U.S. patent application number 09/899942 was filed with the patent office on 2002-01-24 for piperazine derivatives as tachykinin antagonists.
This patent application is currently assigned to FUJISAWA PHARMACEUTICAL CO., LTD.. Invention is credited to Igari, Norihiro, Konishi, Nobukiyo, Manabe, Takashi, Masaaki, Matsuo, Matsuda, Hiroshi, Shigenaga, Shinji, Take, Kazuhiko, Terasaka, Tadashi.
Application Number | 20020010182 09/899942 |
Document ID | / |
Family ID | 27157927 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010182 |
Kind Code |
A1 |
Masaaki, Matsuo ; et
al. |
January 24, 2002 |
Piperazine derivatives as tachykinin antagonists
Abstract
This invention relates to piperazine derivatives of the formula:
1 wherein each symbol is as defined in the description, and its
pharmaceutically acceptable salt, to processes for preparation
thereof, to pharmaceutical composition comprising the same, and to
a use of the same for treating or Tachykinin-mediated diseases in
human being or animals.
Inventors: |
Masaaki, Matsuo; (Osaka,
JP) ; Manabe, Takashi; (Hyogo, JP) ; Konishi,
Nobukiyo; (Kyoto, JP) ; Take, Kazuhiko;
(Osaka, JP) ; Igari, Norihiro; (Hyogo, JP)
; Shigenaga, Shinji; (Hyogo, JP) ; Matsuda,
Hiroshi; (Osaka, JP) ; Terasaka, Tadashi;
(Osaka, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
FUJISAWA PHARMACEUTICAL CO.,
LTD.
Osaka
JP
|
Family ID: |
27157927 |
Appl. No.: |
09/899942 |
Filed: |
July 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09899942 |
Jul 9, 2001 |
|
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09545614 |
Apr 6, 2000 |
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Current U.S.
Class: |
514/253.01 ;
514/254.05; 514/255.01; 544/360; 544/366; 544/385 |
Current CPC
Class: |
A61P 1/08 20180101; A61P
25/00 20180101; C07D 241/04 20130101; C07D 401/14 20130101; A61P
43/00 20180101; A61P 1/00 20180101; C07D 403/04 20130101; C07D
401/12 20130101; C07D 403/06 20130101 |
Class at
Publication: |
514/253.01 ;
514/254.05; 514/255.01; 544/360; 544/366; 544/385 |
International
Class: |
A61K 031/496; A61K
031/495; C07D 43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 1995 |
GB |
9525841.4 |
May 16, 1996 |
AU |
PN 9891 |
Sep 30, 1996 |
AU |
PO 2683 |
Claims
1. A compound of the formula 16wherein Y is bond or lower alkylene,
R.sup.1 is aryl which may have suitable substituent(s), R.sup.2 is
aryl or indolyl each of which may have suitable substituent(s),
R.sup.3 is hydrogen or lower alkyl, R.sup.4 is
chloro(lower)alkenyl; chloro(lower)alkynyl;
pyridyl(lower)alkylamino(lower)alkyl;
pyridyl(lower)alkylamino(lower)alkenyl; N-(lower
alkyl)-N-[pyridyl(lower)- alkyl]amino (lower)alkyl;
triazolylamino(lower)alkyl; lower
alkoxy(lower)alkylamino(lower)alkyl;
bis[(lower)alkoxy(lower)alkyl]amino(- lower)alkyl; N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower)alkyl;
hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;
phenyl(lower)alkyl which may have lower alkanoyl, amino, lower
alkanoylamino, di(lower)alkylaminocarbonyl or nitro; lower
alkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;
benzoyl(lower)alkyl which has lower alkyl, chlorine or
di(lower)alkylamino; benzoyl(lower)alkyl which has halogen and
lower alkyl; dihalobenzoyl(lower)alkyl;
di(lower)alkylbenzoyl(lower)alkyl; 3-fluorobenzoyl(lower)alkyl;
3-(4-fluorobenzoyl)propyl;
4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;
piperazinylcarbonyl(lower)alky- l which has cyclopentyl or
halophenyl; (2-pyridyl)(lower)alkyl; (3-pyridyl)propyl;
(3-pyridyl)(lower)alkynyl; imidazolyl(lower)alkyl which may have
lower alkyl; pyrazolyl(lower)alkyl which may have lower alkyl;
thiomorpholinylcarbonyl(lower)alkyl; (3-azabicyclo[3.2.2]non-3-yl)-
carbonyl(lower)alkyl; or thienylcarbonyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)al- kynyl,
1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,
4,5,6,7-tetrahydrothieno- [3,2-c]pyridinyl(lower)alkyl, saturated
heterocyclic(lower)alkyl, saturated heterocyclic(lower)alkenyl,
saturated heterocyclic(lower)alkyny- l, saturated
heterocyclicamino(lower)alkyl, saturated
heterocyclicamino(lower)alkenyl or saturated
heterocyclicamino(lower)alky- nyl, each of which may have suitable
substituent(s), and a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, in which Y is lower alkylene, R.sup.1
is C.sub.6-C.sub.10 aryl which may have 1 to 3 mono(or di or
tri)halo(lower)alkyl, R.sup.2 is C.sub.6-C.sub.10 aryl or indolyl,
each of which may have 1 to 3 suitable substituent(s) selected from
the group consisting of lower alkyl, lower alkoxy, mono(or di or
tri)halo(lower)alkyl and halogen, R.sup.3 is hydrogen, and R.sup.4
is chloro(lower)alkenyl; chloro(lower)alkynyl;
pyridyl(lower)alkylamino(lowe- r)alkyl;
pyridyl(lower)alkylamino(lower)alkenyl; N-(lower
alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;
triazolylamino(lower)al- kyl; lower
alkoxy(lower)alkylamino(lower)alkyl; bis[(lower)alkoxy(lower)al-
kyl]amino(lower)alkyl; N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl;
hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;
phenyl(lower)alkyl which may have lower alkanoyl, amino, lower
alkanoylamino, di(lower)alkylaminocarbonyl or nitro; lower
alkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;
benzoyl(lower)alkyl which has lower alkyl, chlorine or
di(lower)alkylamino; benzoyl(lower)alkyl which has halogen and
lower alkyl; dihalobenzoyl(lower)alkyl;
di(lower)alkylbenzoyl(lower)alkyl; 3-fluorobenzoyl(lower)alkyl;
3-(4-fluorobenzoyl)propyl;
4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;
piperazinylcarbonyl(lower)alky- l which has cyclopentyl or
halophenyl; (2-pyridyl)(lower)alkyl; (3-pyridyl)propyl;
(3-pyridyl)(lower)alkynyl; imidazolyl(lower)alkyl which may have
lower alkyl; pyrazolyl(lower)alkyl which may have lower alkyl;
thiomorpholinylcarbonyl(lower)alkyl; (3-azabicyclo[3.2.2]non-3-yl)-
carbonyl(lower)alkyl; or thienylcarbonyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)al- kynyl,
1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno
[3,2-c]pyridinyl(lower)alkyl, saturated heterocyclic(lower)alkyl,
saturated heterocyclic(lower)alkenyl, saturated
heterocyclic(lower)alkyny- l, saturated
heterocyclicamino(lower)alkyl, saturated
heterocyclicamino(lower)alkenyl or saturated
heterocyclicamino(lower)alky- nyl [wherein "saturated heterocyclic
moiety" is saturated 3 to 8-membered heteromonocyclic group
containing 1 to 4 nitrogen atom(s); saturated 3 to 8-membered
heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3
nitrogen atom(s); saturated 3 to 8-membered heteromonocyclic group
containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s); or
saturated heterocyclic group of the formula: 17 each of which may
have 1 to 3 suitable substituent(s) selected from the group
consisting of cyclo(lower)alkyl, lower alkanoyl, lower alkyl,
mono(or di or tri)halo(lower)alkyl, lower alkoxy, lower
alkoxy(lower)alkyl, halogen, C.sub.6-C.sub.10 aryl, cyano, oxo and
bivalent group of the formula: 18
3. The compound of claim 2, in which Y is lower alkylene, R.sup.1
is phenyl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,
R.sup.2 is phenyl, naphthyl or indolyl, each of which may have 1 or
2 suitable substituent(s) selected from the group consisting of
lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and
halogen, R.sup.3 is hydrogen, and R.sup.4 is chloro(lower)alkenyl;
chloro(lower)alkynyl; pyridyl(lower)alkylamino(lower)alkyl;
pyridyl(lower)alkylamino(lower)alke- nyl; N-(lower
alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;
triazolylamino(lower)alkyl; lower
alkoxy(lower)alkylamino(lower)alkyl;
bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower)alkyl;
hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;
phenyl(lower)alkyl which may have lower alkanoyl, amino, lower
alkanoylamino, di(lower)alkylaminocarbonyl or nitro; lower
alkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;
benzoyl(lower)alkyl which has lower alkyl, chlorine or
di(lower)alkylamino; benzoyl(lower)alkyl which has halogen and
lower alkyl; dihalobenzoyl(lower)alkyl;
di(lower)alkylbenzoyl(lower)alkyl; 3-fluorobenzoyl(lower)alkyl;
3-(4-fluorobenzoyl)propyl;
4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;
piperazinylcarbonyl(lower)alky- l which has cyclopentyl or
halophenyl; (2-pyridyl)(lower)alkyl; (3-pyridyl) propyl;
(3-pyridyl)(lower)alkynyl; imidazolyl(lower)alkyl which may have
lower alkyl; pyrazolyl(lower)alkyl which may have lower alkyl;
thiomorpholinylcarbonyl(lower)alkyl; (3-azabicyclo[3.2.2]non-3-yl)-
carbonyl(lower)alkyl; or thienylcarbonyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)al- kynyl,
1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno
[3,2-c]pyridinyl(lower)alkyl, saturated heterocyclic(lower)alkyl,
saturated heterocyclic(lower)alkenyl, saturated
heterocyclic(lower)alkyny- l, saturated
heterocyclicamino(lower)alkyl, saturated
heterocyclicamino(lower)alkenyl or saturated
heterocyclicamino(lower)alky- nyl [wherein "saturated heterocyclic
moiety" is pyrrolidinyl, piperidyl, piperazinyl,
hexamethyleneimino, morpholinyl, homomorpholinyl, thiomorpholinyl
or 3-azabicyclo[3.2.2]non-3-yl], each of which may have 1 or 2
suitable substituent(s) selected from the group consisting of
cyclo(lower)alkyl, lower alkanoyl, lower alkyl, mono(or di or
tri)halo(lower)alkyl, lower alkoxy, lower alkoxy(lower)alkyl,
halogen, phenyl, cyano, oxo and bivalent group of the formula:
19
4. The compound of claim 3, in which Y is lower alkylene, R.sup.1
is phenyl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,
R.sup.2 is phenyl which may have 1 or 2 suitable substituent(s)
selected from the group consisting of lower alkyl, lower alkoxy,
mono(or di or tri)halo(lower)alkyl and halogen, naphthyl or
indolyl, R.sup.3 is hydrogen, and R.sup.4 is
(2-pyridyl)(lower)alkyl; (3-pyridyl)propyl;
(3-pyridyl)(lower)alkynyl; imidazolyl(lower)alkyl which may have
lower alkyl; pyrazolyl(lower)alkyl which may have lower alkyl;
pyridyl(lower)alkylamino(lower)alkyl;
pyridyl(lower)alkylamino(lower)alke- nyl; N-(lower
alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;
triazolylamino(lower)alkyl; lower
alkoxy(lower)alkylamino(lower)alkyl;
bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;
1,2,3,6-tetrahydropyridyl(lower)alkyl;
1,2,3,6-tetrahydropyridyl(lower)al- kynyl;
1,2,3,4-tetrahydroisoquinolyl(lower)alkyl; or
4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower) alkyl.
5. The compound of claim 3, in which Y is lower alkylene, R.sup.1
is phenyl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,
R.sup.2 is phenyl which may have 1 or 2 suitable substituent(s)
selected from the group consisting of lower alkyl, lower alkoxy,
mono(or di or tri)halo(lower)alkyl and halogen, naphthyl or
indolyl, R.sup.3 is hydrogen, and R.sup.4 is
morpholinyl(lower)alkyl which may have 1 or 2 lower alkyl;
homomorpholinyl(lower)alkyl; rhiomorpholinyl(lower)alkyl;
(hexamethyleneimino)(lower)alkyl;
(3-azabicyclo[3.2.2]non-3-yl)(lower)alk- yl;
piperazinyl(lower)alkyl which may have phenyl or cyclo(lower)alkyl;
inorpholinyl(lower)alkenyl which may have 1 or 2 lower alkyl;
morpholinyl(lower)alkynyl which may have 1 or 2 lower alkyl, lower
alkoxy(lower)alkyl or mono(or di or tri)halo(lower)alkyl;
thiomorpholinyl(lower) alkenyl; thiomorpholinyl(lower)alkynyl;
pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;
piperazinyl(lower)alkynyl which may have cyclo (lower)alkyl;
morpholinylamino(lower)alkyl; morpholinylamino(lower)alkenyl;
morpholinylamino(lower)alkynyl;
[spiro[indan-1,4'-piperidinel-1'-yl](lowe- r)alkyl;
piperidyl(lower)alkyl which has phenyl, lower alkoxy, lower
alkanoyl, piperidyl or oxo; or piperidyl(lower)alkyl which has
phenyl and cyano.
6. The compound of claim 5, in which Y is lower alkylene, R.sup.1
is phenyl which may have 1 or 2 mono(or di or tri)
halo(lower)alkyl, R.sup.2 is phenyl which may have 1 or 2 suitable
substituent(s) selected from the group consisting of lower alkyl,
lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen,
naphthyl or indolyl, R.sup.3 is hydrogen, and R.sup.4 is
morpholinyl(lower)alkyl which may have 1 or 2 methyl;
homomorpholinyl(lower)alkyl; thiomorpholinyl(lower)alkyl;
(hexamethyleneimino)(lower)alkyl;
(3-azabicyclo[3.2.2]non-3-yl)(lower)alk- yl;
piperazinyl(lower)alkyl which has phenyl or cyclohexyl;
morpholinyl(lower)alkenyl which may have 1 or 2 methyl;
morpholinyl(lower)alkynyl which may have 1 or 2 methyl,
methoxymethyl or fluoromethyl; thiomorpholinyl(lower)alkenyl;
thiomorpholinyl(lower)alkyny- l; pyrrolidinyl(lower)alkynyl which
may have methoxymethyl; piperazinyl(lower)alkynyl which may have
cyclohexyl; morpholinylamino(lower)alkyl;
morpholinylamino(lower)alkenyl; morpholinylamino(lower)alkynyl;
[spiro[indan-1,4'-piperidine]-1'-yl](lowe- r)alkyl;
piperidyl(lower)alkyl which has phenyl, methoxy, acetyl, piperidyl
or oxo; or piperidyl(lower)alkyl which has phenyl and cyano.
7. The compound of claim 6, in which Y is methylene, R.sup.1 is
bis(trifluoromethyl)phenyl, R.sup.2 is phenyl or naphthyl, each of
which may have 1 or 2 suitable substituent(s) selected from the
group consisting of methyl, methoxy, trifluoromethyl and fluorine,
or indolyl, R.sup.3 is hydrogen, and R.sup.4 is
thiomorpholinyl(C.sub.1-C.sub.4)alkyl- ;
morpholinyl(C.sub.2-C.sub.4)alkenyl which may have 1 or 2 methyl;
morpholinyl(C.sub.2-C.sub.5)alkynyl which may have 1 or 2 methyl,
methoxymethyl or fluoromethyl; or
morpholinylamino(C.sub.1-C.sub.4)alkyl.
8. The compound of claim 7, which is selected from the group
consisting of (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3
-ylmethyl)-4-(3-thiomorpholinopropyl)- piperazine, (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2
-butynyl)-2-(2-naphthylmethyl) piperazine, (3)
(2R)-4-(4-Morpholino-2-but- ynyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine, (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylb- enzyl)-4
-[3-(morpholinoamino)propyl]piperazine and (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4
-[(E)-4-morpholino-2-butenyl]piperazine, or a pharmaceutically
acceptable salt thereof.
9. A process for the preparation of compound of the following
general formula: 20wherein Y is bond or lower alkylene, R.sup.1 is
aryl which may have suitable substituent(s), R.sup.2 is aryl or
indolyl each of which may have suitable substituent(s), R.sup.3 is
hydrogen or lower alkyl, R.sup.4 is chloro(lower)alkenyl;
chloro(lower)alkynyl; pyridyl(lower)alkylamino(lower)alkyl;
pyridyl(lower)alkylamino(lower)alke- nyl; N-(lower
alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;
triazolylamino(lower)alkyl; lower
alkoxy(lower)alkylamino(lower)alkyl;
bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl;
hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;
phenyl(lower)alkyl which may have lower alkanoyl, amino, lower
alkanoylamino, di(lower)alkylaminocarbonyl or nitro; lower
alkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;
benzoyl(lower)alkyl which has lower alkyl, chlorine or
di(lower)alkylamino; benzoyl(lower)alkyl which has halogen and
lower alkyl; dihalobenzoyl(lower)alkyl;
di(lower)alkylbenzoyl(lower)alkyl; 3-fluorobenzoyl(lower)alkyl;
3-(4-fluorobenzoyl)propyl;
4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;
piperazinylcarbonyl(lower)alky- l which has cyclopentyl or
halophenyl; (2-pyridyl)(lower)alkyl; (3-pyridyl)propyl;
(3-pyridyl)(lower)alkynyl; imidazolyl(lower)alkyl which may have
lower alkyl; pyrazolyl(lower)alkyl which may have lower alkyl;
thiomorpholinylcarbonyl(lower)alkyl; (3-azabicyclo[3.2.2]non-3-yl)-
carbonyl(lower)alkyl; or thienylcarbonyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)al- kynyl,
1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,
4,5,6,7-tetrahydrothieno- [3,2-c]pyridinyl(lower) alkyl, saturated
heterocyclic(lower)alkyl, saturated heterocyclic(lower)alkenyl,
saturated heterocyclic(lower)alkyny- l, saturated
heterocyclicamino(lower)alkyl, saturated
heterocyclicamino(lower)alkenyl or saturated
heterocyclicamino(lower)alky- nyl, each of which may have suitable
substituent(s), or a salt thereof, which comprises (1) reacting a
compound of the formula: 21 or its reactive derivative at the imino
group or a salt thereof with a compound of the
formulaW.sub.1-R.sup.4 or a salt thereof to provide a compound of
the formula: 22 or a salt thereof, in the above formulas, Y,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above,
and W.sub.1 is a leaving group, or (2) reacting a compound of the
formula: 23 or its reactive derivative at the imino group or a salt
thereof with a compound of the formula: 24 or its reactive
derivative at the carboxy group or a salt thereof to provide a
compound of the formula: 25 or a salt thereof, in the above
formulas, Y, R.sup.1, R.sup.2 and R.sup.3 are each as defined
above, and R.sup.5 is lower alkoxyphenyl(lower)alkyl or lower
alkanoylphenyl, or (3) reacting a compound of the formula: 26 or
its reactive derivative at the carboxy group or a salt thereof with
a compound of the formula:H-R.sup.6 or a salt thereof to provide a
compound of the formula: 27 or a salt thereof, in the above
formulas, Y, R.sup.1, R.sup.2 and R.sup.3 are each as defined
above, X is lower alkylene, and R.sup.6 is piperazinyl which has
cyclopentyl or halophenyl; or thiomorpholinyl, or (4) subjecting a
compound of the formula: 28 or a salt thereof to an acylation
reaction to provide a compound of the formula: 29 or a salt
thereof, in the above formulas, X, Y, R.sup.1, R.sup.2 and R.sup.3
are each as defined above, and R.sup.7 is acyloxy, or (5) reacting
a compound of the formula: 30 or a salt thereof with a compound of
the formula:H-R.sup.8 or a salt thereof to provide a compound of
the formula: 31 or a salt thereof, in the above formulas, X, Y,
R.sup.1, R.sup.2 and R.sup.3 are each as defined above, and R.sup.8
is pyridyl(lower)alkylamino; N-(lower
alkyl)-N-[pyridyl(lower)alkyl]amino; triazolylamino;
morpholinoamino; lower alkoxy(lower)alkylamino;
bis[(lower)alkoxy(lower)alkyl]amino; N-(lower
alkyl)-N-[(lower)alkoxy(low- er)alkyl]amino; imidazolyl; pyrazolyl;
or 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydroisoquinolyl,
4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic,
each of which may have suitable substituent(s), or (6) subjecting a
compound of the formula: 32 or a salt thereof to a reduction
reaction to provide a compound of the formula: 33 or a salt
thereof, in the above formulas, X, Y, R.sup.1, R.sup.2 and R.sup.3
are each as defined above, or (7) reacting a compound of the
formula: 34 or a salt thereof with a compound of the
formula:W.sub.2-R.sup.9 or a salt thereof to provide a compound of
the formula: 35 or a salt thereof, in the above formulas, X, Y,
R.sup.1, R.sup.2 and R.sup.3 are each as defined above, W.sub.2 is
a leaving group, and R.sup.9 is lower alkanoyl.
10. A pharmaceutical composition which comprises, as an active
ingredient, a compound of claim 1 or a pharmaceutically acceptable
salt thereof in admixture with pharmaceutically acceptable
carriers.
11. A use of a compound of claim 1 as a medicament.
12. A method for treating or preventing Tachykinin-mediated
diseases which comprises administering an effective amount of a
compound of claim 1 or a pharmaceutically acceptable salt thereof
to human being or animals.
13. A compound of claim 1 for use as a medicament.
14. Use of a compound of claim 1 for manufacture of a medicament
for treating or preventing Tachykinin-mediated diseases.
Description
TECHNICAL FIELD
[0001] The present invention relates to new piperazine derivatives
and a pharmaceutically acceptable salt thereof.
[0002] More particularly, it relates to new piperazine derivatives
and a pharmaceutically acceptable salt thereof which have
pharmacological activities such as Tachykinin antagonism,
especially Substance P antagonism, Neurokinin A antagonism,
Neurokinin B antagonism, and the like, to a process for preparation
thereof, to a pharmaceutical composition comprising the same, and
to a use of the same as a medicament.
[0003] Accordingly, one object of the present invention is to
provide new and useful piperazine derivatives and a
pharmaceutically acceptable salt thereof which have pharmacological
activities such as Tachykinin antagonism, especially Substance P
antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and
the like.
[0004] Another object of the present invention is to provide a
process for the preparation of said piperazine derivatives and a
salt thereof.
[0005] A further object of the present invention is to provide a
pharmaceutical composition comprising, as an active ingredient,
said piperazine derivatives and a pharmaceutically acceptable salt
thereof.
[0006] Still further object of the present invention is to provide
a use of said piperazine derivatives or a pharmaceutically
acceptable salt thereof as Tachykinin antagonist, especially
Substance P antagonist, Neurokinin A antagonist or Neurokinin B
antagonist, useful for treating or preventing Tachykinin-mediated
diseases, for example, respiratory diseases such as asthma,
bronchitis, rhinitis, cough, expectoration, and the like;
ophthalmic diseases such as conjunctivitis, vernal conjunctivitis,
and the like; cutaneous diseases such as contact dermatitis, atopic
dermatitis, urticaria, and other eczematoid dermatitis, and the
like; inflammatory diseases such as rheumatoid arthritis,
osteoarthritis, and the like; pains or aches (e.g., migraine,
headache, toothache, cancerous pain, back pain, etc.); and the like
in human being or animals.
BACKGROUND ART
[0007] Some piperazine derivatives having pharmaceutical activities
such as Tachykinin antagonism have been known as described in EP
0655442 A1.
DISCLOSURE OF INVENTION
[0008] The object compound of the present invention can be
represented by the following general formula (I): 2
[0009] wherein
[0010] Y is bond or lower alkylene,
[0011] R.sup.1 is aryl which may have suitable substituent(s),
[0012] R.sup.2 is aryl or indolyl each of which may have suitable
substituent(s),
[0013] R.sup.3 is hydrogen or lower alkyl,
[0014] R.sup.4 is chloro(lower)alkenyl;
[0015] chloro(lower)alkynyl;
[0016] pyridyl(lower)alkylamino(lower)alkyl;
[0017] pyridyl(lower)alkylamino(lower)alkenyl;
[0018] N-,(lower
alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl;
[0019] triazolylamino(lower)alkyl;
[0020] lower alkoxy(lower)alkylamino(lower)alkyl;
[0021] bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;
[0022] N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;
[0023] hydroxy(lower)alkyl;
[0024] lower alkylsulfonyloxy(lower)alkyl;
[0025] phenyl(lower)alkyl which may have lower alkanoyl, amino,
lower alkanoylamino, di(lower)alkylaminocarbonyl or nitro;
[0026] lower alkoxyphenyl(lower)alkylcarbonyl;
[0027] lower alkanoylbenzoyl;
[0028] benzoyl(lower)alkyl which has lower alkyl, chlorine or
di(lower)alkylamino;
[0029] benzoyl(lower)alkyl which has halogen and lower alkyl;
[0030] dihalobenzoyl(lower)alkyl;
[0031] di(lower)alkylbenzoyl(lower)alkyl;
[0032] 3-fluorobenzoyl(lower)alkyl;
[0033] 3- (4-fluorobenzoyl)propyl;
[0034] 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;
[0035] piperazinylcarbonyl(lower)alkyl which has cyclopentyl or
halophenyl;
[0036] (2-pyridyl)(lower)alkyl;
[0037] (3-pyridyl)propyl;
[0038] (3-pyridyl)(lower)alkynyl;
[0039] imidazolyl(lower)alkyl which may have lower alkyl;
[0040] pyrazolyl(lower)alkyl which may have lower alkyl;
[0041] thiomorpholinylcarbonyl(lower)alkyl;
[0042] (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; or
thienylcarbonyl(lower)alkyl,
[0043] 1,2,3,6-tetrahydropyridyl(lower)alkyl,
[0044] 1,2,3,6-tetrahydropyridyl(lower)alkynyl,
[0045] 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,
[0046] 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl,
[0047] saturated heterocyclic(lower)alkyl,
[0048] saturated heterocyclic(lower)alkenyl,
[0049] saturated heterocyclic(lower)alkynyl,
[0050] saturated heterocyclicamino(lower)alkyl,
[0051] saturated heterocyclicamino(lower)alkenyl or
[0052] saturated heterocyclicamino(lower)alkynyl, each of which may
have suitable substituent(s),
[0053] and a pharmaceutically acceptable salt thereof.
[0054] It is to be noted that the object compound (I) may include
one or more stereoisomers due to asymmetric carbon atom(s) and
double bond, and all of such isomers and a mixture thereof are
included within the scope of the present invention.
[0055] It is further to be noted that isomerization or
rearrangement of the object compound (I) may occur due to the
effect of the light, acid, base or the like, and the compound
obtained as the result of said isomerization or rearrangement is
also included within the scope of the present invention.
[0056] It is also to be noted that the solvating form of the
compound (I) (e.g. hydrate, etc.) and any form of the crystal of
the compound (I) are included within the scope of the present
invention.
[0057] According to the present invention, the object compound (I)
or a salt thereof can be prepared by processes which are
illustrated in the following schemes.
Process 1
[0058] 3
Process 2
[0059] 4
Process 3
[0060] 5
Process 4
[0061] 6
Process 5
[0062] 7
Process 6
[0063] 8
Process 7
[0064] 9
[0065] wherein
[0066] Y, R.sup.1, R.sub.2, R.sup.3 and R.sup.4 are each as defined
above,
[0067] X is lower alkylene,
[0068] R.sup.5 is lower alkoxyphenyl(lower)alkyl or lower
alkanoylphenyl,
[0069] R.sup.6 is piperazinyl which has cyclopentyl or halophenyl;
or thiomorpholinyl,
[0070] R.sup.7 is acyloxy,
[0071] R.sup.8 is pyridyl(lower)alkylamino;
[0072] N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino;
[0073] triazolylamino; morpholinoamino;
[0074] lower alkoxy(lower)alkylamino;
[0075] bis[(lower)alkoxy(lower)alkyl]amino;
[0076] N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino;
[0077] imidazolyl; pyrazolyl; or 1,2,3,6-tetrahydropyridyl,
[0078] 1,2,3,4-tetrahydroisoquinolyl,
[0079] 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated
heterocyclic, each of which may have suitable substituent(s),
[0080] R.sup.9 is lower alkanoyl, and
[0081] W.sub.1 and W.sub.2 are each a leaving group.
[0082] As to the starting compounds (II), (III), (IV), (V), (VI),
(VII) and (VIII), some of them are novel and can be prepared by the
procedures described in the Preparations and Examples mentioned
later or similar manners thereto.
[0083] Suitable salts and pharmaceutically acceptable salts of the
starting and object compounds are conventional non-toxic salt and
include an acid addition salt such as an organic acid salt (e.g.
acetate, trifluoroacetate, fumarate, maleate, tartrate,
methanesulfonate, benzenesulfonate, formate, toluenesulfonate,
etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide,
hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an
amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or
a metal salt such as an alkali metal salt (e.g. sodium salt,
potassium salt, etc.) and an alkaline earth metal salt (e.g.
calcium salt, magnesium salt, etc.)and an ammonium salt, an organic
base salt (e.g. trimethylamine salt, triethylamine salt, pyridine
salt, picoline salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, etc.), or the like.
[0084] In the above and subsequent descriptions of the present
specification, suitable examples and illustrations of the various
definitions which the present invention intends to include within
the scope thereof are explained in detail as follows.
[0085] The term "lower" is intended to mean 1 to 6, preferably 1 to
4, carbon atom(s), unless otherwise indicated.
[0086] Suitable "lower alkylene" may include straight or branched
one having 1 to 6 carbon atom(s), such as methylene, ethylene,
trimethylene, propylene, tetramethylene, methylmethylene,
methyltrimethylene, hexamethylene, and the like, in which the
preferred one is methylene, ethylene, trimethylene or
methylmethylene.
[0087] Suitable "halogen" and "halogen moiety" in the term
"dihalobenzoyl(lower)alkyl" and "halophenyl" may include fluorine,
chlorine, bromine and iodine.
[0088] Suitable "lower alkyl" and "lower alkyl moiety" in the terms
"pyridyl(lower)alkylamino(lower)alkyl",
"pyridyl(lower)alkylamino(lower)a- lkenyl", "N-(lower
alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl",
"triazolylamino(lower)alkyl", "lower alkoxy(lower)alkylamino
(lower)alkyl", "bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl",
"N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl",
"hydroxy(lower)alkyl", "lower alkylsulfonyloxy(lower)alkyl",
"phenyl(lower)alkyl", "di(lower)alkylaminocarbonyl", "lower
alkoxyphenyl(lower)alkylcarbnonyl", "benzoyl(lower)alkyl",
"di(lower)alkylamino", "benzoyl(lower)alkyl",
"dihalobenzoyl(lower)alkyl"- , "di(lower)alkylbenzoyl(lower)alkyl",
"3-fluorobenzoyl(lower)alkyl", "piperazinylcarbonyl(lower)alkyl",
"(2-pyridyl)(lower)alkyl", "imidazolyl(lower)alkyl",
"pyrazolyl(lower)alkyl", "thiomorpholinylcarbonyl(lower)alkyl",
"(3-azabicyclo[3.2.2non-3-yl)carbo- nyl(lower)alkyl",
"thienylcarbonyl(lower)alkyl", "1,2,3,6-tetrahydropyridy-
l(lower)alkyl", "1,2,3,4-tetrahydroisoquinolyl(lower)alkyl",
"4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl", "saturated
heterocyclic(lower)alkyl", "saturated
heterocyclicamino(lower)alkyl" and "lower alkoxyphenyl(lower)alkyl"
may include straight or branched one having 1 to 6 carbon atom(s),
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,
hexyl and the like, preferably one having 1 to 5 carbon
atom(s).
[0089] Suitable "lower alkenyl moiety" in the terms
"chloro(lower)alkenyl", "pyridyl(lower)alkylamino(lower)alkenyl",
"saturated heterocyclic(lower)alkenyl" and "saturated
hreterocyclicamino(lower)alkenyl" may include vinyl, 1-(or
2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl,
1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or
2- or 3-)methyl-1-(or 2-)propenyl, 1- (or 2- or 3-)ethyl-1-(or
2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl,
and the like, in which more preferable example may be
C.sub.2-C.sub.4 alkenyl.
[0090] Suitable "lower alkynyl moiety" in the terms
"chloro(lower)alkynyl", "(3-pyridyl)(lower)akynyl",
"1,2,3,6-tetrahydropyridyl(lower)alkynyl", "saturated
heterocyclic(lower)alkynyl" and "saturated
heterocyclicamino(lower)alkyny- l" may include ethynyl, 1-propynyl,
propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or
4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl and the like, in which
more preferable example may be C.sub.2-C.sub.5 alkynyl.
[0091] Suitable "aryl" may include phenyl, naphthyl, and the like,
in which the preferred one is C.sub.6-C.sub.10 aryl and the most
preferred one is phenyl.
[0092] Suitable "lower alkanoyl" and "lower alkanoyl moiety" in the
terms "lower alkanoylamino", "lower alkanoylbenzoyl" and "lower
alkanoylphenyl" may include formyl, acetyl, propanoyl, butanoyl,
2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and
the like.
[0093] Suitable "lower alkoxy moiety" in the terms "lower
alkoxyphenyl(lower)alkylcarbonyl" and "lower
alkoxyphenyl(lower)alkyl" may include methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy,
hexyloxy and the like.
[0094] Suitable "saturated heterocylic" and "saturated heterocyclic
moiety" in the terms "saturated heterocyclic(lower) alkyl",
"saturated heterocyclic(lower)alkynyl", "saturated
heterocyclicamino(lower)alkyl", "saturated
heterocyclicamino(lower)alkenyl" and "saturated
heterocyclicamino(lower)alkynyl" may include
[0095] saturated 3 to 8-membered (more preferably 5 to 7-membered)
heteromonocyclic group containing 1 to 4 nitrogen atom(s), for
example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,
hexamethyleneimino, etc;
[0096] saturated 3 to 8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3
nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
[0097] saturated 3 to 8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3
nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl,
etc.;
[0098] saturated heterobicyclic group of the formula: 10
[0099] saturated heterobicyclic group of the formula: 11
[0100] Suitable "substituent" in the terms "aryl which may have
suitable substituent(s)", "aryl or indolyl each of which may have
suitable substituent(s)", "thienylcarbonyl(lower)alkyl,
1,2,3,6-tetrahydropyridyl(- lower)alkyl,
1,2,3,6-tetrahydropyridyl(lower)alkynyl,
1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,
4,5,6,7-tetrahydrothieno[3,2-c- ]pyridinyl(lower)alkyl, saturated
heterocyclic(lower)alkyl, saturated heterocyclic(lower) alkenyl,
saturated heterocyclic(lower)alkynyl, saturated
heterocyclicamino(lower)alkyl, saturated
heterocyclicamino(lower)alkenyl or saturated
heterocyclicamino(lower)alky- nyl, each of which may have suitable
substituent(s)" and 1,2,3,4-tetrahydroisoquinolyl,
4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic
each of which may have suitable substituent(s)" may include lower
alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.),
cyclo(lower)alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy,
isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy,
tert-pentyloxy, hexyloxy, etc.), lower alkoxy(lower)alkyl (e.g.,
methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl,
1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl (e.g., formyl,
acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkenyl (e.g.,
vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or
2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower
alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1
or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or
5-hexynyl, etc.), mono(or di or tri)halo(lower)alkyl (e.g.,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl,
tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or
2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen
(e.g., chlorine, bromine, fluorine and iodine), carboxy, protected
carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl,
etc.), ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl,
phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl wherein lower
alkyl moiety can be referred to the ones as exemplified above,
protected carboxy(lower)alkyl wherein lower alkyl moiety can be
referred to the ones as exemplified above, nitro, amino, protected
amino, di(lower)alkylamino (e.g., dimethylamino, diethylamino,
diisopropylamino, ethylmethylamino, isopropylmethylamino,
ethylisopropylamino, etc.), hydroxy(lower)alkyl, protected
hydroxy(lower)alkyl, acyl, cyano, oxo, mercapto, lower alkylthio
(e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio,
etc.), lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl,
propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.), imino,
morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, morpholino),
bivalent group of the formula: 12
[0101] and the like.
[0102] Suitable "leaving group" may include lower alkoxy (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
pentoxy, etc.), aryloxy (e.g. phenoxy, naphthoxy, etc.), an acid
residue or the like.
[0103] Suitable "acid residue" may be halogen (e.g. chlorine,
bromine, iodine, etc.), sulfonyloxy (e.g. methylsulfonyloxy,
phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.)
or the like.
[0104] Suitable "acyloxy" may include hydroxysulfonyloxy, lower
alkylsulfonyloxy (e.g. methylsulfonyloxy, ethylsulfonyloxy, etc.),
phosphonooxy, and the like.
[0105] Preferred embodiments of the object compound (I) are as
follows:
[0106] Y is lower alkylene (more preferably C.sub.1-C.sub.4
alkylene, most preferably methylene);
[0107] R.sup.1 is aryl (more preferably C.sub.6-C.sub.10 aryl, most
preferably phenyl) which may have 1 to 3 (more preferably 1 or 2;
most preferably 2) suitable substituent(s) [more preferably mono
(or di or tri)halo(lower)alkyl (more preferably
trihalo(lower)alkyl, most preferably trifluoromethyl)];
[0108] R.sup.2 is aryl (more preferably C.sub.6-C.sub.10 aryl, most
preferably phenyl or naphthyl) or indolyl each of which may have 1
to 3 (more preferably 1 or 2, most preferably 2) suitable
substituent(s) [more preferably substituent selected from the group
consisting of lower alkyl (more preferably C.sub.1-C.sub.4 alkyl,
most preferably methyl), lower alkoxy (more preferably
C.sub.1-C.sub.4 alkoxy, most preferably methoxy), mono(or di or
tri)halo(lower)alkyl (more preferably mono(or di or
tri)halo(C.sub.1-C.sub.4)alkyl, most preferably trifluoromethyl)
and halogen (more preferably chlorine or fluorine)];
[0109] R.sup.3 is hydrogen; and
[0110] R.sup.4 is chloro(lower)alkenyl (more preferably
chloro(C.sub.2-C.sub.4)alkenyl, most preferably
4-chloro-2-butenyl); chloro(lower)alkynyl (more preferably
chloro(C.sub.2-C.sub.4)alkynyl, most preferably
4-chloro-2-butynyl); pyridyl(lower)alkylamino(lower)alkyl [more
preferably
pyridyl(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.4)alkyl- , most
preferably 2-[(3-pyridylmethyl)amino]ethyl,
2-[(4-pyridylmethyl)ami- no]ethyl or
3-[(3-pyridylmethyl)amino]propyl]; pyridyl(lower)alkylamino(lo-
wer)alkenyl (more preferably
pyridyl(C.sub.1-C.sub.4)alkylamino(C.sub.2-C.- sub.4)alkenyl, most
preferably 4-[(3-pyridylmethyl)amino]-2-butenyl); N-lower
alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl (more preferably
N-(C.sub.1-C.sub.4
alkyl)-N-[pyridyl(C.sub.1-C.sub.4)alkyl]amino(C.sub.1--
C.sub.4)alkyl, more preferably 2-[N-methyl-N-(3-pyridylmethyl)
amino]ethyl]; triazolylamino(lower)alkyl (more preferably
triazolylamino(C.sub.1-C.sub.4)alkyl, most preferably
3-(1,2,4-triazol-3-ylamino) propyl); lower
alkoxy(lower)alkylamino(lower)- alkyl (more preferably
C.sub.1-C.sub.4 alkoxy(C.sub.1-C.sub.4)alkylamino(C-
.sub.1-C.sub.4)alkyl, most preferably
2-(2-methoxyethyl)aminoethyl);
bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl [more preferably
bis[(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl]amino(C.sub.1-C.sub.4)a-
lkyl, most preferably 3-[bis(2-methoxyethyl)amino]propyl]; N-(lower
alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl [more
preferably N-(C.sub.1-C.sub.4
alkyl)-N-[(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alky-
l]amino(C.sub.1-C.sub.4)alkyl, most preferably
2-[N-methyl-N-(2-methoxyeth- yl)amino]ethyl]; hydroxy(lower)alkyl
(more preferably hydroxy (C.sub.1-C.sub.4)alkyl, most preferably
hydroxypropyl); lower alkylsulfonyloxy(lower)alkyl (more preferably
C.sub.1-C.sub.4 alkylsulfonyloxy(C.sub.1-C.sub.4)alkyl, most
preferably methylsulfonyloxyropyl); phenyl(lower)alkyl (more
preferably phenyl(C.sub.1-C.sub.4)alkyl, most preferably benzyl)
which may have lower alkanoyl (more preferably C.sub.1-C.sub.4
alkanoyl, most preferably acetyl, amino, lower alkanoylamino (more
preferably C.sub.1-C.sub.4 alkanoylamino, most preferably
acetylamino), di(lower)alkylaminocarbonyl (more preferably
di(C.sub.1-C.sub.4)alkylaminocarbonyl, most preferably
diethylaminocarbonyl) or nitro; lower
alkoxyphenyl(lower)alkylcarbonyl (more preferably C.sub.1-C.sub.4
alkoxyphenyl (C.sub.1-C.sub.4) alkylcarbonyl, most preferably
methoxyphenylmethylcarbonyl); lower alkanoylbenzoyl (more
preferably C.sub.1-C.sub.4 alkanoylbenzoyl, most preferably
acetylbenzoyl); benzoyl(lower)alkyl (more preferably
benzoyl(C.sub.1-C.sub.4)alkyl, most preferably benzoylmethyl) which
has lower alkyl (more preferably C.sub.1-C.sub.4 alkyl, most
preferably methyl), chlorine or di(lower)alkylamino (more
preferably di(C.sub.1-C.sub.4) alkylamino, most preferably
dimethylamino); benzoyl(lower)alkyl (more preferably
benzoyl(C.sub.1-C.sub.4)alkyl, most preferably benzoylmethyl) which
has halogen (more preferably fluorine) and lower alkyl (more
preferably C.sub.1-C.sub.4 alkyl, most preferably methyl);
dihalobenzoyl(lower)alkyl [more preferably
dihalobenzoyl(C.sub.1-C.sub.4)alkyl, most preferably
(difluorobenzoyl)methyl]; di(lower)alkylbenzoyl(lower)alkyl [more
preferably di(C.sub.1-C.sub.4)alkylbenzoyl(C.sub.1-C.sub.4)alkyl,
most preferably dimethylbenzoylmethyl]; 3-
fluorobenzoyl(lower)alkyl, more preferably 3-fluorobenzoyl
(C.sub.1-C.sub.4)alkyl, most preferably 3-fluorobenzoylmethyl);
3-(4-fluorobenzoyl)propyl;
4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;
piperazinylcarbonyl(lower)alky- l (more preferably
piperazinylcarbonyl(C.sub.1-C.sub.4)alkyl, most preferably
piperazinylcarbonylmethyl) which has cyclopentyl or halophenyl
(more preferably fluorophenyl); (2-pyridyl)(lower)alkyl (more
preferably (2-pyridyl)(C.sub.1-C.sub.4) alkyl, most preferably
(2-pyridyl)methyl); (3-pyridyl)propyl (more preferably
3-(3-pyridyl)propyl); (3-pyridyl)(lower)alkynyl (more preferably
(3-pyridyl) (C.sub.2-C.sub.4)alkynyl, most preferably
3-(3-pyridyl)-2-propynyl); imidazolyl(lower) alkyl (more preferably
imidazolyl (C.sub.1-C.sub.4)alkyl, most preferably
(1-imidazol-1-yl)methyl, (1H-imidazol-2-yl)methyl or
(1H-imidazol-4-yl)methyl) which may have lower alkyl (more
preferably C.sub.1-C.sub.4 alkyl, most preferably methyl);
pyrazolyl(lower)alkyl (more preferably pyrazolyl
(C.sub.1-C.sub.4)alkyl, most preferably (1H-pyrazol-4-yl)methyl or
3- (1H-pyrazol-4-yl) propyl) which may have lower alkyl (more
preferably C.sub.1-C.sub.4 alkyl, most preferably methyl);
thiomorpholinylcarbonyl(l- ower)alkyl (more preferably
thiomorpholinylcarbonyl (C.sub.1-C.sub.4)alkyl, most preferably
thiomorpholinylcarbonylmethyl);
(3-azabicyclor[3.2.2non-3-yl)carbonyl(lower)alkyl (more preferably
(3-azabicyclo[3.2.2]non-3-yl)carbonyl(C.sub.1-C.sub.4)alkyl, most
preferably (3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl); or
thienylcarbonyl(lower)alkyl (more preferably
thienylcarbonyl(C.sub.1-C.su- b.4)alkyl, most preferably
thienylcarbonylmethyl), 1,2,3,6-tetrahydropyrid- yl(lower)alkyl
(more preferably 1,2,3,6-tetrahydropyridyl(C.sub.1-C.sub.4)- alkyl,
most preferably 3-(1,2,3,6-tetrahydropyridin-1-yl) propyl),
1,2,3,6-tetrahydropyridyl(lower)alkynyl (more preferably
1,2,3,6-tetrahydropyridyl(C.sub.2-C.sub.4)alkynyl, most preferably
4-(1,2,3,6-tetrahydropyridin-1-yl)-2-bultynyl),
1,2,3,4-tetrahydroisoquin- olyl(lower)alkyl (more preferably
1,2,3,4-tetrahydroisoquinolyl(C.sub.1-C.- sub.4) alkyl, most
preferably 1,2,3,4-tetrahydroisoquinolylpropyl),
4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl (more
preferably 4,5,6,7-tetrahydrothieno[3,2-c7-pyridinyl
(C.sub.1-C.sub.4)alkyl, most preferably
4,5,6,7-tetrahydrothieno[3,2-c]pyridinylpropyl), saturated
heterocyclic(lower)alkyl (more preferably saturated
heterocyclic(C.sub.1-C.sub.4)alkyl, more preferably saturated
heterocyclicethyl or saturated heterocyclicpropyl, most preferably
saturated heterocyclicpropyl), saturated heterocyclic(lower)alkenyl
(more preferably saturated heterocyclic(C.sub.2-C.sub.4)alkenyl,
most preferably saturated heterocyclicbutenyl), saturated
heterocyclic(lower)alkynyl (more preferably saturated
heterocyclic(C.sub.2-C.sub.5)alkynyl, most preferably saturated
heterocyclicbutynyl or saturated heterocyclicpentynyl), saturated
heterocyclicamino(lower)alkyl (more preferably saturated
heterocyclicamino(C.sub.1-C.sub.4)alkyl, most preferably saturated
heterocyclicaminopropyl), saturated heterocyclicamino(lower)alkenyl
(more preferably saturated
heterocyclicamino(C.sub.2-C.sub.4)alkenyl, most preferably
saturated heterocyclicaminobutenyl) or saturated
heterocyclicamino(lower)alkynyl (more preferably saturated
heterocyclicamino(C.sub.2-C.sub.5)alkynyl, most preferably
saturated heterocyclicaminobutynyl) wherein "saturated heterocyclic
moiety" is saturated 3 to 8-membered (more preferably 5 to
7-membered) heteromonocyclic group containing 1 to 4 (more
preferably 1 or 2) nitrogen atom(s) (more preferably pyrrolidinyl,
piperidyl, piperazinyl or hexamethyleneimino, most preferably
piperidyl); saturated 3 to 8-membered (more preferably 5 to
7-membered) heteromonocyclic group containing 1 or 2 (more
preferably 1) oxygen atom(s) and 1 to 3 (more preferably 1)
nitrogen atom(s) (more preferably morpholinyl or homomorpholinyl,
most preferably morpholinyl); saturated 3 to 8-membered (more
preferably 5 or 6-membered) heteromonocyclic group containing 1 or
2 (more preferably 1) sulfur atom(s) and 1 to 3 (more preferably 1)
nitrogen atom(s) (more preferably thiomorpholinyl); or saturated
heterocyclic group of the formula: 13
[0111] (more preferably 3-azabicyclo[3.2.2]non-3-yl)], each of
which may have 1 to 3 (more preferably 1 or 2) suitable
substituent(s) [more preferably substituent selected from the group
consisting of cyclo(lower)alkyl (more preferably cyclohexyl), lower
alkanoyl (more preferably C.sub.1-C.sub.4 alkanoyl, most preferably
acetyl), lower alkyl (more preferably C.sub.1-C.sub.4 alkyl, most
preferably methyl), mono(or di or tri)halo(lower)alkyl (more
preferably monohalo(C.sub.1-C.sub.4)alky- l, most preferably
fluoromethyl), lower alkoxy (more preferably C.sub.1-C.sub.4
alkoxy, most preferably methoxy), lower alkoxy(lower)alkyl (more
preferably C.sub.1-C.sub.4 alkoxy(C.sub.1-C.sub.4)alkyl, most
preferably methoxymethyl), halogen (more preferably chlorine), aryl
(more preferably phenyl), cyano, oxo and bivalent group of the
formula: 14
[0112] More preferred embodiments of the object compound (I) are as
follows:
[0113] Y is lower alkylene (more preferably C.sub.1-C.sub.4
alkylene, most preferably methylene);
[0114] R.sup.1 is phenyl which may have 1or 2 mono(or di or
tri)halo(lower) alkyl [more preferably
bis(trihalo(lower)alkyl)phenyl, most preferably
bis(trifluoromethyl)phenyl];
[0115] R.sup.2 is phenyl which may have 1 or 2 suitable
substituent(s) selected from the group consisting of lower alkyl,
lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen [more
preferably di(lower)alkylphenyl, (lower)alkoxyphenyl,
[trihalo(lower)alkylphenyl, [(lower)alkylhalophenyl, halophenyl or
dihalophenyl, most preferably dimethylphenyl, methoxyphenyl,
(trifluoromethyl)phenyl, methylfluorophenyl, fluorophenyl or
difluorochlorophenyl], naphthyl or indolyl;
[0116] R.sup.3 is hydrogen; and
[0117] R.sup.4 is morpholinyl(lower)alkyl which may have 1 or 2
lower alkyl (more preferably methyl), homomorpholinyl(lower)alkyl,
thiomorpholinyl(lower)alkyl, (hexamethyleneimino)(lower)alkyl,
(3-azabicyclo[3.2.2]non-3-yl)(lower)alkyl, piperazinyl(lower)alkyl
which may have phenyl or cyclo(lower)alkyl (more preferably
piperazinyl(lower)alkyl which has phenyl or cyclohexyl),
morpholinyl(lower)alkenyl which may have 1 or 2 lower alkyl (more
preferably methyl), morpholinyl(lower)alkynyl which may have a
substituent selected from the group consisting of lower alkyl (more
preferably methyl), lower alkoxy(lower)alkyl (more preferably
methoxymethyl) and mono(or di or tri)halo(lower)alkyl (more
preferably fluoromethyl), thiomorpholinyl(lower)alkenyl,
thiomorpholinyl(lower)alkyn- yl, pyrrolidinyl(lower)alkynyl which
may have lower alkoxy(lower)alkyl (more preferably methoxymethyl),
piperazinyl(lower)alkynyl which may have cyclo(lower)alkyl (more
preferably cyclohexyl), morpholinylamino(lower)al- kyl,
morpholinylamino(lower)alkenyl, morpholinylamino(lower)alkynyl, or
piperidyl(lower)alkyl which may have 1 or 2 suitable substituent(s)
selected from the group consisting of bivalent group of the
formula: 15
[0118] phenyl, cyano, lower alkanoyl, lower alkoxy, piperidinyl,
and oxo [more preferably
[spiro[indan-1,4'-piperidine]-1'-yl](lower)alkyl,
piperidyl(lower)alkyl which has phenyl, acetyl, methoxy, piperidino
or oxo, or piperidyl(lower)alkyl which has phenyl and cyano].
[0119] The Processes 1 to 7 for preparing the object compound (I)
of the present invention are explained in detail in the
following.
[0120] Process 1
[0121] The object compound (I) or a salt thereof can be prepared by
reacting the compound (II) or its reactive derivative at the imino
group or a salt thereof with the compound (IV) or a salt
thereof.
[0122] Suitable reactive derivative at the imino group of the
compound (II) may include Schiff's base type imino or its
tautomeric enamine type isomer formed by the reaction of the
compound (II) with a carbonyl compound such as aldehyde, ketone or
the like; a silyl derivative formed by the reaction of the compound
(II) with a silyl compound such as bis(trimethylsilyl)acetamide,
mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like;
a derivative formed by reaction of the compound (II) with
phosphorus trichloride or phosgene and the like.
[0123] The reaction is usually carried out in a conventional
solvent such as water, alcohol [e.g. methanol, ethanol, etc.],
acetone, dioxene, acetonitrile, chloroform, methylene chloride,
ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine or any other organic solvent which
does not adversely influence the reaction. These conventional
solvents may also be used in a mixture with water.
[0124] The reaction may also be carried out in the presence of an
inorganric or organic base such as alkali metal carbonate, alkali
metal bicarbonate, tri(lower)alkylamine, pyridine,
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the
like.
[0125] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to heating.
[0126] Process 2
[0127] The object compound (Ia) or a salt thereof can be prepared
by reacting the compound (V) or its reactive derivative at the
carboxy group or a salt thereof with the compound (II) or its
reactive derivative at the imino group or a salt thereof.
[0128] Suitable reactive derivative at the carboxy group of the
compound (V) may include an acid halide, an acid anhydride, an
activated amide, an activated ester, and the like. The suitable
example of the reactive derivative may be an acid chloride; an acid
azide; a mixed acid anhydride with an acid such as substituted
phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric
acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated
phosphoric acid, etc.], dialkylphosphorous acid, lower
alkanesulfonic acid [e.g. methanesulfonic acid, ethanesulfonic
acid, etc.], sulfurous acid, thiosulfuric acid, sulfuric acid,
aliphatic carboxylic acid [e.g. acetic acid, propionic acid,
butyric acid, isobutyric acid, pivalic acid, valeric acid,
isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.]
or aromaticcarboxylic acid [e.g. benzoic acid, etc.]; a symmetrical
and anhydride; an activated amide with imidazole, 4-substituted
imidazole, dimethylpyrazole, triazole or tetrazole; or an activated
ester [e.g. cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl [(CH.sub.3).sub.2N.sup.+.dbd.CH-- -] ester,
vinyl ester, propargyl ester, p-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl
ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester,
p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl
thioester, pyranyl ester, pyridyl ester, piperidyl ester,
8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound
[e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,
N-hydroxysuccinimide, N-hydroxyphthalimide,
1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive
derivatives can optionally be selected from them according to the
kind of the compound (V) to be used.
[0129] The reaction is usually carried out in a conventional
solvent such as water, alcohol [e.g. methanol, ethanol, etc.],
acetone, dioxane, acetonitrile, chloroform, methylene chloride,
ethylene chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine or any other organic solvent which
does not adversely influence the reaction. These conventional
solvents may also be used in a mixture with water.
[0130] In this reaction, when the compound (V) is used in a free
acid form or a salt thereof, the reaction is preferably carried out
in the presence of a conventional condensing agent such as
N,N'-dichlorohexylcarbodiimide- ;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethyla- minocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'-
(3-dimethylaminopropyl)carbodii- mide;
pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexyli- mine; ethoxyacetylene;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; diphenyl phosphorylazide;
thienyl chloride; oxalyl chloride; lower alkyl haloformate [e.g.
ethyl chloroformate, isopropyl chloroformate, etc.];
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
2-ethyl-5-(m-sulfophenyl)isoxazoli- um hydroxide intramolecular
salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-- 1H-benzotriazole;
2-chloro-1-methylpyridinium, iodide;
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
so-called vilsmeier reagent prepared by the reaction of
N,N-dimethylformamide with thionyl chloride, phosgene,
trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the
like.
[0131] The reaction may also be carried out in the presence of an
inorganic or organic base such as alkali metal carbonate, alkali
metal bicarbonate, tri(lower)alkylamine, pyridine,
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the
like.
[0132] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to warming.
[0133] Process 3
[0134] The object compound (Ib) or a salt thereof can be prepared
by reacting the compound (III) or its reactive derivative at the
carboxy group or a salt thereof with the compound (VI) or a salt
thereof.
[0135] The reaction mode and reaction conditions of this reaction
are to be referred to those as explained in Process 2.
[0136] Process 4
[0137] The object compound (Id) or a salt thereof can be prepared
by subjecting the ccmpound (Ic) or a salt thereof to an acylation
reaction.
[0138] The reaction can be carried out in the manner disclosed in
Example 20 mentioned later or similar manners thereto.
[0139] Process 5
[0140] The compound (Ie) or a salt thereof can be prepared by
reacting the compound (Id) or a salt thereof with the compound
(VII) or a salt thereof.
[0141] This reaction is usually carried out in a solvent such as
water, alcohol (e.g., methanol, ethanol, etc.), benzene,
N,N-dimethylformamide, tetrahydrofuran, toluene, methylene
chloride, ethylene dichloride, chloroform, dioxane, acetontrile,
diethyl ether or any other solvents which do not adversely affect
the reaction, or the mixture thereof.
[0142] The reaction temperature is not critical and the reaction is
usually carried out under cooling to heating.
[0143] The reaction may be also carried out in the presence of an
inorganic or an organic base such as alkali metal (e.g., sodium,
potassium, etc.), alkali metal hydroxide (e.g., sodium hydroxide,
potassium hydroxide, etc.), alkali metal hydrogencarbonate (e.g.,
sodium hydrogencarbonate, potassium hydrogencarbonate, etc.),
alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), tri(lower)alkylamine (e.g., trimethylamine,
triethylamine, diisopropylethylamine, etc.), alkali metal hydride
(e.g., sodium hydride, etc), alkali metal(lower)alkoxide (e.g.
sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine,
picoline, dimethylaminopyridine, N-(lower)alkylmorpholine,
N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the
like.
[0144] When the base and/or the starting compound are in liquid,
they can be used also as a solvent.
[0145] Process 6
[0146] The object compound (Ig) or a salt thereof can be prepared
by subjecting the compound (If) or a salt thereof to a reduction
reaction.
[0147] The reaction can be carried out in the manner disclosed in
Example 29 mentioned later or similar manners thereto.
[0148] Process 7
[0149] The object compound (Ih) or a salt thereof can be prepared
by subjecting the compound (Ig) or a salt thereof to acylation
reaction.
[0150] The reaction can be carried out in the manner disclosed in
Example 3 mentioned later or similar manners thereto.
[0151] The object compound (I) and a pharmaceutically acceptable
salt thereof have pharmacological activities such as Tachykinin
antagonism, especially Substance P antagonism, Neurokinin A
antagonism or Neurokinin B antagonism, and therefore are useful for
treating or preventing Tachykinin-mediated diseases, particularly
Substance P-mediated diseases, for example, respiratory diseases
such as asthma, bronchitis (e.g. chronic bronchitis, acute
bronchitis and diffuse panbronchiolitis, etc.), rhinitis, couph,
expectoration, and the like; opthalmic diseases such as
conjunctivitis, vernal conjunctivitis, and the like; cutaneous
diseases such as contact dermatitis, atopic dermatitis, urticaria,
and other eczematoid dermatitis, and the like; inflammatory
diseases such as rheumatoid arthritis, osteoarthritis, and the
like; pains or aches (e.g. migraine, headache, cluster headache,
toothache, cancerous pain, back pain, neuralgia, etc.); and the
like.
[0152] Further, it is expected that the object compound (I) and a
pharmaceutically acceptable salt thereof of the present invention
are useful for treating or preventing ophthalmic diseases such as
glaucoma, uveitis, and the like; gastrointestinal diseases such as
ulcer, ulcerative colitis, irritable bowel syndrome, food allergy,
and the like; inflammatory diseases such as nephritis, and the
like; circulatory diseases such as hypertension, angina pectoris,
cardiac failure, thrombosis, Raynaud's disease, and the like;
epilepsy; spastic paralysis; pollakiuria; cystitis; bladder
detrusor hyperreflexia; urinary incontinence; Parkinson diseases;
dementia; AIDS related dementia; Alzheimer's diseases; Down's
syndrome; Huntington's chorea; carcinoid syndrome; disorders
related to immune enhancement or suppression; disorders caused by
Helicobacter pylori or another spiral urease-positive gram-negative
bacterium; sunburn; angiogenesis or diseases caused by
angiogenesis; and the like.
[0153] It is furthermore expected that the object compound (I) and
a pharmaceutically acceptable salt thereof of the present invention
are useful for treating or preventing chronic obstructive pulmonary
diseases, particularly chronic pulmonary emphysema; iritis;
proliferative vitreoretinopathy; psoriasis; inflammatory intestinal
diseases, particularly Crohn's diseases; hepatitis; superficial
pain on congelation, burn, herpes zoster or diabetic neuropathy;
tenalgia attended to hyperlipidemia; postoperative neuroma,
particularly of mastectomy; vulvar vestibulitis;
hemodialysis-associated itching; lichen planus; laryngopharyngitis;
bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis;
cystic fibrosis; emesis; mental diseases, particularly anxiety,
depression, dysthymic disorders and schizophrenia; demyelinating
diseases such as multiple sclerosis and amyotrophic lateral
sclerosis; attenuation of morphine withdrawal; oedema, such as
oedema caused by thermal injury; small cell carcinomas,
particularly small cell lung cancer (SCLC); hypersensitivity
disorders such as poison ivy; fibrosing and collagen diseases such
as scleroderma and eosinophilic fascioliasis; reflex sympathetic
dystrophy such as shoulder/hand syndrome; addiction disorders such
as alcoholism; stress related somatic disorders; rheumatic diseases
such as fibrositis; and the like.
[0154] Furthermore, the object compound (I) and a pharmaceutically
acceptable salt thereof of the present invention are Central
Nervous System (CNS) penetrant.
[0155] For therapeutic purpose, the compound (I) and a
pharmaceutically acceptable salt thereof of the present invention
can be used in a form of pharmaceutical preparation containing one
of said compound, as an active ingredient, in admixture with a
pharmaceutically acceptable carrier such as an organic or inorganic
solid or liquid excipient suitable for oral, parenteral, external
including topical, enternal, intravenous, intramuscular, inhalant,
nasal, intraarticular, intraspinal, transtracheal or transocular
administration. The pharmaceutical preparations may be solid,
semi-solid or solutions such as capsules, tablets, pellets,
dragees, powders, granules, suppositories, ointments, creams,
lotions, inhalants, injections, cataplasms, gels, tapes, eye drops,
solution, syrups, aerosols, suspension, emulsion, or the like. If
desired, there may be included in these preparations, auxiliary
substances, stabilizing agents, wetting or emulsifying agents,
buffers and other commonly used additives.
[0156] While the dosage of the compound (I) will vary depending
upon the age and condition of a patient, an average single dose of
about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000
mg of the compound (I) may be effective for treating
Tachykinin-mediated diseases such as asthma and the like. In
general, amounts between 0.1 mg/body and about 1,000 mg/body may be
administered per day.
[0157] In order to show the utility of the object compound (I) and
a pharmaceutically acceptable salt thereof, the pharmacological
test data of some representative compounds of the present invention
is shown in the following.
[0158] A. Evaluation of NK.sub.1 Antagonist Transport Efficiency to
the Cental Nervous System Using a h-NK.sub.1 Receptor Binding
Assay
[0159] [I] Test Method
[0160] (1) Administration of Test Compound and Extraction of the
Compound From Brain
[0161] Male SD rats were given an i.v. injection of a solution
containing a test compound (1 mg/kg). 5 Min later the animals were
anesthetized by ether, bled and perfused through the aorta
ascendens with 20 ml of saline. The brain was rapidly removed,
weighed and homogenized in 4 vol. ice-cold distilled water by using
Polytoron (KINEMATICA). To extract the test compound, 500 .mu.l of
the homogenate, 100 .mu.l of methanol, 500 .mu.l of 0.1 N NaOH and
4 ml of ethyl acetate were mixed by shaking for 10 min at room
temperature. The organic phase (2.5 ml) was recovered by
centrifugation at 3,000 rpm for 10 min, dried and dissolved in
dimethyl sulfoxide.
[0162] (2) h-NK.sub.1 Receptor Binding Assay
[0163] (a) Crude CHO Cell Membrane Preparation
[0164] CHO cells permanently expressing h-NK.sub.1 receptors were
harvested and homogenized with a Dounce homogenizer at 4.degree. C.
in a buffer (0.25 M sucrose, 25 mM Tris-HCl (pH 7.4), 10 mM
MgCl.sub.2, 1 mM EDTA, 5 .mu.g/ml p-APMSF). The homogenate was
centrifuged (500.times.g, 10 min), and the pellet was resuspended
in the same buffer, homogenized, and centrifuged. The two
supernatants were combined and centrifuged (100,000.times.g, 1
hour). The crude cell membranes thus isolated were resuspended in a
buffer (25 MM Tris-HCl (pH 7.4), 10 mM MgCl.sub.2, 1 mM EDTA, 5
.mu.g/ml p-APMSF) and stored at -80.degree. C. until use.
[0165] (b) .sup.125I-BH-Substance P Binding to the Prepared
Membrane
[0166] Cell membranes (6 .mu.g/ml) were incubated with
.sup.125I-BH-Substance P (0.1 nM) with or without the extracted
compounds in 0.25 ml of a medium (50 mM Tris-HCl (pH 7.4), 5 mM
MnCl.sub.2, 20 .mu.g/ml chymrostatin, 40 .mu.g/ml bacitracin, 4
.mu.g/ml leupeptin, 5 .mu.g/ml p-APMSF, 200 .mu.g/ml BSA) at
22.degree. C. for 90 min. At the end of the incubation period, the
contents were quickly filtered through a Blue Mat 11740 filter
(pretreated with 0.1% polyethylenimine for 3 hours prior to use) by
using SKATRON Cell Harvester. The filter was then washed with a
washing buffer (50 mM Tris-HCl (pH 7.4), 5 mM MnCl.sub.2) . The
radioactivity was counted by using an auto gamma counter (Packard
RIASTAR 5420A). All data presented are specific binding defined as
that displaceable by 3 .mu.M unlabeled Substance P.
[0167] (II) Test Result
[0168] All of the following Test Compounds showed more than 80%
inhibition rate of .sup.125I-BH-Substance P binding to h-NK.sub.1
receptors as he dose of 1 mg/kg.
[0169] Test Compounds:
[0170] The object compounds of the Examples 7, 11, 12, 22, 23,
24-(2), 26, 35, 36, 37-(2), (4), (5), (6), (8), 44-(1), (2), (4),
(5), (7), 46, 47, 51, 52-(1), 53-(1), 54, 55, 58, 59-(1), (3),
62-(1), 67-(4), (5), (6), (7), (13), 71, 72, 73, 74, 75, 76, 77,
81, 82-(1), 82-(4), 82-(5), 82-(7), 82-(8), 82-(9), 82-(10),
82-(12), 84-(1) and 86
[0171] B. Emesis in the Ferret
[0172] [I] Test Method
[0173] Individually housed adult male ferrets (Marshall Farms, 1.4
to 2.2 kg) were given an i.p. injection of a solution containing a
test compound 30 Min later the emetic responses (retching and
vomiting) were induced by administration of intra-gastric copper
sulfate (40 mg/kg/ml) and observed for the next 30 min. The timing
and number of retches and vomits observed were recorded for each
animal. An individual animal was tested with at least 10 days
between experiments.
[0174] [II] Tess Result
[0175] All of the following Test Compounds showed 100% inhibition
rate of emesis in the ferret at the dose of 3.2 and/or 10
mg/kg.
[0176] Test compounds:
[0177] The object compounds of the Examples 12, 22, 23, 24-(2) and
37-(5), (6)
[0178] The following Preparations and Examples are given for the
purpose of illustrating this invention.
[0179] (to be continued on the next page)
EXAMPLE 1
[0180] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3- -ylmethyl)
piperazine (5 g) and 3-bromopropanol (1.68 g) in
N,N-dimethylformamide (40 ml) was heated at 60.degree. C. in the
presence of potassium carbonate (4.55 g). After 9 hours, the
reaction mixture was poured into water (400 ml) and extracted with
ethyl acetate. The extract was washed with brine and dried over
magnesium sulfate. After evaporation of the solvent, the obtained
residue was purified by column chromatography on silica gel using
dichloromethane-methanol (30:1) as an eluent to give
(2R)-1-[3,5-bis (trifluoromethyl)benzoyl-4-(3-hydroxypropy-
l)-2-(1H-indol-3-ylmethyl) piperazine (5.36 g) as a powder.
[0181] IR (Neat): 3600-3100, 1625, 1275, 1170, 1128, 898
cm.sup.-1
[0182] NMR (DMSO-d.sub.6, .delta.): 1.6-5.0 (16H, m); 6.6-8.2 (8H,
m); 10.84 (1H, s)
[0183] MASS: 514 (M+1), 454
EXAMPLE 2
[0184] The following compound was obtained according to a similar
manner to that of Example 1.
[0185]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(-
3-hydroxypropyl) piperazine
[0186] IR (Nujol): 3400 (br), 3000-2700, 1625, 1430, 1270, 1120
cm.sup.-1
[0187] NMR (DMSO-d.sub.6, .delta.): 1.55-1.75 (2H, m); 2.05-4.9
(19H, m); 6.5-8.2 (6H, m)
[0188] MASS: 503 (M+1)
EXAMPLE 3
[0189] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)piperazine (0.3 g), 2-bromo-4'-chloroacetophenone (0.2 g)
and potassium carbonate (0.16 g) in N,N-dimethylformamide (5 ml)
was stirred at room temperature for 1 hour and 20 minutes. The
reaction mixture was poured into water (20 ml) and extracted with
ethyl acetate. The organic layer was washed with water and dried
over magnesium sulfate. After evaporation of the solvent, the
obtained residue was purified by column chromatography on silica
gel using zoluene-ethyl acetate (4:1) as an eluent. Fractions
containing objective compound were collected and concentrated under
reduced pressure. The obtained product was dissolved in ethyl
acetate, treated with 4N hydrogen chloride in ethyl acetate
solution and then evaporated under reduced pressure. The residue
was triturated with n-hexane to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-
-4-(4-chlorophenylcarbonymethyl)-2 -(1H-indol-3-ylmethyl)piperazine
hydrochloride (0.31 g) as a powder.
[0190] mp: 140.degree. C. (dec.)
[0191] [.alpha.].sub.D.sup.20: -22.6.degree. (C=0.5, MeOH)
[0192] IR (Nujol): 3500-3100, 2700-2150, 1690, 1635, 1275, 1100
cm.sup.-1
[0193] NMR (DMSO-d.sub.6, .delta.): 2.9-5.3 (11H, m); 6.4-8.3 (12H,
m); 10.7- 11.05 (2H, m)
[0194] MASS: 608 (M+1) (free)
EXAMPLE 4
[0195] The following compound was obtained according to a similar
manner to that of Example 3.
[0196] (2R)
-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(5-chloro-2-thienyl)
carbonylmethyl-2-(1H-indol-3-ylmethyl)piperazine hydrochloride
[0197] [a].sup.20.sub.D: -55.2.degree. (C=0.5, MeOH)
[0198] IR (Neat): 3700-3100, 2700-2150, 1635, 1415, 1275, 1130
cm.sup.-1
[0199] NMR (DMSO-d.sub.6, .delta.): 3.0-5.2 (11H, m); 6.8-8.3 (10H,
m); 10.97 (1H, s)
[0200] MASS: 651 (M+1) (free), 614
EXAMPLE 5
[0201] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3- -ylmethyl)
piperazine (0.3 g), 2-bromo-3'-fluoroacetophenone (0.19 g) and
potassium carbonate (0.16 g) in N,N-dimethylformamide (5 ml) was
stirred at room temperature for 1 hour and 20 minutes. The reaction
mixture was poured into water (20 ml) and extracted with ethyl
acetate. The organic layer was washed with water and dried over
magnesium sulfate. After evaporation of the solvent, the resulting
residue was purified by column chromatography on silica gel using
toluene-ethyl acetate (2:1) as an eluent. The obtained product was
dissolved in ethyl acetate (2 ml) and treated with 4N hydrogen
chloride in ethyl acetate solution (164 .mu.l). The resulting
precipitate was collected by filtration and dried at 50.degree. C.
for 5 hours to give (2R) -1-[3,5-bis
(trifluoromethyl)benzoyl]-4-(3-fluorophenylcarbonylmethyl)-2-(1H-indol-3--
ylmethyl)piperazine hydrochloride (0.2 g) as a powder.
[0202] mp: 195.degree. C. (dec.)
[0203] [.alpha.].sub.d.sup.20: -34.2.degree. (C=0.5, MeOH)
[0204] IR (Nujol): 3200, 2650-2200, 1695, 1655, 1270, 1125
cm.sup.-1
[0205] NMR (DMSO-d.sub.6, .delta.): 3.3-5.3 (11H, m); 6.6-8.3 (12H,
m); 10.8-11.4 (2H, m)
[0206] MASS: 592 (M+1 ) (free)
[0207] Anal. Calcd. for
C.sub.30H.sub.24F.sub.7N.sub.3O.sub.2.multidot.HCl- :
[0208] C 57.38; H 4.01; N 6.69
[0209] Found: C 57.23; H 3.79; N 6.49
EXAMPLE 6
[0210] The following compounds were obtained according to a similar
manner to that of Example 5.
[0211] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(3,4-difluorophenylc-
arbonylmethyl)-2 -(1H-indol-3-ylmethyl) piperazine
hydrochloride
[0212] mp: 171.degree. C. (dec.)
[0213] [.alpha.].sub.D.sup.20: -31.6.degree. (C=0.5, MeOH)
[0214] IR (Nujol): 3550-3100, 2650-2150, 1690, 1640, 1510, 1275,
1130 cm.sup.-1
[0215] NMR (DMSO-d.sub.6, .delta.): 3.0-5.3 (11H, m); 7.6-8.3 (11H,
m; 10.7-11.5 (2H, m)
[0216] MASS: 610 (M+1) (free)
[0217] Anal. Calcd. for
C.sub.30H.sub.23F.sub.8N.sub.3O.sub.2.multidot.HCl- :
[0218] C 55.78; H 3.74; N 6.50
[0219] Found: C 55.54; H 3.72; N 6.41
[0220] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl-
)-4-(4-methylphenylcarbonylmethyl) piperazine hydrochloride
[0221] mp: 203.degree. C. (dec.)
[0222] [.alpha.].sub.D.sup.20: -37.4 (C=0.5, MeOH)
[0223] IR (Nujol) 3550-3100, 2650-2150, 1690, 1640, 1280, 1175,
1125 cm.sup.-1
[0224] NMR (DMSO-d.sub.6, .delta.): 2.43 (3H, s); 3.1-5.3 (11H, m);
6.8-8.3 (12H, m); 10.8-11.2 (2H, m)
[0225] MASS: 587 (M+1) (free)
[0226] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(3,4-dimethylphenylc-
arbonylmethyl)-2-(1H-indol-3-ylmethyl) piperazine hydrochloride
[0227] mp: 166.degree. C. (dec.)
[0228] [.alpha.].sub.D.sup.20: -36.8.degree. (C=0.5, MeOH)
[0229] IR (Nujol): 3600-3150, 2700-2300, 1685, 1635, 1275, 1130
cm.sup.-1
[0230] NMR (DMSO-d.sub.6, .delta.): 2.34 (6H, s); 3.2-5.3 (11H, m);
6.6-8.3 (11H, m); 10.6-11.2 (2H, m)
[0231] MASS: 601 (M+1) (free)
[0232] Anal. Calcd. for
C.sub.32H.sub.29F.sub.6N.sub.3O.sub.2.multidot.HCl-
.multidot.1.1H.sub.2O:
[0233] C 58.42; H 4.93; N 6.39
[0234] Found: C 58.46; H 4.90; N 6.27
[0235] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-fluoro-3-methylph-
enylcarbonylmethyl)-2-(1H-indol-3-ylmethyl) piperazine
hydrochloride
[0236] [.alpha.].sub.D.sup.25: -28.8.degree. (C=0.5, MeOH)
[0237] IR (Nujol): 3600-3100, 2700-2200, 1685, 1635, 1275, 1130
cm.sup.-1
[0238] NMR (DMSO-d.sub.6, .delta.): 2.34 (3H, s); 3.1-5.3 (1H, m);
6.6-8.3 (11H, m); 10.7-11.2 (2H, m)
[0239] MASS: 606 (M+1) (free)
EXAMPLE 7
[0240] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)piperazine (228 mg), 1-[4-bromomethyl)phenyl]ethanone
(107 mg) and potassium carbonate (42 mg) in acetonitrile (2 ml) was
refluxed for 4.5 hours. After cooling, the mixture was evaporated
in vacuo. Ethyl acetate and water were added to the residue and the
organic layer was separated, washed with brine, dried over
magnesium sulfate, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel with a mixture of
dichloromethane and methanol as an eluent to give
(2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-
(1H-indol-3-ylmethyl) piperazine (0.30 g). To a solution of this
piperazine (0.30 g) in ethyl acetate was added 4N hydrogen chloride
in ethyl acetate solution (0.13 ml) and the whole was evaporated in
vacuo. The residue was triturated with a mixture of ethyl acetate
and ether to give
(2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-in-
dol-3-ylmethyl) piperazine hydrochloride (283.5 mg) as a
powder.
[0241] mp: 172.degree. C. (dec.)
[0242] [.alpha.].sub.D.sup.28: -30.0.degree. (C=0.27, MeOH)
[0243] IR (Nujol): 3350, 1675, 1655, 1635, 1610, 1275 cm.sup.-1
[0244] NMR (CDCl.sub.3, .delta.) 2.36-5.60 (11H, m); 6.10-9.30
(13H, m); 12.90 (1H, br s)
[0245] MASS: 588 (M) (free)
EXAMPLE 8
[0246] A mixture of
(2R)-1-[3,5-bis(trifloromethyl)benzoyl]-2-(1H-indol-3--
ylmethyl)piperazine (0.3 g), 2-bromo-4'-dimethylaminoacetophenone
(0.2 g) and potassuum carbonate (0.16 g) in N,N-dimethylformamide
(5 m,) was stirred at room temperature for 2 hours. The reaction
mixture was poured into water (20 ml) and extracted with ethyl
acetate. The organic layer was washed with water and dried over
magnesium sulfate. Affer evaporation of the solvent, the resulting
residue was purified by column chromatography on silica gel using
toluene-ethyl acetate (2:1) as an eluent. Fractions containing
objective compound were collected and evaporated under reduced
pressure to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-(4-dimethylaminophenylcarbonylmethyl)-2-(1H-i-
ndol-3-ylmethyl]piperazine (0.26 g).
[0247] mp: 185.degree. C. (dec.)
[0248] [.alpha.].sub.D.sup.20: -44.6.degree. (C=0.5, MeOH)
[0249] IR (Nujol): 3300, 1650, 1590, 1290-1150 cm.sup.-1
[0250] NMR (DMSO-d.sub.6, .delta.) 2.0-4.9 (1H, m); 3.03 (6H, s);
6.55-8.2 (12H, m); 10.80 (1H, s)
[0251] MASS: 617 (M+1)
EXAMPLE 9
[0252] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlo- robenzyl)
piperazine hydrochloride (200 mg), 4-nitrobenzyl chloride (158 mg)
and triethylamine (268 .mu.l) in tetrahydrofuran (5 ml) was
refluxed overnight. After cooling, the precipitates were filtered
off and the filtrate was evaporated in vacuo. The residue was
purified by column chromatography on silica gel with a mixture of
toluene and ethyl acetate as an eluent to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dic-
hlorobenzyl)-4-(4-nitrobenzyl) piperazine (169.8 mg).
[0253] IR (Neat): 3100-2750, 1770, 1730, 1635, 1520, 1440, 1340,
1275, 1130 cm.sup.-1
[0254] NMR (DMSO-d.sub.6, .delta.): 2.10-5.40 (11H, m); 6.85-8.30
(10H, m)
[0255] MASS: 621 (M+1)
EXAMPLE 10
[0256] The following compound was obtained according to a similar
manner to that of Example 9.
[0257]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(-
4-nitrobenzyl) piperazine
[0258] IR (Neat): 3100-2750, 1635, 1515, 1430, 1340, 1275, 1130
cm.sup.-1
[0259] NMR (DMSO-d.sub.6, .delta.): 2.00-4.85 (17H, m); 6.50-8.10
(10H, m)
[0260] MASS: 580 (M+1)
EXAMPLE 11
[0261] To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.25 g) and
4-acetylbenzoic acid (0.09 g) in dichloromethane (8 ml) was added
triethylamine (0.2 ml) at room temperature.
2-Chloro-1-methylpyridinium iodide (0.17 g,) was added, and the
mixture was stirred a room temperature for 2.5 hours. The resulting
mixture was concentrated under reduced pressure and the residue was
partitioned between ethyl acetate and water. The organic layer was
washed with aqueous sodium bicarbonate solution and dried over
magnesium sulfate. After evaporation of the solvent, the residue
was purified by column chromatography using ethyl acetate -
n-hexane (1:1) as an eluent to afford
(2R)-4-(4-acetylbenzoyl)-1-[3,5-bis (trifluoromethyl)benzoyl]-2-
-(3,4-dimethylbenzyl)piperazine (0.31 g).
[0262] NMR (DMSO-d.sub.6, .delta.): 1.9-2.4 (8H, m); 2.5-5.2 (10H,
m); 6.4-8.2 (10H, m)
[0263] MASS: 591 (M+1)
EXAMPLE 12
[0264] To a mixture of (2R)-1-3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (200 mg)
and 4-acetylbenzoic acid (57 mg) in dichloromethane (5 ml) was
added triethylamine (171 .mu.l) at room temperature.
2-Chloro-1-methylpyridiniu- m iodide (107 mg) was added, and the
mixture was stirred at room temperature for 1.5 hours. The
resulting mixture was washed successively with aqueous 0.1N
hydrogen chloride solution, aqueous saturated sodium hydrogen
carbonate solution and brine, and dried over magnesium sulfate.
After evaporation of the solvent, the residue was purified by
column chromatography using toluene-ethyl acetate (5:1) as an
eluent to give (2R)-4-(4-acetylbenzoyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2- (3,4-dichlorobenzyl)piperazine (158
mg).
[0265] [.alpha.].sub.D.sup.20: 11.2.degree. (C=0.5, MeOH)
[0266] IR (Neat): 3100-2850, 1685, 1630, 1440, 1275, 1130
cm.sup.-1
[0267] NMR (DMSO-d.sub.6, .delta.) 2.15-5.15 (9H, m); 2.62 (3H, s);
6.8-8.3 (10H, m)
[0268] MASS: 633 (M+2), 631
[0269] Anal. Calcd. for
C.sub.29H.sub.22F.sub.6Cl.sub.2N.sub.2O.sub.3:
[0270] C 55.17; H 3.51; N 4.44
[0271] Found: C 55.22; H 3.53; N 4.28
EXAMPLE 13
[0272]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)
piperazine fumarate (785 mg) was added to a mixture of 2N sodium
hydroxide solution (5 ml) and ethyl acetate. The organic layer was
separated, washed with brine, dried over magnesium sulfate, and
evaporated in vacuo to give
(2R)-1-[3,5-bis(trifluoroethyl)benzoyl]-2-(3,- 4-dimethylbenzyl)
piperazine. A solution of this piperazine in N,N-dimethylformamide
(7 ml) was added to a mixture of 2-acetylbenzoic acid (230 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295
mg) and 1-hydroxybenzotriazole (208 mg) in N,N-dimethylformamide (3
ml) and the whole was stirred at room temperature overnight. The
mixture was poured into a saturated sodium hydrogen carbonate
solution (78 ml) and the resulting precipitates were filtered off.
The filtrate was evaporated in vacuo to give
(2R)-4-(2-acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimet-
hylbenzyl) piperazine (0.45 g) as a powder.
[0273] mp: 82-85.degree.0 C.
[0274] [.alpha.].sub.D.sup.29: -22.7 (C=0.33, MeOH)
[0275] IR (CHCl.sub.2): 1750, 1635, 1615 cm.sup.-1
[0276] NMR (CDCl.sub.3, .delta.) 1.75-5.40 (18H, m); 6.40-8.10
(10H, m)
[0277] MASS: 591 (M)
EXAMPLE 14
[0278] The following compound was obtained according to a similar
manner to that of Example 13.
[0279] (2R)-4-(3-Acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2- (3,4-dimethylbenzyl)piperazine
[0280] mp: 155.5-157.degree. C.
[0281] [.alpha.].sub.D.sup.24: 5.8.degree. (C=0.26, MeOH)
[0282] IR (Nujol): 1688, 1630 cm.sup.-1
[0283] NMR (CDCl.sub.3, .delta.): 2.05-2.32 (6H, m); 2.63 (3H, s);
2.70-5.40 (9H, m); 6.40-8.15 (10H, m)
[0284] MASS: 592 (M+1)
EXAMPLE 15
[0285] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2- -(1H-indol-3-ylmethyl) piperazine (250
mg), 2-methoxyphenylacetic acid (92 mg) and 1-hydroxybenzotriazole
(75 mg) in dichloromethane (8 ml) was added 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg)
at room temperature. After 3 hours, the reaction mixture was poured
into aqueous sodium bicarbonate solution and extracted with
dichloromethane. The extract was washed with brine and dried over
magnesium sulfate. After evaporation of the solvent, the residue
was purified by column chromatography on silica gel using ethyl
acetate - n-hexane (1:1.5) as an eluent to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methoxyphenylmethy-
lcarbonyl) piperazine (290 mg) as a powder.
[0286] NMR (DMSO-d.sub.6, .delta.): 2.6-5.0 (14H, m); 6.4-8.2 (12H,
m); 10.8 (1H, m)
[0287] MASS: 604 (M+1)
EXAMPLE 16
[0288] The following compounds were obtained according to a similar
manner to that of Example 15.
[0289] (1) (2R)-4-(3-Acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(1H-indol-3-ylmethyl)piperazine
[0290] mp: 186-187.5.degree. C.
[0291] [.alpha.].sub.D.sup.29: 4.2.degree. (C=0.29, MeOH)
[0292] IR (Nujol): 3260, 1690, 1633, 1600, 1275 cm.sup.-1
[0293] NMR (CDCl.sub.3, .delta.): 1.55-5.46 (12H, m); 6.55-8.50
(13H, m)
[0294] MASS: 602 (M)
[0295] (2) (2R)-4-(2-Acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(1H-indol-3-ylmethyl)piperazine
[0296] mp: 190-192.degree. C.
[0297] [.alpha.].sub.D.sup.28: -2.1.degree. (C=0.28, MeOH)
[0298] IR (Nujol): 3300, 2700, 1750, 1720, 1635, 1630, 1275
cm.sup.-1
[0299] NMR (CDCl.sub.3, .delta.): 1.46-5.45 (12H, m); 6.54-8.25
(13H, m)
[0300] MASS: 602 (M)
EXAMPLE 17
[0301] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-
-(carboxymethyl)-2-(1H-indol-3-ylmethyl) piperazine (0.4 g) and
thiomorpholine (0.08 g) in dry N,N-dimethylformamide (4 ml) were
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.16 g) and 1-hydroxybenzotriazole (0.29 g) at room temperature.
After 3 hours, the reaction mixture was poured into aqueous sodium
bicarbonate solution (40 ml) and the resulting precipitate was
collected by filtration. The crude product obtained was purified by
column chromatography on silica gel using toluene-ethyl acetate
(1:2) as an eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(thiom-
orpholinocarbonylmethyl) piperazine (0.42 g).
[0302] [.alpha.].sub.D.sup.19: -10.0.degree. (C=0.5, MeOH)
[0303] IR (Neat): 3650-3100, 1634, 1274, 1170, 1122, 898
cm.sup.-1
[0304] NMR (DMSO-d.sub.6, .delta.): 2.00-5.00 (19H, m); 6.60-8.20
(8H, m); 10.86 (1H, s)
[0305] MASS: 599 (M+1)
EXAMPLE 18
[0306] The following compound was obtained according to a similar
manner to that of Example 17.
[0307]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(4-(4-fluorophenyl)-1-p-
iperazinyl) carbonylmethyl]-2- (1H-indol-3-ylmethyl) piperazine
hydrochloride
[0308] mp: 183.degree. C. (dec.)
[0309] [.alpha.].sub.D.sup.25: -24.0.degree. (C=0.5, MeOH)
[0310] IR (Nujol): 3600-3100, 2650-2150, 1680-1580, 1510, 1275,
1130 cm.sup.-1
[0311] NMR (DMSO-d.sub.6, .delta.): 3.05-5.15 (19H, m); 6.6-8.3
(12H, m); 10.40 (2H, br s); 11.02 (1H, s)
[0312] MASS: 676 (M+1) (free)
EXAMPLE 19
[0313] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4- -(carboxymethyl)-2-
(1H-indol-3-ylmethyl) piperazine (200 mg) and
4-cyclopentylpiperazine (60 mg) in dry N,N-dimethylformamide (5 ml)
were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (82 mg) and 1-hydroxybenzotriazole (58 mg) at room
temperature. After 7 hours, the reaction mixture was poured into
water (30 ml) and extracted with ethyl acetate. The extract was
washed with water and dried over magnesium sulfate. After
evaporation of the solvent, the residue was purified by column
chromatography on silica gel using dichloromethane-methanol (10:1)
as an eluent and then treated with 4N hydrogen chloride in ethyl
acetate solution (80 .mu.l) to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(-
4-cyclopentyl-1-piperazinyl) carbonylmethyl]-2-
(1H-indol-3-ylmethyl)piper- azine hydrochloride (40 mg).
[0314] mp: 270.degree. C. (dec.)
[0315] [.alpha.].sub.D.sup.25: -24.2.degree. (C=0.5, MeOH)
[0316] IR (Nujol): 3270, 2430-2150, 1630, 1275, 1180, 1125
cm.sup.-1
[0317] NMR (DMSO-d.sub.6, .delta.): 1.45-5.0 (28H, m), 6.55-8.25
(8H, m); 10.90 (1H, s); 11.21 (2H, br s)
[0318] MASS: 650 (M+1) (free)
[0319] Anal. Calcd. for
C.sub.33H.sub.37F.sub.6N.sub.5O.sub.2.multidot.HCl- :
[0320] C 57.77; H: 5.58; NT 10.21
[0321] Found : C 57.91; H 5.64; N 10.18
EXAMPLE 20
[0322] A solution of methanesulfonyl chloride (1.1 g) in
dicloromethane (4 ml) was added to a stirred solution of
(2R)-1-[3,5-bis(trifluoromethyl)be-
nzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl) piperazine (4.99
g) and triethylamine (1.1 g) in dichloromethane (50 ml) at ice-bath
temperature over a 20-minute period. After being stirred at the
same temperature for 1 hour, the reaction mixture was diluted with
dichloromethane (50 ml) and then washed with water and aqueous
sodium bicarbonate solution. The dichloromethane layer was dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel using
dichloromethane-methanol (30:1) as an eluent to give
(2R)-1-[3,5-bis
(trfluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-met-
hylsulfonyloxypropyl) piperazine (4.31 g) as a powder.
[0323] MASS: 592 (M+1)
EXAMPLE 21
[0324] The following compound was obtained according to a similar
manner to that of Example 20.
[0325]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(-
3-methylsulfonyloxypropyl) piperazine
[0326] IR (Nujol): 2950-2700, 1635, 1430, 1350, 1275, 1165, 1125
cm.sup.-1
[0327] NMR (DMSO-d.sub.6, .delta.) : 1.8-4.95 (19H, m); 3.19 (3H,
s); 4.31 (2H, t, J=6.2Hz); 6.95-8.2 (6H, m)
[0328] MASS: 581 (M-1)
EXAMPLE 22
[0329] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (0.2 g),
3-azabicyclo[3.2.2]nonane (0.05 g) and triethylamine (0.09 ml) in
N,N-dimethylformamide (1 ml) was heated at 80.degree. C. After 6
hours, the reaction mixture was poured into water (10 ml) andd the
resulting precipitate was collected by filtration. The crude
product was dissolved in ethanol (2 ml) and then treated with 17.6%
hydrogen chloride in ethanol solution (0.3 ml) to give
(2R)-4-[3-(3-azabicyclo(3.2.2]non-3-yl)
propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)
piperazine dihydrochloride (0.12 g) as a powder.
[0330] mp: 194-202.degree. C.
[0331] [.alpha.].sub.D.sup.19: -6.0.degree. (C=0.5, MeOH)
[0332] IR (Nujol): 3600-3100, 2750-2000, 1680-1550, 1275, 1172,
1126, 900 cm.sup.-1
[0333] NMR (DMSO-d.sub.6, .delta.): 1.50-5.20 (29H, m); 6.60-8.25
(8H, m); 9.80 (1H, br s); 10.96 (1H, s); 11.60 (1H, br s)
EXAMPLE 23
[0334] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (0.2 g),
thiomorpholine (0.042 g) and triethylamine (0.09 ml) in dry
acetonitrile (2 ml) was stirred at 90.degree. C. for 15 hours. The
reaction mixture was concentrated under reduced pressure and the
resulting residue was partitioned between ethyl acetate and water.
The organic layer was washed with brine and dried over magnesium
sulfate. After evaporation of the solvent, the residue was purified
by column chromatography on silica gel using ethyl acetate-methanol
(10:1) as an eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thi-
omorpholinopropyl) piperazine. The product obtained was dissolved
in ethanol and treated with 17.6% hydrogen chloride in ethanol
solution to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(-
3-thiomorpholinopropyl) piperazine dihydrochloride (0.19 g) as a
powder.
[0335] [.alpha.].sub.D.sup.20: -4.6 (C=0.5, MeOH)
[0336] IR (Nujol): 3650-3050, 2750-1980, 1635, 1274, 1170, 1123,
900 cm.sup.-1
[0337] NMR (DMSO-d.sub.6, .delta.): 2.20-5.20 (23H, m); 6.50-8.25
(8H, m); 10.96 (1H, s); 11.00-11.90 (2H, m)
[0338] MASS: 599 (M+1) (free)
[0339] (2R)-4-(3-Thiomorpholinopropyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2- (1H-indol-3-ylmethyl)piperazine dimaleate
[0340] mp: 110-115.degree. C.
[0341] [.alpha.].sub.D.sup.21: -14.2.degree. (C=0.25, MeOH)
[0342] IR (Nujol): 3350, 2720, 1690, 1620, 1605, 1280, 1130
cm.sup.-1
[0343] NMR (DMSO-d.sub.6, .delta.): 1.70-5.12 (23H, m), 6.14 (4H,
s), 6.55-8.32 (8H, m), 10.90 (1H, s)
EXAMPLE 24
[0344] The following compounds were obtained according to a similar
manner to that of Example 23.
[0345] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl-
)-4-(3-morpholinopropyl)piperazine dihydrochloride
[0346] mp: 265.degree. C. (dec.)
[0347] [.alpha.].sub.D.sup.31: -6.0.degree. (C=0.5, MeOH)
[0348] IR (Nujol): 3650-3100, 2750-2200, 1655, 1275, 1120
cm.sup.-1
[0349] NMR (DMSO-d.sub.6, .delta.): 2.2-2.45 (2H, m); 3.0-5.25
(21H, m); 6.55-8.25 (8H, m); 10.98 (1H, s); 11.1-12.85 (2H, m)
[0350] MASS: 583 (M+1) (free)
[0351] Anal. Calcd. for
C.sub.29H.sub.32F.sub.6N.sub.4O.sub.2.multidot.2HC-
l.multidot.0.4H.sub.2O:
[0352] C 52.56; H 5.29; N 8.45
[0353] Found: C 52.54; H 5.33; N 8.25
[0354] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-(3-thiomorpholinopropyl) piperazine dihydrochloride
[0355] mp: 272.degree. C. (dec.)
[0356] [.alpha.].sub.D.sup.31: -11.6.degree. (C=0.5, MeOH)
[0357] IR (Nujol): 3650-3100, 2750-2650, 1635, 1270, 1120
cm.sup.-1
[0358] NMR (DMSO-d.sub.6, .delta.): 2.1-2.5 (8H, m); 2.7-5.2 (21H,
m); 6.6-8.25 (6H, m); 11.15-11.75 (2H, m)
[0359] MASS: 588 (M+1) (free)
EXAMPLE 25
[0360] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl) piperazine (200 mg) and
1,2,3,4-tetrahydroisoquinoline (90 mg) in methanol (3 ml) was
stirred for 1.5 hours at reflux temperature. The reaction mixture
was evaporated under reduced pressure and the residue was purified
by column chromatography on silica gel using ethyl acetate-methanol
(10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(1H-indol-3-yl-
methyl)-4-[3-[1,2,3,4-tetrahydroisoquinolin-2-yl]propyl]piperazine
(167 mg) as a powder.
[0361] [.alpha.].sub.D.sup.20: -9.6.degree. (C=0.5, MeOH)
[0362] IR (Neat): 3260, 1630, 1430, 1380, 1350, 1270 cm.sup.-1
[0363] NMR (DMSO-d.sub.6, .delta.): 1.60-4.93 (21H, m); 6.60-8.37
(12H, m); 10.85 (1H, s)
[0364] MASS: 629 (M+1)
EXAMPLE 26
[0365] The following compound was obtained according to a similar
manner to that of Example 25.
[0366]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4--
[3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)
propyl]piperazine
[0367] [.alpha.].sub.D.sup.18: -9.0.degree. (C=0.5, MeOH)
[0368] IR (Neat): 3260, 1630, 1430, 1350, 1275 cm.sup.-1
[0369] NMR (DMSO-d.sub.6, .delta.): 1.55-4.97 (21H, m); 6.30-8.24
(10H, m); 10.85 (1H, s)
[0370] MASS: 635 (M+1)
EXAMPLE 27
[0371] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (150 mg) and
4-cyano-4-phenylpiperidine hydrochloride (70 mg) in methanol (5 ml)
was stirred at reflux temperature in the presence of sodium
carbonate (100 mg). After 2 hours, the reaction mixture was
evaporated under reduced pressure. The residue was extracted with
ethyl acetate and the extract was concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel using ethyl acetate-methanol (10:1) as an eluent to give
(2R)-1-[3,5-bis (trifluoromethyl)benzoyl]-4-[3-(4-cy-
ano-4-phenylpiperidino) propyl]-2-(1H-indol-3-ylmethyl)piperazine
(89 mg) as a powder.
[0372] [.alpha.].sub.D.sup.20: -19.2.degree. (C=0.5, MeOH)
[0373] NMR (DMSO-d.sub.6, .delta.): 1.52-4.96 (23H, m); 6.60-8.26
(13H, m); 10.85 (1H, s)
[0374] MASS: 682 (M+1)
EXAMPLE 28
[0375] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (200 mg) and
spiro[indan-1,4'-piperidine] (70 mg) in acetonitrile (3 ml) was
refluxed for 1.5 hours. The reaction mixture was evaporated under
reduced pressure and then the residue was purified by column
chromatography on silica gel using dichloromethane-methanol (10:1)
as an eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(spiro[indan-1,4
'-piperidine]-1'-yl)propyl]-2-(1H-indol-3-ylmethyl) piperazine (208
mg) as a powder.
[0376] [.alpha.].sub.D.sup.22: -21.4.degree. (C=1.0, MeOH)
[0377] IR (Neat): 3260, 1630, 1435, 1380, 1350, 1275 cm.sup.-1
[0378] NMR (DMSO-d.sub.6, .delta.): 1.45-5.00 (27H, m); 6.62-8.28
(12H, m); 10.88 (1H, s)
[0379] MASS: 683 (M+1)
EXAMPLE 29
[0380] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlo-
robenzyl)-4-(4-nitrobenzyl) piperazine (157 mg), ammonium chloride
(15.7 mg) and iron powder (157 mg) in a mixture of ethanol (5 ml)
and water (1.25 ml) was refluxed for 1.5 hours. After cooling, the
precipitates were filtered off and the filtrate was evaporated in
vacuo. The residue was purified by column chromatography on silica
gel with a mixture of toluene and ethyl acetate as an eluent to
give (2R)-4-(4-aminobenzyl)-1-[-
3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl) piperazine
(128.4 mg).
[0381] IR (Neat): 3350, 2970-2700, 1630, 1515, 1460, 1430, 1275,
1130 cm.sup.-1
[0382] NMR (DMSO-d.sub.6, .delta.): 1.95-5.05 (13H, m); 6.50-8.25
(10H, m)
[0383] MASS: 592 (M+2), 590 (M)
EXAMPLE 30
[0384] The following compound was obtained according to a similar
manner to that of Example 29.
[0385] (2R)-4-(4-Aminobenzyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)piperazine
[0386] IR (Neat): 3450, 3300, 3100-2650, 1625, 1515, 1435, 1275,
1125 cm.sup.-1
[0387] NMR (DMSO-d.sub.6, .delta.): 1.90-4.80 (17H, m); 4.98 (2H,
s); 6.40-8.20 (10H, m)
[0388] MASS: 550 (M+1)
EXAMPLE 31
[0389] Piridine (23 .mu.l) and acetyl chloride (16 .mu.l) were
successively added to a solution of
(2R)-4-(4-aminobenzyl)-1-[3,5-bis(tri-
fluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl) piperazine (113 mg)
and the whole was stirred at room temperature for 1.5 hours. The
mixture was poured into water and the separated oil was extracted
with ethyl acetate. The extract was washed with water, dried over
magnesium sulfate and evaporated in vacuo. The residue was purified
by column chromatography on silica gel with a mixture of toluene
and ethyl acetate as an eluent to give
(2R)-4-(4-acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(-
3,4-dichlorobenzyl) piperazine (98.3 mg). The obtained piperazine
was dissolved in ethyl acetate. 4N Hydrogen chloride in ethyl
acetate solution (43 .mu.l) was added to the solution and the
mixture was evaporated in vacuo. The residue was triturated with
n-hexane to give (2R)-4-(4-acetylaminobenzy)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-d- ichlorobenzyl) piperazine
hydrochloride (92 mg).
[0390] [.alpha.].sub.D.sup.20: -11.8.degree. (C=0.5,MeOH)
[0391] IR (Neat): 3600-3150, 2750-2100, 1635, 1600, 1525, 1415,
1270, 1130 cm.sup.-1
[0392] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H, s); 2.85-5.15 (11H,
m); 6.80-8.30 (10H, m); 10.13 (1H, s)
[0393] MASS: 32 (M+1) (free)
EXAMPLE 32
[0394] The following compound was obtained according to a similar
manner to that of Example 31.
[0395] (2R)-4-(4-Acetylaminobenzyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2- -(3,4-dimethylbenzyl)piperazine
hydrochloride
[0396] [.alpha.].sub.D.sup.25: -23.2.degree. (C=0.5, MeOH)
[0397] IR (Nujol): 3650-3100, 2750-2100, 1640, 1600, 1530, 1275,
1170, 1130 cm.sup.-1
[0398] NMR (DMSO-d.sub.6, .delta.): 1.95-2.10 (9H, m); 2.80-5.05
(11H, m); 6.50-8.30 (10H, m); 10.17 (1H, s); 11.00-11.40 (1H,
m)
[0399] MASS: 592 (M+1) (free)
EXAMPLE 33
[0400]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4--
(thiomorpholinocarbonylmethyl) piperazine was converted to the
corresponding hydrochloride by treatment with 17.6% hydrogen
chloride in ethanol solution.
[0401] IR (Nujol): 3650-3100, 2750-1980, 1638, 1276, 1171, 1129,
900 cm.sup.-1
[0402] NMR (DMSO -d.sub.6, .delta.): 2.55-5.15 (19H, m); 6.60-8.25
(8H, m); 10.99 (1H, s)
[0403] MASS: 599 (M+1) (free)
Preparation 1
[0404] A mixture of formaldehyde (37% in water, 20.7 ml) and
morpholine (17.1 ml) was adjusted to pH 3.5 with diluted sulfuric
acid. Propargyl alcohol (10 g), potassium iodide 0.3 g), and copper
(II) sulfate (0.14 g) were added to the solution and the whole was
stirred at 95.degree. C. for 6 hours. After cooling, the insoluble
material was removed by filtration and the pH of the filtrate was
adjusted to 9 with 24% sodium hydroxide solution. Brine (100 ml)
was added to the solution and the solution was extracted with a
mixture of ethyl acetate and ethanol (10:1) eight times and then
with n-butanol six times. The combined extract was dried over
magnesium sulfate and evaporated in vacuo. The residue was
distilled in reduced pressure to give 4-morpholino-2-butyn-1-ol
(14.03 g).
[0405] bp: 124-131.degree. C.
[0406] IR (Neat): 3350, 2850, 1105, 1000 cm.sup.-1
[0407] NMR (CDCl.sub.3, .delta.): 2.18 (1H, br s), 2.57 (4H, t,
J=4.7Hz), 3.31 (2H, t, J=1.9Hz), 3.75 (4H, t, J=4.7Hz), 4.30 (2H,
t, J=1.9Hz)
[0408] MASS: 156 (M+1)
Preparation 2
[0409] The following compound was obtained according to a similar
manner to that of Preparation I with the exception of purification
by column chromatography on silica gel using a mixture of ethyl
acetate and methanol (30:1) as an eluent instead of distillation in
reduced pressure.
[0410] 4- Thiomorpholino-2-butyn-1-ol
[0411] IR (Neat): 3350, 2900, 2800, 4920, 1330, 1115, 1100
cm.sup.-1
[0412] NMR (CDCl.sub.3, .delta.): 1.93 (1H, br s), 2.65-2.90 (8H,
m), 3.32 (2H, t J=1.9Hz), 4.30 (2H, t, J=1.9Hz)
[0413] MASS: 172 (M+1)
Preparation 3
[0414] Thionyl chloride (2.1 ml) was added to a solution of
4-morpholino-2-butyn-1-ol (1.47 g) in dichloromethane (10 ml) with
ice bath cooling. After stirring for 0.5 hour, the solution was
evaporated in vacuo. The residue was triturated with ethyl acetate
to give 4-morpholino-2-butynyl chloride hydrochloride (1.91 g).
[0415] mp: 162-165.degree. C.
[0416] IR (Nujol): 2640, 2510, 2450, 2350 cm.sup.-1
[0417] NMR (DMSO-d.sub.6, .delta.): 3.31 (4H, br s), 3.92 (4H, br
s), 4.21 (2H, t, J=1.9Hz), 4.57 (2H, t, J=1.9Hz), 12.23 (1H, br
s)
[0418] MASS: 174 (M) (free)
Preparation 4
[0419] The following compound was obtained according to a similar
manner to that of Preparation 3.
[0420] 4-Thiomorpholino-2-butynyl chloride hydrochloride
[0421] m.p: 185-187.degree. C.
[0422] IR (Nujol): 2600, 2450, 2380, 1280, 1260, 1160, 915
cm.sup.-1
[0423] NMR (DMSO-d.sub.6, .delta.): 2.58-4.00 (8H, m), 4.21 (2H, t,
J=2.0Hz), 4.58 (2H, t, J=2.0Hz), 12.08 (1H, br s)
[0424] MASS: 190 (M) (free)
Preparation 5
[0425] A mixture of 4-chloro-1-(4-fluorophenyl-1-butanone (500 mg),
ethylene glycol (247 mg) and catalytic amount of p-toluenesulfonic
acid monohydrate in benzene (5 ml) was refluxed for 20 hours with
continuous removal of water using Dean-Stark apparatus. After
cooling, the solution was washed sucessively with 1N NaOH solution
and brine, dried over magnesium sulfate, and evaporated in vacuo to
give 4-chloro-1- (4-fluorophenyl)-1-butanone cyclic ethylene acetal
(613.2 m.g) as an oi.
[0426] IR (Neat): 2950, 2870, 1600, 1500, 1220, 1030 cm.sup.-1
[0427] NMR (DMSO-d.sub.6, .delta.): 1.60-1.80 (2H, m), 1.90-2.00
(2H, m), 3.61 (2H, t, J=6.5Hz), 3.70-4.10 (4H, m), 7.10-7.50 (4H,
m,)
[0428] MASS: 245 (M+1), 209
EXAMPLE 34
[0429] A mixture of (2R)
-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthy- lmethyl)
piperazine (1.0 g) and 3-bromopropanol (330 mg) in
N,N-dimethylformamide (2.5 ml) was stirred at room temperature in
the presence of powdered potassium carbonate (444 mg). After 17
hours, the reaction mixture was diluted with ethyl acetate (30 ml)
and then washed successively with water and brine, and dried over
magnesium sulfate. Evaporation of the solvent in vacuo qave
(2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-napthylmethyl)
piperazine (1.19 g).
[0430] IR (Neat): 3425, 1635, 1430, 1340, 1275, 1170, 1130
cm.sup.-1
[0431] NMR (CDCl.sub.3, .delta.): 1.50-5.28 (16H, mn), 7.40-7.93
(10H, m)
[0432] MASS: 528 (M+1)
EXAMPLE 35
[0433] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthyl- methyl)
piperazine (200 mg) and 1-(4-chloro-2-butynyl) morpholine
hydrochloride (95 mg) in N,N-dimethylformamide (0.5 ml) was stirred
at room temperature in the presence of powdered potassium carbonate
(177 mg). After 17 hours, the reaction mixture was diluted with
ethyl acetate (30 ml) and then washed successvely with water and
brine, and dried over magnesium sulfate. After evaporation of the
solvent in vacuo, the resulting residue was purified by column
chromatography on silica gel using ethyl acetate as an eluent. The
product obtained was dissolved in ethyl acetate and treated with 4N
hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-morpholino-
-2-butynyl)-2-(2-naphthylmethyl) piperazine dihydrochloride (257
mg).
[0434] [.alpha.].sub.D.sup.21: -21.5.degree. (C=0.5, MeOH)
[0435] IR (Nujol): 3350, 2550, 1630, 1275 cm.sup.-1
[0436] NMR (DMSO-d.sub.6, .delta.): 2.80-5.31 (21H, m), 7.0-8.28
(10H, m)
[0437] MASS: 604 (M+1) (free)
EXAMPLE 36
[0438] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlo- robenzyl)
piperazine hydrochloride (150 mg) and 1-(4-chloro-2-butynyl)morp-
holine hydrochloride (63 mg) in N,N-dimethylformamide (0.5 ml) was
stirred at room temperature in the presence of powdered potassium
carbonate (160 mg). After 17 hours, the reaction mixture was
diluted with ethyl acetate (30 ml) and then washed successively
with water and brine, and dried over magnesizm sulfate. After
evaporation of the solvent in vacuo, the resulting residue was
purified by column chromatography on silica gel using a mixture of
ethyl acetate and methanol (10:1) as an eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morp-
holino-2-butynyl) piperazine. The product obtained was dissolved in
ethyl acetate and treated with 4N hydrogen chloride in ethyl
acetate solution to give
dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine
dihydrochloride (155 mg).
[0439] [.alpha.].sub.D.sup.20: -3.9.degree. (C=0.5, MeOH)
[0440] IR (Neat): 3400, 2350, 1640, 1425, 1275 cm.sup.-1
[0441] NMR (DMSO-d.sub.6, .delta.): 2.91-5.20 (21H, m), 7.0-8.26
(6H, m)
[0442] MASS: 629 (M+1) (free)
EXAMPLE 37
[0443] The following compounds were obtained according to a similar
manner to that of Example 7.
[0444] (1) (2R)-4-(4-Morpholino-2-butynyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
dihydrochloride
[0445] mp: 165-169.degree. C.
[0446] [.alpha.].sub.D.sup.21: -0.4.degree. (C=0.26, MeOH)
[0447] IR (Nujol): 3350, 2550, 2320, 1635, 1550, 1270, 1120
cm.sup.-1
[0448] NMR (DMSO-d.sub.6, .delta.): 2.80-5.25 (21H, m), 6.56-8.30
(8H, m), 10.96 (1H, s)
[0449] MASS: 593 (M) (free)
[0450] (2) (2R)-4-(4-Morpholino-2-butynyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine
dihydrochloride
[0451] mp: 155-162.degree. C.
[0452] [.alpha.].sub.D.sup.21: -11.5.degree. (C=0.26, MeOH)
[0453] IR (Nujol): 3350, 2650, 2300, 1655, 1640, 1275, 1120
cm.sup.-1
[0454] NMR (DMSO-d.sub.6, .delta.): 2.02-2.30 (7H, m,), 2.64-5.30
(20H, m), 6.60-8.30 (6H, m)
[0455] MASS: 582 (M) (free)
[0456] (3) (2R)-4-(4-Thiomorpholino-2-butynyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine
dihydrochloride
[0457] mp: 162-170.degree. C.
[0458] [.alpha.].sub.D.sup.22: -9.4.degree. (C=0.27, MeOH)
[0459] IR (Nujol): 3350, 2650, 2320, 1655, 1640, 1275, 1125
cm.sup.-1
[0460] NMR (DMSO-d.sub.6, .delta.): 2.04-2.35 (7H, m), 2.65-5.25
(20H, m), 6.57-8.28 (6H, m)
[0461] MASS: 598 (M) (free)
[0462] (4) (2R)-4-(4-Thiomorpholino-2-butynyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
dihydrochloride
[0463] mp: 166-170.degree. C.
[0464] [.alpha.].sub.D.sup.22: -1.5.degree. (C=0.26, MeOH)
[0465] IR (Nujol): 3350, 2650, 2300, 1635, 1275, 1125 cm.sup.-1
[0466] NMR (DMSO-d.sub.6, .delta.): 2.58-5.30 (21H, m), 6.54-8.30
(8H, m), 10.98 (1H, br s), 12.10 (2H, br s)
[0467] MASS: 609 (M) (free)
[0468] (5) (2R)-4-(2-Morpholinoethyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrocloride
[0469] mp: 223-228.degree. C.
[0470] [.alpha.].sub.D.sup.27.2: -13.0.degree. (C=0.28, MeOH)
[0471] IR (Nujol): 3350, 2550, 1630, 7450, 1275, 1120 cm.sup.-1
[0472] NMR (DMSO-D.sub.6, .delta.): 1.95-5.25 (27H, m), 6.50-8.32
(6H, m), 10.80-11.90 (2H, br m)
[0473] MASS: 558 (M) (free)
[0474] (6) (2R)-4-(2-Thiomorpholinoethyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
dihydrochloride
[0475] mp: 170-182.degree. C.
[0476] [.alpha.].sub.D.sup.28.5: -4.5.degree. (C=0.39, MeOH)
[0477] IR (Nujol): 3350, 2600, 1640, 1275, 1125 cm.sup.-1
[0478] NMR (DMSO-d.sub.6, .delta.): 2.60-5.30 (21H, m), 6.50-8.30
(8H, m), 10.96 (1H, s), 11.10-12.10 (2H, br m)
[0479] MASS: 585 (M) (free)
[0480] (7) (2R)-4-(2-Morpholinoethyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]- -2-(1H-indol-3-ylmethyl) piperazine
dihydrochloride
[0481] mp: 170-176.degree. C.
[0482] [.alpha.].sub.D.sup.28.5: -3.0.degree. (C=0.30, MeOH)
[0483] IR (Nujol): 3350, 2570, 1640, 1275, 1125 cm.sup.-1
[0484] NMR (DMSO-d.sub.6, .delta.): 2.60-5.30 (21H, m), 6.55-8.40
(8H, m), 10.95 (1H, s), 11.10-12.04 (2H, br m)
[0485] MASS: 569 (M) (free)
[0486] (8) (2R)-4-(2-Thiomorpholinoethyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine
dihydrochloride
[0487] mp: 261.5.degree. C.
[0488] [.alpha.].sub.D.sup.28.5: -1.9.degree. (C=0.29, DMF)
[0489] IR (Nujol): 3350, 2350, 1640, 1275, 1130 cm.sup.-1
[0490] NMR (DMSO-d.sub.6, .delta.): 2.00-5.30 (27H, m), 6.60-8.30
(6H, m), 1.60-12.00 (2H, br m)
[0491] MASS: 574 (M) (free)
EXAMPLE 38
[0492] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3- -ylmethyl)
piperazine (300 mg), 4-chloro-1-(4-fluorophenyl)-1-butanone cyclic
ethylene acetal (161 mg), potassium carbonate (182 mg), and
potassium iodide (109 mg) in acetonitrile (10 ml) was refluxed for
20 hours. After cooling, the insoluble material was removed by
filtration and the filtrate was evaporated in vacuo. The residue
was purified by column chromatography on silica gel with a mixture
of toluene and ethyl acetate as an eluent to give
(2R)-4-[4,4-ethylenedioxy-4-(4-fluorophenyl)- butyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine as a
powder. This compound was further purified by washing with
diisopropyl ether.
[0493] mp: 145-146.degree. C.
[0494] IR (Nujol): 3200, 1620, 1600, 1275, 1120 cm.sup.-1
[0495] NMR (DMSO-d.sub.6, .delta.): 1.35-1.55 (2h, m), 1.80-4.90
(17H, m), 6.55-8.20 (12H, m), 10.87 (1H, br s)
[0496] MASS: 664 (M+1)
EXAMPLE 39
[0497] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-
-(carboxymethyl)-2-(1H-indol-3-ylmethyl) piperazine (0.2 g) and
3-azabicyclo3.2.2]nonane (0.05 g) in dry N,N-dimethylformamide (2
ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.082 g) and 1-hydroxybenzotriazole (0.058 g) at
room temperature. After 6 hours, the reaction mixture was poured
into aqueous sodium bicarbonate solution (20 ml) and the resulting
precipitate was collected by filtration. The crude product obtained
was purified by column chromatography on silica gel using
toluene-ethyl acetate (1:2) as an eluent and treated with 77.6%
hydrogen chloride in ethanol solution to give
(2R)-4-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
hydrochloride (0.2 g) as a white powder.
[0498] [.alpha.].sub.D.sup.20: -32.0.degree. (C=0.5, MeOH)
[0499] IR (Nujol): 3650-3100, 2750-2000, 1637, 1276, 1172, 1130,
900 cm.sup.-1
[0500] NMR (DMSO-d.sub.6, .delta.): 1.50-1.75 (8H, m), 2.07 (2H, br
s), 3.15-5.10 (15H, m), 6.60-8.25 (8H, m), 10.15 (1H, br s), 11.00
(1H, s)
[0501] MASS: 621 (M+1) (free)
EXAMPLE 40
[0502] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-
-(4-carboxybenzyl)-2-(1H-indol-3-ylmethyl) piperazine (150 mg) and
diethylamine hydrochloride (28 mg) in dry dichloromethane (5 ml)
were added a solution of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (40 mg) in
dichloromethane (1 ml) and 1-hydroxybenzotriazole (34 mg) at room
temperature. After 5 hours, the reaction mixture was poured into
aqueous sodium bicarbonate solution (20 ml). The organic layer was
separated and washed with brine and dried over magnesium sulfate.
The crude product obtained was purified by column chromatography on
silica gel using ethyl acetate - n-hexane (4:1) to give
(2R)-1-[3,5-bis (trifluoromethyl)benzoyl-
]-4-[4-(N,N-diethylaminocarbonyl)
benzyl]-2-(1H-indol-3-ylmethyl)piperazin- e (107 mg) as a
powder.
[0503] [.alpha.].sub.D.sup.21: -40.3.degree. (C=0.5, MeOH)
[0504] IR (Neat): 3250, 1620, 1430, 1275, 1130 cm.sup.-1
[0505] NMR (CDCl.sub.3, .delta.): 1.10-5.00 (25H, m) 6.40-8.00 (8H,
m), 9.14 (1H, s)
[0506] MASS: 645 (M+1)
EXAMPLE 41
[0507] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-
-(3-hydroxypropyl)-2-(2-naphthylmethyl) piperazine (1.1 g) and
triethylamine (425 mg) in dichloromethane (10 ml) was added
dropwise methanesulfonyl chloride (252 mg) at ice-bath temperature.
After 2 hours, the reaction mixture was washed with water and then
dried over magnesium sulfate. After evaporation of the solvent, the
resulting residue was chromatographed on silica gel using ethyl
acetate as an eluent to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methy-
lsulfonyloxypropyl) piperazine (988 mg).
[0508] IR (Neat): 1635, 1430, 1350, 1280, 1170, 1130 cm.sup.-1
[0509] NMR (CDCl.sub.3, .delta.): 1.59 (3H, s), 1.90-5.28 (15H, m),
7.40-7.90 (10H, m)
[0510] MASS: 603 (M+1)
EXAMPLE 42
[0511] The following compounds were obtained according to a similar
manner to that of Example 41.
[0512] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-
-4-(3-methylsulfonyloxypropyl) piperazine
[0513] IR (Neat): 1630, 1470, 1430, 1340, 1270 cm.sup.-1
[0514] NMR (CDCl.sub.3, .delta.): 1.55-5.14 (15H, m), 3.04 (3H, s),
7.00-7.95 (6H, m)
[0515] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-(2-methylsulfonyloxypropyl) piperazine
[0516] IR (Neat): 1635, 1430, 1350, 1275, 1170, 1125 cm.sup.-1
EXAMPLE 43
[0517] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthyl-
methyl)-4-(3-methylsulfonyloxypropyl) piperazine (250 mg),
thiomorpholine (43 mg) and triethylamine (46 mg) in dry methanol (5
ml) was refluxed for 2 hours. The reaction mixture was concentrated
under reduced pressure and the resulting residue was purified by
column chromatography on silica gel using ethyl acetate as an
eluent. The product obtained was dissolved in ethyl acetate and
treated with 4N hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis (trifluoromethyl)benzoyl]-2-(2-naphthylm-
ethyl)-4-(3-thiomorpholinopropyl) piperazine dihydrochloride (195
mg).
[0518] [.alpha.].sub.D.sup.23: -23.0.degree. (C=0.5, MeOH)
[0519] IR (Nujol): 3400, 2500, 1640, 1275, 1170, 1130 cm.sup.-1
[0520] NMR (CDCl.sub.3, .delta.): 1.50-5.69 (23H, m), 7.34-7.93
(10H, m)
[0521] MASS: 610 (M+1) (free)
EXAMPLE 44
[0522] The following compounds were obtained according to a similar
manner to that of Example 43.
[0523] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4- -
(2-morpholinoethyl) piperazine dihydrocloride
[0524] [.alpha.].sub.D.sup.23: -25.2.degree. (C=0.5, MeOH)
[0525] IR (Nujol): 3400, 2510, 2425, 1635, 1425, 1275, 1170, 1130
cm.sup.-1
[0526] NMR (DMSO-d.sub.6, .delta.): 2.88-5.31 (21H, m), 7.07-8.24
(10H, m)
[0527] MASS: 580 (M+1) (free)
[0528] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-(2-thiomorpholinoethyl) piperazine dihydrochloride
[0529] [.alpha.].sub.D.sup.22: -23.7.degree. (C=0.5, MeOH)
[0530] IR (Nujol): 2350, 1640, 1270, 1180 cm.sup.-1
[0531] NMR (DMSO-d.sub.6, .delta.): 2.80-5.31 (21H, m), 7.03-8.20
(10H, m)
[0532] MASS: 596 (M+1) (free)
[0533] (3) (2
R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethy-
l)-4-[3-(4-oxopiperidino) propyl]piperazine
[0534] [.alpha.].sub.D.sup.24: -19.0.degree. (C=0.5, MeOH)
[0535] IR (Nujol): 3270, 1720, 1625, 1430, 1340, 1275, 1125
cm.sup.-1
[0536] NMR (CDCl.sub.3, .delta.): 1.66-5.20 (23H, m), 6.69-8.28
(8H, m)
[0537] MASS: 595 (M+1)
[0538] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)
-4-(3-thiomorpholinopropyl) piperazine dihydrochloride
[0539] [.alpha.].sub.D.sup.18: +2.2.degree. (C=0.5, MeOH)
[0540] IR (Nujol): 3400, 2400, 1650, 1280 cm.sup.-1
[0541] NMR (DMSO-d.sub.6, .delta.): 2.10-5.20 (23H, m), 6.92-8.32
(6H, m), 11.12-11.72 (2H, m)
[0542] MASS: 628 (M+1) (free)
[0543] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-
-4-(3-morpholinopropyl) piperazine dihydrochloride
[0544] [.alpha.].sub.D.sup.19: +2.3.degree. (C=0.5, MeOH)
[0545] IR (Nujol): 3400, 2550, 2450, 1650, 1280 cm.sup.-1
[0546] NMR (DMSO-d.sub.6, .delta.): 2.10-5.20 (23H, m), 6.94-8.34
(6H, m), 1.08-11.76 (2H, m)
[0547] MASS: 612 (M+1) (free)
[0548] (6)
(2R)-4-[3-(4-Acetylpiperidino)propyl]-1-[3,5-bis(trifluoromethy-
l)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine dihydrochloride
[0549] [.alpha.].sub.D.sup.20: -7.2.degree. (C=0.5, MeOH)
[0550] IR (Nujol): 3300, 2600, 1700, 1630, 1275 cm.sup.-1
[0551] NMR (DMSO-d.sub.6, .delta.): 1.67-5.24 (24H, m), 2.16 (3H,
s), 6.62-8.28 (8H, m), 10.95 (1H, s)
[0552] MASS: 623 (M+1) (free)
[0553] (7) (2R)-4-[3-(Thiazolidin-3-yl)propyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
dihydrochloride
[0554] [.alpha.].sub.D.sup.25: -5.4.degree. (C=0.5, MeOH)
[0555] IR (Nujol): 3600-3100, 2700-2250, 1660-1580, 1270, 1120
cm.sup.-1
[0556] NMR (DMSO-d.sub.6, .delta.): 2.20-2.40 (2H, m), 3.00-5.20
(19H, m), 6.40-8.25 (8H, m), 10.97 (1H, m), 11.20-11.90 (2H, m)
[0557] MASS: 585 (M+1) (free)
[0558] (8) (2R)-4-[3-(4-Phenyl-1-piperazinyl)propyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
trihydrochloride
[0559] [.alpha.].sub.D.sup.25: -8.0.degree. (C=0.5, MeOH)
[0560] IR (Nujol): 3600-3100, 2750-2300, 1630, 1275, 1120
cm.sup.-1
[0561] NMR (DMSO-d.sub.6, .delta.): 2.05-2.45 (2H, m), 3.05-5.20
(21H, m), 6.60-8.05 (13H, m), 10.97 (1H, s), 11.00-11.85 (3H,
m)
[0562] MASS: 658 (M+1) (free)
[0563] (9) (2R)-4-[3-(4-cyclohexyl-1-piperazinyl)propyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine
trihydrochloride
[0564] mp: 250.degree. C. (dec.)
[0565] [.alpha.].sub.D.sup.25: -7.8.degree. (C=0.5, MeOH)
[0566] IR (Nujol): 3600-3100, 2650-2200, 1640-1600, 1370, 1270,
1120 cm.sup.-1
[0567] NMR (DMSO-d.sub.6, .delta.): 1.00-2.40 ( 11H, m), 3.00-5.30
(23H, m), 6.60-8.30 (8H, m), 10.97 (1H, s), 11.30-12.30 (3H, m)
[0568] MASS: 664 (M+1) (free)
EXAMPLE 45
[0569] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(2-methylsulfonyloxyethyl) piperazine (200 mg),
4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol
(5 ml) was refluxed for 2 hours. The reaction mixture was
concentrated under reduced pressure and the resulting residue was
partitioned between ethyl acetate and aqueous sodium hydrogen
carbonate solution. The organic layer was washed with brine and
dried over magnesium sulfate. After evaporation of the solvent, the
residue was purified by column chromatography on silica gel using a
mixture of ethyl acetate and methanol (10:1) as an eluent to afford
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-y-
lmethyl)-4-[2-(morpholinoamino)ethyl]piperazine (55 mg).
[0570] [.alpha.].sub.D.sup.22: -16.2.degree. (C=0.5, MeOH)
[0571] IR (Nujol): 3300, 1615, 1275 cm.sup.-1
[0572] NMR (DMSO-d.sub.6, .delta.): 2.14-5.10 (21H, m), 6.0-8.26
(8H, m), 10.91 (1h, s)
[0573] MASS: 584 (M+1)
EXAMPLE 46
[0574] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (100 mg) and
4-phenylpiperidine (60 mg) in acetonitrile (3 ml) was refluxed for
2 hours. The reaction mixture was concentrated under reduced
pressure and the resulting residue was purified by column
chromatography on silica gel using ethyl acetate-methanol (5:1) as
an eluent to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4--
phenylpiperidino)propyl]piperazine (90 mg).
[0575] [.alpha.].sub.D.sup.20: -24.6.degree. (C=1.0, MeOH)
[0576] IR (Neat): 3250, 1630, 1430, 1275, 1130 cm.sup.-1
[0577] NMR (DMSO-d.sub.6, .delta.): 1.52-4.93 (24H, m), 6.60-8.28
(13H, m), 10.87 (1H, s)
[0578] MASS: 657 (M+1)
EXAMPLE 47
[0579] A solution of (2R)-2-(3,4-dichlorobenzyl)-1-[3,5-bis
(trifluoromethyl)benzoyl]-4-(2-hydroxyethyl)piperazine (50 mg) in
ethyl acetate (3 ml) was treated with 4N hydrogen chloride in ethyl
acetate solution (0.2 ml) and the resulting mixture was
concentrated in vacuo to give
(2R)-2-(3,4-dichlorobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-
-hydroxyethyl) piperazine hydrochloride (45 mg) as a powder.
[0580] IR (Neat): 3260, 2550, 1640, 1425, 1275 cm.sup.-1
[0581] NMR (DMSO-d.sub.6, .delta.): 2.80-5.53 (13H, m), 6.91-8.32
(6H, m), 10.96 (1H, br s)
[0582] MASS: 530 (M+1) (free)
EXAMPLE 48
[0583] The following compounds were obtained according to a similar
manner to that of Example 47.
[0584] (1) (2R)-4-(4-Aminobenzyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride
[0585] mp: 179.degree. C. (dec.)
[0586] [.alpha.].sub.D.sup.25: -16.6.degree. (C=0.5, MeOH)
[0587] IR (Nujol): 3400-3050, 2650-2300, 1660-1580, 1275, 1125
cm.sup.-1
[0588] NMR (DMSO-d.sub.6, .delta.): 2.00-2.20 (6H, m), 2.80-5.05
(11H, m), 6.45-8.25 (10H, m), 11.40-11.90 (2H, m)
[0589] MASS: 555 (M+1) (free)
[0590] (2) (2R)-4-(4-Nitrobenzyl)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride
[0591] mp: 140.degree. C. (dec.)
[0592] [.alpha.].sub.D.sup.25: -18.4.degree. (C=0.5, MeOH)
[0593] IR (Nujol): 3600-3200, 2650-2200, 1640, 1520, 1350, 1275,
1130 cm.sup.-1
[0594] NMR (DMSO-d.sub.6, .delta.): 2.00-2.20 (6H, m), 2.80-5.00
(11H, m), 6.50-8.40 (10H, m)
[0595] MASS: 580 (M+1) (free)
EXAMPLE 49
[0596] To a solution of
(2R)-4-[4,4-ethylenedioxy-4-(4-fluorophenyl)
butyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperaz-
ine (210 mg) in ethyl acetate was added 4N hydrogen chloride in
ethyl acetate solution (0.5 ml) and the whole was stirred at room
temperature for 23 hours. The solution was evaporated in vacuo. The
residue was triturated with a mixture of ethyl acetate and
diisopropyl ether to give
(2R)-4-[4-florophenyl)-4-oxobutyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2- -(1H-indol-3-ylmethyl) piperazine
hydrochloride (183.7 mg).
[0597] mp: 161.degree. C. (dec.)
[0598] [.alpha.].sub.D.sup.25: -14.2.degree. (C=0.5, MeOH)
[0599] IR (Nujol): 3400-3150, 2650-2300, 1675, 1635, 1595,
1280-1250, 1275, 1125 cm.sup.-1
[0600] NMR (DMSO-d.sub.6, .delta.): 2.00-2.25 (2H, m), 3.05-5.20
(13H, m), 6.55-8.25 (12H, m), 10.95 (1H, s), 11.10-11.50 (1H,
m)
[0601] MASS: 620 (M+1) (free)
Preparation 6
[0602] Tetrahydrofuran (15 ml) was added to 70% solution of sodium
bis(2-methoxyethoxy)aluminum hydride in toluene (49.7 g) under an
atmosphere of nitrogen and then cooled. A solution of
4-morpholino-2-butyn-1-ol (3.0 g) in tetrahydrofuran (15 ml) was
added dropwise maintaining the reaction temperature 4-5.degree. C.
After being stirred for 10 minutes, the reaction mixture was
allowed to warm to room temperature. After 1 hour, water (6 ml) and
10% aqueous sodium hydroxide solution (4.5 ml) were added
cautiously and then filtered. The filtrate was dried over potassium
carbonate and concentrated under reduced pressure to give an oily
product, which was purified by column chromatography on silica gel
using ethyl acetate-methanol (5:1) to afford
(E)-4-morpholino-2-buten-1-ol (1.08 g).
[0603] IR (Neat): 3350, 1450, 1110, 990, 855 cm.sup.-1
[0604] NMR (CDCl.sub.3, .delta.): 2.48 (4H, t, J=4.7Hz), 2.77 (1H,
s), 3.02 (2H, d, J=5.4Hz), 3.73 (4H, t, J=4.7Hz), 4.15 (2H, d,
J=4.0Hz), 5.64-5.96 (2H, m)
[0605] MASS: 158 (M+1)
Preparation 7
[0606] Thionyl chloride (0.96 ml) was added dropwise to a solution
of (E)-4-morpholino-2-buten-1-ol (1.03 g) in dichloromethane (10
ml) at ice-bath temperature. After 3 hours, the reaction mixture
was evaporated under reduced pressure and the resulting residue was
triturated with ethyl acetate to give (E)-4-morpholino-2-butenyl
chloride hydrochloride (0.98 g).
[0607] mp: 155-160.degree. C.
[0608] IR (Nujol): 2750-2700, 1275, 1255, 1120, 1078, 1065, 975
cm.sup.-1
[0609] NMR (DMSO-d.sub.6, .delta.): 2.80-3.55 (4H, m), 3.64-4.10
(6H, m), 4.26 (2H, d, J=5.7Hz), 5.90-6.25 (2H, m), 11.82 (1H, br
s)
[0610] MASS: 176 (M) (free)
EXAMPLE 50
[0611] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3- -ylmethyl)
piperazine (0.20 g), 5-morpholino-3-pentynyl chloride hydrochloride
(0.175 g), potassium carbonate (0.303 g) and potassium iodide (10
mg) in dry acetonitrile (4 ml) was stirred under reflux for 60
hours. After removal of the solvent, the resulting residue was
dissolved with ethyl acetate. The solution was washed with brine,
dried over magnesium sulfate and evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
using toluene-ethyl acetate (1:2) as eluent and treated with 4N
hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H--
indol-3-ylmethyl)-4-(5-morpholino-3-pentynyl) piperazine
dihydrochloride (0.174 g).
[0612] [.alpha.].sub.D.sup.21: -19.5.degree. (C=0.5, MeOH)
[0613] IR (Nujol): 3600-3150, 2700-2300, 1640, 1280, 1170, 1185
cm.sup.-1
[0614] NMR (DMSO-d.sub.6, .delta.): 2.90-5.20 (23H, m), 6.80-8.30
(8H, m), 10.95 (1H, s), 11.79 (2H, br s)
[0615] MASS: (APCI): 608 (M+2), 607 (M+1) (free)
[0616] Anal. Calcd. for
C.sub.31H.sub.32F.sub.6N.sub.4O.sub.2HCl1.5H.sub.2- O:
[0617] C 52.70, H 5.28, N 7.93
[0618] Found: C 52.72, H 5.54, N 7.60
EXAMPLE 51
[0619] To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.2 g),
1-methyl-4-formyl-1H-pyrazole (50 mg), and sodium
triacetoxyborohydride (151 mg) in dichloromethane (2 ml) was added
one drop of acetic acid. After being stirred at room temperature
overnight, the solution was evaporated under reduced pressure. The
resulting residue was partitioned between ethyl acetate and aqueous
sodium hydrogen carbonate solution. The organic layer was
separated, dried over magnesium sulfate and evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel using ethyl acetate-methanol as eluent and treated
with 4N hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)-4-[(1-me- thyl-1H-pyrazol-4-yl)
methyl]piperazine hydrochloride (97 mg).
[0620] mp: 243-244.degree. C.
[0621] [.alpha.].sub.D.sup.18.2: -16.8.degree. (C=0.3, MeOH)
[0622] IR (Nujol): 3350, 2750-2000, 1655, 1635, 1275, 1165, 1130
cm.sup.-1
[0623] NMR (DMSO-d.sub.6, .delta.): 1.97-2:28 (7H, m), 2.78-5.10
(13H, m), 6.50-8.30 (8H, m), 11.24-11.74 (1H, br m)
[0624] MASS (APCI): 539 (M+1) (free)
[0625] Anal. Calcd. for
C.sub.27H.sub.28F.sub.6N.sub.4O.multidot.HCl.multi-
dot.2.7H.sub.2O:
[0626] C 52.00, H 5.56, N 8.98
[0627] Found: C 51.82, H 5.15, N 8.99
EXAMPLE 52
[0628] The following compounds were obtained according to a similar
manner to that of Example 51.
[0629] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[(1-methyl-1H-imidazol-4-yl)methyl]piperazine
dihydrochloride
[0630] [.alpha.].sub.D.sup.26: -11.80.degree. (C=0.5, MeOH)
[0631] IR (Neat): 3350, 2550, 1640, 1430, 1275, 1170, 1130
cm.sup.-1
[0632] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H, s), 2.17 (3H, s),
2.72-5.10 (11H, m), 3.88 (3H, s), 6.60-9.08 (8H, m)
[0633] MASS: 539 (M+1) (free)
[0634] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[(1-methyl-1H-imidazol-2-yl)methyl]piperazine
dihydrochloride
[0635] [.alpha.].sub.D.sup.25: -12.10.degree. (C=0.5, MeOH)
[0636] IR (Neat): 3350, 2500, 1640, 1430, 1280, 1175, 1130
cm.sup.-1
[0637] NMR (DMSO-d.sub.6, .delta.): 2.07 (3H, s), 2.16 (3H, s),
2.53-5.14 (11H, m), 3.94 (3H, s), 6.47-8.26 (8H, m)
[0638] MASS: 539 (M+1) (free)
EXAMPLE 53
[0639] The following compounds were obtained according to a similar
manner to that of Example 43.
[0640] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-(3-morpholinopropyl) piperazine dihydrochloride
[0641] mp: 220-230.degree. C.
[0642] [.alpha.].sub.D.sup.21.5: -17.3.degree. (C=0.3, MeOH)
[0643] IR (Nujol): 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270
cm.sup.-1
[0644] NMR (DMSO-d.sub.6, .delta.) 1.92-5.22 (29H, m), 8.56-8.28
(6H, m), 11.43 (2H, br s)
[0645] MASS (APCI): 572 (M+1) (free)
[0646] Anal. Calcd. for
C.sub.29H.sub.35F.sub.6N.sub.3O.sub.2.multidot.2HC- l:
[0647] C 54.04, H 5.79, N 6.52
[0648] Found: C 53.72, H 5.80, N 6.29
[0649] (2)
(2R)-4-[2-[N,N-Bis(2-methoxyethyl)amino]ethyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine
dihydrochloride
[0650] [.alpha.].sub.D.sup.22: -9.6.degree. (C=0.5, MeOH)
[0651] IR (Nujol): 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270
cm.sup.-1
[0652] NMR (DMSO-d.sub.6, .delta.): 1.92-5.22 (27H, m), 3.32 (6H,
s), 6.56-8.28 (6H, m)
[0653] MASS (APCI): 604 (M+1) (free)
[0654] Anal. Caicd. for
C.sub.30H.sub.39F.sub.6N.sub.3O.sub.3.multidot.2HC-
l.multidot.1.6H.sub.2O:
[0655] C 51.08, H 6.32, N 5.96
[0656] Found: C 51.06, H 6.40, N 6.14
[0657] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl-
)-4-[3-(1,2,3,6-tetrahydropyridin-1-yl)propyl]piperazine
dihydrochloride
[0658] mp: >200.degree. C.
[0659] [.alpha.].sub.D.sup.23: -2.30.degree. (C=0.5, MeOH)
[0660] IR (Nujol): 3500-3100, 2700-2400, 1630 cm.sup.-1
[0661] NMR (DMSO-d.sub.6, .delta.): 2.20-4.20 (21H, m), 5.72 (1H,
d, J=10.2Hz), 5.93 (1H, d, J=10.2Hz), 6.55-8.23 (8H, m), 10.95 (1H,
br s)
[0662] MASS (APCI): 579 (M+1) (free)
[0663] Anal. Calcd. for
C.sub.30H.sub.32F.sub.6N.sub.4O.multidot.2HCl.mult-
idot.2H.sub.2O:
[0664] C 52.41, H 5.57, N 8.15
[0665] Found: C 52.03, H 5.77, N 7.72
[0666] (4)
(2R)-4-[3-(3-Azabicyclo[3.2.2]non-3-yl)propyl]-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl) piperazine
dihydrochloride
[0667] mp: 150.degree. C. (dec.)
[0668] [.alpha.].sub.D.sup.19.1: -2.90.degree. (C=0.5, MeOH)
[0669] IR (Nujol): 3500-3100, 2700-2400, 1630 cm.sup.-1
[0670] NMR (DMSO-d.sub.6, .delta.): 1.60-3.90 (29H, m), 6.90-8.30
(6H, m)
[0671] MASS (APCI): 652 (M+2), 650 (M+1) (free)
[0672] Anal. Calcd. for
C.sub.31H.sub.35Cl.sub.2F.sub.6N.sub.3O.multidot.2-
HCl.multidot.H.sub.2O:
[0673] C 50.22, H 5.30, N 5.67
[0674] Found: C 50.25, H 5.60, N 5.32
[0675] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-
-4-[3-(4,1'-bipiperidin-1-yl)propyl]piperazine trihydrochloride
[0676] mp: >200.degree. C.
[0677] [.alpha.].sub.D.sup.28.4: -3.40.degree. (C=0.5, MeOH)
[0678] IR (Nujol): 3300, 2700-2400, 1630, 1450 cm.sup.-1
[0679] NMR (DMSO-d.sub.6, .delta.): 1.60-3.90 (34H, m), 6.90-8.30
(6H, m)
[0680] MASS (FAB): 693 (M+1), 695 (free)
[0681] Anal. Calcd. for
C.sub.33H.sub.40Cl.sub.2F.sub.6N.sub.4O.multidot.3- HCl:
[0682] C 49.36, H 5.40, N 6.98
[0683] Found: C 49.81, H 5.75, N 6.75
EXAMPLE 54
[0684] A solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimet-
hylbenzyl)-4-(4-morpholino-2-butynyl) piperazine (141 mg) in
methanol (10 ml) was hydrogenated over 10% Pd-C (50 mg) at room
temperature under 2-3 atoms. After removal of the catalyst by
filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
using dichloromethane-methanol as eluent and treated with 4N
hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-mor- pholinobutyl) piperazine
dihydrochloride (106 mg).
[0685] mp: 279.degree. C.
[0686] [.alpha.].sub.D.sup.23: -13.5.degree. (C=0.5, MeOH)
[0687] IR (Nujol): 3300, 2700-2400, 1645, 1500, 1445, 1370, 2970,
1170 cm.sup.-1
[0688] NMR (DMSO-d.sub.6, .delta.): 1.70-5.22 (31H, m), 6.56-8.28
(6H, m), 11.00-11.40 (2H, m)
[0689] MASS (APCI): 586 (M+1) (free)
EXAMPLE 55
[0690] The following compound was obtained according to a similar
manner to that of Example 54.
[0691]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4--
(5-morpholinopentyl) piperazine dihydrochloride
[0692] [.alpha.].sub.D.sup.21: -6.10.degree. (C=0.5, MeOH)
[0693] IR (Neat): 3400-3200, 2700-2400, 1640, 1430 cm.sup.-1
[0694] NMR (DMSO-d.sub.6, .delta.): 1.50-5.20 (27H, m), 6.60-8.30
(8H, m), 10.80-11.50 (3H, m)
[0695] MASS: 611 (M+1) (free)
[0696] Anal. Calcd. for
C.sub.31H.sub.36F.sub.6N.sub.4O.sub.2.multidot.2HC-
l.multidot.1.3H.sub.2O:
[0697] C 52.67, H 5.79, N 7.92
[0698] Found: C 52.66, H 6.13, N 7.76
EXAMPLE 56
[0699] A solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimet-
hylbenzyl)-4-(5-morpholino-3-pentynyl) piperazine (200 mg) was
treated with 4N hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(3,4-dimethylbenzyl)-4-(5-mor- pholino-3-pentynyl)
piperazine dihydrochloride.
[0700] [.alpha.].sub.D.sup.21: -25.2.degree. (C=0.5,MeOH)
[0701] IR (Neat): 3700-3100, 2920, 2750-2250, 1635, 1500, 1430,
1275, 1170, 1120 cm.sup.-1
[0702] NMR (DMSO-d.sub.6, .delta.): 2.05-2.20 (6H, m), 2.75-5.15
(23H, m), 6.65-8.28 (6H, m), 11.60-12.20 (2H, m)
[0703] MASS: 596 (M+1) (free)
[0704] Anal. Calcd. for
C.sub.31H.sub.35F.sub.6N.sub.3O.sub.2HCl.multidot.-
1.5H.sub.2O:
[0705] C 53.53, H 5.80, N 6.04
[0706] Found: C 53.47, H 6.14, N 5.91
EXAMPLE 57
[0707]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)
piperazine fumarate (9.13 g) was treated with aqueous 10% sodium
hydroxide solution (65 ml) and dichloromethane (65 ml). The organic
layer was separated, washed with brine, dried over magnesium
sulfate and evaporated under reduced pressure. A mixture of
(2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine obtained
by the above procedure, potassium carbonate (3.60 g) and
1,4-dichloro-2-butyne (1.9 ml) in N,N-dimethylformamide (72 ml )
was stirred for 4.5 hours at room temperature. The mixture was
poured into water (360 ml) and extracted with ethyl acetate. The
extract was washed with brine, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel using toluene-ethyl acetate as
eluent to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-chloro-2-butynyl)
piperazine (4.86 g).
[0708] IR (Neat): 1706, 1635, 1503, 1275, 1125 cm.sup.-1
[0709] NMR (CDCl.sub.3, .delta.): 2.05-5.20 (19H, m), 6.60-7.84
(6H, m)
[0710] MASS (APCI): 531 (M+1)
EXAMPLE 58
[0711] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimeth-
ylbenzyl)-4-(4-chloro-2-butynyl) piperazine (0.49 g),
3-methylmorpholine hydrochloride (0.15 g), potassium carbonate
(0.39 g) and potassium iodide (10 mg) in dry N,N-dimethylformamide
(5 ml) was stirred for 5 hours at room temperature. The mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with brine, dried over magnesium sulfate and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel using ethyl acetate as eluent and
treated with 4N hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-
(3-methylmorpholino)-2-butynyl]piperazine dihydrochloride (0.28
g).
[0712] mp: 150-160.degree. C.
[0713] [.alpha.].sub.D.sup.28.4: -5.71.degree. (C=1.0, MeOH)
[0714] IR (Nujol): 3300, 2700-2400, 1650, 1430 cm.sup.-1
[0715] NMR (DMSO-d.sub.6, .delta.): 1.20-5.22 (29H, m), 6.60-8.20
(6H, m), 12.20-12.40 (2H, m)
[0716] MASS (APCI): 596 (M+1) (free)
[0717] Anal. Calcd. for
C.sub.31H.sub.35F.sub.6N.sub.3O.sub.2.multidot.2HC-
l.multidot.1.7H.sub.2O:
[0718] C 53.25, H 5.82, N 6.01
[0719] Found: C 53.28, H 5.97, N 5.80
EXAMPLE 59
[0720] The following compounds were obtained according to a similar
manner to that of Example 58.
[0721] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[4-(2-methoxymethylmorpholino)-2-butynyl]piperazine
dihydrochloride
[0722] mp: 150-165.degree. C.
[0723] [.alpha.].sub.D.sup.28.4: -8.86.degree. (C=0.7, MeOH)
[0724] IR (Nujol): 3300, 2700-2400, 1640, 1430 cm.sup.-1
[0725] NMR (DMSO-d.sub.6, .delta.): 2.00-5.22 (28H, m), 3.25 (3H,
s), 6.50-8.20 (6H, m), 12.20-12.40 (2H, m)
[0726] MASS (APCI): 626 (M+1) (free)
[0727] Anal. Calcd. for
C.sub.32H.sub.37F.sub.6N.sub.3O.sub.3.multidot.2HC-
l.multidot.H.sub.2O:
[0728] C 53.64, H 5.77, N 5.86
[0729] Found: C 53.60, H 5.94, N 5.67
[0730] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[4-(2-fluoromethylmorpholino)-2-butynyl]piperazine
dihydrochloride
[0731] mp: 175-180.degree. C.
[0732] [.alpha.].sub.D.sup.28.4: -8.75.degree. (C=0.7, MeOH)
[0733] IR (Nujol): 3300, 2700-2400, 1635, 1500 cm.sup.-1
[0734] NMR (DMSO-d.sub.6, .delta.): 2.00-5.22 (28H, m), 6.50-8.20
(6H, m)
[0735] MASS (APCI): 614 (M+1) (free)
[0736] Anal. Calcd. for
C.sub.31H.sub.34F.sub.7N.sub.3O.sub.2.multidot.2HC-
l.multidot.H.sub.2O:
[0737] C 52.85, H 5.44, N 5.96
[0738] Found: C 52.82, H 5.45, N 5.74
[0739] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine
dihydrochloride
[0740] mp: 180-190.degree. C.
[0741] [.alpha.].sub.D.sup.28.3: -7.24.degree. (C=1.05, MeOH)
[0742] IR (Nujol): 3300, 2700-2400, 1635 cm.sup.-1
[0743] NMR (DMSO-d.sub.6, .delta.): 1.30-1.40 (6H, m), 2.00-5.22
(25H, m), 6.60-8.20 (6H, m), 12.05-12.20 (2H, m)
[0744] MASS (APCI): 610 (M+1H) (free)
[0745] Anal Calcd. for
C.sub.32H.sub.37F.sub.6N.sub.3O.sub.2.multidot.2HCl-
.multidot.2.5H.sub.2O:
[0746] C 52.82, H 6.09, N 5.68
[0747] Found: C 52.84, H 5.89, N 5.78
[0748] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[4-((2S)-2-methoxymethylpyrrolidino)-2-butynyl]piperazine
dihydrochloride
[0749] mp: 195-197.degree. C.
[0750] [.alpha.].sub.D.sup.28.4: -19.79.degree. (C=0.7, MeOH)
[0751] IR (Nujol): 3450, 2700-2400, 1640, 1450 cm.sup.-1
[0752] NMR (DMSO-d.sub.6, .delta.): 2.00-5.22 (28H, m), 3.32 (3H,
s), 6.50-8.20 (6H, m), 11.50-11.70 (2H, m)
[0753] MASS (APCI): 610 (M+1) (free)
[0754] Anal. Calcd. for
C.sub.32H.sub.37F.sub.6N.sub.3O.sub.2.multidot.2HC-
l.multidot.2H.sub.2O:
[0755] C 53.49, H 6.03, N 5.85
[0756] Found: C 53.66, H 5.73, N 5.82
[0757] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[4-(3-methoxymethylmorpholino)-2-butynyl]piperazine
dihydrochloride
[0758] mp: 140-155.degree. C.
[0759] [.alpha.].sub.D.sup.28.4: -7.22.degree. (C=0.63, MeOH)
[0760] IR (Nujol): 3300, 2700-2400, 1635, 1440 cm.sup.-1
[0761] NMR (DMSO-d.sub.6, .delta.): 2.00-5.22 (28H, m), 3.32 (3H,
s), 6.50-8.20 (6H, m)
[0762] MASS (APCI): 626 (M+1) (free)
[0763] Anal. Calcd. for
C.sub.32H.sub.37F.sub.6N.sub.3O.sub.3.multidot.2HC- l:
[0764] C 52.32, H 5.90, N 5.72
[0765] Found: C 52.35, H 6.11, N 5.43
EXAMPLE 60
[0766] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimeth- ylbenzyl)
piperazine (0.38 g), potassium carbonate (0.42 g),
3-(3-pyridyl)-2-propynyl chloride hydrochloride (1.9 ml) and small
amount of potassium iodide in N,N-dimethylformamide (10 ml) was
stirred for 2 hours at 40.degree. C. The mixture was poured into
water and extracted with ethyl acetate. The extract was washed with
brine, dried over magnesium sulfate and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel using ethyl acetate as eluent and treated with 4N
hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[-
3-(3-pyridyl)-2-propynyl]piperazine dihydrochloride (0.26 g).
[0767] mp: 140-150.degree. C.
[0768] [.alpha.].sub.D.sup.28.4: -10.13.degree. (C=0.8, MeOH)
[0769] IR (Nujol): 3300, 2700-2400, 1630, 1450 cm.sup.-1
[0770] NMR (DMSO-d.sub.6, .delta.): 2.00-5.22 (17H, m), 6.50-8.20
(8H, m), 8.70-8.85 (2H, m)
[0771] MASS (APCI): 560 (M+1) (free)
[0772] Anal. Calcd. for
C.sub.30H.sub.27F.sub.6N.sub.3O.multidot.2HCl.mult-
idot.2.8H.sub.2O:
[0773] C 52.76, H 5.11, N 6.15
[0774] Found: C 52.74, H 4.96, N 6.05
EXAMPLE 61
[0775] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chlo-
ro-2-butenyl]-2-(2-naphthylmethyl)piperazine (300 mg),
thiomorpholine (0.054 ml) and powdered potassium carbonate (100 mg)
in dry acetonitrile (3 ml) was heated at 50.degree. C. for 10
hours. Additional potassium carbonate (100 mg) and thiomorpholine
(0.054 ml) were added and then the resulting mixture was further
heated at the same temperature. After 2 hours, the reaction mixture
was cooled and then filtered. The filtrate was concentrated under
reduced pressure and the resulting residue was purified by column
chromatography on silica gel using a mixture of dichloromethane and
methanol (40:1). The obtained product was dissolved in ethyl
acetate and treated with 4N hydrogen chloride in ethyl acetate (0.6
ml) to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(2-naphthylm-
ethyl)-4-((E)-4-thiomorpholino-2-butenyl) piperazine
dihydrochloride (190 mg).
[0776] mp: >230.degree. C.
[0777] [.alpha.].sub.D.sup.28.9: -14.50.degree. (C=0.5, MeOH)
[0778] IR (Nujol): 3650-3100, 2410, 1640, 1274, 1130 cm.sup.-1
[0779] NMR (DMSO-d.sub.6, .delta.): 2.55-5.30 (21H, m), 6.00-6.30
(2H, m), 7.00-8.20 (10H)
[0780] MASS: 622 (M+1) (free)
EXAMPLE 62
[0781] The following compounds were obtained according to a similar
manner to that of Example 61.
[0782] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-[(E)-4-morpholino-2-butenyl]piperazine dihydrochloride
[0783] mp: >230.degree. C.
[0784] [.alpha.].sub.D.sup.28.7: -16.60.degree. (C=0.5, MeOH)
[0785] IR (Nujol): 3600-3100, 2450, 1639, 1273, 1130 cm.sup.-1
[0786] NMR (DMSO-d.sub.6, .delta.): 2.80-5.30 (21H, m) 6.10-6.30
(2H, m), 7.00-8.25 (10H, m)
[0787] MASS: 606 (M+1) (free)
[0788] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[(E)-4-thiomorpholino-2-butenyl]piperazine dihydrochloride
[0789] mp: >230.degree. C.
[0790] [.alpha.].sub.D.sup.25.8: 5.20.degree. (C=0.25, DMSO)
[0791] IR (Nujol): 3600-3100, 2450, 1642, 1274, 1130 cm.sup.-1
[0792] NMR (DMSO-d.sub.6, .delta.): 2.10-5.10 (27H, m), 5.90-6.30
(2H, m), 6.65-7.05 (3H, m), 7.57 (2H, s), 8.05 (1H, s)
[0793] MASS: 600 (M+1) (free)
EXAMPLE 63
[0794] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chlo-
ro-2-butenyl]-2-(3,4-dimethylbenzyl)piperazine (450 mg),
3,3-dimethylmorpholine hydrochloride (130 mg) and powdered
potassium carbonate (350 mg) in dry acetonitrile (5 ml) was heated
at reflux temperature for 3 hours. Additional potassium carbonate
(350 mg) and 3,3-dimethylmorpholine hydrochloride (130 mg) were
added and then the resulting mixture was further heated at reflux
temperature. After 6 hours, the reaction mixture was cooled and
then filtered. The filtrate was concentrated under reduced pressure
and the resulting residue was purified by column chromatography on
silica gel using a mixture of dichloromethane and methanol (50:1).
The obtained product was dissolved in ethyl acetate and treated
with 4N hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl-
benzyl)-4-[(E)-4-(3,3-dimethylmorpholino)-2-butenyl]piperazine
dihydrochloride (370 mg).
[0795] mp: >230.degree. C.
[0796] [.alpha.].sub.D.sup.25.5: -11.70.degree. (C=0.5, MeOH)
[0797] IR (Nujol): 3400, 2450, 1639, 1274, 1130 cm.sup.-1
[0798] NMR (DMSO-d.sub.6, .delta.): 1.34-1.40 (6H, m), 2.10-2.18
(6H, m), 2.70-5.20 (19H, m), 6.10-6.30 (2H, m), 6.65-8.30 (6H, m),
11.20-12.00 (2H, m)
[0799] MASS: 612 (M+1) (free)
EXAMPLE 64
[0800] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimeth- ylbenzyl)
piperazine (1.0 g), (E)-1,4-dichloro-2-butene (0.31 ml) and
powdered potassium carbonate (0.4 g) in dry acetonitrile (10 ml)
was heated at 50.degree. C. After 4 hours, the reaction mixture was
cooled and then filtered. The filtrate was concentrated under
reduced pressure and the resulting residue was purified by column
chromatography on silica gel using a mixture of toluene and ethyl
acetate (4:1) to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4--
chloro-2-butenyl]piperazine (0.53 g) as an oil.
[0801] IR (Neat): 3460, 1638, 1272, 1125, 900 cm.sup.-1
[0802] NMR (CDCl.sub.3, .delta.): 2.00-5.20 (19H, m), 5.75-6.00
(2H, m), 6.60-8.00 (6H, m)
[0803] MASS: 533 (M+1)
EXAMPLE 65
[0804] The following compound was obtained according to a similar
manner to that of Example 64.
[0805]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[(E-
)-4-chloro-2-butenyl]piperazine
[0806] IR (Neat): 1637, 1273, 1128, 900 cm.sup.-1
[0807] NMR (CDCl.sub.3, .delta.): 2.05-5.20 (13H, m), 5.80-6.00
(2H, m), 7.10-8.10 (10H, m)
[0808] MASS: 555 (M+1)
EXAMPLE 66
[0809] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-
-ylmethyl)-4-(3-methylsulfonyloxypropyl) piperazine (150 mg),
4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol
(5 ml) was refluxed for 2 hours. The reaction mixture was
concentrated under reduced pressure and the resulting residue was
partitioned between ethyl acetate and aqueous sodium hydrogen
carbonate solution. The organic layer was washed with brine and
dried over magnesium sulfate. After evaporation of the solvent, the
residue was purified by column chromatography on silica gel using a
mixture of ethyl acetate and methanol (10:1) to afford an oily
product, which was treated with 4N hydrogen chloride in ethyl
acetate solution (0.5 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(morpholinoamino)
propyl]piperazine dihydrochloride (58 mg).
[0810] [.alpha.].sub.D.sup.23: -3.60.degree. (C=0.5, MeOH)
[0811] IR (Nujol): 3300, 2500, 1630, 1420, 1275 cm.sup.-1
[0812] NMR (DMSO-d.sub.6, .delta.): 2.00-5.24 (23H, m), 6.60-8.28
(8H, m), 10.94 (1H, s), 11.50 (1H, br s)
[0813] MASS: 598 (M+1) (free)
EXAMPLE 67
[0814] The following compounds were obtained according to a similar
manner to that of Example 66.
[0815] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl-
)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazine
dihydrochloride
[0816] [.alpha.].sub.D.sup.20: -2.60.degree. (C=0.5, MeOH)
[0817] IR (Nujol): 3350, 2600, 1640, 1280, 1175, 1130 cm.sup.-1
[0818] NMR (DMSO-d.sub.6, .delta.): 1.55 (6H, m), 2.52-5.20 (19H,
m), 6.60-8.24 (8H, m), 10.95 (1H, s)
[0819] MASS: 597 (M+1) (free)
[0820] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl-
)-4-[3-(cis-2,6-dimethylmorpholino)propyl]piperazine
dihydrochloride
[0821] [.alpha.].sub.D.sup.20: -5.30.degree. (C=0.5, MeOH)
[0822] IR (Nujol): 3350, 2600, 1640, 1280 cm.sup.-1
[0823] NMR (DMSO-d.sub.6, .delta.): 1.20 (6H, m), 2.08-5.20 (21H,
m), 6.63-8.33 (8H, m), 10.94 (1H, s)
[0824] MASS: 611 (M+1) (free)
[0825] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[2-(1-imidazolyl)ethyl]piperazine dihydrochloride
[0826] [.alpha.].sub.D.sup.21: -16.20.degree. (C=0.5, MeOH)
[0827] IR (Nujol): 3350, 2700, 2575, 1640, 1430, 1280, 1170, 1130
cm.sup.-1
[0828] NMR (DMSO-d.sub.6, .delta.) : 2.04-5.20 (13H, m), 2.09 (3H,
s), 2.18 (3H, s), 6.55-8.22 (8H, m), 9.29 (1H, s)
[0829] MASS: 539 (M+1) (free)
[0830] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[3- (morpholinoamino)propyl]piperazine dihydrochloride
[0831] [.alpha.].sub.D.sup.20: -14.10.degree. (C=0.5, MeOH)
[0832] IR (Nujol): 3350, 2550, 1640, 1430, 1280 cm.sup.-1
[0833] NMR (DMSO-d.sub.6, .delta.): 1.97-5.14 (23H, m), 2.10 (3H,
s), 2.18 (3H, s), 6.64-8.24 (6H, m), 10.92 (1H, br s)
[0834] MASS: 587 (M+1) (free)
[0835] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[2-(3-pyridylmethylamino)ethyl]piperazine trihydrochloride
[0836] [.alpha.].sub.D.sup.21: 3.50.degree. (C=0.5, MeOH)
[0837] IR (Nujol): 3400, 2600, 1640, 1430, 1280, 1170, 1130
cm.sup.-1
[0838] NMR (DMSO-d.sub.6, .delta.): 2.07-5.20 (13H, m), 2.10 (3H,
s), 2.18 (3H, s), 4.50 (2H, s), 6.60-9.09 (10H, m), 10.32 (1H, br
s)
[0839] MASS: 679 (M+1) (free)
[0840] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-(2-homomorpholinoethyl) piperazine dihydrochloride
[0841] [.alpha.].sub.D.sup.17: -9.90.degree. (C=0.5, MeOH)
[0842] IR (Nujol): 3400, 2600, 2450, 1640, 1430, 1280 cm.sup.-1
[0843] NMR (DMSO-d.sub.6, .delta.): 2.04-5.17 (23H, m), 2.10 (3H,
s), 2.18 (3H, s), 6.62-8.26 (6H, m)
[0844] MASS: 572 (M+1) (free)
[0845] (7)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-(3-homomorpholinopropyl) piperazine dihydrochloride
[0846] [.alpha.].sub.D.sup.19: -10.0.degree. (C=0.5, MeOH)
[0847] IR (Nujol): 3400, 2600, 1635, 1430, 1280 cm.sup.-1
[0848] NMR (DMSO-d.sub.6, .delta.): 1.73-5.20 (25H, m), 2.10 (3H,
s), 2.18 (3H, s), 6.62-8.24 (6H, m)
[0849] MASS: 586 (M+1) (free)
[0850] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl-
)-4-(3-homomorpholinopropyl) piperazine dihydrochloride
[0851] [.alpha.].sub.D.sup.17: -5.50.degree. (C=0.5, MeOH)
[0852] IR (Nujol): 3300, 2650, 1640, 1275 cm.sup.-1
[0853] NMR (DMSO-d.sub.6, .delta.): 1.90-5.23 (25H, m), 6.62-8.34
(8H, m), 10.95 (1H, s)
[0854] MASS: 597 (M+1) (free)
[0855] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-
-4-[3-(4-acetylpiperidino)propyl]piperazine dihydrochloride
[0856] [.alpha.].sub.D.sup.20: 2.20.degree. (C=0.5, MeOH)
[0857] IR (Nujol): 3350, 2650, 1700, 1630, 1275 cm.sup.-1
[0858] NMR (DMSO-d.sub.6, .delta.): 1.69-5.21 (24H, m), 2.16 (3H,
s), 6.97-8.36 (6H, m)
[0859] MASS: 652 (M) (free)
[0860] (10)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl-
)-4-[3-(4-acetylpiperidino)propyl]piperazine dihydrochloride
[0861] [.alpha.].sub.D.sup.20: -11.30.degree. (C=0.5, MeOH)
[0862] IR (Nujol): 3425, 3375, 2500, 1705, 1640, 1275 cm.sup.-1
[0863] NMR (DMSO-d.sub.6, .delta.): 1.67-5.20 (24H, m), 2.16 (6H,
s), 2.18 (3H, s), 6.62-8.25 (6H, m), 10.60 (1H, br s), 11.49 (1H,
br s)
[0864] MASS: 612 (M+1) (free)
[0865] (11)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl-
)-4-(2-morpholinoethyl) piperazine dihydrochloride
[0866] [.alpha.].sub.D.sup.20: 6.10.degree. (C=0.5, MeOH)
[0867] IR (Nujol): 3350, 2600, 1630, 1270 cm.sup.-1
[0868] NMR (DMSO-d.sub.6, .delta.): 2.14-5.16 (21H, m), 6.93-8.27
(6H, m)
[0869] MASS: 598 (M) (free)
[0870] (12)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethy-
l)-4-[3-(4-methoxypiperidino)propyl]piperazine dihydrochloride
[0871] [.alpha.].sub.D.sup.19: -6.70.degree. (C=0.5, MeOH)
[0872] IR (Nujol): 3300, 2550, 1625, 1270 cm.sup.-1
[0873] NMR (DMSO-d.sub.6, .delta.): 1.57-5.20 (24H, m), 3.27 (3H,
s), 6.60-8.28 (8H, m), 10.95 (1H, s)
[0874] MASS: 611 (M+1) (free)
[0875] (13)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl-
)-4-[2-[N- (2-methoxyethyl) -N-methylamino ]ethyl]piperazine
dihydrochloride
[0876] mp: 222.degree. C. (dec.)
[0877] [.alpha.].sub.D.sup.23: -12.50.degree. (C=0.5, MeOH)
[0878] IR (Nujol): 3380, 2400, 1644, 1275, 1130 cm.sup.-1
[0879] NMR (DMSO-d.sub.6, .delta.): 2.0-2.3 (7H, m) , 2.88 (3H, s),
3.33 (3H, s), 2.3-5.3 (18H, m), 6.6-8.3 (6H, m)
[0880] MASS: 560 (M+1) (free)
[0881] (14)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl-
)-4-[3-(hexamethyleneimino)propyl]piperazine dihydrochloride
[0882] [.alpha.].sub.D.sup.26: -11.70.degree. (C=0.5, MeOH)
[0883] IR (Neat): 3400, 2600, 1640, 1430, 1280 cm.sup.-1
[0884] NMR (DMSO-d.sub.6, .delta.): 1.49-5.20 (27H, m), 2.10 (3H,
s), 2.19 (3H, s), 6.67-8.23 (6H, m)
[0885] MASS: 584 (M+1) (free)
[0886] (15)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl-
)-4-[2-(4-pyridylmethylamino)ethyl]piperazine trihydrochloride
[0887] [.alpha.].sub.D.sup.25: -0.20.degree. (C=0.5, MeOH)
[0888] IR (Neat): 3400, 2600, 1640, 1430, 1280, 1175, 1130
cm.sup.-1
[0889] NMR (DMSO-d.sub.6, .delta.): 2.10 (3H, s), 2.18 (3H, s),
2.64-5.20 (13H, m), 4.16 (2H, s), 6.40-8.97 (10H, m)
[0890] MASS: 579 (M+1) (free)
[0891] (16)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl-
)-4-[3-(1,2,4-triazol-3-ylamino) propyl]piperazine
dihydrochloride
[0892] [.alpha.].sub.D.sup.24: -10.50.degree. (C=0.5, MeOH)
[0893] IR (Neat): 3075, 2700, 1675, 1640, 1430, 1280, 1170, 1130
cm.sup.-1
[0894] NMR (DMSO-d.sub.6, .delta.): 2.05-5.20 (15H, m), 2.09 (3H,
s), 2.18 (3H, s), 6.60-8.34 (9H, m)
[0895] MASS: 569 (M+1) (free)
EXAMPLE 68
[0896] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthyl- methyl)
piperazine (300 mg), 4-thiomorpholino-2-butynyl chloride
hydrochloride (170 mg) and powdered potassium carbonate (210 mg) in
dry acetonitrile (3 ml) was refluxed for 7.5 hours in the presence
of potassium iodide (20 mg). The reaction mixture was cooled and
then filtered. The filtrate was concentrated under reduced pressure
and the resulting residue was purified by column chromatography on
silica gel using a mixture of ethyl acetate and methanol (50:1).
The obtained product was dissolved in ethyl acetate and treated
with 4N hydrogen chloride in ethyl acetate solution (0.6 ml) to
give (2R)-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(2-naphthylmethyl)-4-(4-thiom- orpholino-2-butynyl)
piperazine dihydrochloride (300 mg).
[0897] mp: 152-156.degree. C.
[0898] [.alpha.].sub.D.sup.27: -47.30.degree. (C=0.5, MeOH)
[0899] IR (Nujol): 3350, 2500, 1637, 1275, 1125 cm.sup.-1
[0900] NMR (DMSO-d.sub.6, .delta.): 2.70-5.30 (21H, m), 7.00-8.20
(10H, m)
[0901] MASS: 620 (M+1) (free)
EXAMPLE 69
[0902] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimeth-
ylbenzyl)-4-(4-chloro-2-butynyl) piperazine (200 mg),
1-cyclohexylpiperazine (63 mg) and powdered potassium carbonate
(210 mg) in dry N,N-dimethylformamide (2 ml) was stirred for 12
hours at room temperature. Additional 1-cyclohexylpiperazine (25
mg) was added and after 2 hours the reaction mixture was poured
into water (20 ml) and extracted with ethyl acetate. The organic
layer was washed with brine and dried over magnesium sulfate. After
evaporation of the solvent, the resulting residue was purified by
column chromatography on silica gel using a mixture of
dichloromethane and methanol (30:1). The obtained product was
dissolved in ethyl acetate and treated with 4N hydrogen chloride in
ethyl acetate solution (0.6 ml) to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(4-c-
yclohexylpiperazin-1-yl)-2-butynyl]piperazine trihydrochloride (220
mg).
[0903] mp: 175-190.degree. C.
[0904] [.alpha.].sub.D.sup.25.2: -7.20.degree. (C=0.5, MeOH)
[0905] IR (Nujol): 3370, 2750-1920, 1635, 1276, 1126 cm.sup.-1
[0906] NMR (DMSO-d.sub.6, .delta.): 1.02-5.20 (38H, m), 6.60-8.30
(6H, m)
[0907] MASS: 664 (M+1) (free)
EXAMPLE 70
[0908] Potassium carbonate (187 mg) and 2-(chloromethyl) pyridine
hydrochloride (81 mg) were added to a solution of
(2R)-1-[3,5-bis(trifluo- romethyl)benzoyl]-2-(3,4-dimethylbenzyl)
piperazine (200 mg) in N,N-dimethylformamide (4 ml) at room
temperature with stirring. After 2 hours, the reaction mixture was
poured into water (50 ml) and extracted with ethyl acetate. The
organic layer was washed with water and then dried over magnesium
sulfate, and evaporated under reduced pressure. The obtained
residue was purified by column chromatography on silica gel using a
mixture of ethyl acetate and toluene (1:3) and treated with 4N
hydrogen chloride in ethyl acetate solution to afford
(2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-pyridylmethyl)
piperazine dihydrochloride (123 mg).
[0909] [.alpha.].sub.D.sup.23: -28.30.degree. (C=0.5, MeOH)
[0910] IR (Nujol): 3360, 2560, 1640, 1278, 1130 cm.sup.-1
[0911] NMR (DMSO-d.sub.6, .delta.): 2.0-2.3 (10H, m), 2.6-5.8 (9H,
m), 6.6-8.7 (10H, m)
[0912] MASS: 536 (M+1) (free)
EXAMPLE 71
[0913] Lindlar catalyst (Pd-CaCO.sub.3-Pb(OAc).sub.2) (40 mg) was
added to a solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylme-
thyl)-4-(4-morpholino-2-butynyl) piperazine in methanol (8 ml). The
mixture was stirred for 2 hours under hydrogen at 25.degree. C. and
then filtered. The filtrate was concentrated under reduced pressure
and the resulting residue was chromatographed on silica gel with
dichloromethane-methanol (20:1) as eluent to give material which on
treatment with 4N hydrogen chloride in ethyl acetate solution
afforded (2R)
-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[(Z)--
4-morpholino-2-butenyl]piperazine dihydrochloride (104 mg).
[0914] [.alpha.].sub.D.sup.21: .+-.0.40.degree. (C=0.5, MeOH)
[0915] IR (Nujol): 3700-3150, 2750-2300, 1635, 1275, 1170, 1120
cm.sup.-1
[0916] NMR (DMSO-d.sub.6, .delta.): 3.00-4.10 (21H, m), 6.05-6.35
(2H, m), 6.80-8.10 (8H, m), 10.72 (1H, s)
[0917] MASS: 595 (M+1) (free)
EXAMPLE 72
[0918] The following compound was obtained according to a similar
manner to that of Example 71.
[0919]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[-
(Z)-4-morpholino-2-butenyl]piperazine dihydrochloride
[0920] mp: 243-246.degree. C.
[0921] [.alpha.].sub.D.sup.21: -5.30.degree. (C=0.5, MeOH)
[0922] IR (Nujol): 3600-3150, 2600-2300, 1645, 1275, 1170, 1130
cm.sup.-1
[0923] NMR (DMSO-d.sub.6, .delta.): 2.10-2.20 (6H, m), 3.0-4.2
(21H, m), 6.05-5.35 (2H, m), 6.80-7.10 (3H, m), 7.60 (2H, s), 8.09
(1H, s)
[0924] The NMR spectrum of this compound was measured at 90.degree.
C.
[0925] MASS: 584 (M+1) (free)
EXAMPLE 73
[0926] A solution of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol--
3-ylmethyl)-4-(4-morpholino-2-butynyl) piperazine in methanol (10
ml) was hydrogenated in the presence of 10% Pd-carbon (50 mg) at
room temperature. After completion of the reaction (1 hour and 20
minutes), the reaction mixture was filtered and then
chromatographed on silica gel with dichloromethane-methanol (20:1)
to give material which on treatment with 4N hydrogen chloride in
ethyl acetate solution afforded
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-mor-
pholinobutyl) piperazine dihydrochloride (165.1 mg).
[0927] [.alpha.].sub.D.sup.21: -7.10.degree. (C=0.5, MeOH)
[0928] IR (Nujol): 3700-3150, 2720-2450, 1635, 1275, 1180-1080
cm.sup.-1
[0929] NMR (DMSO-d.sub.6, .delta.): 1.70-2.00 (4H, m), 2.95-5.20
(21H, m), 6.60-8.25 (8H, m), 10.95 (1H, s), 11.10-11.80 (2H, m)
[0930] MASS: 597 (M+1) (free)
EXAMPLE 74
[0931] The following compound was obtained according to a similar
manner to that of Example 73.
[0932]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(-
5-morpholinopentyl) piperazine dihydrochloride
[0933] mp: 235-238.degree. C.
[0934] [.alpha.].sub.D.sup.22: -13.90.degree. (C=0.5, MeOH)
[0935] IR (Nujol): 3500-3100, 2600, 1630, 1270, 1180-1060
cm.sup.-1
[0936] NMR (DMSO-d.sub.6, .delta.): 1.2-2.0 (6H, m), 2.0-2.5 (8H,
m), 2.6-5.2 (19H, m), 6.6-8.3 (6H, m), 11.26 (2H, m)
[0937] MASS: 600 (M+1) (free)
EXAMPLE 75
[0938]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)
piperazine (200 mg) and potassium carbonate (187 mg) were added to
a mixture of (E)-4-morpholino-2-butenyl chloride hydrochloride (105
mg) and acetonitrile (3 ml). The resulting mixture was heated at
reflux temperature under stirring. After 16 hours, the reaction
mixture was evaporated under reduced pressure and the residue was
partitioned between ethyl acetate and water. The organic phase was
separated and washed with brine, and dried over magnesium sulfate.
The solvent was removed in vacuo to leave an oil which was
chromatographed on silica gel with dichloromethane-methanol (50:1)
as eluent to give material which on treatment with 4N hydrogen
chloride in ethyl acetate solution (0.2 ml) afforded
(2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[(E)-4-morpholino-2-butenyl]piperazine dihydrochloride (194
mg).
[0939] mp: 236-242.degree. C.
[0940] [.alpha.].sub.D.sup.19.6: -10.8.degree. (C=0.3, MeOH)
[0941] IR (Nujol): 3350, 2900, 1645, 1275, 1185, 1170, 1135
cm.sup.-1
[0942] NMR (DMSO-d.sub.6, .delta.): 2.16 (3H, s), 2.20 (3H, s),
2.60-4.80 (19H, m), 3.91 (4H, t, J=4.8Hz), 6.04-6.40 (2H, m),
6.74-7.15 (3H, m), 7.61 (2H, s), 8.08 (1H, s)
[0943] The NMR spectrum of this compound was measured at 90.degree.
C.
[0944] MASS: 584 (M+1) (free)
EXAMPLE 76
[0945] The following compound was obtained according to a similar
manner to that of Example 75.
[0946]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4--
[(E)-4-morpholino-2-butenyl]piperazine dihydrochloride
[0947] mp: 123-128.degree. C.
[0948] [.alpha.].sub.D.sup.20: -0.2.degree. (C=0.3, MeOH)
[0949] IR (Nujol): 3350, 2750-2000, 1655, 1635, 1275, 1175, 1125
cm.sup.-1
[0950] NMR (DMSO-d.sub.6, .delta.): 2.60-5.00 (17H, m), 3.89 (4H,
t, J=4.8Hz), 6.00-6.40 (2H, m), 6.70-7.50 (5H, m), 7.80 (2H, s),
8.03 (1H, s), 10.74 (1H, s)
[0951] The NMR spectrum of this compound was measured at 90.degree.
C.
[0952] MASS: 595 (M+1) (free)
EXAMPLE 77
[0953] To a stirred mixture of (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2- -(1H-indol-3-ylmethyl) piperazine (0.2
g) and 1-methyl-4-formyl-1H-pyrazol- e (0.05 g) in dichloromethane
(2 ml) under nitrogen atmosphere was added sodium
triacetoxyborohydride (151 mg) at room temperature. After 4 hours,
the reaction mixture was evaporated under reduced pressure, and
ethyl acetate (20 ml) and aqueous sodium hydrogen carbonate
solution (10 ml) were added to the residue. The organic layer was
separated and washed with brine, dried over magnesium sulfate and
then concentrated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel using a mixture of
ethyl acetate and methanol (50:1). The obtained product was
dissolved in ethyl acetate and treated with 4N hydrogen chloride in
ethyl acetate solution to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[(1-m-
ethyl-1H-pyrazol-4-yl)methyl]piperazine hydrochloride (154 mg).
[0954] mp: 122-136.degree. C.
[0955] [.alpha.].sub.D.sup.18.8: -8.50.degree. (C=0.3, MeOH)
[0956] IR (Nujol): 3350, 2750-2000, 1655, 1640, 1275, 1175, 1125
cm.sup.-1
[0957] NMR (DMSO-d.sub.6, .delta.): 2.80-5.20 (14H, m), 6.50-8.30
(10H, m), 10.90 (1H, s), 11.40-11.90 (1H, br s)
[0958] MASS: 550 (M+1) (free)
EXAMPLE 78
[0959] A mixture of
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimeth-
ylbenzyl)-4-[2-(methylsulfonyloxy)ethyl]piperazine (200 mg),
2-ethoxyethylamine (0.044 ml) and triethylamine (0.098 ml) in
acetonitrile (5 ml) was refluxed for 1.5 hours. The reaction
mixture was concentrated under reduced pressure and the resulting
residue was partitioned between ethyl acetate and aqueous sodium
hydrogen carbonate solution. The organic layer was washed with
brine and dried over magnesium sulfate. After evaporation of the
solvent, the residue was purified by column chromatography on
silica gel using a mixture of dichloromethane and methanol (20:1)
to afford an oily product, which was dissolved in ethyl acetate and
treated with 4N hydrogen chloride in ethyl acetate solution to give
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4--
dimethylbenzyl)-4-[2-(2-ethoxyethylamino)ethyl]piperazine
dihydrochloride (64.5 mg)
[0960] [.alpha.].sub.D.sup.22: -6.70.degree. (C=0.5, MeOH)
[0961] IR (Neat): 3400, 2650, 1640, 1430, 1280, 1170, 1150, 900
cm.sup.-1
[0962] NMR (DMSO-d.sub.6, .delta.): 1.63 (3H, m), 2.0-2.30 (6H, m),
2.6-5.3 (20H, m), 6.6-8.3 (6H, m), 9.2-9.6 (1H, br s), 11.2-1.8
(1H, br s)
[0963] MASS: 560(M+1) (free)
Preparation 8
[0964] To a mixture of
N-(tert-butylcarbonyl)-4-fluoro-D-phenylalanine (5.25 g),
N-benzylglycine benzyl ester hydrochloride (5.41 g) and
triethylamine (9.04 ml) in dichloromethane (50 ml) was added
2-chloro-1-methylpyridinium iodide (5.21 g) at room temperature,
and the mixture was stirred for 2.5 hours. The mixture was
evaporated under reduced pressure, and the resulting residue was
dissolved into ethyl acetate. The ethyl acetate solution was washed
with diluted hydrochloric acid, saturated sodium hydrogen carbonate
aqueous solution and brine successively, and dried over magnesium
sulfate. After evaporation of the solvent, the resulting residue
was chromatographed on a silica gel using mixture of toluene and
ethyl acetate as an eluent to give
(2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4-
-fluorophenyl) propanamide (9.62 g).
[0965] [.alpha.].sub.D.sup.23.6: .+-.9.10.degree. (C=0.5, MeOH)
[0966] IR (Nujol): 3350, 1735, 1680, 1650 cm.sup.-1
[0967] NMR (DMSO-d.sub.6, .delta.): 1.24, 1.30 (9H, 2s), 2.70-2.90
(2H, m), 3.85-4.80 (5H, m), 5.12 (2H, d, J=3.2Hz), 6.95-7.45 (14H,
m)
[0968] MASS: 521 (M+1)
Preparation 9
[0969] To an ice-cooled solution of
(2R)-N-benzyl-N-benzyloxycarbonylmethy-
l-2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl) propanamide (9.48
g) in dichloromethane (55 ml) was added 4N hydrogen chloride in
dioxane solution (54.6 ml). The mixture was stirred at the same
temperature for 15 minutes and at room temperature for one hour.
After removal of solvent by evaporation, excess aqueous sodium
hydrogen carbonate solution was added to the resulting residue. The
mixture was warmed at near 50.degree. C. for several minutes and
the resulting precipitates were collected by filtration and washed
with water and dried in vacuo to give
(3R)-1-benzyl-3-(4-fluorobenzyl) piperazine-2,5-dione (5.00 g).
[0970] [.alpha.].sub.D.sup.27.3: -20.30.degree. (C=0.5, MeOH)
[0971] IR (Nujol): 3200, 3050, 1665, 1220 cm.sup.-1
[0972] NMR (DMSO-d.sub.6, .delta.): 2.80 (1H, d, J=17.3Hz), 2.88
(1H, dd, J=13.7Hz, 4.7Hz), 3.15 (1H, dd, J=13.7Hz, 4.1Hz), 3.53
(1H, d, J=17.3Hz), 4.15 (1H, d, J=14.4Hz), 4.26 (1H, m), 4.63 (1H,
d, J=14.4Hz), 6.80-7.40 (9H, m), 8.33 (1H, br s)
[0973] MASS: 313 (M+1)
Preparation 10
[0974] To an ice-cooled suspension of lithium aluminum hydride (1.2
g) in tetrahydrofuran (91 ml) was added
(3R)-1-benzyl-3-(4-fluorobenzyl) piperazine-2,5-dione (4.95 g) by
small portions. The mixture was stirred at the same temperature for
15 minutes and at room temperature for one hour. After removal of
solvent by evaporation, aqueous sodium hydrogen carbonate solution
was added to the resulting residue. The mixture was warmed at near
50.degree. C. for several minutes and the resulting precipitates
were collected by filtration, washed with water and dried in vacuo
to give (3R)-1-benzyl-3-(4-fluorobenzyl) piperazine (4.60 g) as an
oil.
[0975] IR (Neat): 3300, 1215 cm.sup.-1
[0976] NMR (DMSO-d.sub.6, .delta.): 1.90 (2H, m), 2.45-2.90 (5H,
m), 3.30-3.45 (4H, m), 6.95-7.35 (9H, m)
[0977] MASS: 285 (M+1)
Preparation 11
[0978] A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)
benzoyl]-2-(4-fluorobenzyl)piperazine (7.92 g), ammonium formate
(2.38 g) and 10% palladium charcoal (0.79 g) in a mixed solvent of
ethanol (80 ml) and water (8 ml) was stirred for 1.5 hours at
60.degree. C. under nitrogen atmosphere. The reaction mixture was
cooled to room temperature and filtered through Celite.RTM. pad.
The filtrate was concentrated under reduced pressure and the
residue was dissolved into ethyl acetate. The solution was washed
with water and brine successively, dried over magnesium sulfate,
and evaporated under reduced pressure to give (2R)-1-[3,5-bis
(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (6.04 g) as
an oil.
[0979] IR (Neat): 3300, 1630, 1150 cm.sup.-1
[0980] NMR (DMSO-d.sub.6, .delta.): 2.55-3.80 (8H, m), 4.25 (1H,
m), 6.90-7.50 (5H, m), 7.64 (1H, br s), 8.13 (1H, br s)
[0981] MASS: 435 (M+1)
Preparation 12
[0982] The following compounds were prepared by a similar manner to
that of Preparation 8.
[0983] (1)
(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonyla-
mino)-3-(4-methoxyphenyl) propanamide
[0984] [.alpha.].sub.D.sup.24.0: +6.60.degree. (C=0.5, MeOH)
[0985] IR (Neat): 3300, 1740, 1700, 1650, 1240 cm.sup.-1
[0986] NMR (DMSO-d.sub.6, .delta.): 1.27, 1.31 (9H, 2s), 2.76 (2H,
m), 3.69, 3.70 (3H, 2s), 3.95-4.90 (5H, m), 5.13 (2H, d, J=4.9Hz),
6.70-7.36 (14H, m)
[0987] MASS: 533 (M+1)
[0988] (2)
(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonyla-
mino)-3-(4-trifluoromethylphenyl) propanamide
[0989] [.alpha.].sub.D.sup.26.4: +9.00.degree. (C=0.5, MeOH)
[0990] IR (Nujol): 3350, 1735, 1720, 1670, 1650 cm.sup.-1
[0991] NMR (DMSO-d.sub.6, .delta.): 1.19, 1.27 (9H, 2s), 2.90 (2H,
m), 4.00-4.75 (5H, m), 5.12 (2H, s), 7.10-7.60 (15H, m)
[0992] MASS: 571 (M+1)
[0993] (3)
(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonyla-
mino)-3-(1-naphthyl) propanamide
[0994] [.alpha.].sub.D.sup.27.7: -0.60.degree. (C=0.5, MeOH)
[0995] IR (Neat): 3300, 2970, 1740, 1700, 1645 cm.sup.-1
[0996] NMR (DMSO-d.sub.6, .delta.): 1.18, 1.26 (9H, 2s), 3.20-3.50
(2H, m), 3.90-5.20 (7H, m), 7.10-8.10 (17H, m)
[0997] MASS: 553 (M+1)
Preparation 13
[0998] The following compounds were prepared by a similar manner to
that of Preparation 9.
[0999] (1)
(3R)-1-Benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione
[1000] [.alpha.].sub.D.sup.27.9: -38.60.degree. (C=0.5, MeOH)
[1001] IR (Nujol): 3250, 1680, 1640, 1245 cm.sup.-1
[1002] NMR (DMSO-d.sub.6, .delta.): 2.60 (1H, d, J=17.2Hz), 2.80
(1H, dd, J=13.6Hz, 4.7Hz), 3.09 (1H, dd, J=13.6Hz, 3.8Hz), 3.46
(1H, d, J=17.2Hz), 3.67 (3H, s), 4.11 (1H, d, J=14.4Hz), 4.22 (1H,
br s), 4.65 (1H, d, J=14.4Hz), 6.63 (2H, d, J=8.7Hz), 6.93 (2H, d,
J=8.7Hz), 7.10-7.40 (5H, m), 8.30 (1H, br s)
[1003] MASS: 325 (M+1)
[1004] (2)
(3R)-1-Benzyl-3-(4-trifluoromethylbenzyl)piperazine-2,5-dione
[1005] [.alpha.].sub.D.sup.26.8: -12.00.degree. (C=0.5, MeOH)
[1006] IR (Nujol): 3250, 1680, 1650 cm.sup.-1
[1007] NMR (DMSO-d.sub.6, .delta.): 2.85 (1H, d, J=17.4Hz), 3.00
(1H, dd, J=13.4Hz, 4.8Hz), 3.25 (1H, dd, J=13.4Hz, 4.4Hz), 3.59
(1H, d, J=17.4Hz), 4.08 (1H, d, J=14.4Hz), 4.35 (1H, br s), 4.74
(1H, d, J=14.4Hz), 7.00-7.15 (2H, m), 7.25-7.35 (5H, m), 7.48 (2H,
d, J=8.1Hz), 8.41 (1H, s)
[1008] MASS: 363 (M+1)
[1009] (3)
(3R)-1-Benzyl-3-(1-naphthylmethyl)piperazine-2,5-dione
[1010] IR (Nujol): 3250, 1685, 1655 cm.sup.-1
[1011] NMR (DMSO-d.sub.6, .delta.): 2.92 (1H, d, J=17.2Hz),
3.40-3.65 (3H, m), 4.31 (3H, s), 7.03 (2H, m), 7.29 (5H, m), 7.54
(2H, m), 7.82 (1H, dd, J=6.5Hz, 3.0Hz), 7.94 (1H, m), 8.14 (1H, m),
8.31 (1H, d, J=3.0Hz)
[1012] MASS: 345 (M+1)
Preparation 14
[1013] The following compounds were prepared by a similar manner to
that of Preparation 10.
[1014] (1) (3R)-1-Benzyl-3-(4-methoxybenzyl)piperazine
[1015] IR (Neat): 3250, 1240 cm.sup.-1
[1016] NMR (DMSO-d.sub.6, .delta.): 1.60-2.00 (4H, m), 2.40-2.90
(5H, m), 3.30-3.50 (2H, m), 3.70 (3H, s), 6.81 (2H, d, J=8.6Hz),
7.07 (2H, d, J=8.6Hz), 7.15-7.40 (6H, m)
[1017] MASS: 297 (M+1)
[1018] (2) (3R)-1-Benzyl-3-(4-trifluoromethylbenzyl)piperazine
[1019] [.alpha.].sub.D.sup.27.2: -5.80.degree. (C=0.5, MeOH)
[1020] IR (Neat): 3250, 2925, 2800, 1320 cm.sup.-1
[1021] NMR (DMSO-d.sub.6, .delta.): 1.72 (1H, t, J=10.0Hz), 1.91
(1H, m), 2.55-2.95 (6H, m), 3.30-3.50 (3H, m), 7.15-7.35 (6H, m),
7.40 (2H, d, J=8.0Hz), 7.60 (2H, d, J=8.0Hz)
[1022] MASS: 335 (M+1)
[1023] (3) (3R)-1-Benzyl-3-(1-naphthylmethyl)piperazine
[1024] [.alpha.].sub.D.sup.27.6: -21.80.degree. (C=0.5, MeOH)
[1025] IR (Neat): 3300, 3050, 2925, 2800 cm.sup.-1
[1026] NMR (DMSO-d.sub.6, .delta.): 1.75-2.05 (2H, m), 2.50-3.60
(9H, m), 7.10-7.65 (9H, m), 7.77 (1H, d, J=7.9Hz), 7.90 (1H, m),
8.12 (1H, dd, J=7.1Hz, 2.3Hz)
[1027] MASS: 317 (M+1)
Preparation 15
[1028] The following compounds were prepared by a similar manner to
that of Preparation 11.
[1029] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)
piperazine
[1030] [.alpha.].sub.D.sup.28.1: -32.60.degree. (C=0.5, MeOH)
[1031] IR (Neat): 3300, 1630, 1280 cm.sup.-1
[1032] NMR (DMSO-d.sub.6, .delta.) : 2.40-3.55 (9H, m), 3.72 (3H,
s), 6.70-8.45 (7H, m)
[1033] MASS: 447 (M+1)
[1034] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-trifluoromethylbe-
nzyl) piperazine
[1035] NMR (DMSO-d.sub.6, .delta.): 2.60-3.70 (9H, m), 7.15-7.40
(2H, m), 7.50-7.75 (4H, m), 8.12 (1H, s)
[1036] MASS: 485 (M+1)
[1037] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1-naphtnylmethyl)
piperazine
[1038] [.alpha.].sub.D.sup.28.1: -24.70.degree. (C=0.5, MeOH)
[1039] IR (Neat): 3340, 3050, 2950, 2825, 1630 cm.sup.-1
[1040] NMR (DMSO-d.sub.6, .delta.): 2.50-4.30 (9H, m), 7.10-8.55
(10H, m)
[1041] MASS: 467 (M+1)
Preparation 16
[1042] A mixture of 1-methyl-1H-pyrazole-4-carboxaldehyde (2.0 g)
and triethyl phosphonoacetate (4.52 g) in N,N-dimethylformamide (20
ml) was stirred under ice-cooling. After several minutes, sodium
hydride (1.09 g, 60% in mineral oil) was added to the mixture,
which was stirred for 1 hour at the same temperature. The resulting
mixture was poured into ice-water, neutralized with aqueous
ammonium acetate solution and extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium sulfate
and concentrated under reduced pressure. The resulting residue was
chromatographed on a silica gel using a mixture of hexane and ethyl
acetate as an eluent to give ethyl
(E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate.
[1043] IR (Nujol): 2975, 1700, 1635 cm.sup.-1
[1044] NMR (DMSO-d.sub.6, .delta.): 1.32 (3H, t, J=7.1Hz), 4.23
(2H, q, J=7.1Hz), 6.16 (1H, d, J=16.0Hz), 7.54 (1H, s), 7.55 (1H,
d, J=16.0Hz), 7.69 (1H, s)
Preparation 17
[1045] A solution of 2-(E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate
(1.04 g) in tetrahydrofuran (50 ml) was hydrogenated over 10%
palladium charcoal (0.2 g) at room temnerature at 2 atm of
hydrogen. After removal of catalyst by filtration through
Celite.RTM. pad the filtrate was concentrated under reduced
pressure to give ethyl 3-(1-methyl-1H-pyrazol-- 4-yl)
propionate.
[1046] IR (Neat): 2950, 1725 cm.sup.-1
[1047] NMR (DMSO-d.sub.6, .delta.): 1.24 (3H, t, J=7.1Hz), 2.50
(2H, t, J=7.5Hz), 2.78 (2H, t, J=7.5Hz), 3.84 (3H, s), 4.13 (2H, q,
J=7.1Hz), 7.18 (1H, s), 7.31 (1H, s)
[1048] MASS: 183 (M+1)
Preparation 18
[1049] To an ice-cooled solution of ethyl
3-(1-methyl-1H-pyrazol-4-yl) propionate (1.05 g) in tetrahydrofuran
(10 ml) was added lithium aluminum hydride (0.22 g) under nitrogen
atmosphere. After the mixture was stirred for 30 minutes, water and
15% sodium hydroxide aqueous solution were added successively to
the mixture. The resulting precipitates were filtered off through
Celite.RTM. pad and the filtrate was extracted with ethyl acetate.
The organic layer was washed with water, dried over magnesium
sulfate and concentrated under reduced pressure to give
3-(1-methyl-1H-pyrazol-4-yl)-1-propanol.
[1050] IR (Neat): 3300, 2930 cm.sup.-1
[1051] NMR (DMSO-d.sub.6, .delta.): 1.87 (2H, m), 2.55 (2H, t,
J=7.6Hz), 3.68 (2H, t, J=6.1Hz), 3.85 (3H, s), 7.16 (1H, s), 7.31
(1H, s)
[1052] MASS: 141 (M+1)
Preparation 19
[1053] To a solution of oxalyl chloride (0.361 ml) in
dichloromethane (10 ml) cooled below -65.degree. C. with a dry
ice-acetone bath, a solution of dimethyl sulfoxide (0.381 ml) in
dichloromethane (1 ml) was added with efficient stirring over 10
minutes. After 20 minutes below -65.degree. C., a solution of
3-(1-methyl-1H-pyrazol-4-yl)-1-propanol in dichloromethane (2 ml)
was added to the mixture over 10 minutes below -65.degree. C. and
the mixture was stirred at the same temperature for 20 minutes and
then at -45.about.-40.degree. C. for 30 minutes. After addition of
triethylamine dropwise to the mixture over 10 minutes followed by
stirring for 15 minutes, 1N hydrochloric acid solution was added to
the mixture. The resulting mixture was extracted with a mixture of
dichloromethane and methanol several times. The extract was
concentrated under reduced pressure and the resulting residue was
chromatographed on a silica gel using a mixture of dichloromethane
and methanol as an eluent to give
3-(1-methyl-1H-pyrazol-4-yl)-1-propanal.
[1054] IR (Neat): 2925, 1720 cm.sup.-1
[1055] NMR (DMSO-d.sub.6, .delta.): 2.65-2.90 (4H, m), 3.86 (3H,
s), 7.17 (1H, s), 7.32 (1H, s), 9.80 (1H, s)
[1056] MASS: 139 (M+1)
EXAMPLE 79
[1057] To a mixture of 3,5-bis(trifluoromethyl)benzoic acid (4.13
g) and pyridine (0.041 ml) in tetrahydrofuran (12.5 ml) was added
oxalyl chloride (3.25 g) over 15 minutes at 22-38.degree. C. and
the mixture was stirred at 55.degree. C. for 4 hours. The acid
chloride solution obtained above procedure was added to an
ice-cooled solution of (3R)-1-benzyl-3-(4-fluorobenzyl) piperazine
(4.51 g) and triethylamine (4.83 g) in dichloromethane (45 ml)
under 5.degree. C. for 30 minutes. After being stirred for 2 hours
at room temperature, the mixture was washed with water and brine
successively, and dried over magnesium sulfate. After evaporation
of the solvent, the resulting residue was chromatographed on a
silica gel using a mixture of toluene and ethyl acetate as an
eluent to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)ben-
zoyl]-2-(4-fluorobenzyl) piperazine (0.87 g) as a syrup.
[1058] [.alpha.].sub.D.sup.27.5: -11.50.degree. (C=0.5, MeOH)
[1059] IR (Neat): 1740, 1150 cm.sup.-1
[1060] NMR (DMSO-d.sub.6, .delta.): 2.00-4.40 (11H, m), 6.80-7.50
(10H, m), 7.74 (1H, br s), 8.13 (1H, br)
[1061] MASS: 525 (M+1)
EXAMPLE 80
[1062] The following compounds were prepared by a similar manner to
that of Example 79.
[1063] (1)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxyb-
enzyl) piperazine
[1064] [.alpha.].sub.D.sup.28.0: -21.40.degree. (C=0.5, MeOH)
[1065] IR (Neat): 1740, 1640, 1270 cm.sup.-1
[1066] NMR (DMSO-d.sub.6, .delta.): 1.70-2.40 (3H, m), 2.60-3.80
(11H, m), 6.60-7.60 (10H, m), 7.65-8.55 (2H, m)
[1067] MASS: 537 (M+1)
[1068] (2)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-trifluor-
omethylbenzyl) piperazine
[1069] IR (Neat): 2950, 2800, 1765, 1740, 1640 cm.sup.-1
[1070] NMR (DMSO-d.sub.6, .delta.): 1.70-4.30 (11H, m), 7.13 (1H,
d, J=7.8Hz), 7.20-7.70 (10H, m), 8.13 (1H, d, J=7.8Hz)
[1071] MASS: 575 (M+1)
[1072] (3)
(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1-naphthyl-
methyl) piperazine
[1073] [.alpha..sub.D.sup.27.5: -9.70.degree. (C=0.5, MeOH)
[1074] IR (Nujol): 1640 cm.sup.-1
[1075] NMR (DMSO-d.sub.6, .delta.): 2.00-4.40 (11H, m), 7.00-8.55
(15H, m)
[1076] MASS: 557 (M+1)
EXAMPLE 81
[1077] The following compound was prepared by a similar manner to
that of Example 66.
[1078] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-
(3,4-dimethylbenzyl)-4--
[3-(cis-2,6-dimethylmorpholino)propyl]piperazine
dihydrochloride
[1079] [.alpha.].sub.D.sup.21.0: -11.10.degree. (C=0.5, MeOH)
[1080] IR (Neat): 3400, 2550, 2450, 1640, 1430, 1280, 1175, 1130
cm.sup.-1
[1081] NMR (DMSO-d.sub.6, .delta.): 1.14 (6H, m), 2.05-5.24 (19H,
m), 2.10 (3H, s), 2.18 (3H, s), 6.64-8.24 (6H, m)
[1082] MASS: 600 (M+1) (free)
[1083] Anal. Calcd. for
C.sub.31H.sub.39F.sub.6N.sub.3O.sub.2.multidot.2HC-
l.multidot.2.35H.sub.2O
[1084] C 52.08, H 6.29, N 5.77
[1085] Found: C 52.08, H 6.44, N 5.88
EXAMPLE 82
[1086] The following compounds were obtained according to a similar
manner to that of Example 23.
[1087] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[N-(3-pyridylmethyl)-3-aminopropyl]piperazine
trihydrochloride
[1088] [.alpha.].sub.D.sup.28.4: -13.60.degree. (C=0.25, MeOH)
[1089] IR (Neat): 3600-3100, 2800-1950, 1270, 1125 cm.sup.-1
[1090] NMR (DMSO-d.sub.6, .delta.): 2.09-5.20 (24H, m), 6.60-9.00
(10H, m)
[1091] MASS: 593 (M+1) (free)
[1092] Anal. Calcd. for
C.sub.21H.sub.34F.sub.6N.sub.4O.multidot.3HCl.mult- idot.4H.sub.2O
:
[1093] C 48.10, H 5.86, N 7.24
[1094] Found: C 47.89, H 5.75, N 7.02
[1095] (2)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethybenzyl)--
4-(N-morpholino-2-aminoethyl) piperazine dihydrochloride
[1096] [.alpha.].sub.D.sup.28.5: -26.80.degree. (C=0.25, MeOH)
[1097] IR (Neat): 3600-3000, 2800-2000, 1630, 1274, 1120
cm.sup.-1
[1098] NMR (DMSO-d.sub.6, .delta.): 2.02-5.20 (28H, m), 6.50-8.30
(6H, m)
[1099] MASS: 573 (M+1) (free)
[1100] Anal. Calcd. for
C.sub.28H.sub.34F.sub.6N.sub.4O.sub.2.multidot.2HC-
l.multidot.9/2H.sub.2O.multidot.1/4CH.sub.3CO.sub.2
C.sub.2H.sub.5:
[1101] C 46.53, H 6.33, N 7.48
[1102] Found: C 46.64, H 6.23, N 6.67
[1103] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-(N-morpholino-4-amino-2-butynyl) piperazine dihydrochloride
[1104] [.alpha.].sub.D.sup.28.0: -9.80.degree. (C=0.25, MeOH)
[1105] IR (Neat): 3600-3000, 2600-1950, 1630, 1273, 1120
cm.sup.-1
[1106] NMR (DMSO-d.sub.6, .delta.): 2.10-5.20 (28H, m), 6.20-8.30
(6H, m)
[1107] MASS: 597 (M+1) (free)
[1108] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[N-methyl-N-(3-pyridylmethyl)-2-aminoethyl]piperazine
trihydrocloride
[1109] [.alpha.].sub.D.sup.28.4: -11.80.degree. (C=0.25, MeOH)
[1110] IR (Nujol): 3600-3100, 2700-1950, 1630, 1275, 1122
cm.sup.-1
[1111] NMR (DMSO-d.sub.6, .delta.): 2.10-5.20 (24H, m), 6.60-7.80
(6H, m), 8.10-8.35 (2H, m), 8.70-8.95 (2H, m)
[1112] MASS: 593 (M+1) (free)
[1113] Anal. Calcd. for
C.sub.31H.sub.34F.sub.6N.sub.4O.multidot.3HCl.mult-
idot.7/2H.sub.2O :
[1114] C 48.67, H 5.80, N 7.32
[1115] Found: C 48.88, H 5.88, N 6.79
[1116] (5)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[(E)-N-(3-pyridylmethyl)-4-amino-2-butenyl]piperazine
trihydrochloride
[1117] [.alpha.].sub.D.sup.28.5: -10.40.degree. (C=0.25, MeOH)
[1118] IR (Neat): 3600-3100, 2800-1950, 1630, 1274, 1124
cm.sup.-1
[1119] NMR (DMSO-d.sub.6, .delta.): 2.09-5.20 (22H, m), 6.05-6.25
(2H, m), 6.60-9.00 (10H, m)
[1120] MASS: 605 (M+1) (free)
[1121] Anal. Calcd. for
C.sub.32H.sub.34F.sub.6N.sub.4O.multidot.3HCl.mult- idot.5H.sub.2O
:
[1122] C 47.80, H 5.89, N 6.97
[1123] Found: C 47.81, H 5.53, N 6.48
[1124] (6)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-[(E)-N-morpholino-4-amino-2-butenyl]piperazine
dihydrochloride
[1125] [.alpha.].sub.D.sup.28.5: -6.40.degree. (C=0.25, MeOH)
[1126] IR (Nujol): 3600-3000, 2750-1950, 1620, 1273, 1120
cm.sup.-1
[1127] NMR (DMSO-d.sub.6, .delta.): 2.09-5.20 (28H, m), 5.80-8.30
(8H, m)
[1128] MASS: 599 (M+1) (free)
[1129] Anal. Calcd. for
C.sub.30H.sub.36F.sub.6N.sub.4O.sub.2.multidot.2HC-
l.multidot.7/2H.sub.2O:
[1130] C 49.05, H 6.17, N 7.63
[1131] Found: C 49.15, H 6.16, N 7.41
[1132] (7)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-[N- (3-pyridylmethyl)-2-aminoethyl]piperazine trihydrochloride
[1133] [.alpha.].sub.D.sup.28.5: -11.00.degree. (C=0.25, MeOH)
[1134] IR (Neat): 3600-3100, 2800-1950, 1630, 1273, 1120
cm.sup.-1
[1135] NMR (DMSO-d.sub.6, .delta.):2.50-5.20 (16H, m), 7.00-9.00
(14H, m)
[1136] MASS: 601 (M+1) (free)
[1137] Anal. Calcd. for
C.sub.32H.sub.30F.sub.6N.sub.4O.multidot.3HCl.mult-
idot.4H.sub.2O:
[1138] C 49.15, H 5.28, N 7.16
[1139] Found: C 49.26, H 5.24, N 6.80
[1140] (8)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-(N-morpholino-2-aminoethyl) piperazine dihydrochloride
[1141] [.alpha.].sub.D.sup.28.6: -34.80.degree. (C=0.25, MeOH)
[1142] IR (Neat): 3600-3100, 2800-1950, 1630, 1273, 1120
cm.sup.-1
[1143] NMR (DMSO-d.sub.6, .delta.):2.50-5.30 (22H, m), 7.00-8.20
(10H, m)
[1144] MASS: 595 (M+1) (free)
[1145] Anal. Calcd. for
C.sub.30H.sub.32F.sub.6N.sub.4O.sub.2.multidot.2HC-
l.multidot.11/3H.sub.2O:
[1146] C 49.12, H 5.68, N 7.64
[1147] Found: C 49.04, H 5.57, N 7.39
[1148] (9)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-(N-morpholino-3-aminopropyl) piperazine dihydrochloride
[1149] [.alpha.].sub.D.sup.28.6: -40.10.degree. (C=0.25, MeOH)
[1150] IR (Nujol): 3650-3100, 2800-1970, 1636, 1275, 1123
cm.sup.-1
[1151] NMR (DMSO-d.sub.6, .delta.): 2.20-5.30 (24H, m), 7.00-8.20
(10H, m), 10.60-11.80 (3H, m)
[1152] MASS: 610 (M+1) (free)
[1153] Anal. Calcd. for
C.sub.31H.sub.34F.sub.6N.sub.4O.sub.2.multidot.2HC-
l.multidot.3H.sub.2O:
[1154] C 50.62, H 5.75, N 7.62
[1155] Found: C 50.72, H 5.58, N 6.99
[1156] (10) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-
naphthylmethyl)-4-[(E)-N-(3-pyridylmethyl)-4-amino-2-butenyl]piperazine
trihydrochloride
[1157] [.alpha.].sub.D.sup.28.4: -20.40.degree. (C=0.25, MeOH)
[1158] IR (Nujol): 3650-3100, 2750-1930, 1620, 1272, 1122
cm.sup.-1
[1159] NMR (DMSO-d.sub.6, .delta.): 3.00-5.30 (16H, m), 6.00-6.30
(2H, m), 7.00-9.10 (14H, m)
[1160] MASS: 627 (M+1) (free)
[1161] Anal. Calcd. for
C.sub.34H.sub.32F.sub.6N.sub.4O.multidot.3HCl.mult-
idot.2H.sub.2O:
[1162] C 52.89, H 5.09, N 7.26
[1163] Found: C 52.73, H 5.09, N 7.16
[1164] (11)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)--
4-[(E)-N-morpholino-4-amino-2-butenyl]piperazine
dihydrochloride
[1165] [.alpha.].sub.D.sup.28.6: -13.00.degree. (C=0.25, MeOH)
[1166] IR (Neat): 3650-3000, 2750-1970, 1630, 1274 cm.sup.-1
[1167] NMR (DMSO-d.sub.6, .delta.): 2.80-5.30 (22H, m), 6.15-6.50
(2H, m), 7.00-8.25 (10H, m)
[1168] MASS: 621 (M+1) (free)
[1169] (12)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)--
4-[N-(3-pyridylmethyl)-3-aminopropyl]piperazine
trihydrochloride
[1170] [.alpha.].sub.D.sup.28.6: -24.60.degree. (C=0.25, MeOH)
[1171] IR (Nujol): 3600-3100, 2750-1950, 1630, 1273, 1121
cm.sup.-1
[1172] NMR (DMSO-d.sub.6, .delta.):2.20-5.30 (18H, m), 7.00-9.10
(14H, m)
[1173] MASS: 615 (M+1) (free)
[1174] Anal. Calcd. for
C.sub.33H.sub.32F.sub.6N.sub.4O.multidot.3HCl.mult-
idot.10/3H.sub.2O:
[1175] C 50.56, H 5.36, N 7.15
[1176] Found: C 50.53, H 5.38, N 6.94
EXAMPLE 83
[1177] The following compounds were obtained according to a similar
manner to that of Example 35.
[1178] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-
-(4-homomorpholino-2-butynyl) piperazine dihydrochloride
[1179] [.alpha.].sub.D.sup.28.0: -19.80.degree. (C=0.5, MeOH)
[1180] IR (Neat): 3400, 2500, 1640, 1430, 1280, 1175, 1130
cm.sup.-1
[1181] NMR (DMSO-d.sub.6, .delta.):1.95-5.34 (23H, m), 7.05-8.20
(10H, m)
[1182] MASS: 618 (M+1) (free)
[1183] Anal. Calcd. for
C.sub.33H.sub.33F.sub.6N.sub.3O.sub.2.multidot.2HC-
l.multidot.2.9H.sub.2O:
[1184] C 53.37, H 5.53, N 5.66
[1185] Found: C 53.38, H 5.47, N 5.67
[1186] (2) (2
R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-4-methylb-
enzyl)-4-[(E)-4-morpholino-2-butenyl]piperazine dihydrochloride
[1187] [.alpha.].sub.D.sup.28.0: -4.50.degree. (C=0.5, MeOH)
[1188] IR (Nujol): 2400, 1645, 1275, 1135 cm.sup.-1
[1189] NMR (DMSO-d.sub.6, .delta.): 2.20 (3H, s), 2.80-5.20 (21H,
m), 6.00-8.26 (8H, m)
[1190] MASS: 588 (M+1) (free)
[1191] Anal. Calcd. for
C.sub.29H.sub.32F.sub.7N.sub.3O.sub.2.multidot.2HC- l:
[1192] C 52.74, H 5.19, N 6.36
[1193] Found: C 52.39, H 5.20, N 6.29
[1194] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-4-methylbe-
nzyl)-4-[(E)-4-chloro-2-butenyl]piperazine
[1195] IR (Neat): 1640, 1430, 1275, 1130 cm.sup.-1
[1196] NMR (DMSO-d.sub.6, .delta.): 1.91-4.93 (13H, m), 5.71-8.20
(8H, m)
[1197] MASS: 537 (M+1)
[1198] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-
-4-(4-morpholino-2-butynyl]piperazine dihydrochloride
[1199] mp: 98-101.degree. C.
[1200] NMR (DMSO-d.sub.6, .delta.): 2.0-5.2 (25H, m), 5.74 (1H, br
d), 5.89 (1H, br d), 6.6-8.2 (6H, m)
[1201] MASS: 578 (M+1) (free)
[1202] Anal. Calcd. for
C.sub.31H.sub.33F.sub.6N.sub.3O.multidot.2HCl.mult-
idot.2H.sub.2O:
[1203] C 54.23, H 5.73, N 6.12
[1204] Found: C 53.99, H 5.83, N 5.93
EXAMPLE 84
[1205] The following compounds were obtained according to a similar
manner to that of Example 50.
[1206] (1)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)-4-(-
4-thiomorpholino-2-butynyl) piperazine dihydrochloride
[1207] mp: 180.degree. C. (dec.)
[1208] [.alpha.].sub.D.sup.28.0: +5.00.degree. (C=0.5, MeOH)
[1209] IR (Nujol): 3350, 1630, 1125 cm.sup.-1
[1210] NMR (DMSO-d.sub.6, .delta.): 2.60-4.30 (21H, m), 6.85-7.25
(3H, m), 7.46 (2H, br s), 7.75 (1H, br s), 8.16 (1H, d,
J=9.4Hz)
[1211] MASS: 588 (M+1) (free)
[1212] Anal. Calcd. for
C.sub.28H.sub.28F.sub.7N.sub.3OS.multidot.2HCl.mul-
tidot.H.sub.2O:
[1213] C 49.56, H 4.75, N 6.19
[1214] Found: C 49.47, H 5.13, N 5.93
[1215] (2)
(2)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-(-
4-thiomorpholino-2-butynyl) piperazine dihydrochloride
[1216] mp: 197.degree. C. (dec.)
[1217] [.alpha.].sub.D.sup.28.1: -8.60.degree. C=0.5, MeOH)
[1218] IR (Nujol): 2500, 1640, 1275 cm.sup.-1
[1219] NMR (DMSO-d.sub.6, .delta.): 2.60-4.70 (24H, m), 6.70-8.30
(7H, m)
[1220] MASS: 600 (M+1) (free)
[1221] Anal. Calcd. for
C.sub.29H.sub.31F.sub.6N.sub.3O.sub.2S.multidot.2H-
Cl.multidot.1.3H.sub.2O:
[1222] C 50.05, H 5.16, N 6.04
[1223] Found: C 50.06, H 5.36, N 5.77
[1224] (3)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-trifluoromethylbe-
nzyl)-4-(4-thiomorpholino-2-butynyl) piperazine dihydrochloride
[1225] mp: 173.degree. C. (dec.)
[1226] [.alpha.].sub.D.sup.28.0: +9.60.degree. (C=0.5, MeOH)
[1227] IR (Nujol): 2400, 1640 cm.sup.-1
[1228] NMR (DMSO-d.sub.6, .delta.): 2.70-5.30 (21H, m), 7.22 (1H,
d, J=7.7Hz), 7.41 (1H, s), 7.50-7.80 (4H, m), 8.18 (1H, d,
J=7.0Hz)
[1229] MASS: 638 (M+1) (free)
[1230] Anal. Calcd. for
C.sub.29H.sub.28F.sub.9N.sub.3OS.multidot.2HCl.mul-
tidot.1.3H.sub.2O:
[1231] C 47.46, H 4.48, N 5.73
[1232] Found: C 47.43, H 4.51, N 5.51
[1233] (4)
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1-naphthylmethyl)-4-
-(4-thiomorpholino-2-butynyl) piperazine dihydrochloride
[1234] mp: 191.degree. C. (dec.)
[1235] [.alpha.].sub.D.sup.28.0: +15.60.degree. (C=0.5, MeOH)
[1236] IR (Nujol): 2500, 1635 cm.sup.-1
[1237] NMR (DMSO-d.sub.6, .delta.):2.65-4.80 (21H, m), 7.10-8.60
(10H, m)
[1238] MASS: 620 (M+1) (free)
[1239] Anal. Calcd. for
C.sub.32H.sub.31F.sub.6N.sub.3OS.multidot.2HCl.mul-
tidot.0.4H.sub.2O:
[1240] C 54.92, H 4.87, N 6.00
[1241] Found: C 54.88, H 5.04, N 5.65
EXAMPLE 85
[1242] The following compound was obtained according to a similar
manner to that of Example 51.
[1243]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[-
3-(1-methyl-1H-pyrazol-4-yl) propyl]piperazine hydrochloride
[1244] mp: 163-165.degree. C.
[1245] [.alpha.].sub.D.sup.25.3: -19.80.degree. (C=0.5, MeOH)
[1246] IR (Nujol): 2550, 1635 cm.sup.-1
[1247] NMR (DMSO-d.sub.6, .delta.): 1.90-2.25 (6H, m), 3.00-4.00
(15H, br), 6.65-8.25 (8H, m)
[1248] MASS: 567 (M+1) (free)
[1249] Anal. Calcd. for
C.sub.29H.sub.32F.sub.6N.sub.4O.multidot.HCl.multi-
dot.H.sub.2O:
[1250] C 56.08, H 5.68, N 9.02
[1251] Found: C 56.44, H 5.76, N 8.98
EXAMPLE 86
[1252] The following compound was obtained according to a similar
manner to that of Example 61.
[1253] (2R)
-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-
-[4- (3,3-dimethylmorpholino)-2-butenyl]piperazine
dihydrochloride
[1254] mp: 210.degree. C. (dec.)
[1255] [.alpha.].sub.D.sup.28.4: +0.63.degree. (C=0.11, MeOH)
[1256] IR (Nujol): 3660-3300, 2700-2300, 1640, 1445, 1430, 1370,
1270 cm.sup.-1
[1257] NMR (DMSO-d.sub.6, .delta.): 1.30-1.55 (6H, m), 2.85-5.25
(19H, m), 6.05-6.30 (2H, m), 6.65-8.25 (8H, m), 10.97 (1H, br s),
11.40-12.20 (2H, m)
[1258] MASS: 623 (M+1) (free)
EXAMPLE 87
[1259] The following compound was obtained according to a similar
manner to that of Example 54.
[1260]
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[-
3-(3-pyridyl)propyl]piperazine dihydrochloride
[1261] mp: 163-168.degree. C.
[1262] [.alpha.].sub.D.sup.24.7: +5.77.degree. (C=1.3, MeOH)
[1263] IR (Nujol): 3600-3300, 2700-2300, 1635, 1445, 1430, 1370,
1280 cm.sup.-1
[1264] NMR (DMSO-d.sub.6, .delta.): 1.92-5.22 (29H, m), 6.56-8.28
(6H, m), 11.43 (2H, br s)
[1265] MASS: 564 (M+1) (free)
[1266] Anal. Calcd. for
C.sub.30H.sub.31F.sub.6N.sub.3O.multidot.2HCl.mult-
idot.2.4H.sub.2O:
[1267] C 53.01, H 5.60, N 6.18
[1268] Found: C 53.04, H 5.98, N 5.77
* * * * *