyl)-piperazin-1-yl)methyl)phenylmethyl-
)acetamide hydrochloride 1/4 ethyl acetate
(1) Synthesis of 4-fluoro-2-isopropoxynitrobenzene
[1024] ##STR148##
[1025] By similar reaction and treatment to that in Example 41(1)
using isopropyl alcohol instead of ethanol, the title compound was
obtained as an orange oil.
[1026] .sup.1H-NMR(CDCl.sub.3).delta.: 1.42(6H,d,J=6.6 Hz),
4.63(1H,septet,J=6.6 Hz), 6.65-6.79(2H,m), 7.45-7.90(1H,m).
[1027] IR(KBr): 3091, 2983, 1620, 1589 cm.sup.-1
[1028] MS(EI): 199(M.sup.+)
(2) Synthesis of 4-fluoro-2-isopropoxyaniline
[1029] ##STR149##
[1030] By similar reaction and treatment to that in Example 40(2)
using 4-fluoro-2-isopropoxynitrobenzene instead of
4-fluoro-2-methoxynitrobenzene, the title compound was obtained as
a black oil.
[1031] .sup.1H-NMR(CDCl.sub.3).delta.: 1.35(6H,d,J=5.9 Hz),
3.47(2H,br.s), 4.48(1H,septet,J=5.9 Hz), 6.44-6.65(3H,m).
[1032] IR(KBr): 3460, 3373, 2980, 1614, 1589 cm.sup.-1
[1033] MS(EI): 169(M.sup.+)
(3) Synthesis of 1-(4-fluoro-2-isopropoxyphenyl)piperazine
dihydrochloride
[1034] ##STR150##
[1035] By similar reaction and treatment to that in Example 40(3)
using 4-fluoro-2-isopropoxyaniline instead of
4-fluoro-2-methoxyaniline, the title compound was obtained as
purple crystals.
[1036] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.31(6H,d,J=5.9 Hz),
3.25(8H,br.s), 4.67(1H,septet,J=5.9 Hz), 6.71(1H,dt,J=8.6,2.6 Hz),
7.93(1H,dd,J=11,2.6 Hz), 7.08(1H,dd,J=5.9,2.6 Hz),
9.61(2H,br.s).
[1037] IR(KBr): 3442, 2983, 2925, 1626, 1522 cm.sup.-1
[1038] MS(EI): 238(M.sup.+)
(4) Synthesis of
N-(4-((4-(4-fluoro-2-isopropoxyphenyl)piperazin-1-yl)methyl)phenylmethyl)-
acetamide hydrochloride 1/4 ethyl acetate
[1039] ##STR151##
[1040] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluoro-2-isopropoxyphenyl)piperazine dihydrochloride
instead of phenylpiperazine, the title compound was obtained as
white crystals.
[1041] m.p.=211.5-213.degree. C.
[1042] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.28(6H,d,J=5.9 Hz),
1.89(3H,s), 3.01-3.24(4H,m), 3.30-3.43(4H,m), 4.28(2H,d,J=5.9 Hz),
4.34(2H,s), 4.64(1H,septet,J=5.9 Hz), 6.67(1H,dd,J=7.9,2.6 Hz),
6.85-6.92(2H,m), 7.33(2H,d,J=7.9 Hz), 7.61(2H,d,J=7.9 Hz),
8.43(1H,t,J=5.9 Hz), 11.1(1H,br.s).
[1043] IR(KBr): 3435, 3280, 2931, 1645, 1603, 1541 cm.sup.-1
[1044] MS(EI): 399(M.sup.+)
[1045] Elemental analysis:
[1046] Calculated: C;63.36, H;7.17, N;9.64
[1047] Found: C;62.94, H;7.26, N;9.17
Example 43
Synthesis of
N-(4-((4-(4-fluoro-2-hydroxyphenyl)-piperazin-1-yl)methyl)phenylmethyl)ac-
etamide dihydrochloride 1/2 hydrate
(1) Synthesis of 1-acetyl-4-(4-fluoro-2-nitrophenyl)piperazine
[1048] ##STR152##
[1049] To a solution of 1-acetylpiperazine (20 g) in acetonitrile
(50 ml) were added 2,5-difluoronitrobenzene (25 g) and potassium
carbonate (22 g) and the mixture was refluxed under heating at room
temperature for 4.5 hr. The reaction mixture was poured into water
and extracted with ethyl acetate. The extract was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated to give a red oil. The oil was crystallized
from ethyl acetate-isopropyl ether to give the title compound (36
g) as a red solid.
[1050] .sup.1H-NMR(CDCl.sub.3).delta.: 2.13(3H,s), 2.98-3.01(4H,m),
3.61(2H,dd,J=5.3,4.6 Hz), 3.77(2H,dd,J=5.3,4.6 Hz),
7.16-7.31(2H,m), 7.53(1H,dd,J=7.9,3.3 Hz).
[1051] IR(KBr): 3088, 2931, 1641, 1583 cm.sup.-1
[1052] MS(EI): 267(M.sup.+)
(2) Synthesis of
1-acetamido-4-(2-amino-4-fluorophenyl)piperazine
[1053] ##STR153##
[1054] By similar reaction and treatment to that in Example 40(2)
using 1-acetamido-4-(4-fluoro-2-nitrophenyl)piperazine instead of
4-fluoro-2-methoxynitrobenzene, the title compound was obtained as
a pale-brown solid.
[1055] .sup.1H-NMR(CDCl.sub.3).delta.: 2.14(3H,s), 2.78-2.84(4H,m),
3.57-3.59(2H,m), 3.73(1H,br.s), 4.16(1H,br.s), 6.31-6.61(2H,m),
6.85-7.58(1H,m).
[1056] IR(KBr): 3429, 3319, 2960, 1626, 1506 cm.sup.-1
[1057] MS(EI): 237(M.sup.+)
(3) Synthesis of
1-acetyl-4-(4-fluoro-2-hydroxyphenyl)piperazine
[1058] ##STR154##
[1059] To a solution of
1-acetyl-4-(2-amino-4-fluorophenyl)piperazine (25 g) and conc.
sulfuric acid (42 ml) in water (210 ml) was added dropwise a
solution of sodium nitrite (13 g) in water (46 ml) under
ice-cooling. This reaction mixture was stirred at the same
temperature for 4 hr and at room temperature for 6 hr. To the
reaction mixture was added an aqueous sodium hydroxide solution to
make it alkaline and acetyl chloride was added dropwise. The
mixture was stirred at the same temperature for 30 min, passed
through Celite and extracted with ethyl acetate. The extract was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated to give a black oil. The oil
was subjected to silica gel column chromatography (developing
solvent; chloroform:methanol=9:1) to give a black solid. This solid
was recrystallized from ethyl acetate-isopropyl ether to give the
title compound (0.66 g) as a pale-brown solid, m.p.=183-185.degree.
C.
[1060] 1H-NMR(CDCl.sub.3).delta.:
2.15(3H,s),2.80-2.86(4H,m),3.63(2H,dd,J=5.3,4.6 Hz),
3.78(2H,dd,J=5.3,4.6 Hz), 6.57(1H,dd,J=8.6,2.6 Hz),
6.69(1H,dd,J=8.9,2.6 Hz), 7.05(1H,dd,J=8.6,5.9 Hz),
7.16(1H,br.s).
[1061] IR(KBr): 3290, 2916, 1630, 1601, 1502 cm.sup.-1
[1062] MS(EI): 238(M.sup.+)
[1063] Elemental analysis:
[1064] Calculated: C;60.49, H;6.35, N;11.76
[1065] Found: C;60.71, H;6.27, N;11.80
(4) Synthesis of 1-(4-fluoro-2-hydroxyphenyl)piperazine
dihydrochloride
[1066] ##STR155##
[1067] 1-Acetyl-4-(4-fluoro-2-hydroxyphenyl)piperazine (0.64 g) was
dissolved in a 1.2N aqueous hydrochloric acid solution (16 ml) and
refluxed under heating for 7 days. The reaction mixture was
concentrated under reduced pressure to give a pale-brown solid.
This solid was recrystallized from methanol-ethyl acetate to give
the title compound (0.65 g) as pale-brown crystals.
[1068] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.29(8H,br.s),
5.33(1H,br.s), 6.62(1H,dt,J=8.6,2.6 Hz), 6.80(1H,dd,J=9.9,2.6 Hz),
7.14-7.20(1H,m), 9.52(2H,br.s).
[1069] IR(KBr): 3415, 3016, 2995, 1628, 1608 cm.sup.-1
[1070] MS(EI): 169(M.sup.+)
(5) Synthesis of
N-(4-((4-(4-fluoro-2-hydroxyphenyl)piperazin-1-yl)methyl)phenylmethyl)ace-
tamide dihydrochloride 1/2 hydrate
[1071] ##STR156##
[1072] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluoro-2-hydroxyphenyl)piperazine dihydrochloride
instead of phenylpiperazine, the title compound was obtained as
pale-red crystals.
[1073] m.p.=255-257.degree. C.
[1074] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.04-3.37(9H,m), 4.28(2H,d,J=5.3 Hz), 4.33(2H,s),
6.57(1H,dt,J=8.6,2.6 Hz), 6.69(1H,dd,J=11,2.6 Hz),
6.91(1H,dd,J=8.6,6.6 Hz), 7.33(2H,d,J=7.9 Hz), 7.60(2H,d,J=7.9 Hz),
8.45(1H,t,J=5.9 Hz), 11.2(1H,br.s).
[1075] IR(KBr): 3246, 3089, 2885, 1618, 1597 cm.sup.-1
[1076] MS(EI): 357(M.sup.+)
[1077] Elemental analysis:
[1078] Calculated: C;54.67, H;6.19, N;9.56
[1079] Found: C;54.90, H;6.26, N;9.47
Example 44
Synthesis of
N-(4-((4-(2-chloro-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
(1) Synthesis of 1-(2-chloro-4-fluorophenyl)piperazine
dihydrochloride
[1080] ##STR157##
[1081] By similar reaction and treatment to that in Example 40(3)
using 2-chloro-4-fluoroaniline instead of
4-fluoro-2-methoxyaniline, the title compound was obtained as
pale-brown crystals, m.p.=203-204.5.degree. C.
[1082] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.19(8H,dd,J=12,5.9 Hz),
7.17-7.29(2H,m), 7.43-7.51(1H,m), 9.45(2H,br.s).
[1083] IR(KBr): 3371, 2956, 2823, 1672, 1569 cm.sup.-1
[1084] MS(EI): 214(M.sup.+)
[1085] Elemental analysis:
[1086] Calculated: C;47.83, H;5.22, N;11.16
[1087] Found: C;47.58, H;5.25, N;11.12
(2) Synthesis of
N-(4-((4-(2-chloro-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
[1088] ##STR158##
[1089] By similar reaction and treatment to that in Example 1(5)
using 1-(2-chloro-4-fluorophenyl)piperazine dihydrochloride instead
of phenylpiperazine, the title compound was obtained as pale-red
crystals.
[1090] m.p.=255-257.degree. C.
[1091] 1H-NMR(CDCl.sub.3).delta.: 2.03(3H,s), 2.62(4H,t,J=4.6 Hz),
3.00(4H,t,J=4.6 Hz), 3.57(2H,s), 4.43(2H,d,J=5.3 Hz),
5.71(1H,br.s), 6.89-7.03(2H,m), 7.11(1H,dd,J=8.6,2.6 Hz),
7.25(2H,d,J=7.9 Hz), 7.34(2H,d,J=8.6 Hz).
[1092] IR(KBr): 3277, 2949, 2821, 1633, 1556 cm.sup.-1
[1093] MS(EI): 375(M.sup.+)
[1094] Elemental analysis:
[1095] Calculated: C;63.91, H;6.17, N;11.18
[1096] Found: C;63.76, H;6.26, N;11.07
Example 45
Synthesis of
N-(4-((4-(2-bromo-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide dihydrochloride
(1) Synthesis of 1-(2-bromo-4-fluorophenyl) piperazine
dihydrochloride
[1097] ##STR159##
[1098] By similar reaction and treatment to that in Example 40(3)
using 2-bromo-4-fluoroaniline instead of 4-fluoro-2-methoxyaniline,
the title compound was obtained as pale-brown crystals,
m.p.=208-210.degree. C.
[1099] .sup.1H-NMR(DMSO-d.sub.6).delta.: 3.17(8H,dd,J=8.6,5.3 Hz),
7.26(2H,d,J=5.9 Hz), 7.60(1H,d,J=8.6 Hz), 9.47(2H,br.s).
[1100] IR(KBr): 2945, 2796, 2725, 1741, 1591 cm.sup.-1
[1101] MS(EI): 258(M.sup.+)
[1102] Elemental analysis:
[1103] Calculated: C;40.63, H;4.43, N;9.48
[1104] Found: C;40.99, H;4.54, N;9.22
(2) Synthesis of
N-(4-((4-(2-bromo-4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide dihydrochloride
[1105] ##STR160##
[1106] By similar reaction and treatment to that in Example 1(5)
using 1-(2-bromo-4-fluorophenyl)piperazine dihydrochloride instead
of phenylpiperazine, the title compound was obtained as pale-brown
crystals.
[1107] m.p.=231-235.degree. C.
[1108] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.13-3.38(8H,m), 4.28(2H,d,J=5.9 Hz), 4.37(2H,d,J=4.6 Hz),
7.19-7.57(2H,m), 7.33(2H,d,J=7.9 Hz), 7.58-7.65(1H,m),
7.63(2H,d,J=7.9 Hz), 8.46(1H,t,J=5.9 Hz), 11.5(1H,d,J=2.6 Hz).
[1109] IR(KBr): 3228, 2979, 2958, 1753, 1668 cm.sup.-1
[1110] MS(EI): 419(M.sup.+-1)
[1111] Elemental analysis:
[1112] Calculated: C;48.70, H;5.11, N;8.52
[1113] Found: C;48.67, H;5.19, N;8.47
Example 46
Synthesis of
N-(4-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide dihydrochloride
(1) Synthesis of 1-(4-fluoro-2-methylphenyl)piperazine
dihydrochloride
[1114] ##STR161##
[1115] By similar reaction and treatment to that in Example 40(3)
using 4-fluoro-2-methylaniline instead of
4-fluoro-2-methoxyaniline, the title compound was obtained as
pale-brown crystals, m.p.=258-260.degree. C.
[1116] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.27(3H,s),
3.45(8H,dd,J=5.1,4.4 Hz), 3.19(4H,br.s), 6.97-7.10(3H,m),
9.64(2H,br.s).
[1117] IR(KBr): 3007, 2925, 2792, 1622, 1593 cm.sup.-1
[1118] MS(EI): 194(M.sup.+)
[1119] Elemental analysis:
[1120] Calculated: C;49.45, H;6.41, N;10.49
[1121] Found: C;49.23, H;6.51, N;10.51
(2) Synthesis of
N-(4-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide dihydrochloride
[1122] ##STR162##
[1123] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride instead
of phenylpiperazine, the title compound was obtained as white
crystals.
[1124] m.p.=115-117.degree. C.
[1125] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.28(3H,s),
2.58(4H,br.s), 2.86(4H,t,J=4.6 Hz), 3.56(2H,s), 4.42(2H,d,J=5.9
Hz), 5.76(1H,br.s), 6.78-6.99(3H,m), 7.24(2H,d,J=7.9 Hz),
7.32(2H,d,J=7.9 Hz).
[1126] IR(KBr): 3278, 2949, 2821, 1651, 1552 cm.sup.-1
[1127] MS(EI): 355(M.sup.+)
[1128] Elemental analysis:
[1129] Calculated: C;70.96, H;7.37, N;11.82
[1130] Found: C;70.64, H;7.44, N;11.61
Example 47
Synthesis of
N-(4-((4-(2,4,6-trifluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetam-
ide dihydrochloride
(1) Synthesis of 1-(2,4,6-trifluorophenyl)piperazine
dihydrochloride
[1131] ##STR163##
[1132] To a solution of 2,4,6-trifluoroaniline (4.4 g) an
bis(2-chloroethyl)amine hydrochloride (6.4 g) in water (4.2 ml) was
added dropwise a solution of sodium carbonate (3.8 g) in water (8.9
ml) over 40 min under reflux under heating and the mixture was
further refluxed under heating for 5.5 hr. To the reaction mixture
was added an aqueous solution (8.9 ml) of sodium hydroxide (3.6 g)
and the mixture was further refluxed under heating for 2.5 hr. The
reaction mixture was extracted with ethyl acetate. The extract was
washed with water and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated to give a dark brown
oil. The oil was subjected to silica gel column chromatography
(developing solvent; chloroform:methanol=9:1) to give the title
compound (0.61 g) as a pale-brown solid.
.sup.1H-NMR(DMSO-d.sub.6).delta.: 2.86(2H,br.s), 3.03(2H,br.s),
4.07(4H,br.s), 7.13(2H,t,J=9.5 Hz).
[1133] IR(KBr): 3205, 2954, 2846, 1633, 1594 cm.sup.-1
[1134] MS(EI): 216(M.sup.+)
(2) Synthesis of
N-(4-((4-(2,4,6-trifluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetam-
ide dihydrochloride
[1135] ##STR164##
[1136] By similar reaction and treatment to that in Example 1(5)
using 1-(2,4,6-trifluorophenyl)piperazine dihydrochloride instead
of phenylpiperazine, the title compound was obtained as white
crystals.
[1137] m.p.=235-240.degree. C. (decomposition)
[1138] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.09-3.31(6H,m), 3.58(2H,t,J=12 Hz), 4.28(2H,d,J=5.9 Hz),
4.34(2H,d,J=4.6 Hz), 7.19(2H,t,J=9.2 Hz), 7.32(2H,d,J=7.9 Hz),
7.62(2H,d,J=7.9 Hz), 8.47(1H,t,J=5.9 Hz), 11.5(1H,br.s).
[1139] IR(KBr): 3259, 2926, 2856, 1635, 1598 cm.sup.-1
[1140] Elemental analysis:
[1141] Calculated: C;53.34, H;5.37, N;9.33
[1142] Found: C;53.35, H;5.59, N;9.34
Example 48
Synthesis of
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide
(1) Synthesis of 4-chloromethylacetophenone
[1143] ##STR165##
[1144] To a solution of 4-chloromethylbenzoyl chloride (40 g) and
tris(acetylacetonato) iron (0.75 g) in tetrahydrofuran (400 ml) was
added dropwise methylmagnesium bromide (3M, tetrahydrofuran
solution)(70 ml) under ice-cooling and the mixture was stirred at
0.degree. C. for 2 hr. The reaction mixture was poured into water
and passed through Celite. The Celite was washed with ethyl acetate
and the filtrate was combined. The mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give a black red oil. The oil was subjected to silica gel column
chromatography (developing solvent; hexane:ethyl acetate=9:1, then
ethyl acetate) to give the title compound (19 g) as a pale-brown
oil.
[1145] .sup.1H-NMR(CDCl.sub.3).delta.: 2.60(3H,s), 4.61(2H,s),
7.48(2H,d,J=7.9 Hz), 7.95(2H,d,J=7.9 Hz).
[1146] IR(KBr): 3005, 2964, 1683, 1609, 1574 cm.sup.-1
[1147] MS(EI): 168(M.sup.+)
(2) Synthesis of 1-(4-chloromethylphenyl)ethanol
[1148] ##STR166##
[1149] To a solution of sodium borohydride (4.9 g) in methanol (70
ml) was added dropwise a solution of 4-chloromethylacetophenone (22
g) in methanol(60 ml) under ice-cooling, and the mixture was
stirred at room temperature for 1 hr. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated to give a pale-brown substance.
The substance was subjected to silica gel column chromatography
(developing solvent; hexane:ethyl acetate=2:1) to give the title
compound (17 g) as a colorless oil.
[1150] .sup.1H-NMR(CDCl.sub.3).delta.: 1.49(3H,d,J=6.6 Hz),
4.59(2H,s), 4.91(1H,q,J=6.6 Hz), 7.73(4H,s).
[1151] IR(KBr): 3360, 2974, 1513, 1445 cm.sup.-1
[1152] MS(EI): 170(M.sup.+)
(3) Synthesis of N-(1-(4-chloromethylphenyl)ethyl)acetamide
[1153] ##STR167##
[1154] To a solution of 1-(4-chloromethylphenyl)ethanol (17 g) in
acetonitrile (102 ml) was added dropwise conc. sulfuric acid (5.7
ml) under ice-cooling. The mixture was stirred at .sup.0.degree. C.
for 3.5 hr and left standing overnight. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with an aqueous sodium hydrogencarbonate solution and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated to give a white solid. This solid was
recrystallized from ethyl acetate-isopropyl ether to give the title
compound (17 g) as white crystals.
[1155] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=6.6 Hz),
1.98(3H,s), 4.57(2H,s), 5.12(1H,dq,J=7.3,6.6 Hz), 5.77(1H,br.s),
7.30(2H,d,J=7.9 Hz), 7.36(2H,d,J=7.9 Hz).
[1156] IR(KBr): 3267, 3061, 2978, 1631, 1540 cm.sup.-1
[1157] MS(EI): 211(M.sup.+)
(4) Synthesis of
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide
[1158] ##STR168##
[1159] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and
N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals, m.p.=101-103.degree. C.
[1160] .sup.1H-NMR(CDCl.sub.3).delta.: 1.49(3H,d,J=6.6 Hz),
1.99(3H,s), 2.60(4H,dd,J=5.3,4.6 Hz), 3.11(4H,dd,J=5.3,4.6 Hz),
3.55(2H,s), 5.13(1H,dq,J=7.3,6.6 Hz), 5.65(1H,d,J=7.3 Hz),
6.83-6.98(4H,m), 7.27(2H,d,J=7.9 Hz), 7.32(2H,d,J=7.9 Hz).
[1161] IR(KBr): 3355, 2943, 2816, 1645, 1507 cm.sup.-1
[1162] MS(EI): 355(M.sup.+)
[1163] Elemental analysis:
[1164] Calculated: C;70.96, H;7.37, N;11.82
[1165] Found: C;70.88, H;7.51, N;11.79
Example 49
Synthesis of
N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetam-
ide
[1166] ##STR169##
[1167] By similar reaction and treatment to that in Example 1(5)
using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide
instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound was obtained as white crystals, m.p.=109-111.degree.
C.
[1168] .sup.1H-NMR(CDCl.sub.3).delta.: 1.49(3H,d,J=6.6 Hz),
1.99(3H,s), 2.62(4H,t,J=4.6 Hz), 3.04(4H,t,J=4.6 Hz), 3.56(2H,s),
5.13(1H,quintet,J=7.3 Hz), 5.65(1H,d,J=7.9 Hz), 6.74-6.94(3H,m),
7.27(2H,d,J=7.9 Hz), 7.32(2H,d,J=7.9 Hz).
[1169] IR(KBr): 3351, 2946, 2811, 1644, 1505 cm.sup.-1
[1170] MS(EI): 373(M.sup.+)
[1171] Elemental analysis:
[1172] Calculated: C;67.54, H;6.75, N;11.25
[1173] Found: C;67.38, H;6.80, N;11.21
Example 50
Synthesis of
N-(1-methyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide
(1) Synthesis of 1-(4-chloromethylphenyl)-1-methylethanol
[1174] ##STR170##
[1175] To a solution of 4-chloromethylbenzoyl chloride (40 g) in
tetrahydrofuran (400 ml) was added dropwise methyl magnesium
bromide (3M, tetrahydrofuran solution) (70 ml) under ice-cooling
and the mixture was stirred at 0.degree. C. for 4 hr. The reaction
mixture was poured into an aqueous ammonium chloride solution and
extracted with ethyl acetate. The extract was washed with saturated
brine and dried over anhydrous magnesium sulfate and the solvent
was evaporated to give a yellow oil. The oil was subjected to
silica gel column chromatography (developing solvent; hexane:ethyl
acetate=9:1) to give an orange oil. The oil was subjected to silica
gel column chromatography (developing solvent; hexane:ethyl
acetate=4:1) to give the title compound (10 g) as a pale-brown oil,
m.p.=101-103.degree. C.
[1176] .sup.1H-NMR(CDCl.sub.3).delta.: 1.58(6H,s), 4.58(2H,s),
7.36(2H,d,J=8.6 Hz), 7.48(2H,d,J=8.6 Hz).
[1177] IR(KBr): 3407, 2976, 2932, 1677, 1610 cm.sup.-1
[1178] MS(EI): 184(M.sup.+)
(2) Synthesis of
N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide
[1179] ##STR171##
[1180] By similar reaction and treatment to that in Example 48(3)
using 1-(4-chloromethylphenyl)-1-methylethanol instead of
1-(4-chloromethylphenyl)ethanol, the title compound was obtained as
a pale-brown substance, m.p.=101-103.degree. C.
[1181] .sup.1H-NMR(CDCl.sub.3).delta.: 1.66(6H,s), 1.95(3H,s),
4.56(2H,s), 5.82(1H,br.s), 7.33(2H,d,J=8.6 Hz), 7.37(2H,d,J=8.6
Hz).
[1182] IR(KBr): 3317, 3074, 2974, 1658, 1553 cm.sup.-1
[1183] MS(EI): 225(M.sup.+)
(3) Synthesis of
N-(1-methyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide
[1184] ##STR172##
[1185] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead
of N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals, m.p.=110-111.degree. C.
[1186] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.60(4H,dd,J=5.3,4.6 Hz), 3.19(4H,dd,J=5.3,4.6 Hz), 3.54(2H,s),
5.70(1H,br.s), 6.84(1H,t,J=7.3 Hz), 6.91(2H,d,J=7.9 Hz),
7.25(2H,ddd,J=5.3,4.6,2.0 Hz), 7.30(2H,d,J=8.6 Hz), 7.35(2H,d,J=8.6
Hz).
[1187] IR(KBr): 3325, 2923, 2810, 1659, 1601 cm.sup.-1
[1188] MS(EI): 351(M.sup.+)
[1189] Elemental analysis:
[1190] Calculated: C;75.18, H;8.32, N;11.96
[1191] Found: C;75.10, H;8.28, N;11.87
Example 51
Synthesis of
N-(1-methyl-1-(4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenyl)ethyl)-
acetamide
[1192] ##STR173##
[1193] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and
N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as pale-brown crystals, m.p.=104.5-106.degree. C.
[1194] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.60(4H,dd,J=5.3,4.6 Hz), 3.11(4H,dd,J=5.3,4.6 Hz), 3.54(2H,s),
5.70(1H,br.s), 6.83-7.02(4H,m), 7.29(2H,d,J=8.6 Hz),
7.32(2H,d,J=8.6 Hz).
[1195] IR(KBr): 3323, 3002, 2811, 1658, 1549 cm.sup.-1
[1196] MS(EI): 369(M.sup.+)
[1197] Elemental analysis:
[1198] Calculated: C;71.52, H;7.64, N;11.37
[1199] Found: C;71.43, H;7.65, N;11.25
Example 52
Synthesis of
N-(1-methyl-1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)eth-
yl)acetamide hydrochloride 1/4 hydrate
[1200] ##STR174##
[1201] By similar reaction and treatment to that in Example 1(5)
using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine and
N-(1-(4-chloromethylphenyl)-1-methylethyl)-acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as pale-brown crystals.
[1202] m.p.=240.5-242.degree. C.
[1203] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.54(6H,s), 1.85(3H,s),
3.21-3.41(8H,m), 4.32(2H,d,J=4.0 Hz), 6.80-7.28(3H,m),
7.38(2H,d,J=7.9 Hz), 7.59(2H,d,J=7.9 Hz), 8.17(1H,s),
11.6(1H,br.s).
[1204] IR(KBr): 3287, 2976, 2468, 1645, 1596 cm.sup.-1
[1205] MS(EI): 387(M.sup.+)
[1206] Elemental analysis:
[1207] Calculated: C;61.68, H;6.71, N;9.81
[1208] Found: C;61.42, H;6.62, N;9.65
Example 53
Synthesis of
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide
(1) Synthesis of (4-chloromethylphenyl)ethyl ketone
[1209] ##STR175##
[1210] By similar reaction and treatment to that in Example 48(1)
using ethylmagnesium bromide (3M, ether solution) instead of
methylmagnesium bromide (3M, tetrahydrofuran solution), the title
compound was obtained as a pale-yellow substance.
[1211] .sup.1H-NMR(CDCl.sub.3).delta.: 1.23(3H,t,J=7.3 Hz),
3.00(2H,q,J=7.3 Hz), 4.61(2H,s), 7.48(2H,d,J=8.6 Hz),
7.96(2H,d,J=8.6 Hz).
[1212] IR(KBr): 2980, 2939, 1716, 1687, 1574 cm.sup.-1
[1213] MS(EI): 182(M.sup.+)
(2) Synthesis of 1-(4-chloromethylphenyl)propanol
[1214] ##STR176##
[1215] By similar reaction and treatment to that in Example 48(2)
using (4-chloromethylphenyl)ethyl ketone instead of
4-chloromethylacetophenone, the title compound was obtained as a
colorless oil.
[1216] .sup.1H-NMR(CDCl.sub.3).delta.: 0.92(3H,t,J=7.3 Hz),
1.65-1.89(2H,m), 4.58(2H,s), 4.60(1H,t,J=6.6 Hz), 7.33(2H,d,J=8.6
Hz), 7.37(2H,d,J=8.6 Hz).
[1217] IR(KBr): 3371, 2964, 2933, 1614, 1514 cm.sup.-1
[1218] MS(EI): 184(M.sup.+)
(3) Synthesis of N-(1-(4-chloromethylphenyl)propyl)acetamide
[1219] ##STR177##
[1220] By similar reaction and treatment to that in Example 48(3)
using 1-(4-chloromethylphenyl)propanol instead of
1-(4-chloromethylphenyl) ethanol, the title compound was obtained
as a white substance.
[1221] .sup.1H-NMR(CDCl.sub.3).delta.: 0.89(3H,t,J=7.3 Hz),
1.70-1.93(2H,m), 1.98(3H,s), 4.57(2H,s), 4.88(1H,q,J=7.9 Hz),
5.68(1H,d,J=7.3 Hz), 7.27(2H,d,J=7.9 Hz), 7.35(2H,d,J=7.9 Hz).
[1222] IR(KBr): 3299, 2964, 2933, 1639, 1553 cm.sup.-1
[1223] MS(EI): 225(M.sup.+)
(4) Synthesis of
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)-propyl)acetamide
[1224] ##STR178##
[1225] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)propyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as pale-brown crystals, m.p.=109-110.5.degree. C.
[1226] .sup.1H-NMR(CDCl.sub.3).delta.: 0.89(3H,dd,J=7.9,7.3 Hz),
1.74-1.91(2H,m), 1.99(3H,s), 2.60(4H,dd,J=5.3,4.6 Hz),
3.20(4H,dd,J=5.3,4.6 Hz), 3.55(2H,s), 4.88(1H,dt,J=7.9,7.3 Hz),
5.65(1H,d,J=7.9 Hz), 6.84(1H,t,J=7.3 Hz), 6.92(2H,d,J=7.9 Hz),
7.24(2H,d,J=7.9 Hz), 7.31(2H,d,J=7.9 Hz).
[1227] IR(KBr): 3310, 2924, 2812, 1649, 1540 cm.sup.-1
[1228] MS(EI): 351(M.sup.+)
[1229] Elemental analysis:
[1230] Calculated: C;75.18, H;8.32, N;11.96
[1231] Found: C;75.00, H;8.41, N;11.86
Example 54
Synthesis of
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)propyl)acetamide
[1232] ##STR179##
[1233] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and
N-(1-(4-chloromethylphenyl)propyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as pale-brown crystals, m.p.=113-114.degree. C.
[1234] .sup.1H-NMR(CDCl.sub.3).delta.: 0.89(3H,dd,J=7.9,7.3 Hz),
1.74-1.90(2H,m), 1.99(3H,s), 2.60(4H,dd,J=5.3,4.6 Hz),
3.11(4H,dd,J=5.3,4.6 Hz), 3.54(2H,s), 4.88(1H,dt,J=7.9,7.3 Hz),
5.66(1H,d,J=7.9 Hz), 6.83-6.99(4H,m), 7.23(2H,d,J=7.9 Hz),
7.32(2H,d,J=7.9 Hz).
[1235] IR(KBr): 3308, 2960, 2811, 1647, 1510 cm.sup.-1
[1236] MS(EI): 369(M.sup.+)
[1237] Elemental analysis:
[1238] Calculated: C;71.52, H;7.64, N;11.37
[1239] Found: C;71.48, H;7.75, N;11.35
Example 55
Synthesis of
N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)propyl)aceta-
mide
[1240] ##STR180##
[1241] By similar reaction and treatment to that in Example 1(5)
using 1-(2,4-difluorophenyl)piperazine instead of phenylpiperazine
and N-(1-(4-chloromethylphenyl)propyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as pale-brown crystals, m.p.=137-138.degree. C.
[1242] .sup.1H-NMR(CDCl.sub.3).delta.: 0.89(3H,t,J=7.3 Hz),
1.74-1.90(2H,m), 1.99(3H,s), 2.62(4H,t,J=4.6 Hz), 3.04(4H,t,J=4.6
Hz), 3.55(2H,s), 4.88(1H,dt,J=7.8,7.3 Hz), 5.69(1H,d,J=7.8 Hz),
6.74-6.94(3H,m), 7.23(2H,d,J=7.9 Hz), 7.31(2H,d,J=7.9 Hz).
[1243] IR(KBr): 3316, 2946, 2828, 1647, 1508 cm.sup.-1
[1244] MS(EI): 387(M.sup.+)
[1245] Elemental analysis:
[1246] Calculated: C;68.20, H;7.02, N;10.84
[1247] Found: C;68.26, H;7.08, N;10.79
Example 56
Synthesis of
N-(l1-ethyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide
(1) Synthesis of 1-(4-chloromethylphenyl)-1-ethylpropanol
[1248] ##STR181##
[1249] By similar reaction and treatment to that in Example 50(1)
using ethylmagnesium bromide (3M, ether solution) instead of
methylmagnesium bromide (3M, tetrahydrofuran solution), the title
compound was obtained as a brown oil.
[1250] .sup.1H-NMR(CDCl.sub.3).delta.: 0.76(6H,dd,J=7.9,7.3 Hz),
1.73-1.93(4H,m), 4.59(2H,s), 7.36(4H,s).
[1251] IR(KBr): 3473, 2968, 2937, 1612, 1511 cm.sup.-1
[1252] MS(EI): 183(M+-Et)
(2) Synthesis of
N-(1-(4-chloromethylphenyl)-1-ethylpropyl),acetamide
[1253] ##STR182##
[1254] By similar reaction and treatment to that in Example 48(3)
using 1-(4-chloromethylphenyl)-1-ethylpropanol instead of
1-(4-chloromethylphenyl)ethanol, the title compound was obtained as
a pale-brown oil.
[1255] .sup.1H-NMR(CDCl.sub.3).delta.: 0.73(6H,dd,J=7.9,7.3
Hz),1.91-2.21(4H,m),2.01(3H,s), 4.57(2H,s), 5.54(1H,s),
7.29(2H,d,J=8.6 Hz), 7.35(2H,d,J=8.6 Hz).
[1256] IR(KBr): 3288, 2979, 2966, 1644, 1551 cm.sup.-1
[1257] MS(EI): 254(M++1)
(3) Synthesis of
N-(1-ethyl-1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)propyl)acetamide
[1258] ##STR183##
[1259] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-ethylpropyl)acetamide instead
of N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals, m.p.=139-140.degree. C.
[1260] .sup.1H-NMR(CDCl.sub.3).delta.: 0.73(6H,dd,J=7.9,7.3 Hz),
1.93-2.22(4H,m),2.03(3H,s), 2.61(4H,dd,J=5.3,4.6 Hz),
3.20(4H,dd,J=5.3,4.6 Hz), 3.54(2H,s), 5.51(1H,br.s),
6.84(1H,t,J=7.3 Hz), 6.92(2H,d,J=7.9 Hz), 7.21-7.33(6H,m).
[1261] IR(KBr): 3269, 2973, 2827, 1648, 1602 cm.sup.-1
[1262] MS(EI): 379(M.sup.+)
[1263] Elemental analysis:
[1264] Calculated: C;75.95, H;8.76, N;11.07
[1265] Found: C;75.96, H;8.96, N;10.92
Example 57
Synthesis of
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)-phenyl)cyclopropyl)acetamide
(1) Synthesis of methyl 1-phenylcyclopropanecarboxylate
[1266] ##STR184##
[1267] To a solution of 1-phenylcyclopropanecarboxylic acid (9.8 g)
in methanol (121 ml) was added conc. sulfuric acid (0.1 ml) and the
mixture was refluxed under heating for 8 hr. The reaction mixture
was neutralized by adding an aqueous potassium carbonate solution
and concentrated under reduced pressure. The concentrate was
extracted with ethyl acetate. The extract was washed with an
aqueous sodium hydrogencarbonate solution and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give the title compound (8.5 g) as a colorless oil.
[1268] .sup.1H-NMR(CDCl.sub.3).delta.: 1.20(2H,dd,J=6.6,3.7 Hz),
1.61(2H,dd,J=6.6,3.7 Hz), 3.62(3H,s), 7.24-7.36(5H,m).
[1269] IR(KBr): 3059, 2953, 1724, 1603 cm.sup.-1
[1270] MS(EI): 176(M.sup.+)
(2) Synthesis of methyl
1-(4-chloromethylphenyl)-cyclopropanecarboxylate
[1271] ##STR185##
[1272] To a solution of methyl 1-phenylcyclopropanecarboxylate (8.5
g) in methylene chloride (70 ml) was added titanium tetrachloride
(8.0 ml) under ice-cooling. To this solution was added dropwise a
solution of methoxymethyl chloride (5.5 ml) in methylene chloride
(30 ml) under ice-cooling. The mixture was stirred at room
temperature for 5 hr and left standing overnight. The reaction
mixture was poured into water and extracted with ethyl acetate. The
extract was washed with an aqueous sodium hydrogencarbonate
solution and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated to give a pale-brown oil. The
oil was subjected to silica gel column chromatography (developing
solvent; hexane: ethyl acetate=4:1) to give the title compound (7.9
g) as a colorless oil.
[1273] .sup.1H-NMR(CDCl.sub.3).delta.: 1.19-1.21(2H,m),
1.58-1.64(2H,m), 3.62(3H,s), 4.57(2H,s), 7.33(4H,s).
[1274] IR(KBr): 3016, 2954, 1717, 1604 cm.sup.-1
[1275] MS(EI): 224(M.sup.+)
(3) Synthesis of methyl
1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate
[1276] ##STR186##
[1277] By similar reaction and treatment to that in Example 1(5)
using methyl 1-(4-chloromethylphenyl)cyclopropanecarboxylate
instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound was obtained as a pale-yellow solid.
[1278] .sup.1H-NMR(CDCl.sub.3).delta.: 1.19(2H,dt,J=4.0,3.3 Hz),
1.60(2H,dt,J=4.0,3.3 Hz), 2.61(4H,dd,J=5.3,4.6 Hz),
3.20(4H,dd,J=5.3,4.6 Hz), 3.55(2H,s), 3.62(3H,s), 6.84(1H,t,J=7.3
Hz), 6.91(2H,d,J=8.6 Hz), 7.25-7.32(6H,m).
[1279] IR(KBr): 2934, 2923, 1713, 1601 cm.sup.-1
[1280] MS(EI): 350(M.sup.+)
(4) Synthesis of
(4-((4-phenylpiperazin-1-yl)methyl)phenylcyclo-propanecarboxylic
acid
[1281] ##STR187##
[1282] Methyl
1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)-cyclopropanecarboxylate
(1.9 g) was dissolved in a mixed solution of methanol (50 ml) and
tetrahydrofuran (10 ml) and lithium hydroxide monohydrate (0.46 g)
was added. The mixture was refluxed under heating for 4 hr. The
reaction mixture was neutralized with hydrochloric acid, and
concentrated under reduced pressure and extracted with ethyl
acetate. The extract was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated to give the
title compound (1.2 g) as a pale-brown solid.
[1283] .sup.1H-NMR(CDCl.sub.3).delta.: 1.07(2H,t,J=3.3 Hz),
1.40(2H,t,J=3.3 Hz), 2.50(4H,t,J=4.6 Hz), 3.11(4H,t,J=4.6 Hz),
3.48(2H,s), 3.73(1H,br.s), 6.76(1H,t,J=7.3 Hz), 6.91(2H,d,J=8.6
Hz), 7.16-7.29(6H,m).
[1284] IR(KBr): 2934, 2822, 1697, 1600 cm.sup.-1
[1285] MS(EI): 336(M.sup.+)
(5) Synthesis of
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide
[1286] ##STR188##
[1287] To a solution of
(4-((4-phenylpiperazin-1-yl)methyl)-phenylcyclopropanecarboxylic
acid (1.0 g) and triethylamine (0.42 ml) in tetrahydrofuran (70 ml)
was added ethyl chlorocarbonate (0.29 ml) under ice-cooling and the
mixture was stirred at 0.degree. C. for 1 hr and 20 min. To this
solution was added a solution of sodium azide (0.2 g) in water (3
ml) under ice-cooling, and the mixture was stirred for 30 min and
left standing overnight. The reaction mixture was poured into water
and extracted with ethyl acetate. The extract was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated to give a brown oil. The oil was dissolved
in benzene (20 ml) and refluxed under heating for 40 min. The
reaction mixture was ice-cooled and methylmagnesium bromide (3M,
tetrahydrofuran solution) (0.93 ml) was added dropwise. The mixture
was stirred at room temperature for 1 hr. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated to give a colorless oil. The
oil was subjected to silica gel column chromatography (developing
solvent; ethyl acetate:methanol=20:1) to give a white solid. This
solid was recrystallized from ethyl acetate-isopropyl ether to give
the title compound (0.52 g) as white crystals,
m.p.=129-139.5.degree. C.
[1288] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(4H,br.s), 1.99(3H,s),
2.58(4H,dd,J=5.3,4.6 Hz), 3.18(4H,dd,J=5.3,4.6 Hz), 3.51(2H,s),
6.15(1H,br.s), 6.84(1H,t,J=7.3 Hz), 6.91(2H,d,J=7.9 Hz),
7.09-7.32(6H,m).
[1289] IR(KBr): 3308, 2824, 1658, 1603, 1517 cm.sup.-1
[1290] MS(EI): 349(M.sup.+)
[1291] Elemental analysis:
[1292] Calculated: C;75.61, H;7.99, N;12.05
[1293] Found: C;75.36, H;7.79, N;11.85
Example 58
Synthesis of
N-(1-(4-((4-phenylpiperazin-1-yl)methyl)-phenyl)ethyl)acetamide
dihydrochloride 1/4 hydrate
(1) N-(1-phenylethyl)acetamide
[1294] ##STR189##
[1295] To a solution of 1-phenylethylamine (10.45 g) and
triethylamine (14.4 ml) in dichloromethane (100 ml) was added
dropwise acetic anhydride (9.0 ml) at room temperature. The mixture
was stirred at room temperature for 5 hr. The reaction mixture was
poured into ice water (200 ml) and extracted with chloroform. The
organic layer was dried over anhydrous sodium sulfate and the
solvent was evaporated. The obtained residue was left standing at
room temperature for 3 hr. The obtained crude crystals were washed
several times with hexane to give the title compound (14.0 g) as
white crystals.
[1296] .sup.1H-NMR(CDCl.sub.3).delta.: 1.46(3H,d,J=6.6 Hz),
1.95(3H,s), 5.10(1H,dt,J=5.4,5.4 Hz), 6.10(1H,brs), 7.30(5H,m)
[1297] IR(KBr): 3282, 3062, 2979, 1645, 1552 cm.sup.-1
[1298] MS(EI): 163(M.sup.+)
(2) N-(1-(4-formylphenyl)ethyl)acetamide
[1299] ##STR190##
[1300] To a solution of N-(1-phenylethyl)acetamide (5.0 g) in
dichloromethane (100 ml) was added dropwise titanium tetrachloride
(16.7 ml) at below 5.degree. C. over 30 min. Thereto was added
dropwise a solution of dichloromethyl methyl ether (14.1 ml) in
dichloromethane (30 ml) solution at below 5.degree. C. over 30 min.
The mixture was stirred at 25.degree. C. for 3 hr, at room
temperature for 12 hr, and then at 25.degree. C. for 3 hr, and
poured into ice water (800 ml) and extracted with ethyl acetate.
The extract was washed successively with a saturated sodium
hydrogencarbonate solution (500 ml) and saturated brine (500 ml),
and dried over anhydrous sodium sulfate. The solvent was evaporated
and the obtained residue was purified by silica gel column
chromatography (elution solvent ;hexane:ethyl acetate=1:3) to give
the title compound (0.35 g) as a colorless oil.
[1301] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=7.3 Hz),
2.01(3H,s), 5.17(1H,dt,J=7.1,7.1 Hz), 6.04(1H,brs), 7.47(2H,d,J=7.9
Hz), 7.84(2H,d,J=8.6 Hz), 9.98(1H,s)
[1302] MS(EI): 191(M.sup.+)
(3) N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide
dihydrochloride 1/4 hydrate
[1303] ##STR191##
[1304] A solution of N-(1-(4-formylphenyl)ethyl)acetamide (0.32 g)
and sodium borohydride (63 mg) in-ethanol (10 ml) was stirred at
room temperature for 1 hr. Thereto was added 2N hydrochloric acid
(1 ml) to stop the reaction, and the reaction mixture was poured
into ice water (100 ml) and extracted with ethyl acetate. The
extract was washed successively with saturated sodium
hydrogencarbonate solution (500 ml) and saturated brine (500 ml)
and dried over anhydrous sodium sulfate. The solvent was evaporated
and the obtained residue was purified by silica gel column
chromatography (elution solvent; hexane:ethyl acetate=2:5, later
1:4) to give N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg)
as a colorless oil. A solution of the obtained
N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) and thionyl
chloride (0.050 ml) in chloroform (5 ml) was stirred at 60.degree.
C. for 1 hr. This was diluted with ethyl acetate (100 ml) and
poured into a saturated sodium hydrogencarbonate solution (100 ml)
to separate the organic layer. The aqueous layer was extracted with
ethyl acetate (100 ml) and combined with the organic layer obtained
earlier. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated and
the obtained residue was purified by silica gel column
chromatography (elution solvent; ethyl acetate alone) to give
N-(1-(4-chloromethylphenyl)ethyl)acetamide (92 mg) as yellow
crystals.
[1305] By similar reaction and treatment to that in Example 1(5)
using the obtained N-(1-(4-chloromethylphenyl)ethyl)acetamide
instead of N-(4-chloromethylphenylmethyl)acetamide, and treatment
with a solution of 1M hydrochloric acid in ether, the title
compound (40 mg) was obtained as white crystals,
m.p.=196-200.degree. C.
[1306] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.34(3H,s), 1.85(3H,s),
3.20(4H,m), 3.33(2H,m), 3.78(2H,m), 4.34(2H,s), 6.86(1H,t,J=7.3
Hz), 6.97(2H,d,J=8.6 Hz), 7.26(1H,t,J=7.9 Hz), 7.38(2H,d,J=8.6 Hz),
7.61(2H,d,J=8.6 Hz), 8.40(2H,d,J=7.9 Hz), 11.41(1H,brs).
[1307] IR(KBr): 3437, 3244, 3055, 2987, 1639 cm.sup.-1
[1308] MS(EI): 337(M.sup.+)
[1309] Elemental analysis:
[1310] Calculated: C, 60.79; H, 7.17; N, 10.13.
[1311] Found: C, 60.69; H, 7.27; N, 9.84.
Example 59
Synthesis of
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamide
(1) (4-azidomethylphenyl)methyl ketone
[1312] ##STR192##
[1313] A solution of 4-chloromethylacetophenone (8.8 g) obtained in
Example 48(1) and sodium azide in dimethylformamide (52 ml) was
stirred at 50.degree. C. for 3 hr. The reaction mixture was poured
into ice water (200 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated and the obtained residue
was purified by silica gel column chromatography (elution solvent;
hexane: ethyl acetate=4:1) to give the title compound (8.61 g) as a
yellow oil.
[1314] .sup.1H-NMR(CDCl.sub.3).delta.: 2.61(3H,s), 4.42(2H,s),
7.42(2H,d,J=7.9 Hz), 7.97(2H,d,J=8.6 Hz).
[1315] IR(neat): 2102, 1684, 1608 cm.sup.-1
(2) N-(4-(1-hydroxyethyl)phenylmethyl)acetamide
[1316] ##STR193##
[1317] To a suspension of aluminum lithium hydride (5.31 g) in
tetrahydrofuran (500 ml) was added dropwise a solution of
(4-azidomethylphenyl)methyl ketone (8.18 g) in tetrahydrofuran (100
ml) at below 5.degree. C. over 30 min. The mixture was stirred at
30.degree. C. for 2 hr. A saturated aqueous sodium sulfate solution
(30 ml) was added and the mixture was stirred for 1 hr. The
insoluble matter was filtered off and the solvent was evaporated.
The obtained residue was dissolved in ethyl acetate (100 ml), 2N
aqueous sodium hydroxide solution (30 ml) and water (70 ml).
Thereto was added dropwise acetic anhydride (4.8 ml) with vigorous
agitation at 10-15.degree. C. over 10 min. The mixture was stirred
at room temperature for 1 hr. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate and combined
with the organic layer. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated and the obtained residue was purified by silica gel
column chromatography (elution solvent;methanol:chloroform=3:97,
later 5:95) to give the title compound (5.37 g) as a rather brown
oil.
[1318] .sup.1H-NMR(CDCl.sub.3).delta.: 1.46(3H,d,J=6.6 Hz),
1.98(3H,s), 2.21(1H,brs), 4.36(2H,d,J=5.3 Hz), 4.87(1H,q,J=6.4 Hz),
6.88(1H,brs), 7.22(2H,d,J=8.6 Hz), 7.32(2H,d,J=7.9 Hz).
[1319] IR(neat): 3296, 2972, 2821, 1653, 1556 cm.sup.-1
[1320] MS(EI): 193(M.sup.')
(3) N-(4-(1-chloroethyl)phenylmethyl)acetamide
[1321] ##STR194##
[1322] To a solution of N-(4-(1-hydroxyethyl)phenylmethyl)acetamide
(5.26 g) in chloroform (40 ml) was added dropwise a solution of
thionyl chloride (2.1 ml) in chloroform (10 ml) at below 5.degree.
C. over 20 min. The mixture was stirred at 30.degree. C. for 1 hr.
The mixture was poured into a saturated sodium hydrogencarbonate
solution and extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate and the solvent was evaporated. The
obtained residue was purified by silica gel column chromatography
(elution solvent;methanol:chloroform=4:96) to give the title
compound (4.08 g) as white crystals.
[1323] m.p.=58-62.degree. C.
[1324] .sup.1H-NMR(CDCl.sub.3).delta.: 1.83(3H,d,J=6.6 Hz),
1.99(3H,s), 4.39(2H,d,J=5.9 Hz), 5.07(1H,q,J=6.8 Hz), 6.12(1H,brs),
7.25(2H,d,J=7.9 Hz), 7.37(2H,d,J=7.9 Hz).
[1325] IR(KBr): 3286, 1649, 1547 cm.sup.-1
[1326] MS(EI): 211((M+1)+)
[1327] Elemental analysis:
[1328] Calculated: C, 62.41; H, 6.67; N, 6.62.
[1329] Found: C, 62.68; H, 6.81; N, 6.59.
(4)
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamid-
e
[1330] ##STR195##
[1331] By similar reaction-and treatment to that in Example 1(5)
using 1-(4-fluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide
instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound was obtained as white crystals, m.p.=128-130.degree.
C.
[1332] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.87(3H,s), 2.37-2.77(4H,m), 3.03(4H,t,J=5.0 Hz), 3.39(1H,q,J=7.3
Hz), 4.23(2H,d,J=5.3 Hz), 6.86-7.05(4H,m), 7.21(2H,d,J=7.9 Hz),
7.27(2H,d,J=8.6 Hz), 8.30(1H,t,J=5.6 Hz).
[1333] IR(KBr): 3323, 2818, 1651, 1535, 1510 cm.sup.-1
[1334] MS(EI): 355(M.sup.+)
[1335] Elemental analysis:
[1336] Calculated: C, 70.96; H, 7.37; N, 11.82.
[1337] Found: C, 71.09; H, 7.41; N, 11.74.
Example 60
Synthesis of
N-(1-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)-
acetamide
(1) N-(1-(4-(1-hydroxyethyl)phenyl)-1-methylethyl)acetamide
[1338] ##STR196##
[1339] To a solution of
N-(1-(4-acetylphenyl)-1-methylethyl)acetamide (50.0 g) in methanol
(400 ml) was added dropwise sodium borohydride (4.3 g)at below
5.degree. C. over 30 min. The mixture was stirred at room
temperature for 2 hr and 2N hydrochloric acid (60 ml) was added.
The mixture was treated by a conventional method and the obtained
crude crystals were recrystallized from ethanol to give the title
compound (42.17 g) as white crystals.
[1340] m.p.=146-149.degree. C.
[1341] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.52(6H,s), 1.81(3H,s), 4.67(1H,q,J=6.4 Hz), 7.23(4H,s),
7.99(1H,s).
[1342] MS(EI): 221(M.sup.+)
(2) N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide
[1343] ##STR197##
[1344] N-(1-(4-(1-Hydroxyethyl)phenyl)-1-methylethyl)acetamide was
chlorinated in the same manner as in Example 59(3) to give the
title compound as white crystals.
[1345] .sup.1H-NMR(CDCl.sub.3).delta.: 1.67(6H,s), 1.83(3H,d,J=6.6
Hz), 1.95(3H,s), 5.07(1H,q,J=6.8 Hz), 5.88(1H,brs), 7.39(4H,s).
[1346] MS(EI): 239(M.sup.+)
(3)
N-(1-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenyl)-1-methyleth-
yl)acetamide
[1347] ##STR198##
[1348] By similar reaction and treatment to that in Example 1(5)
using 1-(4-fluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine and
N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)-acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals.
[1349] m.p.=156-157.degree. C.
[1350] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.53(6H,s), 1.83(3H,s), 2.40-2.56(4H,m), 3.03(4H,t,J=4.6 Hz),
3.38(1H,m), 6.87-7.05(4H,m), 7.21(2H,d,J=8.6 Hz), 7.26(2H,d,J=8.6
Hz), 7.98(1H,s)
[1351] IR(KBr): 3327, 2818, 1659, 1547, 1512 cm.sup.-1
[1352] MS(EI): 383(M.sup.+)
[1353] Elemental analysis:
[1354] Calculated: C, 72.03; H, 7.88; N, 10.96.
[1355] Found: C, 71.90 H, 7.99; N, 10.76.
Example 61
Synthesis of
N-(1-(4-(1-(4-(2,4-difluorophenyl)-piperazin-1-yl)ethyl)phenyl)-1-methyle-
thyl)acetamide
[1356] ##STR199##
[1357] By similar reaction and treatment to that in Example 1(5)
using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine and
N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide obtained in
Example 60(2) instead of N-(4-chloromethylphenylmethyl)acetamide,
the title compound was obtained as a white amorphous solid.
[1358] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.53(6H,s), 1.83(3H,s), 2.42-2.57(4H,m), 2.93(4H,m),
3.39(1H,q,J=6.6 Hz), 6.92-7.18(3H,m), 7.21(2H,d,J=8.6 Hz),
7.27(2H,d,J=8.6 Hz), 7.99(1H,s).
[1359] IR(KBr): 3331, 2975, 2821, 1659, 1547, 1508 cm.sup.-1
[1360] MS(EI): 401(M.sup.+)
[1361] Elemental analysis:
[1362] Calculated: C, 68.80; H, 7.28; N, 10.47.
[1363] Found: C, 68.76; H, 7.38; N, 10.28.
Example 62
Synthesis of
N-(1-(4-(1-(4-phenylpiperazin-1-yl)ethyl)-phenyl)-1-methylethyl)acetamide
[1364] ##STR200##
[1365] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide
obtained in Example 103(2) instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals.
[1366] m.p.=169-171.degree. C.
[1367] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.31(3H,d,J=7.3 Hz),
1.53(6H,s), 1.83(3H,s), 2.38-2.58(4H,m), 3.09(4H,t,J=4.6 Hz),
3.38(1H,q,J=6.6 Hz), 6.75(1H,t,J=7.3 Hz), 6.88(2H,d,J=7.9 Hz),
7.18(2H,t,J=7.3 Hz), 7.22(2H,d,J=8.6 Hz), 7.27(2H,d,J=8.6 Hz),
7.98(1H,s)
[1368] IR(KBr): 3286, 2974, 2823, 1655, 1603 cm.sup.-1
[1369] MS(EI): 365(M.sup.+)
[1370] Elemental analysis:
[1371] Calculated: C, 75.58; H, 8.55; N, 11.50.
[1372] Found: C, 75.28; H, 8.60; N, 11.41.
Example 63
Synthesis of
N-(4-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamid-
e
[1373] ##STR201##
[1374] By similar reaction and treatment to that in the
above-mentioned Examples, the title compound was obtained.
[1375] m.p.=96-97.degree. C.
Example 64
Synthesis of
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)propyl)phenylmethyl)acetamide
[1376] ##STR202##
[1377] By similar reaction and treatment to that in the
above-mentioned Examples, the title compound was obtained.
[1378] m.p.=134-135.degree. C.
Example 65
Synthesis of
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acet-
amide
(1) Synthesis of methyl
1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxy-
late
[1379] ##STR203##
[1380] By similar reaction and treatment to that in Example 1(5)
using methyl 1-(4-chloromethylphenyl)cyclopropanecarboxylate
obtained in Example 75(2) instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(4-fluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as a pale-yellow
oil.
[1381] .sup.1H-NMR(CDCl.sub.3).delta.: 1.16-1.20(2H,m),
1.58-1.62(2H,m), 2.59-2.63(4H,m), 3.09-3.13(4H,m), 3.55(2H,s),
3.62(3H,s), 6.83-6.98(4H,m), 7.25-7.32(4H,m).
[1382] MS(EI): 368(M.sup.+)
(2) Synthesis of
1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxy-
lic acid
[1383] ##STR204##
[1384] Methyl
1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-phenyl)cyclopropanecarbox-
ylate (2.26 g) was dissolved in ethanol (18 ml) and a solution of
sodium hydroxide (0.49 g) in water (4.6 ml) was added, and the
mixture was heated at 70.degree. C. for 2 hr. The solvent was
evaporated, and the residue was dissolved in water (200 ml). The
solution was neutralized with hydrochloric acid and extracted with
ethyl acetate (300 ml). The extract was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated to give the title compound (1.73 g) as white crystals,
m.p.=74-77.degree. C.
[1385] .sup.1H-NMR(CDCl.sub.3).delta.: 1.13-1.17(2H,m),
1.57-1.65(2H,m), 2.76-2.79(4H,m), 3.11-3.12(4H,m), 3.62(2H,s),
6.81-6.98(4H,m), 7.22-7.34(4H,m), 7.70(1H,br.s).
[1386] MS(EI): 354(M.sup.+)
(3) Synthesis of
N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acet-
amide
[1387] ##STR205##
[1388] To a suspension of
1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxy-
lic acid(1.73 g) in water(1.7 ml) was added acetone (7 ml) and
dissolved therein. A solution of triethylamine (0.75 ml) in acetone
(10 ml) was added under ice-cooling and a solution of ethyl
chlorocarbonate (0.56 ml) in acetone (4 ml) was added dropwise over
15 min. The mixture was stirred at 0.degree. C. for 30 min. To this
solution was added dropwise a solution of sodium azide (0.48 g) in
water (3 ml) under ice-cooling over 10 min. The mixture was stirred
for 30 min. The reaction mixture was poured into ice water (100 ml)
and extracted with diethyl ether. The extract was dried over
anhydrous magnesium sulfate and the solvent was evaporated to give
an oil. The oil was dissolved in toluene (17 ml) and heated at
100.degree. C. for 1 hr. The reaction mixture was ice-cooled and
methylmagnesium iodide (1M, diethyl ether solution) (4.3 ml) was
added. The mixture was stirred at room temperature for 30 min. The
reaction mixture was poured into aqueous ammonium chloride and
extracted with water and ethyl acetate (100 ml). The extract was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography (developing solvent;
ethyl acetate:methanol=100:1) and recrystallized from ethyl
acetate-isopropyl ether to give the title compound (0.52 g) as
white crystals.
[1389] m.p.=124-126.degree. C.
[1390] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26 and 1.36(4H,s and
d,J=4.0 Hz), 2.00(3H,s), 2.56-2.62(4H,m), 3.08-3.13(4H,m), 3.51 and
3.54(2H,s and s), 6.09 and 6.12(1H,s and s), 6.83-6.98(4H,m),
7.10-7.32(4H,m).
[1391] MS(EI): 367(M.sup.+)
[1392] Elemental analysis:
[1393] Calculated: C, 71.91; H, 7.13; N, 11.44.
[1394] Found: C, 71.57; H, 7.23; N, 11.41.
Example 66
Synthesis of N-(1-(4-((4-(2,
4-difluorophenyl)-piperazin-1-yl)methyl)phenyl)cyclopropyl)acetamide
(1) Synthesis of methyl 1-(4-((4-(2,
4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate
[1395] ##STR206##
[1396] By similar reaction and treatment to that in Example 1(5)
using methyl 1-(4-chloromethylphenyl)cyclopropanecarboxylate
obtained in Example 75(2) instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(2,4-difluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as an orange
oil.
[1397] .sup.1H-NMR(CDCl.sub.3).delta.: 1.11-1.20(2H,m),
1.58-1.62(2H,m), 2.61-2.65(4H,m), 3.02-3.06(4H,m), 3.56(2H,s),
3.62(3H,s), 6.74-6.94(3H,m), 7.25-7.32(4H,m).
[1398] MS(EI): 386(M.sup.+)
(2) Synthesis of
1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecar-
boxylic acid
[1399] ##STR207##
[1400] By similar reaction and treatment to that in Example 65(2)
using methyl
1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclopr-
opanecarboxylate instead of methyl
1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxy-
late, the title compound was obtained as white crystals.
[1401] m.p.=70-74.degree. C.
[1402] .sup.1H-NMR(CDCl.sub.3).delta.: 1.13-1.19(2H,m),
1.57-1.65(2H,m), 2.81(4H,m), 3.04-3.05(4H,m), 3.62(2H,s),
6.73-7.36(8H,m)
[1403] MS(EI): 372(M.sup.+)
(3) Synthesis of
N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropyl)-
acetamide
[1404] ##STR208##
[1405] By similar reaction and treatment to that in Example 65(3)
using
1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclopropaneca-
rboxylic acid instead of
1-(4-((4-(4-fluorophenyl)-piperazin-1-yl)methyl)phenyl)cyclopropanecarbox-
ylic acid, the title compound was obtained as white crystals.
[1406] m.p.=124-125.degree. C.
[1407] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26 and 1.32(4H,s and
d,J=4.0 Hz), 2.00(3H,s), 2.58-2.63(4H,m), 3.00-3.04(4H,m), 3.52 and
3.55(2H,s and s), 6.11 and 6.13(1H,s and s), 6.75-6.93(3H,m),
7.09-7.32(4H,m).
[1408] MS(EI): 385(M.sup.+)
[1409] Elemental analysis:
[1410] Calculated: C, 68.55; H, 6.54; N, 10.90.
[1411] Found: C, 68.50; H, 6.61; N, 10.96.
Example 67
Synthesis of
N-(1-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)ace-
tamide
(1) Synthesis of N-(1-phenylcyclopropyl)acetamide
[1412] ##STR209##
[1413] By similar reaction and treatment to that in Example 65(3)
using 1-phenylcyclopropanecarboxylic acid instead of
1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxy-
lic acid, the title compound was obtained as pale-yellow
crystals,
[1414] m.p.=94-95.degree. C.
[1415] .sup.1H-NMR(CDCl.sub.3).delta.: 1.24 and 1.33-1.36(4H,s and
m), 1.96 and 1.97(3H,s and s), 6.36(1H,br.s), 7.13-7.35(5H,m).
[1416] MS(EI): 175(M.sup.+)
(2) Synthesis of N-(1-(4-acetylphenyl)cyclopropyl)acetamide
[1417] ##STR210##
[1418] By similar reaction and treatment to that in Example 16(2)
using N-(1-phenylcyclopropyl) acetamide instead of
N-phenylmethylacetamide, the title compound was obtained as white
crystals, m.p.=128-131.degree. C.
[1419] .sup.1H-NMR(CDCl.sub.3).delta.: 1.33 and 1.46(4H,s and s),
1.96 and 2.02(3H,s and s), 2.56 and 2.59(3H,s and s), 6.26 and
6.36(1H,br.s and br.s), 7.21-7.28(2H,m), 7.84-7.93(2H,m).
[1420] MS(EI): 217(M.sup.+)
(3) Synthesis of
N-(1-(4-(1-hydroxyethyl)phenyl)-cyclopropyl)acetamide
[1421] ##STR211##
[1422] By similar reaction and treatment to that in Example 16(3)
using N-(1-(4-acetylphenyl)cyclopropyl)acetamide instead of
N-((4-acetylphenyl)methyl)acetamide, the title compound was
obtained as white crystals, m.p.=114-116.degree. C.
[1423] .sup.1H-NMR(CDCl.sub.3).delta.: 1.25 and 1.35(4H,s and
d,J=3.3 Hz), 1.46 and 1.50(3H,d,J=6.6 Hz and s), 1.87 and
1.92(1H,d,J=4.0 Hz and d,J=3.3 Hz), 1.97 and 1.98(3H,s and s),
4.82-4.90(1H,m), 6.17(1H,br.s), 7.11-7.35(4H,m).
[1424] MS(EI): 219(M.sup.+)
(4) Synthesis of
N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide
[1425] ##STR212##
[1426] By similar reaction and treatment to that in Example 16(4)
using N-(1-(4-(1-hydroxyethyl)phenyl)cyclopropyl)acetamide instead
of N-((4-(1-hydroxyethyl)phenyl)methyl)acetamide, the title
compound was obtained as white crystals, m.p.=104-107.degree.
C.
[1427] .sup.1H-NMR(CDCl.sub.3).delta.: 1.25 and 1.35-1.38(4H,s and
m), 1.81 and 1.85(3H,d,J=6.6 Hz and s), 1.98(1H,s), 5.06(1H,q,J=6.6
Hz), 6.25 and 6.29(1H,br.s and br.s), 7.11-7.40(4H,m).
[1428] MS(EI): 237(M.sup.+)
(5) Synthesis of
N-(1-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)ace-
tamide
[1429] ##STR213##
[1430] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead
of N-(4-chloromethylphenylmethyl)acetamide and
1-(4-fluorophenyl)-piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=149-150.degree. C.
[1431] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H,s), 1.35-1.39(4H,m),
2.00(3H,s), 2.48-2.66(4H,m), 3.05-3.10(4H,m), 3.32-3.45(1H,m),
6.12-6.14(1H,m), 6.81-6.98(4H,m), 7.08-7.30(4H,m).
[1432] MS(EI): 381(M.sup.+)
[1433] Elemental analysis:
[1434] Calculated: C, 72.41; H, 7.40; N, 11.01.
[1435] Found: C, 72.33; H, 7.39; N, 10.94.
Example 68
Synthesis of
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)ace-
tamide dihydrochloride monohydrate
(1) Synthesis of 2-(4-methylphenyl)-2-methylpropionitrile
[1436] ##STR214##
[1437] A suspension of 60% sodium hydride (50 g) and
tetrahydrofuran (225 ml) was heated to 40.degree. C. and a solution
of 4-methylphenylacetonitrile (74.5 g) in tetrahydrofuran (75 ml)
was added dropwise over 30 min. The mixture was stirred at
40.degree. C. for 30 min and a solution of methyl iodide (78 ml) in
tetrahydrofuran (75 ml) was added dropwise over 30 min. The mixture
was stirred at 40.degree. C. for 1 hr. The reaction mixture was
poured into water (2000 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the obtained
residue was purified by distillation under reduced pressure to give
the title compound (83.66 g) as a colorless oil.
[1438] Boiling point=88-91.degree. C./4 mmHg
[1439] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s.), 2.34(3H,s),
7.19(2H,d,J=7.9 Hz), 7.35(2H,d,J=7.9 Hz).
[1440] MS(EI): 159(M.sup.+)
(2) Synthesis of 2-(4-methylphenyl)-2-methylpropionic acid
[1441] ##STR215##
[1442] A solution of 2-(4-methylphenyl)-2-methylpropionitrile
(53.61 g), sodium hydroxide (40.4 g), diethylene glycol (160.8 ml)
and water (60.6 ml) was refluxed for 18 hr. The reaction mixture
was poured into water (3000 ml) and conc. hydrochloric acid (90 ml)
was added. The generated crystals were collected by filtration to
give the title compound (60.0 g) as pale-brown crystals,
m.p.=78-81.degree. C.
[1443] .sup.1H-NMR(CDCl.sub.3).delta.: 1.57(6H,s), 2.32(3H,s),
7.14(2H,d,J=8.6 Hz), 7.28(2H,d,J=8.6 Hz).
[1444] MS(EI): 178(M.sup.+)
(3) Synthesis of methyl 2-(4-methylphenyl)-2-methylpropionate
[1445] ##STR216##
[1446] A solution of 2-(4-methylphenyl)-2-methylpropionic acid
(60.0 g), sulfuric acid (0.6 ml) and methanol (300 ml) was refluxed
for 19 hr. The solvent was evaporated, and water (200 ml) was added
and the mixture was extracted with chloroform. The extract was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated to give the title compound
(61.52 g) as a pale-brown oil.
[1447] .sup.1H-NMR(CDCl.sub.3).delta.: 1.56(6H,s), 2.32(3H,s),
3.64(3H,s), 7.13(2H,d,J=8.6 Hz), 7.22(2H,d,J=8.6 Hz).
[1448] MS(EI): 192(M.sup.+)
(4) Synthesis of methyl
2-(4-azidomethylphenyl)-2-methylpropionate
[1449] ##STR217##
[1450] A solution of methyl 2-(4-methylphenyl)-2-methylpropionate
(58.5 g), N-bromosuccinimide (54.2 g), benzoyl peroxide (1.2 g) and
carbon tetrachloride (300 ml) was refluxed for 40 min. After being
cooled, the reaction mixture was filtrated. The filtrate was washed
with an aqueous sodium sulfite solution and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give methyl 2-(4-bromomethylphenyl)-2-methylpropionate (80.0 g)
as a pale-brown oil. To a solution of this oil in dimethylformamide
(500 ml) was added sodium azide (21.14 g) and the mixture was
stirred at 80.degree. C. for 40 min. The reaction mixture was
poured into water (1000 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the obtained
residue was purified by silica gel column chromatography
(developing solvent; hexane,hexane:ethyl acetate=20:1) to give the
title compound (48.1 g) as a pale-yellow oil.
[1451] .sup.1H-NMR(CDCl.sub.3).delta.: 1.58(6H,s), 3.64(3H,s),
4.31(2H,s), 7.25-7.37(4H,m).
(5) Synthesis of methyl
2-(4-aminomethylphenyl)-2-methylpropionate
[1452] ##STR218##
[1453] A solution of methyl
2-(4-azidomethylphenyl)-2-methylpropionate (48.1 g) and
triphenylphosphine (59.5 g) in a mixed solvent of tetrahydrofuran
(480 ml) and water (24 ml) was refluxed for 30 min. The solvent was
evaporated, and the obtained residue was purified by silica gel
column chromatography (developing solvent; chloroform:methanol
10:1, chloroform:methanol:aqueous ammonia=10:1:0.3) to give the
title compound (29.4 g) as a pale-yellow oil.
[1454] .sup.1H-NMR(CDCl.sub.3).delta.: 1.57(6H,s), 2.42(3H,s),
3.63(3H,s), 3.83(2H,s), 7.25-7.32(4H,m).
(6) Synthesis of methyl
2-(4-acetamidomethylphenyl)-2-methylpropionate
[1455] ##STR219##
[1456] To a solution of methyl
2-(4-aminomethylphenyl)-2-methylpropionate (29.4 g) and
triethylamine (23.8 ml) in dichloroethane (300 ml) was added
dropwise acetyl chloride (11.1 ml) at 5.degree. C. over 30 min. The
mixture was stirred at room temperature for 30 min. The reaction
mixture was poured into water and the organic layer was separated.
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated and the
obtained residue was purified by silica gel column chromatography
(developing solvent; ethyl acetate:hexane=3:1, ethyl acetate) to
give the title compound (23.47 g) as a pale-yellow oil.
[1457] .sup.1H-NMR(CDCl.sub.3).delta.: 1.56(6H,s), 1.98(3H,s),
3.63(3H,s), 4.37(2H,d,J=5.3 Hz), 7.21-7.31(4H,m).
[1458] MS(EI): 249(M.sup.+)
(7) Synthesis of 2-(4-acetamidomethylphenyl)-2-methylpropionic
acid
[1459] ##STR220##
[1460] To a solution of methyl
2-(4-acetylaminomethylphenyl)-2-methylpropionate (23.47 g) in
ethanol (160 ml) was added a solution of sodium hydroxide (7.53 g)
in water (94 ml) and the mixture was stirred at 70.degree. C. for 1
hr. The solvent was evaporated, and conc. hydrochloric acid was
added. The resulting crystals were collected by filtration to give
the title compound (14.0 g) as pale-yellow crystals,
[1461] m.p.=166-169.degree. C.
[1462] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.45(6H,s), 1.85(3H,s),
4.21(2H,d,J=5.9 Hz), 7.20(2H,d,J=8.6 Hz), 7.29(2H,d,J=8.6 Hz),
8.28(1H,br), 12.27(1H,br.s).
[1463] MS(EI): 235(M.sup.+)
(8) Synthesis of
N-(4-(1-benzyloxycarbonylamino-1-methylethyl)-phenylmethyl)acetamide
[1464] ##STR221##
[1465] To a solution of
2-(4-acetylaminomethylphenyl)-2-methylpropionic acid (14 g) in a
mixed solvent of acetone (40 ml) and dimethylformamide (30 ml) was
added triethylamine (8.75 ml) under ice-cooling and a solution of
ethyl chlorocarbonate (6.76 g) in acetone (20 ml) was added
dropwise over 10 min. The mixture was stirred at 0.degree. C. for
15 min. To this solution was added dropwise a solution of sodium
azide (4.26 g) in water (28 ml) under ice-cooling over 10 min, and
the mixture was stirred for 30 min. The reaction mixture was poured
into ice water (500 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the obtained oil
was dissolved in toluene (100 ml) and heated at 80.degree. C. for 2
hr. To this solution was added benzyl alcohol (6.77 ml) and the
mixture was stirred at 80.degree. C. for 42 hr. To the reaction
mixture was added isopropyl alcohol to allow crystallization to
give the title compound (14.62 g) as white crystals,
m.p.=132-135.degree. C.
[1466] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.51(6H,s), 1.86(3H,s),
4.21(4H,d,J=5.3 Hz), 4.93(2H,m), 7.14-7.42(9H,m), 7.65(1H,br.s),
8.26-8.30(1H,br).
(9) Synthesis of
N-(4-(1-amino-1-methylethyl)phenylmethyl)acetamide
[1467] ##STR222##
[1468] To a solution of
N-(4-(1-benzyloxycarbonylamino-1-methylethyl)phenylmethyl)acetamide
(9.57 g) in methanol (200 ml) and chloroform (200 ml) was added 10%
palladium-carbon (5.0 g) and the mixture was stirred for 5 hr while
introducing a hydrogen gas. The reaction mixture was passed through
Celite and the solvent was evaporated to give the title compound
(5.8 g) as a pale-yellow amorphous solid.
[1469] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.63(6H,s), 1.87(3H,s),
4.23(2H,d,J=5.9 Hz), 7.28(2H,d,J=7.9 Hz), 7.52(2H,d,J=7.9 Hz),
8.47(1H,br), 8.77(2H,br.s).
(10) Synthesis of ethyl
N-ethoxycarbonylmethyl-N-(4-fluorophenyl)-aminoacetate
[1470] ##STR223##
[1471] To a solution of 4-fluoroaniline (10 g) and bromoethyl
acetate (31.56 g) in dimethylformamide (120 ml) was added potassium
carbonate (31.09 g) and the mixture was stirred at 80.degree. C.
for 1.5 hr. Bromoethyl acetate (13.5 g) and potassium carbonate
(6.22 g) were further added and the mixture was stirred for 3 hr.
The reaction mixture was poured into water (500 ml) and extracted
with ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
and the obtained residue was purified by silica gel column
chromatography (developing solvent; hexane:ethyl acetate=7:1, ethyl
acetate) to give the title compound (13.51 g) as a yellow oil.
[1472] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(6H,t,J=7.3 Hz),
4.10(2H,s), 4.20(4H,q,J=7.3 Hz), 6.51-6.61(2H,m),
6.86-6.96(2H,m).
[1473] MS(EI): 283(M.sup.+)
(11) Synthesis of N,N-bis(2-hydroxyethyl)-4-fluorophenylamine
[1474] ##STR224##
[1475] To a solution of
N-ethoxycarbonylmethyl-N-(4-fluorophenyl)-aminoethyl acetate (13.51
g) in tetrahydrofuran (135 ml) was added lithium borohydride (4.15
g) and the mixture was stirred at 60.degree. C. for 1 hr. The
reaction mixture was poured into water (300 ml) and extracted with
ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give the title compound (9.2 g) as a yellow oil.
[1476] .sup.1H-NMR(CDCl.sub.3).delta.: 3.42-3.46(4H,m),
3.71-3.74(4H,m), 4.24(2H,br.s), 6.56-6.64(2H,m),
6.87-6.94(2H,m).
[1477] MS(EI): 199(M.sup.+)
(12) Synthesis of N,N-bis(2-chloroethyl)-4-fluorophenylamine
[1478] ##STR225##
[1479] To a solution of N,N-bis(2-hydroxyethyl)-4-fluorophenylamine
(9.2 g) in methylene chloride (92 ml) was added dropwise thionyl
chloride (7.1 ml) over 10 min under ice-cooling. The mixture was
stirred at room temperature for 1 hr and the reaction mixture was
further refluxed for 1.5 hr. The mixture was poured into aqueous
sodium hydrogencarbonate to make it alkaline and the organic layer
was separated. The organic layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated and the obtained residue was purified by silica gel
column chromatography (developing solvent; hexane:ethyl
acetate=10:1) to give the title compound (4.88 g) as an organge
oil.
[1480] .sup.1H-NMR(CDCl.sub.3).delta.: 3.56-3.70(8H,m),
6.60-6.67(2H,m), 6.91-7.00(2H,m).
(13) Synthesis of
N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)ace-
tamide dihydrochloride monohydrate
[1481] ##STR226##
[1482] To a solution of
N-(4-(1-amino-1-methylethyl)phenylmethyl)-acetamide (1.55 g) and
N,N-di(2-chloroethyl)-4-fluoroaniline (1.5 g) in dimethyl sulfoxide
(30 ml) were added potassium carbonate (3.12 g) and potassium
iodide (2.50 g) and the mixture was stirred at 80.degree. C. for 24
hr. The reaction mixture was poured into water (300 ml) and
extracted with ethyl acetate. The extract was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated and the obtained residue was purified by silica gel
chromatography (developing solvent; ethyl acetate:hexane=3:1) and
treated with 1M hydrochloric acid-ether in ethanol to give the
title compound (0.33 g) as white crystals.
[1483] m.p.=179-181.degree. C.
[1484] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87 and 1.89(9H,s and s),
2.88-2.96(2H,m), 3.35-3.44(4H,m), 3.61-3.66(2H,m), 4.28(2H,d,J=5.9
Hz), 6.95-7.12(4H,m), 7.36(2H,d,J=8.6 Hz), 7.82(2H,d,J=8.6 Hz),
8.48(1H,t,J=5.9 Hz).
[1485] MS(EI): 369(M.sup.+)
[1486] Elemental analysis:
[1487] Calculated: C, 57.39; H, 7.01; N, 9.13.
[1488] Found: C, 57.63; H, 6.96; N, 9.19.
Example 69
Synthesis of
N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide
[1489] ##STR227##
[1490] By similar reaction and treatment to that in Example 1(5)
using 1-(2-pyrimidyl)piperazine instead of phenylpiperazine and
N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example
66(3) instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound was obtained as white crystals.
[1491] m.p.=124-126.degree. C.
[1492] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.33(3H,d,J=7.3 Hz),
1.84(3H,s),2.40(4H,t,J=5.3 Hz), 3.47(2H,s), 3.72(4H,t,J=5.0 Hz),
4.91(1H,dq,J=7.3,7.3 Hz), 6.60(1H,t,J=5.0 Hz), 7.27(4H,s),
8.25(1H,d,J=7.9 Hz), 8.34(2H,d,J=4.6 Hz).
[1493] IR(KBr): 3309, 1643, 1587, 1547 cm.sup.-1
[1494] MS(EI): 339(M.sup.+)
[1495] Elemental analysis:
[1496] Calculated: C, 67.23; H, 7.42; N, 20.63.
[1497] Found: C, 67.18; H, 7.50; N, 20.52.
Example 70
Synthesis of
N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)phenyl)cyclopropyl)ace-
tamide
[1498] ##STR228##
[1499] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead
of N-(4-chloromethylphenylmethyl)acetamide and
1-(2-pyrimidyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=124-125.degree. C.
[1500] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26(3H,s), 1.34-1.41(4H,m),
2.00(3H,s), 2.38-2.54(4H,m), 3.33-3.45(1H,m), 3.76-3.81(4H,m), 6.10
and 6.16(1H,s and s), 6.42-6.46(1H,m), 7.08-7.30(4H,m),
8.27(2H,d,J=4.6 Hz).
[1501] MS(EI): 365(M.sup.+)
[1502] Elemental analysis:
[1503] Calculated: C, 69.01; H, 7.45; N, 19.16.
[1504] Found: C, 68.97; H, 7.47; N, 19.05.
Example 71
Synthesis of
N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acet-
amide
(1) Synthesis of
N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide
[1505] ##STR229##
[1506] To a solution of N-(1-phenylcyclopropyl)acetamide (5.0 g) in
methylene chloride (35 ml) was added titanium tetrachloride (6.26
ml) under ice-cooling and to this solution was added dropwise a
solution of methoxymethyl chloride (4.33 ml) in methylene chloride
(15 ml) over 10 min under ice-cooling. The mixture was stirred at
room temperature for 14 hr. The reaction mixture was poured into
ice water and extracted with chloroform (50 ml). The extract-was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography (developing solvent;
ethyl acetate) to give the title compound (3.71 g) as white
crystals, m.p.=124-127.degree. C.
[1507] .sup.1H-NMR(CDCl.sub.3).delta.: 1.25 and 1.37(4H,s and s),
1.98(3H,s), 4.54 and 4.57(2H,s and s), 6.17-6.28(1H,m),
7.12-7.36(4H,m).
[1508] MS(EI): 223(M.sup.+)
(2) Synthesis of
N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acet-
amide
[1509] ##STR230##
[1510] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(2-pyrimidyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=145-146.degree. C.
[1511] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26 and 1.36(4H,s and
d,J=5.3 Hz), 2.00(3H,s), 2.45-2.51(4H,m), 3.49and3.52(2H,sands),
3.79-3.84(4H,m), 6.14(1H,s), 6.44-6.48(1H,m), 7.09-7.32(4H,m),
8.29(2H,d,J=4.6 Hz).
[1512] MS(EI): 351(M.sup.+)
[1513] Elemental analysis:
[1514] Calculated: C, 68.35; H, 7.17; N, 19.93.
[1515] Found: C, 68.30; H, 7.07; N, 19.77.
Example 72
Synthesis of
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(1) 4-acetamidomethylbenzoic acid
[1516] ##STR231##
[1517] To a solution of 4-(aminomethyl)benzoic acid (20.46 g) in
ethyl acetate (100 ml) was added an aqueous solution (100 ml) of
sodium hydroxide (12 g) and acetic anhydride (14 ml) was further
added at 5-7.degree. C. The reaction mixture was stirred at room
temperature for 1 hr. The reaction mixture was made acidic with 10%
hydrochloric acid and extracted with ethyl acetate:ethanol (10:1).
The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated to give a
pale-yellow solid (27.2 g). The obtained solid was crystallized
from ethyl acetate:ethanol (1:1, 500 ml) to give the title compound
(16.7 g) as white crystals, m.p.=200-202.degree. C.
[1518] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
4.32(2H,d,J=5.9 Hz), 7.36(2H,d,J=7.9 Hz), 7.89(2H,d,J=8.6 Hz),
8.41(1H,m), 12.84(1H,br.s)
[1519] IR(KBr): 3298, 1691, 1646, 1539 cm.sup.-1
[1520] MS(EI): 193(M.sup.+)
[1521] Elemental analysis:
[1522] Calculated: C, 62.17; H, 5.74; N, 7.25.
[1523] Found: C, 62.01; H, 5.71; N, 7.21.
(2) methyl 4-acetamidomethylbenzoate
[1524] ##STR232##
[1525] 4-Acetamidomethylbenzoic acid (4.0 g) was dissolved in 0.5%
hydrogen chloride-methanol solution (100 ml). The mixture was
stirred at 40.degree. C. for 3.5 hr and poured into ice water (300
ml) and extracted with ethyl acetate. The extract was washed with a
saturated aqueous sodium hydrogencarbonate solution and saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a pale-yellow solid (4.3 g). The obtained solid
was crystallized from ethyl acetate (50 ml) to give the title
compound (3.2 g) as a pale-yellow white crystals,
m.p.=110-111.degree. C.
[1526] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.90(3H,s), 3.84(3H,s),
4.33(2H,d,J=5.9 Hz), 7.39(2H,d,J=8.6 Hz), 7.92(2H,d,J=7.9 Hz),
8.43(1H,m)
[1527] IR(KBr): 3277, 1727, 1643, 1556 cm.sup.-1
[1528] MS(EI): 207(M.sup.+)
[1529] Elemental analysis:
[1530] Calculated: C, 63.76; H, 6.32; N, 6.76.
[1531] Found: C, 63.76; H, 6.38; N, 6.76.
(3) N-(4-hydroxymethylphenylmethyl)acetamide
[1532] ##STR233##
[1533] To a suspension of aluminum lithium hydride (570 mg) in
tetrahydrofuran (80 ml) was added a solution of methyl
4-acetamidomethylbenzoate (3.1 g) in tetrahydrofuran (20 ml) under
ice-cooling. The reaction mixture was stirred at room temperature
for 1.5 hr. A saturated aqueous sodium sulfate solution (7 ml) was
added at 10.degree. C., and the mixture was stirred at room
temperature for 1 hr. The sediment was filtered off and the solvent
was evaporated to give the title compound (2.8 g) as a white
solid.
[1534] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.86(3H,s),
4.22(2H,d,J=5.9 Hz), 4.46(2H,s), 5.13(1H,br.s), 7.19(2H,d,J=7.9
Hz), 7.25(2H,d,J=8.6 Hz), 8.30(1H,m)
[1535] MS(EI): 179(M.sup.+)
(4) N-(4-chloromethylphenylmethyl)acetamide
[1536] ##STR234##
[1537] To a solution of N-(4-hydroxymethylphenylmethyl)acetamide
(1.5 g) in chloroform (50 ml) was added thionyl chloride (0.73 ml)
and the mixture was refluxed under heating for 1 hr. The solvent
was evaporated and the obtained residue was crystallized from ethyl
acetate to give the title compound (1.8 g) as pale-yellow
crystals.
[1538] m.p.=116-118.degree. C.
[1539] .sup.1H-NMR(CDCl.sub.3).delta.: 2.01(3H,s), 4.40(2H,d,J=5.9
Hz), 4.56(2H,s), 6.20(1H,br.s), 7.26(2H,d,J=8.6 Hz),
7.34(2H,d,J=7.9 Hz)
[1540] MS(EI): 197(M.sup.+)
(5)
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide
[1541] ##STR235##
[1542] A solution of N-(4-chloromethylphenylmethyl) acetamide (15.0
g), 1-(2-pyrimidyl)piperazine dihydrochloride (19.8 g) and
potassium carbonate (42.0 g) in dimethylformamide (200 ml) was
stirred at 80.degree. C. for 8.5 hr. The reaction mixture was
poured into water (500 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a brown oil
(24.0 g). The obtained brown oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=20:1) to
give a pale-brown oil (18.7 g). The obtained pale-brown oil was
crystallized from ethyl acetate: hexane (5:1, 100 ml) and the
crystals were recrystallized from ethyl acetate:hexane (10:1, 100
ml) to give the title compound (12.8 g) as white crystals,
[1543] m.p.=120-121.degree. C.
[1544] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.38-2.42(4H,m), 3.47(2H,s), 3.70-3.73(4H,m), 4.24(2H,d,J=5.9 Hz),
6.60(1H,t,J=4.6 Hz), 7.20-7.29(4H,M), 8.30(1H,t,J=5.3 Hz),
8.34(2H,d,J=4.6 Hz)
[1545] IR(KBr): 3292, 2792, 1651, 1587 cm.sup.-1
[1546] MS(EI): 325(M.sup.+)
[1547] Elemental analysis:
[1548] Calculated: C, 66.44; H, 7.12; N, 21.52.
[1549] Found: C, 66.48; H, 7.19; N, 21.72.
Example 73
Synthesis of
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
dihydrochloride monohydrate
[1550] ##STR236##
[1551] To a solution of
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(5.1 g) in ethanol (40 ml) was added 1M hydrogen chloride-ether (40
ml) and the solvent was evaporated under reduced pressure to give a
pale-brown substance (7.2 g). The obtained pale-brown substance was
crystallized and recrystallized from ethyl acetate/ethanol to give
the title compound (3.8 g) as white crystals,
[1552] m.p.=194-195.degree. C.
[1553] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
2.95-3.10(2H,m), 3.25-3.35(2H,m), 3.40-3.55(2H,m), 4.25-4.32(4H,m),
4.65-4.71(2H,m), 5.20-5.40(3H,m), 6.78(1H,t,J=5.3 Hz),
7.32(2H,d,J=7.9 Hz), 7.61(2H,d,J=7.9 Hz), 8.45(2H,d,J=4.6 Hz),
8.50(1H,t,J=5.9 Hz), 11.80(1H,brs)
[1554] IR(KBr): 3417, 3290, 1627, 1544 cm.sup.-1
[1555] MS(EI): 325(M.sup.+)
[1556] Elemental analysis:
[1557] Calculated: C, 51.93; H, 6.54; N, 16.82.
[1558] Found: C, 52.26; H, 6.40; N, 16.86.
Example 74
Synthesis of
2-(4-(4-(aminomethyl)phenylmethyl)-piperazin-1-yl)pyrimidine
[1559] ##STR237##
[1560]
N-(4-((4-(Pyrimidin-2-yl)piperazin-1-yl)methyl)-phenylmethyl)aceta-
mide (4.0 g) was dissolved in 10% hydrochloric acid (50 ml) and the
solution was refluxed under heating for 12.5 hr. To the reaction
mixture was added 10% aqueous sodium hydroxide solution to make it
alkaline, and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated and the obtained residue
was crystallized from diisopropyl ether to give the title compound
(2.2 g) as pale-yellow crystals, m.p.=70-72.degree. C.
[1561] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.38-2.42(4H,m),
2.70-3.10(2H,brs), 3.47(2H,s), 3.70-3.73(6H,m), 6.62(1H,t,J=4.6
Hz), 7.23-7.30(4H,m), 8.34(2H,d,J=5.3 Hz)
[1562] IR(KBr): 3358, 2939, 2817, 1585 cm.sup.-1
[1563] MS(EI): 283(M.sup.+)
[1564] Elemental analysis:
[1565] Calculated: C, 67.81; H, 7.47; N, 24.71.
[1566] Found: C, 67.52; H, 7.42; N, 24.12.
Example 75
Synthesis of
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)propionamide
1/4 hydrate
[1567] ##STR238##
[1568] A solution of
2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (0.5
g), propionic chloride (0.18 ml) and triethylamine (0.3 ml) in
methylene chloride (20 ml) was stirred at room temperature for 2
hr. The reaction mixture was washed with water and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to give a pale-yellow substance (0.8 g). The obtained
pale-yellow substance was crystallized from hexane/ethyl acetate
(1:1, 50 ml) to give the title compound (0.5 g) as pale-yellow
crystals.
[1569] m.p.=103-105.degree. C.
[1570] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.03(3H,t,J=7.9 Hz),
2.15(2H,q,J=7.9 Hz), 2.40-2.43(4H,m), 3.49(2H,s), 3.70-3.74(4H,m),
4.25(2H,d,J=5.9 Hz), 6.60(1H,t,J=4.6 Hz), 7.19-7.30(4H,m),
8.25(1H,t,J=5.9 Hz), 8.34(2H,d,J=4.6 Hz)
[1571] IR(KBr): 3290, 2935, 1635, 1587 cm.sup.-1
[1572] MS(EI): 339(M.sup.+)
[1573] Elemental analysis:
[1574] Calculated: C, 66.35; H, 7.47; N, 20.36.
[1575] Found: C, 66.31; H, 7.50; N, 19.97.
Example 76
Synthesis of
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)formamide
[1576] ##STR239##
[1577] A mixture of acetic anhydride (0.30 ml) and formic acid
(0.13 ml) was stirred at 50-60.degree. C. for 1 hr. To the obtained
acetic formic anhydride was added a solution of
2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidin (0.42 g)
in methylene chloride (10 ml) under ice-cooling and the mixture was
stirred at 5-10.degree. C. for 2 hr. The reaction mixture was
concentrated under reduced pressure and the obtained residue was
purified by silica gel column chromatography (developing solvent;
chloroform:methanol=9:1) to give a yellow oil (0.46 g). The
obtained yellow oil was crystallized from ethyl acetate/diisopropyl
ether to give the title compound (0.45 g) as pale-yellow crystals,
m.p.=97-98.degree. C.
[1578] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.38-2.42(4H,m),
3.48(2H,s), 3.70-3.73(4H,m), 4.30(2H,d,J=5.9 Hz), 6.60(1H,t,J=4.6
Hz), 7.22-7.31(4H,m), 8.15(1H,s), 8.34(2H,d,J=4.6 Hz),
8.45-8.55(1H,m)
[1579] IR(KBr): 3383, 2868, 1664, 1581 cm.sup.-1
[1580] MS(EI): 311(M.sup.+)
[1581] Elemental analysis:
[1582] Calculated: C, 65.57; H, 6.80; N, 22.49.
[1583] Found: C, 65.38; H, 6.78; N, 22.27.
Example 77
Synthesis of ethyl
N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)succinamide
dihydrochloride 1/2 hydrate
[1584] ##STR240##
[1585] A solution of
2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (1.3
g), ethylsuccinyl chloride (0.7 ml) and triethylamine (0.7 ml) in
methylene chloride (40 ml) was stirred at room temperature for 4.5
hr. To the reaction mixture was added chloroform (100 ml), washed
with saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure to give a brown oil
(2.0 g). The obtained brown oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=9:1) to
give a pale-brown oil (2.0 g). To the obtained pale-brown oil was
added 1M hydrogen chloride-ether (12 ml) in ethanol and the mixture
was concentrated under reduced pressure and crystallized from ethyl
acetate/ethanol to give the title compound (1.4 g) as white
crystals,
[1586] m.p.=120-123.degree. C.
[1587] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.17(3H,t,J=7.3 Hz),
2.40-2.55(4H,m), 2.95-3.10(2H,m), 3.30-3.35(2H,m), 3.45-3.55(2H,m),
4.05(2H,q,J=7.3 Hz), 4.25-4.35(4H,m), 4.65-4.75(2H,m),
4.80-4.90(2H,m), 6.77(1H,t,J=4.6 Hz), 7.31(2H,d,J=7.9 Hz),
7.60(2H,d,J=7.9 Hz), 8.45(2H,d,J=4.6 Hz), 8.52(1H,t,J=5.9 Hz),
11.78(1H,brs)
[1588] IR(KBr): 3421, 3292, 2981, 1728, 1626 cm.sup.-1
[1589] MS(EI): 411(M.sup.+)
[1590] Elemental analysis:
[1591] Calculated: C, 53.55; H, 6.54; N, 14.19.
[1592] Found: C, 53.81; H, 6.66; N, 14.28.
Example 78
Synthesis of
N-(4-((4-(4,6-difluoropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide
(1) N-(4-((4-acetylpiperazin-1-yl)methyl)phenylmethyl)acetamide
[1593] ##STR241##
[1594] A solution of N-(4-chloromethylphenylmethyl)acetamide (7.7
g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in
dimethylformamide (50 ml) was stirred at 80.degree. C. for 5 hr.
The reaction mixture was poured into water (250 ml) and extracted
with chloroform. The extract was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated to
give a yellow oil. The obtained yellow oil was purified by silica
gel column chromatography (developing solvent;
chloroform:methanol=9:1) to give the title compound (11.5 g) as a
colorless transparent oil.
[1595] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.06(3H,s),
2.37-2.44(4H,m), 3.43-3.46(2H,m), 3.50(2H,s), 3.58-3.61(2H,m),
4.41(2H,d,J=5.9 Hz), 6.00(1H,brs), 7.22-7.30(4H,m)
[1596] MS(EI): 289(M.sup.+)
(2) N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide
[1597] ##STR242##
[1598] A solution of
N-(4-((4-acetylpiperazin-1-yl)methyl)-phenylmethyl)acetamide (11.5
g) and sodium hydroxide (4.0 g) in ethanol (20 ml)-water (20 ml)
was refluxed under heating for 18 hr. The reaction mixture was
extracted with chloroform and the extract was dried over anhydrous
sodium sulfate. The solvent was evaporated to give a pale-brown oil
(9.1 g). The obtained pale-brown oil was purified by silica gel
column chromatography (developing solvent;
chloroform:methanol:aqueous ammonia=9:1:0.3) to give the title
compound (7.4 g) as a pale-yellow oil.
[1599] .sup.1H-NMR(CDCl.sub.3).delta.: 2.01(3H,s), 2.35-2.40(4H,m),
2.84-2.87(4H,m), 3.46(2H,s), 4.40(2H,d,J=5.30 Hz), 5.91(1H,brs),
7.20-7.30(4H,m)
[1600] MS(EI): 247(M.sup.+)
(3)
N-(4-((4-(4,6-difluoropyrimidin-2-yl)piperazin-1-yl)methyl)-phenylmeth-
yl)acetamide
[1601] ##STR243##
[1602] To a solution of 2,4,6-trifluoropyrimidine (1.4 g) and
potassium carbonate (2.1 g) in acetonitrile (30 ml) was added a
solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide
(2.5 g) in acetonitrile (20 ml) over 5 min under ice-cooling. The
mixture was stirred at the same temperature for 1.5 hr. The
reaction mixture was poured into water (100 ml) and extracted with
ethyl acetate. The extract was washed with brine and dried over
anhydrous sodium sulfate. The solvent was evaporated to give a
white solid (3.2 g). The obtained white solid was purified by
silica gel column chromatography (developing solvent;
chloroform:methanol=50:1) to give a crude purification product (1.3
g) of
N-(4-((4-(4,6-difluoropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide and a crude purification product (1.1 g) of
N-(4-((4-(2,6-difluoropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide. The crude purification product of
N-(4-((4-(4,6-difluoropyrimidin-2-yl)piperazin-1-yl)methyl)-phenylmethyl)-
acetamide was crystallized from ethyl acetate: diisopropyl ether to
give the title compound (1.0 g) as white crystals,
[1603] m.p.=128-129.degree. C.
[1604] .sup.1H-NMR(CDCl.sub.3).delta.: 2.03(3H,s), 2.46(4H,t,J=5.3
Hz), 3.52(2H,s), 3.79(4H,t,J=5.3 Hz), 4.43(2H,d,J=5.3 Hz),
5.66(1H,t,J=1.3 Hz), 5.75(1H,brs), 7.23-7.32(4H,m)
[1605] IR(KBr): 3288, 2918, 1635, 1552 cm.sup.-1
[1606] MS(EI): 361(M.sup.+)
[1607] Elemental analysis:
[1608] Calculated: C, 59.82; H, 5.86; N, 19.38.
[1609] Found: C, 59.83; H, 5.85; N, 19.44.
Example 79
Synthesis of
N-(4-((4-(2,6-difluoropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide
[1610] ##STR244##
[1611] The roughly purified product (1.1 g) of
N-(4-((4-(2,6-difluoropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide obtained in Example 78(3) was crystallized from ethyl
acetate:diisopropyl ether to give the title compound (1.0 g) as
white crystals, m.p.=127-128.degree. C.
[1612] .sup.1 H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.50(4H,t,J=5.3
Hz), 3.53(2H,s), 3.55-3.70(4H,m), 4.42(2H,d,J=5.9 Hz),
5.87(1H,d,J=2.0 Hz), 5.85-6.95(1H,brs), 7.23-7.31(4H,m)
[1613] IR(KBr): 3259, 2946, 2823, 1624, 1560 cm.sup.-1
[1614] MS(EI): 361(M.sup.+)
[1615] Elemental analysis:
[1616] Calculated: C, 59.82; H, 5.86; N, 19.38.
[1617] Found: C, 59.89; H, 5.86; N, 19.44.
Example 80
Synthesis of
N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide
[1618] ##STR245##
[1619] To a solution of 2,4,6-trichloropyrimidine (1.0 g) and
potassium carbonate (0.84 g) in acetonitrile (20 ml) was added a
solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide
(1.0 g) obtained in Example 78(2) in acetonitrile (20 ml) under
ice-cooling over 5 min. The mixture was stirred at the same
temperature for 30 min. The reaction mixture was poured into water
(100 ml) and extracted with ethyl acetate. The extract was washed
with brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a pale-brown oil (1.6 g). The obtained
pale-brown oil was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=50:1) to give a crude
purification product (0.28 g) of
N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide and a crude purification product (0.9 g) of
N-(4-((4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide. The crude purification product of
N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide was crystallized from ethyl acetate:hexane to give the
title compound (0.2 g) as white crystals, m.p.=139-140.degree.
C.
[1620] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.40-2.43(4H,m), 3.48(2H,s), 3.68-3.72(4H,m), 4.23(2H,d,J=5.9 Hz),
6.90(1H,s), 5.75(1H,brs), 7.19-7.29(4H,m), 8.30(1H,t,J=5.9 Hz)
[1621] IR(KBr): 3259, 2858, 1639, 1570 cm.sup.-1
[1622] MS(EI): 394(M.sup.+)
[1623] Elemental analysis:
[1624] Calculated: C, 54.83; H, 5.37; N, 17.76.
[1625] Found: C, 54.93; H, 5.43; N, 17.37.
Example 81
Synthesis of
N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
hydrochloride 1/2 hydrate
(1) 1-(thiazol-2-yl)piperazine
[1626] ##STR246##
[1627] To piperazine (48 g) dissolved by heating at 110.degree. C.
was added dropwise 2-bromothiazole (5 ml) over 20 min. The mixture
was stirred at 150.degree. C. for 1 hr, poured into water (150 ml)
and extracted with chloroform. The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give the title compound (9.5 g) as a
pale-yellow oil.
[1628] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.78(4H,t,J=5.3 Hz),
3.29(4H,t,J=5.3 Hz), 6.80(1H,d,J=4.0 Hz), 7.15(1H,d,J=4.0 Hz)
[1629] MS(EI): 169(M.sup.+)
(2)
N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide
hydrochloride 1/2 hydrate
[1630] ##STR247##
[1631] A solution of N-(4-chloromethylphenylmethyl)acetamide(1.8
g), 1-(thiazol-2-yl)piperazine (1.5 g) and potassium carbonate (1.8
g) in dimethylformamide (20 ml) was stirred at 80.degree. C. for
2.5 hr. The reaction mixture was poured into water (100 ml) and
extracted with ethyl acetate. The extract was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a brown oil. The obtained brown oil was purified
by silica gel column chromatography (developing solvent;
chloroform:methanol=9:1) to give a pale-brown oil (2.3 g). The
obtained pale-brown oil was dissolved in ethanol (200 ml) and 1M
hydrogen chloride-ether (7 ml) was added. The solvent was
evaporated under reduced pressure. The obtained residue was
crystallized from ethyl acetate:ethanol (1:1, 100 ml) and the
crystals were recrystallized from ethyl acetate:ethanol:methanol
(1:1:1, 100 ml) to give the title compound (1.2 g) as white
crystals, m.p.=120-121.degree. C.
[1632] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
3.00-3.35(4H,m), 3.50-3.65(2H,m), 3.70-3.80(4H,m), 3.90-4.10(2H,m),
4.28(2H,d,J=5.9 Hz), 4.35(2H,S), 6.99(1H,d,J=4.0 Hz),
7.24(1H,d,J=4.0 Hz), 7.32(1H,d,J=7.9 Hz), 7.61(1H,d,J=7.9 Hz),
8.48(1H,t,J=5.9 Hz), 11.86(1H,brs)
[1633] IR(KBr): 3311, 2526, 2507, 1641, 1521 cm.sup.-1
[1634] MS(EI): 330(M.sup.+)
[1635] Elemental analysis:
[1636] Calculated: C, 54.32; H, 6.44; N, 14.90.
[1637] Found: C, 54.10; H, 6.31; N, 14.73.
Example 82
Synthesis of
N-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
[1638] ##STR248##
[1639] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0
g), 1-(2-pyridyl)piperazine (1.4 g) and potassium carbonate (4.2 g)
in dimethylformamide (20 ml) was stirred at 60-70.degree. C. for
2.5 hr. The reaction mixture was poured into water and extracted
with ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated to
give a brown oil. The obtained brown oil was purified by silica gel
column chromatography (developing solvent;
chloroform:methanol=20:1) to give a pale-yellow oil (2.5 g). The
obtained pale-yellow oil was crystallized from ethyl acetate and
the crystals were recrystallized from ethyl acetate to give the
title compound (1.4 g) as white crystals, m.p.=100-101.degree.
C.
[1640] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
2.40-2.45(2H,m), 2.45-2.30(2H,m), 3.40-3.50(4H,m), 4.23(2H,d,J=5.9
Hz), 6.62(1H,dd,J=5.3,7.3 Hz), 6.78(1H,d,J=8.6 Hz),
7.20-7.29(4H,m), 7.47-7.54(1H,m), 8.09(1H,dd,J=1.3,4.6 Hz),
8.25-8.35(1H,m)
[1641] IR(KBr): 3319, 2940, 2809, 1645, 1594 cm.sup.-1
[1642] MS(EI): 324(M.sup.+)
[1643] Elemental analysis:
[1644] Calculated: C, 70.34; H, 7.46; N, 17.27.
[1645] Found: C, 70.10; H, 7.50; N, 17.05.
Example 83
Synthesis of
N-(4-((4-(pyridin-3-yl)piperazin-1-yl)methylphenylmethyl)acetamide
1/2 hydrate
(1) 1-(pyridin-3-yl)piperazine
[1646] ##STR249##
[1647] A suspension of 3-aminopyridine (2.0 g) and
bis(2-chloroethyl)amine hydrochloride (3.8 g) in o-xylene (40 ml)
was stirred at 140.degree. C. for 20 hr. The reaction mixture was
extracted with water and the aqueous layer was made alkaline with a
2N aqueous sodium hydroxide solution and extracted with chloroform.
The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated and the
obtained residue was purified by silica gel column chromatography
(developing solvent; chloroform:methanol:aqueous ammonia=9:1:0.5)
to give the title compound (0.55 g) as a black brown oil.
[1648] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.83(4H,d,J=5.3 Hz),
3.08(4H,d,J=5.3 Hz), 7.17-7.21(1H,m), 7.26-7.30(1H,m),
7.97(1H,d,J=2.6 Hz), 8.27(1H,d,J=3.3 Hz)
[1649] MS(EI): 163(M.sup.+)
(2)
N-(4-((4-(pyridin-3-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
1/2 hydrate
[1650] ##STR250##
[1651] A solution of N-(4-chloromethylphenylmethyl) acetamide (0.67
g), 1-(3-pyridyl)piperazine (0.55 g) and potassium carbonate (0.93
g) in dimethylformamide (10 ml) was stirred at 80.degree. C. for 4
hr. The reaction mixture was poured into water and extracted with
chloroform. The extract was washed with saturated brine and dried
over anhydrous sodium sulfate. The solvent was evaporated to give a
black oil. The obtained black oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=4:1) to
give a brown solid. The obtained brown solid was crystallized from
ethyl acetate-methanol to give the title compound (200 mg) as white
crystals, m.p.=139-140.degree. C.
[1652] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.48-2.51(4H,m), 3.15-3.20(4H,m), 3.49(2H,s), 4.23(2H,d,J=5.9 Hz),
7.17-7.31(6H,m), 7.98(1H,d,J=3.3 Hz), 8.27(1H,d,J=2.6 Hz),
8.30(1H,t,J=5.9 Hz)
[1653] IR(KBr): 3455, 3232, 3041, 1660, 1568 cm.sup.-1
[1654] MS(EI): 324(M.sup.+)
[1655] Elemental analysis:
[1656] Calculated: C, 68.44; H, 7.56; N, 16.80.
[1657] Found: C, 68.32; H, 7.59; N, 16.72.
Example 84
Synthesis of
N-(4-((4-(pyridin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(1) 1-(pyridin-4-yl)piperazine
[1658] ##STR251##
[1659] To piperazine (3.6 g) dissolved at 110.degree. C. was added
4-bromopyridine (1.0 g) and the mixture was stirred at
140-150.degree. C. for 1 hr. The reaction mixture was poured into
water and extracted with chloroform. The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give the title compound (0.64 g) as a
pale-yellow solid.
[1660] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.78(4H,t,J=5.3 Hz),
3.20(4H,t,J=5.3 Hz), 6.77(2H,dd,J=1.3,6.6 Hz), 8.14(2H,d,J=6.6
Hz)
MS(EI): 163(M.sup.+)
(2)
N-(4-((4-(pyridin-4-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide
[1661] ##STR252##
[1662] A solution of N-(4-chloromethylphenylmethyl) acetamide (0.85
g), 1-(pyridin-4-yl)piperazine (0.64 g) and potassium carbonate
(0.81 g) in dimethylformamide (10 ml) was stirred at 60-70.degree.
C. for 5 hr. The reaction mixture was poured into water and
extracted with chloroform. The extract was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated and the obtained residue was purified by silica gel
column chromatography (developing solvent; chloroform:methanol=9:1)
to give a yellow solid (0.6g). The obtained yellow solid was
crystallized from ethyl acetate-methanol to give the title compound
(0.37 g) as white crystals, m.p.=164-166.degree. C.
[1663] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.89(3H,s),
2.43-2.46(2H,m), 2.49-2.51(2H,m), 3.27-3.30(4H,m), 3.49(2H,s),
4.23(2H,d,J=5.9 Hz), 6.78-6.79(2H,m), 7.20-7.28(4H,m),
8.13-8.15(2H,m), 8.32(1H,m)
[1664] IR(KBr): 3033, 2952, 2931, 1664, 1599 cm.sup.-1
[1665] MS(EI): 324(M.sup.+)
[1666] Elemental analysis:
[1667] Calculated: C, 70.34; H, 7.46; N, 17.27.
[1668] Found: C, 70.29; H, 7.37; N, 17.26.
Example 85
Synthesis of
N-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetami-
de hydrochloride 1/2 ethyl acetate
(1) 1-acetyl-4-(6-fluoropyridin-2-yl)piperazine
[1669] ##STR253##
[1670] A solution of 2,6-difluoropyridine (9.0 g),
1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in
acetonitrile (100 ml) was refluxed under heating for 18 hr. The
reaction mixture was poured into water and extracted with ethyl
acetate. The extract was washed with brine and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a pale-brown
solid (8.7 g). The obtained pale-brown solid was crystallized from
ethyl acetate-hexane to give the title compound (5.5 g) as
pale-brown crystals.
[1671] m.p.=102-103.degree. C.
[1672] .sup.1H-NMR(CDCl.sub.3).delta.: 2.14(3H,s), 3.48-3.55(2H,m),
3.56-3.65(4H,m), 3.71-3.75(2H,m), 6.22(1H,dd,J=2.6,7.9 Hz),
6.43(1H,dd,J=2.6,8.6 Hz), 7.57(1H,dd,J=7.9,16.5 Hz)
[1673] IR(KBr): 3077, 2890, 2852, 1646, 1608 cm.sup.-1
[1674] MS(EI): 223(M.sup.+)
[1675] Elemental analysis:
[1676] Calculated: C, 59.18; H, 6.32; N, 18.82.
[1677] Found: C, 59.25; H, 6.34; N, 18.83.
(2) 1-(6-fluoropyridin-2-yl)piperazine
[1678] ##STR254##
[1679] A solution of 1-acetyl-4-(6-fluoropyridin-2-yl)piperazine
(5.5 g) and sodium hydroxide (3.0 g) in methanol (30 ml)-water (30
ml) was refluxed under heating for 5 hr. The reaction mixture was
poured into water and extracted with ethyl acetate. The solvent was
evaporated to give the title compound (4.6 g) as a pale-yellow
oil.
[1680] .sup.1H-NMR(CDCl.sub.3).delta.: 2.93-2.97(4H,m),
3.48-3.51(4H,m), 6.16(1H,dd,J=2.6,7.9 Hz), 6.40(1H,dd,J=2.6,7.9
Hz), 7.52(1H,dd,J=7.9,16.5 Hz)
(3)
N-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)-phenylmethyl)ace-
tamide hydrochloride 1/2 ethyl acetate
[1681] ##STR255##
[1682] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.5
g), 1-(6-fluoropyridin-2-yl)piperazine (1.3 g) and potassium
carbonate (1.6 g) in dimethylformamide (20 ml) was stirred at
80.degree. C. for 6 hr. The reaction mixture was poured into water
and extracted with ethyl acetate.
[1683] The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated and the
obtained residue was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=9:1) to give a pale-brown
oil (2.9 g). The obtained pale-brown oil was treated with 1M
hydrogen chloride-ether and crystallized from ethyl acetate-ethanol
to give the title compound (2.2 g) as pale-yellow crystals.
[1684] m.p.=112-115.degree. C. (decomposition)
[1685] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.78(1.5H,t,J=7.3 Hz),
1.90(3H,s), 1.99(1.5H,s), 2.95-3.13(2H,m), 3.25-3.45(4H,m),
4.03(1H,q,J=7.3 Hz), 4.25-4.35(6H,m), 6.39(1H,dd,J=2.6,7.9 Hz),
6.78(1H,dd,J=2.6,7.9 Hz), 7.32(2H,d,J=7.9 Hz), 7.60(2H,d,J=7.9 Hz),
7.75(1H,m), 8.47(1H,t,J=5.9 Hz), 11.69(1H,brs)
[1686] IR(KBr): 3263, 2987, 2541, 1666, 1614 cm.sup.-1
[1687] MS(EI): 342(M.sup.+)
[1688] Elemental analysis:
[1689] Calculated: C, 57.46; H, 6.43; N, 12.76.
[1690] Found: C, 57.85; H, 6.86; N, 12.67.
Example 86
Synthesis of
N-(4-((4-(5-chloropyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetami-
de
(1) 1-(5-chloropyridin-2-yl)piperazine
[1691] ##STR256##
[1692] To piperazine (29.0 g) dissolved at 115.degree. C. was added
2,5-dichloropyridine (5.1 g) and the mixture was stirred at
140-150.degree. C. for 1 hr. The reaction mixture was poured into a
1N aqueous sodium hydroxide solution and extracted with ethyl
acetate. The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated to give the
title compound (5.0 g) as a pale-brown solid.
[1693] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.76(4H,t,J=5.3 Hz),
3.38(4H,t,J=5.3 Hz), 6.81(1H,d,J=8.6 Hz), 7.56(1H,dd,J=3.3,8.6 Hz),
8.09(1H,d,J=2.6 Hz)
[1694] MS(EI): 197(M.sup.+)
(2)
N-(4-((4-(5-chloropyridin-2-yl)piperazin-1-yl)methyl)-phenylmethyl)ace-
tamide
[1695] ##STR257##
[1696] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.5
g), 1-(5-chloropyridin-2-yl)piperazine (1.5 g) and potassium
carbonate (1.6 g) in dimethylformamide (20 ml) was stirred at
70-80.degree. C. for 8.5 hr. The reaction mixture was poured into
water and extracted with ethyl acetate. The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a brown solid (3.1 g). The obtained
brown solid was crystallized ethyl acetate to give the title
compound (1.3 g) as pale-yellow crystals,
[1697] m.p.=155-156.degree. C.
[1698] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.35-2.45(4H,m), 3.45-3.50(6H,m), 4.23(2H,d,J=5.9 Hz),
6.84(1H,d,J=9.2 Hz), 7.19-7.29(4H,m), 7.58(1H,dd,J=2.6,9.2 Hz),
8.09(1H,d,J=2.6 Hz), 8.31(1H,t,J=5.3 Hz)
[1699] IR(KBr): 3313, 2915, 2815, 1645, 1591 cm.sup.-1
[1700] MS(EI): 358(M.sup.+)
[1701] Elemental analysis:
[1702] Calculated: C, 63.59; H, 6.45; N, 15.61.
[1703] Found: C, 63.55; H, 6.48; N, 15.48.
Example 87
Synthesis of
N-(4-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide
(1) 1-(pyrazin-2-yl)piperazine
[1704] ##STR258##
[1705] To piperazine (48.0 g) dissolved at 110.degree. C. was added
2-chloropyrazine (5.0 ml) and the mixture was stirred at
150.degree. C. for 2 hr. The reaction mixture was poured into an
aqueous sodium hydroxide solution and extracted with chloroform.
The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated to give the
title compound (6.4 g) as a brown oil.
[1706] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.97-3.01(4H,m),
3.54-3.58(4H,m), 7.84(1H,d,J=2.6 Hz), 8.06(1H,dd,J=1.3,2.6 Hz),
8.13(1H,d,J=1.3 Hz)
[1707] MS(EI): 164(M.sup.+)
(2)
N-(4-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide
[1708] ##STR259##
[1709] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.6
g), 1-(pyrazin-2-yl)piperazine (1.3 g) and potassium carbonate (1.6
g) in dimethylformamide (20 ml) was stirred at 70-80.degree. C. for
7 hr. The reaction mixture was poured into water and extracted with
chloroform. The extract was washed with saturated brine and dried
over anhydrous sodium sulfate. The solvent was evaporated and the
obtained residue was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=20:1) to give a
pale-yellow solid (1.8 g). The obtained pale-yellow solid was
crystallized from hexane-ethyl acetate to give the title compound
(1.2 g) as pale-yellow crystals,
[1710] m.p.=118-119.degree. C.
[1711] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.40-2.45(4H,m), 3.49(2H,s), 3.50-3.55(4H,m), 4.24(2H,d,J=5.9 Hz),
7.20-7.29(4H,m), 7.82(1H,d,J=2.6 Hz), 8.06(1H,d,J=1.3 Hz),
8.29-8.35(2H,m)
[1712] IR(KBr): 3307, 2929, 2845, 1639, 1578 cm.sup.-1
[1713] MS(EI): 325(M.sup.+)
[1714] Elemental analysis:
[1715] Calculated: C, 66.44; H, 7.12; N, 21.52.
[1716] Found: C, 66.49; H, 7.10; N, 21.34.
Example 88
Synthesis of
N-(4-((4-(5-nitrothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamid-
e
(1) 1-(5-nitrothiazol-2-yl)piperazine
[1717] ##STR260##
[1718] To a solution of piperazine (18.2 g) and potassium carbonate
(12.6 g) in acetonitrile (150 ml) was added 2-bromo-5-nitrothiazole
(14.7 g) at 40.degree. C. and the mixture was stirred at 60.degree.
C. for 40 min. The reaction mixture was poured into water and
extracted with chloroform. The extract was washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a brown solid (11.2 g). The obtained brown solid
was purified by silica gel column chromatography (developing
solvent; chloroform:methanol=9:1) to give the title compound (4.8
g) as yellow crystals.
[1719] .sup.1H-NMR(DMSO-d.sub.6).delta.: 2.80(4H,t,J=5.3 Hz),
3.55(4H,t,J=5.3 Hz), 8.37(1H,s)
[1720] MS(EI): 214(M.sup.+)
(2)
N-(4-((4-(5-nitrothiazol-2-yl)piperazin-1-yl)methyl)-phenylmethyl)acet-
amide
[1721] ##STR261##
[1722] A solution of N-(4-chloromethylphenylmethyl)acetamide (0.5
g), 1-(5-nitrothiazol-2-yl)piperazine (0.5 g) and potassium
carbonate (0.5 g) in dimethylformamide (15 ml) was stirred at
80.degree. C. for 3.5 hr. The reaction mixture was poured into
water and extracted with ethyl acetate. The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a yellow solid (1.5 g). The obtained
pale-yellow solid was crystallized from ethyl acetate to give the
title compound (0.5 g) as yellow crystals, m.p.=151-152.degree.
C.
.sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s), 2.40-2.50(4H,m),
3.52(2H,s), 3.60-3.70(4H,m), 4.23(2H,d,J=5.9 Hz), 7.23-7.29(4H,m),
8.31(1H,t,J=5.3 Hz), 8.37(1H,s)
[1723] IR(KBr): 3296, 2964, 1651, 1558, 1504 cm.sup.-1
[1724] MS(EI): 375(M.sup.+)
[1725] Elemental analysis:
[1726] Calculated: C, 54.38; H, 5.64; N, 18.65.
[1727] Found: C, 54.26; H, 5.65; N, 18.38.
Example 89
Synthesis of
N-(4-((4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide
[1728] ##STR262##
[1729] The roughly purified product (0.9 g) of
N-(4-((4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide obtained in Example 88(3) was crystallized from ethyl
acetate to give the title compound (0.7 g) as white crystals,
m.p.=165-166.degree. C.
[1730] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.35-2.45(4H,m), 3.48(2H,s), 3.60-3.70(4H,m), 4.23(2H,d,J=5.9 Hz),
6.99(1H,s), 7.19-7.29(4H,m), 8.29(1H,t,J=5.9 Hz)
[1731] IR(KBr): 3249, 2910, 1646, 1598 cm.sup.-1
[1732] MS(EI): 394(M.sup.+)
[1733] Elemental analysis:
[1734] Calculated: C, 54.83; H, 5.37; N, 17.76.
[1735] Found: C, 54.88; H, 5.41; N, 17.60.
Example 90
Synthesis of
N-(4-((4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-
acetamide 1/2 hydrate
(1) 1-acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine
[1736] ##STR263##
[1737] To a solution of 2,4,6-trifluoropyrimidine (2.0 g) and
potassium carbonate (3.1 g) in acetonitrile (15 ml) was added a
solution of 1-acetylpiperazine (1.9 g) in acetonitrile (5 ml) over
10 min under ice-cooling and the mixture was stirred at room
temperature for 1 hr. The reaction mixture was poured into water
and extracted with ethyl acetate. The extract was washed with brine
and dried over anhydrous sodium sulfate. The solvent was evaporated
to give a pale-yellow oil. The obtained pale-yellow oil was
purified by silica gel column chromatography to give the title
compound (1.8 g) and
1-acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine (1.7 g) both as a
white solid.
[1738] .sup.1H-NMR(CDCl.sub.3).delta.: 2.15(3H,s), 3.55-3.65(2H,m),
3.65-3.70(2H,m), 3.80-3.90(4H,m), 5.75(1H,t,J=2.0 Hz)
[1739] MS(EI): 242(M.sup.+)
(2) 1-(4,6-dimethoxypyrimidin-2-yl)piperazine
[1740] ##STR264##
[1741] A solution of
1-acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.7 g) and
sodium hydroxide (0.84 g) in methanol (20ml)-water (10 ml) was
refluxed under heating for 7.5 hr. The reaction mixture was poured
into water and extracted with chloroform. The extract was washed
with brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a colorless transparent oil (2.5 g). The
obtained colorless transparent oil was purified by silica gel
column chromatography (developing solvent;
chloroform:methanol=50:1) to give the title compound (1.0 g) as a
pale-yellow solid.
[1742] .sup.1H-NMR(CDCl.sub.3).delta.: 2.90(4H,t,J=5.3 Hz),
3.77(4H,t,J=5.3 Hz), 3.85(6H,s), 5.36(1H,s)
[1743] IR(KBr): 2985, 2944, 1583, 1564 cm.sup.-1
[1744] MS(EI): 224(M.sup.+)
[1745] Elemental analysis:
[1746] Calculated: C, 53.55; H, 7.19; N, 24.98.
[1747] Found: C, 53.65; H, 7.24; N, 24.85.
(3)
N-(4-((4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmeth-
yl)acetamide 1/2 hydrate
[1748] ##STR265##
[1749] A solution of N-(4-chloromethylphenylmethyl)acetamide (0.93
g), 1-(4,6-dimethoxypyrimidin-2-yl)piperazine (0.94 g) and
potassium carbonate (0.97 g) in dimethylformamide (10 ml) was
stirred at 80.degree. C. for 1.5 hr. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated to give a brown oil (2.0 g).
The obtained brown oil was crystallized from ethyl
acetate:diisopropyl ether(1:3, 40 ml) to give the title compound
(1.3 g) as pale-yellow crystals, m.p.=130-131.degree. C.
[1750] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.40-2.50(4H,m), 3.45-3.60(2H,m), 3.65-3.75(4H,m), 3.78(6H,s),
4.24(2H,d,J=5.9 Hz), 5.39(1H,s), 7.20-7.30(4H,m), 8.32(1H,t,J=5.3
Hz)
[1751] IR(KBr): 3317, 2829, 1641, 1578 cm.sup.-1
[1752] MS(EI): 385(M.sup.+)
[1753] Elemental analysis:
[1754] Calculated: C, 60.90; H, 7.15; N, 17.75.
[1755] Found: C, 61.13; H, 6.99; N, 17.75.
Example 91
Synthesis of
N-(4-((4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-
acetamide (Another Method)
[1756] ##STR266##
[1757] A solution of
N-(4-((piperazin-1-yl)methyl)phenylmethyl)-acetamide (5.0 g)
obtained in Example 88(2), 2-chloro-4,6-dimethoxypyrimidine (3.9 g)
and potassium carbonate (4.2 g) in acetonitrile (50 ml) was
refluxed under heating for 5 hr. The reaction mixture was poured
into ice water and extracted with ethyl acetate. The extract was
washed with brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a pale-brown solid. The obtained
pale-brown solid was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=9:1) and crystallized from
diisopropyl ether to give the title compound (5.0 g) as white
crystals.
[1758] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.40-2.50(4H,m), 3.45-3.60(2H,m), 3.65-3.75(4H,m), 3.78(6H,s),
4.24(2H,d,J=5.9 Hz), 5.39(1H,s), 7.20-7.30(4H,m), 8.32(1H,t,J=5.3
Hz)
Example 92
Synthesis of
N-(4-((4-(2,6-dimethoxypyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)-
acetamide 1/2 hydrate
(1) 1-acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine
[1759] ##STR267##
[1760] By the manipulation of Example 90(1), the title compound
(1.7 g) was obtained as a white solid.
[1761] .sup.1H-NMR(CDCl.sub.3).delta.: 2.15(3H,s), 3.55-3.70(4H,m),
3.70-3.85(4H,m), 5.95(1H,d,J=2.0 Hz)
[1762] MS(EI): 242(M.sup.+)
(2) 1-(2,6-dimethoxypyrimidin-4-yl)piperazine
[1763] ##STR268##
[1764] A solution of
1-acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine (1.5 g) and
sodium hydroxide (0.8 g) in methanol (10 ml)-water (10 ml) was
refluxed under heating for 4 hr. The reaction mixture was poured
into water and extracted with chloroform. The extract was washed
with brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a color less transparent oil (1.8g). The
obtained colorless transparent oil was purified by silica gel
column chromatography (developing solvent;
chloroform:methanol=50:1) to give the title compound (1.2 g) as a
colorless transparent oil.
[1765] .sup.1H-NMR(CDCl.sub.3).delta.: 2.90-3.00(4H,m),
3.53-3.57(4H,m), 3.90(3H,s), 3.91(3H,s), 5.48(1H,s)
[1766] MS(EI): 224(M.sup.+)
(3)
N-(4-((4-(2,6-dimethoxypyrimidin-4-yl)piperazin-1-yl)methyl)phenylmeth-
yl)acetamide 1/2 hydrate
[1767] ##STR269##
[1768] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0
g), 1-(2,6-dimethoxypyrimidin-4-yl)piperazine (1.1 g) and potassium
carbonate (1.0 g) in dimethylformamide (10 ml) was stirred at
80.degree. C. for 2 hr. The reaction mixture was poured into water
and extracted with ethyl acetate. The extract was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give a brown oil (2.1 g). The obtained
brown oil was purified by silica gel column chromatography
(developing solvent; chloroform:methanol=9:1) and crystallized from
ethyl acetate:diisopropyl ether (1:2, 30 ml) to give the title
compound (1.0 g) as white crystals, m.p.=89-90.degree. C.
[1769] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.87(3H,s),
2.30-2.40(4H,m), 3.47(2H,s), 3.50-3.57(4H,m), 3.77(3H,s),
3.78(3H,s), 4.23(2H,d,J=5.9 Hz), 5.70(1H,s), 7.22-7.28(4H,m),
8.29(1H,t,J=5.9 Hz)
[1770] IR(KBr): 3269, 1652, 1608, 1564 cm.sup.-1
[1771] MS(EI): 385(M.sup.+)
[1772] Elemental analysis:
[1773] Calculated: C, 60.90; H, 7.15; N, 17.75.
[1774] Found: C, 60.78; H, 7.12; N, 17.67.
Example 93
Synthesis of
N-(4-((4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide
(1) 2-chloro-4,6-dimethylpyrimidine
[1775] ##STR270##
[1776] A solution of 2-hydroxy-4,6-dimethylpyrimidine (5.0 g) in
phosphorous oxychloride (19 ml) was refluxed under heating for 9
hr. The reaction mixture was added dropwise to an aqueous sodium
hydroxide solution and extracted with ethyl acetate. The extract
was washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated to give a yellow oil (3.0 g).
The obtained yellow oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=30:1) to
give the title compound (2.4 g) as a pale-yellow oil.
[1777] .sup.1H-NMR(CDCl.sub.3).delta.: 2.49(6H,s), 6.98(1H,s)
(2)
N-(4-((4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethy-
l)acetamide
[1778] ##STR271##
[1779] A solution of
N-(4-((piperazin-1-yl)methyl)phenylmethyl)-acetamide (1.7 g)
obtained in Example 88(2), 2-chloro-4,6-dimethylpyrimidine (1.0 g)
and potassium carbonate (3.0 g) in acetonitrile (50 ml) was
refluxed under heating for 7 hr. The reaction mixture was poured
into water and extracted with ethyl acetate. The extract was washed
with brine and dried over anhydrous sodium sulfate. The solvent was
evaporated to give a yellow oil. The obtained yellow oil was
purified by silica gel column chromatography (developing solvent;
chloroform:methanol=20:1) and crystallized from diisopropyl ether
and recrystallized from ethyl acetate-hexane to give the title
compound (1.1 g) as white crystals.
[1780] m.p.=127-128.degree. C.
[1781] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.27(6H,s),
2.47(4H,t,J=5.3 Hz), 3.52(2H,s), 3.83(4H,t,J=5.3 Hz),
4.42(2H,d,J=5.9 Hz), 5.79(1H,brs), 6.25(1H,s), 7.22-7.33(4H,m)
[1782] IR(KBr): 3301, 1643, 1573 cm.sup.-1
[1783] MS(EI): 353(M.sup.+)
[1784] Elemental analysis:
[1785] Calculated: C, 67.96; H, 7.70; N, 19.81.
[1786] Found: C, 68.03; H, 7.76; N, 19.73.
Example 94
Synthesis of
N-(1-methyl-1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)ace-
tamide
[1787] ##STR272##
[1788] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead
of N-(4-chloromethylphenylmethyl)acetamide and
1-(thiazol-2-yl)piperazine instead of phenylpiperazine, the title
compound was obtained as pale-yellow crystals, m.p.=118-120.degree.
C.
[1789] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.56(4H,t,J=5.3 Hz), 3.49(4H,t,J=5.3 Hz), 3.52(2H,s),
5.72(1H,br.s), 6.55(1H,d,J=3.3 Hz), 7.19(1H,d,J=4.0 Hz),
7.26-7.36(4H,m).
[1790] MS(FAB): 359(M.sup.+)
[1791] Elemental analysis:
[1792] Calculated: C, 63.66; H, 7.31; N, 15.63.
[1793] Found: C, 63.70; H, 7.34; N, 15.65.
Example 95
Synthesis of
N-(1-methyl-1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)a-
cetamide
(1) Synthesis of 4-(1-acetamide-1-methylethyl)benzoic acid
[1794] ##STR273##
[1795] To a solution of sodium hydroxide (164.2 g) in water (500
ml) was added dropwise bromine (70 ml) over 30 min under
ice-cooling. To this solution was added dropwise a solution of
N-(1-(4-acetylphenyl)-1-methylethyl) acetamide (100 g) in dioxane
(1000 ml) over 1 hr and the mixture was stirred at 10.degree. C.
for 30 min. To the reaction mixture was added a solution of sodium
sulfite (19 g) in water (2000 ml) and stirred. Thereto was added
hydrochloric acid and the resulting crystals were collected by
filtration to give the title compound (73.4 g) as pale-brown
crystals, m.p.=235-237.degree. C.
[1796] .sup.1H-NM(DMSO-d.sub.6).delta.: 1.54(6H,s), 1.83(3H,s),
7.42(2H,d,J=8.6 Hz), 7.86(2H,d,J=8.6 Hz), 8.14(1H,s),
12.72(1H,br.s).
[1797] MS(EI): 221(M.sup.+)
(2) Synthesis of methyl 4-(1-acetamido-1-methylethyl)benzoate
[1798] ##STR274##
[1799] A suspension of 4-(1-acetamido-1-methylethyl)benzoic acid
(73.4 g) and sulfuric acid (0.7 ml) in methanol (370 ml) was
refluxed for 16 hr. The solvent was evaporated and 10% aqueous
sodium hydrogencarbonate (500 ml) was added and the mixture was
extracted with ethyl acetate (500 ml). The extract was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated and the obtained residue was recrystallized
from ethyl acetate-isopropyl ether to give the title compound (39.0
g) as pale-yellow crystals,
[1800] m.p.=165-167.degree. C.
[1801] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.53(6H,s), 1.83(3H,s),
3.83(3H,s), 7.44(2H,d,J=8.6 Hz), 7.87(2H,d,J=8.6 Hz),
8.15(1H,s).
[1802] MS(EI): 235(M.sup.+)
(3) Synthesis of
N-(1-(4-hydroxymethylphenyl)-1-methylethyl)-acetamide
[1803] ##STR275##
[1804] To a solution of methyl
4-(1-acetamido-1-methylethyl)benzoate (37.14 g) in tetrahydrofuran
(370 ml) was added lithium borohydride (6.88 g) and the mixture was
refluxed for 19 hr. The reaction mixture was poured into water
(1000 ml) and extracted with ethyl acetate (1000 ml). The extract
was washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated and the obtained residue was
recrystallized from ethyl acetate to give the title compound (18.24
g).
[1805] m.p.=126-129.degree. C.
[1806] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.52(6H,s), 1.81(3H,s),
4.44(2H,d,J=5.3 Hz), 5.06(1H,t,J=5.3 Hz), 7.18-7.27(4H,m),
7.98(1H,br.s).
[1807] MS(EI): 207(M.sup.+)
(4) Synthesis of
N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide
[1808] ##STR276##
[1809] To a solution of
N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide (18.24 g) in
chloroform (180 ml) was added dropwise thionyl chloride (7.07 ml)
over 10 min under ice-cooling and the mixture was stirred at room
temperature for 20 hr. The reaction mixture was poured into water
(1000 ml) and the organic layer was separated. The organic layer
was washed with aqueous sodium hydrogencarbonate and saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated to give the title compound (19.17 g) as pale-yellow
crystals, m.p.=124-125.degree. C.
[1810] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.52(6H,s),
1.82(3H,s),4.71(2H,s),7.28-7.35(4H,m), 8.05(1H,s).
[1811] MS(EI): 225(M.sup.+)
(5) Synthesis of
N-(1-methyl-1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)a-
cetamide
[1812] ##STR277##
[1813] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead
of N-(4-chloromethylphenylmethyl)acetamide and
1-(2-pyrimidyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=137-138.degree. C.
[1814] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.96(3H,s),
2.50(4H,t,J=5.3 Hz), 3.51(2H,s), 3.82(4H,t,J=5.3 Hz),
5.76(1H,br.s), 6.46(1H,t,J=4.6 Hz), 7.28-7.36(4H,m),
8.29(2H,t,J=4.6 Hz).
[1815] MS(EI): 353(M.sup.+)
[1816] Elemental analysis:
[1817] Calculated: C, 67.96; H, 7.70; N, 19.81.
[1818] Found: C, 67.94; H, 7.65; N, 19.80.
Example 96
Synthesis of
N-(1-(4-((4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-1--
methylethyl)acetamide
[1819] ##STR278##
[1820] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained
in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(4,6-dimethoxypyrimidin-2-yl)piperazine obtained in Example
90(2) instead of phenylpiperazine, the title compound was obtained
as white crystals, m.p.=199-202.degree. C.
[1821] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.53(6H,s), 1.82(3H,s),
2.38-2.41(4H,m), 3.46(2H,s), 3.71(4H,m), 3.78(6H,s), 5.38(1H,s),
7.20-7.28(4H,m), 7.99(1H,s).
[1822] MS(FAB): 414(MH+)
[1823] Elemental analysis:
[1824] Calculated: C, 63.90; H, 7.56; N, 16.94.
[1825] Found: C, 63.73; H, 7.64; N, 16.82.
Example 97
Synthesis of
N-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide and
N-(4-((4-(4-chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmeth-
yl)acetamide
[1826] ##STR279##
[1827] To a suspension of
N-(4-((piperazin-1-yl)methyl)-phenylmethyl)acetamide (1.0 g)
obtained in Example 78(2) and 2,4-dichloropyrimidine (0.60 g) in
acdetonitrile (20 ml) was added potassium carbonate (0.84 g) and
the mixture was stirred at room temperature for 2 hr. The reaction
mixture was poured into water (200 ml) and extracted with ethyl
acetate (100 ml). The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
and the obtained residue was purified by silica gel column
chromatography (developing solvent; ethyl
acetate:methanol=20:1-10:1) to give
N-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (0.61 g) as white crystals and
N-(4-((4-(4-chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide (10 mg) as white crystals.
N-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide
[1828] m.p.=132-133.degree. C.
[1829] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.49(4H,t,J=5.3
Hz), 3.52(2H,s), 3.65(4H,br.), 4.42(2H,d,J=5.9 Hz), 5.96(1H,br.s),
6.36(1H,d,J=6.6 Hz), 7.23-7.31(4H,m), 8.00(1H,d,J=6.6 Hz).
[1830] MS(FAB): 360(MH+)
[1831] Elemental analysis:
[1832] Calculated: C, 60.08; H, 6.16; N, 19.46.
[1833] Found: C, 60.08; H, 6.11; N, 19.43.
N-(4-((4-(4-chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)aceta-
mide
[1834] m.p.=122-124.degree. C.
[1835] .sup.1H-NMR(CDCl.sub.3).delta.: 2.01(3H,s), 2.47(4H,t,J=5.3
Hz), 3.52(2H,s), 3.80-3.83(4H,t), 4.41(2H,d,J=5.3 Hz),
5.99(1H,br.s), 6.48(1H,d,J=4.6 Hz), 7.22-7.32(4H,m),
8.13(1H,d,J=5.3 Hz).
[1836] MS(FAB): 360(MH+)
Example 98
Synthesis of
N-(1-((4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
(1) Synthesis of 2-chloro-4-methoxypyrimidine
[1837] ##STR280##
[1838] To a solution of 2,4-dichloropyrimidine (32.4 g) in methanol
(200 ml) was added dropwise a solution of sodium methoxide (11.7 g)
in methanol (120 ml) over 40 min and the mixture was stirred for 30
min. The reaction mixture was poured into water (500 ml) and
extracted with chloroform (300 ml). The extract was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated and the obtained residue was recrystallized
from hexane to give the title compound (21.5 g) as white crystals,
m.p.=50-52.degree. C.
[1839] .sup.1H-NMR(CDCl.sub.3).delta.: 4.02(3H,s), 6.68(1H,d,J=5.3
Hz), 8.29(1H,d,J=5.3 Hz).
[1840] MS(EI): 144(M.sup.+)
(2) Synthesis of 1-(4-methoxypyrimidin-2-yl)piperazine
[1841] ##STR281##
[1842] A suspension of 2-chloro-4-methoxypyrimidine (21.5 g) and
piperazine (64.0 g) in acetonitrile (200 ml) was refluxed for 30
min. The reaction mixture was poured into water (500 ml) and
extracted with chloroform (400 ml). The extract was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated to give the title compound (26.0 g) as a
pale-yellow oil.
[1843] .sup.1H-NMR(CDCl.sub.3).delta.: 2.90-2.94(4H,m),
3.76-3.80(4H,m), 3.88(3H,s), 5.97(1H,d,J=5.9 Hz), 8.05(1H,d,J=5.3
Hz).
[1844] MS(EI): 194(M.sup.+)
(3) Synthesis of
N-(1-((4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
[1845] ##STR282##
[1846] By similar reaction and treatment to that in Example 1(5)
using 1-(4-methoxypyrimidin-2-yl)piperazine instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=144-145.degree. C.
[1847] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.46-2.50(4H,m),
3.53(2H,s), 3.79-3.82(4H,m), 3.86(3H,s), 4.42(2H,d,J=5.3 Hz),
5.84(1H,br.s), 5.96(1H,d,J=5.9 Hz), 7.23-7.33(4H,m),
8.03(1H,d,J=5.3 Hz).
[1848] MS(EI): 355(M.sup.+)
[1849] Elemental analysis:
[1850] Calculated: C, 64.21; H, 7.09; N, 19.70.
[1851] Found: C, 63.98; H, 6.93; N, 19.60.
Example 99
Synthesis of
N-(4-((4-(4-(N,N-dimethylamino)pyrimidin-2-yl)piperazin-1-yl)methyl)pheny-
lmethyl)acetamide
(1) Synthesis of 2-chloro-4-(N,N-dimethylamino)pyrimidine
[1852] ##STR283##
[1853] To a 20% dimethylamine-ethanol solution (15.4 g) of
2,4-dichloropyrimidine (3.0 g) was added triethylamine (3 ml) under
ice-cooling, and the mixture was stirred for 30 min. The reaction
mixture was poured into water (100 ml) and extracted with ethyl
acetate (100 ml). The extract was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated and
the obtained residue was purified by silica gel column
chromatography (developing solvent; ethyl acetate:hexane=1:1) to
give the title compound (1.90 g) as white crystals,
m.p.=77-79.degree. C.
[1854] .sup.1H-NMR(CDCl.sub.3).delta.: 3.11(6H,s), 6.31(1H,d,J=5.9
Hz), 8.00(1H,d,J=5.9 Hz).
[1855] MS(EI): 157(M.sup.+)
(2) Synthesis of
N-(4-((4-(4-(N,N-dimethylamino)pyrimidin-2-yl)piperazin-1-yl)methyl)pheny-
lmethyl)acetamide
[1856] ##STR284##
[1857] By similar reaction and treatment to that in Example 1-(5)
using N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide obtained
in Example 78(2) instead of N-(4-chloromethylphenylmethyl)acetamide
and 2-chloro-4-(N,N-dimethylamino)pyrimidine instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=152-155.degree. C.
[1858] .sup.1H-NMR(CDCl.sub.3).delta.: 1.99(3H,s), 2.44-2.48(4H,m),
3.02(6H,s), 3.51(2H,s), 3.75-3.78(4H,m), 4.40(2H,d,J=5.3 Hz),
5.77(1H,d,J=5.9 Hz), 6.08(1H,br.s), 7.21-7.32(4H,m),
7.88(1H,d,J=5.9 Hz).
[1859] MS(EI): 368(M.sup.+)
[1860] Elemental analysis:
[1861] Calculated: C, 65.19; H, 7.66; N, 22.81.
[1862] Found: C, 64.84; H, 7.59; N, 22.53.
Example 100
Synthesis of
N-(1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetam-
ide
[1863] ##STR285##
[1864] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in
Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead of
phenylpiperazine, the title compound was obtained as pale-yellow
crystals, m.p.=184-185.degree. C.
[1865] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26 and 1.36(4H,s and
d,J=4.0 Hz), 1.99(3H,s), 2.51-2.57(4H,m), 3.46-3.53(6H,m),
6.21(1H,br), 6.54-6.56(1H,m), 7.09-7.31(5H,m).
[1866] MS(EI): 356(M.sup.+)
[1867] Elemental analysis:
[1868] Calculated: C, 64.02; H, 6.79; N, 15.72.
[1869] Found: C, 63.83; H, 6.55; N, 15.58.
Example 101
Synthesis of
N-(1-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide
[1870] ##STR286##
[1871] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in
Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=136-137.degree. C.
[1872] .sup.1H-NMR(CDCl.sub.3).delta.: 1.49(3H,d,J=7.3 Hz),
1.98(3H,s), 2.55(4H,t,J=5.3 Hz), 3.49(4H,t,J=5.3 Hz), 3.53(2H,s),
5.12(1H,dt,J=7.3 Hz), 5.74-5.77(1H,br), 6.56(1H,d,J=3.3 Hz),
7.18(1H,d,J=3.3 Hz), 7.25-7.33(4H,m).
[1873] MS(EI): 344(M.sup.+)
[1874] Elemental analysis:
[1875] Calculated: C, 62.76; H, 7.02; N, 16.26.
[1876] Found: C, 62.74; H, 6.92; N, 16.21.
Example 102
Synthesis of
N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acet-
amide
[1877] ##STR287##
[1878] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in
Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2)
instead of phenylpiperazine, the title compound was obtained as
white crystals,
[1879] m.p.=109-111.degree. C.
[1880] .sup.1H-NMR(CDCl.sub.3).delta.: 1.49(3H,d,J=7.3 Hz),
1.98(3H,s), 2.50-2.53(4H,m), 3.51-3.55(6H,m), 5.13(1H,dq,J=7.3 Hz),
5.73-5.75(1H,br), 6.13-6.17(1H,m), 6.37-6.41(1H,m),
7.26-7.33(4H,m), 7.46-7.55(1H,m).
[1881] MS(EI): 356(M.sup.+)
[1882] Elemental analysis:
[1883] Calculated: C, 67.39; H, 7.07; N, 15.72.
[1884] Found: C, 67.29; H, 7.00; N, 15.76.
Example 103
Synthesis of
N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)-1-methyle-
thyl)acetamide
[1885] ##STR288##
[1886] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained
in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2)
instead of phenylpiperazine, the title compound was obtained as
white crystals,
[1887] m.p.=133-134.degree. C.
[1888] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.50-2.54(4H,m), 3.51-3.55(6H,m), 5.71(1H,br.s), 6.13-6.16(1H,m),
6.36-6.41(1H,m), 7.26-7.36(4H,m), 7.46-7.55(1H,m).
[1889] MS(EI): 370(M.sup.+)
[1890] Elemental analysis:
[1891] Calculated: C, 68.08; H, 7.35; N, 15.12.
[1892] Found: C, 68.10; H, 7.15; N, 15.14.
Example 104
Synthesis of
N-(1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acetamide
[1893] ##STR289##
[1894] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in
Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title
compound was obtained as pale-yellow crystals, m.p.=120-121.degree.
C.
[1895] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.50-2.54(4H,m), 3.51-3.55(6H,m), 5.71(1H,br), 6.13-6.16(1H,m),
6.36-6.41(1H,m), 7.26-7.36(4H,m), 7.46-7.55(1H,m).
[1896] MS(EI): 338(M.sup.+)
[1897] Elemental analysis:
[1898] Calculated: C, 70.98; H, 7.74; N, 16.55.
[1899] Found: C, 70.91; H, 7.70; N, 16.51.
Example 105
Synthesis of
N-(1-methyl-1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)ace-
tamide
[1900] ##STR290##
[1901] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained
in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title
compound was obtained as white crystals, m.p.=129-130.degree.
C.
[1902] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.53-2.57(4H,m), 3.52-3.55(6H,m), 5.71(1H,br.s), 6.58-6.64(2H,m),
7.26-7.36(4H,m), 7.42-7.49(1H,m), 8.17-8.18(1H,m).
[1903] MS(EI): 352(M.sup.+)
[1904] Elemental analysis:
[1905] Calculated: C, 71.56; H, 8.01; N, 15.90.
[1906] Found: C, 71.59; H, 7.93; N, 15.88.
Example 106
Synthesis of
N-(1-(4-((4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-1-meth-
ylethyl)acetamide
[1907] ##STR291##
[1908] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained
in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2)
instead of phenylpiperazine, the title compound was obtained as
white crystals, m.p.=160-162.degree. C.
[1909] .sup.1H-NMR(CDCl.sub.3).delta.: 1.70(6H,s), 1.97(3H,s),
2.47-2.51(4H,m), 3.52(2H,s), 3.79-3.83(4H,m), 3.87(3H,s),
5.71(1H,br), 5.96(1H,d,J=5.3 Hz), 7.26-7.36(4H,m), 8.04(1H,d,J=5.3
Hz).
[1910] MS(EI): 383(M.sup.+)
[1911] Elemental analysis:
[1912] Calculated: C, 65.77; H, 7.62; N, 18.26.
[1913] Found: C, 65.69; H, 7.46; N, 18.37.
Example 107
Synthesis of
N-(1-(4-((4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)a-
cetamide
[1914] ##STR292##
[1915] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in
Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2)
instead of phenylpiperazine, the title compound was obtained as
pale-yellow crystals, m.p.=113-115.degree. C.
[1916] .sup.1H-NMR(CDCl.sub.3).delta.: 1.49(3H,d,J=7.3 Hz),
1.98(3H,s), 2.46-2.50(4H,m), 3.52(2H,s), 3.79-3.83(4H,m),
3.86(3H,s), 5.13(1H,dq,J=7.3 Hz), 5.70-5.72(1H,br), 5.96(1H,d,J=5.3
Hz), 7.26-7.34(4H,m), 8.03(1H,d,J=5.9 Hz).
[1917] MS(EI): 369(M.sup.+)
[1918] Elemental analysis:
[1919] Calculated: C, 65.02; H, 7.37; N, 18.96.
[1920] Found: C, 64.90; H, 7.15; N, 19.21.
Example 108
Synthesis of
N-(4-((4-(4,6-diethoxypyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)a-
cetamide
(1) 1-acetyl-4-(4,6-diethoxypyrimidin-2-yl)piperazine
[1921] ##STR293##
[1922] A solution of
1-acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.5 g) and
sodium ethoxide (1.3 g) in ethanol (15 ml) was refluxed under
heating for 1 hr. The reaction mixture was poured into ice water
and extracted with ethyl acetate. The extract was washed with brine
and dried over anhydrous sodium sulfate. The solvent was evaporated
to give the title compound (1.8 g) as a pale-brown solid.
[1923] .sup.1H-NMR(CDCl.sub.3).delta.:1.36(6H,t,J=7.3 Hz),
2.14(3H,s), 3.48-3.52(2H,m), 3.64-3.68(2H,m), 3.73-3.83(4H,m),
4.27(4H,q,J=7.3 Hz), 5.38(1H, S)
[1924] MS(EI): 294(M.sup.+)
(2) 1-(4,6-diethoxypyrimidin-2-yl)piperazine
[1925] ##STR294##
[1926] A solution of
1-acetyl-4-(4,6-diethoxypyrimidin-2-yl)piperazine (1.8 g) and
sodium hydroxide (1.0 g) in ethanol (10 ml)-water (10 ml) was
refluxed under heating for 11 hr. The reaction mixture was poured
into water and extracted with chloroform. The extract was dried
over anhydrous sodium sulfate and the solvent was evaporated to
give the title compound (1.6 g) as a pale-brown oil.
[1927] .sup.1H-NMR(CDCl.sub.3).delta.:1.35(6H,t,J=7.3 Hz),
2.89(4H,t,J=5.3 Hz), 3.74(4H,t,J=5.3 Hz), 4.26(4H,q,J=7.3 Hz),
5.32(1H, s)
[1928] MS(EI): 252(M.sup.+)
(3)
N-(4-((4-(4,6-diethoxypyrimidin-2-yl)piperazin-1-yl)methyl)-phenylmeth-
yl)acetamide
[1929] ##STR295##
[1930] A solution of N-(4-chloromethylphenylmethyl)acetamide (1.2
g), 1-(4,6-diethoxypyrimidin-2-yl)piperazine (1.7 g) and potassium
carbonate (1.3 g) in dimethylformamide (20 ml) was stirred at
80.degree. C. for 4.5 hr. The reaction mixture was poured into
water (150 ml) and extracted with ethyl-acetate. The extract was
washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated to give a brown oil (2.9 g).
The obtained brown oil was purified by silica gel column
chromatography to give a pale-yellow oil (2.4 g). The obtained
pale-yellow oil was crystallized from ethyl acetate/hexane (2:1, 30
ml) to give the title compound (1.7 g) as white crystals,
m.p.=119-120.degree. C.
[1931] .sup.1H-NMR(CDCl.sub.3).delta.: 1.34(6H,t,J=7.3 Hz),
2.03(3H,S), 2.45(4H,t,J=5.3 Hz), 3.52(2H,s), 3.77(4H,t,J=5.3 Hz),
4.25(4H,q,J=7.3 Hz), 4.42(4H,d,J=5.9 Hz), 5.32(1H,s),.
5.71(1H,brs), 7.22-7.33(4H,m)
[1932] IR(KBr): 3288, 2977w 1643, 1578 cm.sup.-1
[1933] MS(EI): 413(M.sup.+)
[1934] Elemental analysis:
[1935] Calculated: C, 63.90; H, 7.56; N, 16.94.
[1936] Found: C, 63.81; H, 7.47; N, 16.72.
Example 109
Synthesis of
N-(4-((4-(4,6-bis(dimethylamino)-pyrimidin-2-yl)piperazin-1-yl)methyl)phe-
nylmethyl)acetamide
(1)
1-acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine
[1937] ##STR296##
[1938] 1-Acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.9 g)
was dissolved in 12% dimethylamine-ethanol solution (30 ml) and the
mixture was stirred at room temperature for 1 hr. The reaction
mixture was concentrated under reduced pressure. Water was added to
the residue and the mixture was extracted with ethyl acetate. The
extract was washed with brine and dried over anhydrous sodium
sulfate. The solvent was evaporated to give the title compound (2.1
g) as a yellow solid.
[1939] .sup.1H-NMR(CDCl.sub.3).delta.: 2.13(3H,s), 3.06(6H,s),
3.47-3.51(2H,m), 3.64-3.68(2H,m), 3.74-3.81(4H,m), 5.33(1H,d,J=1.3
Hz)
[1940] MS(EI): 267(M.sup.+)
(2) 1-acetyl-4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine
[1941] ##STR297##
[1942]
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine
(1.0 g) was dissolved in 12% dimethylamine-ethanol solution (30 ml)
in an autoclave, and the mixture was stirred at 100.degree. C. for
5 hr. The reaction mixture was concentrated under reduced pressure
and chloroform was added to the reside. The chloroform solution was
washed with brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to give the title compound (1.3 g) as a
pale-yellow solid.
[1943] .sup.1H-NMR(CDCl.sub.3).delta.: 2.13(3H,s), 3.02(12H,s),
3.48-3.52(2H,m), 3.65-3.68(2H,m), 3.73-3.82(4H,m), 4.91(1H,s)
[1944] MS(EI): 292(M.sup.+)
(3) 1-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine
[1945] ##STR298##
[1946] A solution of
1-acetyl-4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (1.3 g)
and sodium hydroxide (0.5 g) in ethanol (15 ml)-water (15 ml) was
refluxed under heating for 9.5 hr. The reaction mixture was
concentrated under reduced pressure, and ethyl acetate was added to
the residue and the mixture was washed with brine. The organic
layer was dried over anhydrous sodium sulfate and the solvent was
evaporated to give the title compound (0.9 g) as a pale-brown
oil.
[1947] .sup.1H-NMR(CDCl.sub.3).delta.: 1.73(1H,s), 2.87-2.89(4H,m),
3.01(12H,s), 3.70-3.74(4H,m), 4.89(1H, s)
[1948] MS(EI): 250(M.sup.+)
(4)
N-(4-((4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazin-1-yl)methyl)p-
henylmethyl)acetamide
[1949] ##STR299##
[1950] A solution of N-(4-chloromethylphenylmethyl)acetamide (0.7
g), 1-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (0.9 g) and
potassium carbonate (0.7 g) in dimethylformamide (10 ml) was
stirred at 80.degree. C. for 6 hr. The reaction mixture was poured
into water (100 ml) and extracted with ethyl acetate. The extract
was washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated to give a brown solid (1.6 g).
The obtained brown solid was crystallized from ethyl
acetate/ethanol (2:1, 30 ml) to give the title compound (0.9 g) as
pale-yellow crystals.
[1951] m.p.=189-190.degree. C. (decomposition)
[1952] .sup.1H-NMR(CDCl.sub.3).delta.: 2.00(3H,s), 2.43-2.47(4H,m),
2.99(12H,s), 3.51(2H,s), 3.74-3.77(4H,m), 4.40(2H,d,J=5.3 Hz),
4.88(1H,s), 5.80(1H,brs), 7.21-7.32(4H, m)
[1953] IR(KBr): 3291, 2935, 2819, 1645, 1578 cm.sup.-1
[1954] MS(EI): 411(M.sup.+)
[1955] Elemental analysis:
[1956] Calculated: C, 64.21; H, 8.08; N, 23.82.
[1957] Found: C, 63.81; H, 7.79; N, 22.96.
Example 110
Synthesis of
N-(4-((4-(4-dimethylamino-6-methoxypyrimidin-2-yl)piperazin-1-yl)methyl)p-
henylmethyl)acetamide
(1) 1-(4-dimethylamino-6-methoxypyrimidin-2-yl)piperazine
[1958] ##STR300##
[1959]
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine
(1.0 g) obtained in Example 109(1) and sodium methoxide (1.1 g)
were refluxed under heating in methanol (10 ml) for 28 hr. The
reaction mixture was poured into water (100 ml) and extracted with
chloroform. The extract was dried over anhydrous sodium sulfate and
the solvent was evaporated to give the title compound (1.1 g) as a
pale-yellow oil.
[1960] .sup.1H-NMR(CDCl.sub.3).delta.: 2.88-2.92(4H,m), 3.01(6H,s),
3.72-3.76(4H,m), 3.84(3H,s), 5.15(1H,s)
[1961] MS(EI): 237(M.sup.+)
(2)
N-(4-((4-(4-dimethylamino-6-methoxypyrimidin-2-yl)piperazin-1-yl)methy-
l)phenylmethyl)acetamide
[1962] ##STR301##
[1963] A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9
g), 1-(4-dimethylamino-6-methoxypyrimidin-2-yl)piperazine (1.1 g)
and potassium carbonate (1.0 g) in dimethylformamide (10 ml) was
stirred at 80.degree. C. for 8.5 hr. The reaction mixture was
poured into water (100 ml) and extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
sodium sulfate. The solvent was evaporated to give a brown oil (1.9
g). The obtained brown oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=9:1) to
give a yellow oil (1.6 g). The obtained yellow oil was crystallized
from ethyl acetate/hexane (1:1, 20 ml) to give the title compound
(1.0 g) as pale-yellow crystals. m.p.=115-118.degree. C.
[1964] .sup.1H-NMR(CDCl.sub.3).delta.: 2.01(3H,s), 2.43-2.47(4H,m),
2.99(6H,s), 3.52(2H,s), 3.75-3.79(4H,m), 3.81(3H,s),
4.40(2H,d,J=5.9 Hz), 5.14(1H,s), 5.86(1H,brs), 7.21-7.32(4H, m)
[1965] IR(KBr): 3261, 2939, 2834, 1635, 1589 cm.sup.-1
[1966] MS(EI): 398(M.sup.+)
[1967] Elemental analysis:
[1968] Calculated: C, 63.29; H, 7.59; N, 21.09.
[1969] Found: C, 63.38; H, 7.45; N, 20.64.
Example 111
Synthesis of
N-(4-((4-(5-bromothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamid-
e
(1) 4-acetyl-1-(thiazol-2-yl)piperazine
[1970] ##STR302##
[1971] A solution of 1-(thiazol-2-yl)piperazine (6.7 g) obtained by
similar manipulation to that in Example 81(1), acetic anhydride
(5.6 ml) and sodium hydroxide (2.4 g) in water (50 ml)-ethyl
acetate (50 ml) was stirred under ice-cooling for 1 hr. The
reaction mixture was extracted with ethyl acetate and dried over
anhydrous sodium sulfate. The solvent was evaporated to give a
pale-yellow solid (6.9 g). The obtained pale-yellow solid was
crystallized from ethyl acetate-hexane (1:1, 100 ml) to give the
title compound (5.0 g) as white crystals.
[1972] .sup.1H-NMR(CDCl.sub.3).delta.: 2.14(3H,s), 3.44-3.48(2H,m),
3.55-3.62(4H,m), 3.74-3.78(2H,m), 6.62(1H,d,J=3.3 Hz),
7.21(1H,d,J=3.3 Hz)
[1973] MS(EI): 211(M.sup.+)
(2) 4-acetyl-1-(5-bromothiazol-2-yl)piperazine
[1974] ##STR303##
[1975] A solution of 4-acetyl-1-(thiazol-2-yl)piperazine (3.1 g)
and N-bromosuccinimide (2.9 g) in acetic acid (14 ml) was stirred
at room temperature for 1 hr. The reaction mixture was neutralized
with 1N aqueous sodium hydroxide solution and extracted with ethyl
acetate. The extract was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated to give a
pale-brown solid (2.9 g). The obtained pale-brown solid was
purified by silica gel column chromatography (developing solvent;
chloroform:methanol=20:1) to give the title compound (2.1 g) as a
pale-brown solid.
[1976] .sup.1H-NMR(CDCl.sub.3).delta.: 2.14(3H,s), 3.37-3.41(2H,m),
3.48-3.51(2H,m), 3.56-3.60(2H,m), 3.72-3.76(2H,m), 7.09(1H,s)
[1977] MS(EI): 291((M+1)+)
(3) 1-(5-bromothiazol-2-yl)piperazine
[1978] ##STR304##
[1979] 4-Acetyl-1-(5-bromothiazol-2-yl)piperazine (2.0 g) was
dissolved in 6N hydrochloric acid and refluxed under heating for
4.5 hr. The reaction mixture was neutralized with 1N aqueous sodium
hydroxide solution and extracted with ethyl acetate. The extract
was washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated to give a brown oil (1.5 g).
The obtained brown oil was purified by silica gel column
chromatography (developing solvent; chloroform:methanol=9:1) to
give the title compound (1.1 g) as a pale-yellow solid.
[1980] .sup.1H-NMR(CDCl.sub.3).delta.: 2.95-2.98(4H,m),
3.37-3.41(4H,m), 7.06(1H,s)
[1981] MS(EI): 248((M+1)+)
(4)
N-(4-((4-(5-bromothiazol-2-yl)piperazin-1-yl)methyl)-phenylmethyl)acet-
amide
[1982] ##STR305##
[1983] A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9
g), 1-(5-bromothiazol-2-yl)piperazine (1.1 g) and potassium
carbonate (0.9 g) in dimethylformamide (10 ml) was stirred at
70.degree. C. for 9 hr. Water (100 ml) was poured into the reaction
mixture to allow precipitation of crystals. The crystals were
collected by filtration and washed with water to give the title
compound (1.5 g) as yellow crystals,
[1984] m.p.=160-163.degree. C.
[1985] .sup.1H-NMR(CDCl.sub.3).delta.: 2.01(3H,s), 2.50-2.54(4H,m),
3.40-3.44(4H,m), 3.52(2H,s), 4.41(2H,d,J=5.3 Hz), 5.91(1H,brs),
7.05(1H,s), 7.22-7.31(4H, m)
[1986] IR(KBr): 3309, 2935, 2821, 1645, 1529 cm.sup.-1
[1987] MS(EI): 410((M+1)+)
[1988] Elemental analysis:
[1989] Calculated: C, 49.88; H, 5.17; N, 13.69.
[1990] Found: C, 49.94; H, 5.13; N, 13.54.
Example 112
Synthesis of
N-(4-((4-(5-chlorothiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetami-
de
(1) 4-acetyl-1-(5-chlorothiazol-2-yl)piperazine
[1991] ##STR306##
[1992] By similar reaction and treatment to that in Example 111(2)
using N-chlorosuccinimide instead of N-bromosuccinimide, the title
compound was obtained as pale-yellow crystals.
[1993] .sup.1H-NMR(CDCl.sub.3).delta.: 2.14(3H,s), 3.36-3.40(2H,m),
3.47-3.50(2H,m), 3.57-3.60(2H,m), 3.72-3.76(2H,m), 7.00(1H,s)
[1994] MS(EI): 245(M.sup.+)
(2) 1-(5-chlorothiazol-2-yl)piperazine
[1995] ##STR307##
[1996] By similar reaction and treatment to that in Example 111(3)
using 4-acetyl-1-(5-chlorothiazol-2-yl)piperazine instead of
4-acetyl-1-(5-bromothiazol-2-yl)piperazine, the title compound was
obtained as a pale-brown oil.
[1997] .sup.1H-NMR(CDCl.sub.3).delta.: 2.95-2.98(4H,m),
3.36-3.40(4H,m), 6.98(1H,s)
[1998] MS(EI): 203(M.sup.+)
(3)
N-(4-((4-(5-chlorothiazol-2-yl)piperazin-1-yl)methyl)-phenylmethyl)ace-
tamide
[1999] ##STR308##
[2000] By similar reaction and treatment to that in Example 111(4)
using 1-(5-chlorothiazol-2-yl)piperazine instead of
1-(5-bromothiazol-2-yl)piperazine, the title compound was obtained
as pale-brown crystals,
[2001] m.p.=142-145.degree. C. (decomposition).
[2002] .sup.1H-NMR(CDCl.sub.3).delta.: 2.02(3H,s), 2.51-2.54(4H,m),
3.39-3.43(4H,m), 3.53(2H,s), 4.41(2H,d,J=5.3 Hz), 5.88(1H,brs),
6.96(1H,s), 7.22-7.31(4H, m)
[2003] MS(EI): 364(M.sup.+)
[2004] Elemental analysis:
[2005] Calculated: C, 55.96; H, 5.80; N, 15.35.
[2006] Found: C, 55.81; H, 5.68; N, 15.38.
Example 113
Synthesis of
N-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamide
dihydrochloride 1/2 hydrate
[2007] ##STR309##
[2008] By similar reaction and treatment to that in Example 1(5)
using 1-(2-pyrimidyl)piperazine dihydrochloride instead of
phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide
instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound was obtained as a yellow amorphous solid.
[2009] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.72(3H,d,J=6.6 Hz),
1.89(3H,s), 2.75-3.15(3H,m), 3.30-3.90(3H,m), 4.27(2H,d,J=5.3 Hz),
4.45(1H,m), 4.66(2H,m), 6.76(1H,t,J=4.9 Hz), 7.33(2H,d,J=7.9 Hz),
7.63(2H,d,J=7.9 Hz), 8.44(2H,d,J=4.6 Hz), 8.47(1H,t,J=4.6 Hz).
[2010] IR(KBr): 3244, 2920, 1659, 1626 cm.sup.-1
[2011] Elemental analysis:
[2012] Calculated: C, 54.16; H, 6.70; N, 16.62.
[2013] Found: C, 53.92; H, 7.01; N, 16.39.
Example 114
Synthesis of
N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl-)phenyl)-1-methylethyl-
)acetamide
[2014] ##STR310##
[2015] By similar reaction and treatment to that in Example 1(5)
using 1-(2-pyrimidyl)piperazine dihydrochloride instead of
phenylpiperazine and
N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as a white amorphous solid.
[2016] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.53(6H,s), 1.83(3H,s), 2.25-2.50(4H,m), 3.69(4H,m),
6.58(1H,t,J=4.6 Hz), 7.21(2H,d,J=8.6 Hz), 7.26(2H,d,J=7.9 Hz),
7.97(1H,s), 7.32(2H,s,J=5.3 Hz)
[2017] IR(KBr): 3331, 2976, 1657, 1585 cm.sup.-1
[2018] MS(EI): 367(M.sup.+)
[2019] Elemental analysis:
[2020] Calculated: C, 68.63; H, 7.95; N, 19.06.
[2021] Found: C, 68.23; H, 7.68; N, 18.82.
Example 115
Synthesis of
N-(4-(1-(4-(thiazol-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamide
1/2 ethanol 1/2 hydrate
[2022] ##STR311##
[2023] By similar reaction and treatment to that in Example 1(5)
using 1-(2-thiazolyl)piperazine instead of phenylpiperazine and
N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as a brown oil.
[2024] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.87(3H,s), 2.38-2.50(4H,m), 3.37(4H,m), 3.45(1H,q,J=6.6 Hz),
4.23(2H,d,J=5.9 Hz), 6.81(2H,d,J=3.3 Hz), 7.13(2H,d,J=3.3 Hz),
7.20(2H,d,J=8.6 Hz), 7.27(2H,d,J=7.9 Hz), 8.29(1H,t,J=5.3 Hz).
[2025] IR(neat): 3284, 2816, 1653 cm.sup.-1
[2026] MS(EI): 344(M.sup.+)
[2027] Elemental analysis:
[2028] Calculated: C, 60.61; H, 7.50; N, 14.88.
[2029] Found: C, 60.61; H, 7.15; N, 14.98.
Example 116
Synthesis of
N-(1-(4-(1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methylethyl)ac-
etamide 1/4 ethanol
[2030] ##STR312##
[2031] By similar reaction and treatment to that in Example 1(5)
using 1-(2-pyridyl)piperazine instead of phenylpiperazine and
N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound was
obtained as white crystals.
[2032] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.30(3H,d,J=6.6 Hz),
1.53(6H,s), 1.83(3H,s), 2.30-2.60(4H,m), 3.37(1H,m), 3.43(4H,m),
6.60(1H,d,J=4.6,6.6 Hz), 6.75(1H,d,J=8.6 Hz), 7.22(2H,d,J=8.6 Hz),
7.27(2H,d,J=8.6 Hz), 7.49(1H,m), 7.98(1H,s), 8.09(1H,m)
[2033] IR(KBr): 3329, 3066, 1659, 1594 cm.sup.-1
[2034] MS(EI): 366(M.sup.+)
[2035] Elemental analysis:
[2036] Calculated: C, 71.49; H, 8.37; N, 14.91.
[2037] Found: C, 71.89; H, 8.07; N, 14.69.
Example 117
Synthesis of
N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropy-
l)acetamide
[2038] ##STR313##
[2039] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in
Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2)
instead of phenylpiperazine, the title compound was obtained as
white crystals, m.p.=135-136.degree. C.
[2040] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26 and 1.36(4H,s and
d,J=4.6 Hz), 1.99(3H,s), 2.48-2.53(4H,m), 3.49-3.55(6H,m),
6.12-6.17(2H,m), 6.36-6.40(1H,m), 7.10-7.31(4H,m),
7.45-7.55(1H,m).
[2041] MS(EI): 368(M.sup.+)
[2042] Elemental analysis:
[2043] Calculated: C, 68.46; H, 6.84; N, 15.21.
[2044] Found: C, 68.51; H, 6.92; N, 15.18.
Example 118
Synthesis of
N-(1-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl)acetam-
ide
[2045] ##STR314##
[2046] By similar reaction and treatment to that in Example 1(5)
using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in
Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide
and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title
compound was obtained as white crystals, m.p.=145-147.degree.
C.
[2047] .sup.1H-NMR(CDCl.sub.3).delta.: 1.26 and 1.36(4H,s and d,
J=5.3 Hz), 2.00(3H,s), 2.51-2.56(4H,m), 3.50-3.56(6H,m),
6.13(1H,br), 6.58-6.64(1H,m), 7.10-7.32(4H,m), 7.42-7.49(1H,m),
8.16-8.19(1H,m).
[2048] MS(EI): 350(M.sup.+)
[2049] Elemental analysis:
[2050] Calculated: C, 71.97; H, 7.48; N, 15.99.
[2051] Found: C, 72.10; H, 7.52; N, 15.94.
Example 119
Synthesis of
(S)-N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-
acetamide
(1) Synthesis of (S)-N-(1-phenylethyl)acetamide
[2052] ##STR315##
[2053] To a solution of (S)-(-)-1-phenylethylamine (121 g) and
triethylamine (168 ml) in dichloroethane (1200 ml) was added
dropwise acetyl chloride (78.2 ml) over 1 hr under ice-cooling and
the mixture was stirred at room temperature for 2 hr. The reaction
mixture was poured into water (1000 ml) and the organic layer was
separated. The organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give the title compound (143.4 g) as pale-yellow crystals,
m.p.=99-101.degree. C.
[2054] .sup.1H-NMR(CDCl.sub.3).delta.: 1.44(3H,d,J=6.6 Hz),
1.92(3H,s), 5.08(1H,dq,J=7.3 Hz), 6.37(1H,br), 7.20-7.34(5H,m).
[2055] MS(EI): 163(M.sup.+)
(2) Synthesis of (S)-N-(1-(4-acetylphenyl)ethyl)acetamide
[2056] ##STR316##
[2057] To a solution of (S)-1-phenylethylacetamide (143.4 g) and
acetyl chloride (93.7 ml) in dichloroethane (700 ml) was added
aluminum chloride (257.7 g) over 30 min under ice-cooling. The
mixture was stirred at 10.degree. C. for 30 min and at 60.degree.
C. for 3 hr. The reaction mixture was poured into ice water (1500
ml) and the organic layer was separated. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography (developing solvent;
ethyl acetate) and recrystallized from ethyl acetate-hexane to give
the title compound (76.4 g) as white crystals, m.p.=125-128.degree.
C.
[2058] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=6.6 Hz),
2.00(3H,s), 2.58(3H,s), 5.15(1H,dq,J=7.3 Hz), 5.98(1H,br.d,J=6.6
Hz), 7.40(2H,d,J=8.6 Hz), 7.92(2H,d,J=7.9 Hz).
[2059] MS(EI): 205(M.sup.+)
(3) Synthesis of (S)-4-(1-acetamidoethyl)benzoic acid
[2060] ##STR317##
[2061] By similar reaction and treatment to that in Example 95(1)
using (S)-N-(1-(4-acetylphenyl)ethyl)acetamide instead of
N-(1-(4-acetylphenyl)-1-methylethyl) acetamide, the title compound
was obtained as yellow crystals, m.p.=186-190.degree. C.
[2062] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.35(3H,d,J=7.3 Hz),
1.86(3H,s), 4.96(1H,dq,J=7.3 Hz), 7.42(2H,d,J=8.6 Hz),
7.91(2H,d,J=7.9 Hz), 8.36(1H,d,J=7.9 Hz), 12.87(1H,br.s).
[2063] MS(EI): 207(M.sup.+)
(4) Synthesis of methyl (S)-4-(1-acetamidoethyl)benzoate
[2064] ##STR318##
[2065] By similar reaction and treatment to that in Example 95(2)
using (S)-4-(1-acetamidoethyl)benzoic acid instead of
4-(1-acetamido-1-methylethyl)benzoic acid, the title compound was
obtained as white crystals.
[2066] m.p.=125-127.degree. C.
[2067] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=7.3 Hz),
2.00(3H,s), 3.91(3H,s), 5.16(1H,dq,J=7.3 Hz), 5.85-5.87(1H,br),
7.36-7.39(2H,m), 7.98-8.01(2H,m).
[2068] MS(EI): 221(M.sup.+)
(5) Synthesis of
(S)-N-(1-(4-hydroxymethylphenyl)ethyl)acetamide
[2069] ##STR319##
[2070] By similar reaction and treatment to that in Example 1(3)
using methyl (S)-4-(1-acetamidoethyl)benzoate instead of methyl
4-acetamidomethylbenzoate, the title compound was obtained as white
crystals, m.p.=103-104.degree. C.
[2071] .sup.1H-NMR(CDCl.sub.3).delta.: 1.45(3H,d,J=7.3 Hz),
1.93(3H,s), 2.53(1H,br.s), 4.63(2H,s), 5.07(1H,dq,J=7.3 Hz),
6.02(1H,br.d,J=7.3 Hz), 7.24-7.32(4H,m).
[2072] MS(EI): 193(M.sup.+)
(6) Synthesis of (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide
[2073] ##STR320##
[2074] By similar reaction and treatment to that in Example 95(4)
using (S)-N-(1-(4-hydroxymethylphenyl)ethyl)acetamide instead of
N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide, the title
compound was obtained as white crystals, m.p.=114-116.degree.
C.
[2075] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=7.3 Hz),
1.98(3H,s), 4.57(2H,s), 5.12(1H,dq,J=7.3 Hz), 5.70(1H,br),
7.29-7.38(4H,m).
[2076] MS(EI): 211(M.sup.+)
[2077] [.alpha.].sub.D.sup.25 -145.0.degree.
(c=1.00,CHCl.sub.3)
(7) Synthesis of
(S)-N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-
acetamide
[2078] ##STR321##
[2079] By similar reaction and treatment to that in Example 1(5)
using (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2)
instead of phenylpiperazine, the title compound was obtained as a
pale-yellow oil.
[2080] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=6.6 Hz),
1.97(3H,s), 2.49-2.53(4H,m), 3.50-3.54(6H,m), 5.12(1H,dq,J=7.3 Hz),
5.84-5.87(1H,br), 6.12-6.16(1H,m), 6.36-6.40(1H,m),
7.25-7.32(4H,m), 7.46-7.55(1H,m).
[2081] MS(EI): 356(M.sup.+)
Example 120
Synthesis of
(R)-N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-
acetamide
(1) Synthesis of (R)-N-(1-phenylethyl)acetamide
[2082] ##STR322##
[2083] By similar reaction and treatment to that in Example 119(1)
using (R)-(+)-1-phenylethylamine instead of
(S)-(-)-1-phenylethylamine, the title compound was obtained as
white crystals.
[2084] m.p.=100-102.degree. C.
[2085] .sup.1H-NMR(CDCl.sub.3).delta.: 1.47(3H,d,J=7.3 Hz),
1.96(3H,s), 5.11(1H,dq,J=7.3 Hz), 5.95(1H,br), 7.22-7.36(5H,m).
[2086] MS(EI): 163(M.sup.+)
(2) Synthesis of (R)-N-(1-(4-acetylphenyl)ethyl)acetamide
[2087] ##STR323##
[2088] By similar reaction and treatment to that in Example 119(2)
using (R)-1-phenylethylacetamide instead of
(S)-1-phenylethylacetamide, the title compound was obtained as
white crystals, m.p.=125-127.degree. C.
[2089] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=6.6 Hz),
1.99(3H,s), 2.58(3H,s), 5.14(1H,dq,J=7.3 Hz), 6.17(1H,br.d,J=6.6
Hz), 7.39(2H,d,J=7.9 Hz), 7.91(2H,d,J=7.9 Hz).
[2090] MS(EI): 205(M.sup.+)
(3) Synthesis of (R)-4-(1-acetamidoethyl)benzoic acid
[2091] ##STR324##
[2092] By similar reaction and treatment to that in Example 95(1)
using (R)-N-(1-(4-acetylphenyl)ethyl)acetamide instead of
N-(1-(4-acetylphenyl)-1-methylethyl) acetamide, the title compound
was obtained as pale-yellow crystals, m.p.=189-192.degree. C.
[2093] .sup.1H-NMR(DMSO-d.sub.6).delta.: 1.35(3H,d,J=7.3 Hz),
1.86(3H,s), 4.96(1H,dq,J=7.3 Hz), 7.42(2H,d,J=8.6 Hz),
7.91(2H,d,J=7.9 Hz), 8.36(1H,d,J=7.9 Hz), 12.85(1H,br.s).
[2094] MS(EI): 207(M.sup.+)
(4) Synthesis of methyl (R)-4-(1-acetamidoethyl)benzoate
[2095] ##STR325##
[2096] By similar reaction and treatment to that in Example 95(2)
using (R)-4-(1-acetamidoethyl)benzoic acid instead of
4-(1-acetamido-1-methylethyl)benzoic acid, the title compound was
obtained as white crystals.
[2097] m.p.=126-128.degree. C.
[2098] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=7.3
Hz),.2.00(3H,s), 3.91(3H,s), 5.16(1H,dq,J=7.3 Hz),
5.85-5.87(1H,br), 7.36-7.39(2H,m), 7.98-8.01(2H,m).
[2099] MS(EI): 221(M.sup.+)
(5) Synthesis of
(R)-N-(1-(4-hydroxymethylphenyl)ethyl)acetamide
[2100] ##STR326##
[2101] By similar reaction and treatment to that in Example 1(3)
using methyl (R)-4-(1-acetamidoethyl)benzoate instead of methyl
4-acetamidomethylbenzoate, the title compound was obtained as white
crystals, m.p.=102-104.degree. C.
[2102] .sup.1H-NMR(CDCl.sub.3).delta.: 1.44(3H,d,J=6.6 Hz),
1.92(3H,s), 2.67(1H,br.s), 4.62(2H,s), 5.06(1H,dg,J=7.3 Hz),
6.09(1H,br.d,J=7.3 Hz), 7.23-7.31(4H,m).
[2103] MS(EI): 193(M.sup.+)
(6) Synthesis of (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide
[2104] ##STR327##
[2105] By similar reaction and treatment to that in Example 95(4)
using (R)-N-(1-(4-hydroxymethylphenyl)ethyl)acetamide instead of
N-(1-(4-hydroxymethylphenyl)-1-methylethyl) acetamide, the title
compound was obtained as white crystals, m.p.=113-114.degree.
C.
[2106] .sup.1H-NMR(CDCl.sub.3).delta.: 1.46(3H,d,J=7.3 Hz),
1.96(3H,s), 4.56(2H,s), 5.11(1H,dq,J=7.3 Hz), 5.88(1H,br),
7.28-7.37(4H,m).
[2107] MS(EI): 211(M.sup.+)
[2108] [.alpha.].sub.D.sup.25 145.8.degree. (c=1.00
,CHCl.sub.3)
(7) Synthesis of
(R)-N-(1-(4-((4-(6-fluoropyridin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-
acetamide
[2109] ##STR328##
[2110] By similar reaction and treatment to that in Example 1(5)
using (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2)
instead of phenylpiperazine, the title compound was obtained as a
pale-yellow oil.
[2111] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=6.6 Hz),
1.97(3H,s), 2.49-2.53(4H,m), 3.50-3.54(6H,m), 5.12(1H,dq,J=7.3 Hz),
5.90-5.93(1H,br), 6.12-6.16(1H,m), 6.36-6.40(1H,m),
7.25-7.32(4H,m), 7.46-7.55(1H,m).
[2112] MS(EI): 356(M.sup.+)
Example 121
Synthesis of
(S)-N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetam-
ide
[2113] ##STR329##
[2114] By similar reaction and treatment to that in Example 1(5)
using (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(4-fluorophenyl)piperazine-dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=114-115.degree. C.
[2115] .sup.1 H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=6.6 Hz),
1.98(3H,s), 2.57-2.61(4H,m), 3.09-3.12(4H,m), 3.54(2H,s),
5.12(1H,dq,J=7.3 Hz), 5.73(1H,br.d,J=7.3 Hz), 6.83-6.98(4H,m),
7.25-7.33(4H,m).
[2116] MS(EI): 355(M.sup.+)
[2117] Elemental analysis:
[2118] Calculated: C, 70.96; H, 7.37; N, 11.82.
[2119] Found: C, 70.97; H, 7.37; N, 11.76.
[2120] [.alpha.].sub.D.sup.25 -87.0.degree. (c=1.00,CHCl.sub.3)
Example 122
Synthesis of
(R)-N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)acetam-
ide
[2121] ##STR330##
[2122] By similar reaction and treatment to that in Example 1(5)
using (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide and
1-(4-fluorophenyl)piperazine dihydrochloride instead of
phenylpiperazine, the title compound was obtained as white
crystals, m.p.=114-115.degree. C.
[2123] .sup.1H-NMR(CDCl.sub.3).delta.: 1.48(3H,d,J=7.3 Hz),
1.98(3H,s), 2.57-2.61(4H,m), 3.09-3.12(4H,m), 3.54(2H,s),
5.12(1H,dq,J=7.3 Hz), 5.72(1H,br.d,J=7.3 Hz), 6.83-6.98(4H,m),
7.25-7.33(4H,m).
[2124] MS(EI): 355(M.sup.+)
[2125] Elemental analysis:
[2126] Calculated: C, 70.96; H, 7.37; N, 11.82.
[2127] Found: C, 71.03; H, 7.35; N, 11.79.
[2128] [.alpha.].sub.D.sup.25 87.40 (c=1.00,CHCl.sub.3)
Example 123
Synthesis of
N-(1-(4-(1-(4-(6-fluoropyridin-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methyl-
ethyl)acetamide
[2129] ##STR331##
[2130] By similar reaction and treatment to that in Example 1(5)
using 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2)
instead of phenylpiperazine and
N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound can be
obtained.
Example 124
Synthesis of
N-(4-(1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetamide
[2131] ##STR332##
[2132] By similar reaction and treatment to that in Example 1(5)
using 1-(2-pyridyl)piperazine instead of phenylpiperazine and
N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of
N-(4-chloromethylphenylmethyl)acetamide, the title compound can be
obtained.
Example 125
Synthesis of
N-(1-(4-(1-(4-(6-fluoropyridin-2-yl)piperazin-1-yl)ethyl)phenyl)methyl)ac-
etamide
[2133] ##STR333##
[2134] By similar reaction and treatment to that in Example 1(5)
using 1-(6-fluoropyridin-2-yl)piperazine instead of
phenylpiperazine and N-((4-(1-chloroethyl)phenyl)methyl)acetamide
instead of N-(4-chloromethylphenylmethyl)acetamide, the title
compound can be obtained.
Example 126
Synthesis of
(S)-N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamid-
e
(1) Synthesis of (S)-4-(1-aminoethyl)benzoic acid
[2135] ##STR334##
[2136] By similar reaction and treatment to-that in Example 68(2)
using (S)-4-(1-acetamidoethyl)benzoic acid obtained in Example
119(3) instead of 2-(4-methylphenyl)-2-methylpropionitrile, the
title compound can be obtained.
(2) Synthesis of methyl (S)-4-(1-aminoethyl)benzoate
[2137] ##STR335##
[2138] By similar reaction and treatment to that in Example 95(2)
using (S)-4-(1-aminoethyl)benzoic acid instead of
4-(1-acetamido-1-methylethyl)benzoic acid, the title compound can
be obtained.
(3) Synthesis of methyl
(S)-4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)benzoate
[2139] ##STR336##
[2140] By similar reaction and treatment to that in Example 68(13)
using methyl (s)-4-(1-aminoethyl)benzoate instead of
N-(4-(1-amino-1-methylethyl)phenylmethyl)acetamide, the title
compound can be obtained.
(4) Synthesis of
(S)-4-(1-(4-hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2141] ##STR337##
[2142] By similar reaction and treatment to that in Example 1(3)
using methyl
(S)-4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)benzoate instead
of methyl 4-acetamidomethylbenzoate, the title compound can be
obtained.
(5) Synthesis of
(S)-4-(1-(4-chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2143] ##STR338##
[2144] By similar reaction and treatment to that in Example 95(4)
using
(S)-4-(1-(4-hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide,
the title compound can be obtained.
(6) Synthesis of
(S)-4-(1-(4-azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2145] ##STR339##
[2146] By similar reaction and treatment to that in Example 59(1)
using
(S)-4-(1-(4-chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of 4-chloromethylacetophenone, the title compound can be
obtained.
(7) Synthesis of
(S)-4-(1-(4-aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2147] ##STR340##
[2148] By similar reaction and treatment to that in Example 68(5)
using
(S)-4-(1-(4-azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of methyl 2-(4-azidomethylphenyl)-2-methylpropionate, the
title compound can be obtained.
(8) Synthesis of
(S)-N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamid-
e
[2149] ##STR341##
[2150] By similar reaction and treatment to that in Example 68(6)
using
(S)-4-(1-(4-aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of methyl 2-(4-aminomethylphenyl)-2-methylpropionate, the
title compound can be obtained.
Example 127
Synthesis of
(R)-N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamid-
e
(1) Synthesis of (R)-4-(1-aminoethyl)benzoic acid
[2151] ##STR342##
[2152] By similar reaction and treatment to that in Example 68(2)
using (R)-4-(1-acetamideethyl)benzoic acid obtained in Example
120(3) instead of 2-(4-methylphenyl)-2-methylpropionitrile, the
title compound can be obtained.
(2) Synthesis of methyl (R)-4-(1-aminoethyl)benzoate
[2153] ##STR343##
[2154] By similar reaction and treatment to that in Example 95(2)
using (R)-4-(1-aminoethyl)benzoic acid instead of
4-(1-acetamido-1-methylethyl)benzoic acid, the title compound can
be obtained.
(3) Synthesis of methyl
(R)-4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)benzoate
[2155] ##STR344##
[2156] By similar reaction and treatment to that in Example 68(13)
using methyl (R)-4-(1-aminoethyl)benzoate instead of
N-(4-(1-amino-1-methylethyl)phenylmethyl)acetamide, the title
compound can be obtained.
(4) Synthesis of
(R)-4-(1-(4-hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2157] ##STR345##
[2158] By similar reaction and treatment to that in Example 1(3)
using methyl
(R)-4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)benzoate instead
of methyl 4-acetamidomethylbenzoate, the title compound can be
obtained.
(5) Synthesis of
(R)-4-(1-(4-chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2159] ##STR346##
[2160] By similar reaction and treatment to that in Example 95(4)
using
(R)-4-(1-(4-hydroxymethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide,
the title compound can be obtained.
(6) Synthesis of
(R)-4-(1-(4-azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2161] ##STR347##
[2162] By similar reaction and treatment to that in Example 59(1)
using
(R)-4-(1-(4-chloromethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of 4-chloromethylacetophenone, the title compound can be
obtained.
(7) Synthesis of
(R)-4-(1-(4-aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
[2163] ##STR348##
[2164] By similar reaction and treatment to that in Example 68(5)
using
(R)-4-(1-(4-azidomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of methyl 2-(4-azidomethylphenyl)-2-methylpropionate, the
title compound can be obtained.
(8) Synthesis of
(R)-N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)acetamid-
e
[2165] ##STR349##
[2166] By similar reaction and treatment to that in Example 68(6)
using
(R)-4-(1-(4-aminomethylphenyl)ethyl)-1-(4-fluorophenyl)piperazine
instead of methyl 2-(4-aminomethylphenyl)-2-methylpropionate, the
title compound can be obtained.
[2167] In the same manner as in the above Examples, the following
compounds can be produced.
Example 128
N-(4-((4-(1-methylimidazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetami-
de
[2168] ##STR350##
Example 129
N-(1-(4-((4-(1-methylimidazol-2-yl)piperazin-1-yl)methyl)phenyl-1-methylet-
hyl)acetamide
[2169] ##STR351##
Example 130
N-(1-(4-((4-(1-methylimidazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)acet-
amide
[2170] ##STR352##
Example 131
N-(4-(1-(4-(1-methylimidazol-2-yl)piperazin-1-yl)ethyl)phenylmethyl)acetam-
ide
[2171] ##STR353##
Example 132
N-(1-(4-(1-(4-(1-methylimidazol-2-yl)piperazin-1-yl)ethyl)phenyl)-1-methyl-
ethyl)acetamide
[2172] ##STR354##
Example 133
N-(1-(4-((4-(1-methylimidazol-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropy-
l)acetamide
[2173] ##STR355##
Example 134
N-(4-((4-(5-methylthiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamid-
e
[2174] ##STR356##
Example 135
N-(4-((4-(4-methylthiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamid-
e
[2175] ##STR357##
Example 136
N-(4-((4-(4,5-dimethylthiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acet-
amide
[2176] ##STR358##
Example 137
N-(1-(4-((4-(5-methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)aceta-
mide
[2177] ##STR359##
Example 138
N-(1-(4-((4-(5-methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylet-
hyl)acetamide
[2178] ##STR360##
Example 139
N-(1-(4-((4-(4-methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)-1-methylet-
hyl)acetamide
[2179] ##STR361##
Example 140
N-(1-(4-((4-(4,5-dimethylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)-1-meth-
ylethyl)acetamide
[2180] ##STR362##
Example 141
N-(1-(4-((4-(5-methylthiazol-2-yl)piperazin-1-yl)methyl)phenyl)cyclopropyl-
)acetamide
[2181] ##STR363##
[2182] The action and effect of the present invention is explained
in more detail in the following by Experimental Examples.
Experimental Example 1
Effect on TNF-.alpha., IL-10 Production in Mice (in vivo)
[2183] To female BALB/c mice (purchased from Japan Charles River)
was intraperitoneally administered LPS (lipopolysaccharide: 500
.mu.g/kg, derived from Escherichia coli 055:B5, manufactured by
Difco). Since the TNF-.alpha. concentration in serum reaches a peak
at 90 min after LPS administration, the TNF-.alpha. concentration
in the serum at this point was measured using FACTOR TEST
mTNF-.alpha. (manufactured by Genzyme) and the IL-10 concentration
at the same point of time was also measured using Murine IL-10
ELISA Kit (manufactured by Endogen). The test compound was orally
administered at 30 min before LPS administration, and the
TNF-.alpha. concentration and IL-10 concentration were measured in
the same manner. The results are shown in Table 1. The effect of
the test compound on the TNF-.alpha. production and IL-10
production was calculated by the following formula as the ratio
relative to the test compound non-administration group.
TABLE-US-00001 TABLE 1 Concentration .times. .times. on .times.
.times. administration .times. .times. of .times. .times. test
.times. .times. compound Concentration .times. .times. without
.times. .times. administration .times. .times. of .times. .times.
test .times. .times. compound .times. 100 .times. .times. ( % )
##EQU1## Example TNF-.alpha. production (%) IL-10 production (%) 20
17 770 48 12 888 51 16 533 58 19 499 72 20 510 81 11 1035 82 11
742
Experimental Example 2
Effect on TNF-.alpha., IL-10 Production by Human Monocyte (in
vitro)
[2184] Blood is taken from healthy volunteers and monocytes are
separated using a lymphocyte separation medium (Flow Laboratories).
The cells are suspended in RPMI-1640 medium supplemented with 10%
FCS (fetal calf serum: manufactured by Gibco). Monocytes
(5.times.10.sup.6/ml) are stimulated using LPS (1 .mu.g/ml) and PMA
(phorbol 12-myristate 13-acetate, 10 ng/ml, manufactured by Sigma)
and incubated with test compounds having various concentrations at
37.degree. C. under humid conditions containing 5% CO.sub.2. After
incubation for 24 hr, the TNF-.alpha. concentrations in the
supernatant are measured using Cytoscreen human TNF-.alpha. ELISA
Kit (manufactured by Biosource).
Experimental Example 3
Effect on Endotoxin Shock (Life and Death)
[2185] To female BALB/c mice (purchased from Japan Charles River)
was intraperitoneally administered LPS (E. coli 055 B5, 10 mg/kg).
The test compound was orally administered at 30 min before LPS
administration. The survival of the mice was monitored for 3 days
from the next day. As the test compound, the compound of Example 20
was used. As a result, all mice in the test compound
non-administration group (9 mice per group) died but 8 mice in the
test compound administration group (9 mice per group) survived,
showing markedly significant effect.
Experimental Example 4
Therapeutic Effect on Adjuvant Arthritis
[2186] Killed Mycobacterium tuberculosis was inoculated to male
Lewis rats (purchased from Seac Yoshitomi, Ltd.) at the tail base
to cause adjuvant arthritis. For 6 days from day 15 to day 20 when
arthritis was developed, the test compound was orally administered
at 30 mg/kg. The volume of the limb was measured with the lapse of
time from day 15. As the test compound, the compound of Example 20
was used. The changes in the volume of the limb from day 15 to day
20 were measured. As a result, the volume of the limb increased by
0.344 ml in the test compound non-administration rats and decreased
by 0.186 ml in the test compound administered rats. It was
clarified that the inventive compound markedly inhibited the onset
of adjuvant arthritis.
Experimental Example 5
Therapeutic Effect on Collagen Arthritis
[2187] Bovine-derived type II collagen (purchased from Koragen
gijutsu kenkyukai) is intradermally injected twice to DBA/lJ mice
(purchased from Seac Yoshitomi, Ltd.) at the tail base, together
with complete Freund's adjuvant H37Rv (purchased from Wako Pure
Chemical Industries, Ltd.) at day 0 and day 21. From day 22 to day
33 after the injection, the test compound is orally administered.
The swelling of the joints of the four limbs is observed and scored
in 0 (no change) -3 (edema of 5 fingers). The joint swelling score
of each mouse is the total scores of the four limbs.
Experimental Example 6
Affinity for Dopamine D.sub.2 Receptor; .sup.3H-Spiperone
Binding
[2188] Preparation of crude synaptic membranes and a binding test
were performed according to the method of I. Creese et al.
[European Journal of Pharmacology, vol. 46, p.377 (1977)]. The
crude synaptic membranes were prepared from freeze preserved rat
corpus striatum, and the membrane specimen and .sup.3H-spiperone
were reacted in the presence of the test compound at 37.degree. C.
for 20 min. After the completion of the reaction, the reaction
mixtures were immediately filtered by suction on Whatman GF/B
filter.TM. and the radioactivity on the filter was measured by Top
Count. Every reaction was carried out in the presence of 100 nM
ketanserin. The non-specific binding was determined in the presence
of 100 .mu.M(.+-.)-sulpiride. The 50% inhibition concentration
(IC.sub.50) of the test compound was calculated by two-point
interpolation, from which inhibitory constant (Ki value) was
determined.
Experimental Example 7
Affinity for Serotonin 2 Receptor; .sup.3H-Ketanserin Binding
[2189] Preparation of crude synaptic membranes and a binding test
were performed according to the method of Leysen J. E. et al.
[Molecular Pharmacology, vol. 21, p. 301 (1982)]. The crude synapse
membranes were prepared from freeze preserved rat cerebral cortex,
and the membrane specimen and .sup.3H-ketanserin were incubated in
the presence of the test compounds at 37.degree. C. for 20 min.
After the completion of the reaction, the reaction mixture was
immediately filtered by suction on Whatman GF/B filter.TM. and the
radioactivity on the filter was measured by Top Count. The
non-specific binding was determined in the presence of 10 .mu.M
ritanserin. The 50% inhibition concentration (IC.sub.50) of the
test compound was calculated by two-point interpolation, from which
inhibitory constant (Ki value) was determined.
Experimental Example 8
Affinity for Adrenalin .alpha.1 Receptor;.sup.3H-Prazosin
Binding
[2190] Preparation of crude synaptic membranes and a binding test
were performed according to European Journal of Pharmacology, vol.
55, p. 323 (1979). The crude synaptic membranes were prepared from
freeze preserved rat cerebral tissue, and the membrane specimen and
.sup.3H-prazosin were incubated in the presence of the test
compound at 25.degree. C. for 30 min. After the completion of the
reaction, the reaction-mixture was immediately filtered by suction
on Whatman GF/B filter.TM. and the radioactivity on the filter was
measured by Top Count. The non-specific binding was determined in
the presence of 100 .mu.M WB4101. The 50% inhibition concentration
(IC.sub.50) of the test compound was calculated by two-point
interpolation, from which inhibitory constant (Ki value) was
determined.
Experimental Example 9
Affinity for Serotonin 1A Receptor; .sup.3H-8-OH-DPAT Binding
[2191] The specific serotonin 1A (5-HTA) receptor binding test was
performed according to the method described in J. Neurochem., 44,
1685 (1985). The crude synaptosome fractions were prepared from the
hippocampus of 9 to 10-week-old Wistar rats and suspended in 50 mM
Tris-hydrochloric acid buffer (pH 7.4) containing 1 mM manganese
chloride and used for the test. To the synaptosome suspension were
added several concentrations of the test compounds and
tritium-labeled 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT: final
concentration 1 nM) and the mixture was reacted at 37.degree. C.
for 12 min. After the completion of the reaction, the reaction
mixture was immediately filtered by suction on Whatman GF/B filter
(trademark), the filter was washed with 50 mM Tris-hydrochloric
acid buffer (pH 7.4) and the radioactivity on the filter was
measured by Top Count. The non-specific binding was determined in
the presence of 1 FM WAY-100635. The 50% inhibition concentration
(IC.sub.50) of the test compound was calculated by two-point
interpolation, from which inhibitory constant (Ki value) was
determined.
[2192] The results of Experimental Examples 6-9 are shown in Table
2. In the Table, * shows IC.sub.50 value. TABLE-US-00002 TABLE 2
Example D.sub.2 5-HT.sub.1A 5-HT.sub.2 .alpha.1 20 >1000*
>1000* >1000* >1000* 48 >1000* >1000* >1000*
>1000* 51 >1000* >1000* >1000* >1000* 58 >1000*
>1000* >1000* >1000* 72 >1000* >1000* >1000*
>1000* 81 >1000* >1000* >1000* >1000*
Experimental Example 10
Toxicity Test
[2193] In a single administration toxicity test, the test compound
is administered to male and female SD rats (3 rats/group) and
beagle (1 dog/group) and the toxicity by single administration is
evaluated using the incidence of death, general condition and body
weight as indices. In a repeat administration toxicity test, the
test compound is repeatedly administered to male and female SD rats
(6 rats/group) and male and female beagles (2 dogs/group) for 2
weeks and the toxicity by repeat administration is evaluated using
the general condition, body weight, intake, hematological test,
blood biochemiocal test, organ weight and autopsy (inclusive of
histopathological test) as indices.
Experimental Example 11
Evaluation of Bioavailability in Rats
[2194] The test compound is intravenously and orally administered
to SD female rats (5 rats per group). The blood is taken with the
lapse of time and the drug concentration in plasma is measured by
High Performance Liquid Chromatography. The bioavailability (BA) is
calculated by the following formula. AUC .times. .times. on .times.
.times. oral administration AUC .times. .times. on .times. .times.
intravenous administration .times. dose .times. .times. of .times.
.times. intravenous administration dose .times. .times. of .times.
.times. oral administration .times. 100 .times. ( % ) ##EQU2## AUC
.times. : .times. .times. area .times. .times. under .times.
.times. plasma .times. .times. concentration .times. - .times. time
.times. .times. curve ##EQU2.2##
INDUSTRIAL APPLICABILITY
[2195] As is evident from the above-mentioned pharmacological
experiment and various experiments, since the compound (I) of the
present invention and a pharmaceutically acceptable salt thereof
are free of or show only strikingly reduced expression of an effect
on the central nervous system, they have highly safe and superior
TNF-.alpha. production inhibitory effect and/or IL-10 production
promoting effect, and are useful for the prophylaxis or treatment
of various diseases caused by abnormal TNF-.alpha. production,
diseases curable with IL-10, such as chronic inflammatory diseases,
acute inflammatory diseases, inflammatory diseases due to
infection, autoimmune diseases, allergic diseases, and TNF-.alpha.
mediated diseases.
[2196] This application is based on application Nos. 280880/1997
and 261100/1998 filed in Japan, the contents of which are
incorporated hereinto by reference.
* * * * *