U.S. patent application number 10/855357 was filed with the patent office on 2004-11-04 for nitrogen-containing cyclic compound and pharmaceutical composition containing the compound.
This patent application is currently assigned to Eisai Co., Ltd.. Invention is credited to Hatakeyama, Shinji, Iimura, Yoichi, Kaneda, Yoshihisa, Kaneko, Toshihiko, Kimura, Manami, Kurusu, Nobuyuki, Niidome, Tetsuhiro, Shinmyo, Daisuke, Suzuki, Yuichi, Teramoto, Tetsuyuki, Yamamoto, Noboru, Yoshikawa, Yukie.
Application Number | 20040220193 10/855357 |
Document ID | / |
Family ID | 18539929 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040220193 |
Kind Code |
A1 |
Yamamoto, Noboru ; et
al. |
November 4, 2004 |
Nitrogen-containing cyclic compound and pharmaceutical composition
containing the compound
Abstract
The present invention provides a novel compound having a
superior calcium antagonism, in particular, a neuron-selective
calcium antagonism. Namely, it provides a compound represented by
the following formula, a salt thereof or a hydrate of them. 1 In
the formula, Ar indicates an optionally substituted 5- to
14-membered aromatic ring etc.; the ring A indicates any one ring
selected from a piperazine, a homopiperazine, a piperidine and the
like; the ring B indicates an optionally substituted C.sub.3-14
hydrocarbon ring etc.; E indicates a single bond, a group
represented by the formula --CO--, etc.; X indicates a single bond,
an oxygen atom etc.; R.sup.1 indicates a hydrogen atom, a halogen
atom, a hydroxyl group etc.; and D.sup.1, D.sup.2, W.sup.1 and
W.sup.2 are the same as or different from each other and each
represents a single bond or an optionally substituted C.sub.1-6
alkylene chain.
Inventors: |
Yamamoto, Noboru; (Ibaraki,
JP) ; Suzuki, Yuichi; (Ibaraki, JP) ; Kimura,
Manami; (Chiba, JP) ; Niidome, Tetsuhiro;
(Ibaraki, JP) ; Iimura, Yoichi; (Ibaraki, JP)
; Teramoto, Tetsuyuki; (Brooklilne, MA) ; Kaneda,
Yoshihisa; (Ibaraki, JP) ; Kaneko, Toshihiko;
(Ibaraki, JP) ; Kurusu, Nobuyuki; (Ibaraki,
JP) ; Shinmyo, Daisuke; (Ibaraki, JP) ;
Yoshikawa, Yukie; (Ibaraki, JP) ; Hatakeyama,
Shinji; (Ibaraki, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Eisai Co., Ltd.
|
Family ID: |
18539929 |
Appl. No.: |
10/855357 |
Filed: |
May 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10855357 |
May 28, 2004 |
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10169837 |
Jul 10, 2002 |
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10169837 |
Jul 10, 2002 |
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PCT/JP01/00288 |
Jan 18, 2001 |
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Current U.S.
Class: |
514/252.13 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
217/04 20130101; C07D 307/81 20130101; C07D 333/38 20130101; C07D
333/60 20130101; C07D 211/64 20130101; C07D 207/09 20130101; C07D
271/06 20130101; A61P 25/04 20180101; C07D 211/46 20130101; C07D
333/28 20130101; C07D 277/42 20130101; C07D 403/04 20130101; C07D
417/12 20130101; C07D 235/30 20130101; C07D 405/06 20130101; C07D
211/22 20130101; C07D 211/58 20130101; C07D 213/74 20130101; C07D
217/22 20130101; C07D 209/42 20130101; C07D 215/12 20130101; C07D
215/38 20130101; C07D 401/06 20130101; C07D 241/04 20130101; C07D
417/04 20130101; A61P 25/00 20180101; C07D 263/58 20130101; C07D
211/32 20130101; C07D 409/06 20130101; C07D 263/20 20130101; C07D
277/82 20130101; C07D 307/54 20130101; C07D 295/185 20130101; C07D
319/20 20130101; C07D 409/12 20130101; C07D 213/57 20130101; C07D
261/08 20130101; C07D 295/215 20130101; C07D 207/14 20130101; C07D
211/34 20130101; C07D 235/14 20130101; C07D 413/12 20130101; C07D
215/06 20130101; C07D 295/145 20130101; C07D 401/12 20130101; C07D
413/14 20130101; C07D 213/36 20130101; C07D 207/337 20130101; C07D
243/08 20130101; C07D 277/28 20130101; C07D 471/10 20130101; C07D
487/08 20130101; C07D 211/26 20130101; C07D 263/32 20130101; C07D
333/24 20130101; C07D 209/14 20130101; C07D 409/14 20130101; C07D
215/227 20130101; C07D 401/04 20130101; C07D 413/04 20130101; C07D
307/52 20130101; C07D 295/192 20130101; C07D 207/16 20130101 |
Class at
Publication: |
514/252.13 |
International
Class: |
A61K 031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 20, 2000 |
JP |
2000-12176 |
Claims
1. A method for treating stroke, inhibiting neural cell death or
protecting cerebral neurons, wherein said method comprises:
applying an effective amount of a pharmaceutical composition to a
patient in need thereof; wherein said pharmaceutical composition
comprises: a compound, a salt thereof or the hydrate of the
compound or salt, said compound represented by the following
formula (I): 362wherein r is a hydrogen atom or a nitrile; and a
pharmaceutically acceptable carrier.
2. The method of claim 1, wherein said compound, salt thereof or
hydrate of them in the pharmaceutical composition is selected from
the group consisting of:
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cy-
anophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2--
(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl-
)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-
-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.
3. A method for treating or improving a neural disease or
condition, wherein said method comprises: applying an effective
amount of a pharmaceutical composition to a patient in need
thereof; wherein said pharmaceutical composition comprises: a
compound, a salt thereof or the hydrate of the compound or salt,
said compound represented by the following formula (I): 363wherein
R is a hydrogen atom or a nitrile; and a pharmaceutically
acceptable carrier.
4. The method of claim 3, wherein the neural disease or condition
is at least one selected from the group consisting of wherein said
disease is acute ischemic stroke, cerebral apoplexy, cerebral
infarction, head trauma, cerebral neural cell death, cerebral
circulation metabolic affection, cerebral dysfunction, spasm,
schizophrenia, migraine, epilepsy, manic-depression, AIDS dementia
complications, edema, anxiety disorder, diabetic neuropathy,
cerebral vascular dementia, and multiple sclerosis.
5. The method according to claim 3, wherein the neural disease or
condition is at least one selected from the group consisting of
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease and neural degenerative
diseases.
6. The method according to claim 3, wherein the neural disease or
condition is multiple sclerosis.
7. The method of claim 3, wherein said compound, salt thereof or
hydrate of them in the pharmaceutical composition is selected from
the group consisting of:
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cy-
anophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2--
(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl-
)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-
-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.
8. A method for treating stroke, inhibiting neural cell death or
protecting cerebral neurons, said method comprising: administering
a pharmacologically effective amount of a compound, a salt thereof
or a hydrate of them to a patient in need thereof; wherein said
compound is represented by the following formula (I): 364wherein R
is a hydrogen atom or a nitrile.
9. The method of claim 8, wherein said compound, salt thereof or
hydrate of them is selected from the group consisting of:
1-[4-cyano-5-methyl-4-(-
5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]pipera-
zine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy-
)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[-
2-(3-cyanophenoxy)ethyl]piperazine.
10. A method for suppressing a neural cell death or protecting a
cerebral neural cell, said method comprising: administering a
pharmacologically effective amount of a compound, a salt thereof or
a hydrate of them to a patient in need thereof; wherein said
compound is represented by the following formula (I): 365wherein R
is a hydrogen atom or a nitrile.
11. The method of claim 10, wherein said compound, salt thereof or
hydrate of them in the pharmaceutical composition is selected from
the group consisting of:
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cy-
anophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2--
(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl-
)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-
-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.
12. A method for treating or improving a neural disease or
condition, said method comprising: administering a
pharmacologically effective amount of a compound, a salt thereof or
a hydrate of them to a patient in need thereof; wherein said
compound is represented by the following formula (I): 366wherein R
is a hydrogen atom or a nitrile; wherein said disease or condition
is at least one selected from the group consisting of acute
ischemic stroke, cerebral apoplexy, cerebral infarction, head
trauma, cerebral neural cell death, cerebral circulation metabolic
affection, cerebral dysfunction, spasm, schizophrenia, migraine,
epilepsy, manic-depression, AIDS dementia complications, edema,
anxiety disorder, diabetic neuropathy and cerebral vascular
dementia.
13. The method of claim 12, wherein said compound, salt thereof or
hydrate of them in the pharmaceutical composition is selected from
the group consisting of:
1-(4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cy-
anophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2--
(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl-
)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-
-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.
14. A method for treating a disease, wherein said method comprises:
applying a pharmacologically effective amount of a compound, a salt
thereof or a hydrate of them to a patient in need thereof; wherein
said compound is represented by the following formula (I):
367wherein R is a hydrogen atom or a nitrile; and the neural
disease is selected from the group consisting of acute ischemic
stroke, cerebral apoplexy, head trauma, migraine, epilepsy and
diabetic neuropathy.
15. The method of claim 14, wherein said compound, salt thereof or
hydrate of them in the pharmaceutical composition is selected from
the group consisting of:
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cy-
anophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2--
(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl-
)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-
-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.
16. A method for treating multiple sclerosis, wherein said method
comprises: administering a pharmacologically effective amount of a
compound, a salt thereof or a hydrate of them to a patient in need
thereof; wherein said compound is represented by the following
formula (I): 368wherein R is a hydrogen atom or a nitrile.
17. The method of claim 16, wherein said compound, salt thereof or
hydrate of them in the pharmaceutical composition is selected from
the group consisting of:
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cy-
anophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2--
(3-cyanophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl-
)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and
1-[4-cyano-4-(3-cyano-5-
-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel compound useful as
a calcium antagonist, a salt thereof, a hydrate of them, a
production process thereof, and a pharmaceutical composition
thereof; and specifically relates to a neuron-selective calcium
antagonist, in particular a novel compound having a P/Q-type
calcium channel and/or an N-type calcium channel inhibiting
activity, etc.
PRIOR ART
[0002] In Japan, the number of patients with cerebral apoplexy is
about 1.4 million or more per year, and the medical expenses
therefor are estimated to be about two billion yen. Cerebral
apoplexy is the second cause of death next to malignant tumor and
is the biggest cause for bedridden man often suffering from severe
secondary diseases. A key to the treatment of cerebral apoplexy is
to deal with the acute stage, and the treatment at the acute stage
influences the life and function prognosis of the patient and
significantly influences secondary diseases.
[0003] For the purpose of improving blood stream, several drugs
such as ozagrel sodium (thromboxane synthase inhibitor), argatroban
(anti-thrombin agent) as an agent for treatment of chronic arterial
occlusion, t-PA (alteplase: tissue plasminogen activator which
should be used within 3 hours after the onset) as thrombolytic
agent etc. are now approved of, or in off lavel use. However, the
therapy according to a conventional medicine is the complicate
procedures as described in (1) to (6), and cautious judgment by a
specialist on the basis of enough knowledge and experience has been
required. Namely, (1) in the case of thrombus-type cerebral
infarction, respiratory control, blood pressure control and blood
transfusion control are first conducted. (2) Blood gas and blood
pressure are periodically measured. (3) At the acute stage,
reactive high blood pressure is observed, but if complications in
the heart and kidney are not observed, treatment for decreasing
blood pressure is not conducted. (4) Then, in the early-acute stage
case with no low absorption range observed in CT, the
thrombus-lytic agent "urokinase" is used. (5) In the case where
these agents are not applicable or in the case where 24 hours or
more has elapsed after the onset, "ozagrel sodium" is administered.
Or "argatroban" is administered. However, argatroban is not
applicable to lacuna infarction. (6) To prevent the development of
cerebral edema, "glycerin" or "mannitol" is administered at a
suitable dosage.
[0004] Further, the therapeutic effects of the drugs used
heretofore are not satisfactory and further there is the danger
that bleeding is often accompanied by their pharmacological effect.
Accordingly, there is the problem that it is difficult for those
except of skilled medical specialists to use these drugs.
[0005] On the other hand, the following literatures describe that
compounds having an inhibitory action on N type or P/Q type calcium
channels can serve as an agent for inhibiting the death of neural
cells or for protecting cerebral neural cells, an agent for
treating or improving nervous diseases, an agent for treating or
improving acute ischemic stroke, head trauma, death of neural
cells, Alzheimer disease, cerebral circulatory metabolism
disturbance, cerebral function disturbance or pain, an anti-spasm
agent, an agent for treating or improving schizophrenia and an
agent for preventing, treating or improving migraine, epilepsy,
maniac-depressive psychosis, neural degenerative diseases
(Parkinson disease, Alzheimer disease, amyotrophic lateral
sclerosis, Huntington disease), cerebral ischemia, epilepsy, head
trauma, AIDS dementia complications, edema, anxiety disorder
(generalized anxiety disorder) and diabetic neuropathy, and as an
agent for preventing, treating or improving edema, anxiety
disorder, schizophrenia, diabetic neuropathy and migraine.
[0006] (1) Acute ischemia stroke: Annj. Rev. Physiol., 52 543-559,
1990.
[0007] (2) Head trauma: SCRIP, No. 2203, 24, 1997.
[0008] (3) Ischemia--death of cerebral neural cells: Advances in
Pharmacology, 22, 271-297, 1991.
[0009] (4) Alzheimer disease: Trends in Neuroscience, 16, 409,
1993.
[0010] (5) Cerebral circulatory metabolism disturbance:
Nichiyakurishi, 85, 323-328, 1985.
[0011] (6) Cerebral function disturbance: Acta Neurol. Scand.,
78:2, 14-200, 1998.
[0012] (7) Analgesic: Drug of the Future, 23(2), 152-160, 1998.
[0013] (8) Cerebral ischemia, migraine, epilepsy, maniac-depressive
psychosis: Casopis Lekau Ceskych., 130(22-23), 625-630, 1991.
[0014] (9) Neural degenerative diseases (Parkinson disease,
Alzheimer disease, amyotrophic lateral sclerosis, Huntington
disease), cerebral ischemia, epilepsy, head trauma, and AIDS
dementia complications: Revista de Neurologia., 24(134), 1199-1209,
1996.
[0015] (10) Edema: Brain Research, 776,140-145,1997.
[0016] (11) Anxiety disorder (generalized anxiety disorder),
schizophrenia: Jyunkanseigyo (Circulation
Control),14(2),139-145,1993.
[0017] (12) Diabetic neuropathy: Shinkeinaika (Neurological
Medicine),50,423-428,1999.
[0018] (13) Migraine: Neurology,50(4),1105-1110,1998.
DISCLOSURE OF THE INVENTION
[0019] In light of this, the present inventors have intensively
studied for investigating a preparation which has a superior effect
of treatment and amelioration for cerebral acute ischemic stroke
for which no useful preparation is not found and has high safety
which does not cause bloodshed tendency, focusing on a
neuron-selective, potential-dependent calcium channel antagonist
which directly effects on neural cell and inhibits the progression
of infarction nidus. As a result, the present inventors have
succeeded in synthesizing a novel nitrogen-containing compound
which is represented by the formula (I), a salt thereof and a
hydrate thereof, and further surprisingly have found that these
compounds, a salt thereof or a hydrate thereof have the superior
suppression action of neural cell death and protective action of
cerebral neuron based on the P/Q type or N-type calcium channel
antagonism, that cell infarction property and toxicity are
remarkably reduced in comparison with a conventional calcium
antagonist and that the compound and the like are superior in
safety, and have completed the present invention. 2
[0020] In the formula, Ar is (1) a C.sub.6-14 aromatic hydrocarbon
cyclic group which may be substituted, (2) a 5- to 14-membered
aromatic heterocyclic group which may be substituted, (3) a
C.sub.1-6 alkyl group substituted with a C.sub.6-14 aromatic
hydrocarbon cyclic group which may be substituted or (4) a
C.sub.1-6 alkyl group substituted with a 5- to 14-membered aromatic
heterocyclic group which may be substituted; the ring A indicates a
piperazine ring, homopiperazine ring, piperidine ring,
homopiperidine ring, pyrrolidine ring or diazabicyclo[2,2,1]heptane
ring which may be substituted, respectively; the ring B indicates
(1) a C.sub.3-14 hydrocarbon ring which may be substituted or (2) a
5- to 14-membered heterocyclic ring which may be substituted; E
indicates (1) a single bond, a group represented by the formula (2)
--CO-- or (3) --CH(OH)--; X indicates (1) a single bond, (2) an
oxygen atom, (3) a sulfur atom, (4) a C.sub.1-6 alkylene chain
which may be substituted, a group represented by (5) the formula
--NR.sup.2-- (wherein R.sup.2 indicates a hydrogen atom, or a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a lower acyl
group or a C.sub.1-6 alkylsulfonyl group which may be substituted),
(6) --CO--, (7) --COO--, (8) --OOC--, (9) --CONR.sup.3-- (wherein
R.sup.3 indicates a hydrogen atom or a C.sub.1-6 alkyl group which
may be substituted), (10) --NR.sup.4CO-- (wherein R.sup.4 indicates
a hydrogen atom or a C.sub.1-6 alkyl group which may be
substituted), (11) --SO--, (12) --SO.sub.2--, (13) --SONR.sup.5--
(wherein R.sup.5 indicates a hydrogen atom or a C.sub.1-6 alkyl
group which may be substituted), (14) --NR.sup.6SO-- (wherein
R.sup.6 indicates a hydrogen atom or a C.sub.1-6 alkyl group which
may be substituted), (15) --SO.sub.2NR.sup.7-- (wherein R.sup.7
indicates a hydrogen atom or a C.sub.1-6 alkyl group which may be
substituted), (16) --NR.sup.8SO.sub.2-- (wherein R.sup.8 indicates
a hydrogen atom or a C.sub.1-6 alkyl group which may be
substituted), (17) >C.dbd.N--OR.sup.9 (wherein R.sup.9 indicates
a hydrogen atom or a C.sub.1-6 alkyl group which may be
substituted), (18) --NR.sup.10--W.sup.3--O-- (wherein R.sup.10
indicates a hydrogen atom or a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a lower acyl group or a C.sub.1-6 alkylsulfonyl
group which may be substituted; and W.sup.3 indicates a C.sub.1-6
alkylene group which may be substituted), (19) --NH--CO--NH--, (20)
--NH--CS--NH--, (21) --C(.dbd.NR.sup.15)NR.sup.16-- (wherein
R.sup.15 and R.sup.16 are the same as or different from each other
and each indicates a hydrogen atom, nitrile group, a C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a C.sub.3-8 cycloalkyl
group or a C.sub.3-8 cycloalkenyl group), (22) --NHC(.dbd.NH)--,
(23) --O--CO--S--, (24) --S--CO--O--, (25) --OCOO--, (26)
--NHCOO--, (27) --OCONH--, (28) --CO(CH.sub.2).sub.mO-- (wherein m
indicates 0 or an integer of 1 to 6), (29) --CHOH-- or (30)
--CHOH(CH.sub.2).sub.nO-- (wherein n indicates 0 or an integer of 1
to 6); R.sup.1 indicates (1) a hydrogen atom, (2) a halogen atom,
(3) hydroxyl group, (4) a C.sub.1-6 alkyl group which may be
substituted with one or more groups selected from hydroxyl group, a
halogen atom and nitrile group, (5) a C.sub.2-6 alkenyl group which
may be substituted with one or more groups selected from hydroxyl
group, a halogen atom and nitrile group, (6) a C.sub.2-6 alkynyl
group which may be substituted with one or more groups selected
from hydroxyl group, a halogen atom and nitrile group, (7) a
C.sub.3-8 cycloalkyl group which may be substituted with one or
more groups selected from hydroxyl group, a halogen atom and
nitrile group, (9) a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, (10)
an amino-C.sub.1-6 alkyl group in which the nitrogen may be
substituted, (11) a group represented by the formula
--N(R.sup.11)R.sup.12-- (wherein R.sup.11 and R.sup.12 are the same
as or different from each other and each indicates a hydrogen atom
or a C.sub.1-6 alkyl group), (12) an aralkyl group, (13)
morpholinyl group, (14) thiomorpholinyl group, (15) piperidyl
group, (16) a pyrrolidinyl group or (17) a piperazinyl group; and
D.sup.1, D.sup.2, W.sup.1 and W.sup.2 are the same as or different
from each other and each indicates (1) a single bond or (2) a
C.sub.1-6 alkylene chain which may be substituted,
[0021] provided that, in the above definition,
1-[4-cyano-5-methyl-4-(2-cy-
ano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)eth-
yl]piperazine; and
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorop-
henoxy)ethyl]piperazine are excluded.
[0022] Namely, the first aspect of the present invention is 1) a
compound represented by the above formula (I), a salt thereof or a
hydrate of them, and further, 2) in the above-mentioned 1), Ar may
be a C.sub.6-14 aromatic hydrocarbon ring or 5- to 14-membered
aromatic heterocyclic ring, which may be substituted, 3) in the
above-mentioned 1), Ar may be a thiophene ring or benzene ring,
which may be substituted, 4) in the above 1), Ar may be a
C.sub.6-14 aromatic hydrocarbon ring or 5- to 14-membered aromatic
heterocyclic ring, which may be substituted with any one or more
groups selected from nitrile group and a halogen atom, 5) in the
above-mentioned 1), Ar may be a thiophene ring or a benzene ring
which may be substituted with any one or more groups selected from
nitrile group and a halogen atom, respectively, 6) in the
above-mentioned 1), the ring A may be piperazine ring,
homopiperazine ring or piperidine ring, 7) in the above-mentioned
1), the ring A may be a piperazine ring, 8) in the above-mentioned
1), the ring A may be a piperazine ring, a homopiperazine ring or a
piperidine ring which may be substituted with any one or more
groups selected from hydroxyl group, a halogen atom, cyano group, a
C.sub.1-6 alkyl group which may be substituted, a C.sub.2-6 alkenyl
group which may be substituted, a C.sub.2-6 alkynyl group which may
be substituted, a C.sub.1-6 alkoxy group which may be substituted,
a C.sub.2-6 alkenyloxy group which may be substituted, a C.sub.1-6
alkylcarbonyl group which may be substituted, a C.sub.2-6
alkenylcarbonyl group which may be substituted, a C.sub.1-6
alkoxycarbonyl group which may be substituted and a C.sub.2-6
alkenyloxycarbonyl group which may be substituted, 9) in the
above-mentioned 1), the ring B maybe a C.sub.6-14 aromatic
hydrocarbon ring or a 5- to 14-membered aromatic heterocyclic ring
which may be substituted, respectively, 10) in the above-mentioned
1), the ring B may be a benzene, a thiophene, a pyridine, a
1,4-benzodioxane, an indole, a benzothiazole, a benzoxazole, a
benzimidazole, a 2-keto-1-benzimidazole, a thiazole, an oxazole, an
isoxazole, a 1,2,4-oxadiazole, an indanone, a benzofuran, a
quinoline, a 1,2,3,4-tetrahydroquinoline, a naphthalene or a
1,2,3,4-tetrahydronaphtha- lene which may be substituted,
respectively, 11) in the above-mentioned 1), the ring B may be a
C.sub.6-14 aromatic hydrocarbon ring or a 5- to 14-membered
aromatic heterocyclic ring which maybe substituted with any one or
more groups selected from a halogen atom, nitrile group, a
C.sub.1-6 alkyl group, a lower acyl group, a C.sub.1-6
alkylsulfonyl group and an aralkyl group, respectively, 12) in the
above-mentioned 1), D.sup.1 and D.sup.2 may be the same as or
different from each other and each may be (1) a single bond or (2)
a C.sub.1-6 alkylene chain which may be substituted with any one or
more groups selected from hydroxyl group, a halogen atom, nitrile
group, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group and a
C.sub.1-6 alkoxy group, 13) in the above-mentioned 1), E may be a
single bond, 14) in the above-mentioned D.sup.1 and D.sup.2 may be
a C.sub.1-6 alkylene chain; and E maybe a single bond, 15) in the
above-mentioned 1), the partial structure -D.sup.1-E-D.sup.2- may
be a C.sub.1-4 alkylene group, 16) in the above-mentioned 1),
W.sup.1 and W.sup.2 may be the same as or different from each other
and each may be (1) a single bond or (2) a C.sub.1-6 alkylene chain
which may be substituted with any one or more groups selected from
hydroxyl group, a halogen atom, nitrile group, a C.sub.1-6 alkyoxy
group and a C.sub.2-6 alkenyloxy group, 17) in the above-mentioned
1), W.sup.1 may be (1) a single bond or (2) a C.sub.1-6 alkylene
chain which may be substituted with any one or more groups selected
from (i) nitrile group, (ii) a C.sub.1-6 alkyl group which may be
substituted with any one or more groups selected from a C.sub.1-6
alkoxy group and a C.sub.2-6 alkenyloxy group and (iii) a C.sub.2-6
alkenyl group; and W.sup.2 may be a single bond, 18) in the
above-mentioned 1), W.sup.1 and W.sup.2 may be the same as or
different from each other and each may be a C.sub.1-6 alkylene
chain substituted with any one or more groups selected from a
C.sub.1-6 alkyl group and a C.sub.2-6 alkenyl group, and further
the above-mentioned C.sub.1-6 alkyl group and/or C.sub.2-6 alkenyl
group may be bound together to form a ring or the above-mentioned
C.sub.1-6 alkyl group or C.sub.2-6 alkenyl group is bound to the
ring B or X to form a ring, 19) in the above-mentioned 1), X maybe
(1) a single bond, (2) oxygen atom, a group represented by (3) the
formula --NR.sup.2-- (wherein R.sup.2 indicates a hydrogen atom, or
a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a lower acyl
group or a C.sub.1-6 alkylsulfonyl group which may be substituted),
(4) --NR.sup.10--W.sup.3--O-- (wherein R.sup.10 indicates a
hydrogen atom, or a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl
group, a lower acyl group or a C.sub.1-6 alkylsulfonyl group which
may be substituted; and W.sup.3 is a C.sub.1-6 alkylene group which
may be substituted) or (5) --NH--SO.sub.2--, 20) in the
above-mentioned 1), X may be (1) oxygen atom, a group represented
by (2) the formula --NR.sup.2-- (wherein R.sup.2indicates a
hydrogen atom, or a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl
group, a lower acyl group or a C.sub.1-6 alkylsulfonyl group which
may be substituted) or (3) --NH--SO.sub.2--, 21) in the
above-mentioned 1), the partial structure --W.sup.1--X--W.sup.2--
may be a C.sub.1-6 alkylene group which may be substituted, 22) in
the above-mentioned 1), W.sup.1 may be a C.sub.1-6 alkylene chain
which may be substituted; W.sup.2 is a single bond; and X may be
oxygen or a group represented by the formula --NR.sup.2-- (wherein
R.sup.2 has the same meaning as the above-mentioned definition),
23) in the above-mentioned 22), the substituent of W.sup.1 may be
any one or more groups selected from (1) nitrile group, (2) a
C.sub.1-6 alkyl group which may be substituted with a C.sub.1-6
alkyoxy group or a C.sub.2-6 alkenyloxy group and (3) a C.sub.2-6
alkenyl group; and R.sup.2 may be a C.sub.1-6 alkyl group which may
be substituted, 24) in the above-mentioned 1), R.sup.1 may be a
C.sub.1-6 alkyl group, 25) in the above-mentioned 1), R.sup.1 may
be methyl group, ethyl group, n-propyl group or isopropyl group,
26) the compound in the above-mentioned 1) maybe a compound
represented by the formula: 3
[0023] in the formula, R.sup.1 has the same meaning as in the above
definition; R.sup.13 and R.sup.14 are the same as or different from
each other and each indicates (1) a hydrogen atom, (2) a halogen
atom, (3) hydroxyl group, (4) mercapto group, (5) a C.sub.1-6 alkyl
group which may be substituted with any one or more groups selected
from hydroxyl group and a halogen atom, (6) a C.sub.1-6 alkoxy
group which may be substituted with any one or more groups selected
from hydroxyl group, a halogen atom and a C.sub.1-6 alkoxycarbonyl
group, (7) a nitro group, (8) an amino group which may be
substituted, (9) cyano group, (10) carboxyl group, (11) a C.sub.1-6
alkoxycarbonyl group, (12) a C.sub.1-6 thioalkoxy group, (13) a
C.sub.1-6 alkylsulfonyl group, (14) a lower acyl group, (15) a
C.sub.6-14 aromatic hydrocarbon cyclic group which may be
substituted, (16) a 5- to 14-membered aromatic heterocyclic group
which may be optionally substituted, (17) an aryloxy group or (18)
an aralkyloxy group, or (19) R.sup.13s themselves or R.sup.14s
themselves may be bound together to form (i) an aliphatic ring
which may be substituted, (ii) a heterocyclic ring which may be
substituted or (iii) an alkylenedioxy group; n indicates 0 or an
integer of 1 to 3; p indicates an integer of 1 to 6; q indicates an
integer of 1 to 6; and r indicates 0 or an integer of 1 to 5,
[0024] provided that, in the above definition,
1-[4-cyano-5-methyl-4-(2-cy-
ano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)eth-
yl]piperazine; and
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorop-
henoxy)ethyl]piperazine are excluded and 27) the compound in the
above-mentioned 1) may be a compound represented by the formula:
4
[0025] in the formula, R.sup.1 and R.sup.2have the same meanings as
defined above; R.sup.13 and R.sup.14 are the same as or different
from each other and each indicates (1) a hydrogen atom, (2) a
halogen atom, (3) hydroxyl group, (4) mercapto group, (5) a
C.sub.1-6 alkyl group which may be substituted with any one or more
groups selected from hydroxyl group and a halogen atom, (6) a
C.sub.1-6 alkoxy group which may be substituted with any one or
more groups selected from hydroxyl group, a halogen atom and a
C.sub.1-6 alkoxycarbonyl group, (7) nitro group, (8) an amino group
which may be substituted, (9) cyano group, (10) carboxyl group,
(11) a C.sub.1-6 alkoxycarbonyl group, (12) a C.sub.1-6 thioalkoxy
group, (13) a C.sub.1-6 alkylsulfonyl group, (14) a lower acyl
group, (15) a C.sub.6-14 aromatic hydrocarbon cyclic group which
may be substituted, (16) a 5- to 14-membered aromatic heterocyclic
group which may be substituted, (17) an aryloxy group or (18) an
aralkyloxy group, or (19) R.sup.13s themselves or R.sup.14s
themselves may be bound together to form (i) an aliphatic ring
which may be substituted, (ii) a heterocyclic ring which may be
substituted or (iii) an alkylenedioxy group; n indicates 0 or an
integer of 1 to 3; p indicates an integer of 1 to 6; q indicates an
integer of 1 to 6; r indicates 0 or an integer of 1 to 5, and 28)
in the above-mentioned 1), the compound may be any one selected
from 4-[(4-cyano-5-methyl-4-phenyl)hexyl]-N-(4-fluorophenyl)-N'--
(2-methylpropyl)-1(2H)-pyrazinecarboxyimidamide;
1-isopropyl-4-[4-(1-isobu-
tyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-phenylbutyl cyanide;
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethy-
l]piperazine;
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy-
)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(5-
-cyano-2-thienyl)propyl]piperazine;
1-[4-cyano-5-methyl-4-(3-thienyl)hexyl-
]-4-[2-(3-cyanophenoxy)ethyl]piperazine;
1-{4-cyano-5-methyl-4-[4-(2-cyano-
)-thienyl]hexyl}-4-[2-(3-cyanophenoxy)ethyl]piperazine;
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzoxazolyl)amino]piperidine;
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cyanoethyl)--
N-benzylamino]pyrrolidine;
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-
-(3R)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine;
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(benzothiazolyl]piperazine;
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-methoxy)benzothiazolyl]piper-
azine;
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzoxazolyl]piperazine;
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-quinolinyl]piperazine;
4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-
-phenylbutyl cyanide;
4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-
-1-yl]-1-isopropyl-1-phenylbutyl cyanide; ethyl
4-(4-cyano-5-methyl-4-phen-
ylhexyl)-1-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate;
1-[(2-oxo-1,2-dihydro-3-quinolyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)he-
xyl]piperidine;
4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfony-
lamino)phenyl]methyl}piperazine;
4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[-
2-(methanesulfonylamino)phenyl]methyl}piperidine;
(S)-3-phenyl-2-amino-pro- panoic acid
{1-[4-cyano-5-methyl-5-(2-thionyl)hexyl]piperazinyl}amide;
4-[4-(4-phenylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide;
4-[4-(4-cyano-4-phenylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide; and
4-[4-(4-benzylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylb- utyl
cyanide.
[0026] Further, the second characteristic of the present invention
is 29) a pharmaceutical composition containing the compound
represented by the formula: 5
[0027] (in the formula, Ar is (1) a C.sub.6-14 aromatic hydrocarbon
cyclic group which may be substituted, (2) a 5- to 14-membered
aromatic heterocyclic group which may be substituted, (3) a
C.sub.1-6 alkyl group substituted with a C.sub.1-14 aromatic
hydrocarbon cyclic group which may be substituted or (4) a
C.sub.1-6 alkyl group substituted with a 5- to 14-membered aromatic
heterocyclic group which may be substituted; the ring A indicates a
piperazine ring, a homopiperazine ring, a piperidine ring, a
homopiperidine ring, a pyrrolidine ring, a diazabicyclo[2,
2,1]heptane ring which may be substituted, respectively; the ring B
indicates (1) a C.sub.3-14 hydrocarbon ring which may be
substituted or (2) a 5- to 14-membered heterocyclic ring which may
be substituted; E indicates (1) a single bond, a group represented
by (2) the formula --CO-- or (3) --CH(OH)--; X indicates (1) a
single bond, (2) oxygen atom, (3) sulfur atom, (4) a C.sub.1-6
alkylene chain which may be substituted, a group represented by (5)
the formula --NR.sup.2-- (wherein R.sup.2 indicates a hydrogen
atom, or a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
lower acyl group or a C.sub.1-6 alkylsulfonyl group which may be
substituted.), (6) --CO--, (7) --COO--, (8) --OOC--, (9)
--CONR.sup.3-- (wherein R.sup.3 indicates a hydrogen atom or a
C.sub.1-6 alkyl group which may be substituted), (10)
--NR.sup.4CO-- (wherein R.sup.4 indicates a hydrogen atom or a
C.sub.1-6 alkyl group which may be substituted), (11) --SO--, (12)
--SO.sup.2--, (13) --SONR.sub.5-- (wherein R.sup.5 indicates a
hydrogen atom or a C.sub.1-6 alkyl group which may be substituted),
(14) --NR.sup.6SO-- (wherein R.sup.6 indicates a hydrogen atom or a
C.sub.1-6 alkyl group which may be substituted), (15)
--SO.sub.2NR.sup.7-- (wherein R.sup.7 indicates a hydrogen atom or
a C.sub.1-6 alkyl group which may be substituted), (16)
--NR.sup.8SO.sub.2-- (wherein R.sup.8 indicates a hydrogen atom or
a C.sub.1-6 alkyl group which may be substituted), (17)
>C.dbd.N--CR.sup.9 (wherein R.sup.9 indicates a hydrogen atom or
a C.sub.1-6 alkyl group which may be substituted), (18)
--NR.sup.10--W.sup.3--O-- (wherein R.sup.10 indicates a hydrogen
atom, or a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
lower acyl group or a C.sub.1-6 alkylsulfonyl group which may be
substituted; and W.sup.3 indicates a C.sub.1-6 alkylene group which
may be substituted), (19) --NH--CO--NH--, (20) --NH--CS--NH--, (21)
--C(.dbd.NR.sup.15)NR.sup.16-- (wherein R.sup.15 and R.sup.16 are
the same as or different from each other and each indicates a
hydrogen atom, nitrile group, a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.3-8 cycloalkyl group or a C.sub.3-8
cycloalkenyl group), (22) --NHC(.dbd.NH)--, (23) --O--CO--S--, (24)
--S--CO--O--, (25) --OCOO--, (26) --NHCOO--, (27) --OCONH--, (28)
--CO(CH.sub.2).sub.mO-- (wherein m indicates 0 or an integer of 1
to 6), (29) --CHOH-- or (30) --CHOH(CH.sub.2).sub.nO-- (wherein n
indicates 0 or an integer of 1 to 6.); R.sup.1 indicates (1) a
hydrogen atom, (2) a halogen atom, (3) hydroxyl group, (4) a
C.sub.1-6 alkyl group which may be substituted with one or more
groups selected from hydroxyl group, a halogen atom and nitrile
group, (5) a C.sub.2-6 alkenyl group which may be substituted with
one or more groups selected from hydroxyl group, a halogen atom and
nitrile group, (6) a C.sub.2-6 alkynyl group which may be
substituted with one or more groups selected from hydroxyl group, a
halogen atom and nitrile group, (7) a C.sub.3-8 cycloalkyl group
which may be substituted with one or more groups selected from
hydroxyl group, a halogen atom and nitrile group, (9) a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, (10) an amino-C.sub.1-6 alkyl group
in which the nitrogen atom may be substituted, (11) a group
represented by the formula --N(R.sup.11)R.sup.12-- (wherein
R.sup.11 and R.sup.12 are the same as or different from each other
and each indicates a hydrogen atom or a C.sub.1-6 alkyl group),
(12) an aralkyl group, (13) morpholinyl group, (14) thiomorpholinyl
group, (15) piperidyl group, (16) pyrrolidinyl group or (17)
piperazinyl group; and D.sup.1, D.sup.2, W.sup.1 and W.sup.2 are
the same as or different from each other and each indicates (1) a
single bond or (2) a C.sub.1-6 alkylene chain which may be
substituted,
[0028] provided that, in the above definition,
1-[4-cyano-5-methyl-4-(2-cy-
ano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine;
1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)eth-
yl]piperazine; and
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorop-
henoxy)ethyl]piperazine are excluded), a salt thereof or a hydrate
of them, and further, 30) the composition in the above-mentioned
29) may be a calcium antagonist, 31) the composition in the
above-mentioned 29) may be a neuron-selective calcium antagonist,
32) the composition in the above-mentioned 29) may be a P/Q-type
calcium channel and/or an N-type calcium channel inhibitor, 33) the
composition in the above-mentioned 29) may be an agent for
treating, preventing or improving a disease against which the
inhibitory action of at least one of P/Q-type calcium channel and
N-type calcium channel is efficacious, 34) the composition in the
above-mentioned 29) may be an agent for inhibiting the death of
neural cell or for protecting cerebral neural cells, 35) the
composition in the above-mentioned 29) may be an agent for
treating, preventing or improving neural disease, 36) the neural
disease in the above-mentioned 35) may be acute ischemic stroke,
cerebral apoplexy, cerebral infarction, head trauma, cerebral
neural cell death, Alzheimer disease, Parkinson disease,
amyotrophic lateral sclerosis, Huntington disease, cerebral
circulatory metabolism disturbance, cerebral function disturbance,
pain, spasm, schizophrenia, migraine, epilepsy, manic-depression,
neural degenerative diseases, cerebral ischemia, AIDS dementia
complications, edema, anxiety disorder, diabetic neuropathy,
cerebral vascular dementia and multiple sclerosis and 37) the
composition in the above-mentioned 29) may be an analgesic.
[0029] The present invention provides a method for preventing,
treating or improving a disease against which a calcium antagonism
is effective, a disease against which a neuron-selective calcium
antagonism is effective or a disease against which a P/Q-type
calcium channel inhibitory action and/or an N-type calcium channel
inhibitory action is effective, by administering a
pharmacologically effective amount of the compound represetend by
the above formula (I), a salt thereof or a hydrate of them to a
patient.
[0030] The present invention provides a method for preventing,
treating or improving neural disease or pain.
[0031] Further, the present invention provides use of the compound
represented by the above formula (I), a salt thereof or a hydrate
of them for producing a calcium antagonist, a neuron-selective
calcium antagonist, a P/Q-type calcium channel and/or an N-type
calcium channel inhibitor, an agent for treating, preventing or
improving a disease against which a P/Q-type calcium channel and/or
an N-type calcium channel inhibitory action is efficacious, an
agent for inhibiting the death of neural cells or for protecting
cerebral neural cells.
[0032] Additionally, the present invention provides use of the
compound represented by the above formula (I), a salt thereof or a
hydrate of them for producing an agent for treating, preventing or
improving neural diseases or an analgesic.
[0033] The neural disease is any one of disease selected from acute
ischemic stroke, cerebral apoplexy, cerebral infarction, head
trauma, cerebral neural cell death, Alzheimer's disease,
Parkinson's disease, amyotrophic lateral sclerosis, Huntington's
disease, cerebral circulation metabolic affection, cerebral
dysfunction, pain, spasm, schizophrenia, migraine, epilepsy,
manic-depression, neural degenerative diseases, cerebral ischemia,
AIDS dementia complications, edema, anxiety disorder, diabetic
neuropathy, cerebral vascular dementia and multiple sclerosis.
[0034] The meanings of the symbols, terms and the like described in
the specification of the present application are illustrated below,
and the present invention is illustrated in detail.
[0035] The structural formula of a compound happens to represent a
fixed isomer for convenience in the specification of the present
application, but the present invention includes all of geometrical
isomers which occur in the structure of the compound, optical
isomers based on an asymmetric carbon, stereo-isomers, the isomers
of tautomers and the like, and a mixture of the isomer. The present
invention is not limited to the indication of the formulae for
convenience, and may be one of the isomers and a mixture thereof.
Accordingly, in the compounds of the present invention, there may
exist an optically active body and a racemic body which have an
asymmetric carbon atom in the molecule, but they are not limited in
the present invention, and both of them are included therein.
Further, crystal polymorphism happens to exist, but is not
similarly limited, and the crystal form may be either single or a
mixture of crystal forms and may be a hydrate in addition to an
anhydride. A so-called metabolite which occurs due to decomposition
of the compounds according to the present invention in vivo is also
included in the scope of claim for patent of the present
invention.
[0036] The term "and/or" in the specification of the present
application is used for the meanings which contain both the case of
"and" and the case of "or". Accordingly, for example, "A and/or B"
includes both the case of "A and B" and the case of "A or B", and
indicates that it may be either of the cases.
[0037] The "neural disease" in the specification of the present
application mainly indicates acute ischemic stroke, cerebral
apoplexy, cerebral infarction, head trauma, cerebral neural cell
death, Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis, Huntington's disease, cerebral circulation
metabolic affection, cerebral dysfunction, pain, spasm,
schizophrenia, migraine, epilepsy, manic-depression, neural
degenerative diseases, cerebral ischemia, AIDS dementia
complications, edema, anxiety disorder, diabetic neuropathy,
cerebral vascular dementia and multiple sclerosis.
[0038] The "analgesic" in the specification of the present
application means a medicine which mitigates or removes pain by
changing the perception of stimulation of a nociceptor without
causing narcoticism and unconsciousness.
[0039] The "halogen atom" used in the specification of the present
application means atoms such as fluorine atom, chlorine atom,
bromine atom and iodine atom, preferably fluorine atom, chlorine
atom and bromine atom, and more preferably fluorine atom and
chlorine atom.
[0040] The "C.sub.1-6 alkyl group" used in the specification of the
present application means an alkyl group having 1 to 6 carbon
atoms, and the preferable examples thereof include linear or
branched alkyl groups such as methyl group, ethyl group, n-propyl
group, isopropyl group, n-butyl group, isobutyl group, sec-butyl
group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group,
1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl
group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl
group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,
1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl
group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group,
2-ethylbutyl group, 2-methylpentyl group and 3-methylpentyl
group.
[0041] The "C.sub.2-6 alkenyl group" used in the specification of
the present application means an alkenyl group having 2 to 6 carbon
atoms, and is preferably a linear or branched alkenyl group such as
vinyl group, allyl group, 1-propenyl group, 2-propenyl
group,isopropenyl group, 2-methyl-1-propenyl group,
3-methyl-1-propenyl group, 2-methyl-2-propenyl group,
3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group,
3-butenyl group, 1-pentenyl group, 1-hexenyl group,
1,3-hexanedienyl group and 1,6-hexanedienyl group.
[0042] The "C.sub.2-6alkynyl group" used in the specification of
the present application means an alkynyl group having 2 to 6 carbon
atoms, and is preferably a linear or branched alkynyl group such as
ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group,
2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group,
1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl
group, 1-hexynyl group, 1,3-hexanediynyl group and 1,6-hexanediynyl
group.
[0043] The "C.sub.1-6 alkoxy group" used in the specification of
the present application means a "C.sub.1-6 alkyloxy group" in which
an oxygen atom is bonded with a group having the same meaning as
the C.sub.1-6 alkyl group in the fore-mentioned definition, and the
preferable examples thereof include methoxy group, ethoxy group,
n-propoxy group, isopropoxy group, sec-propoxy group, n-butoxy
group, isobutoxy group, sec-butoxy group, tert-butoxy group,
n-pentyloxy group, isopentyloxy group, sec-pentyloxy group,
n-hexoxy group, isohexoxy group, 1,1-dimethylpropyloxy group,
1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group,
2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group,
1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group,
1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,
1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group,
2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group,
2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy
group, 3-methylpentoxy group, hexyloxy group etc.
[0044] The "C.sub.1-6 alkenyloxy group" used in the specification
of the present application means a group in which oxygen atom is
bound to a group having the same meaning as the C.sub.1-6 alkenyl
group defined above, and the preferable examples thereof include
vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy
group, isopropenyloxy group, 2-methyl-1-propenyloxy group,
3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group,
3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy
group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group,
1,3-hexanedienyloxy group, 1,6-hexanedienyloxy group etc.
[0045] The "C.sub.3-8 cycloalkyl group" used in the specification
of the present application means a cycloalkyl group in which the
ring is formed by 3 to 8 carbon atoms, and the preferable group
includes cyclopropyl group, cyclobutyl group, cyclopentyl group,
cyclohexyl group, cycloheptyl group, cyclooctyl group etc. Further,
the "C.sub.3-8cycloalkane" used in the specification of the present
application means a ring corresponding to the above-mentioned
C.sub.3-8 cycloalkyl group.
[0046] The "C.sub.3-8 cycloalkenyl group" used in the specification
of the present application means a C.sub.3-8 cycloalkenyl group in
which a ring is formed by 3 to 8 carbon atoms, and the examples
thereof include a group represented by the formula: 67
[0047] The "aromatic cyclic group" used in the specification of the
present application is a term meaning a C.sub.6-14 aromatic
hydrocarbon cyclic group or a 5- to 14-membered aromatic
heterocyclic group.
[0048] (1) Examples of the above-mentioned "C.sub.6-14 aromatic
hydrocarbon cyclic group" include mono-cyclic, di-cyclic or
tri-cyclic C.sub.6-14 aromatic hydrocarbon groups such as phenyl
group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl
group, hepthalenyl group, biphenyl group, indathenyl group,
acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl
group, anthracenyl group, cyclopentacyclooctenyl group,
benzocyclooctenyl group, and the like.
[0049] (2) Examples of the "5- to 14-membered aromatic heterocyclic
group" include a mono-cyclic, di-cyclic or tri-cyclic 5- to
14-membered aromatic heterocyclic ring which contains any one or
more of hetero atoms selected from nitrogen atom, sulfur atom and
oxygen atom, and for example:
[0050] (i) aromatic heterocyclic rings containing nitrogen such as
pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl
group, pyrazinyl group, triazolyl group, tetrazolyl group,
benzotriazolyl group, pyrazolyl group, imidazolyl group,
benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl
group, purinyl group, indazolyl group, quinolyl group, isoquinolyl
group, quinolizyl group, phthalazyl group, naphthylidinyl group,
quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl
group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl
group, phenanthridinyl group, carbazolyl group, carbazolinyl group,
perimidinyl group, phenanthrolinyl group, phenacinyl group,
imidazopyridinyl group, imidazopyrimidinyl group and
pyrazolopyridinyl group;
[0051] (ii) aromatic heterocyclic rings containing sulfur such as
thienyl group and benzothienyl group;
[0052] (iii) aromatic heterocyclic rings containing oxygen such as
furyl group, pyranyl group, cyclopentapyranyl group, benzofuranyl
group and isobenzofuranyl group; and
[0053] (iv) aromatic heterocyclic rings containing 2 or more
different kinds of hetero atoms selected from nitrogen atom, sulfur
atom and oxygen atom, such as thiazolyl group, isothiazolyl group,
benzothiazolyl group, benzthiazolyl group, phenothiazinyl group,
isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl
group, benzoxazolyl group, oxadiazolyl group, pyrazolooxazolyl
group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl
group, pyridoxazinyl group may be proposed.
[0054] The "C.sub.3-14hydrocarbon ring" used in the specification
of the present application means a C.sub.3-8 cycloalkane, a
C.sub.3-8 cycloalkene or a C.sub.6-14 aromatic hydrocarbon ring,
and the meanings of these rings refer to the same meaning as a
C.sub.3-8 cycloalkane, a C.sub.3-8 cycloalkene and a C.sub.6-14
aromatic hydrocarbon ring defined above.
[0055] The "5- to 14-membered heterocyclic ring" used in the
specification of the present application means a 5- to 14-membered
heterocyclic ring containing any one or more of hetero atoms
selected from nitrogen atom, sulfur atom and oxygen atom, and an
aromatic heterocyclic ring and a non-aromatic heterocyclic ring are
included in the ring. Here, (1) the above-mentioned "5- to
14-membered aromatic heterocyclic ring" have the same meaning as a
5- to 14-membered aromatic heterocyclic ring defined above.
Further, (2) the preferable ring as the "5- to 14-membered
non-aromatic heterocyclic ring" includes 5- to 14-membered
non-aromatic heterocyclic rings such as pyrrolidine ring, pyrroline
ring, piperidine ring, piperazine ring, imidazoline ring,
pyrazolidine ring, imidazolidine ring, morpholine ring,
tetrahydrofuran ring, tetrahydropyran ring, aziridine ring, oxirane
ring, oxathiorane ring, pyridone ring etc., and condensed rings
such as phthalimide ring, succinimide ring etc.
[0056] The "hydrocarbon group" used in the specification of the
present application specifically means a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-8
cycloalkyl, a C.sub.3-8 cycloalkenyl group or a C.sub.6-14 aromatic
hydrocarbon cyclic group, and the respective meanings are the same
as defined above.
[0057] Meaning of Ar
[0058] In the compound represented by the above formula (I)
according to the present invention, Ar indicates (1) a C.sub.6-14
aromatic hydrocarbon cyclic group which may be substituted, (2) a
5- to 14-membered aromatic heterocyclic group which may be
substituted, (3) a C.sub.1-6 alkyl group substituted with a
C.sub.6-14 aromatic hydrocarbon cyclic group which may be
substituted or (4) a C.sub.1-6 alkyl group substituted with a 5- to
14-membered aromatic heterocyclic group which may be
substituted.
[0059] Examples of the above-mentioned "C.sub.6-14 aromatic
hydrocarbon cyclic group" preferably include phenyl group,
pentalenyl group, indenyl group, naphthyl group,
1,2,3,4-tetrahydronaphthyl group, azulenyl group, hepthalenyl
group, benzocyclooctenyl group, tetranyl group, phenanthrenyl group
etc., and more preferably phenyl group, naphthyl group etc.
[0060] Further, the preferable examples of the "5- to 14-membered
aromatic heterocyclic group" include pyrrolyl group, pyridyl group,
pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl
group, tetrazolyl group, benzotriazolyl group, pyrazolyl group,
imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl
group, indolizinyl group, purinyl group, indazolyl group, quinolyl
group, isoquinolyl group, quinolizyl group, phthalazyl group,
naphthylidinyl group, quinoxalyl group, quinazolinyl group,
cinnolinyl group, pteridinyl group, imidazotriazinyl group,
pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group,
carbazolyl group, carbazolinyl group, perimidinyl group,
phenanthrolinyl group, phenacinyl group, imidazopyridinyl group,
imidazopyrimidinyl group, pyrazolopyridinyl group, thienyl group,
benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl
group, benzofuranyl group, isobenzofuranyl group, thiazolyl group,
isothiazolyl group, benzothiazolyl group, benzthiazolyl group,
phenothiazinyl group, isoxazolyl group, furazanyl group,
phenoxazinyl group, oxazolyl group, benzoxazolyl group, oxadiazolyl
group, pyrazolooxazolyl group, imidazothiazolyl group,
thienofuranyl group, phlopyrrolyl group, pyridoxazinyl group etc.,
more preferably thienyl group, pyridyl group etc., and further
preferably thienyl group.
[0061] When Ar is the "C.sub.6-14 aromatic hydrocarbon cyclic group
optionally substituted" or the "5- to 14-membered aromatic
heterocyclic group optionally substituted", examples of the
"substituent" include (i) hydroxyl group, (ii) a halogen atom (for
example, fluorine atom, chlorine atom, bromine atom and an iodine
atom), (iii) nitrile group, (iv) a C.sub.1-6 alkyl group
(preferably, methyl group, ethyl group, n-propyl group, isopropyl
group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl
group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl
group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl
group, n-hexyl group, 1-methyl-2-ethylpropyl group,
1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,
1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl
group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group,
2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group
etc.), (v) a C.sub.2-6alkenyl group (preferably, vinyl group, allyl
group, 1-propenyl group, 2-propenyl group, isopropenyl group,
2-methyl-1-propenyl group, 3-methyl-1-propenyl group,
2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl
group, 2-butenyl group, 3-butenyl group, 1-pentenyl group,
1-hexenyl group, 1,3-hexanedienyl group, 1,6-hexanedienyl group
etc.), (vi) a C.sub.2-6alkynyl group (preferably, ethynyl group,
1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl
group, 3-butynyl group, 3-methyl-1-propynyl group,
1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl
group, 1-hexynyl group, 1,3-hexanediynyl group, 1,6-hexanediynyl
group etc.), (vii) a C.sub.1-6alkoxy group (preferably, methoxy
group, ethoxy group, n-propoxy group, isopropoxy group, sec-propoxy
group, n-butoxy group, isobutoxy group, sec-butoxy group,
tert-butoxy group, n-pentyloxy group, isopentyloxy group,
sec-pentyloxy group, n-hexoxy group, isohexoxy group,
1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group,
2,2-dimethylpropyloxy group, 2-ethylpropoxy group,
1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,
1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group,
1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group,
2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy group,
1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy
group, 2-methylpentoxy group, 3-methylpentoxy group, hexyloxy group
etc.), (viii) C.sub.1-6 alkylthio group (preferably, methylthio
group, ethylthio group, n-propylthio group, isopropylthio group,
n-butylthio group, isobutylthio group, sec-butylthio group,
tert-butylthio group, n-pentylthio group, 1,1-dimethylpropylthio
group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group,
1-ethylpropylthio group, 2-ethylpropylthio group, n-hexylthio
group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio
group, 1,1,2-trimethylpropylthio group, 1-propylpropylthio group,
1-methylbutylthio group, 2-methylbutylthio group,
1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group,
2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group,
2,3-dimethylbutylthio group, 2-ethylbutylthio group,
2-methylpentylthio group, 3-methylpentylthio group etc.), (ix) a
C.sub.1-6 alkoxycarbonyl group, (x) a hydroxyl C.sub.1-6alkyl
group, (xi) a halogenated C.sub.1-6alkyl group, (xii) a
hydroxyimino C.sub.1-6alkyl group, (xiii) nitro group, (xiv) an
amino group in which the nitrogen atom may be substituted, (xv) a
carbamoyl group in which the nitrogen atom may be substituted,
(xvi) a sulfamoyl group in which the nitrogen atom may be
substituted, (xvii) a lower acyl group, (xviii) an aromatic acyl
group, (xix) a C.sub.1-6 alkylsulfonyl group such as methylsulfonyl
group, etc., and the "substitutent" is preferably (a) hydroxyl
group, (b) a halogen atom, (c) nitrile group, (d) a C.sub.1-6alkyl
group, (e) a C.sub.1-6alkylsulfonyl group, (f) a C.sub.1-6 alkoxy
group, (g) a C.sub.1-6 alkylthio group etc., and, more preferably,
nitrile group or a halogen atom (for example, fluorine atom
etc.).
[0062] Further, examples of the more preferable "C.sub.6-14
aromatic hydrocarbon cyclic group which may be substituted" or "5-
to 14-membered aromatic heterocyclic group which may be
substituted" in the definition of Ar include a thiophene, a
pyridine, a benzene or a naphthalene ring which may be substituted
with any one or more groups selected from a halogen atom and cyano
group. The most preferable example includes a thiophene ring which
may be substituted with any one or more groups selected from a
halogen atom and cyano group, and namely, a ring represented by the
formula: 8
[0063] wherein R.sup.13a, R.sup.13b and R.sup.13c are the same as
or different from each other, and each indicates a hydrogen atom, a
halogen atom or cyano group.
[0064] In the compound represented by the above formula (I)
according to the present invention, when Ar is the "C.sub.1-6 alkyl
group substituted with a C.sub.6-14 aromatic hydrocarbon cyclic
group which may be substituted" or the "C.sub.1-6 alkyl group
substituted with 5- to 14-membered aromatic heterocyclic group
which may be substituted", the "C.sub.6-14 aromatic hydrocarbon
cyclic group which may be substituted" or the "5- to 14-membered
aromatic heterocyclic group which may be substituted" has the same
meaning as the C.sub.6-14 aromatic hydrocarbon cyclic group which
may be substituted or the 5- to 14-membered aromatic heterocyclic
group which may be substituted in the above-mentioned definition,
respectively. The C.sub.1-6alkyl group substituted with those
groups means a C.sub.1-6alkyl group substituted with such groups.
Here, preferable examples of the "C.sub.1-6alkyl group" include
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl
group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group,
2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group,
n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl
group, 1,1,2-trimethylpropyl group, 1-propylpropyl group,
1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group,
1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl
group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl
group, 3-methylpentyl group etc. Preferable examples of the
"C.sub.1-6 alkyl group substituted with an aromatic group which may
be substituted" include a benzyl group, a phenethyl group, a
phenylpropyl group, a naphthylmethyl group, a naphthylethyl group,
a naphthylpropyl group, a pyridylmethyl group, a pyrazinylmethyl
group, a pyrimidinylmethyl group, a pyrrolylmethyl group, an
imidazolylmethyl group, a pyrazolylmethyl group, aquinolylmethyl
group, an isoquinolylmethyl group, furfuryl group, thienylmethyl
group, thiazolylmethyl group etc., which maybe optionally
substituted respectively with one ore more groups selected from
nitrile group, ahalogen atom (for example, fluorine atom, chlorine
atom, bromine atom, iodine atom etc.) etc.
[0065] Further, preferable examples of the "C.sub.1-6
alkoxycarbonyl group" in the definition of Ar include
methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl
group, isopropoxycarbonyl group, sec-propoxycarbonyl group,
n-butoxycarbonyl group, isobutoxycarbonyl group,
sec-butoxycarbonylcarbonyl group, tert-butoxycarbonylcarbonyl
group, n-pentoxycarbonyl group, isopentoxycarbonyl group,
sec-pentoxycarbonyl group, tert-pentoxycarbonyl group,
n-hexoxycarbonyl group, isohexoxycarbonyl group,
1,2-dimethylpropoxycarbonyl group, 2-ethylpropoxycarbonyl group, a
1-methyl-2-ethylpropoxycarbonyl group,
1-ethyl-2-ethylpropoxycarbonyl group,
1,1,2-trimethylpropoxycarbonyl group, 1,1-dimethylbutoxycarbonyl
group, 2,2-dimethylbutoxycarbonyl group, 2-ethylbutoxycarbonyl
group, 1,3-dimethylbutoxycarbonyl group, 2-methylpentoxycarbonyl
group, 3-methylpentoxycarbonyl group etc.
[0066] Preferable examples of the above-mentioned "hydroxy
C.sub.1-6 alkyl group" include linear or branched C.sub.1-6 alkyl
groups such as hydroxymethyl group, 1-hydroxyethyl group,
2-hydroxyethyl group, 3-hydroxy-n-propyl group, hydroxy-isopropyl
group, hydroxy-sec-propyl group, hydroxy-n-butyl group,
hydroxy-isobutyl group, hydroxy-sec-butyl group, hydroxy-tert-butyl
group, hydroxy-n-pentyl group, hydroxy-iso-pentyl group,
hydroxy-n-hexyl group and hydroxy-iso-hexyl group.
[0067] The above-mentioned "halogenated C.sub.1-6 alkyl group"
means a group in which one or more of the same or different halogen
atoms are bound to the "C.sub.1-6 alkyl group" having the same
meaning as the C.sub.1-6 alkyl group defined above, and preferable
examples thereof include fluoromethyl group, difluoromethyl group,
trifluoromethyl group, chloromethyl group, 1-fluoroethyl group,
2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl
group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group etc.
[0068] The above-mentioned "hydroxyimino C.sub.1-6 alkyl group"
means a group in which hydroxyimino group is bound to a group
having the same meaning as the C.sub.1-6 alkyl group defined
above.
[0069] The "amino group in which a nitrogen atom may be optionally
substituted" means an amino group which is represented by the
formula --N(R.sup.15)R.sup.16-- (wherein R.sup.15and R.sup.16 are
the same as or different from each other and each indicates (1) a
hydrogen atom, (2) a C.sub.1-6alkyl group, a C.sub.1-6alkenyl group
or a C.sub.1-6 alkynyl group which may be substituted respectively
with one or more groups selected from a halogen atom, a C.sub.3-8
cycloalkyl group, a C.sub.3-8 cycloalkenyl group and a C.sub.1-6
alkoxy group, (3) a C.sub.3-8 cycloalkyl group or a C.sub.3-8
cycloalkenyl group which may be substituted with a halogen atom,
(4) a carbonyl group substituted with any one of groups selected
from a C.sub.1-6alkyl group, a C.sub.1-6alkenyl group, a
C.sub.1-6alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.3-8
cycloalkenyl group, a C.sub.1-6 alkoxy group, a C.sub.6-14 aromatic
hydrocarbon cyclic group, a 5- to 14-membered aromatic heterocyclic
group and a 5- to 14-membered non-aromatic heterocyclic group which
may be substituted with a halogen atom, respectively, (5) a
carbamoyl group substituted with any one of groups selected from a
C.sub.1-6 alkyl group, a C.sub.1-6 alkenyl group, a C.sub.1-6
alkynyl group, a C.sub.6-14 aromatic hydrocarbon cyclic group and a
5- to 14-membered aromatic heterocyclic group or (6) a sulfonyl
group substituted with any one of groups selected from a C.sub.1-6
alkyl group, a C.sub.1-6 alkenyl group and a C.sub.1-6 alkynyl
group, or (7) R.sup.15 and R.sup.16 may be bound together to form a
3- to 10-membered non-aromatic heterocyclic group containing the
nitrogen atom to which they are bound, and the heterocyclic group
may be substituted with one or more of groups selected from
hydroxyl group, a halogen atom, a C.sub.1-6 alkoxy group etc.).
[0070] Examples of the preferable amino group include unsubstituted
amino group, methylamino group, dimethylamino group, ethylamino
group, diethylamino group, methylethylamino group, acetamide
(CH.sub.3CONH--) group, propionamide group, methanesulfonamide
group, ethanesulfonamide group, pyrrolidinyl group, pyrazolinyl
group, piperidinyl group, piperazinyl group, 4-morpholinyl group,
4-thiomorpholinyl etc. The more preferable examples of the "amino
group which may be substituted" include an amino group which may be
substituted with one or two groups selected from a C.sub.1-6 alkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.3-8 cycloalkyl group and a C.sub.3-8 cycloalkenyl group.
[0071] The above-mentioned "carbamoyl group in which the nitrogen
atom may be substituted" means a carbamoyl group in which the
nitrogen atom may be substituted with a group selected from a
C.sub.1-6alkyl group, a C.sub.2-6alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.3-8 cycloalkyl group and a C.sub.3-8 cycloalkenyl
group. Further, the carbamoyl group naturally includes a case in
which the nitrogen atom of the carbamoyl group is a portion of a
cyclic amine. The preferable examples of the "carbamoyl group in
which the nitrogen atom may be substituted" includes unsubstituted
carbamoyl group, N-methylcarbamoyl group, N,N-dimethylcarbamoyl
group, N-ethylcarbamoyl group, N,N-diethylcarbamoyl group,
N-methyl-N-ethylcarbamoyl group, 1-pyrrolidinylcarbonyl group,
1-pyrazolinylcarbonyl group, 1-piperidylcarbonyl group,
1-piperazinylcarbonyl group, 4-morpholinylcarbonyl group,
4-thiomorpholinylcarbonyl group etc.
[0072] The above-mentioned "sulfamoyl group in which the nitrogen
atom may be substituted" means a sulfamoyl group in which the
nitrogen atom may be optionally substituted with a group selected
from a C.sub.1-6alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.3-8
cycloalkenyl group etc. Further, the sulfamoyl group naturally
includes a case in which the nitrogen atom of the sulfamoyl group
is a portion of a cyclic amine. The preferable examples of the
"sulfamoyl group in which the nitrogen atom may be substituted"
include unsubstituted sulfamoyl group (--SO.sub.2NH.sub.2),
N-methylsulfamoyl group (--SO.sub.2NHCH.sub.2),
N,N-dimethylsulfamoyl group (--SO.sub.2NH(CH.sub.3).sub.2),
N-ethylsulfamoyl group (--SO.sub.2NHC.sub.2H.sub.5),
N,N-diethylsulfamoyl group (--SO.sub.2NH(C.sub.2H.sub.5).sub.2),
N-methyl-N-ethylsulfamoyl group
(--SO.sub.2N(CH.sub.3)C.sub.2H.sub.5), 1-pyrrolidinylsulfonyl
group, 1-pyrazolinylsulfonyl group, 1-piperidylsulfonyl group,
1-piperazinylsulfonyl group, 4-morpholinylsulfonyl group,
4-thiomorpholinylsulfonyl group etc.
[0073] The above-mentioned "lower acyl group" means a linear or
molecular chain acyl group derived from a fatty acid having 1 to 6
carbons, and the preferable examples of the group include formyl
group, acetyl group, propionyl group, butyryl group, isobutyryl
group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl
group etc.
[0074] Meaning of the Ring A
[0075] In the compound represented by the above formula (I)
according to the present invention, the ring A indicates any one
ring selected from piperazine ring, homopiperazine ring, piperidine
ring, homopiperidine ring, pyrrolidine ring and
diazabicyclo[2,2,1]heptane ring. Examples of the ring A preferably
include a piperazine ring, a homopiperazine ring, a piperidine
ring, a homopiperidine ring, a pyrrolidine ring, more preferably a
piperidine ring, a piperazine ring, and further more preferably a
piperazine ring. When the ring A is piperazine ring, piperidine
ring, pyrrolidine ring or diazabicyclo[2,2,1]heptane ring, an
aspect represented by the formula: 9
[0076] is listed as the preferable aspect in which the bonding
chains D.sup.2and W.sup.1 are bound to the ring A, and as more
preferable one, listed is the formula: 10
[0077] Meaning of Ring B
[0078] In the compound represented by the above formula (I)
according to the present invention, the ring B indicates (1) a
C.sub.3-14 hydrocarbon ring which may be substituted, or (2) a 5-
to 14-memberedheterocyclic ring which may be substituted.
[0079] (1) The "C.sub.3-14 hydrocarbon ring" in the definition of
the ring B means a C.sub.3-8 cycloalkane, a C.sub.3-8 cycloalkene
or a C.sub.6-14 aromatic hydrocarbon ring. When the ring B is "a
C.sub.3-8 cycloalkane", examples of the ring preferably include 3-
to 8-membered cycloalkanes such as cyclopropane, cyclobutane,
cyclopentane, cyclohexane, cycloheptane etc., and more preferably
cyclopropane, cyclobutane, cyclopentane, cyclohexane etc. When the
ring B is "a C.sub.3-8 cycloalkene", examples of the ring
preferable include 3- to 8-membered cycloalkenes such as
cyclopropene, cyclobutene, cyclopentene, cyclohexene and
cycloheptene, and further, a non-aromatic unsaturated hydrocarbon
ring in which a carbon-carbon double bond in an aromatic
hydrocarbon ring is partially saturated. Cyclopropene, cyclobutene,
cyclopentene, cyclohexene etc. are more preferred. When the ring B
is a "C.sub.6-14 aromatic hydrocarbon ring", the ring preferably
includes benzene ring, pentalene ring, indene ring, naphthalene
ring, 1,2,3,4-tetrahydronaphthal- ene ring, azulene ring, heptalene
ring, benzocyclooctene ring, phenanthrene ring etc., and the
condensed ring of a C.sub.3-8 cycloalkane with an aromatic
hydrocarbon ring and the condensed ring of a C.sub.3-8cycloalkene
with an aromatic hydrocarbon ring are also included in the
"C.sub.6-14 aromatic hydrocarbon ring".
[0080] (2) The "5- to 14-membered heterocyclic ring" in the
definition of the ring B indicates a 5- to 14-membered non-aromatic
heterocyclic ring or a 5- to 14-membered aromatic heterocyclic
ring. When the ring B is the "5- to 14-membered non-aromatic
heterocyclic ring", the ring preferably includes pyrrolidine ring,
pyrroline ring, piperazine ring, imidazoline ring, pyrazolidine
ring, imidazolidine ring, morpholine ring, tetrahydropyran ring,
aziridine ring, oxirane ring, phthalimide ring, succinimide ring
etc. When the ring B is a "5- to 14-membered aromatic heterocyclic
ring", the preferable ring includes pyrrole ring, pyridine ring,
pyridazine ring, pyrimidine ring, pyrazine ring, pyrazole ring,
imidazole ring, indole ring, isoindolyl ring, indolizine ring,
purine ring, indazole ring, quinoline ring, isoquinoline ring,
quinolizine ring, phthalazine ring, naphthylidine ring, quinoxaline
ring, quinazoline ring, benzimidazole ring, cinnoline ring,
pteridine ring, imidazotriazine ring, pyrazinopyridazine ring,
acridine ring, phenanthridine ring, carbazole ring, carbazoline
ring, perimidine ring, phenanthroline ring, phenacine ring,
thiophene ring, benzothiophene ring, furan ring, pyran ring,
cyclopentapyran ring, benzofuran ring, isobenzofuran ring, thiazole
ring, isothiazole ring, benzthiazole ring, benzothiazole ring,
phenothiazine ring, isoxazole ring, furazane ring, phenoxazine
ring, pyrazolooxazole ring, imidazothiazole ring, thienofuran ring,
furopyrrole ring, pyridoxazine ring, 1,4-benzodioxane ring,
benzoxazole ring, 2-keto-1-imidazole ring, oxazole ring,
1,2,4-oxadiazole ring, indanone ring, 1,2,3,4-tetrahydroquinoline
ring etc.
[0081] Examples of the "substituent" in the "C.sub.3-14 hydrocarbon
ring which may be substituted" or the "5- to 14-membered
heterocyclic ring which may be substituted" in the ring B include
one or more groups selscted from (1) hydroxyl group, (2) a halogen
atom (for example, fluorine atom, chlorine atom, bromine atom,
iodine atom etc.), (3) nitrile group, (4) a C.sub.1-6alkyl group
which may be substituted (for example, a C.sub.1-6 alkyl group
which may be substituted with one or moregroupsselected from
hydroxyl group, a halogen atom, nitrile group, hydroxyimino group
etc.), (5) a C.sub.2-6 alkenyl group which may be substituted (for
example, a C.sub.2-6alkenyl group which may be substituted with one
or more groups selected from hydroxyl group, a halogen atom,
nitrile group, hydroxyimino group etc.), (6) a C.sub.1-6alkoxy
group which may be substituted (for example, a C.sub.1-6 alkenyl
group which may be substituted with one or more groups selected
from hydroxyl group, a halogen atom, nitrile group, hydroxyimino
group etc.), (7) a C.sub.1-6 alkylthio group which may be
substituted, (8) a C.sub.1-6 alkoxycarbonyl group, (9) nitro group,
(10) an amino group in which the nitrogen atom may be substituted,
(11) a carbamoyl group in which the nitrogen atom may be
substituted, (12) a sulfamoyl group in which the nitrogen atom may
be substituted, (13) a lower acyl group, (14) an aromatic acyl
group, (15) a C.sub.1-6 alkylsulfonyl group (for example,
methylsulfonyl group, ethylsulfonyl group etc.), (16) a C.sub.6-14
aromatic hydrocarbon cyclic group, (17) a 5- to 14-membered
aromatic heterocyclic group, and (18) an aralkyl group (for
example, benzyl group, phenethyl group etc.), and it is preferably
(i) hydroxyl group, (ii) a halogen atom (for example, fluorine
atom, chlorine atom, bromine atom etc.), (iii) nitrile group, (iv)
a C.sub.1-6 alkyl group (for example, methyl group, ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group,
tert-butyl group etc.), (v) a C.sub.6-14 aromatic hydrocarbon
cyclic group, (vi) a 5- to 14-membered aromatic heterocyclic group,
etc., and more preferably, nitrile group, fluorine atom, chlorine
atom etc.
[0082] The most preferable aspect of the ring B is a C.sub.6-14
aromatic hydrocarbon ring or a 5- to 14-membered aromatic
heterocyclic ring which may be substituted, respectively. Specific
examples include a benzene ring, a thiophene ring, a pyridine ring,
a 1,4-benzodioxane ring, an indole ring, a benzothiazole ring, a
benzoxazole ring, a benzimidazole ring, a 2-keto-1-imidazole ring,
a thiazole ring, a oxazole ring, an isoxazole ring, a
1,2,4-oxadiazole ring, an indanone ring, a benzofurane ring, a
quinoline ring, a l,2,3,4-tetrahydroquinoline ring, a naphthalene
ring, a 1,2,3,4-tetrahydronaphthalene ring etc., which may be
substituted with one or more groups selected from nitrile group, a
halogen atom (for example, fluorine atom, chlorine atom, bromine
atom etc.), a C.sub.6-14 aromatic hydrocarbon cyclic group (for
example, phenyl group, naphthyl group etc.), a 5- to 14-membered
aromatic heterocyclic group (for example, pyridyl group, thienyl
group, furyl group etc.), a C.sub.1-6 alkyl group (for example,
methyl group, ethyl group, n-propyl group, isopropyl group,
isobutyl group etc.), a lower acyl group and a
C.sub.1-6alkylsulfonyl group (for example, methylsulfonyl group,
ethylsulfonyl group etc.), respectively.
[0083] Meaning of E
[0084] In the compound represented by the above formula (I)
according to the present invention, the bonding chain E indicates a
single bond, a group represented by the formula --CO-- or
--CH(OH)--. The most preferable aspect in E is a single bond.
[0085] Meaning of X
[0086] In the compound represented by the above formula (I)
according to the present invention, the bonding chain X indicates
(1) a single bond, (2) oxygen atom, (3) sulfur atom, (4) a
C.sub.1-6 alkylene chain which may be substituted, a group
represented by (5) the formula --NR.sup.2-- (wherein R.sup.2
indicates a hydrogen atom, or a C.sub.1-6alkyl group, a
C.sub.3-8cycloalkyl group, a lower acyl group or a C.sub.1-6
alkylsulfonyl group which may be substituted), (6) --CO--, (7)
--COO--, (8) --OOC--, (9) --CONR.sup.3--0 (wherein R.sup.3indicates
a hydrogen atom or a C.sub.1-6 alkyl group which may be
substituted), (10) --NR.sub.4CO-- (wherein R.sup.4 indicates a
hydrogen atom, or a C.sub.1-6 alkyl group which may be optionally
substituted), (11) --SO--, (12) --SO.sub.2--, (13) --SONR.sup.5--
(wherein R.sup.5 indicates a hydrogen atom, or a C.sub.1-6 alkyl
group which may be substituted), (14) --NR.sup.6SO-- (wherein
R.sup.6 indicates a hydrogen atom, or a C.sub.1-6 alkyl group which
may be substituted), (15) --SO.sub.2NR.sup.7-- (wherein
R.sup.7indicates a hydrogen atom, or a C.sub.1-6 alkyl group which
may be substituted), (16) --NR.sup.8SO.sub.2-- (wherein R.sup.8
indicates a hydrogen atom, or a C.sub.1-6 alkyl group which may be
substituted), (17) >C.dbd.N--OR.sup.9 (wherein R.sup.9 indicates
a hydrogen atom, or a C.sub.1-6 alkyl group which maybe
substituted), (18) --NR.sup.10--W.sup.3--O-- (wherein R.sup.10
indicates a hydrogen atom, or a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a lower acyl group or a C.sub.1-6 alkylsulfonyl
group which may be substituted; and W.sup.3 indicates a C.sub.1-6
alkylene group which may be substituted), (19) --NH--CO--NH--, (20)
--NH--CS--NH--, (21) --C(.dbd.NR.sup.15)NR.sup.16-- (wherein
R.sup.15and R.sup.16 are the same as or different from each other
and indicates a hydrogen atom, nitrile group, a C.sub.1-6 alkyl
group, a C.sub.2-6 alkenyl group, a C.sub.3-8 cycloalkyl group or a
C.sub.3-8 cycloalkenyl group), (22) --NHC(.dbd.NH)--, (23)
--O--CO--S--, (24) --S--CO--O--, (25) --OCOO--, (26) --NHCOO--,
(27) --OCONH--, (28) --CO(CH.sub.2).sub.mO-- (wherein m indicates 0
or an integer of 1 to 6), (29) --CHOH--, or (30)
--CHOH(CH.sub.2).sub.nO-- (wherein n indicates 0 or an integer of 1
to 6).
[0087] When X is the "C.sub.1-6 alkylene chain which may be
substituted", the "C.sub.1-6 alkylene chain" indicates a chain
derived from a linear or branched C.sub.1-6 alkane, and the
examples thereof include methylene, ethylene, ethylidene,
trimethylene, isopropylidene, propylene, tetramethylene,
1,2-butylene, 1,3-butylene, 2,3-butylene, isobutylene etc.
[0088] In the definition of X, the most preferable examples of the
"C.sub.1-6 alkyl group which may be substituted" indicated by
R.sup.2 to R.sup.10 include a C.sub.1-6alkyl group (for example,
methyl group, ethyl group, n-propyl group, isopropyl group etc.)
which may be substituted with one or more groups selected from
hydroxyl group, a halogen atom (for example, fluorine atom,
chlorine atom, bromine atom, iodine atom etc.), nitrile group,
nitro group, a C.sub.1-6 alkoxy group (for example, methoxy group,
ethoxy group, n-propoxy group, isopropoxy group etc.), etc.
[0089] In the definition of X, the preferable examples of the
"C.sub.3-8 cycloalkyl group" indicated by R.sup.2 and R.sup.10
includes cyclopropanyl group, cyclobutanyl group, cyclopentanyl
group, cyclohexanyl group, cycloheptanyl group etc., and the group
is more preferably cyclopropanyl group, cyclobutanyl group,
cyclopentanyl group, cyclohexanyl group etc.
[0090] In the definition of X, the preferable examples of the
"lower acyl group" indicated by R.sup.2 and R.sup.10 include formyl
group, acetyl group, propionyl group, butyryl group, isobutyryl
group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl
group etc.
[0091] In the definition of X, the preferable examples of the
"C.sub.1-6 alkylsulfonyl group" indicated by R.sup.2 and R.sup.10
include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl
group, isopropylsulfonyl group, sec-propylsulfonyl group,
n-butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl
group, tert-butylsulfonyl group, n-pentylsulfonyl group,
isopentylsulfonyl group, sec-pentylsulfonyl group,
tert-pentylsulfonyl group, n-hexylsulfonyl group, isohexylsulfonyl
group, 1,2-dimethylpropylsulfonyl group, 2-ethylpropylsulfonyl
group, 1-methyl-2-ethylpropylsulfonyl group,
1-ethyl-2-methylpropylsulfonyl group, 1,1,2-trimethylpropylsulfonyl
group, 1,1,2-trimethylpropylsulfonyl group,
1,1-dimethylbutylsulfonyl group, 2,2-dimethylbutylsulfonyl group,
2-ethylbutylsulfonyl group, 1,3-dimethylbutylsulfonyl group,
2-methylpentylsulfonyl group, 3-methylpentylsulfonyl group etc.
[0092] In the definition of X, R.sup.15 and R.sup.16 are the same
as or different from each other and each indicates a hydrogen atom,
nitrile group, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group,
a C.sub.3-8 cycloalkyl group or a C.sub.3-8 cycloalkylene group.
The preferable groups of both of them are the same as or different
from each other and each means a hydrogen atom, nitrile group,
methyl group, ethyl group, n-propyl group, isopropyl group,
cyclopropyl group, cyclopentyl group, cyclohexyl group etc. It is
more preferable that R.sup.15 is nitrile group, ethyl group,
n-propyl group, isopropyl group or cyclohexyl group, and R.sup.16
is a hydrogen atom. Further, the most preferable aspect of the
formula --C(.dbd.NR.sup.15)NR.sup.16-- is a chain represented by
the formula --C(.dbd.NCN)NH--.
[0093] The meanings of the respective groups listed in the
definition of X are described above. (1) The preferable aspect of X
is a single bond, oxygen atom, sulfur atom, a C.sub.1-6 alkylene
chain which may be substituted, a group represented by the formula
--NR.sup.2-- (wherein R.sup.2 indicates a hydrogen atom, or a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a lower acyl
group or a C.sub.1-6 alkylsulfonyl group which may be substituted),
--CO--, --NR.sup.10--W.sup.3--O-- (wherein R.sup.10 indicates a
hydrogen atom, or a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl
group, a lower acyl group or a C.sub.1-6 alkylsulfonyl group which
may be substituted; and W.sup.3 indicates a C.sub.1-6alkylene group
which may be substituted) and --NH--SO.sub.2--. (2) The more
preferable aspect is oxygen atom, a C.sub.1-6 alkylene chain which
may be substituted, a group represented by the formula --NR.sup.2--
(wherein R.sup.2 indicates a hydrogen atom, or a C.sub.1-6alkyl
group, a C.sub.3-8 cycloalkyl group, a lower acyl group or a
C.sub.1-6alkylsulfonyl group which may be substituted), --CO--,
--NR.sup.10--W.sup.3--O-- (wherein R.sup.10 indicates a hydrogen
atom, or a C.sub.1-6 alkyl group, a C.sub.3-8cycloalkyl group, a
lower acyl group or a C.sub.1-6 alkylsulfonyl group which may be
substituted; and W.sup.3 indicates a C.sub.1-6 alkylene group which
may be substituted) and --NH--SO.sub.2--. (3) The further more
preferable aspect is oxygen atom, a C.sub.1-6 alkylene chain which
may be substituted, a group represented by the formula --NR.sup.2--
(wherein R.sup.2 indicates a hydrogen atom, or a C.sub.1-6 alkyl
group, a C.sub.3-8 cycloalkyl group, a lower acyl group or a
C.sub.1-6 alkylsulfonyl group which may be substituted), --CO--,
and --NH--SO.sub.2--. (4) The most preferable aspect is oxygen atom
or a group represented by the formula --NR.sup.2-- (wherein R.sup.2
indicates a hydrogen atom, or a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a lower acyl group or a C.sub.1-6 alkylsulfonyl
group which may be substituted).
[0094] Meaning of R.sup.1
[0095] The group represented by R.sup.1 in the above formula (I)
indicates (1) a hydrogen atom, (2) a halogen atom, (3) hydroxyl
group, (4) a C.sub.1-6 alkyl group which may be substituted with
one or more groups selected from hydroxyl group, a halogen atom and
nitrile group, (5) a C.sub.2-6 alkenyl group which may be
substituted with one or more groups selected from hydroxyl group, a
halogen atom and nitrile group, (6) a C.sub.2-6 alkynyl group which
may be substituted with one or more groups selected from hydroxyl
group, a halogen atom and nitrile group, (7) a C.sub.3-8 cycloalkyl
group which may be substituted with one or more groups selected
from hydroxyl group, a halogen atom and nitrile group, (9) a
C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, (10) an amino-C.sub.1-6
alkyl group in which the nitrogen atom may be substituted, (11) the
formula --N(R.sup.11)R.sup.12-- (wherein R.sup.11 and R.sup.12 are
the same as or different from each other and each indicates a
hydrogen atom or a C.sub.1-6 alkyl group), (12) an aralkyl group,
(13) morpholinyl group, (14) thiomorpholinyl group, (15) piperidyl
group, (16) pyrrolidinyl group or (17) piperazinyl group.
[0096] The preferable atom as the above-mentioned "halogen atom"
includes fluorine atom, chlorine atom and bromine atom, and more
preferably includes fluorine atom and chlorine atom.
[0097] The "C.sub.1-6 alkyl group" in R.sup.1 preferably includes
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, isobutyl group, sec-butyl group tert-butyl group etc., more
preferably methyl group, ethyl group, n-propyl group and isopropyl
group, further preferably n-propyl group and isopropyl group, and
most preferably isopropyl group.
[0098] The "C.sub.2-6alkenyl group" in R.sup.1 preferably includes
vinyl group, allyl group, 1-propenyl group, isopropenyl group,
1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group,
2-buten-1-yl group, 2-buten-2-yl group etc., and more preferably
vinyl group, allyl group, isopropenyl group etc.
[0099] The preferable examples of the "C.sub.2-6 alkynyl group" in
R.sup.1 include ethynyl group, 1-propynyl group, 2-propynyl group,
butynyl group, pentynyl group, hexynyl group etc.
[0100] The preferable examples of the "C.sub.3-8 cycloalkyl group"
in R.sup.1 include cyclopropanyl group, cyclobutanyl group,
cyclopentanyl group, cyclohexanyl group etc.
[0101] The preferable examples of the "C.sub.1-6 alkoxy-C.sub.1-6
alkyl group" in R.sup.1 indicate a C.sub.1-6 alkyl group
substituted with a group having the same meaning as the C.sub.1-6
alkoxy group defined above, and the preferable group includes
methoxymethyl group, ethoxymethyl group, 1-methoxyethyl group,
2-methoxyethyl group, 1-ethoxyethyl group, 2-methoxy-n-propyl
group, 3-methoxy-n-propyl group, 2-(n-propoxy)ethyl group etc.
[0102] The preferable examples as the "C.sub.1-6alkyl group
substituted with nitrile group" in R.sup.1 includes cyanomethyl
group, 2-cyanoethyl group, 3-cyano-n-propyl group,
2-cyano-isopropyl group, 2-cyano-n-butyl group, 2-cyano-sec-butyl
group, 2-cyano-tert-butyl group, 2-cyano-n-pentyl group,
3-cyano-n-hexyl group etc.
[0103] The preferable examples as the "amino-C.sub.1-6 alkyl group
in which the nitrogen atom may be substituted" in R.sup.1 includes
aminomethyl group, methylaminomethyl group, dimethylaminomethyl
group, ethylaminomethyl group, diethylaminomethyl group,
methylethylaminomethyl group, acetamidomethyl group,
pyrrolidinylmethyl group, 2-pyrazolinylethyl group,
1-piperidylethyl group, piperazinylmethyl group etc.
[0104] The preferable examples as the "aralkyl group" in R.sup.1
includes benzyl group, phenethyl group, phenylpropyl group,
naphthylmethyl group, naphthylethyl group, naphthylpropyl group
etc.
[0105] The meanings of the respective groups listed in the
definition of R.sup.1 are described above, and the preferable
aspect of R.sup.1 includes a hydrogen atom, a halogen atom,
hydroxyl group, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group,
a C.sub.2-6 alkynyl group, a C.sub.3-8cycloalkyl group, a hydroxyl
C.sub.1-6alkyl group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
cyano-C.sub.1-6 alkyl group and a C.sub.1-6 alkyl group substituted
with a halogen atom. The more preferable aspect thereof includes a
halogen atom, hydroxyl group, a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group and a C.sub.2-6 alkynyl group, and the further
preferable aspect includes a C.sub.1-6 alkyl group (particularly,
methyl group, ethyl group, n-propyl group, isopropyl group).
[0106] Meanings of D.sup.1, D.sup.2 , W.sup.1 and W.sup.2
[0107] In the compound represented by the above formula (I)
according to the present invention, D.sup.1, D.sup.2, W.sup.1 and
W.sup.2 are the same as or different from each other and each
respectively indicates (1) a single bond or (2) an optionally
substituted C.sub.1-6 alkylene chain.
[0108] The preferable aspect of the "C.sub.1-6 alkylene chain" in
the above-mentioned "C.sub.1-6 alkylene chain which may be
substituted" includes methylene chain, ethylene chain, ethylidene
chain, trimethylene chain, isoproylidene chain, propylene chain,
tetramethylene chain, 1,2-butylene chain, 1,3-butylene chain,
2,3-butylene chain, isobutylene chain etc.
[0109] Further, a chain being asymmetric in left and right is
included in these C.sub.1-6 alkylene chains, but in this case, the
binding direction is not limited, and both of the binding
directions are also included in the "C.sub.1-6 alkylene chain".
[0110] The preferable aspect of the "substituent" in the
above-mentioned "C.sub.1-6 alkylene chain which may be substituted"
includes (i) a hydroxy group, (ii) a halogen atom (for example,
fluorine atom, chlorine atom, bromine atom, iodine atom etc.),
(iii) nitrile group, (iv) a C.sub.1-6alkyl group (for example,
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, tert-butyl group etc.), (v) a C.sub.2-6 alkenyl group (for
example, vinyl group, allyl group, 1-propenyl group, 2-propenyl
group, isopropenyl group, 2-methyl-1-propenyl group,
3-methyl-1-propenyl group, 2-methyl-2-propenyl group etc.), (vi) a
C.sub.1-6alkoxy group (for example, methoxy group, ethoxy group,
n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy
group etc.), etc.
[0111] Further, when the "substituent" is a c.sub.1-6 alkyl group
and/or a C.sub.2-6 alkenyl group, these substituents can be bound
together to form a 5- to 14-membered ring, and in the case of
W.sup.1 and W.sup.2, these substituents can be bonded with the ring
B or X to form a 5- to 14-membered ring.
[0112] As the preferable aspect, D.sup.1, D.sup.2, W.sup.1 and
W.sup.2 are the same as or different from each other and each
include (1) a single bond or (2) a methylene chain, ethylene chain,
ethylidene chain, trimethylene chain, isopropylidene chain,
propylene chain, tetramethylene chain, 1,2-butylene chain,
1,3-butylene chain, 2,3-butylene chain, isobutylene chain etc.,
which may be substituted respectively with one or more groups
selected from hydroxyl group, a halogen atom and nitrile group.
[0113] The respective meanings of E, X, D.sup.1, D.sup.2, W.sup.1
and W.sup.2 are described above. Here, the preferable aspect of the
partial sturucture -D.sup.1-E-D.sup.2- includes ethylene chain
(--CH.sub.2--CH.sub.2--), ethylidene chain (--CH(CH.sub.3)--),
trimethylene chain (--(CH.sub.2).sub.3--), isopropylidene chain
(--CH(CH.sub.3).sub.2--), propylene chain
(--CH(CH.sub.3)CH.sub.2--), tetramethylene chain
(--(CH.sub.2).sub.4--), 1,2-butylene chain
(--CH(C.sub.2H.sub.5)CH.sub.2--), 1,3-butylene chain
(--CH(CH.sub.3)CH.sub.2CH.sub.2--), 2,3-butylene chain
(--CH(CH.sub.3)CH(CH.sub.3)--), isobutylene chain
(--CH(CH.sub.3).sub.2CH- .sub.2--) etc. The more preferable aspect
includes trimethylene chain (--(CH.sub.2).sub.3--), isopropylidene
chain (--CH(CH.sub.3).sub.2--), propylene chain
(--CH(CH.sub.3)CH.sub.2--), tetramethylene chain
(--(CH.sub.2).sub.4--), 1,2-butylene chain
(--CH(C.sub.2H.sub.5)CH.sub.2-- -) etc., and the further preferable
aspect includes tetramethylene chain (--(CH.sub.2).sub.3--) etc.
Further, the preferable aspect of the partial structure
--W.sup.1--X--W.sup.2-- includes a single bond, a chain represented
by the formula --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--NR.sup.2--, --(CH.sub.2).sub.3--O-- or
--(CH.sub.2 ).sub.3--NR.sup.2--.
[0114] The aspects of the compound represented by the above formula
(I) according to the present invention are not specifically
limited, and those skilled in the art can freely combine the groups
listed in the above definitions concerning each of Ar, the ring A,
the ring B, E, X, R.sup.1, D.sup.1, D.sup.2, W.sup.1 and W.sup.2,
and carry out all compounds within the scope. The more preferable
aspects among them include the case where Ar is an optionally
substituted 5- to 14-membered aromatic heterocyclic group; the ring
A is piperazine ring, piperidine ring or pyrrolidine ring; and the
ring B is a C.sub.6-14 aromatic hydrocarbon group or 5- to
14-membered aromatic heterocyclic group which may be substituted; E
is a single bond; and X is a single bond, oxygen atom, an
optionally substituted C.sub.1-6 alkylene group or a group
represented by the formula --NR.sup.2-- (wherein R.sup.2 has the
same meaning as defined above). As the further preferable aspect, a
compound represented by the formula: 11
[0115] (wherein the respective symbols in the formulae have the
same meanings as defined above), a salt thereof or a hydrate of
them.
[0116] Compounds obtained in Examples described later are naturally
included in the preferable aspects of the compound according to the
present invention, and typical compounds are mentioned below.
[0117]
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N-(4-fluorophenyl)-N'-(2-methy-
lpropyl)-1(2H)-pyrazinecarboxyimidamide;
[0118]
1-isopropyl-4-[4-(1-isobutyl-1N-benzo[d]imidazol-2-yl)piperazino]-1-
-phenylbutyl cyanide;
[0119]
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenox-
y)ethyl]piperazine;
[0120]
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]-
piperazine;
[0121]
1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(5-cyano-2-thi-
enyl)propyl]piperazine;
[0122]
1-[4-cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]-
piperazine;
[0123]
1-{4-cyano-5-methyl-4-[4-(2-cyano)thienyl]hexyl}-4-[2-(3-cyanopheno-
xy)ethyl]piperazine;
[0124]
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzoxazolyl)amino]piper-
idine;
[0125]
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cyanoe-
thyl)-N-benzylamino]pyrrolidine;
[0126]
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-[N-(2-cyanoe-
thyl)-N-benzylamino]pyrrolidine;
[0127]
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(benzothiazolyl)piperazine;
[0128]
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-methoxy)benzothiazolyl-
]piperazine;
[0129]
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzoxazolyl]piperazine;
[0130]
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-quinolinyl]piperazine;
[0131]
4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopr-
opyl-1-phenylbutyl cyanide;
[0132]
4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopro-
pyl-1-phenylbutyl cyanide;
[0133] ethyl
4-(4-cyano-5-methyl-4-phenylhexyl)-1-[2-(4-fluorophenoxy)ethy-
l]-2-piperazinecarboxylate;
[0134]
1-[(2-oxo-1,2-dihydro-3-quinolyl)methyl]-4-[(4-cyano-5-methyl-4-phe-
nyl)hexyl]piperidine;
[0135]
4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[2-methanesulfonylamino]phe-
nyl]methyl}piperazine;
[0136]
4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[2-methanesulfonylamino]phe-
nyl]methyl}piperidine;
[0137] (S)-3-phenyl-2-aminopropanoic
acid{1-[4-cyano-5-methyl-5-(2-thionyl-
)hexyl]piperazinyl}amide;
[0138]
4-[4-(4-phenylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide;
[0139]
4-[4-(4-cyano-4-phenylpiperidinyl)piperidinyl]-1-isopropyl-1-phenyl-
butyl cyanide; and
[0140]
4-[4-(4-benzylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide.
[0141] The compound represented by the above formula (I) according
to the present invention, a salt thereof or a hydrate of them can
be produced by known production processes or processess according
to the processes. As the known production processes, for example, a
production process described in JP-A 2000-169462 (a production
process described in paragraphs "0054" to "0065" in the
Publication), and production processes described in JP-A
2000-12207, 2000-12208 and 2000-12209 are listed.
[0142] Further, the raw material compound in the production of the
compound (I) may form a salt or a hydrate, and is not specifically
limited so far as it does not inhibit the reaction. When the
compound (I) according to the present invention is obtained as a
free body, it can be converted to a salt which the above compound
(I) may form, according to a conventional process. When the
compound according to the present invention is prepared as a free
body, it can be converted to a salt according to a conventional
process. Various isomers (for example, geometrical isomer, optical
isomers based on an asymmetric carbon, stereo-isomers, the isomers
of tautomers and the like) which are obtained for the compound (I)
according to the present invention can be purified and isolated by
conventional separation procedures (for example, recrystallization,
a diastereomer salt method, an enzyme division method, various
chromatography and the like).
[0143] The "salt" in the specification of the present application
is not specifically limited so far as it forms a salt with the
compound according to the present invention and is
pharmacologically accepted, and is preferably a salt of hydrogen
halide acid (for example, hydrofluorate, hydrochloride,
hydrobromate, hydroiodate and the like), a salt of an inorganic
acid (for example, sulfate, nitrate, perchlorate, phosphate,
carbonate, bicarbonate and the like), a salt of an organocarboxylic
acid (for example, a salt of acetic acid, a salt of trifluoroacetic
acid, a salt of oxalic acid, a salt of maleic acid, a salt of
tartaric acid, a salt of fumaric acid, a salt of citric acid, and
the like), a salt of an organosulfonic acid (for example,
methanesulfonate, trifluoromethanesulfonate, ethanesulfonate,
benzenesulfonate, toluenesulfonate, camphorsulfonate, and the
like), a salt of an amino acid (for example, a salt of aspartic
acid, a salt of glutamic acid, and the like), a quaternary ammonium
salt, an alkali metal salt (for example, sodium salt, potassium
salt and the like), an alkali earth metal salt (for example,
magnesium salt, calcium salt and the like), and the like.
Hydrochloride, a salt of oxalic acid, a salt of trifluoroacetic
acid, and the like are more preferable.
[0144] The compound represented by the fore-mentioned formula (I)
or a salt thereof, or a hydrate thereof can be formulated by an
ordinary method, and preferable preparations include tablets,
powders, granules, parvules, coated tablets, capsules, syrups,
troches, inhalants, suppositorium, injections, paste medicines, eye
ointments, eye drops, nasal drops, eardrops, poultices, lotions and
the like. For preparations, excipients, binders, disintegrants,
lubricants, colorants, and flavoring agents which are
conventionally used, if necessary, stabilizers, emulsifiers,
absorption accelerators, surfactants, pH regulators, antiseptics,
antioxidants and the like can be used. Ingredients which are
conventionally used for the raw materials of pharmaceutical
preparations can be formulated by a normal method. As these
ingredients, for example, there are listed animal and vegetable
oils such as soy bean flexure, tallow and synthetic glyceride;
hydrocarbons such as liquid paraffin, squalane and solid paraffin;
ester oils such as octyldodecyl myristate and isopropyl myristate;
higher alcohols such as cetostearyl alcohol and behenic alcohol;
silicone resins; silicone oils; surfactants such as polyoxyethylene
fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid
ester, polyoxyethylene sorbitan fatty acid ester,
polyoxyethylene-hardened castor oil and
polyoxyethylene-polyoxypropylene block copolymer; water-soluble
polymers such as hydroxy ethyl cellulose, polyacrylic acid,
carboxyvinyl polymer, polyethylene glycol, poly(vinyl pyrrolidone)
and methyl cellulose; lower alcohol such as ethanol and
isopropanol; polyvalent alcohols such as glycerin, propylene
glycol, dipropylene glycol and sorbitol; sugars such as glucose and
dextrose; inorganic powders such as silicic anhydride, aluminum
magnesium silicate and aluminum silicate; purified water and the
like. Specifically, as excipients used are: lactose, corn starch,
white sugar, dextrose, mannitol, sorbit, crystal cellulose, silicon
dioxide and the like; as binders used are: polyvinyl alcohol,
polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gum
tragacanth, gelatin, shellac, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, polypropylene
glycol-polyoxyethylene block copolymer, meglumine, calcium citrate,
dextrin, pectin and the like; as disintegrants used are: starch,
agar, gelatin powder, crystalline cellulose, calcium carbonate,
sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl
cellulose calcium and the like; as lubricants used are: magnesium
stearate, talc, polyethylene glycol, silica, hardened vegetable oil
and the like; as colorants used is: any colorant which is approved
to be added to pharmaceuticals; as flavoring agents used are: cocoa
powder, menthol, aroma powder, peppermint oil, borneol, cinnamon
powder and the like; as antioxidants used are: ascorbic acid,
a-tocopherol and the like which are approved to be added to
pharmaceuticals.
[0145] For example, (1) oral preparations are made as powders, fine
granules, granules, tablets, coated tablets, capsules etc.
according to a conventional method after adding the compound
according to the present invention, a salt thereof or a hydrate of
them, fillers, and further, if necessary, binders, disintegrants,
lubricants, colorants, flavoring agents etc. (2) In case of tablets
and granules, sugar coating and gelatin coating and additionally,
if necessary, appropriate coating are allowed to be carried out.
(3) In case of syrups, preparations for injection, eye drops and
the like, pH regulators, resolving aids, isotonizing agents and the
like, and if necessary, dissolution assistants, stabilizers,
buffers, suspending agents, antioxidants and the like are added and
formulated according to a conventional method. In case of the
preparations, a freeze-dry product can be also made, and injections
can be administered in vein, subcutis and a muscle. Preferable
examples of the suspending agent include methyl cellulose,
polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth
powder, carboxymethyl cellulose sodium, polyoxyethylene sorbitan
monolaurate and the like; preferable examples of the resolving aids
include polyoxyethylene hardened castor oil, polysorbate 80,
nicotinamide, polyoxyethylene sorbitan monolaurate and the like;
preferable examples of the stabilizer include sodium sulfite, meta
sodium sulfite, diethyl ether and the like; Preferable examples in
the preservative include methyl p-oxybenzoate, ethyl p-oxybenzoate,
sorbic acid, phenol, cresol, chlorocresol and the like. (4)
Further, in the case of external preparations, the preparation
process is not specifically limited, and the external preparations
can be produced by a conventional method. As the raw material of a
base drug used, various raw materials which are conventionally used
for pharmaceuticals, quasi drug, cosmetics and the like can be
used. For example, raw materials such as animal and vegetable oils,
a mineral oil, an ester oil, waxes, higher alcohols, fatty acids, a
silicone oil, a surfactant, phosphatides, alcohols, polyvalent
alcohols, water-soluble polymers, clay minerals, purified water and
the like are listed. According to requirement, a pH regulator, an
antioxidant, a chelating agent, antiseptic and fungicide, a
coloring agent, flavors and the like can be added. Further, if
necessary, ingredients having differential derivation action, blood
flow accelerator, antibacterial, antiphlogistine, cell activator,
vitamins, amino acids, a humectant, keratolysis medicine and the
like can be formulated. The dose of the pharmaceuticals according
to the present invention is different depending on the extent of
symptom, age, sexuality, body weight, administration form, modality
of salt, the difference of sensitiveness for medicine, the specific
modality of affection, but in the case of an adult, for oral
administration, approximately 30 .mu.g to 1000 mg per day in
general, preferably 100 .mu.g to 500 mg, and more preferably 100
.mu.g to 100 mg of the pharmaceutical is administered at one time
or several times. For injection administration, approximately 1 to
3000 .mu.g/kg in general, and preferably 3 to 1000 .mu.g/kg of the
pharmaceutical is administered at one time or several times.
[0146] The compound represented by the above formula (I) according
to the present invention, a salt thereof or a hydrate of them is
useful as a calcium antagonist and specifically, a neuron-selective
calcium antagonist. The compound according to the present invention
has a novel compound having a P/Q-type calcium channel and an
N-type calcium channel inhibiting activity, and is useful as an
agent for treating or preventing a disease against which a P/Q-type
calcium channel inhibitory action and an N-type calcium channel
inhibitory action are effective. Further, the compound represented
by the above formula (I) according to the present invention, a salt
thereof or a hydrate of them has a remarkably low extent of cell
affection in comparison with a conventional antagonist, and is a
safe calcium antagonist whose toxicity is reduced. Accordingly, the
compound according to the present invention, a salt thereof or a
hydrate of them is useful as a neural cell death depressor, a
cerebral neural cell demulcent, an agent for treating or preventing
neural disease and an analgesic. In particular, it is useful as an
agent for treating, preventing or improving acute ischemic stroke,
cerebral apoplexy, cerebral infarction, head trauma, cerebral
neural cell death, Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis, Huntington's disease, cerebral
circulation metabolic affection, cerebral dysfunction, pain, spasm,
schizophrenia, migraine, epilepsy, manic-depression, neural
degenerative diseases, cerebral ischemia, AIDS dementia
complications, edema, anxiety disorder, diabetic neuropathy,
cerebral vascular dementia, multiple sclerosis etc.
BRIEF DESCRIPTION OF DRAWINGS
[0147] FIG. 1 shows a HPLC chart in Reference Example 97.
[0148] FIG. 2 shows a HPLC chart in Reference Examples 100 and 101,
the spectrum of No. 1 in the drawing shows a spectrum in Reference
Example 100 and the spectrum of No. 2 shows a spectrum in Reference
Example 101, respectively.
[0149] FIG. 3 shows a HPLC chart in Reference Example 103.
EXAMPLES
[0150] Examples are shown below as the best modes for carrying out
the present invention, but those Reference Examples, Examples
(further, a pharmacologically acceptable salt thereof or a hydrate
of them, and the pharmaceutical containing thereof) and Test
Examples are only illustrative, and the compound according to the
present invention is not limited to specific examples below at any
case. Those skilled in the art can add various variations to not
only Examples shown below, but also the Scope of Claim for Patent
in the specification of the present application to carry out the
present invention to a maximum extent, and such variations are
included in the Scope of Claim for Patent in the specification of
the present application.
[0151] Further, the symbol "Z" used in Reference Examples or
Examples below means benzyloxycarbonyl group, and "HPLC" means high
performance liquid chromatography, respectively.
Reference Example 1
2-[(4-Cyano-5-methyl-4-phenyl)hexyl]-5-benzyl-2,5-diazabicyclo[2,2,1]hepta-
ne
[0152] 12
[0153] The title compound was obtained as a pale brown oil in
accordance with the method described in Example 15 (15%).
[0154] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.04-1.16 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.45-1.57 (m, 1H),
1.64 (dd, J=9.6 Hz, J=33.6 Hz, 2H), 1.94 (dt, J=4.4 Hz, J=12.4 Hz,
1H), 2.07-2.23 (m, 2H), 2.30-2.38 (m, 1H), 2.50-2.71 (m, 5H), 3.19
(d, J=14 Hz, 2H), 3.66 (q, J=14 Hz, 2H), 7.19-7.40 (m, 10H).
Reference Example 2
3-Methyl-2-(2-naphthyl)butyronitrile
[0155] 13
[0156] 3.00 g (17.9mmol) of 2-naphthylacetonitrile was dissolved in
10 ml of dimethyl sulfoxide, and 2.43 g (19.7 mmol) of
2-bromopropane, 330 mg (0.90 mmol, cat) of tetra-n-butylammonium
iodide and 10 ml of 50% potassium hydroxide were successively added
thereto. After completion of the reaction, brine was added, and the
mixture was extracted with ether. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 150 g of silica gel
(ethyl acetate:hexane=1:10), to give 2.42 g (11.6 mnol, 64.6%) of
the title compound as a yellow oil.
[0157] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.07 (d, J=6.8 Hz,
3H), 1.11 (d, J=6.8 Hz, 3H), 2.10-2.30 (m, 1H), 3.84 (d, J=3.84 Hz,
1H), 7.38 (dd, J=1.8 Hz, 8.6 Hz, 1H), 7.48-7.55 (m, 2H), 7.79-7.88
(m, 4H)
Reference Example 3
4-Cyano-5-methyl-4-(2-naphthyl)hexanol
[0158] 14
[0159] 1.00 g (4.78 mmol) of 3-methyl-2-(2-naphthyl)butyronitrile
was dissolved in 20 ml of dimethylformamide, 191 mg (4.78 mmol, 60%
by weight) of sodium hydride was added thereto, and the mixture was
heated. After 30 minutes, it was cooled to a room temperature, 0.93
ml (4.00 mmol) of (3-bromopropoxy)-tert-butyldimethylsilane was
added thereto. After completion of the reaction, brine was added
thereto, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium sulfate
and evaporated, to give a crude product. The crude product was
subjected to 50 g of silica gel (ethyl acetate:hexane=1:18), to
give 1.40 g of a mixture of the objective product, a raw material
and an impurity. The mixture was used for the following reaction
without purification. Namely, 1.40 g of the abve-mentioned crude
4-cyano-5-methyl-5-(2-naphthyl)hexanoxy-tert-butyldi- methylsilane
was dissolved in 20 ml of tetrahydrofuran, and 5 ml (5 mmol) of
tetraammonium fluoride was added thereto. After completion of the
reaction, brine was added thereto, and the mixture was extracted
with ethyl acetate. The organic layer was washed with an aqueous
saturated ammonium chloride and brine, dried over magnesium sulfate
and evaporated, to give a crude product. The crude product was
subjected to 50 g of silica gel (ethyl acetate:hexane=1:4), to give
590 mg (2.21 mmol, 46.2%, 2 steps) of the title compound as a
yellow oil.
[0160] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.80 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 1H), 1.27 (d, J=6.8 Hz, 3H), 1.57-1.69 (m, 1H),
2.02-2.12 (m, 1H), 2.20-2.37 (m, 2H), 3.58 (t, J=6.2 Hz, 2H), 7.38
(dd, J=2.0 Hz, 8.4 Hz, 1H), 7.48-7.56 (m, 2H), 7.84-7.91 (m, 3H),
7.95 (brd-s, 1H)
Reference Example 4
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-tert-butoxvcarbonylaminopyrrolidine
[0161] 15
[0162] 2.76 g (8.44 mmol) of 4-cyano-5-methyl-4-phenylhexyl iodide
was dissolved in 50.0 ml of acetonitrile, 1.29 ml (9.28 mmol) of
triethylamine and 1.88 g (10.1 mmol) of
3-tert-butoxycarbonylaminopyrroli- dine were added thereto, and the
mixture was heated to 60.degree. C. After completion of the
reaction, the mixture was partitioned between ethyl acetate and
brine. The organic layer was dried over magnesium sulfate, and then
evaporated, to give a crude product. The crude product was
subjected to 50 g of Cromatorex NH silica gel (ethyl
acetate:hexane=2:1), to give 2.97 g (7.76 mmol, 91.3%) of the title
compound as a pale yellow syrup.
[0163] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.8 Hz, 3H), 1.05-1.25 (m, 1H), 1.43 (s, 9H),
1.50-1.65 (m, 2H), 1.88-2.00 (m, 1H), 2.00-2.28 (m, 4H), 2.28-2.60
(m, 4H), 2.65-2.70 (m, 1H), 4.05-4.20 (brd-s, 1H), 4.82-4.95
(brd-s, 1H), 7.26-7.59 (m, 5H)
Reference Example 5
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-aminopyrrolidine
[0164] 16
[0165] 2.36 g (6.12 mmol) of
1-[(4-cyano-5-methyl-4-phenyl)lhexyl]-3-tert--
butoxycarbonylaminopyrrolidine was dissolved in a mixed solution of
5 ml of tetrahydrofuran and 10 ml of methanol, and a 4N hydrogen
chloride-ethyl acetate solution was added thereto. After completion
of the reaction, the mixture was adjusted to basic with a 2N
aqueous sodium hydroxide, and extracted with chloroform. The
organic layer was dried over magnesium sulfate, and then
evaporated, to give 1.66 g (5.82 mmol, 95.1%, an orange syrup) of a
crude product.
[0166] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.4,
3H), 1.20 (d, J=6.8, 3H), 1.08-1.24 (m, 1H), 1.42-1.62 (m, 2H),
1.84-2.00 (m, 3H), 2.08-2.28 (m, 4H), 2.32-2.48 (m, 3H), 2.58-2.67
(m, 2H), 3.42-3.51 (m, 1H), 7.26-7.40 (m, 5H)
Reference Example 6
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidine
[0167] 17
[0168] 700 mg (2.45 mmol) of
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-aminop- yrrolidine was
dissolved in 15 ml of methanol, 0.19 ml (2.85 mmol) of
acrylonitrile was added thereto, and the mixture was heated under
reflux. After completion of the reaction, the mixture was
evaporated, to give a crude product. The crude product was
subjected to 20 g of Cromatorex NH silica gel (ethyl acetate 100%),
to give 775 mg (2.29 mmol, 93.5%) of the title compound as an
orange syrup.
[0169] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.07-1.24 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.08-1.24 (m, 1H),
1.46-1.62 (m, 2H), 1.86-1.96 (m, 1H), 2.04-2.24 (m, 4H), 2.28-2.46
(m, 4H), 2.46-2.62 (m, 2H), 2.49 (t, J=6.8 Hz 2H), 2.85 (t, J=6.8
Hz, 2H), 3.22-3.30 (m, 1H), 7.26-7.40 (m, 5H)
Reference Example 7
3-Fluorophenoxyacetaldehyde
[0170] 18
[0171] 2.00 g (17.8 mmol) of m-fluorophenol was dissolved in 50 ml
of dimethylformamide, 785 mg (19.6 mmol, 60% by weight, mineral) of
sodium hydride and 3.21 ml (21.3 mmol) of
bromoacetaldehydediethylacetal were successively added thereto, and
the mixture was heated to 60.degree. C. After completion of the
reaction, brine was added thereto and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over magnesium sulfate and then evaporated, to give a crude
product. The crude product was subjected to 105 g of Cromatorex NH
silica gel (ethyl acetate:hexane=1:40), to give 3.17 g (13.9 mmol,
78.1%) of the title compound as a yellow oil.
[0172] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.25 (t, J=7.0 Hz, 6H),
3.55-3.82 (m, 4H), 3.99 (d, J=5.0 Hz, 2H), 4.82 (t, J=5.0 Hz, 1H),
6.61-6.72 (m, 3H), 7.17-7.25 (m, 1H)
[0173] 1.68 g (7.38 mmol) of the above acetal was dissolved in 30
ml of acetone and 20 mL of a 2.5N hydrochloric acid, and the
mixture was heated. After completion of the reaction, the mixture
was extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate and then evaporated, to give
800 mg of a crude product which contains the objective compound
below. The crude product was subjected to the above-mentioned
reaction without purification. 19
Reference Example 8
1-Benzyl-3-[N-(2-cyanoethyl)amino]pyrrolidine
[0174] 20
[0175] 4.00 g (22.7 mmol) of 1-benzyl-3-aminopyrrolidine was
dissolved in 70 ml of methanol, 1.49 ml (22.7 mmol) of
acrylonitrile was added thereto, and the mixture was heated to
70.degree. C. After completion of the reaction, the reaction
solution was evaporated, and the resulting crude product was
subjected to 100 g of Cromatorex NH silica gel (ethyl acetate
100%), to give 4.60 g (20.1 mmol, 88.4%) of the title compound as a
yellow oil.
[0176] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.54-1.66 (m, 1H),
2.10-2.22 (m, 1H), 2.40-2.60 (m, 2H), 2.49 (t, J=6.8 Hz, 2H),
2.67-2.78 (m, 2H), 2.86 (t, J=6.8 Hz, 2H), 3.30-3.38 (m, 1H),
3.57-3.73 (m, 2H), 7.22-7.36 (m, 5H)
Reference Example 9
1-Benzyl-3-[N-(2-cyanoethyl)-N-{2-(4-cyanophenoxy)ethyl}amino]pyrrolidine
[0177] 21
[0178] 2.03 g (8.87 mmol) of
1-benzyl-3-[(N-(2-cyanoethyl)amino)pyrrolidin- e was dissolved in
50 ml of dichloroethane, and 1.30 g (8.06 mmol) of
4-cyanophenoxyacetaldehyde separately synthesized, 1.02 ml (17.7
mmol) of acetic acid and 2.56 g (12.1 mmol) of sodium
triacetoxyborohydride were successively added thereto. After
completion of the reaction, the mixture was adjusted to basic with
a 2N aqueous sodium hydroxide, and extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium
sulfate and evaporated, to give a crude product. The crude product
was subjected to 250 g of Cromatorex NH silica gel (ethyl
acetate:hexane=2:3), to give 2.39 g (6.38 mmol, 79.2%) of the title
compound as a yellow syrup.
[0179] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.70-1.84 (m, 1H),
2.03-2.14 (m, 1H), 2.40-2.54 (m, 1H), 2.47 (t, J=6.8 Hz, 2H),
2.55-2.68 (m, 2H), 2.76-2.88 (m, 1H), 2.91-3.09 (m, 4H), 3.48-3.68
(m, 2H), 3.64-3.74 (m, 1H), 4.03 (t, J=5.6 Hz, 2H), 6.9 (t, J=9.2
Hz, 2H), 7.24-7.40 (m, 5H), 7.57 (t, J=9.2 Hz, 2H)
Reference Example 10
3-[(N-(2-Cyanoethyl)-N-{2-(4-cyanophenoxy)ethyl}amino]pyrrolidine
[0180] 22
[0181]
1-Benzyl-3-[(N-(2-cyanoethyl)-N-{2-(4-cyanophenoxy)ethyl}amino)pyrr-
olidine was dissolved in dichloroethane, AceCl (0.84 ml, 7.66 mmol)
was added thereto, and the mixture was heated under reflux. After
about one hour, AceCl (0.12 ml) was added thereto, and the mixture
was continued to be heated. After completion of the reaction, the
mixture was evaporated. To the residue was added 30 ml of methanol
was added thereto, followed by heating under reflux. After one
hour, the reaction solution was evaporated. The residue was
extracted with 2N hydrochloric acid, washed with ether, and then
adjusted to pH 11-12 with a 2N aqueous sodium hydroxide. The
mixture was extracted with ethyl acetate, dried over magnesium
sulfate evaporated, to give a crude product. The crude product was
subjected to 50 g of Cromatorex NH silica gel (ethyl
acetate:methanol=1:0-3:1), to give 1.12 g (3.93 mmol, 61.6%) of the
title compound as a yellow oil.
[0182] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.64-1.76 (m, 1H),
1.94-2.06 (m, 1H), 2.52 (t, J=6.8 Hz, 2H), 2.56-2.70 (m, 2H),
2.77-2.86 (m, 1H), 2.91-3.20 (m, 5H), 3.36-3.51 (m, 1H), 4.08 (t,
J=5.6 Hz, 2H), 6.96 (t, J=9.2 Hz, 2H), 7.60 (t, J=9.2 Hz, 2H)
Reference Example 11
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(methoxycarbonyl)methyl]piperazine
[0183] 23
[0184] 1.00 g (3.50 mmol) of
1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazin- e and 0.54 ml (3.85
mmol) of triethylamine were dissolved in 25 ml of tetrahydrofuran.
Under ice-cooling, 0.35 ml (3.85 mmol) of methyl bromoacetate was
added drop wise there into. After completion of there action, brine
was added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium sulfate
and evaporated, to give a crude product. The crude product was
subjected to 50 g of Cromatorex NH silica gel (ethyl
acetate:hexane=1:2), to give 1.22 g (3.41 mmol, 97.5%) of the title
compound as an orange oil.
[0185] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.20 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.48-1.64 (m, 1H),
1.84-1.93 (m, 1H), 2.06-2.18 (m, 2H), 2.24-2.31 (m, 2H), 2.31-2.46
(m, 4H), 2.46-2.60 (m, 4H), 3.19 (s, 2H), 3.71 (s, 3H), 7.24-7.39
(m, 5H)
Reference Example 12
3-Fluorobenzamideoxime
[0186] 24
[0187] To 200 ml of an ethanol solution of 10.0 g (82.6 mmol) of
3-fluorobenzcyanide were added 8.61 g (124 mmol) of hydroxylamine
hydrochloride and 22.8 g (165 mmol) of potassium carbonate,
followed by heating under ref lux. After completion of the
reaction, the mixture evaporated. To the residue was added brine,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with brine, dried over magnesium sulfate and evaporated,
to give a crude product. The crude product was subjected to 100 g
of silica gel (ethyl acetate:hexane=1:2-1:4), to give 8.00 g (51.9
mmol, 62.8%) of the title compound as a yellow solid.
[0188] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.75-4.85 (m, 2H),
7.09-7.59 (m, 4H)
Reference Example 13
N-Z-4-Piperidineethanol
[0189] 25
[0190] 4.70 g (36.4 mmol) of 4-piperidineethanol and 10.0 g (72.8
mmol) of potassium carbonate were dissolved in ether (50 ml) and
water (50 ml). Under ice-cooling, ZCl (4.44 ml, 25.0 mmol) was
dissolved in 30 ml of ether, and the solution was added dropwise
thereinto. The physical property of the resulting title compound is
described below. After completion of the reaction, brine was added
and the mixture was extracted with ether. The organic layer was
washed with brine and an aqueous saturated ammonium chloride, dried
over magensium sulfate and evaporated, to give a crude product. The
crude product was subjected to 100 g of silica gel (ethyl
acetate:hexane=1:2), to give 5.48 g (20.8 mmol, 57.2%) of the title
compound as a colorless oil.
[0191] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.05-1.25 (m, 2H),
1.40-1.75 (m, 5H), 2.70-2.85 (m, 2H), 3.71 (t, J=6.59 Hz, 2H),
4.10-4.25 (m, 2H), 5.12 (s, 2H), 7.28-7.39 (m, 5H)
Reference Example 14
1-Benzyloxycarbonyl-4-[2-(4-fluorophenoxy)ethyl]piperidine
[0192] 26
[0193] 2.00g (7.60mmol) of N-Z-4-piperidineethanol, 1.70 g (15.2
mmol) of 4-fluorophenol and 2.39 g (9.12 mmol) of
triphenylphosphine were dissolved in 50 ml of tetrahydrofuran, and
the mixture was ice-cooled. After 10 minutes, 1.44 ml (9.12 mmol)
of diethylazocarboxylate was added dropwise thereinto, and then the
mixture was stirred at room temperature. After completion of the
reaction, brine was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
magnesium sulfate and evaporated, to give a crude product. The
crude product was subjected to 100 g of silica gel (ethyl
acetate:hexane=1:3), to give 2.19 g (6.12 mmol, 80.6%) of the title
compound as a colorless oil.
[0194] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.10-1.30 (m, 2H),
1.65-1.80 (m, 5H), 2.70-2.90 (m, 2H), 3.96 (t, J=6.0 HZ, 2H),
4.10-4.28 (m, 2H), 5.13 (s, 2H), 6.79-6.84 (m, 2H), 6.93-6.99 (m,
2H), 7.28-7.38 (m, 5H)
Reference Example 15
4-[2-(4-Fluorophenoxy)ethyl]piperidine
[0195] 27
[0196] 2.19 g (6.12 mmol) of
1-benzyloxycarbonyl-4-[2-(4-fluorophenoxy)eth- yl]piperidine was
dissolved in 40 ml of methanol, 300 mg of 10% palladium-carbon was
added, and replacement with hydrogen was carried out. After
completion of the reaction, the mixture was filtered, and the
filtrate was evaporated, to give a crude product. The crude product
was subjected to 50 g of Cromatorex NH silica gel (ethyl
acetate:hexane=1:3-ethyl acetate:methanol=6:1), to give 1.30 g
(5.82 mmol, 95.1%) of the title compound as a yellow oil.
[0197] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.10-1.23 (m, 2H),
1.60-1.77 (m, 5H), 2.59 (dt, J=2.4 Hz, 12.2 Hz, 2H), 3.96 (t, J=6.0
HZ, 2H), 4.10-4.28 (m, 2H), 5.13 (s, 2H), 6.79-6.85 (m, 2H),
6.92-6.99 (m, 2H)
Reference Example 16
1-Benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine
[0198] 28
[0199] 5.00 g (36.4 mmol) of 3-pyridinepropanol was dissolved in
150 ml of acetonitrile, 4.55 ml (38.3 mmol) of benzylbromide was
added, and the mixture was heated at 70.degree. C. After 2 hours,
heating was stopped, and the mixture was evaporated. Then, the
residue was dissolved in 100 ml of methanol, and the mixture was
cooled to 0.degree. C. 4.12 g (109 mmol) of sodium borohydride was
added thereto. After completion of the reaction, 50 ml of water was
added thereto, and the mixture was evaporated. Then, the residue
was partitioned between ethyl acetate and brine. After drying the
organic layer over magnesium sulfate, the mixture was evaporated,
to give a crude product. The crude product was subjected to 150 g
of Cromatorex NH silica gel (ethyl acetate:hexane=1:6-1:1), to give
6.48 g (28.0 mmol, 77.0%) of the title compound as a yellow
oil.
[0200] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.65-1.74 (m, 2H),
2.02-2.13 (m, 4H), 2.55 (t, J=6.0 Hz, 2H), 2.93-2.98 (m, 2H), 3.57
(s, 2H), 3.64 (t, J=6.4 Hz, 2H), 5.38-5.42 (m, 1H), 7.22-7.37 (m,
5H)
Reference Example 17
1-Benzyl-4-hydroxypropylpiperidine
[0201] 29
[0202] 6.48 g of
1-benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine was dissolved
in 60 ml of methanol, 88 mg of PtO.sub.2 was added, and atmosphere
was replaced with hydrogen. After completion of the reaction, the
mixture was filtered, and the filtrate was evaporated, to give 4.50
g (19.3 mmol, 68.9%) of the title compound as a yellow oil.
[0203] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.16-1.33 (m, 5H),
1.33-1.41-(brd-s, 1H), 1.53-1.74 (m, 4H), 1.87-1.98 (m, 2H),
2.83-2.90 (m, 2H), 3.48 (s, 2H), 3.62 (t, J=6.4 Hz, 2H), 7.16-7.27
(m, 5H)
Reference Example 18
1-Benzyl-4-methanesulfonyloxypropylpiperidine
[0204] 30
[0205] 2.58 g (11.1 mmol) of 1-benzyl-4-hydroxypropylpiperidine and
3.26 ml (23.4 mmol) of triethylamine were dissolved in 50 ml of
tetrahydrofuran, and 1.67 ml (21.6 mmol) of methanesulfonyl
chloride was added dropwise. After completion of the reaction, the
mixture was partitioned between ethyl acetate and brine. The
organic layer was dried over magnesium sulfate, and then
evaporated, to give a crude product. The crude product was
subjected to 50 g of Cromatorex NH silica gel (ethyl
acetate:hexane=1:1), to give 2.90 g (9.31 mmol, 83.9%) the title
compound as a yellow oil. The physico-chemical data of the target
compound was as indicated below.
[0206] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.18-1.37 (m, 5H),
1.58-1.68 (m, 2H), 1.71-1.80 (m, 2H), 1.88-1.97 (m, 2H), 2.84-2.90
(m, 2H), 3.00 (s, 3H), 3.48 (s, 2H), 4.21 (t, J=6.8 Hz, 2H),
7.13-7.32 (m, 5H)
Reference Example 19
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperidine
[0207] 31
[0208] 2.43 g (6.49 mmol) of
1-benzyl-4-[(4-cyano-5-methyl-4-phenyl)hexyl]- piperidine was
dissolved in 30 ml of 1,2-dichloroethane, 0.85 ml (7.79 mmol) of
AceCl was added thereto, and the mixture was heated under reflux.
After 45 minutes, the mixture was evaporated. Then, 30 ml of
methanol was added thereto, and the mixture was heated under reflux
again. After completion of the reaction, the mixture was
evaporated, extracted with water and washed with ether. The
resulting aqueous layer was adjusted to basic, and then the mixture
was partitioned between ethyl acetate and brine. The organic layer
was dried over magnesium sulfate, and then evaporated, to give 1.62
g (5.69 mmol, 87.7%) a yellow crude product. The physico-chemical
data of the title compound was as indicated below.
[0209] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.86-1.04 (m, 3H), 1.07-1.28 (m, 3H), 1.19 (d, J=6.4 Hz, 3H),
1.29-1.44 (m, 1H), 1.48-1.58 (m, 2H), 1.74-1.85 (m, 1H), 2.04-2.14
(m, 2H), 2.49 (dt, J=2.4 Hz, 12.0 Hz, 2H), 2.95-3.02 (m, 2H),
7.26-7.40 (m, 5H)
Reference Example 20
3-Cyano-3-(2-thienyl)propanol
[0210] 32
[0211] Under a nitrogen atmosphere, sodium borohydride (650 mg) was
added in an ice bath to a DMF solution (25 ml) of
thiophene-2-acetonitrile (1 g) and
(3-bromopropoxy)-tert-butyldimethylsilane (2.06 g). After 20
minutes, the organic layer was separated by adding an aqueous
saturated ammonium chloride and ethyl acetate were added thereto.
The resulting organic layer was washed with water and brine, and
dried over anhydrous magnesium sulfate. After filtering off the
drying agent, the mixture was evaporated. The resulting residue was
dissolved in acetonitrile (20 mL), a 1 M tetrabutylammonium
fluoride/tetrahydrofuran solution (9.7 ml) was added thereto, and
the mixture was stirred at a room temperature. After 18 hours, the
organic layer was separated by adding water and ethyl acetate. The
resulting organic layer was rinsed with water and brine, and dried
over magnesium sulfate. After filtering off the drying agent, the
mixture was evaporated. The resulting residue was purified by
silica gel column chromatography (hexane:ethyl acetate system), to
give the title compound as a red oil (637 mg, 43%).
[0212] .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 2.08-2.16 (m, 1H),
3.08 (t, J=7.0 Hz, 2H), 3.75 (t, J=7.0 Hz, 2H), 4.15-4.20 (m, 1H),
7.14 (dd, J=3.8 Hz, 4.8 Hz, 1H), 7.65 (dd, J=0.8 Hz, 4.8 Hz, 1H),
7.75 (dd, J=0.8 Hz, 3.8 Hz, 1H).
Reference Example 21
2-[(3-Cyano-3-phenyl)propyl]-1,3-dioxolane
[0213] 33
[0214] Under a nitrogen atmosphere, sodium amide (1.11 g) was added
to a tetrahydrofuran solution (25 ml) of phenylacetonitrile (3 g).
After 30 minutes, a tetrahydrofuran solution (25 ml) of
2-(2-bromoethyl)-1,3-dioxo- lane (4.64 g) was added to the reaction
solution through a dropping funnel. After stirring 2 hours, an
aqueous saturated ammonium chloride and ethyl acetate were added
thereto, to separate the organic layer. The resulting organic layer
was washed with water and brine, and dried over anhydrous magnesium
sulfate. After filtering off the drying agent, the mixture was
evaporated. The resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate system), to give the title
compound (3.47 g, 62%).
[0215] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.75-1.90 (m, 2H),
1.95-2.10 (m, 2H), 3.80-4.00 (m, 5H),4.91 (t, J=4.4 Hz, 1H),
7.30-7.42 (m, 5H).
Reference Example 22
Ethyl 4-methyl-3-phenylpentanoate
[0216] 34
[0217] Under a nitrogen atmosphere, ethyl
trimethylsilylethylacetate (5.19 g) was added at -78.degree. C. to
a solution of a lithium diisopropylamide/tetrahydrofuran solution
(1.5 M, 21.6 mL) added to tetrahydrofuran solution (100 mL). After
20 minutes, a tetrahydrofuran solution (10 ml) of isobutyrophenone
(4.0 g) was added thereto, and the temperature of the mixture was
naturally returned to room temperature. After stirring 18 hours,
sodium bisulfate monohydrate (0.6 g) was added and the mixture was
stirred. Further, after 10 minutes, the organic layer was separated
by adding a 0.2N hydrochloric acid solution (250 mL) and ethyl
acetate (200 mL) thereto. The resulting organic layer was washed
with water and brine, and dried over anhydrous magnesium sulfate.
After filtering off the drying agent, the mixture was evaporated.
756 Mg among the resulting crude product (7.9 g) was dissolved in
methanol (5 mL), a catalytic amount of 10% palladium carbon (9.5
mg) was added, and the mixture was stirred under hydrogen
atmosphere. After 4 hours, the catalyst was filtered off, and the
filtrate was concentrated. The resulting residue was purified by
silica gel column chromatography (hexane:ethyl acetate system), to
give the title compound as a colorless oil (350 mg).
[0218] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.75 (d, J=6.4 Hz,
3H), 0.95 (d, J=6.8 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H), 1.80-1.90 (m,
1H), 2.58 (dd, J=10 Hz, 15.2 Hz, 1H), 2.77 (dd, J=5.6 Hz, 15.2 Hz,
1H), 2.84-2.91 (m, 1H), 7.12-7.29 (m, 5H).
Reference Example 23
4-Methyl-3-phenylpentanol
[0219] 35
[0220] Under a nitrogen atmosphere, ethyl 4-methylpentanoate (350
mg) was dissolved in tetrahydrofuran (10 mL) at -78.degree. C., a
lithium aluminum hydride/tetrahydrofuran solution (1.0 M, 1.58 mL)
was added, and the mixture was stirred. While the temperature of
the mixture was naturally returned to room temperature, the mixture
was stirred, and after 1.5 hours, water (0.05 mL), a 2N aqueous
sodium hydroxide (0.05 mL) and water (0.15 mL) were successively
added thereto, and the mixture was stirred. Further, diethyl ether
was added thereto, and then the resulting insoluble matters were
filtered off and the filtrate was evaporated. The resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate system), to give the title compound as a colorless oil (257
mg, 42%: 2 steps).
[0221] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.73 (d, J=6.8 Hz,
3H),0.97 (d, J=6.4 Hz, 3H), 1.78-1.88 (m, 2H), 2.04-2.14 (m, 1H),
2.36-2.46 (m, 1H), 3.34-3.54 (m, 2H), 7.20-7.16 (m, 2H), 7.17-7.22
(m, 1H), 7.25-7.31 (m, 2H).
Reference Example 24
4-Methyl-3-phenylpentanoic acid
[0222] 36
[0223] Under a nitrogen atmosphere, sodium hydride (60%, 1.2 g) was
added at 0.degree. C. to a tetrahydrofuran solution (30 mL) of
tert-butyldiethylphosphonoacetate (4.9 g). After 10 minutes, the
temperature of the mixture was naturally returned to room
temperature, and the mixture was stirred. After 1 hour, a
tetrahydrofuran solution (10 mL) of isobutyrophenone (4.0 g) was
added. After stirring for 13 hours, the organic layer was separated
by adding water and ethyl acetate thereto. The resulting organic
layer was washed with water and brine, and dried over anhydrous
magnesium sulfate. After filtering off the drying agent, the
mixture was evaporated. 5.48 g among the resulting crude product
(6.1 g) was dissolved in methanol (30 mL), a catalytic amount of
10% palladium carbon (250 mg) was added, and the mixture was
reacted under pressuring by hydrogen (3.9 kg/cM.sup.2). After 1.3
hours, the catalyst was filtered off, and then the filtrate was
concentrated. The resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate system). The resulting
product (3.0 g) was dissolved in acetone (50 mL) and 5N
hydrochloric acid (20 mL), and the mixture was stirred for 3 hours
under reflux conditions. The solution was evaporated, to give the
title compound as a reddish yellow oil (1.96 g, 58%: 3 steps).
[0224] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.75 (d, J=6.8 Hz,
3H), 0.94 (d, J=6.8 Hz, 3H), 1.80-1.91 (m, 1H), 2.62 (dd, J=10.0
Hz, 15.6 Hz, 1H) 2.80 (dd, J=5.6 Hz, 15.6 Hz, 1H), 2.82-2.91 (m,
1H), 7.11-7.16 (m, 2H), 7.13-7.22 (m, 1H), 7.23-7.29 (m, 2H).
Reference Example 25
N-Methyl-N-methoxy-4-methyl-3-phenylpentaneamide
[0225] 37
[0226] Under a nitrogen atmosphere, a dimethylformamide solution of
diethyl cyanophosphonate (1.97 g) and triethylamine (1.63 mL) was
added to a tetrahydrofuran solution (24 mL) of
4-methyl-3-phenyl-pentanoic acid (1.96 g), N,O-dimethylhydroxyamine
hydrochloride (1.18 g) and triethylamine (1.63 mL) at 0.degree. C.
After 19 hours, the organic layer was separated by adding diethyl
ether and an aqueous saturated ammonium chloride thereto. The
resulting organic layer was washed with water and brine, and dried
over anhydrous magnesium sulfate. After filtering off the drying
agent, the mixture was evaporated. The resulting residue was
purified by silica gel column chromatography (hexane:ethyl acetate
system), to give the title compound (1.13 g, 47%).
[0227] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.6 Hz,
3H), 0.97 (d, J=6.6 Hz, 3H), 1.84-1.96 (m, 1H), 2.74-2.86 (m, 2H),
2.97-3.05 (m, 1H), 3.06 (s, 3H), 3.57 (s, 3H), 7.15-7.21 (m, 3H),
7.24-7.29 (m, 2H).
Reference Example 26
4-Methyl-3-phenylpentanal
[0228] 38
[0229] Under a nitrogen atmosphere,
N-methyl-N-methoxy-4-methyl-3-phenyl-p- entaneamide (215 mg) was
dissolved in tetrahydrofuran (9.1 mL) at -78.degree. C., and a
diisobutylaluminum hydride/toluene solution (1.5 M, 1.2 mL) was
added. After one hour, methanol (3 mL) was added to the reaction
system, the temperature of the mixture was returned to room
temperature after termination of foaming, and the mixture was
continuously stirred. The organic layer was separated by adding
diethyl ether, water and a 1N aqueous hydrochloric acid thereto.
The resulting organic layer was washed with water and brine, and
dried over anhydrous magnesium sulfate. After filtering off the
drying agent, the mixture was evaporated, to give the title
compound as a colorless oil (200 mg). The resulting compound was
used for the next reaction without purification.
[0230] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.6 Hz,
3H), 0.95 (d, J=6.8 Hz, 3H), 1.82-1.92 (m, 1H), 2.70-2.84 (m, 2H),
2.90-2.98 (m, 1H), 7.13-7.32 (m, 5H), 9.59-9.61 (m, 1H).
Reference Example 27
4-Methyl-3-phenylhexanal
[0231] 39
[0232] Under a nitrogen atmosphere, a
n-butyllithium/tetrahydrofuran solution (1.53 M, 1.2 mL) was added
to a tetrahydrofuran solution of (methoxymethyl)
triphenylphosphonium chloride (627 mg) at -78.degree. C., and then
the temperature of the mixture was raised to 0.degree. C. After 20
minutes, the outer temperature was lowered to -78.degree. C., and
then 4-methyl-3-phenyl-pentanal (200 mg) was added thereto together
with tetrahydrofuran (4 mL). After 45 minutes, the temperature of
the mixture was returned to room temperature, and the mixture was
further stirred for 20 minutes. The organic layer was separated by
adding diethyl ether and an aqueous saturated ammonium chloride
thereto. The resulting organic layer was washed with water and
brine, and dried over anhydrous magnesium sulfate. After filtering
off the drying agent, the mixture was evaporated, to give the title
compound as a colorless oil (200 mg). The resulting compound was
dissolved in isopropanol(2 mL)/water(2 mL), p-toluenesulfonic acid
(6 mg) was added thereto, and then the reaction was carried out for
8.5 hours under refluxing. The organic layer was separated by
adding diethyl ether and an aqueous saturated ammonium chloride
thereto. The resulting organic layer was washed with water and
brine, and dried over anhydrous magnesium sulfate. After filtering
off the drying agent, the mixture was evaporated. The residue was
purified by NH silica gel column chromatography (hexane:ethyl
acetate system), to give the title compound as a colorless oil (103
mg, 59%, 3 steps).
[0233] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.72 (d, J=6.8 Hz,
3H), 0.99 (d, J=6.6 Hz, 3H), 1.76-1.90 (m, 2H), 2.12-2.28 (m, 4H),
7.07-7.10 (m, 2H), 7.18-7.22 (m, 1H), 7.26-7.35 (m, 2H), 9.63-9.65
(m, 1H).
Reference Example 28
1-[(2-Vinyl-2-(4-fluorophenoxy)ethyl]piperazine
[0234] 40
[0235] The title compound was synthesized in accordance with the
method of Example 104 described in JP-A 11-206862.
[0236] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.50-2.60 (m, 4H),
2.59 (dd, J=4.0 Hz, 13.6 Hz, 1H), 2.77 (dd, J=7.5 Hz, 13.6 Hz, 1H),
2.86-2.90 (m, 4H), 4.70-4.76 (m, 1H), 5.22 (brd, J=10.6 Hz, 1H),
5.27 (brd, J=17.2 Hz, 1H), 5.87 (ddd, J=5.7 Hz, 10.6 Hz, 17.2 Hz,
1H), 6.82-6.89 (m, 2H), 6.89-6.97 (m, 2H).
Reference Example 29
4-Bromo-2-thiophenecarboaldehyde dimethylacetal
[0237] 41
[0238] (90%) 4-Bromo-2-thiophenecarboaldehyde (10.0 g) was
dissolved in methanol (50 ml), and an ion-exchange resin, Amberlite
IR120B (5 g) was added thereto. After heating under reflux for 10
hours, the mixture was cooled as it was to room temperature, and
the ion-exchange resin was filtered off. The filtrate was
evaporated, and the resulting residue was purified by (NH) silica
gel column chromatography (hexane), to give the title compound as a
pale yellow oil (8.93 g, 72%).
[0239] .sup.1H-NMR (400 MHz, CDCl.sub.3) (3.36 (s, 6H), 5.59 (d,
J=0.8 Hz, 1H), 7.00 (dd, J=0.8 Hz, J=1.6 Hz, 1H), 7.20 (d, J=1.6
Hz, 1H).
Reference Example 30
3-Cyano-5-thiophenecarboaldehyde
[0240] 42
[0241] Method 1)
[0242] 4-Bromo-2-thiophenecarboaldehyde dimethylacetal (6.82 g) was
dissolved in DMF (50 ml), and copper cyanide (4.29 g) was added
thereto. After heating under reflux for 3 hours, the mixture was
cooled as it was to room temperature and ethyl acetate was added
thereto. The mixture was washed with an aqueous ammonia, water,
0.1N aqueous hydrochloric acid and brine, dried over anhydrous
magnesium sulfate and then evaporated, to give an oil. The residue
was dissolved in an 80% aqueous acetic acid (100 ml), and the
mixture was stirred at 0.degree. C. for one hour. The mixture was
washed with brine. After cooling as it was to room temperature,
ethyl acetate was added thereto. The mixture was washed with an
aqueous saturated sodium bicarbonate and brine, dried over
anhydrous magnesium sulfate and then evaporated. The resulting
residue was purified by silica gel column chromatography
(hexane/ethyl acetate system), and then recrystallized from ethyl
acetate-hexane, to give the title compound as pale yellowish white
crystals (2.44 g, 62%).
[0243] Method 2)
[0244] 4-Bromo-2-thiophenecarboaldehyde (5.00 g) was dissolved in
DMF (40 ml), and copper cyanide (3.52 g) was added thereto. After
heating under reflux for 3 hours, the mixture was cooled as it was
to room temperature and ethyl acetate was added thereto. The
mixture was washed with an aqueous ammonia, water, 0.1N aqueous
hydrochloric acid and further brine, dried over anhydrous magnesium
sulfate and then evaporated. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate system), and
then recrystallized from ethyl acetate-hexane, to give the title
compound as pale yellowish white crystals (2.30 g, 71%).
[0245] The physico-chemical data of the title compound was as
indicated below.
[0246] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (d, J=1.2 Hz,
1H), 8.27 (d, J=1.2 Hz, 1H), 9.95 (d, J=1.2 Hz, 1H).
Reference Example 31
3-Cyano-5-(1-hydroxy-2-methylpropyl)thiophene
[0247] 43
[0248] 3-Cyano-5-thiophenecarboaldehyde (2.00 g) was dissolved in
anhydrous ether (100 ml) and anhydrous tetrahydrofuran (THF) (20
ml), and an ether solution (10.9 ml) of (2.0 M) isopropylmagnesium
chloride was added thereto. After stirring at 0.degree. C. for 2
hours, ethyl acetate was added thereto. The mixture was washed with
an aqueous saturated ammonium chloride and further brine, dried
over anhydrous magnesium sulfate and then evaporated. The resulting
residue was purified by silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound as a pale
yellow oil (1.25 g, 47%).
[0249] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.00 (d, J=6.8 Hz, 3H), 1.99 (sext, J=6.8 Hz, 1H), 2.42 (d,
J=4 Hz, 1H), 4.68 (dd, J=4 Hz, J=6 Hz, 1H), 7.08-7.10 (m, 1H), 7.85
(d, J=1.6 Hz, 1H).
Reference Example 32
3-Cyano-5-(1-oxo-2-methylpropyl)thiophene
[0250] 44
[0251] Oxalyl chloride (0.70 ml) was dissolved in methylene
chloride (10 ml), and then the mixture was cooled to -60 to
-50.degree. C. Dimethyl sulfoxide (0.57 ml) was added thereto, and
the mixture was stirred for 2 minutes. Further, a methylene
chloride solution (6 ml) of
3-cyano-5-(1-hydroxy-2-methylpropyl)thiophene (1.21 g) was added
thereto at -60 to -50.degree. C., and the mixture was stirred for
15 minutes. Then, triethylamine (4.65 ml) was added, and the
temperature of the mixture was raised to a room temperature. Ethyl
acetate was added, and the mixture was washed with water and
further brine, dried over anhydrous magnesium sulfate and then
evaporated. The resulting residue was recrystallized from ethanol,
to give the title compound as pale yellowish white crystals (0.59
g) Further, the filtrate was purified by silica gel column
chromatography (hexane/ethyl acetate system), to give the title
compound (0.41 g, total yield: 1.00 g, 84%).
[0252] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (d, J=6.8 Hz,
6H), 3.36 (Qui, J=6.8 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 8.18 (d,
J=0.8 Hz, 1H).
Reference Example 33
[1-Cyano-1-(3-cyano-5-thienyl)-2-methylpropyl]diethylphosphate
[0253] 45
[0254] 3-Cyano-5-(1-oxo-2-methylpropyl)thiophene (0.90 g) was
dissolved in THF (50 ml), and a DMF solution (30.1 ml) of (0.5 M)
lithium cyanide and (90%) diethylcyanophosphonate (2.29 ml) were
added thereto. After stirring at room temperature for 30 minutes,
ethyl acetate and hexane were added thereto. The mixture was washed
with water and further brine, dried over anhydrous magnesium
sulfate and then evaporated. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate system), to
give the title compound as a pale yellow oil (1.72 g,
quantitatively).
[0255] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.96 (d, J=6.8 Hz,
3H), 1.27-1.34 (m, 9H), 2.49 (qui, J=6.8 Hz, 1H), 4.00-4.21 (m,
4H), 7.56 (d, J=1.2 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H).
Reference Example 34
3-Cyano-5-(1-cyano-2-methylpropyl)thiophene
[0256] 46
[0257]
[1-Cyano-1-(3-cyano-5-thienyl)-2-methylpropyl]diethylphosphate (45
mg) was dissolved in ethyl acetate (5 ml), (10%) palladium-carbon
(20 mg) was added, and hydrogenation was carried out at room
temperature and a normal pressure for 2 hours. The catalyst was
filtered off, and the filtrate was evaporated. The resulting
residue was purified by preparative thin layer silica gel column
chromatography (hexane/ethyl acetate system), to give the title
compound as a pale yellow oil (22 mg, 88%).
[0258] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.09 (d, J=6.8 Hz,
3H), 1.14 (d, J=6.8 Hz, 3H), 2.20 (sext, J=6.8 Hz, 1H), 3.96 (d,
J=6.8 Hz, 1H), 7.26 (s, 1H), 7.91 (d, J=1.6 Hz, 1H).
Reference Example 35
Ethyl 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanate
[0259] 47
[0260] Potassium tert-butoxide (35 mg) was suspended in DMF (5 ml),
and a DMF solution (5 ml) of
3-cyano-5-(1-cyano-2-methylpropyl]thiophene (0.60 g) was added
thereto. After stirring at room temperature for 3.5 hours, ethyl
acetate was added. The mixture was washed with an aqueous saturated
ammonium chloride and further brine, dried over anhydrous magnesium
sulfate and then evaporated. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate system), to
give the title compound as a pale yellow oil (0.55 g, 60%).
[0261] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94 (d, J=6.8 Hz,
31H), 1.23 (d, J=6.8 Hz, 3H), 1.24 (t, J=6.8 Hz, 3H), 2.04-2.15 (m,
3H), 2.45-2.60 (m, 2H), 4.04-4.17 (m, 2H), 7.30 (d, J=1.2 Hz, 1H),
7.93 (d, J=1.6 Hz, 1H).
Reference Example 36
4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexanol
[0262] 48
[0263] Ethyl 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanate (0.55
g) was dissolved in THF (10 ml), lithium borohydride (46 mg) was
added, and the mixture was heated under reflux for 1.5 hours. After
cooling as it was to room temperature, 1N aqueous hydrochloric acid
and water were added at 0.degree. C., and the mixture was extracted
with ethyl acetate. The mixture was further washed with brine,
dried over anhydrous magnesium sulfate and then evaporated. The
resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound pale as a
yellow oil (1.25 g, 47%). Further, the catalyst was filtered off,
and the filtrate was evaporated. The resulting residue was purified
by preparative thin layer silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound as a pale
yellow oil (0.39 g, 83%).
[0264] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.8 Hz, 3H), 1.19-1.41 (m, 1H), 1.45-1.70 (m, 1H),
1.65-1.77 (m, 1H), 1.88 (dt, J=4 Hz, J=13.2 Hz, 1H), 2.09 (qui,
J=6.8 Hz, 1H), 2.30 (dt, J=4 Hz, J=12.4 Hz, 1H), 3.66 (t, J=6.4 Hz,
2H), 7.30 (d, J=1.2 Hz, 1H), 7.92 (s, 1H).
Reference Example 37
N-(2-Cyanoethyl)-N-(2-iodoethyl)aniline
[0265] 49
[0266] 2.00 g (10.5 mmol) of
N-(2-cyanoethyl)-N-(2-hydroxyethyl)aniline was dissolved in 60.0 ml
of acetonitrile, and 2.20 ml (15.8 mmol) of triethylamine and 0.90
ml (11.6 mmol) of mesyl chloride were successively added thereto.
After completion of the reaction, brine was added thereto, and the
objective product was extracted with ether. The organic layer was
washed with brine, and then dried over anhydrous magnesium sulfate.
The solvent was evaporated, to give a crude product. The crude
product was dissolved in acetone, and 12.0 g (80.1 mmol) of sodium
iodide was added. After completion of the reaction, brine was added
thereto, and the objective product was extracted with ethyl
acetate. The organic layer was washed with brine, and then dried
over anhydrous magnesium sulfate. The solvent was evaporated, to
give a crude product. The crude product was subjected to silica gel
(eluted with ethyl acetate:hexane=1:3), to give 2.78 g (9.26 mmol,
88.2%) of the title compound as a yellow syrup.
[0267] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.62 (t, J=7.0 Hz,
2H), 3.26 (t, J=8.0 Hz, 2H), 3.71-3.81 (m, 4H), 6.66-6.72 (m, 2H),
6.81-6.86 (m, 1H), 7.25-7.32 (m, 2H)
Reference Example 38
1-{2-[N-(2-Cyanoethyl)anilino]ethyl}piperazine
[0268] 50
[0269] 2.78 g (9.26 mmol) of the above-mentioned iodide was
dissolved in 50.0 ml of acetonitrile, and 2.5 g (13.4 mmol) of
1-tert-butoxycarbonylpi- perazine and 1.29 ml (13.4 mmol) of
triethylamine were successively added, and the mixture was heated
to 60.degree. C. After completion of the reaction, brine was added
thereto, and the objective product was extracted with ethyl
acetate. The organic layer was washed with brine, and then dried
over anhydrous magnesium sulfate. The solvent was evaporated, to
give a crude product. The crude product was dissolved in 40 ml of
methanol, and 30 ml of a 4N hydrogen chloride-ethyl acetate
solution was added. After completion of the reaction, water and 10
ml of 5N HCl were added, and the mixture was washed with ethyl
acetate. Then the aqueous layer was adjusted to pH 11 with a 5N
aqueous sodium hydroxide, and then the objective product was
extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate andthe solventwas evaporated, to give
1.81 g (7.01 mmol, 75.7%) of the title compound as a yellow syrup,
as a crude product.
[0270] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.00-2.10 (brd-s,
1H), 2.45-2.58 (m, 4H), 2.54 (t, J=6.8 Hz, 2H), 2.69 (t, J=7.2 Hz,
2H), 2.92 (t, J=5.0 Hz, 4H), 3.51 (t, J=6.8 Hz, 2H), 3.71 (t, J=7.2
Hz, 2H), 6.65-6.72 (m, 2H), 6.73-6.79 (ml, 1H), 7.22-7.29 (m,
2H)
Reference Example 39
3-(1.3-Dioxolan-2-yl)thiophene
[0271] 51
[0272] 20.3 g (181 mmol) of 3-thiophenealdehyde, 50 ml of ethylene
glycol and 2.00 g (7.96 mmol) of PPTS were dissolved in 230 ml of
toluene, and dehydration was carried out using Dean-stark. After
completion of the reaction, the mixture was extracted with ethyl
acetate. The extract was washed with brine, and then dried over
anhydrous magnesium sulfate. The solvent was evaporated, to give a
crude product. The crude product was subjected to silica gel (ethyl
acetate:hexane=1:10), to give 12.1 g (77.3 mmol, 86.7%) of the
title compound as a yellow oil.
[0273] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.97-4.15 (m, 4H),
5.91 (s, 2H), 7.16 (ddd, J=0.4 Hz, 1.2 Hz, 5.2 Hz, 1H), 7.32 (dd,
J=2.8 Hz, 5.2 Hz, 1H), 7.42 (ddd, J=0.4 Hz, 1.2 Hz, 2.8 Hz, 1H)
Reference Example 40
3-(1.3-Dioxolan-2-yl)-2-thiophenecarboaldehyde
[0274] 52
[0275] 5.00 g (32.0 mmol) of 3-(1,3-dioxolan-2-yl)thiophene was
dissolved in 100 ml of THF. 24.5 ml (1.5 mol/l) of n-butyllithium
was added dropwise thereinto. After stirring for 0.5 hour, the
mixture was cooled to -70.degree. C., 3.10 ml (40.0 mmol) of DMF
was added, and then the mixture was transferred to an ice bath.
After stirring for about 2 hours, an aqueous saturated ammonium
chloride was added, and the mixture was extracted with
ethylacetate. The extract waswashed with brine, and then dried over
anhydrous magnesium sulfate. The solvent was evaporated, to give a
crude product. The crude product was subjected to silica gel (ethyl
acetate:hexane=1:2), to give 3.68 g (20.0 mmol, 62.4%) of the title
compound as a yellow oil.
[0276] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.97-4.15 (m, 4H),
5.91 (s, 2H), 7.16 (ddd, J=0.4 Hz, 1.2 Hz, 5.2 Hz, 1H), 7.32 (dd,
J=2.8 Hz, 5.2 Hz, 1H), 7.42 (ddd, J=0.4 Hz, 1.2 Hz, 2.8 Hz, 1H)
Reference Example 41
3-(1,3-Dioxolan-2-yl)-2-thiopheneacetonitrile
[0277] 53
[0278] 20 ml of a THF solution of 4.49 g (40.0 mmol) of potassium
tert-butoxide was cooled to -45 to -30.degree. C., and 20 ml of a
THF solution of 3.90 g (20.0 mmol) of TOSmic and 20 ml of a THF
solution of 3.68 g (20.0 mmol) of
3-(1,3-dioxolan-2-yl)-2-thiophenecarboaldehyde were successively
added thereto. After 40 minutes, 60 ml of methanol was added at
-15.degree. C. After heating under reflux for 15 minutes, an
aqueous saturated ammonium chloride was added, and the mixture was
extracted with ethyl acetate. The extract was washed with brine,
and then dried over anhydrous magnesium sulfate. The solvent was
evaporated, to give a crude product. The crude product was
subjected to Cromatorex NH silica gel (ethyl acetate:hexane=1:4),
to give 1.43 g (7.32 mmol, 36.6%) of the title compound as a yellow
oil.
[0279] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.00-4.15 (m, 4H),
4.04 (s, 2H), 5.91 (s, 1H), 7.06 (d, J=5.6 Hz, 2H), 7.21 (d, J=5.6
Hz, 2H)
Reference Example 42
2-[3-(1,3-Dioxolan-2-yl)-2-thienyl]-4-methylbutyronitrile
[0280] 54
[0281] 1.43 g (7.32 mmol) of
3-(1,3-dioxolan-2-yl)-2-thiopheneacetonitrile was dissolved in 2 ml
of dimethyl sulfoxide, and 1.08 g (8.78 mmol) of 2-bromopropane,
100 mg (cat) of tetra-n-butylammonium iodide and 3 ml of 50%
potassium hydroxide were successively added. After 25 minutes, 300
mg of 2-bromopropane, further after 50 minutes, 1 ml of 50%
potassium hydroxide and 2 ml of DMSO were added. After completion
of the reaction, brine was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and evaporated, to obtain a crude
product. The crude product was subjected to 100 g of silica gel
(ethyl acetate:hexane=1:8), to give 853 mg (3.59 mmol, 49.1%) of
the title compound as a yellow oil.
[0282] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.03 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.4 Hz, 3H), 2.17-2.27 (m, 1H), 3.97-4.13 (m, 4H),
4.31 (d, J=8.0 Hz, 1H), 7.06 (d, J=5.2 Hz, 2H), 7.24 (d, J=5.2 Hz,
2H)
Reference Example 43
2-(3-Formyl-2-thienyl)-4-methylbutyronitrile
[0283] 55
[0284] 2.16 g (9.10 mmol) of
2-[3-(1,3-dioxolan-2-yl)-2-thienyl]-4-methylb- utyronitrile was
dissolved in 40 ml of acetone, 115 ml of 5N HCl was added, and the
mixture was heated at 70.degree. C. for 3 minutes. After completion
of the reaction, brine was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over magnesium sulfate and evaporated, to give a crude product. The
crude product was subjected to 75 g of silica gel (ethyl
acetate:hexane=1:2), to give 1.66 g (8.58 mmol, 94.3%) of the title
compound as a brown oil.
[0285] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (d, J=6.8 Hz,
3H), 1.14 (d, J=6.8 Hz, 3H), 2.18-2.29 (m, 1H), 4.97 (d, J=6.4 Hz,
1H), 7.34 (d, J=5.2 Hz, 2H), 7.44 (d, J=5.2 Hz, 2H), 10.01 (s,
1H)
Reference Example 44
2-(3-Cyano-2-thienyl)-4-methylbutyronitrile
[0286] 56
[0287] 1.66 g (8.58 mmol) of
2-(3-formyl-2-thienyl)-4-methylbutyronitrile was dissolved in 40 ml
of ethanol, 10 ml of an aqueous solution containing 894 mg (12.9
mmol) of hydroxylamine hydrochloride and 1.41 g (17.2 mmol) of
sodium acetate was added thereto, and then the mixture was heated
at 80.degree. C. After completion of the reaction, brine was added,
and the objective product was extracted with ethyl acetate. The
organic layer was washed with brine, and then dried over anhydrous
magnesium sulfate. The solvent was evaporated, to give a crude
oxime. The oxime was dissolved in 50 ml of dimethylformamide, and
5.56 g (34.3 mmol) of carbodiimidazole was added. Then, the mixture
was heated at 60.degree. C., and further after 50 minutes, 2.40 ml
(17.2 ml) of triethylamine was added thereto. After completion of
the reaction, brine was added under cooling, and the objective
product was extracted with ethyl acetate. The organic layer was
washed with brine, and then dried over anhydrous magnesium sulfate.
The solvent was evaporated, to give a crude product. The crude
product was subjected to silica gel (eluted with ethyl
acetate:hexane=1:9), to give 1.07 mg (5.47 mmol, 63.7%) of the
title compound as an orange oil.
[0288] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.10 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 2.27-2.38 (m, 1H), 4.20 (d, J=7.2 Hz,
1H), 7.22 (d, J=5.6 Hz, 2H), 7.40 (d, J=5.6 Hz, 2H)
Reference Example 45
Ethyl 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexanolate
[0289] 57
[0290] 1.07 g (5.47 mmol) of
2-(3-cyano-2-thienyl)-4-methylbutyronitrile and 0.71 ml (6.56 mmol)
of ethyl acrylate were dissolved in 30 ml of tetrahydrofuran. 123
mg (1.09 mmol, cat.) of potassium tert-butoxide was added little by
little to the solution at room temperature. After completion of the
reaction, brine, an aqueous saturated ammonium chloride and 2N HCl
were successively added, and the objective product was extracted
with ethyl acetate. The organic layer was successively washed with
brine and brine, and then dried over anhydrous magnesium sulfate.
The solvent was evaporated, to give a crude product. The crude
product was subjected to silica gel (eluted with ethyl
acetate:hexane=1:9), to give 904 mg (3.11 mmol, 56.9%) of the title
compound as a yellow oil.
[0291] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94 (d, J=6.8 Hz,
3H), 1.24 (t, J=7.2 Hz, 3H), 1.29 (d, J=6.4 Hz, 3H), 2.04-2.26 (ml,
1H), 2.46-2.74 (m, 4H), 4.07-4.16 (m, 2H), 7.29 (d, J=5.3 Hz, 2H),
7.31 (d, J=5.3 Hz, 2H)
Reference Example 46
4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexanol
[0292] 58
[0293] 500 mg (1.72 mmol) of ethyl
4-cyano-5-methyl-4-(3-cyano-2-thienyl)h- exanolate was dissolved in
10 ml of THF, 37.5 mg (1.72 mmol) of lithium borohydride was added,
and the mixture was heated under reflux. After one hour 20 minutes,
heating was stopped, and 2N HCl was added under ice-cooling. The
mixture was extracted with ethyl acetate, and the extract was
successively washed with brine and water, and then dried over
anhydrous magnesium sulfate. The solvent was evaporated, to obtain
a crude product. The crude product was subjected to silica gel
(eluted with ethyl acetate:hexane=35:65), to give 244 mg (0.98
mmol, 57.1%) of the title compound as a colorless oil.
[0294] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94 (d, J=6.4 Hz,
3H), 1.26 (d, J=6.8 Hz, 3H), 1.24-1.39 (m, 1H), 1.68-1.82 (m, 1H),
2.28-2.48 (m, 2H), 2.59-2.70 (m, 1H), 3.64-3.72 (m, 2H), 7.28-7.29
(m, 2H)
Reference Example 47
4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl iodide
[0295] 59
[0296] 244 mg (0.98 mmol) of
4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexanol was dissolved in 10
ml of acetonitrile and 0.16 ml (1.18 mmol) of triethylamine, and
83.6 .mu.l (1.08 mmol) of mesyl chloride was added thereto. After
about 5 minutes, 1.47 g (9.80 mmol) of sodium iodide was added.
After completion of the reaction, brine and ethyl acetate were
added, and the ethyl acetate layer was washed with an aqueous
sodium thiosulfate aqueous solution and brine, dried over anhydrous
magnesium sulfate and evaporated, to give a crude product. The
crude product was subjected to silica gel (eluted at ethyl
acetate:hexane=1:10), to give 334 mg (0.93 mmol, 95.1%) of the
title compound as a yellow oil.
[0297] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.8 Hz,
3H), 1.27 (d, J=6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.98-2.10 (m, 1H),
2.27-2.36 (m, 1H), 2.42-2.52 (m, 1H), 2.60-2.71 (m, 1H), 3.12-3.22
(m, 2H), 7.29-7.31 (m, 2H)
Reference Example 48
4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl iodide
[0298] 60
[0299] 1.05 g (4.23 mmol) of
4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexanol was dissolved in 40
ml of acetonitrile and 0.80 ml (5.71 mmol) of triethylamine. 0.39
ml (5.07 mmol) of mesyl chloride was added thereto. After about 10
minutes, 6.34 g (42.3 mmol) of sodium iodide was added. After
completion of the reaction, brine and ethyl acetate were added. The
ethyl acetate layer was washed with an aqueous sodium thiosulfate
and brine, dried over magnesium sulfate and evaporated, to give a
crude product. The crude product was subjected to silica gel
(eluted with ethyl acetate:hexane=1:2), to give 1.39 g (3.88 mmol,
91.7%) of the title compound as a yellow oil.
[0300] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.8 Hz,
3H), 1.27 (d, J=6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.98-2.10 (m, 1H),
2.27-2.36 (m, 1H), 2.42-2.52 (m, 1H), 2.60-2.71 (m, 1H), 3.12-3.22
(m, 2H), 7.29-7.31 (m, 2H)
Reference Example 49
Methyl 3-(5-bromo-2-thienyl)propanonate
[0301] 61
[0302] 3.50 g (20.6 mmol) of methyl 3-(2-thienyl)propanonate which
was synthesized according to the method described in J. Med. Chem.,
1992, 35(21), 3870. was dissolved in 20 ml of DMF, 3.85 g (21.6
mmol) of NBS dissolved in 10 ml of DMF was added thereto, and the
mixture was heated at 80.degree. C. After 2 hours, brine was added,
and the mixture was extracted with ether. The organic layer was
washed with brine, dried over magnesium sulfate and evaporated, to
give a crude product. The crude product was subjected to silica gel
(ethyl acetate:hexane=1:9), to give 4.62 g (18.6 mmol, 90.1%) of
the title compound as a pale yellow oil.
[0303] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.65 (t, J=7.4 Hz,
2H), 3.08 (t, J=7.4 Hz, 2H), 3.69 (s, 3H), 6.58 (d, J=3.6 Hz, 1H),
6.85 (d, J=3.6 Hz, 1H)
Reference Example 50
Methyl 3-(5-cyano-2-thienyl)propanonate
[0304] 62
[0305] 4.62 g (18.6 mmol) of methyl 3-(5-bromo-2-thienyl)
propanonate, 1.75 g (14.9 mmol) of Zn(CN).sub.2 and 516 mg (0.93
mmol) of DPPF were suspended in a solution of 100 ml of DMF and 1
ml of water, then 341 mg (0.37 mmol) of Pd.sub.2dba.sub.3 was
added, and the mixture was heated at 120.degree. C. After 2 hours,
the mixture was cooled as it was and extracted with ether. The
organic layer was washed with brine and and 2N HCl, dried over
magnesium sulfate and evaporated, to give a crude product. The
crude product was subjected to silica gel (ethyl
acetate:hexane=1:9), to give 2.96 g (18.6 mmol, 100%) of the title
compound as a green oil.
[0306] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.71 (t, J=7.4 Hz,
2H), 3.19 (t, J=7.4 Hz, 2H), 3.71 (s, 3H), 6.85 (d, J=3.6 Hz, 1H),
7.46 (d, J=3.6 Hz, 1H)
Reference Example 51
3-(2-Thienyl)propanol
[0307] 63
[0308] 1.32 g (7.75 mmol) of methyl 3-(2-thienyl)propanonate was
dissolved in 50 ml of THF. After cooling to -20.degree. C., 6.00 ml
of LiAlH.sub.4 (1.0 M solution) was added. After completion of the
reaction, the mixture was quenched using water and 5N NaOH, and
filtered through Celite. The filtrate was concentrated, and the
resulting crude product was subjected to silica gel (ethyl
acetate:hexane=1:1), to give 1.05 g (7.38 mmol, 95.2%) of the title
compound as a colorless oil.
[0309] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.29 (t, J=6.0 Hz,
1H), 1.90-2.00 (m, 2H), 2.95 (t, J=7.6 Hz, 2H), 3.72 (q, J=6.0 Hz,
2H), 6.80-6.83 (m, 1H), 6.91-6.94 (m, 1H), 7.11-7.14 (m, 1H)
Reference Example 52
3-(5-Cyano-2-thienyl)propanol
[0310] 64
[0311] 2.96 g (18.6 mmol) of methyl 3-(5-cyano-2-thienyl)
propanoate was dissolved in 100 ml of THF, 450 mg (18.6 mmol) of
lithium borohydride was added, and the mixture was heated under
reflux. After one hour, heating was stopped and 2N HCl was added
under ice-cooling. The mixture was extracted with ethyl acetate,
and the extract was successively washed with brine and water, and
then dried over anhydrous magnesium sulfate. The solvent was
evaporated, to give a crude product. The crude product was
subjected to silica gel (eluted at ethyl acetate:hexane=25:75 to
50:50), to give 1.37 g (8.19 mmol, 44.0%) of the title compound as
a green oil.
[0312] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.32-1.37 (m, 1H),
1.90-2.00 (m, 2H), 2.99 (t, J=7.6 Hz, 2H), 3.68-3.76 (m, 2H), 6.84
(d, J=3.6 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H)
Reference Example 53
tert-Butyl 4-[3-(2-thienyl)propyl]-1-piperazinecarboxylate
[0313] 65
[0314] 1.05 g (7.38 mmol) of 3-(2-thienyl)propanol was dissolved in
60 ml of acetonitrile, and 2.58 ml (18.5 mmol) of triethylamine and
0.63 ml (8.12 mmol) of mesyl chloride were added to the solution.
After 25 minutes, 2.07 g (11.1 mmol) of tert-butyl
1-piperadinecarboxylate, 3.32 g (22.7 mmol) of sodium iodide and 6
ml of water were added, and the mixture was heated to 60.degree. C.
After completion of the reaction, brine was added, and the
objective product was extracted with ethyl acetate. The organic
layer was washed with brine, and then dried on anhydrous magnesium
sulfate. The solvent was evaporated, to give a crude product. The
crude product was subjected to Cromatorex NH silica gel (eluted at
ethyl acetate:hexane=2:8), to give 1.94 g (6.25 mmol, 84.7%) of the
title compound as a pale yellow oil.
[0315] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (s, 9H),
1.83-1.91 (m, 2H), 2.35-2.42 (m, 2H), 2.87 (t, J=7.6 Hz, 2H),
3.40-3.46 (m, 4H), 6.77-6.80 (m, 1H), 6.91 (dd, J=3.2 Hz, 5.2 Hz,
1H), 7.11 (dd, J=1.2 Hz, 5.2 Hz, 1H)
Reference Example 54
tert-Butyl
4-[3-(5-cyano-2-thienyl)propyl]-1-piperazinecarboxylate
[0316] 66
[0317] The title compound was synthesized in accordance with the
method for producing tert-butyl
4-[3-(2-thienyl)propyl]-1-piperazinecarboxylate in Reference
Example 53 (yield: 74.2%).
[0318] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (s, 9H),
1.83-1.91 (m, 2H), 2.34-2.41 (m, 6H), 2.91 (t, J=7.6 Hz, 2H),
3.41-3.46 (m, 4H), 6.81 (d, J=4.0 Hz, 1H), 7.46 (d, J=4.0 Hz,
1H)
Reference Example 55
1-[3-(2-Thienyl)propyl]piperazine
[0319] 67
[0320] 1.94 g (6.25 mmol) of tert-butyl 4-[3-(2-thienyl)
propyl]-1-piperazinecarboxylate was dissolved in 20 ml of methanol,
and 15 ml of a 4N hydrogen chloride-ethyl acetate solution was
added. After completion of the reaction, the mixture was
evaporated. The residue was adjusted to pH 11 with a 2N aqueous
sodium hydroxide, then the objective product was extracted with
chloroform and dried over anhydrous magnesium sulfate. The solvent
was evaporated, to give 1.23 g (5.85 mmol, 93.6%) of the title
compound as a yellow oil, as a crude product.
[0321] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.84-1.92 (m, 2H),
2.35-2.48 (m, 6H), 2.83-2.93 (m, 6H), 6.77-6.80 (m, 1H), 6.91 (dd,
J=3.2 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 5.2 Hz, 1H)
Reference Example 56
1-[3-(5-Cyano-2-thienyl)propyl]piperazine
[0322] 68
[0323] The title compound was synthesized in accordance with the
method for producing 1-[3-(2-thienyl)propyl]piperazine in Reference
Example 55 (yield: 96.0%).
[0324] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.83-1.91 (m, 2H),
2.33-2.44 (m, 6H), 2.87-2.94 (m, 6H), 6.81 (d, J=4.0 Hz, 1H), 7.46
(d, J=4.0 Hz, 1H)
Reference Example 57
2-(Chloromethyl)benzoxazole
[0325] The title compound was produced in accordance with the
method described in STNTHETIC COMMUNICATION 19(16) 2921-2924 (1989)
(yield: quantitative).
[0326] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.77 (s, 2H),
7.34-7.43 (m, 2H), 7.54-7.58 (m, 1H), 7.73-7.77 (m, 1H)
Reference Example 58
Benzyl 4-[(2-benzoxazoyl)methyl]-1-piperazinecarboxylate
[0327] 69
[0328] 2.00 g (11.9 mmol) of 2-(chloromethyl)benzoxazole was
dissolved in 50 ml of acetonitrile, 1.66 ml (11.9 mmol) of
triethylamine and 3.15 g (14.3 mmol) of benzyl
1-piprezinecarboxylate were added thereto, and the mixture was
stirred at 80.degree. C. After 2 hours, the reaction solution was
concentrated, brine was added thereto, and the objective product
was extracted with ethyl acetate. The organic layer was washed with
brine, and then dried on anhydrous magnesium sulfate. The solvent
was evaporated, to give a crude product. The crude product was
subjected to Cromatorex NH silica gel (ethyl acetate:hexane=25:75),
to give 3.57 g (10.2 mmol, 85.7%) of the title compound as a yellow
syrup.
[0329] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.56-2.68 (brd-s,
4H), 3.56-3.62 (m, 4H), 3.89 (s, 2H), 5.12 (s, 2H), 7.28-7.37 (m,
7H), 7.52-7.55 (m, 1H), 7.70-7.74 (m, 1H)
Reference Example 59
1-[(2-Benzoxazoyl)methyl]piperazine
[0330] 70
[0331] 3.57 g (10.2 mmol) of benzyl
4-[(2-benzoxazoyl)methyl]-1-piperazine- carboxylate was dissolved
in 50 ml of methanol, and 400 mg of 10% Pd-C was added. After
replacing the atmosphere with hydrogen, the mixture was stirred.
After completion of the reaction, the reaction solution was
filtered and evaporated, to give 2.15 g (9.89 mmol, 97.0%) of the
title compound as a yellow oil, as a crude product.
[0332] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.56-2.66 (m, 4H),
2.93-2.98 (m, 4H), 3.87 (s, 2H), 7.31-7.36 (m, 2H), 7.51-7.56 (m,
1H), 7.69-7.74 (m, 1H)
Reference Example 60
2-(Chloromethyl)-5-cyanobenzoxazole
[0333] 71
[0334] The title compound was synthesized in accordance with the
method described in STNTHETIC COMMUNICATION 19(16) 2921-2924 (1989)
(yield: 79.8%).
[0335] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.78 (s, 2H),
7.66-7.73 (m, 2H), 8.08-8.10 (m, 1H)
Reference Example 61
Benzyl
4-[{2-(5-cyanobenzoxazoyl)}methyl]-1-piperazinecarboxylate
[0336] 72
[0337] The title compound was synthesized in accordance with the
method for the production of benzyl
4-[(2-benzoxazoyl)methyl]-1-piperazinecarbox- ylate in Reference
Example 58 (yield: 85.6%).
[0338] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.57-2.70 (brd-s,
4H), 3.56-3.63 (m, 4H), 3.92 (s, 2H), 5.13 (s, 2H), 7.30-7.38 (m,
5H), 7.62-7.68 (m, 2H), 8.04-8.05 (m, 1H)
Reference Example 62
1-[{2-(5-Cyanobenzoxazoyl)}methyl]piperazine
[0339] 73
[0340] The title compound was synthesized in accordance with the
method described in Reference Example 59 (yield: 58.0%).
[0341] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.59-2.66 (m, 4H),
2.93-3.00 (m, 4H), 3.90 (s, 2H), 7.62-7.67 (m, 2H), 8.03-8.05 (m,
1H)
Reference Example 63
Ethyl 4-cyano-5-methyl-4-(3-thienyl)hexanoate
[0342] 74
[0343] 3-Methyl-2-(3-thienyl)butanenitrile (6.23 g) obtained using
3-thienylacetonitrile as a starting material in accordance with the
method of Example 114 described in JP-A 11-206862 and ethyl
acrylate (4.53 g) were dissolved in dimethylformamide (15 ml), and
added at a room temperature to a solution of potassium
tert-butoxide (423 mg) in dimethylformamide solution (60 ml). After
stirring 5 hours as it was, the organic layer was separated by
adding an aqueous saturated ammonium chloride and diethyl ether
thereto. The resulting organic layer was washed with water and
brine, and dried over anhydrous magnesium sulfate. The drying agent
was filtered off, and then the filtrate was evaporated. The residue
was purified by silica gel column chromatography (hexane/ethyl
acetate system), to give the title compound as a yellow oil (6.66
g, 67%).
[0344] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), 2.00-2.18 (m,
3H), 2.38-2.50 (m, 2H), 4.02-4.14 (m, 2H), 6.94 (dd, J=1.4 Hz, 5.0
Hz, 1H), 7.29 (dd, J=1.4 Hz, 2.8 Hz, 1H), 7.37 (dd, J=2.9 Hz, 5.0
Hz, 1H).
Reference Example 64
4-Cyano-5-methyl-4-(3-thienyl)hexanol
[0345] 75
[0346] A tetrahydrofuran solution (35 ml) in which ethyl
4-cyano-5-methyl-4-(3-thienyl)hexanoate (6.66 g) was dissolved was
added dropwise to a tetrahydrofuran solution (50 ml) of lithium
aluminum hydride (686 mg). After stirring for 2 hours, 2N aqueous
NaOH and water were added to treat the mixture, and the resulting
precipitates were filtered. The resulting filtrate was evaporated,
and the residue was purified by silica gel column chromatography
(ethyl acetate/hexane system), to give the title compound as a
yellow oil (5.30 g, 95%).
[0347] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (d, J=6.8 Hz,
3H), 1.17 (d, J=6.6 Hz, 3H), 1.18-1.22 (m, 1H), 1.22-1.36 (m, 1H),
1.56-1.72 (m, 1H), 1.90 (ddd, J=4.6 Hz, 12.1 Hz, 13.4 Hz, 1H),
2.04-2.12 (m, 1H), 2.14-1.22 (m, 1H), 3.58-3.65 (m, 2H), 6.95 (dd,
J=1.5 Hz, 5.1 Hz, 1H), 7.28 (dd, J=1.5 Hz, 3.0 Hz, 1H), 7.35 (dd,
J=3.0 Hz, 5.1 Hz, 1H).
Reference Example 65
1-Iodo-4-cyano-5-methyl-4-(3-thienyl)hexane
[0348] 76
[0349] Under nitrogen atmosphere, methanesulfonyl chloride (0.20
ml) was added to an acetonitrile solution (9.0 ml) of
4-cyano-5-methyl-4-(3-thien- yl)hexanol (400 mg) and triethylamine
(0.75 ml) at a room temperature, and the mixture was stirred. After
2 hours, water and ethyl acetate were added, to separate the
organic layer. The resulting organic layer was washed with water
and brine, and dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the filtrate was evaporated. The
resulting residue was dissolved in acetone (18 ml), sodium iodide
(2.68 g) was added, and the mixture was stirred at 40.degree. C.
for 2 hours. The organic layer was separated by adding water and
ethyl acetate thereto. The resulting organic layer was washed with
water and brine, and dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the filtrate was evaporated, to
give the title compound as a yellow oil (670 mg).
[0350] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.46-1.60 (m, 1H), 1.86-2.00 (m, 1H),
2.02-2.20 (m, 2H), 3.05-3.20 (m, 2H), 6.95 (dd, J=1.2 Hz, 5.2 Hz,
1H), 7.28 (dd, J=1.2 Hz, 2.8 Hz, 1H), 7.37 (dd, J=2.8 Hz, 5.2 Hz,
1H).
Reference Example 66
Ethyl 4-cyano-5-methyl-4-[4-(2-cyano)thienyl]hexanoate
[0351] 77
[0352] Under a nitrogen atmosphere, ethyl
4-cyano-5-methyl-4-(3-thienyl)he- xanoate (1.8 g) was dissolved in
dimethylformamide (7 mL), a solution of N-bromosuccinimide (1.33
g)/dimethylformamide (7 mL) was added dropwise thereinto at room
temperature over 30 minutes. After stirring at 50.degree. C. for
4.5 hours, the organic layer was separated by adding water and
diethyl ether thereto. The resulting organic layer was washed with
water and brine, and dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the filtrate was evaporated, to
give ethyl 4-cyano-5-methyl-4-[4-(2-bromo)thienyl]hexanoate (2.42
g) as a yellow oil. The resulting bromo compound (2.42 g) was
dissolved in a solution in which zinc cyanide (637 mg) and 1,1'-bis
(diphenylphosphino) ferrocene (188 mg) were dissolved in a mixed
solution of dimethylformamide (17 mL)/water (0.17 mL) under a
nitrogen atmosphere. Palladium-dibenzilideneacetone complex (124
mg) was added thereto. After replacing the atmosphere with nitrogen
three times, the mixture was stirred at 120.degree. C. for 5 hours.
The organic layer was separated by adding water, diethyl ether and
an aqueous ammonia water thereto. The resulting organic layer was
washed with water and brine, and dried over anhydrous magnesium
sulfate. After filtering off the drying agent, the filtrate was
evaporated. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate system), to give the title
compound as a yellow oil (338 mg, 17%, 2 steps). (Reference
literature: P. E. Maligres et al, "Tetrahedron 40(1999)
8193-8195")
[0353] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.4 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.95-2.15 (m,
3H), 2.40-2.53 (m, 2H), 4.04-4.14 (m, 2H), 7.48 (d, J=1.6 Hz, 1H),
7.58 (d, J=1.6 Hz, 1H).
Reference Example 67
4-Cyano-5-methyl-4-(2-cyano-4-thienyl)hexanol
[0354] 78
[0355] The title compound was obtained as a yellow oil in
accordance with the above-mentioned LiBH.sub.4 reduction method
(30%).
[0356] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.20-1.33 (m, 1H), 1.60-1.72 (m, 1H),
1.86-1.96 (m, 1H), 2.00-2.12 (m, 1H), 2.16-2.26 (m, 1H), 3.60-3.68
(m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H).
Reference Example 68
1-Iodo-4-cyano-5-methyl-4-[4-(2-cyano)thienyl]hexane
[0357] 79
[0358] The title compound was synthesized as a yellow oil in
accordance with the methods described in Reference Examples 63, 64
and 65 (91%).
[0359] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.20-1.30 (m, 1H), 1.40-1.55 (m, 1H).
1.90-2.00 (m, 1H), 2.00-2.12 (m, 1H), 2.16-2.26 (m, 1H), 3.06-3.17
(m, 1H), 3.17-3.23 (m, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.6
Hz, 1H).
Reference Example 69
2-(2-Cyano-4-fluorophenoxy)ethylpiperazine
[0360] 80
[0361] Under nitrogen atmosphere, potassium tert-butoxide (869 mg)
was added to a tetrahydrofuran solution (10 ml) of benzyl
4-(2-hydroxyethyl)-1-piperazinecarboxylate (1.86 g) in an ice bath.
After stirring for one hour, the reaction system was transferred to
a dry ice-methanol bath, and after 10 minutes, a
2,5-difluorobenzonitrile (1.09 g)/tetrahydrofuran solution (5 ml)
was added thereto. After stirring for 2 hours while the temperature
of the reaction system was naturally returned to a room
temperature, an aqueous saturated ammonium chloride and diethyl
ether were added thereto, to separate the organic layer. The
resulting organic layer was washed with water and brine, and dried
over anhydrous magnesium sulfate. After filtering off the drying
agent, the filtrate was evaporated. The residue was purified by
silica gel column chromatography (hexane:ethyl acetate system), to
give a colorless oil as an intermediate (1.10 g, 46%). The
intermediate (1.10 g) was dissolved in methanol (10 mL), 10%
palladium carbon (100 mg) was added, and the mixture was stirred at
room temperature under hydrogen atmosphere. After 1.5 hours, the
reaction catalyst was filtered through Celite, and the filtrate was
evaporated. The resulting title compound (647 mg, 80%) obtained was
used for the next reaction as it was.
[0362] Free Body;
[0363] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.55-2.63 (m, 4H),
2.87 (t, J=5.7 Hz, 2H), 2.89-2.92 (m, 4H), 4.19 (t, J=5.7 Hz, 2H),
6.93 (dd, J=4 Hz, 8.8 Hz, 1H), 7.21-7.29 (m, 2H).
Reference Example 70
4-Cyano-5-methyl-4-[4-(2.5-dibromo)thienyl]hexanol
[0364] 81
[0365] Under nitrogen atmosphere,
4-cyano-5-methyl-4-(3-thienyl)hexanol (500 mg) was dissolved in
dimethylformamide (5 mL), and N-bromosuccinimide (1.0 g) was added
thereto at room temperature. After stirring at 100.degree. C. for
one hour, water and diethyl ether were added thereto, to separate
the organic layer. The resulting organic layer was washed with
water and brine, and dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the filtrate was evaporated. The
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate system), to give the title compound as a
yellow oil (670 mg, 78%).
[0366] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.31-1.44 (m, 1H), 1.60-1.74 (m, 1H),
2.08 (ddd, J=4.3 Hz, 12.1 Hz, 13.6 Hz, 1H), 2.43 (ddd, J=4.6 Hz,
12.3 Hz, 13.6 Hz, 1H), 2.59 (sept, J=6.8 Hz, 1H), 7.05 (s, 1H).
Reference Example 71
2-(4-Methylsulfonylphenoxy)ethylpiperazine
[0367] 82
[0368] Under a nitrogen atmosphere, 4-(methylthio) phenol (4.2 g)
and bromoethanol (5.6 g) were dissolved in dimethylformamide
solution (60 ml), potassium carbonate (12.4 g) was added, and the
mixture was heating under stirring at 100.degree. C. After 3 hours,
the mixture was cooled to room temperature, then the organic layer
was separated by adding diethyl ether and water thereto. The
resulting organic layer was washed with water and brine, and dried
over anhydrous magnesium sulfate. After filtering off the drying
agent, the mixture was evaporated. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate system), to
give (4-methylthiophenoxy)ethanol (3.55 g, 64%) as white crystals.
The product (1.0 g) was dissolved in dichloromethane (50 ml), the
mixture was cooled on a methanol-dry ice bath,
methachloroperbenzoic acid (3.6 g) was added, and the mixture was
stirred. After cooling naturally to room temperature over 2 hours,
a 1N aqueous sodium bicarbonate and 1N Na.sub.2S.sub.2O.sub.3 were
added. After stirring, the mixture was extracted with
dichloromethane, and dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the mixture was evaporated. The
residue was dissolved in acetonitrile (18 ml), triethylamine (2.3
ml) and methanesulfonyl chloride (0.5 ml) were added, and the
mixture was stirred at room temperature. After 1.5 hours, sodium
iodide (4.9 g) and tert-butyl-1-piperazinecarboxylate (1.2 g) were
added, and the mixture was heated under stirring at 60.degree. C.
After stirring for 4.5 hours, the organic layer was separated by
adding ethyl acetate and water. The resulting organic layer was
washed with water and brine, and dried over anhydrous magnesium
sulfate. After filtering the drying agent, the mixture was
evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate system), to give
tert-butyl-2-(4-methylthiophenoxy)ethyl-1-piperazinecarboxylate
(1.15 g) as white crystals. The product (1.15 g) was dissolved in
methanol (10 ml), and the solution was added to a 4N hydrochloric
acid-ethyl acetate solution (30 ml) in an ice bath. After stirring
at room temperature overnight, the resulting white crystals were
collected by filtration and washed with diethyl ether. A 1N aqueous
sodium hydroxide and dichloromethane were added to the crystals, to
separate the organic layer. The resulting organic layer was
evaporated, to give the title compound as a yellow oil (820 mg,
53%; 3 steps).
[0369] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.52-2.60 (m, 4H),
2.83 (t, J=5.8 Hz, 2H), 2.93 (brt, J=4.8 Hz, 4H), 3.03 (s, 3H),
4.18 (t, J=5.8 Hz, 2H), 7.03 (brd, J=9.0 Hz, 2H), 7.86 (brd, J=9.0
Hz, 2H).
Reference Example 72
2-(3-Acetylphenoxy)ethylpiperazine
[0370] 83
[0371] Under a nitrogen atmosphere, 3-hydroxyacetophenone (4.1 g)
and brominated ethanol (5.6 g) were dissolved in dimethylformamide
solution (60 ml), and potassium carbonate (12.4 g) was added, and
the mixture was heated under stirring at 100.degree. C. After 3
hours, the mixture was cooled to room temperature, and the organic
layer was separated by adding water and diethyl ether thereto. The
resulting organic layer was washed with water and brine, and dried
over anhydrous magnesium sulfate. After filtering off the drying
agent, the mixture was evaporated. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate system), to
give (3-acetylphenoxy) ethanol (3.28 g, 61%) as white crystals. The
product (977 mg) was dissolved in acetonitrile (18 ml),
triethylamine (2.3 ml) and methanesulfonyl chloride (0.5 ml) were
added, and the mixture was stirred at room temperature. After 1.5
hours, sodium iodide (4.9 g) and tert-butyl-1-piperazinecarboxylate
(1.2 g) were added, and the mixture was heated under stirring at
60.degree. C. After stirring for 4.5 hours, the organic layer was
separated by adding water and ethyl acetate thereto. The resulting
organic layer was washed with water and brine, and dried over
anhydrous magnesium sulfate. After filtering off the drying agent,
the mixture was evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate system), to give
tert-butyl-2-(3-acetylphenoxy)ethyl-1-piperazinecarboxylate (1.33
g) as a yellow oil. The product (1.33 g) was dissolved in methanol
(10 ml), and the solution was added to a 4N hydrochloric acid-ethyl
acetate solution (30 ml). The mixture was stirred at a room
temperature overnight, the resulting white crystals were collected
by filtration and washed with diethyl ether. The organic layer was
separated by adding a 1N aqueous sodium hydroxide and
dichloromethane to the crystals. The resulting organic layer was
evaporated, to give the title compound (830 mg, 62%; 2 steps) as a
yellow oil.
[0372] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.52-2.60 (m, 4H),
2.60 (s, 3H), 2.82 (t, J=5.8 Hz, 2H), 2.93 (brt, J=4.9 Hz, 4H),
4.16 (t, J=5.8 Hz, 2H), 7.12 (ddd, J=1.1 Hz, 2.6 Hz, 8.2 Hz, 1H),
7.34-7.40 (m, 1H), 7.50 (dd, J=1.5 Hz, 2.6 Hz, 1H), 7.54 (ddd,
J=1.1 Hz, 1.5 Hz, 7.5 Hz, 1H).
Reference Example 73
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]piperazine
[0373] 84
[0374] tert-Butyl-1-piperazinecarboxylate (540 mg) was added to an
acetonitrile solution (11 ml) of
1-iodo-4-cyano-5-methyl-4-(2-thienyl)hex- ane (744 mg) and
triethylamine (0.93 ml) synthesized according to Example 84, and
the mixture was stirred at 50.degree. C. for 5 hours under nitrogen
atmosphere. The reaction solution was evaporated, and then the
resulting crude product was purified by silica gel column
chromatography (hexane/ethyl acetate system), to give a colorless
oil (705 mg, 81%). The resulting product (705 mg) was dissolved in
methanol (5 ml), a 4N hydrochloric acid-ethyl acetate solution (15
ml) was added, and the mixture was stirred for 10 hours. Diethyl
ether and ethyl acetate were added, and the mixture was stirred in
an ice bath. The resulting hydrochloride of the title compound was
collected by filtration (white crystals, 490 mg, 75%). The
hydrochloride of the title compound obtained was extracted with
dichloromethane and an aqueous saturated sodium bicarbonate, to be
converted into a free body, and it was used for the next
reaction.
[0375] Hydrochloride:
[0376] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.82 (d, J=6.8
Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.30-1.55 (m, 1H), 1.60-1.83 (m,
1H), 1.83-2.00 (m, 1H), 2.22-2.30 (m, 2H), 3.00-3.80 (m, 10H), 7.07
(dd, J=5.1 Hz, 3.5 Hz, 1H), 7.11 (dd, J=3.5 Hz, 1.3 Hz, 1H), 7.59
(dd, J=5.1 Hz, 1.3 Hz, 1H), 9.30-9.70 (m, 2H). ESI-MS (m/e): 292
(M+H).
Reference Example 74
1-[3-Cyano-4-methyl-3-(2-thienyl)pentyl]piperazine
[0377] 85
[0378] The title compound was synthesized in accordance with the
production method of Reference Example 73.
[0379] Free Body:
[0380] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.6 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.88-1.98 (m, 1H),
2.20-2.18 (m, 2H), 2.28-2.52 (m, 6H), 2.83-2.90 (m, 4H), 6.94-6.98
(m, 1H), 7.10-7.13 (m, 1H), 7.25-7.30 (m, 1H).
Reference Example 75
4-(1,4-Diazepan-1-yl)-1-isopropyl-1-phenylbutyl cyanide
[0381] 86
[0382] The title compound was synthesized from
tert-butyl-1-homopiperazine- carboxylate in accordance with
Reference Example 73.
[0383] Free Body:
[0384] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.02-1.20 (m, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.44-1.62 (m, 1H),
1.64-1.74 (m, 2H), 1.85-1.95 (m, 1H), 2.06-2.20 (m, 2H), 2.36-2.48
(m, 2H), 2.50-2.59 (m, 4H), 2.80-2.86 (m, 2H), 2.89 (t, J=6.1 Hz,
2H), 7.25-7.34 (m, 1H), 7.36-7.40 (m, 4H).
Reference Example 76
1-(Vinylsulfonyl)piperidine
[0385] 87
[0386] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.47-1.60 (m, 2H),
1.60-1.70 (m, 4H), 3.07-3.18 (m, 4H), 5.99 (d, J=9.9 Hz, 1H), 6.20
(d, J=16.7 Hz, 1H), 6.41 (dd, J=16.7 Hz, 9.9 Hz, 1H).
Reference Example 77
1,2,3,4-Tetrahydro-1-quinolinylvinylsulfone
[0387] 88
[0388] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.95-2.05 (m, 2H),
2.81 (t, J=6.8 Hz, 2H), 3.75-3.85 (m, 2H), 5.91 (d, J=10.4 Hz, 1H),
6.23 (d, J=16.4 Hz, 1H), .6.46 (dd, J=16.4 Hz, 10.4 Hz, 1H),
7.00-7.20 (m 3H), 7.65 (d, J=8.4 Hz, 1H).
Reference Example 78
5-(2,5-Dihydro-1H-1-pyrrolyl)-2-isopropyl-5-oxo-2-(2-thienyl)pentanenitril-
e
[0389] 89
[0390] Under nitrogen atmosphere, diethyl cyanophosphonate (618 mg)
was added to a tetrahydrofuran solution (15 ml) of 3-pyrroline (262
mg) and 4-cyano-4-(2-thienyl)-5-methylhexanoic acid (692 mg) at
room temperature, and the mixture was stirred overnight. After the
reaction solution was evaporated, the crude product was purified by
silica gel column chromatography (hexane/ethyl acetate system), to
give the title compound as a yellow oil (440 mg).
[0391] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.22 (d, J=6.6 Hz, 3H), 2.00-2.30 (m, 3H), 2.40-0.60 (m, 2H),
4.00-4.30 (m, 4H), 5.70-5.80 (m, 1H), 5.80-5.90 (m, 1H), 6.87-7.00
(m 1H), 7.15 (m, 1H), 7.23-7.26 (m, 1H).
[0392] In the physico-chemical data of the following compounds, the
values obtained when NMR was measured for a free body and ESI-MS
was measured for a hydrochloride. Further, the hydrochloride was
produced in accordance with the method described in JP-A
11-206862.
Reference Example 79
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-tert-butoxycarbonyl-
aminopyrrolidine
[0393] 90
[0394] 867 mg (3.49 mmol) of
4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanol was dissolved in 20
ml of acetonitrile. 0.58 ml (1.20 eq) of triethylamine and 0.30 ml
(1.10 eq) of mesyl chloride were added thereto. After 10 minutes,
brine was added, and the objective product was extracted with ethyl
acetate. The organic layer was washed with brine, and then dried
over anhydrous magnesium sulfate. The solvent was evaporated, to
give a crude product. The product was dissolved in 30 ml of
acetonitrile, 1.57 g (3.00 eq) of sodium iodine, 0.54 ml (1.10 eq)
of triethylamine and 845 mg (4.54 mmol) of
(3R)-3-tert-butoxycarbonylaminopy- rrolidine were added, and the
mixture was heated at 60.degree. C. After completion of the
reaction, brine was added, and the objective product was extracted
with ethyl acetate. The organic layer was washed with brine, and
then dried over anhydrous magnesium sulfate. The solvent was
evaporated, to give a crude product. The crude product was
subjected to 100 g of Cromatorex NH silica gel (ethyl
acetate:hexane=25 to 35% of ethyl acetate), to give 1.34 g (3.21
mmol, 92.0%) of the title compound as a yellow oil. The
physico-chemical data of the compound was as below.
[0395] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.21 (d, J=6.8 Hz, 3H), 1.17-1.30 (m, 1H), 1.44 (s, 9H),
1.50-1.70 (m, 1H), 1.72-1.84 (m, 1H), 2.00-2.12 (m, 1H), 2.15-2.30
(m, 3H), 2.31-2.49 (m, 4H), 2.49-2.55 (m, 1H), 2.62-2.75 (m, 1H),
4.07-4.20 (m, 1H), 4.70-4.82 (brd-s, 1H), 7.15 (d, J=3.6 Hz, 1H),
7.52 (d, J=3.6 Hz, 1H)
Reference Example 80
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-aminopyrrolidine
[0396] 91
[0397]
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-tert-butoxyc-
arbonylaminopyrrolidine (1.34 g=3.21 mmol) obtained in Reference
Example 79 was dissolved in 10 ml of methanol, and 10 ml of a 4N
hydrochloric acid-ethyl acetate solution was added. After
completion of the reaction, the mixture was adjusted to basic with
a 5N sodium hydroxide, and extracted with chloroform. The organic
layer was dried over magnesium sulfate, and then evaporated, to
give 998 mg (3.15 mmol, 99.5%, a red oil) of a crude product. The
physico-chemical data of the compound was as below.
[0398] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.4 Hz, 3H), 1.18-1.32 (m, 1H), 1.39-1.71 (m, 2H),
1.75-1.85 (m, 1H), 2.01-2.19 (m, 2H), 2.19-2.29 (m, 2H), 2.32-2.41
(m, 2H), 2.42-2.51 (m, 1H), 2.57-2.66 (m, 2H), 3.45-3.52 (m, 1H),
7.15 (d, J=3.6 Hz, 1H), 7.52 (d, J=3.6 Hz, 1H)
Reference Example 81
Production of
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-[N-(2-
-cyanoethyl)amino]pyrrolidine
[0399] 92
[0400] 998 mg (3.15 mmol) of
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexy-
l]-(3R)-3-aminopipyrrolidine obtained in Reference Example 80 was
dissolved in 25 ml of methanol, 0.26 ml (3.94 mmol) of
acrylonitrile was added, and the reaction solution was heated under
reflux. After completion of the reaction, the mixture was
evaporated, to give a crude product. The crude product was
subjected to 50 g of Cromatorex NH silica gel (100% of ethyl
acetate), to give 1.01 g (2.73 mmol, 86.7%) of the title compound
as an orange oil. The physico-chemical data of the compound was as
below.
[0401] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.21 (d, J=6.4 Hz, 3H), 1.20-1.31 (m, 1H), 1.48-1.71 (m, 2H),
1.76-1.86 (m, 1H), 2.02-2.15 (m, 2H), 2.18-2.29 (m, 1H), 2.30-2.39
(m, 3H), 2.43-2.56 (m, 4H), 2.56-2.64 (m, 1H), 2.86 (t, J=6.4 Hz,
2H), 3.25-3.33 (m, 1H), 7.16 (d, J=4.0 Hz, 1H), 7.52 (d, J=4.0 Hz,
1H)
Reference Example 82
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]piperazine
[0402] 93
[0403]
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-(tert-butoxycarbo-
nyl)piperazine was synthesized from
4-cyano-4-(5-cyano-2-thienyl)-5-methyl- hexyl iodide and tert-butyl
1-piperazinecarboxylate in accordance with the production method of
Example 77. The title compound was obtained by carrying out the
deprotection of a Boc group in. accordance with the production
method of Reference Example 79. The physico-chemical data of the
compound was as below.
[0404] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.21 (d, J=6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.59-1.83 (m, 2H),
2.01-2.11-1.80 (m, 1H), 2.17-2.40 (m, 7H), 2.80-2.92 (m, 4H), 7.15
(d, J=4.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H)
Reference Example 83
1-[4-Cyano-5-methyl-4-(4-fluorophenyl)hexyl]piperazine
[0405] 94
[0406] The title compound was synthesized in accordance with
Reference Example 73.
[0407] Free Body:
[0408] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.08-1.17 (m, 1H), 1.19 (d, J=6.6 Hz, 3H), 1.52-1.62 (m, 1H),
1.81-1.89 (m, 1H), 2.04-2.18 (m, 2H), 2.22-2.29 (m, 6H), 2.83-2.87
(m, 4H), 7.04-7.08 (m, 2H), 7.32-7.36 (m, 2H).
Reference Example 84
1-[4-Cyano-5-methyl-4-(3-fluorophenyl)hexyl]piperazine
[0409] 95
[0410] The title compound was synthesized in accordance with
Reference Example 73.
[0411] Free Body:
[0412] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.79 (d, J=6.6 Hz,
3H), 0.81-1.19 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.54-1.59 (m, 1H),
1.81-1.89 (m, 1H), 2.05-2.29 (m, 8H), 2.83-2.87 (m, 4H), 6.97-7.03
(m, 1H), 7.06-7.10 (m, 1H), 7.17-7.20 (m, 1H), 7.32-7.37 (m,
1H).
Reference Example 85
1-[4-Cyano-5-methyl-4-(2-fluorophenyl)hexyl]piperazine
[0413] 96
[0414] The title compound was synthesized in accordance with
Reference Example 73.
[0415] Free Body:
[0416] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80 (d, J=6.8 Hz,
3H), 1.10-1.16 (m, 1H), 1.22 (d, J=6.6 Hz, 3H), 1.55-1.64 (m, 1H),
2.03-2.11 (m, 1H), 2.17-2.34 (m, 7H), 2.43-2.50 (m, 1H), 2.80-2.87
(m, 4H), 7.01-7.06 (m, 1H), 7.13-7.17 (m, 1H), 7.26-7.34 (m, 1H),
7.56-7.61 (m, 1H).
Reference Example 86
1-[4-Cyano-5-methyl-4-(2-tolyl)hexyl]piperazine
[0417] 97
[0418] The title compound was obtained as a colorless oil in
accordance with Reference Example 73.
[0419] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6.8 Hz,
3H), 1.10-1.24 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.50-1.64 (m, 1H),
2.02-2.14 (m, 1H), 2.14-2.30 (m, 1H), 2.20-2.40 (m, 6H), 2.36-2.54
(m, 1H), 2.50 (s, 3H), 2.78-2.90 (m, 4H), 7.10-7.24 (m, 3H),
7.46-7.56 (m, 1H).
Reference Example 87
1-[4-Cyano-5-methyl-4-(2-methoxyphenyl)hexyl]piperazine
[0420] 98
[0421] The title compound was obtained as a colorless oil in
accordance with Reference Example 73.
[0422] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.75 (d, J=6.4 Hz,
3H), 1.00-1.20 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.45-1.60 (m, 1H),
1.90-2.00 (m, 1H), 2.20-2.40 (m, 6H), 2.35-2.50 (m, 1H), 2.65-2.75
(m, 1H), 2.75-2.90 (m, 4H), 3.80 (s, 3H), 6.87 (d, J=8.4 Hz, 1H),
6.95 (t, J=7.6 Hz, 1H), 7.24-7.32 (m, 1H), 7.55 (d, J=7.6 Hz,
1H).
Reference Example 88
1-[4-Cyano-5-methyl-4-(2-chlorophenyl)hexyl]piperazine
[0423] 99
[0424] The title compound was obtained as a colorless oil in
accordance with Reference Example 73.
[0425] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.02-1.18 (m, 1H), 1.23 (d, J=6.8 Hz, 3H), 1.45-1.60 (m, 1H),
1.95-2.10 (m, 1H), 2.20-2.40 (m, 6H), 2.64-2.76 (m, 1H), 2.80-2.90
(m, 4H), 2.88-3.02 (m, 1H), 7.22-7.32 (m, 2H), 7.34-7.40 (m, 1H),
7.71-7.77 (m, 1H).
Reference Example 89
1-Benzyl-4-[3-[1-4-fluorophenyl)cyclohexyl]-1-oxopropyl]piperazine
[0426] 100
[0427] Methyl 4-fluorophenylacetate (10.0 g) was dissolved in
tetrahydrofuran (150 ml), and 60% sodium hydride (5.95 g) was added
under ice-cooling. After stirring for 10 minutes under ice cooling,
1,5-dibromopentane (11.3 ml) was added dropwise thereinto over one
hour. After stirring at room temperature overnight, ice-water was
added thereto, and the mixture was extracted with ethyl acetate.
The extract was washed with brine, dried over anhydrous magnesium
sulfate and evaporated. The resulting residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate system),
to give 7.37 g (53%) of an oil.
[0428] The above-mentioned oil (7.37 g) was dissolved in
tetrahydrofuran (100 ml), and a diethyl ether solution (18.7 ml) of
1.0 M lithium aluminum hydride was added dropwise thereinto at -50
to -40.degree. C. After stirring at this temperature for 20
minutes, water, a 5N aqueous sodium hydroxide and further water
were added under ice-cooling. The insoluble matters were filtered
off through Celite, and the filtrate was evaporated. The resulting
residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate system), to give 3.43 g (53%) of an
oil.
[0429] Oxalyl chloride (1.05 ml) was dissolved in methylene
chloride (25 ml), and a methylene chloride solution (5 ml) of
dimethyl sulfoxide (0.85 ml) was added dropwise at -60 to
-50.degree. C. After stirring for 2 minutes, a methylene chloride
solution (10 ml) of the above-mentioned oil (2.08 g) was added
dropwise therinto within 5 minutes. After stirring for 15 minutes
at this temperature, triethylamine (6.96 ml) was added. After
stirring for 5 minutes, the temperature was raised to room
temperature. The mixture was washed with water and brine, dried
over anhydrous magnesium sulfate and evaporated, to give 1.91 g
(93%) of an oil.
[0430] 60% Sodium hydride (0.55 g) was suspended in tetrahydrofuran
(10 ml), and triethylphosphonoacetate (2.73 ml) in tetrahydrofuran
(5 ml) was added dropwise thereinto under ice-cooling. After
stirring for 15 minutes under ice-cooling, a tetrahydrofuran
solution (15 ml) of the above-mentioned oil (1.89 g) was added
dropwise thereinto. After stirring for 15 minutes at this
temperature, the mixture was further stirred at room temperature
for one hour. An aqueous saturated ammonium chloride was added
thereto and the mixture was extracted with ethyl acetate. The
extract was washed with brine, dried over anhydrous magnesium
sulfate and evaporated. The resulting residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate system),
to give 2.07 g (82%) of an oil.
[0431] The above-mentioned oil (1.02 g) was dissolved in ethanol
(20 ml), 10% palladium-carbon (0.2 g) was added, and hydrogenation
was carried out at room temperature under a normal pressure for 30
minutes. After filtering off the catalyst, the filtration was
evaporated. The resulting residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate system), to give 0.97 g
(94%) of an oil.
[0432] The above-mentioned oil (9.03 g) was dissolved in ethanol
(50 ml), and a 2N aqueous sodium hydroxide (50 ml) was added. After
heating under reflux for 2 hours, the mixture was cooled to room
temperature, and evaporated. The resulting residue was suspended in
ethyl acetate, and the mixture was adjusted to pH 2 with 5N
hydrochloric acid. After drying over anhydrous magnesium sulfate,
the mixture was evaporated. The resulting residue was
recrystallized from ethyl acetate/n-hexane, to give 6.45 g (79%) of
white crystals.
[0433] 1-Benzylpiperazine (2.82 g) was dissolved in
N,N-dimethylformamide (40 ml), and the above-mentioned crystals
(4.00 g) and 1-hydroxybenzotriazole (2.16 g) were added. Under
ice-cooling, a N,N-dimethylformamide solution (30 ml) of
1,3-dicyclohexylcarbodiimide (3.63 g) was added dropwise thereinto.
After stirring at room temperature overnight, the insoluble matters
were filtered off, and the filtrate was extracted with ethyl
acetate and 1N hydrochloric acid. The extract was washed with a 2N
aqueous sodium hydroxide and brine, dried over anhydrous magnesium
sulfate and evaporated. The resulting residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate system),
to give 6.23 g (95%) of the title compound as an oil.
[0434] .sup.1NMR (400MHZ, CDCl.sub.3) .delta. 1.29-1.50 (m, 4H),
1.50-1.63 (m, 4H), 1.80-1.94 (m, 4H), 1.99-2.07 (m, 2H), 2.27 (t,
J=4.8 Hz, 2H), 2.34 (t, J=4.8 Hz, 2H), 3.10 (t, J=4.8 Hz, 2H), 3.47
(s 2H), 3.54 (t, J=4.8 Hz, 2H), 6.96-7.02 (m, 2H), 7.22-7.34 (m,
7H).
[0435] ESI-Mass; 409 (MH.sup.+).
Reference Example 90
1-Benzyl-4-[3-[1-(4-fluorophenyl)cyclohexyl]propyl]piperazine
[0436] 101
[0437]
1-Benzyl-4-[3-[1-(4-fluorophenyl)cyclohexyl]-1-oxopropyl]piperazine
(5.90 g) was dissolved in tetrahydrofuran (100 ml), and 80% lithium
aluminum hydride (1.03 g) was added thereto under ice-cooling.
After heating under reflux for 1.5 hours, the mixture was cooled as
it was to room temperature. Under ice-cooling, water, a 1N aqueous
sodium hydroxide and further water were added thereto, and the
insoluble matters were filtered off. The filtrate was evaporated,
and the resulting residue was recrystallized from ethanol, to give
4.48 g (79%) of the title compound as white crystals.
[0438] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.06-1.15 (m, 2H),
1.28-1.58 (m, 12H), 1.98-2.06 (m, 2H), 2.14 (t, J=8 Hz, 2H),
2.20-2.54 (m, 8H), 3.47 (s 2H), 6.93-7.00 (m, 2H), 7.20-7.32 (m,
7H).
[0439] ESI-Mass; 395 (MH.sup.+).
Reference Example 91
4-[3-[1-4-Fluorophenyl)cyclohexyl]propyl]piperazine
[0440] 102
[0441]
1-Benzyl-4-[3-[1-(4-fluorophenyl)cyclohexyl]propyl]piperazine (4.00
g) was dissolved in methanol (100 ml), and 20% palladium
hydroxide-carbon (0.4 g) was added, and hydrogenation was carried
out at room temperature under a normal pressure for 6 hours. After
filtering off the catalyst, the filtrate was evaporated, to give
3.09 g of the title compound as an oil (quantitative).
[0442] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.07-1.17 (m, 2H),
1.28-1.60 (m, 10H), 1.75 (bs, 1H), 1.99-2.07 (m, 2H), 2.12 (t, J=8
Hz, 2H), 2.25 (bs, 4H), 2.82 (t, J=4.8 Hz, 2H), 6.94-7.01 (m, 2H),
7.21-7.27 (m, 2H).
[0443] ESI-Mass; 305 (MH.sup.+).
Reference Example 92
Ethyl
4-(4-cyano-5-methyl-4-phenylhexyl)-2-piperazinecarboxylate
[0444] 103
[0445] Ethyl
1-benzyl-4-(4-cyano-5-methyl-4-phenylhexyl)-2-piperazinecarbo-
xylate (857 mg) was dissolved in ethanol (15 ml), and 770 mg of 10%
Pd--C was added. After replacing the atmosphere with hydrogen, the
mixture was stirred. After completion of the reaction, the solution
was evaporated, to give 639 mg (93%) of the title compound as a
crude product.
[0446] Free Body:
[0447] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.6 Hz,
3H), 1.08-1.16 (m, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.22-1.29 (m, 3H),
1.53-1.64 (m, 1H), 1.86-1.95 (m, 1H), 2.05-2.33 (m, 6H), 2.41-2.49
(m, 1H), 2.74-2.83 (m, 2H), 2.97-3.04 (m, 1H), 3.47-3.52 (m, 1H),
4.14-4.21 (m, 2H), 7.26-7.31 (m, 1H), 7.34-7.39 (m, 4H).
Reference Example 93
Ethyl 4-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate
[0448] 104
[0449] Ethyl
1-benzyl-4-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate (977
mg) synthesized in accordance with Example 241 described later was
dissolved in ethanol (15 ml), and 210 mg of 10% Pd--C was added.
After replacing the atmosphere with hydrogen, the mixture was
stirred. After completion of the reaction, the solution was
evaporated, to give 752 mg (100%) of the title compound as a crude
product.
[0450] Free Body:
[0451] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24-1.28 (m, 3H),
2.33-2.34 (m, 1H), 2.48-2.50 (m, 1H), 2.72-2.91 (m, 4H), 3.04-3.10
(m, 2H), 3.56-3.59 (m, 1H), 4.04-4.08 (m, 2H), 4.16-4.22 (m, 2H),
6.82-6.86 (m, 2H), 6.94-6.99 (m, 2H).
[0452] Among the production intermediates for producing the
compound according to the present invention, optically active
intermediates can be produced in accordance with known production
methods or methods according to them, and additionally, for
example, can be produced according to the following methods.
Reference Example 94
3-Methyl-2-(2-thienyl)butanenitrile
[0453] 105
[0454] 47.6 g (0.39 mol) of 2-thiopheneacetonitrile and 57.0 g
(0.46 mol) of 2-bromopropane were dissolved in 100 ml of DMSO, anda
50% KOH aqueous solution was added dropwise to the solution. After
completion of the reaction, water was added, and the mixture was
extracted with toluene. After washing with brine and an aqueous
saturated ammonium chloride, the mixture was dried over magnesium
sulfate and evaporated, to give a crude product. The crude product
was subjected to distillation under a reduced pressure (2 to 3
mmHg: 132 to 137 deg), to give 46.4 g (0.28 mol, 72.7%) of the
title compound as a colorless oil. The physico-chemical data of the
compound was as below.
[0455] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.08 (d, J=6.8 Hz,
3H), 1.12 (d, J=6.8 Hz, 3H), 2.14-2.24 (m, 1H), 3.95 (d, J=6.0 Hz,
1H), 6.99 (dd, J=4.0 Hz, 5.20 Hz, 1H), 7.05-7.08 (m, 1H), 7.27 (dd,
J=1.2 Hz, 5.2 Hz, 1H)
Reference Example 95
Ethyl 4-cyano-5-methyl-4-(2-thienyl)hexanolate
[0456] 106
[0457] 1.49 g (13.3 mmol, cat.) of potassium tert-butoxide was
dissolved in 120 ml of DMF, and a mixed solution of 43.9 g (0.27
mol) of 3-methyl-2-(2-thienyl)butanenitrile and 30.2 ml (0.28 mol)
of ethyl acrylate was added little by little to the solution at
room temperature. (when a raw material remains, ethyl acrylate and
potassium tert-butoxide were additionally added.) It was
exothermically continued during the addition. After completion of
the reaction, 100 ml of brine and 200 ml of an aqueous saturated
ammonium chloride were successively added, and the objective
product was extracted with 500 ml of hexane. The organic layer was
washed with 400 ml of brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, to give 67.0 g of a crude
product of an ester (ethyl
4-cyano-5-methyl-4-(2-thienyl)hexanolate) as a yellow oil. The
physico-chemical data of the compound was as below.
[0458] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.22 (d, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 2.01-2.19 (m,
3H), 2.41-2.58 (m, 2H), 4.01-4.15 (m, 2H), 6.96 (dd, J=3.6 Hz, 5.1
Hz 1H), 7.12 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.29 (dd, J=1.2 Hz, 5.1
Hz, 1H)
Reference Example 96
Cyclohexylamine salt of dl-4-cyano-4-(2-thienyl)-5-methylhexanoic
acid
[0459] 107
[0460] 67.0 g of the above-mentioned ester obtained in Example was
dissolved in 500 ml of tetrahydrofuran, 200 ml of 5N NaOH and 50 ml
of ethanol were added to the solution, and the mixture was stirred.
After completion of the reaction, the solution was evaporated. The
aqueous layer containing the objective product was washed 4 times
with 200 ml of toluene. Then, 320 ml of 5N HCl was added thereto,
to adjust pH to 1-2, and the objective product was extracted with
750 ml of toluene. The organic layer was washed with brine, and
then dried over anhydrous magnesium sulfate. The solvent was
evaporated, to give 55.6 g (yellow oil) as a crude carboxylic acid.
The carboxylic acid was dissolved in 150 ml of toluene, and 22.5 g
(0.23 mol) of cyclohexylamine was added. The resulting white
crystals were collectedby filtration, to give 55.6 g (0.17 mol) of
the title compound. The physico-chemical data of the compound was
as below.
[0461] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.4 Hz, 3H), 1.20-1.40 (m, 6H), 1.57-1.67 (m, 1H),
1.72-1.81 (m, 2H), 1.92-2.11 (m, 3H), 2.30-2.42 (m, 1H), 2.44-2.54
(m, 1H), 2.85-2.96 (m, 1H), 6.95 (dd, J=3.2 Hz, 5.2 Hz 1H), 7.11
(dd, J=1.2 Hz, 3.2 Hz, 1H), 7.25-7.28 (m, 1H)
Reference Example 97
Ethylamine salt of 4-cyano-4-(2-thienyl)-5-methylhexanoic acid
(S)-1-(4-methylphenyl)
[0462] 108
[0463] 55 g (0.16 mol) of cyclohexylamine salt of
dl-4-cyano-4-(2-thienyl)- -5-methylhexanoic acid was suspended in
100 ml of 5N HCl and 50 ml of water, and the mixture was extracted
with 300 ml of toluene. The extract was washed with 2N HCl and
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, to give 38.7 g crude carboxylic acid. 38.7 g of the
crude dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid was dissolved
in 120 ml of toluene. 18.8 g (0.14 mol, 0.85 eq) of
(S)-1-(4-methylphenyl) ethylamine/40 ml of toluene was added to the
solution containing this carboxylic acid. To the mixture was added
the crystals (6 mg) of the title compound previously prepared, and
the mixture was cooled as it was. The resulting diastereomer salt
(Salt 1) was collected by filtration. The Salt 1 was dissolved by
heating in 250 ml of toluene, and the mixture was cooled as it was
to room temperature under stirring. The resulting diastereomer salt
(Salt 2: optical purity of 90.5% ee) was collected by filtration,
to give 21.3 g (57.2 mmol, 35.1%) (optical purity of 90.5% ee) of
the title compound.
Example 2
[0464] dl-4-Cyano-4-(2-thienyl)-5-methylhexanoic acid (96.6 mmol)
was converted into a salt in accordance with the above-mentioned
dividing method and crystallized, and then recrystallization was
repeated twice, to give 14.5 g (38.9 mmol, 40.3%) (optical purity
of 95% ee<) of the title compound. The physico-chemical data of
the compound was as below. Further, the condition for HPLC analysis
was shown below, and the analysis data (HPLC chart) were shown in
FIG. 1.
[0465] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.4 Hz, 3H), 1.42 (d, J=6.8 Hz, 3H), 1.95-2.11 (m,
3H), 2.33 (s, 3H), 2.30-2.50 (m, 2H), 3.74 (brd-s, 3H), 6.95 (dd,
J=3.6 Hz, 5.2 Hz, 1H), 7.10 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.14 (d,
J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz; 2H), 7.25-7.29 (m, 1H)
[0466] Condition for HPLC Analysis:
[0467] Column: Daicel Chemical Industries, Ltd., CHIRALCEL OJ,
4.6.times.250 mm
[0468] Mobile phase: 20% (B),
[0469] (A) Mixed solution of n-hexane/trifluoroacetic acid
(1000:1)
[0470] (B) Mixed solution of n-hexane/isopropanol/trifluoroacetic
acid (500:500:1)
[0471] Flow rate: 0.5 ml/min.
[0472] Detector: UV 231 nm
[0473] Retention time: 15.5 min.
Reference Example 98
4-Cyano-4-(2-thienyl)-5-methylhexanoic
acid.cndot.(S)-1-phenylethylamine salt
[0474] 109
[0475] Optically active 4-cyano-4-(2-thienyl)-5-methylhexanoic
acid.cndot.(S)-1-phenylethylamine salt (107.7 g, 39%) (white
crystals, optical purity of 96.9% ee) could be obtained also by
using (S)-1-phenylethylamine (67.4 g) and toluene (990 ml) to
dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid (168.8 g) in
accordance with the method of Reference Example 97. The
physico-chemical data of the compound was as below.
[0476] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 0.94 (d, J=7 Hz,
3H), 1.23 (d, J=7 Hz, 3H), 1.65 (d, J=7 Hz, 3H), 2.02 (ddd, J=15
Hz, 12 Hz, 4 Hz, 1H), 2.14 (ddd, J=14 Hz, 12 Hz, 4 Hz, 1H), 2.18
(qq, J=7 Hz, 7 Hz, 1H), 2.33 (ddd, J=15 Hz, 12 Hz, 4 Hz, 1H), 2.52
(ddd, J=14 Hz, 12 Hz, 4 Hz, 1H), 4.44 (q, J=7 Hz, 1H), 7.04 (dd,
J=5 Hz, 3 Hz, 1H), 7.14 (dd, J=3 Hz, 1 Hz, 1H), 7.44 (dd, J=5 Hz, 1
Hz, 1H), 7.40-7.50 (m, 5H).
[0477] EI-Mass (m/z): 135, 177, 195, 273 (M.sup.+)
[0478] Melting point: 136-144.degree. C.
[0479] Condition for HPLC Analysis:
[0480] Column: Daicel Chemical Industries Ltd., (Tokyo) CHIRALCEL
OJ,
[0481] Mobile phase: 10% (B),
[0482] (A) n-hexane/trifluoroacetic acid (1000:1)
[0483] (B) n-hexane/2-propanol/trifluoroacetic acid (500:500:1)
[0484] Flow rate: 0.5 ml/min.
[0485] Detector: UV 231 nm
[0486] Retention time: 26.2 min.
Reference Example 99
4-Cyano-4-(2-thienyl)-5-methylhexanoic
acid.cndot.(R)-1-phenylethylamine salt
[0487] 110
[0488] The title compound was obtained as white crystals using
(R)-1-phenylethylamine and
dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid in accordance with
the method of Reference Example 98.
[0489] Melting point: 136-144.degree. C.
[0490] Condition of HPLC Analysis:
[0491] Column: Daicel Chemical Industries Ltd., (Tokyo) CHIRALCEL
OJ,
[0492] Mobile phase: 10% (B),
[0493] (A) n-hexane/trifluoroacetic acid (1000:1)
[0494] (B) n-hexane/2-propanol/trifluoroaceticacid (500:500:1)
[0495] Flow rate: 0.5 ml/min.
[0496] Detector: UV 231 nm
[0497] Retention time: 19.9 min.
Reference Example 100
4-Cyano-4-(3-thienyl)-5-methylhexanoic
acid.cndot.(S)-1-(4-methylphenyl)et- hylamine salt
[0498] 111
[0499] 5.6 g (optical purity of 86.7% ee) of the title compound was
obtained as white crystals from
dl-A-cyano-4-(3-thienyl)-5-methylhexanoic acid (11.4 g) and
(S)-1-(4-methylphenyl)ethylamine (5.45 g) synthesized in accordance
with Reference Examples 96 and 97. The physico-chemical data of the
compound was as below. Further, the condition for HPLC analysis was
shown below, and the analysis data (HPLC chart) were shown in FIG.
2.
[0500] Free Body: 4-Cyano-4-(3-thienyl)-5-methylhexanoic acid;
[0501] .sup.1H-NMR (400 MHz, CDCl3) .delta. 0.85 (d, J=6.8 Hz, 3H),
1.19 (d, J=6.6 Hz, 3H), 2.02-2.18 (m, 3H), 2.38-2.58 (m, 2H), 6.94
(dd, J=3.1 Hz, 1.5 Hz, 1H), 7.30 (dd, J=3.1 Hz, 1.5 Hz, 1H), 7.38
(dd, J=5.1 Hz, 3.1 Hz, 1H).
[0502] Salt: 4-Cyano-4-(3-thienyl)-5-methylhexanoic
acid.cndot.(S)-1-(4-methylphenyl)ethylamine salt
[0503] .sup.1H-NMR (400 MHz, CDCl3) .delta. 0.83 (d, J=6.8 Hz, 3H),
1.15 (d, J=6.6 Hz, 3H), 1.42 (d, J=6.6 Hz, 3H), 1.80-2.10 (m, 3H),
2.27-2.42 (m, 2H), 2.33 (s, 3H), 4.14 (q, J=6.8 Hz, 1H), 6.91 (dd,
J=5.1 Hz, 1.5 Hz, 1H), 7.13 (brd, J=8.0 Hz, 2H), 7.20 (brd, J=8.0
Hz, 2H). 7.24 (dd, J=3.1 Hz, 1.5 Hz, 1H), 7.33 (dd, J=5.1 Hz, 3.1
Hz, 1H). Melting point: 140-143.degree. C.
[0504] Condition of HPLC Analysis:
[0505] Column: Daicel Chemical Industries Ltd., (Tokyo) CHIRALCEL
OJ,
[0506] Mobile phase: Hexane:IPA:TFA (900:100:1)
[0507] Flow rate: 0.5 ml/min.
[0508] Detector: UV 235 nm
[0509] Retention time: 15.7 min.
Reference Example 101
Optically active 4-cyano-4-(3-thienyl)-5-methylhexanoic acid
[0510] 112
[0511] The free body of the title compound (3.94 g) was obtained by
treating 4-cyano-4-(3-thienyl)-5-methylhexanoic
acid.cndot.(S)-1-(4-methy- lphenyl)ethylamine salt (5.6 g) with an
aqueous hydrochloric acid, in accordance with the method of
Reference Example 97, to produce the title free compound (3.94 g).
The physico-chemical data of the compound was as below. Further,
the condition of HPLC analysis are shown below, and the analysis
data (HPLC chart) are shown in FIG. 2.
[0512] .sup.1H-NMR (400 MHz, CDCl3) .delta. 0.85 (d, J=6.8 Hz, 3H),
1.19 (d, J=6.6 Hz, 3H), 2.02-2.18 (m, 3H), 2.38-2.58 (m, 2H), 6.94
(dd, J=3.1 Hz, 1.5 Hz, 1H), 7.30 (dd, J=3.1 Hz, 1.5 Hz, 1H), 7.38
(dd, J=5.1 Hz, 3.1 Hz, 1H).
Reference Example 102
4-Cyano-4-(3-thienyl)-5-methylhexanoic
acid.cndot.(R)-1-(4-methylphenyl)et- hylamine salt
[0513] 113
[0514] The title compound (35%, optical purity of 88.5% ee) was
obtained as white crystals using (R)-1-(4-methylphenyl) ethylamine
and dl-4-cyano-4-(3-thienyl)-5-methylhexanoic acid, in accordance
with the production method of Example. Melting point:
140-143.degree. C.
[0515] Condition of HPLC Analysis:
[0516] Column: Daicel Chemical Industries Ltd., (Tokyo) CHIRALCEL
OJ,
[0517] Mobile phase: Hexane:IPA:TFA (900:100:1)
[0518] Flow rate: 0.5 ml/min.
[0519] Detector: UV 235 nm
[0520] Retention time: 12.8 min.
Reference Example 103
4-Cyano-4-(2-thienyl)-5-methylhexanoic
acid.cndot.(R)-1-(4-methylphenyl)et- hylamine salt
[0521] 114
[0522] The title compound was produced using
(R)-1-(4-methylphenyl)ethylam- ine and
dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid, in accordance with
the production method of Reference Example 97. The condition of
HPLC analysis are shown below, and the analysis data (HPLC chart)
are shown in FIG. 3.
[0523] Condition of HPLC Analysis:
[0524] Column: Daicel Chemical Industries, Ltd., CHIRALCEL OJ,
4.6.times.250 mm
[0525] Mobile phase: 20% (B),
[0526] (A) Mixed solution of n-hexane/trifluoroacetic acid
(1000:1)
[0527] (B) Mixed solution of n-hexane/isopropanol/trifluoroacetic
acid (500:500:1)
[0528] Flow rate: 0.5 ml/min.
[0529] Detector: UV 231 nm
[0530] Retention time: 12.8 min.
Reference Example 104
4-Cyano-4-(2-thienyl)-5-methylhexanol (optically active
compound)
[0531] 115
[0532] 4-Cyano-4-(2-thienyl)-5-methylhexanoic
acid.cndot.(S)-1-(4-methylph- enyl)ethylamine salt obtained from
Reference Example 97 was returned to its carboxylic acid free form
in accordance with Reference Example 97. 8.31 g (35.0 mmol) of this
form was dissolved in 140 ml of tetrahydrofuran, 3 drops of
N,N-dimethylformamide were added by Pasteur pipette, and the
mixture was ice-cooled. To the reaction solution was added dropwise
3.5 ml (40.3 mmol) of oxalyl chloride, followed by warming to room
temperature and stirring for 1.5 hours. After evaporating the
reaction solvent, 80 ml of tetrahydrofuran was added and the
solution was ice-cooled again. 75 ml of methanol and 6.10 ml (43.8
mmol) of triethylamine were added thereto, and the solution was
stirred while warming to room temperature. After completion of the
reaction, the solution was extracted with ethyl acetate. The
extract was washed with an aqueous saturated sodium bicarbonate and
brine, and dried over magnesium sulfate. The solvent was
evaporated, and the resulting crude product obtained was crudely
purified by silica gel column chromatography (hexane/ethyl acetate
system), to give 8.00 g (31.8 mmol, 90.9%) of a methyl ester. 8.00
g (31.8 mmol, 90.9%) of the ester was dissolved in 50 ml of
tetrahydrofuran. The solution was added dropwise into a THF
suspension of 845 mg (22.3 mmol) of lithium aluminum hydride cooled
to the outer temperature of -50 to -40.degree. C., followed by
heating to the outer temperature of -20.degree. C. over 0.5 hour.
After completion of the reaction, the solution was cooled again,
0.9 ml of water, 0.9 ml of 5N NaOH and 2.70 ml of water were
successively added, and then filtered through Celite. Then, the
filtrate was evaporated, and the resulting crude product was
purified by silica gel column chromatography (n-hexane/ethyl
acetate system), to give 6.60 g (29.6 mmol, 93.1%) of the title
compound as a colorless oil. The physico-chemical data of the
compound was as below.
[0533] Carboxylic Acid A:
[0534] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.4 Hz, 3H), 2.01-2.23 (m, 3H), 2.47-2.58 (m, 2H),
6.97 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.12 (dd, J=1.2 Hz, 3.6 Hz, 1H),
7.29 (dd, J=1.2 Hz, 5.2 Hz, 1H)
[0535] Methyl Ester Obtained from Carboxylic Acid A:
[0536] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.22 (d, J=6.4 Hz, 3H), 2.03-2.20 (m, 3H), 2.43-2.58 (m, 2H),
3.64 (s, 3H), 6.96 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.12 (dd, J=1.2 Hz,
3.6 Hz, 1H), 7.29 (dd, J=1.2 Hz, 5.2 Hz, 1H)
[0537] Alcohol A:
[0538] .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.33-1.46 (m, 1H), 1.65-1.77 (m, 1H),
1.80-1.90 (m, 1H), 2.08 (sept, J=6.8 Hz, 1H), 2.27 (ddd, J=4.4 Hz,
12.0 Hz, 13.2 Hz, 1H), 3.63 (brd-s, 2H), 6.96 (dd, J=3.6 Hz, 5.2
Hz, 1H), 7.11-7.14 (m, 1H), 7.27 (dd, J=1.2 Hz, 5.2 Hz, 1H)
Reference Example 105
4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexanol (optically active
compound)
[0539] 116
[0540] Bromination reaction and successively cyanation reaction
were carried out using the alcohol A obtained in Reference Example
104, as a starting material in accordance with Example 80. Namely,
optically active 4-cyano-4-(5-bromo-2-thienyl)-5-methylhexanol was
synthesized by the bromination reaction, and the cyanation reaction
was carried out without purifying it, to give the title compound at
a yield of 77.9%. The physico-chemical data of the compound was as
below.
[0541] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94 (d, J=6.59
Hz, 3H), 1.22 (d, J=6.78 Hz, 3H), 1.28-1.42 (m, 1H), 1.66-1.78 (m,
1H), 1.83-1.93 (m, 1H), 2.03-2.16 (m, 1H), 2.32 (ddd, J=4.40 Hz,
12.4 Hz, 13.2 Hz, 1H), 3.58-3.74 (m, 2H), 7.16 (d, J=3.60 Hz, 1H),
7.52 (d, J=3.60 Hz, 1H)
Example 1
1-[4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-acetylphenoxy)ethyl]piperazine
[0542] 117
[0543] The title compound was synthesized in accordance with the
method of Example 86-5) described in JP-A 11-206862.
[0544] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.20 (m, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.60 (m, 1H),
1.80-1.95 (m, 1H), 2.05-2.20 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.48
(m, 4H), 2.48-2.65 (m, 4H), 2.59 (s, 3H), 2.81 (t, J=5.8 Hz, 2H),
4.13 (t, J=5.8 Hz, 2H), 7.08-7.13 (m, 1H), 7.26-7.32 (m, 1H),
7.34-7.40 (m, 5H), 7.46-7.50 (m, 1H), 7.52-7.56 (m, 1H).
[0545] Further, the free body is treated in accordance with the
method of Example 20 described in JP-A 11-206862, to give the
hydrochloride of the title compound.
[0546] ESI-Mass; 448 (MH.sup.+)
Example 2
1-[4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(1-benzyl-2-pyrrolidine)methyl]pipe-
razine
[0547] 118
[0548] In acetonitrile (3 ml) was dissolved
1-benzyl-2-pyrrolidinemethanol (83 mg), followed by adding
triethylamine (0.18 ml) andmesyl chloride (0.037 ml). After
stirring at room temperature for one hour, an acetonitrile solution
(3 ml) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piper- azine (124 mg)
was added. After heating under reflux for 3 hours, the mixture was
left to be cooled to room temperature. Ethyl acetate was added
thereto, and the mixture was washed with water and brine. After
drying over anhydrous magnesium sulfate, it was evaporated. The
resulting residue was purified by (NH) silica gel column
chromatography (hexane/ethyl acetate system), to give the title
compound as a pale yellow oil (58 mg, 29%). Further, the free body
was converted into a hydrochloride in a conventional method, to
give the hydrochloride of the title compound.
[0549] Free Body:
[0550] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.18 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.73 (m, 4H),
1.83-2.00 (m, 3H), 2.07-2.18 (m, 2H), 2.20-2.64 (m, 13H), 2.87-2.93
(m, 1H), 3.23 (d, J=12.8 Hz, 1H), 4.19 (d, J=12.8 Hz, 1H),
7.19-7.39 (m, 10H).
[0551] Hydrochloride:
[0552] ESI-Mass; 459 (MH.sup.+)
Example 3
1-[4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzofuranyl)methyl]piperazine
[0553] 119
[0554] In 1,2-dichloroethane (6 ml) was dissolved
1-[4-cyano-5-methyl-4-ph- enyl)hexyl]piperazine (0.19 g), followed
by adding benzofuran-2-carboaldeh- yde (0.11 g), acetic acid (0.095
ml) and sodium triacetoxyborohydride. After stirring for 3 hours at
a room temperature, ethyl acetate was added thereto and the mixture
was washed with water and further brine. After drying over
anhydrous magnesium sulfate, it was evaporated. The resulting
residue was purified by (NH) silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound as apale
yellow oil (0.28 g, quantitatively). Further, the free body was
converted into a hydrochloride in a conventional method, to give a
hydrochloride of the title compound.
[0555] Free Body:
[0556] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 1.05-1.18 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.48-1.60 (m, 1H),
1.87 (dt, J=4.4 Hz, J=12 Hz, 1H), 2.07-2.17 (m, 2H), 2.27 (t, J=7.2
Hz, 2H), 2.38 (bs, 4H), 2.52 (bs, 4H), 3.66 (s, 2H), 6.57 (s, 1H),
7.17-7.30 (m, 3H), 7.32-7.37 (m, 4H), 7.44-7.53 (m, 2H).
[0557] Hydrochloride:
[0558] ESI-Mass; 416 (MH.sup.+)
Example 4
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[-1-methyl-2-benzimidazolyl)methyl]-
pipiperazine
[0559] 120
[0560] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 3 (86%). Further, the free
body was converted into a hydrochloride in a conventional
method.
[0561] Free Body:
[0562] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.18 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.47-1.60 (m, 1H),
1.90 (dt, J=4.4 Hz, J=12.4 Hz, 1H), 2.05-2.38 (m, 8H), 2.50 (bs,
4H), 3.79 (s, 2H), 3.84 (s, 3H), 7.21-7.40 (m, 8H), 7.71-7.75 (m,
1H).
[0563] Hydrochloride:
[0564] ESI-Mass; 430 (MH.sup.+)
Example 5
1-[-4-Cyano-5-methyl-4-phenyl)hexyl]-4-[-3-indolyl)methyl]piperazine
[0565] 121
[0566] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 3 (76%). Further, the
hydrochloride of the title compound was obtained in a conventional
method.
[0567] Free Body:
[0568] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 1.04-1.18 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.47-1.60 (m, 1H),
1.86 (dt, J=4.4 Hz, J=12.4 Hz, 1H), 2.03-2.16 (m, 2H), 2.22-2.32
(m, 2H), 2.33 (bs, 4H), 2.49 (bs, 4H), 3.70 (s, 2H), 7.05-7.20 (m,
4H), 7.23-7.48 (m, 5H), 7.70 (d, J=6.8 Hz, 1H), 8.25-8.40 (m,
1H).
[0569] Hydrochloride:
[0570] ESI-Mass; 415 (MH.sup.+)
Example 6
1-[-4-cyano-5-methyl-4-phenyl)hexyl]-4-[-2-quinolinyl)methyl]piperazine
[0571] 122
[0572] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 3 (62%). Further, the
hydrochloride of the title compound was obtained in a conventional
method.
[0573] Free Body:
[0574] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.18 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H),
1.90 (dt, J=4.4 Hz, J=12 Hz, 1H), 2.07-2.18 (m, 2H), 2.24-2.35 (m,
2H), 2.38 (bs, 4H), 2.54 (bs, 4H), 3.82 (s, 2H), 7.24-7.30 (m, 1H),
7.32-7.38 (m, 4H), 7.51 (d, J=8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H),
7.66-7.72 (m, 1H), 7.79 (d, J=8 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H),
8.10 (d, J=8.4 Hz, 1H).
[0575] Hydrochloride:
[0576] ESI-Mass; 427 (MH.sup.+)
Example 7
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[-4-phenyl-3-pyridyl)methyl]piperaz-
ine
[0577] 123
[0578] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 3 (47%). Further, the
hydrochloride of the target compound was obtained in a conventional
method.
[0579] Free Body:
[0580] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 1.04-1.18 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.47-1.59 (m, 1H),
1.87 (dt, J=4 Hz, J=12 Hz, 1H), 2.06-2.34 (m, 8H), 2.34 (bs, 4H),
3.39 (s, 2H), 7.18 (d, J=4.8 Hz, 1H), 7.25-7.46 (m, 10H), 8.52 (d,
J=4.8 Hz, 1H), 8.63 (s, 1H).
[0581] Hydrochloride:
[0582] ESI-Mass; 427 (MH.sup.+)
Example 8
1-[-4-Cyano-5-methyl-4-phenyl)hexyl]-4-(1,2,3,4-tetrahydro-2-naphthoyl)pip-
erazine
[0583] 124
[0584] 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine (150 mg) was
dissolved in N,N-dimethylformamide (5 ml). To the mixture were
added 1-hydroxybenzotriazole (71 mg) and
1,2,3,4-tetrahydro-2-naphthenoic acid (93 mg), followed by further
adding a N,N-dimethylformamide solution (2 ml) of
dicyclohexylcarbodiimide (120 mg). After stirring overnight at room
temperature, the insoluble matters were filtered off and ethyl
acetate was added to the filtrate. A small amount of 1N
hydrochloric acid was added and the mixture was stirred. Then, the
mixture was washed with an aqueous saturated sodium carbonate and
further with brine, dried over anhydrous magnesium sulfate, and
then evaporated. The resulting residue was purified by (NH) silica
gel column chromatography (n-hexane/ethyl acetate system), to give
the title compound as a pale yellow oil (220 mg, 94%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0585] Free Body:
[0586] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.04-1.20 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.50-1.63 (m, 1H),
1.86-2.04 (m, 3H), 2.09-2.23 (m, 2H), 2.24-2.36 (m, 6H), 2.75-2.94
(m, 4H), 3.03-3.12 (m, 1H), 3.49 (t, J=4.8 Hz, 2H), 3.56-3.68 (m,
2H), 7.06-7.13 (m, 4H), 7.27-7.40 (m, 5H).
[0587] Hydrochloride:
[0588] ESI-Mass; 444 (MH.sup.+)
Example 9
1[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(1.2.3.4-tetrahydro-2-naphthyl)meth-
yl]piperazine
[0589] 125
[0590] In tetrahydrofuran (5 ml) was dissolved
1-[4-cyano-5-methyl-4-pheny-
l]hexyl]-4-(1,2,3,4-tetrahydro-2-naphthoyl)piperazine (150 mg),
followed by adding 1.0 M borane/tetrahydrofuran complex (1.35 ml)
under ice-cooling. After stirring at room temperature for 5 hours,
the mixture was evaporated. Methanol (5 ml) and 2N hydrochloric
acid (5 ml) were added to the residue, followed by stirring at
80.degree. C. for one hour. After cooling as it was to room
temperature, the mixture was evaporated. Ethyl acetate was added
thereto, and the mixture was washed with an aqueous saturated
sodium carbonate and further brine, dried over anhydrous magnesium
sulfate, and then evaporated. The resulting residue was purified by
preparative thin layer silica gel column chromatography (methylene
chloride/methanol), to give the title compound as a pale yellow oil
(72 mg, 50%). Further, the hydrochloride of the free body (the
title compound) was obtained in a conventional method.
[0591] Free Body:
[0592] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.04-1.20 (m, 2H), 1.20 (d, J=6.8 Hz, 3H), 1.29-1.43 (m, 2H),
1.51-1.63 (m, 2H), 1.65-1.73 (m, 1H), 1.90 (dt, J=4.4 Hz, J=12 Hz,
1H), 1.90-2.00 (m, 4H), 2.08-2.19 (m, 2H), 2.25-2.48 (m, 7H),
2.77-2.92 (m, 3H), 7.04-7.10 (m, 4H), 7.26-7.48 (m, 5H).
[0593] Hydrochloride:
[0594] ESI-Mass; 430 (MH.sup.+)
Example 10
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1.4-benzodioxanoyl]piperazine
[0595] 126
[0596] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 8 (86%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0597] Free Body:
[0598] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.08-1.20 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.51-1.63 (m, 1H),
1.92 (dt, J=4.4 Hz, J=12 Hz, 1H), 2.09-2.23 (m, 2H), 2.25-2.40 (m,
6H), 3.49-3.57 (m, 2H), 3.63-3.76 (m, 2H), 4.30 (dd, J=8 Hz, J=12
Hz, 1H), 4.46 (dd, J=2.8 Hz, J=12 Hz, 1H), 4.79 (dd, J=2.8 Hz, J=8
Hz, 1H), 6.83-6.91 (m, 4H), 7.27-7.40 (m, 5H).
[0599] Hydrochloride:
[0600] ESI-Mass; 448 (MH.sup.+)
Example 11
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1.4-benzodioxanyl)methyl]pipera-
zine
[0601] 127
[0602] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 9 (56%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0603] Free Body:
[0604] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.16-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H),
1.89 (dt, J=4.4 Hz, J=12.8 Hz, 1H), 2.08-2.19 (m, 2H), 2.24-2.34
(m, 2H), 2.36 (bs, 4H), 2.52 (bs, 4H), 2.61 (ddd, J=5.6 Hz, J=13.2
Hz, J=40.4 Hz, 2H), 3.96 (dd, J=7.6 Hz, J=11.6 Hz, 1H), 4.24-4.31
(m, 2H), 6.79-6.89 (m, 4H), 7.26-7.39 (m, 5H).
[0605] Hydrochloride:
[0606] ESI-Mass; 434 (MH.sup.+)
Example 12
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(1-methyl-2-indoloyl)piperazine
[0607] 128
[0608] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 8 (82%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0609] Free Body:
[0610] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.08-1.20 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H),
1.87-1.97 (m, 1H), 2.08-2.22 (m, 2H), 2.28-2.38 (m, 6H), 3.72 (bs,
4H), 3.81 (s, 3H), 6.56 (s, 1H), 7.10-7.16 (m, 1H), 7.25-7.39 (m,
7H), 7.61 (d, J=8 Hz, 1H).
[0611] Hydrochloride:
[0612] ESI-Mass; 443 (MH.sup.+)
Example 13
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(1-methyl-2-indolyl)methyl]piperaz-
ine
[0613] 129
[0614] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 9 (40%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0615] Free Body:
[0616] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.20 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.49-1.62 (m, 1H),
1.89 (dt, J=4.4 Hz, J=12 Hz, 1H), 2.07-2.17 (m, 2H), 2.21-2.37 (m,
6H), 2.44 (bs, 4H), 3.60 (s, 2H), 3.76 (s, 3H), 6.34 (s, 1H), 7.07
(t, J=8 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 7.25-7.38 (m, 6H), 7.54 (d,
J=8 Hz, 1H).
[0617] Hydrochloride:
[0618] ESI-Mass; 429 (MH.sup.+)
Example 14
2-[(4-Cyano-5-methyl-4-phenyl)hexyl]-5-[2-(4-fluorophenoxy)ethyl]-2,5-diaz-
abicyclo[2,2,1]heptane
[0619] 130
[0620] In methanol (5 ml) was dissolved
2-[(4-cyano-5-methyl-4-phenyl)hexy-
l]-5-benzyl-2,5-diazabicyclo[2,2,1]heptane (37 mg). To the mixture
was added 20% palladium hydroxide-carbon (10 mg), followed by
subjecting to hydrogenation at room temperature under normal
pressure for 8 hours. After the catalyst was filtered off, the
filtrate was evaporated, to give the residue as a pale yellow oil
(29 mg). In N,N-dimethylformamide (3 ml) was dissolved the residue,
followed by adding a N,N-dimethylformamide solution (2 ml) of
triethylamine (0.027 ml) and 2-(4-fluorophenoxy) ethyl bromide (25
mg). After stirring at 50.degree. C. overnight, the solution was
left to be cooled to room temperature. Ethyl acetate was added
thereto, and the mixture was washed with water and further brine.
After drying over anhydrous magnesium sulfate, it was evaporated.
The resulting residue was purified by preparative thin layer silica
gel column chromatography (methylene chloride/methanol), to give
the title compound as a pale yellow oil (20 mg, 48%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0621] Free Body:
[0622] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.06-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.45-1.57 (m, 1H),
1.66-1.73 (m, 2H), 1.95 (dt, J=4.4 Hz, J=12 Hz, 1H), 2.11 (qui,
J=6.8 Hz, 1H), 2.14-2.23 (m, 1H), 2.32-2.40 (m, 1H), 2.51-2.61 (m,
2H), 2.63-2.81 (m, 3H), 2.91 (dqui, J=6 Hz, J=40.4 Hz, 2H), 3.21
(s, 1H), 3.36 (s, 1H), 3.94-4.03 (m, 2H), 6.79-6.85 (m, 2H),
6.92-7.00 (m, 2H), 7.26-7.40 (m, 5H).
[0623] Hydrochloride:
[0624] ESI-Mass; 436 (MH.sup.+)
Example 15
8-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-phenyl-1.3.8-triazaspiro[4.5]decan--
4-one
[0625] 131
[0626] In acetonitrile (6 ml) was dissolved
4-cyano-5-methyl-4-phenylhexan- ol (120 mg), followed by adding
triethylamine (0.23 ml) and mesyl chloride (0.051 ml) at room
temperature. After stirring at room temperature for one hour, an
acetonitrile solution (3 ml) of 1-phenyl-1,3,8-triazaspiro-[-
4,5]decan-4-one (140 mg) was added thereto. After heating under
reflux for 2.5 hours, the solution was left tobe cooled to room
temperature. Ethyl acetate was added thereto, and the mixture was
washed with water and further brine. After drying over anhydrous
magnesium sulfate, it was evaporated. The resulting residue was
purified by preparative thin layer silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound as a pale
yellow oil (61 mg, 26%). Further, the hydrochloride of the free
body (the title compound) was obtained in a conventional
method.
[0627] Free Body:
[0628] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.79 (d, J=6.4 Hz,
3H), 1.22 (d, J=6.4 Hz, 3H), 1.26 (t, J=7.2 Hz, 2H), 1.55-1.73 (m,
3H), 1.94-2.05 (m, 1H), 2.08-2.25 (m, 2H), 2.38-2.52 (m, 2H),
2.60-2.90 (m, 6H), 4.72 (s, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.90 (d,
J=8 Hz, 2H), 7.24-7.31 (m, 2H), 7.33-7.41 (m, 4H), 7.62 (bs,
1H).
[0629] Hydrochloride:
[0630] ESI-Mass; 431 (MH.sup.+)
Example 16
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-keto-1-benzimidazolinyl)piperidi-
ne
[0631] 132
[0632] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (23%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0633] Free Body:
[0634] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.79 (d, J=6.8 Hz,
3H), 1.11-1.34 (m, 2H), 1.23 (d, J=6.8 Hz, 3H), 1.55-1.67 (m, 1H),
1.73-1.82 (m, 2H), 1.90-2.05 (m, 2H), 2.08-2.23 (m, 3H), 2.30-2.52
(m, 4H), 2.88-3.02 (m, 2H) 4.28-4.38 (m, 1H) 7.00-7.07 (m, 2H),
7.09-7.13 (m, 1H), 7.22-7.32 (m, 2H), 7.33-7.43 (m, 4H),
10.12-10.30 (m, 1H).
[0635] Hydrochloride:
[0636] ESI-Mass; 417 (MH.sup.+)
Example 17
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzoxazolyl)amino]piperidine
[0637] 133
[0638] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (30%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0639] Free Body:
[0640] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.08-1.19 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.47-1.62 (m, 3H),
1.75-1.83 (m, 1H), 1.89 (dt, J=4.4 Hz, J=13.6 Hz, 1H), 2.00 (bt,
J=12.4 Hz, 1H), 2.04-2.20 (m, 4H), 2.25-2.31 (m, 2H), 2.72 (bt,
J=11.6 Hz, 2H), 3.69-3.80 (m, 1H), 4.92-5.02 (m, 1H), 6.99-7.05 (m,
1H), 7.13-7.17 (m, 1H), 7.20-7.25 (m, 1H), 7.25-7.32 (m, 1H),
7.33-7.40 (m, 5H).
[0641] Hydrochloride:
[0642] ESI-Mass; 417 (MH.sup.+)
Example 18
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzothiazolyl)aminopiperidine
[0643] 134
[0644] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (52%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0645] Free Body:
[0646] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.06-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.46-1.62 (m, 3H),
1.77 (bs, 1H), 1.85-1.94 (m, 1H), 1.96-2.05 (m, 1H), 2.05-2.18 (m,
4H), 2.25-2.32 (m, 2H), 2.70 (bt, J=12.4 Hz, 2H), 3.56-3.66 (m,
1H), 5.24 (bd, J=6.8 Hz, 1H), 7.04-7.09 (m, 1H), 7.25-7.32 (m, 2H),
7.33-7.39 (m, 4H), 7.50-7.58 (m, 2H).
[0647] Hydrochloride:
[0648] ESI-Mass; 433 (MH.sup.+)
Example 19
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzothiazolyl)(methyl)amino]pi-
peridine
[0649] 135
[0650] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (30%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0651] Free Body:
[0652] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.08-1.20 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.51-1.64 (m, 1H),
1.74-2.20 (m, 9H), 2.30 (t, J=7.2 Hz, 2H), 2.82-2.93 (m, 2H), 3.05
(s, 3H), 3.94-4.05 (m, 1H), 7.01-7.06 (m, 1H), 7.24-7.33 (m, 2H),
7.34-7.40 (m, 4H), 7.51-7.59 (m, 2H).
[0653] Hydrochloride:
[0654] ESI-Mass; 447 (MH.sup.+)
Example 20
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzothiazolyl)(2-propyl)amino]-
piperidine
[0655] 136
[0656] In N,N-dimethylformamide (3 ml) was dissolved
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzothiazolyl)amino]piperidin-
e (50 mg) synthesized in Example 18, followed by adding 60% sodium
hydride (7 mg). After stirring at 50.degree. C. for one hour,
2-bromopropane (0.012 ml) was added. After further stirring at
50.degree. C. overnight, 2-bromopropane (0.012 ml) was additionally
added. After further stirring at 50.degree. C. for 6 hours, 60%
sodium hydride (7 mg) was additionally added. After further
stirring at 50.degree. C. overnight, the solution was left to be
cooled to room temperature. Ethyl acetate was added, and the
mixture was washed with water and further brine. After drying over
anhydrous magnesium sulfate, it was evaporated. The resulting
residue was purified by (NH) silica gel column chromatography
(hexane/ethyl acetate system) to give the title compound as a pale
yellow oil (31 mg, 57%). Further, the hydrochloride of the free
body (the title compound) was obtained in a conventional
method.
[0657] Free Body:
[0658] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.4 Hz,
3H), 1.08-1.20 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.50 (d, J=6.8 Hz,
6H), 1.69-2.34 (m, 13H), 2.63-2.74 (m, 2H), 2.81-2.90 (m, 1H),
6.86-6.91 (m, 1H), 6.96-7.02 (m, 1H), 7.11-7.16 (m, 1H), 7.25-7.32
(m, 2H), 7.33-7.41 (m, 4H).
[0659] Hydrochloride:
[0660] ESI-Mass; 475 (MH.sup.+)
Example 21
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(1-methyl-2-benzimidazolyl)amino]p-
iperidine
[0661] 137
[0662] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (12%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0663] Free Body:
[0664] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.06-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.42-1.61 (m, 3H),
1.84-1.93 (m, 1H), 1.98-2.20 (m, 6H), 2.27 (t, J=7.2 Hz, 2H),
2.69-2.76 (m, 2H), 3.45 (s, 3H), 3.86-4.01 (m, 2H), 7.01-7.12 (m,
3H), 7.26-7.31 (m, 1H), 7.33-7.39 (m, 4H), 7.45 (d, J=7.6 Hz,
1H).
[0665] Hydrochloride:
[0666] ESI-Mass; 430 (MH.sup.+)
Example 22
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[[1-2-propyl)-2-benzimidazolyl]amin-
o]piperidine
[0667] 138
[0668] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (54%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0669] Free Body:
[0670] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.08-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.40-1.55 (m, 3H),
1.57 (d, J=6.8 Hz, 6H), 1.85-1.93 (m, 2H), 2.02-2.20 (m, 5H), 2.28
(t, J=7.2 Hz, 2H), 2.67-2.75 (m, 2H), 3.85-4.00 (m, 2H), 4.33 (qui,
J=6.8 Hz, 1H), 6.97-7.10 (m, 2H), 7.20-7.32 (m, 2H), 7.34-7.39 (m,
4H), 7.46-7.48 (m, 1H).
[0671] Hydrochloride:
[0672] ESI-Mass; 458 (MH.sup.+)
Example 23
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5.6-dimethoxy-1-indanon)-2-yl]met-
hylpiperidine
[0673] 139
[0674] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 15 (30%). Further, the
hydrochloride of the free body (the title compound) was obtained in
a conventional method.
[0675] Free Body:
[0676] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.08-1.36 (m, 4H), 1.20 (d, J=6.8 Hz, 3H), 1.38-1.95 (m, 8H),
2.08-2.18 (m, 2H), 2.18-2.32 (m, 2H), 2.65-2.83 (m, 4H), 3.22 (dd,
J=8 Hz, J=17.6 Hz, 1H), 3.90 (s, 3H), 3.96 (s, 3H), 6.86(s, 1H),
7.16 (s, 1H), 7.26-7.41 (m, 5H).
[0677] Hydrochloride:
[0678] ESI-Mass; 489 (MH.sup.+)
Example 24
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[[2-(4-fluorophenoxy)ethyl](2-cyano-
ethyl)amino]piperidine
[0679] 140
[0680] The title compound was obtained as a pale yellow oil (21%)
in accordance with the method of Example 35 described later.
Further, the hydrochloride of the free body (the title compound)
was obtained in a conventional method.
[0681] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.18 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.42-1.61 (m, 3H),
1.66-1.80 (m, 3H), 1.83-1.92 (m, 2H), 2.08-2.17 (m, 2H), 2.19-2.32
(m, 2H), 2.43-2.53 (m, 1H), 2.44 (t, J=6.8 Hz, 2H), 2.78-2.94 (m,
6H), 3.92 (t, J=6 Hz, 2H), 6.79-6.85 (m, 2H), 6.94-7.00 (m, 2H),
7.27-7.39 (m, 5H).
[0682] Hydrochloride:
[0683] ESI-Mass; 491 (MH.sup.+)
Example 25
1-[4-Cyano-5-methyl-4-(2-naphthyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piper-
azine
[0684] 141
[0685] In acetonitrile (5 ml) was dissolved 310 mg (1.16 mmol) of
4-cyano-5-methyl-4-(2-naphthyl)hexanol, followed by adding 190
.mu.L (1.36 mmol) of triethylamine and 105 .mu.l (1.36 mmol) of
mesyl chloride. After completion of mesylation, 1.11 g (7.38 mmol)
of sodium iodide, 255 mg (1.85 mmol) of potassium carbonate, 414 mg
(1.85 mmol) of 1-[2-(4-fluorophenoxy)ethyl]piperazine, 5 ml of
dimethylformamide and 1 ml of water were added thereto, followed by
heating to 60.degree. C. After completion of the reaction, brine
was added thereto and the objective product was extracted with
ethyl acetate. The organic layer was washed with brine, and then
dried over anhydrous magnesium sulfate. The solvent was evaporated,
to give a crude product. The crude product was subjected to (NH)
silica gel (eluted with ethyl acetate/hexane=2/3), to give 384 mg
(0.81 mmol, 69.9%) of the title compound as a yellow syrup.
[0686] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.79 (d, J=6.8 Hz,
3H), 1.05-1.15 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 1.50-1.65 (m, 1H),
1.93-2.05 (m, 1H), 2.18-2.60 (m, 12H), 2.75 (t, J=5.8 Hz, 1H), 4.02
(t, J=5.8 Hz, 2H), 6.78-6.83 (m, 2H), 6.91-6.97 (m, 2H), 7.36 (dd,
J=2.0 Hz, 8.8 Hz, 1H), 7.48-7.54 (m, 2H), 7.81-7.88 (m, 3H), 7.94
(brd-s, 1H)
[0687] ESI-Mass; 474 (M+H.sup.+)
Example 26
1-[4-Cyano-5-methyl-4-(1-naphthyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piper-
azine
[0688] 142
[0689] The title compound was obtained as a colorless oil in
accordance with the method of Example 25 (yield: 57.8%).
[0690] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.70-0.90 (m, 3H),
0.95-1.10 (m, 1H), 1.20-1.40 (m, 4H), 1.50-1.65 (m, 1H), 1.93-2.05
(m, 1H), 2.10-2.56 (m, 10H), 2.56-2.70 (m, 1H), 2.73 (t, J=5.8 Hz,
1H), 2.90-3.00 (m, 1H), 4.01 (t, J=5.8 Hz, 2H), 6.78-6.83 (m, 2H),
6.91-6.97 (m, 2H), 7.40-7.50 (m, 3H), 7.78-7.92 (m, 3H), 8.22-8.31
(brd-s, 1H)
[0691] ESI-Mass; 474 (M+H.sup.+)
Example 27
1-[4-Cyano-5-methyl-4-(2-pyridyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]pipera-
zine
[0692] 143
[0693] 4-Cyano-5-methyl-4-(2-pyridyl)hexanol synthesized in
accordance with the method of Example 25 was oxidized by
SO.sub.3-pyridine, which is a conventional method. The resulting
crude aldehyde compound was subjected to reductive amination
reaction in accordance with the method of Example 42 which is
described later, to synthesize the title compound as a colorless
oil (yield: 69.1%).
[0694] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.74 (d, J=6.8 Hz,
3H), 0.90-1.10 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.24-1.30 (m, 1H),
1.53-1.66 (m, 1H), 2.03-2.23 (m, 2H), 2.24-2.74 (m, 1H), 2.81 (t,
J=5.4 Hz, 2H), 4.06 t, J=5.4 Hz, 2H), 6.79-6.85 (m, 2H), 6.92-6.98
(m, 2H), 7.21 (ddd, J=1.2 Hz, 4.8 Hz, 8.0 Hz, 1H), 7.57 (dt, J=1.2
Hz, 8.0 Hz, 1H), 7.69 (dt, J=2.0 Hz, 8.0 Hz, 1H), 8.58-8.62 (m,
1H)
[0695] ESI-Mass; 425 (M+H.sup.+)
Example 28
1-[4-Cyano-5-methyl-4-(4-pyridyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]pipera-
zine
[0696] 144
[0697] The title compound was obtained as a yellow oil in
accordance with the method of Example 25 (yield: 70%).
[0698] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.79 (d, J=6.8 Hz,
3H), 1.00-1.20 (m, 1H), 1.22 (d, J=6.4 Hz, 3H), 1.50-1.64 (m, 1H),
1.85-2.00 (m, 1H), 2.08-2.25 (m, 2H), 2.26-2.75 (m, 10H), 2.82 (t,
J=5.4 Hz, 2H), 4.07 (t, J=5.4 Hz, 2H), 6.79-6.85 (m, 2H), 6.92-6.98
(m, 2H), 7.31 (dd, J=1.6 Hz, 4.4 Hz, 2H), 8.63 (dd, J=1.6 Hz, 4.4
Hz, 2H)
[0699] ESI-Mass; 425 (M+H.sup.+)
Example 29
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-phenylpiperazine
[0700] 145
[0701] In acetonitrile (2 ml) was dissolved 100 mg (0.30 mmol) of
4-cyano-5-methyl-5-phenylhexyl iodide. To the mixture were added 55
mg (0.36 mmol) of potassium carbonate and 60 mg (0.36 mmol) of
phenylpiperazine, followed by heating to 60.degree. C. After
completion of the reaction, the solution was partitioned with ethyl
acetate and brine. The organic layer was dried over magnesium
sulfate, and then evaporated, to give a crude product. The crude
product was subjected to 20 g of Chromatorex NH silica gel (ethyl
acetate/hexane=1/5), to give 137 mg (quantitative) of the title
compound as a colorless syrup. The physico-chemical data of the
title compound was as below.
[0702] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.4 Hz,
3H), 1.08-1.26 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.52-1.66 (m, 1H),
1.88-1.98 (m, 1H), 2.08-2.23 (m, 2H), 2.28-2.37 (m, 2H), 2.42-2.52
(m, 4H), 3.10-3.20 (m, 4H), 6.82-6.86 (m, 1H), 6.88-6.92 (m, 2H),
7.22-7.32 (m, 4H), 7.34-7.40 (m, 3H)
[0703] ESI-Mass; 362 (M+H.sup.+)
Example 30
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-phenylethyl)piperazine
[0704] 146
[0705] The title compound was synthesized by using
1-(2-phenylethyl)pipera- zine in accordance with the method of
Example 29 (yield: 100%: a colorless oil).
[0706] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.4 Hz,
3H), 1.08-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.63 (m, 1H),
1.84-1.93 (m, 1H), 2.07-2.19 (m, 2H), 2.24-2.60 (m, 12H), 2.74-2.82
(m, 2H), 7.16-7.21 (m, 3H), 7.24-7.31 (m, 3H), 7.35-7.38 (m,
4H)
[0707] ESI-Mass; 390 (M+H.sup.+)
Example 31
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(3-phenylpropyl)piperazine
[0708] 147
[0709] The title compound was synthesized by using
1-(3-phenylpropyl)piper- azine in accordance with the method of
Example 29 (yield; 100%: a colorless oil).
[0710] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.04-1.20 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.50-1.62 (m, 1H),
1.74-1.92 (m, 3H), 2.06-2.18 (m, 2H), 2.20-2.50 (m, 12H), 2.61 (t,
J=7.6 Hz, 2H), 7.14-7.19 (m, 3H), 7.23-7.31 (m, 3H), 7.34-7.37 (m,
4H)
[0711] ESI-Mass; 404 (M+H.sup.+)
Example 32
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(3-fluorophe-
noxy)ethyl}amino]pyrrolidine
[0712] 148
[0713] In dichloromethane (7 ml) was dissolved 250 mg (0.74 mmol)
of
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidine-
, followed by successively adding 171 mg (1.11 mmol) of
3-fluorophenoxyacetaldehyde separately synthesized, 0.08 ml (1.48
mmol) of acetic acid and 235 mg (1.11 mmol) of sodium
triacetoxyborohydride. After completion of the reaction, the
solution was adjusted to basic with a 2N sodium hydroxide, and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate, and evaporated, to give a
crude product. The crude product was subjected to 25 g of
Chromatorex NH silica gel (ethyl acetate/hexane=1/3), to give 290
mg (0.61 mmol, 82.2%) of the title compound as a colorless
syrup.
[0714] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.25 (m, H), 1.20 (d, J=6.8 Hz, 3H), 1.47-1.80 (m, 2H),
1.85-2.28 (m, 4H), 2.29-2.70 (m, 6H), 2.48 (t, J=6.8 Hz, 2H),
2.90-3.25 (m, 4H), 3.40-3.55 (m, 1H), 3.98 (t, J=5.6 Hz, 2H),
6.56-6.62 (m, 1H), 6.63-6.90 (m, 3H), 7.18-7.25 (m, 1H), 7.26-7.40
(m, 5H)
[0715] ESI-Mass; 477 (M+H.sup.+)
Example 33
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-N-2-cyanoethyl)-N-{2-(3-cyanophenox-
y)ethyl}amino]pyrrolidine
[0716] 149
[0717] In dichloromethane (7 ml) was dissolved 250 mg (0.74 mmol)
of
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidine-
, followed by successively adding 179 mg (1.11 mmol) of
3-cyanophenoxyacetaldehyde separately synthesized in the same
manner as in the production of 3-fluorophenoxyacetaldehyde, 0.08 ml
(1.48 mmol) of acetic acid and 235 mg (1.11 mmol) of sodium
triacetoxyborohydride. After completion of the reaction, the
solution was adjusted to basic with a 2N sodium hydroxide and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 25 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1/3), to give 318 mg (0.66 mmol,
88.9%) of the title compound as a colorless syrup.
[0718] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.25 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.47-1.80 (m, 2H),
1.85-2.28 (m, 4H), 2.29-2.72 (m, 6H), 2.48 (t, J=6.8 Hz, 2H),
2.90-3.05 (m, 4H), 3.42-3.55 (m, 1H), 4.01 (t, J=5.6 Hz, 2H),
7.11-7.15 (m, 2H), 7.23-7.40 (m, 7H)
[0719] ESI-Mass; 484 (M+H.sup.+)
Example 34
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(2-cyanophen-
oxy)ethyl}amino]pyrrolidine
[0720] 150
[0721] In dichloromethane (7 ml) was dissolved 263 mg (0.78 mmol)
of
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidine-
, followed by successively adding 251 mg (1.56 mmol) of
3-cyanophenoxyacetaldehyde separately synthesized, 0.09 ml (1.56
mmol) of acetic acid and 247 mg (1.17 mmol) of sodium
triacetoxyborohydride. After completion of the reaction, the
solution was adjusted to basic with a 2N sodium hydroxide, and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 25 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1/3), to give 311 mg (0.64 mmol,
82.4%) of the title compound as a yellow syrup.
[0722] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.25 (m, 1H), 1.19 (d, J=6.4 Hz, 3H), 1.45-1.80 (m, 2H),
1.85-2.16 (m, 3H), 2.16-2.70 (m, 7H), 2.54 (t, J=6.8 Hz, 2H),
2.90-3.12 (m, 4H), 3.45-3.60 (m, 1H), 4.11 (t, J=6.8 Hz, 2H),
6.40-7.04 (m, 2H), 7.26-7.40 (m, 5H), 7.50-7.58 (m, 2H)
[0723] ESI-Mass; 484 (M+H.sup.+)
Example 35
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(4-cyanophen-
oxy)ethyl}amino]pyrrolidine
[0724] 151
[0725] In acetonitrile (5.00 ml) was dissolved 217 mg (1.00 mmol)
of 4-cyano-5-methyl-5-phenylhexylhexanol, followed by cooling to
0.degree. C. To the mixture were added 320 .mu.l (2.30 eq) of
triethylamine and 85 .mu.l (1.10 eq) of mesyl chloride, followed by
heating to room temperature. After 15 minutes, 450 mg (3.00 eq) of
sodium iodide and 370 mg (1.30 mmol) of
3-[N-(2-cyanoethyl)-N-{2-(4-cyanophenoxy)ethyl}amino]py- rrolidine
were added, and the mixture was heated to 60.degree. C. After
completion of the reaction, brine was added and the objective
product was extracted with ethyl acetate. The organic layer was
washed with brine, and then dried over anhydrous magnesium sulfate.
The solvent was evaporated, to give a crude product. The crude
product was subjected to 37 g of Cromatorex NH silica gel (ethyl
acetate/hexane=1/1), to give 316 mg (0.65 mmol, 65%) of the title
compound as a yellow syrup.
[0726] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.10-1.25 (m, 1H), 1.19 (d, J=6.4 Hz, 3H), 1.48-1.63 (m, 1H),
1.65-1.77 (m, 1H), 1.78-1.97 (m, 1H), 1.98-2.17 (m, 2H), 2.19-2.30
(m, 1H), 2.30-2.73 (m, 6H), 2.48 (t, J=6.8 Hz, 2H), 2.90-3.07 (m,
4H), 3.43-3.56 (m, 1H), 4.04 (t, J=5.8 Hz, 2H), 6.94 (d, J=9.2 Hz,
2H), 7.27-7.34 (m, 1H), 7.34-7.40 (m, 4H), 7.59 (d, J=9.2 Hz,
2H)
[0727] ESI-Mass; 484 (M+H.sup.+)
Example 36
1-[((4-Cyano-5-methyl-4-(2-thienyl))hexyl]-3-[N-(2-cyanoethyl)-N-{2-(4-cya-
nophenoxy)ethyl}amino]pyrrolidine
[0728] 152
[0729] The title compound was synthesized by using
4-cyano-5-methyl-5-(2-t- hienyl)hexanol in accordance with the
method of Example 35 (yield: 38%; a pale yellow syrup).
[0730] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.25-1.40 (m, 1H), 1.55-1.85 (m, 2H),
1.98-2.12 (m, 3H), 2.18-2.78 (m, 7H), 2.48 (t, J=6.8 Hz, 2H),
2.90-3.10 (m, 4H), 3.44-3.58 (m, 1H), 4.05 (t, J=5.6 Hz, 2H),
6.92-6.98 (m, 3H), 7.10-7.13 (m, 1H), 7.25-7.29 (m, 1H), 7.59 (d,
J=8.8 Hz, 2H)
[0731] ESI-Mass; 490 (M+H.sup.+)
Example 37
1-[(4-Cyano-5-methyl-4-(2-thienyl))hexyl]-3-[N-(2-cyanoethyl)-N-{2-(3-cyan-
ophenoxy)ethyl]amino]pyrrolidine
[0732] 153
[0733] The title compound was synthesized by using
4-cyano-5-methyl-5-(2-t- hienyl)hexanol and
3-cyanophenoxyacetaldehyde in accordance with the method of Example
35 (yield: 98%; a pale yellow syrup).
[0734] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.28-1.45 (m, 1H), 1.58-1.90 (m, 2H),
2.00-2.15 (m, 3H), 2.20-2.31 (m, 1H), 2.32-2.80 (m, 6H), 2.49 (t,
J=6.8 Hz, 2H), 2.90-3.08 (m, 4H), 3.47-3.62 (m, 1H), 4.02 (t, J=5.6
Hz, 2H), 6.96 (dd, J=5.2 Hz, 3.6 Hz, 1H), 7.11-7.16 (m, 3H),
7.24-7.29 (m, 2H), 7.38 (dd, J=7.8 Hz, 9.0 Hz, 1H)
[0735] ESI-Mass; 490 (M+H.sup.+)
Example 38
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(6-phenylpyridine-3-yl)methyl]pipe-
razine
[0736] 154
[0737] (6-Phenylpyridin-3-yl)methanol (185 mg, 1.00 mmol) and
triethylamine 0.29 ml were dissolved in 5 ml of acetonitrile, and
85.1 .mu.l (1.10 mmol) of methanesulfonyl chloride was added
dropwise thereinto. After confirming the extinction of a raw
material by thin layer chromatography, 340 mg (1.19 mmol) of
1-[(4-cyano-5-methyl-4-phenyl- )hexyl]piperazine was added to the
reaction solution at room temperature, and successively 899 mg of
sodium iodide, 5 ml of dimethylformamide and 1 ml of water were
added. Then, the mixture was heated to 80.degree. C. After
completion of the reaction, brine was added and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 50 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1/2), to give 300 mg (0.66 mmol,
66.3%) of the title compound as a yellow oil.
[0738] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.26 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.48-1.64 (m, 1H),
1.84-1.97 (m, 1H), 2.06-2.22 (m, 2H), 2.23-2.60 (m, 10H), 3.54 (s,
2H), 7.24-7.32 (m, 1H), 7.32-7.43 (m, 5H), 7.43-7.50 (m, 2H),
7.66-7.74 (m, 2H), 7.95-7.99 (m, 2H), 8.58 (brd-s, 1H)
[0739] ESI-Mass; 453 (M+H.sup.+)
Example 39
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5-phenylisoxazo-3-yl)methyl]piper-
azine
[0740] 155
[0741] (5-Phenylisoxazol-3-yl)methanol (61.3 mg, 0.35 mmol) and
triethylamine 0.10 ml were dissolved in 3 ml of acetonitrile,
followed by adding dropwise 27.1 .mu.l (0.35 mmol) of
methanesulfonyl chloride thereinto. After confirming the extinction
of a raw material by thin layer chromatography, 100 mg (0.35 mmol)
of 1-[(4-cyano-5-methyl-4-phenyl- )hexyl]piperazine was added to
the reaction solution at room temperature, and successively 262 mg
of sodium iodide and 2 ml of dimethylformamide were added. Then,
the mixture was heated to 70.degree. C. After completion of the
reaction, brine was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
magnesium sulfate and evaporated, to give a crude product. The
crude product was subjected to 15 g of Cromatorex NH silica gel
(ethyl acetate/hexane=2/3), to give 45 mg (0.10 mmol, 29.0%) of the
title compound as a yellow syrup.
[0742] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.26 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.48-1.64 (m, 1H),
1.86-1.98 (m, 1H), 2.06-2.20 (m, 2H), 2.25-2.70 (m, 10H), 3.63 (s,
2H), 6.54 (s, 1H), 7.24-7.32 (m, 1H), 7.32-7.39 (m, 4H), 7.39-7.49
(m, 3H), 7.74-7.79 (m, 2H)
[0743] ESI-Mass; 443 (M+H.sup.+)
Example 40
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-phenylthiazo-4-yl)methyl]pipera-
zine
[0744] 156
[0745] (2-Phenylthiazol-4-yl)methanol (66.9 mg, 0.35 mmol) and 0.10
ml of triethylamine were dissolved in 3 ml of acetonitrile, and
27.1 .mu.l (0.35 mmol) of methanesulfonyl chloride was added
dropwise thereinto. After confirming the extinction of a raw
material by thin layer chromatography, 100 mg (0.35 mmol) of
1-[(4-cyano-5-methyl-4-phenyl)hexyl- ]piperazine was added to the
reaction solution at room temperature. Further, 262 mg of sodium
iodide, 2 ml of dimethylformamide and 2 ml of acetonitrile were
added thereto, followed by heating to 70.degree. C. After
completion of the reaction, brine was added thereto and the mixture
was extracted with ethylacetate. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 15 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1/2), to give 63 mg (0.14 mmol,
40.0%) of the title compound as a colorless syrup.
[0746] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.25 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.48-1.64 (m, 1H),
1.82-1.98 (m, 1H), 2.05-2.22 (m, 2H), 2.23-2.80 (m, 10H), 3.74 (s,
2H), 7.13 (s, 1H), 7.25-7.32 (m, 1H), 7.32-7.39 (m, 4H), 7.39-7.45
(m, 3H), 7.91-7.95 (m, 2H)
[0747] ESI-Mass; 459 (M+H.sup.+)
Example 41
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-phenyloxazo-4-yl)methyl]piperaz-
ine
[0748] 157
[0749] (2-Phenyloxazol-4-yl) methanol (61.3 mg, 0.35 mmol) and 0.10
ml of triethylamine were dissolved in 3 ml of acetonitrile, and
27.1 .mu.l (0.35 mmol) of methanesulfonyl chloride was added
dropwise thereinto. After confirming the extinction of a raw
material by thin layer chromatography, 100 mg (0.35 mmol) of
1-[(4-cyano-5-methyl-4-phenyl)hexyl- ]piperazine was added to the
reaction solution at room temperature. Further, 262 mg of sodium
iodide and 2 ml of dimethylformamide were added thereto, followed
by heating to 70.degree. C. After completion of the reaction, brine
was added thereto and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium
sulfate and evaporated, to give a crude product. The crude product
was subjected to 15 g of Cromatorex NH silica gel (ethyl
acetate/hexane=2/3), to give 41 mg (0.09 mmol, 26.5%) of the title
compound as a colorless syrup.
[0750] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.07-1.24 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.49-1.64 (m, 1H),
1.84-1.96 (m, 1H), 2.06-2.20 (m, 2H), 2.26-2.74 (m, 10H), 3.54 (s,
2H), 7.24-7.32 (m, 1H), 7.32-7.39 (m, 4H), 7.41-7.46 (m, 3H), 7.58
(s, 1H), 8.01-8.06 (m, 2H)
[0751] ESI-Mass; 443 (M+H.sup.+)
[0752] Further, in the above-mentioned Examples,
(6-phenylpyridin-3-yl)met- hanol and
(5-phenylisoxazol-3-yl)methanol are synthesized in accordance with
the method described in Med.Chem.1998, 41, 2390-2410,
(2-phenyloxazol-4-yl)methanol was synthesized in accordance with
the method described in Org.Chem.1996, 61, 6496-6497, and
(2-phenylthiazol-4-yl)methanol was synthesized in accordance with
the method described in Bull. Chem. Soc. Jpn. 71, 1391-1396
(1998).
Example 42
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-phenyl-2-oxo-3-oxazolidinyl)e-
thyl]piperazine
[0753] 158
[0754] 5 ml of 2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde
dimethylacetal was dissolved in 5 ml of acetone and 6 mL of 2.5N
hydrochloric acid, and the mixture was heated. After completion of
the reaction, the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium sulfate
and evaporated, to give 300 mg of a crude product of
2-(4-phenyl-2-oxo-3-oxazolidinyl)acetal- dehyde. The crude product
was used for the following reaction without purification. Namely,
2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde was dissolved in 5 ml
of dichloroethane, and 300 mg (1.46 mmol) of the above-mentioned
2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde, 0.11 ml (2.00 mmol)
of acetic acid and 318 mg (1.50 mmol) of sodium
triacetoxyborohydride were successively added. After completion of
the reaction, the solution was adjusted to basic with a 2N sodium
hydroxide, and extracted with ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate and evaporated, to
give a crude product. The crude product was subjected to 50 g of
Cromatorex NH silica gel (ethyl acetate/hexane=1/1), to give 477 mg
(0.94 mmol, 94.2%) of the title compound as a colorless syrup.
[0755] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.08-1.22 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.48-1.63 (m, 1H),
1.85-1.96 (m, 1H), 2.06-2.18 (m, 2H), 2.20-2.52 (m, 12H), 2.84 (dt,
J=6.4 Hz, 14.4 Hz, 1H), 3.57 (dt, J=6.4 Hz, 14.4 Hz, 1H), 4.05 (dd,
J=7.6 Hz, 8.8 Hz, 1H), 4.61 (t, J=8.8 Hz, 1H), 4.90-4.98 (m, 1H),
7.25-7.32 (m, 2H), 7.34-7.43 (m, 8H)
[0756] ESI-Mass; 475 (M+H.sup.+)
Example 43
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(3-phenyl-2-oxo-5-oxazolidinyl)met-
hyl]piperazine
[0757] 159
[0758] 5-(Hydroxymethyl)-3-phenyl-2-oxooxazolidine was synthesized
in accordance with the method described in J. Med. Chem. 989
673-1681. The 5-(hydroxymethyl)-3-phenyl-2-oxooxazolidine (193 mg,
1.00 mmol) and 0.29 ml of triethylamine were dissolved in 5 ml of
acetonitrile, followed by adding dropwise 85.1 .mu.l (1.10 mmol) of
methanesulfonyl chloride thereinto. After confirming the extinction
of a raw material by thin layer chromatography, 340 mg (1.19 mmol)
of 1-[(4-cyano-5-methyl-4-phenyl- ) hexyl]piperazine was added to
the reaction solution at a room temperature, and successively 899
mg of sodium iodide, 5 ml of dimethylformamide and 1 ml of water
were added. Then, the mixture was heated to 60.degree. C. After
completion of the reaction, brine was added and the mixture was
extracted with ethylacetate. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 50 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1/1), to give 110 mg (0.24 mmol,
23.9%) of the title compound as a yellow oil.
[0759] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.10-1.25 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.65 (m, 1H),
1.86-2.03 (m, 1H), 2.05-2.22 (m, 2H), 2.22-2.80 (m, 12H), 3.75-3.82
(m, 1H), 4.06 (t, J=8.8 Hz, 1H), 4.70-4.80 (m, 1H), 7.11-7.16 (m,
1H), 7.27-7.33 (m, 1H), 7.33-7.40 (m, 6H), 7.51-7.56 (m, 2H)
[0760] ESI-Mass; 461 (M+H.sup.+)
Example 44
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5-phenyl-1,2,4-oxadiazol-3-yl)met-
hyl]piperazine
[0761] 160
[0762] In tetrahydrofuran (3 ml) were dissolved 95.3 Mg (0.70 mmol)
of benzamidoxime and molecular sieve 4A (400 mg). To the mixture
were added 32 mg (0.8 mmol) of sodium hydride and further 20 mg
were added, followed by heating to 60.degree. C. After 10 minutes,
3 ml of tetrahydrofuran solution of 500 mg (1.40 mmol) of
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4--
[(methoxycarbonyl)methyl]piperazine was added thereto, followed by
heating under reflux. After completion of the reaction, brine was
added and the mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried over magnesium sulfate and
evaporated, to give a crude product. The crude product was
subjected to preparative chromatography (ethyl acetate: 10%) and
further subjected to 25 g of Cromatorex NH silica gel (ethyl
acetate/hexane=3:5), to give 127 mg (0.29 mmol, 40.9%) of the title
compound as a colorless oil.
[0763] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.4 Hz,
3H), 1.04-1.20 (m, 1H), 1.19 (d, J=6.4 Hz, 3H), 1.45-1.60 (m, 1H),
1.80-1.92 (m, 1H), 2.05-2.18 (m, 2H), 2.22-2.31 (3m, 2H), 2.31-2.50
(m, 4H), 2.55-2.70 (m, 4H), 3.90 (s, 2H), 4.06 (t, J=8.8 Hz, 1H),
4.70-4.80 (m, 1H), 7.25-7.32 (m, 1H), 7.33-7.37 (m, 4H), 7.45-7.51
(m, 3H), 8.06-8.10 (m, 2H)
[0764] ESI-MS; 444 (M+H.sup.+)
Example 45
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5-(3-fluorophenyl)-1,2,4-oxadiazo-
l-3-yl)methyl]piperazine
[0765] 161
[0766] The title compound was synthesized by using
3-fluorobenzamidoxime in accordance with the method for producing
1-[(4-cyano-5-methyl-4-phenyl-
)hexyl]-4-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]piperazine in
Example 44 (yield; 26%: a pale yellow syrup).
[0767] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.22 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H),
1.83-1.96 (m, 1H), 2.05-2.20 (m, 2H), 2.20-2.54 (m, 6H), 2.55-2.76
(m, 4H), 3.90 (s, 2H), 4.06 (t, J=8.8 Hz, 1H), 4.70-4.80 (m, 1H),
7.17-7.25 (m, 1H), 7.25-7.32 (m, 1H), 7.32-7.38 (m, 4H), 7.42-7.48
(m, 1H), 7.77-7.82 (m, 1H), 7.86-7.90 (m, 1H)
[0768] ESI-MS; 462 (M+H.sup.+)
Example 46
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-(4-fluorophenoxy)ethyl]piperidi-
ne
[0769] 162
[0770] In acetonitrile (2 ml) was dissolved 100 mg (0.30 mmol) of
4-cyano-5-methyl-4-phenylhexyl iodide. To the mixture were added 55
mg (0.36 mmol) of sodium carbonate and 80 mg (0.36 mmol) of
4-[(2-(4-fluorophenoxy)ethyl)piperidine, followed by heating to
60.degree. C. After completion of the reaction, the mixture was
partitioned between ethyl acetate and brine. The organic layer was
dried over magnesium sulfate and then evaporated, to give a crude
product. The crude product was subjected to 40 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1:5), to give 120 mg (0.28 mmol,
94.7%) of the title compound as a colorless syrup. The
physico-chemical data of the title compound was as below.
[0771] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.24 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.22-1.32 (m, 2H),
1.42-1.80 (m, 7H), 1.81-1.92 (m, 2H), 2.07-2.18 (m, 2H), 2.20-2.28
(m, 2H), 2.70-2.80 (m, 2H), 3.93 (t, J=6.8 Hz, 2H), 6.78-6.83 (m,
2H), 6.92-6.98 (m, 2H), 7.25-7.38 (m, 5H)
[0772] ESI-MS; 423 (M+H.sup.+)
Example 47
1-Benzyl-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine
[0773] 163
[0774] In DMF (70 ml) was dissolved 2.39 g (15.0 mmol) of
3-methyl-2-phenylpentanenitrile. To the mixture was added 600 mg
(60% by weight, 15.0 mmol) of sodium hydride, followed by heating
to 60.degree. C. After 30 minutes, the reaction solution was
returned to room temperature, 2.90 g (9.31 mmol) of
1-benzyl-4-methanesulfonyloxypropylpip- eridine dissolved in 10 ml
of DMF was added, and the mixture was heated again. After
completion of the reaction, the mixture was partitioned between
ethyl acetate and brine. The organic layer was dried over magnesium
sulfate, and then evaporated, to give a crude product. The crude
product was subjected to 100 g of silica gel (ethyl
acetate/hexane=1/100 to 1/0), to give 2.57 g (6.86 mmol, 73.7%) of
the title compound as a yellow oil.
[0775] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.85-0.98 (m, 1H), 1.06-1.26 (m, 6H), 1.18 (d, J=6.4 Hz, 3H),
1.30-1.44 (m, 1H), 1.44-1.56 (m, 2H), 1.74-1.90 (m, 3H), 2.03-2.15
(m, 2H), 2.76-2.86 (m, 2H), 3.44 (s, 2H), 7.20-7.38 (m, 10H)
Example 48
1-[(2-(4-Fluorophenoxy)ethyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidi-
ne
[0776] 164
[0777] In acetonitrile (5 ml) was dissolved 200 mg (0.70 mmol) of
4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine. To the mixture were
added 69 mg (0.50 mmol) of potassium carbonate and 110 mg (0.50
mmol) of 4-fluorophenoxyethyl bromide, followed by heating to
60.degree. C. After completion of the reaction, the mixture was
partitioned between ethyl acetate and brine. The organic layer was
dried over magnesium sulfate, and then evaporated, to give a crude
product. The crude product was subjected to 40 g of Cromatorex NH
silica gel (ethyl acetate/hexane=1/7), to give 160 mg (0.38 mmol,
76.0%) of the title compound as a colorless syrup. The
physico-chemical data of the compound was as below.
[0778] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.85-0.98 (m, 1H), 1.10-1.30 (m, 5H), 1.19 (d, J=6.8 Hz, 3H),
1.30-1.43 (m, 1H), 1.50-1.66 (m, 2H), 1.74-1.85 (m, 1H), 1.92-2.03
(m, 2H), 2.05-2.14 (m, 2H), 2.72 (t, J=6.0 Hz, 2H), 2.88-2.95 (m,
2H), 4.03 (t, J=6.0 Hz, 2H), 6.79-6.84 (m, 2H), 6.92-6.98 (m, 2H),
7.26-7.38 (m, 5H)
[0779] ESI-MS; 423 (M+H.sup.+)
Example 49
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-cyano-3-(2-thienyl)propyl]pipipe-
razine
[0780] 165
[0781] The free body of the title compound was obtained as a yellow
oil from 3-cyano-3-(2-thienyl)propanol (114 mg) and
1-[(4-cyano-5-methyl-4-ph- enyl)hexyl]piperazine(90 mg) (refer to
Formula 86 shown in JP-A 10-280103) (63 mg, 22%).
[0782] Free Body:
[0783] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.73 (m, 2H),
1.82-1.95 (m, 2H), 1.95-2.08 (m, 2H), 2.08-2.18 (m, 2H), 2.20-2.45
(m, 10H), 4.10-4.15 (m, 1H), 6.90-6.99 (m, 1H), 7.04-7.06 (m, 1H),
7.26-7.30 (m, 1H), 7.35-7.40 (m, 5H).
[0784] Further, 63 mg of the above-mentioned free body (the title
compound) was treated in a conventional method, to give 60 mg of
the hydrochloride.
[0785] Hydrochloride:
[0786] ESI-Mass; 449 (MH.sup.+)
Example 50
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(4-cyano-4-(4'-fluorophenyl)butyl)-
piperazine
[0787] 166
[0788] 2-[(3-Cyano-3-phenyl)propyl}-1,3-dioxolane (1.77 g) was
dissolved in a solution of 2N HCl (15 mL) and tetrahydrofuran (15
mL). After stirring at room temperature for 13 hours, 2N NaOH (15
mL) and ethyl acetate were added thereto, to separate the organic
layer. The resulting organic layer was washed with water and brine,
and dried over anhydrous magnesium sulfate. After filtering off the
drying agent, the mixture was evaporated. 99 mg among the residue
obtained (5-oxo-2-phenylpropanenitril- e),
1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (99 mg) and acetic
acid (0.1 mL) were dissolved in dichloromethane (3.5 mL), and
sodium triacetoxyborohydride (147 mg) was added. After stirring at
room temperature for 18 hours 30 minutes, the mixture was
neutralized by adding an aqueous saturated sodium bicarbonate
thereto, and then extracted with dichloromethane. The resulting
organic layer was dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the mixture was evaporated. The
resulting residue was purified by NH silica gel column
chromatography (hexane/ethyl acetate system), to give the title
compound (136 mg, 88%: yield was calculated based on
1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine).
[0789] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.04-1.19 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.50-1.70 (m, 3H),
1.80-2.00 (m, 3H), 2.08-2.20 (m, 2H), 2.20-2.45 (m, 12H), 3.80-3.88
(m, 1H), 7.25-7.40 (m, 9H).
[0790] Further, 136 mg of the above-mentioned free body (the title
compound) was treated according to a conventional method, to give
141 mg of the hydrochloride.
[0791] Hydrochloride:
[0792] ESI-Mass; 461 (MH.sup.+)
Example 51
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[4-hydroxime-4-(4'-fluorophenyl)but-
yl]piperazine
[0793] 167
[0794] An acetonitrile solution (10 mL) in which
1-[(4-cyano-5-methyl-4-ph- enyl)hexyl]piperazine (100 mg),
4-chloro-4'-fluorobutyrophenone (91 mg) and triethylamine (0.1 mL)
were dissolved was stirred under a reflux condition. After 6 hours,
the reaction solution was cooled to a room temperature, the organic
layer was seprated by adding water and ethyl acetate. The resulting
organic layer was washed with water and brine, and dried over
anhydrous magnesium sulfate. After filtering off the drying agent,
the filtrate was evaporated. The resulting residue was purified
with silica gel column chromatography (methanol/ethyl acetate
system), to give
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[4-(4-fluorophenyl)butane-1-o-
n]piperazine as a precursor (56 mg). 27 mg among the product was
dissolved in ethanol (2 mL), and hydroxyammonium chloride (8.3 mg)
and sodium acetate (9.8 mg) were added, and the mixture was stirred
under a reflux condition. After 2 hours, the solution was cooled to
a room temperature, and the organic layer was separated by adding
water and ethyl acetate. The resulting organic layer was washed
with water and brine, and dried over anhydrous magnesium sulfate.
After filtering off the drying agent, the filtrate was evaporated.
The resulting residue was purified by silica gel column
chromatography (methanol/ethyl acetate system), to give the title
compound as a colorless oil (17 mg).
[0795] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 1.06-1.20 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H),
1.75-1.82 (m, 2H), 1.82-1.92 (m, 1H), 2.05-2.20 (m, 2H), 2.22-2.55
(m, 12H), 2.72-2.78 (m, 2H), 6.99-7.05 (m, 2H), 7.25-7.30 (m, 1H),
7.31-7.36 (m, 4H), 7.58-7.62 (m, 2H).
[0796] Further, 17 mg of the above-mentioned free body (the title
compound) was treated in a conventional method, to give 14 mg the
hydrochloride.
[0797] Hydrochloride:
[0798] ESI-Mass; 465 (MH.sup.+)
Example 52
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(4-methyl-3-phenylpentane)piperazin-
e
[0799] 168
[0800] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 49 (85 mg, 60%).
[0801] Free Body:
[0802] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.71 (d, J=6.6 Hz,
3H), 0.76 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H), 1.03-1.16 (m,
2H), 1.18 (d, J=6.8 Hz, 3H), 1.46-1.60 (m, 3H), 1.70-2.16 (m, 6H),
2.18-2.42 (m, 10H), 7.07-7.13 (m, 2H), 7.14-7.18 (m, 1H), 7.20-7.32
(m, 4H), 7.33-7.36 (m, 4H).
[0803] Further, the hydrochloride (80 mg) of the title compound was
obtained by treating the free body in a similar method as in
Example 1.
[0804] Hydrochloride:
[0805] ESI-Mass; 446 (MH.sup.+)
Example 53
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(4-methyl-3-phenyl-hexane)piperazin-
e
[0806] 169
[0807] The title compound was obtained in accordance with the
method of Example 1 described in JP-A 11-206862 (150 mg, yield:
94%).
[0808] Free Body:
[0809] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.69 (d, J=6.86
Hz, 3H), 0.76 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.03-1.16
(m, 2H), 1.19 (d, J=6.6 Hz, 3H), 1.18-1.28 (m, 2H), 1.65-1.90 (m,
4H), 2.05-2.14 (m, 3H), 2.14-2.44 (m, 1H), 7.07-7.13 (m, 2H),
7.14-7.18 (m, 1H), 7.20-7.32 (m, 3H), 7.33-7.36 (m, 4H).
[0810] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0811] Hydrochloride:
[0812] ESI-Mass; 460 (MH.sup.+)
Example 54
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)buty-3-yl]piper-
azine
[0813] 170
[0814] The title compound was obtained as a pale yellow oil (183
mg, 38%) in accordance with the method of Example 104 described in
JP-A 11-206862.
[0815] Free Body:
[0816] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.04-1.19 (m, 1H), 1.19 (d, J=6.6 Hz, 3H), 1.50-1.64 (m, 1H),
1.82-1.92 (m, 1H), 2.06-2.18 (m, 2H), 2.22-2.28 (m, 2H), 2.28-2.40
(m, 4H), 2.48-2.64 (m, 5H), 2.75 (dd, J=7.7 Hz, 13.4 Hz, 1H),
4.65-4.73 (m, 1H), 5.20 (d, J=10.6 Hz, 1H), 5.25 (d, J=17.4 Hz,
1H), 5.85 (ddd, J=5.8 Hz, 10.6 Hz, 17.4 Hz, 1H), 6.81-6.88 (m, 2H),
6.88-6.97 (m, 2H), 7.25-7.31 (m, 1H), 7.32-7.40 (m, 4H).
[0817] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0818] Hydrochloride:
[0819] ESI-Mass; 450 (MH.sup.+)
Example 55
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-allyloxy-2-(4-fluorophenoxy)prop-
yl]piperazine
[0820] 171
[0821] The title compound was obtained as a colorless oil (67 mg,
62%) in accordance with the method of Example 104 described in JP-A
11-206862.
[0822] Free Body:
[0823] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.18 (m, 1H), 1.19 (d, J=6.4 Hz, 3H), 1.48-1.66 (m, 1H),
1.87 (dt, J=4.4 Hz, 12.4 Hz, 1H), 2.06-2.18 (m, 2H), 2.22-2.40 (m,
6H), 2.44-2.54 (m, 1H), 2.68-2.74 (m, 2H), 2.93-3.00 (m, 1H),
3.95-3.98 (m, 2H), 4.06 (d, J=5.2 Hz, 2H), 5.16 (brd, J=10.4 Hz,
1H), 5.24 (dd, J=1.6 Hz, 17.2 Hz, 1H), 5.81-5.92 (m, 1H), 6.80-6.97
(m, 4H), 7.24-7.33 (m, 1H), 7.34-7.39 (m, 4H).
[0824] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0825] Hydrochloride:
[0826] ESI-Mass; 494 (MH.sup.+)
Example 56
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-(n-propanoxy)-2-(4-fluorophenoxy-
)propyl]piperazine
[0827] 172
[0828] In hydrogen atmosphere,
1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-a-
rloxy-2-(4-fluorophenoxy)propyl]piperazine (85 mg) was dissolved in
ethanol (3.5 mL) at room temperature. To the mixture was added 10%
palladium-carbon (10 mg), followed by stirring. After 3 hours 20
minutes, palladium-carbon was separated by filtration, and then the
filtrate was evaporated. The resulting residue was purified by NH
silica gel column chromatography (hexane/ethyl acetate system), to
give the title compound (34 mg, 40%).
[0829] Free Body:
[0830] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.6 Hz,
3H), 0.88 (dt, J=2.7 Hz, 7.2 Hz, 3H), 1.05-1.20 (m, 1H), 1.19 (d,
J=6.6 Hz, 3H), 1.50-1.60 (m, 4H), 1.82-1.92 (m, 1H), 2.05-2.20 (m,
3H), 2.20-2.60 (m, 9H), 2.66-2.78 (m, 2H), 3.31-3.41 (m, 2H), 3.61
(d, J=5.5 Hz, 1H), 4.06 (d, J=5.1 Hz, 1H), 6.81-6.98 (m, 4H),
7.25-7.32 (m, 1H), 7.32-7.40 (m, 4H).
[0831] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0832] Hydrochloride:
[0833] ESI-Mass; 496 (MH.sup.+)
Example 57
1-[(4-Cyano-5-methyl--4-phenyl)hexyl]-4-[3-hydoxy-2-(4-fluorophenoxy)propy-
l]piperazine
[0834] 173
[0835] In tetrahydrofuran (5 ml) was dissolved
1-[(4-cyano-5-methyl-4-phen-
yl)hexyl]-4-[3-allyloxy-2-(4-fluorophenoxy)propyl]piperazine (125
mg), followed by adding sodium borohydride (14.4 mg) and then
iodine(64 mg)/tetrahydrofuran (2 mL). After stirring for one hour,
the organic layer was separated by adding ethyl acetate and water.
The resulting organic layer was washed with water and brine, and
dried over anhydrous magnesium sulfate. After filtering off the
drying agent, the filtrate was evaporated. The residue was purified
by NH silica gel column chromatography (hexane/ethyl acetate
system), to give the title compound as a pale yellow oil (70 mg,
61%). The hydrochloride was obtained by treating the free body (the
title compound) in a similar method as in Example 1.
[0836] Hydrochloride:
[0837] ESI-Mass; 436 (MH.sup.+)
Example 58
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1,2,3,4-tetrahydroquinolyl)ethy-
l]piperazine
[0838] 174
[0839] The title compound was obtained from
1,2,3,4-tetrahydroquinoline in accordance with the method of
Example 89 described in JP-A 11-206862 (34%).
[0840] Free Body:
[0841] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.20 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.66 (m, 1H),
1.85-1.98 (m, 2H), 2.05-2.20 (m, 2H), 2.24-2.56 (m, 11H), 2.73
(brt, J=6.4 Hz, 2H), 3.29 (brt, J=5.6 Hz, 3H), 3.36-3.41 (m, 2H),
3.39 (brt, J=7.8 Hz, 2H), 3.45-3.52 (m, 2H), 6.52-6.59 (m, 2H),
6.90-6.94 (m, 1H), 7.00-7.15 (m, 1H), 7.26-7.32 (m, 1H), 7.34-7.38
(m, 4H).
[0842] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0843] Hydrochloride:
[0844] ESI-Mass; 445 (MH.sup.+)
Example 59
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N-(4-fluorophenyl)-N'-(2-methylpropyl-
)-1(2H) -pyrazinecarboxyimidamide
[0845] 175
[0846] Under a nitrogen atmosphere, to a solution of
1-(fluorophenyl)-3-isobutylurea (300 mg), triphenylphosphine (561
mg) and triethylamine (0.3 mL) added in dichloromethane (10 ml)
were added a solution of carbon tetrabromide (948 mg) dissolved in
dichloromethane (4 ml). After 45 minutes, the reaction solution was
cooled to room temperature, and the organic layer was separated by
adding water and dichloromethane thereto. The resulting organic
layer was washed with water and brine, and dried over anhydrous
magnesium sulfate. After filtering off the drying agent, the
filtrate was evaporated. The resulting residue was immediately
purified by NH silica gel column chromatography (hexane/ethyl
acetate system), to give a colorless oily carbodiimide as an
intermediate. The carbodiimide and
1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg) were
dissolved in 2-propanol (10 mL), followed by stirring under a
reflux condition. After 2 hours, the solvent was evaporated, and
the resulting residue was purified by NH silica gel column
chromatography (hexane/ethyl acetate system), to give the title
compound as a colorless solid (174 mg, 25%, 2 steps).
[0847] Free Body:
[0848] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.88-0.91 (m, 6H), 1.05-1.18 (m, 1H), 1.20 (d, J=6.8 Hz, 3H),
1.50-1.65 (m, 2H), 1.67-1.80 (m, 2H), 1.88-1.98 (m, 1H), 2.06-2.20
(m, 2H), 2.22-2.36 (m, 4H), 2.79 (brd, J=6.8 Hz, 1H), 3.05 (dd,
J=6.0 Hz, 6.8 Hz, 1H), 3.14-3.20 (m, 1H), 4.82-4.91 (m, 1H),
6.52-6.58 (m, 1H), 6.72-6.78 (m, 1H), 6.91-7.04 (m, 3H), 7.22-7.31
(m, 4H), 7.35-7.38 (m, 3H).
[0849] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0850] Hydrochloride:
[0851] ESI-Mass; 478 (MH.sup.+)
Example 60
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N-(4-fluorobenzyl)-N'-(2-methylpropyl-
)-1(2H) -pyrazinecarboxyimidamide
[0852] 176
[0853] The title compound was obtained as a colorless oil in
accordance with the method of Example 59 (62%).
[0854] Free Body:
[0855] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.80-0.88 (m, 6H), 1.05-1.18 (m, 1H), 1.20 (d, J=6.4 Hz, 3H),
1.43-1.60 (m, 1H), 1.84-1.95 (m, 1H), 2.05-2.20 (m, 2H), 2.25-2.40
(m, 6H), 2.87-2.95 (m, 2H), 3.22-3.38 (m, 4H), 3.49 (s, 2H),
4.35-4.45 (m, 2H), 7.02-7.09 (m, 2H), 7.27-7.34 (m, 3H), 7.34-7.41
(m, 4H).
[0856] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0857] Hydrochloride:
[0858] ESI-Mass; 492 (MH.sup.+)
Example 61
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N,N'-dicyclohexylpyrazinecarboxyimida-
mide
[0859] 177
[0860] The title compound was obtained as a colorless oil in
accordance with the method of Example 59 (62%).
[0861] Free Body:
[0862] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.04-1.46 (m, 9H), 1.21 (d, J=6.8 Hz, 3H), 1.46-1.74 (m, 6H),
1.74-1.86 (m, 6H), 1.86-1.18 (m, 2H), 2.07-2.22 (m, 2H), 2.24-2.40
(m, 6H), 3.05-3.16 (m, 2H), 3.23-3.32 (m, 4H), 3.41-3.52 (m, 1H),
7.28-7.34 (m, 1H), 7.35-7.42 (m, 4H).
[0863] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0864] Hydrochloride:
[0865] ESI-Mass; 492 (MH.sup.+)
Example 62
N-Cyano-4-[(4-cyano-5-methyl-4-phenyl)hexyl]-N'-[(4-fluorophenoxy)ethyl]py-
razinecarboxyimidamide
[0866] 178
[0867] In nitrogen atmosphere,
N-cyano-N'-ethyl(4-fluorophenoxy)-O-phenyli- sourea (168 mg) and
1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg) were
dissolved in 2-propanol (5 mL), followed by stirring under reflux.
After 24 hours, the solvent was evaporated, and the resulting
residue was purified by NH silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound as a
colorless solid (98 mg, 71%).
[0868] Free Body:
[0869] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.6 Hz,
3H), 1.08 (d, J=6.6 Hz, 3H), 1.20-1.34 (m, 1H), 1.50-1.70 (m, 1H),
1.92 (ddd, J=4.9 Hz, 11.6 Hz, 13.6 Hz, 1H), 2.05-2.23 (m, 2H),
2.24-2.38 (m, 6H), 3.43-3.50 (m, 2H), 3.78-3.82 (m, 2H), 4.04-4.09
(m, 2H), 5.00-5.05 (m, 1H), 6.80-6.85 (m, 2H), 6.92-7.01 (m, 2H),
7.27-7.32 (m, 1H), 7.34-7.39 (m, 4H).
[0870] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0871] Hydrochloride:
[0872] ESI-Mass; 491 (MH.sup.+)
Example 63
(2-Thienyl)-[(4-cyano-5-methyl-4-phenyl)hexylpiperazino]methaneimine
[0873] 179
[0874] The title compound was obtained as a colorless oil in
accordance with the method of Example 62 (62%).
[0875] Free Body:
[0876] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.05-1.20 (m, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.64 (m, 1H),
1.88-2.08 (m, 1H), 2.08-2.22 (m, 2H), 2.28-2.38 (m, 6H), 3.32-3.44
(m, 4H), 7.00 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.14 (dd, J=1.2 Hz, 3.6
Hz, 1H), 7.26-7.32 (m, 1H), 7.34 (dd, J=1.2 Hz, 5.2 Hz, 1H),
7.35-7.39 (m, 4H).
[0877] The hydrochloride of the title compound was obtained by
treating the free body in a similar method as in Example 1.
[0878] Hydrochloride:
[0879] ESI-Mass; 345 (MH.sup.+)
Example 64
1-Isopropyl-4-[4-isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-phenylbut-
yl cyanide
[0880] 180
[0881] 2-Chloro-1-isobutyl-1H-benzo[d]imidazole (4 g) and
1-[(4-cyano-5-methyl-4-hexyl]piperazine (5 g) were dissolved in
tetrahydrofuran (10 mL), followed by stirring on an oil bath at
150.degree. C. for 6 hours in an open system. The reaction product
was purified by NH silica gel (ethyl acetate/hexane system), to
give the title compound as a brown oil (6.8 g, 85%).
[0882] Free Body:
[0883] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 0.83 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.20-1.35 (m,
1H), 1.21 (d, J=6.8 Hz, 3H), 1.52-1.67 (m, 1H), 1.95-2.07 (m, 1H),
2.08-2.23 (m, 1H), 2.23-2.43 (m, 4H), 2.43-2.50 (m, 4H), 3.21-3.25
(m, 4H), 3.80 (d, J=7.6 Hz, 2H), 7.08-7.64 (m, 9H)
[0884] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a similar method as in Example 1.
[0885] Hydrochloride:
[0886] ESI-Mass; 458 (MH.sup.+)
Example 65
Bis-1,4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine
[0887] 181
[0888] In nitrogen atmosphere, thionyl chloride (4 mL) was added to
(4-cyano-5-methyl-4-phenyl)hexanol (2.33 g) under ice cooling,
followed by heating under stirring under reflux condition. After 2
hours, the mixture was evaporated. Then, the resulting residue was
purified by silica gel column chromatography (hexane/ethyl acetate
system), to give (4-cyano-5-methyl-4-phenyl)hexyl chloride (2.35 g,
93%) as a yellow oil. The resulting chloride (454 mg),
[(4-cyano-5-methyl-4-phenyl)hexyl]pipera- zine (166 mg) and sodium
iodide (289 mg) were dissolved in acetonitrile (5 mL), followed by
stirring under a reflux condition. After 2 hours, the mixture was
cooled to a room temperature, and the organic layer was separated
by adding ethyl acetate and water thereto. The resulting organic
layer was washed with water and brine, and dried over anhydrous
magnesium sulfate. After the drying agent was filtered off, the
mixture was evaporated. The residue was purified by NH silica gel
column chromatography (hexane/ethyl acetate), to give the title
compound as a pale yellow oil (213 mg, 23%).
[0889] Free Body:
[0890] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
6H), 1.02-1.16 (m, 2H), 1.19 (d, J=6.8 Hz, 6H), 1.46-1.60 (m, 2H),
1.80-1.92 (m, 2H), 2.40-2.17 (m, 4H), 2.17-2.36 (m, 12H), 7.23-7.31
(m, 2H), 7.33-7.37 (m, 8H).
[0891] Further, the hydrochloride was obtained by treating the free
body (the title compound) in the same manner as in Example 1.
[0892] Hydrochloride:
[0893] ESI-Mass; 485 (MH.sup.+)
Example 66
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(3-cyano-4-methyl-3-phenyl)pentyl]-
piperazine
[0894] 182
[0895] The title compound was obtained as a pale yellow oil in
accordance with the method of Example 65 (yield: 52%).
[0896] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 0.765 (d, J=6.4 Hz, 3H), 1.00-1.18 (m, 1H), 1.18 (d, J=6.4 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.44-1.60 (m, 1H), 1.80-2.00 (m, 4H),
2.00-2.18 (m, 4H), 2.18-2.44 (m, 10H), 7.26-7.32 (m, 2H), 7.33-7.40
(m, 8H).
[0897] Further, the hydrochloride of the title compound was
obtained by treating the free body (the title compound) in the same
manner as in Example 1.
[0898] Hydrochloride:
[0899] ESI-Mass; 471 (MH.sup.+)
Example 67
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1',2'-methylenedioxyphenyl)ethy-
l]piperidine
[0900] 183
[0901] The title compound was obtained in accordance with the
method of Example 49 (yield: 51%).
[0902] Free Body:
[0903] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 3H), 1.20 (d, J=6.4 Hz, 3H), 1.48-1.76 (m, 7H),
1.80-1.94 (m, 2H), 2.06-2.18 (m, 2H), 2.18-2.28 (m, 2H), 2.53-2.60
(m, 2H), 2.70-2.80 (m, 2H), 5.92 (s, 2H), 6.82-6.70 (m, 2H),
6.70-6.78 (m, 1H), 7.26-7.40 (m, 5H).
[0904] Further, the hydrochloride was obtained by treating the free
body (the title compound) in the same method as in Example 1.
[0905] Hydrochloride:
[0906] ESI-Mass; 433 (MH.sup.+)
Example 68
1-[(4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(4-cyanophenoxy)ethy-
l]piperazine
[0907] 184
[0908] In acetonitrile (5 ml) was dissolved
4-cyano-4-(3-cyano-5-thienyl)-- 5-methylhexanol (0.13 g). To the
mixture were added triethylamine (0.21 ml) and mesyl chloride
(0.048 ml), followed by stirring at room temperature for one hour.
Water was added thereto, and the mixture was extracted with ethyl
acetate and further washed with brine. After drying over anhydrous
magnesium sulfate, the mixture was evaporated, to give a pale
yellow oil. The resulting oil was dissolved in DMF (2 ml), followed
by adding a DMF solution (4 ml) of
1-[2-(4-cyanophenoxy)ethyl]piperazine (0.14 g), triethylamine (0.21
ml) and sodium iodide (0.15 g). After stirring at 60.degree. C.
overnight, ethyl acetate was added thereto, and the mixture was
washed with water and further brine. After drying over anhydrous
magnesium sulfate, the solvent was evaporated, and the resulting
residue was purified by NH silica gel column chromatography
(hexane/ethyl acetate system), to give the title compound as a pale
yellow oil (0.09 g, 33%).
[0909] Free Body:
[0910] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 d, J=6.8 Hz,
3H), 1.20 (d, J=6.8 Hz, 3H), 1.21-1.31 (m, 1H), 1.60-1.73 (m, 1H),
1.77 (dt, J=4 Hz, J=13.2 Hz, 1H), 2.06 (qui, J=6.8 Hz, 1H), 2.20
(dt, J=4 Hz, J=13.2 Hz, 1H), 2.33 (t, J=7.6 Hz, 2H), 2.42 (bs, 4H),
2.58 (bs, 4H), 2.82 (t, J=5.6 Hz, 2H), 4.13 (t, J=5.6 Hz, 2H), 6.95
(d, J=8.8 Hz, 2H), 7.28 (d, J=1.2 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H),
7.90 (d, J=1.2 Hz, 1H).
[0911] Further, the hydrochloride was obtained by treating the
above free body (the title compound) in a conventional method.
[0912] Hydrochloride:
[0913] ESI-Mass; 462 (MH.sup.+)
Example 69
1-[(4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-2-(3-cyanophenoxy)ethyl-
]piperazine
[0914] 185
[0915] The title compound was obtained as a pale yellow oil (0.15
g, 58%) from 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanol and
1-[2-(3-cyanophenoxy)ethyl]piperazine in the same manner as in
Example 68.
[0916] Free Body:
[0917] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.8 Hz, 3H), 1.22-1.32 (m, 1H), 1.60-1.73 (m, 1H),
1.79 (dt, J=4 Hz, J=12.4 Hz, 1H), 2.07 (qui, J=6.8 Hz, 1H), 2.21
(dt, J=4 Hz, J=12.4 Hz, 1H), 2.34 (t, J=7.2 Hz, 2H), 2.43 (bs, 4H),
2.59 (bs, 4H), 2.82 (t, J=5.6 Hz, 2H), 4.11 (t, J=5.6 Hz, 2H),
7.12-7.40 (m, 5H), 7.91 (s, 1H).
[0918] Further, the hydrochloride was obtained by treating the free
body (the title compound) in a conventional method.
[0919] Hydrochloride:
[0920] ESI-Mass; 462 (MH.sup.+)
Example 70
1-[(4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethy-
l]piperazine
[0921] 186
[0922] In acetonitrile (10.0 ml) was dissolved 400 mg (1.61 mmol)
of 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexanol, followed by
cooling to 0.degree. C. To the mixture were added 0.26 ml (1.85
mmol) of triethylamine and 0.14 ml (1.77 mmol) of mesyl chloride,
followed by heating to room temperature. After 20 minutes, ether
and brine were added thereto. The ether layer was washed with an
aqueous saturated sodium bicarbonate and dried over anhydrous
magnesium sulfate. The solvent was evaporated, to give a crude
product. The half amount (ca. 0.1 mmol) of the crude mesyl compound
was dissolved in 8.00 ml of dimethylformamide. To the mixture were
added 724 mg (4.83 mmol) of sodium iodide, 111 mg (0.81 mmol) of
potassium carbonate and 243 mg (1.05 mmol) of
1-[2-(3-cyanophenoxy)ethyl]piperazine, followed by heating to
60.degree. C. After completion of the reaction, brine was added
thereto, and the objective product was extracted with ethyl
acetate. The organic layer was washed with brine, and then dried
over anhydrous magnesium sulfate. The solvent was evaporated, to
give a crude product. The crude product was subjected to Cromatorex
NH silica gel (eluted with ethyl acetate/hexane=1/1), to give 289
mg (0.63 mmol, 77.3%) of the title compound as a yellow syrup.
[0923] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.80
Hz, 3H), 1.21 (d, J=6.40 Hz, 3H), 1.20-1.38 (m, 1H), 1.60-1.86 (m,
2H), 2.01-2.12 (m, 1H), 2.18-2.30 (m, 1H), 2.30-2.75 (m, 1H),
2.80-2.90 (m, 2H), 4.08-4.18 (m, 2H), 7.11-7.18 (m, 3H), 7.23-7.28
(m, 1H), 7.34-7.40 (m, 1H), 7.52 (d, J=3.60 Hz, 1H)
[0924] ESI-Mass; 462 (MH.sup.+)
Example 71
1-[(4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-{N-(2-cyanoethyl)ani-
lino}ethyl]piperazine
[0925] 187
[0926] The title compound was synthesized using
[2-{N-(2-cyanoethyl)anilin- o}ethyl]piperazine in accordance with
the method for producing
1-[(4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)eth-
yl]piperazine in Example 70 (yield; 90.1%: a pale yellow oil).
[0927] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.20-1.33 (m, 1H), 1.21 (d, J=6.4 Hz, 3H), 1.58-1.73 (m, 1H),
1.73-1.84 (m, 1H), 2.02-2.11 (m, 1H), 2.23 (dt, J=4.0 Hz, 12.8 Hz,
1H), 2.31-2.64 (m, 12H), 2.68 t, J=7.2 Hz, 2H), 3.51 (t, J=6.8 Hz,
2H), 3.69 (t, J=7.2 Hz, 2H), 6.67 (d, J=8.0 Hz, 3H), 6.76 (t, J=7.4
Hz, 1H), 7.15 (d, J=4.00 Hz, 1H), 7.23-7.30 (m, 2H), 7.52 (d, J=4.0
Hz, 1H)
[0928] ESI-MS; 489 (M+H.sup.+)
Example 72
1-(4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl-
]piperazine
[0929] 188
[0930] In 1.5 ml of acetonitrile was dissolved 111 mg (0.31 mmol)
of 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl iodide. To the
mixture were added 56.2 .mu.l (0.40 mmol) of triethylamine and 109
mg (0.47 mmol) of 1-(3-cyanophenoxyethyl)piperazine, followed by
stirring for 3 days. The organic layer separated by adding ethyl
acetate and brine to the reaction solution was dried over magnesium
sulfate, and then evaporated, to give a crude product. The crude
product was subjected to 12.5 g of Cromatorex NH silica gel (ethyl
acetate/hexane=1/2), to give 144 mg (quantitative) of the title
compound as a yellow syrup.
[0931] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.15-1.28 (m, 1H), 1.26 (d, J=6.4 Hz, 3H), 1.60-1.75 (m, 1H),
2.17-2.27 (m, 1H), 2.27-2.70 (m, 12H), 2.81 (t, J=6.0 Hz, 2H), 4.10
(t, J=6 Hz, 2H), 7.11-7.16 (m, 2H), 7.22-7.26 (m, 1H), 7.26-7.28
(m, 2H), 7.33-39 (m, 1H)
[0932] ESI-Mass; 462 (MH.sup.+)
Example 73
1-[(4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)eth-
yl]piperazine
[0933] 189
[0934] The title compound was synthesized in accordance with the
method of Example 72 (yield: 82.3%).
[0935] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.15-1.29 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 1.60-1.74 (m, 1H),
2.17-2.27 (m, 1H), 2.27-2.70 (m, 12H), 2.80 (t, J=6.0 Hz, 2H), 4.08
(t, J=6.0 Hz, 2H), 6.59-6.70 (m, 3H), 7.16-7.24 (m, 1H), 7.26-7.28
(m, 2H) ESI-MS; 455 (M+H.sup.+)
Example 74
1-[(4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(4-fluorophenoxy)eth-
yl]piperazine
[0936] 190
[0937] The title compound was synthesized in accordance with the
method of Example 72 (yield: 70.2%).
[0938] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.14-1.29 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 1.60-1.74 (m, 1H),
2.17-2.27 (m, 1H), 2.27-2.70 (m, 12H), 2.78 (t, J=6.0 Hz, 2H), 4.05
(t, J=6.0 Hz, 2H), 6.81-6.85 (m, 2H), 6.93-6.98 (m, 1H), 7.26-7.28
(m, 2H) ESI-MS; 455 (M+H.sup.+)
Example 75
1-[(4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]pipera-
zine
[0939] 191
[0940] The title compound was synthesized using
4-cyano-5-methyl-4-(2-thie- nyl)hexyl iodide in accordance with the
method of Example 72 (yield: 94.7%).
[0941] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.6 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.20-1.38 (m, 1H), 1.55-1.72 (m, 1H),
1.73-1.83 (m, 1H), 2.02-2.12 (m, 1H), 2.12-2.22 (m, 1H), 2.28-2.35
(m, 2H), 2.35-2.65 (m, 8H), 2.81 (t, J=5.9 Hz, 2H), 4.10 (t, J=5.9
Hz, 2H), 6.93-6.97 (m, 1H), 7.10-7.17 (m, 3H), 7.22-7.30 (m, 2H),
7.33-7.39 (m, 1H). ESI-MS; 437 (M+H.sup.+)
Example 76
1-[(4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]pipera-
zine
[0942] 192
[0943] The title compound was synthesized using
4-cyano-5-methyl-4-(2-thie- nyl)hexyl iodide in accordance with the
method of Example 72 (yield: 40.9%).
[0944] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.56-1.70 (m, 1H),
1.72-1.81 (m, 1H), 2.01-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.27-2.34
(m, 2H), 2.34-2.62 (m, 8H), 2.81 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.0
Hz, 2H), 6.92-6.96 (m, 3H), 7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H),
7.24-7.27 (m, 2H), 7.57 (d, J=8.8 Hz, 2H).
[0945] ESI-MS; 437 (M+H.sup.+)
Example 77
1-[(4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(5-cyano-2-thieny)pr-
opyl]piperazine
[0946] 193
[0947] In acetonitrile (3 ml) was dissolved 200 mg (0.56 mmol) of
4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl iodide. To the mixture
were added 78.0 .mu.l (0.56 mmol) of triethylamine and 178 mg (0.76
mmol) of 1-[3-(5-cyano-2-thieny)propyl]piperazine, followed by
stirring at 55.degree. C. After 5 hours, the reaction solution was
concentrated, and the residue was subjected to Cromatorex NH silica
gel (ethyl acetate/hexane=1/2), to give 243 mg (0.52 mmol, 92.8%)
of the title compound as a yellow syrup.
[0948] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.18-1.31 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.60-1.72 (m, 1H),
1.73-1.91 (m, 3H), 2.00-2.10 (m, 1H), 2.17-2.27 (m, 1H), 2.28-2.50
(m, 12H), 2.88 (t, J=7.6 Hz, 2H), 6.80 (d, J=4.0 Hz, 1H), 7.15 (d,
J=4.0 Hz, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H)
[0949] ESI-Mass; 466 (M+H.sup.+)
Example 78
1-[(4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(2-thienyl)propyl]pi-
perazine
[0950] 194
[0951] The title compound was synthesized in accordance with the
production method described in Example 77 (yield: 96.4%).
[0952] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.19-1.31 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.60-1.72 (m, 1H),
1.72-1.81 (m, 1H), 1.82-1.91 (m, 2H), 2.00-2.10 (m, 1H), 2.17-2.24
(m, 1H), 2.27-2.54 (m, 12H), 2.85 (t, J=7.6 Hz, 2H), 6.78 (dd,
J=0.8 Hz, 3.6 Hz, 1H), 6.91 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.10 (dd,
J=0.8 Hz, 5.2 Hz, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.51 (d, J=4.0 Hz,
1H)
[0953] ESI-MS; 441 (M+H.sup.+)
Example 79
1-[(4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[3-(5-cyano-2-thieny)propyl]pip-
erazine
[0954] 195
[0955] The title compound was synthesized using
4-cyano-5-methyl-4-(2-thie- nyl)hexyl iodide in accordance with the
production method described in Example 77 (yield: 96.4%).
[0956] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.23-1.37 (m, 1H), 1.60-1.70 (m, 1H),
1.72-1.90 (m, 3H), 2.02-2.09 (m, 1H), 2.11-2.20 (m, 1H), 2.26-2.52
(m, 12H), 2.88 (t, J=7.6 Hz, 2H), 6.80 (d, J=3.6 Hz, 1H), 6.94 (dd,
J=3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.26 (dd,
J=1.2 Hz, 5.2 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H)
[0957] ESI-MS; 441 (M+H.sup.+)
Example 80
1-[(4-Cyano-5-methyl-4-(4-cyano-2-thienyl)hexyl]-4-[3-(2-thieny)propyl]pip-
erazine
[0958] 196
[0959] The title compound was produced in the synthesis condition
of tert-butyl 4-[3-(2-thienyl)propyl]-1-piperazinecrboxylate which
is described below (yield: 23.6%), by using
4-cyano-5-methyl-4-(4-cyano-2-th- ienyl)hexanol and
1-[3-(2-thienyl)propyl]piperazine synthesized according to the
method of Example 69.
[0960] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.8 Hz, 3H), 1.22-1.32 (m, 1H), 1.59-1.72 (m, 1H),
1.72-1.91 (m, 3H), 2.02-2.12 (m, 1H), 2.15-2.24 (m, 1H), 2.28-2.56
(m, 12H), 2.85 (t, J=7.6 Hz, 2H), 6.77-6.80 (m, 1H), 6.91 (dd,
J=3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 5.2 Hz, 1H), 7.28 (d,
J=1.2 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H)
[0961] ESI-MS; 441 (M+H.sup.+)
Example 81
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[(2-benzoxazoyl)methyl]piperazin-
e
[0962] 197
[0963] In acetonitrile (5 ml) was dissolved 230 mg (0.82 mmol) of
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]piperazine synthesized in a
similar manner as the above-mentioned
1-[3-(5-cyano-2-thienyl)propyl]pipe- razine. To the mixture were
added 120 mg (0.72 mmol) of 2-(chloromethyl)benzoxazole and 0.10 ml
(0.72 mmol) of triethylamine, followed by heating to 50.degree. C.
After 5 hours, the reaction solution was concentrated, and the
residue was subjected to Cromatorex NH silica gel (ethyl
acetate/hexane=1/2), to give 244 mg (0.58 mmol, 80.5%) of the title
compound as a yellow syrup.
[0964] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.89 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.20-1.38 (m, 1H), 1.55-1.69 (m, 1H),
1.71-1.81 (m, 1H), 2.00-2.09 (m, 1H), 2.10-2.19 (m, 1H), 2.28-2.53
(m, 6H), 2.55-2.73 (m, 4H), 3.86 (s, 2H), 6.93 (dd, J=3.6 Hz, 5.2
Hz, 1H), 7.10 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.24 (dd, J=1.2 Hz, 5.2
Hz, 1H), 7.30-7.36 (m, 2H), 7.50-7.55 (m, 1H), 7.68-7.73 (m,
1H)
[0965] ESI-Mass; 423 (M+H.sup.+)
Example 82
1-[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[(2-benzoxazoyl)methyl]p-
iperazine
[0966] 198
[0967] In acetonitrile (3 ml) was dissolved 200 mg (0.56 mmol) of
4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl iodide. To the mixture
were added 78.0 .mu.l (0.56 mmol) of triethylamine and 146 mg (0.67
mmol) of 1-[(2-benzoxazoyl)methyl]piperazine, followed by stirring
at 55.degree. C. After 14 hours, the reaction solution was
concentrated, and the residue was subjected to Cromatorex NH silica
gel (ethyl acetate/hexane=1/2), to give 237 mg (0.53 mmol, 94.6%)
of the title compound as a yellow syrup.
[0968] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.8 Hz, 3H), 1.20-1.30 (m, 1H), 1.59-1.70 (m, 1H),
1.70-1.80 (m, 1H), 2.00-2.09 (m, 1H), 2.15-2.25 (m, 1H), 2.33 (t,
J=7.2 Hz, 2H), 2.37-2.52 (m, 4H), 2.57-2.72 (m, 4H), 3.87 (s, 2H),
7.14 (d, J=4.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.50 (d, J=4.0 Hz, 1H),
7.51-7.55 (m, 1H), 7.68-7.73 (m, 1H)
[0969] ESI-Mass; 448 (M+H.sup.+)
Example 83
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[{2-(5-cyanobenzoxazoyl)}methyl]-
piperazine
[0970] 199
[0971] The title compound was synthesized in accordance with the
production method described in Example 82 (yield: 89.3%).
[0972] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.22-1.36 (m, 1H), 1.56-1.70 (m, 1H),
1.71-1.80 (m, 1H), 2.00-2.09 (m, 1H), 2.10-2.19 (m, 1H), 2.29-2.36
(m, 2H), 2.36-2.52 (m, 4H), 2.56-2.71 (m, 4H), 3.89 (s, 2H), 6.93
(dd, J=3.6 Hz, 5.2 Hz, 1H), 7.10 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.25
(dd, J=1.2 Hz, 5.2 Hz, 1H), 7.60-7.66 (m, 2H), 8.02-8.04 (m,
1H)
[0973] ESI-MS; 448 (M+H.sup.+)
Example 84
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]pipera-
zine
[0974] 200
[0975] In nitrogen atmosphere,
1-[2-(4-fluorophenoxy)ethyl]piperazine (50 mg) synthesized in
accordance with the method described in Production Example 1 in
JP-A 11-206862 was added to an acetonitrile solution (3 ml) of
1-iodo-4-cyano-5-methyl-4-(3-thienyl)hexane (50 mg) and
triethylamine (0.06 ml) at room temperature. After stirring at
50.degree. C. for 4 hours, the solvent was evaporated, and the
resulting residue was purified by Cromatorex NH silica gel column
chromatography (hexane/ethyl acetate system), to give the title
compound as a yellow oil (62 mg, 96%).
[0976] Free Body:
[0977] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.8 Hz,
3H), 1.16 (d, J=6.6 Hz, 3H), 1.55-1.65 (m, 1H), 1.74-1.84 (m, 1H),
2.02-2.12 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 2.30-2.47 (m, 4H),
2.47-2.65 (m, 4H), 2.79 (t, J=6.0 Hz, 2H), 4.07 (t, J=6.0 Hz, 2H),
6.58-6.70 (m, 3H), 6.92 (dd, J=1.5 Hz, 5.0 Hz, 1H), 7.17-7.24 (m,
1H), 7.26-7.28 (m, 1H), 7.33 (dd, J=3.0 Hz, 5.0 Hz, 1H).
[0978] Further, 62 mg of the above-mentioned free body (the title
compound) was dissolved in methanol, followed by adding an
excessive 4N hydrochloric acid/ethyl acetate solution thereto.
After stirring, the mixture was evaporated. After water was added
to the resulting residue, the aqueous solution was frozen by being
immersed in a dry ice-methanol bath. The solvent was removed by
freeze-dry process over day and night, to give the hydrochloride of
the title compound (white amorphous, 62 mg).
[0979] Hydrochloride:
[0980] ESI-Mass; 430 (MH.sup.+)
Example 85
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperaz-
ine
[0981] 201
[0982] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(85%).
[0983] Free Body:
[0984] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.8 Hz,
3H), 1.16 (d, J=6.6 Hz, 3H), 1.15-1.30 (m, 1H), 1.54-1.66 (m, 1H),
1.75-1.85 (m, 1H), 2.02-2.15 (m, 2H), 2.25-2.33 (m, 2H), 2.33-2.48
(m, 4H), 2.48-2.65 (m, 4H), 2.80 (t, J=5.7 Hz, 2H), 4.10 (t, J=5.7
Hz, 2H), 6.93 (dd, J=1.3 Hz, 5.1 Hz, 1H), 7.10-7.30 (m, 2H),
7.20-7.26 (m, 1H), 7.26-7.28 (m, 1H), 7.32-7.39 (m, 2H).
[0985] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[0986] Hydrochloride:
[0987] ESI-Mass; 437 (MH.sup.+)
Example 86
1-[4-Cyano-5-methyl-4-[4-(2-cyano)thienyl]hexyl]-4-8
2-(3-fluorophenoxy)ethyl]piperazine
[0988] 202
[0989] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(76%).
[0990] Free Body:
[0991] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (d, J=6.8 Hz,
3H), 1.01-1.02 (m, 1H), 1.17 (d, J=6.6 Hz, 3H), 1.50-1.70 (m, 1H),
1.75-1.85 (m, 1H), 2.00-2.08 (m, 1H), 2.08-2.18 (m, 1H), 2.27-2.33
(m, 2H), 2.33-2.48 (m, 4H), 2.48-2.66 (m, 4H), 2.80 (t, J=5.8 Hz,
2H), 4.07 (t, J=5.8 Hz, 2H), 6.59-6.70 (m, 3H), 7.17-7.25 (m, 1H),
7.46 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H).
[0992] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[0993] ESI-Mass; 455 (MH.sup.+)
Example 87
1-[4-Cyano-5-methyl-4-[4-(2-cyano)-thienyl]hexyl]-4-[2-(3-cyanophenoxy)eth-
yl]piperazine
[0994] 203
[0995] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(78%).
[0996] Free Body:
[0997] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (d, J=6.8 Hz,
3H), 1.01-1.02 (m, 1H), 1.17 (d, J=6.6 Hz, 3H), 1.50-1.65 (m, 1H),
1.75-1.85 (m, 1H), 2.00-2.09 (m, 1H), 2.09-2.18 (m, 1H), 2.27-2.33
(m, 2H), 2.33-2.48 (m, 4H), 2.48-2.66 (m, 4H), 2.81 (t, J=5.8 Hz,
2H), 4.10 (t, J=5.8 Hz, 2H), 7.12-7.16 (m, 2H), 7.23-7.28 (m, 1H),
7.36 (dt, J=0.8 Hz, 7.8 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.56 (d,
J=1.6 Hz, 1H).
[0998] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[0999] ESI-Mass; 462 (MH.sup.+)
Example 88
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(2-cyano-4-fluorophenoxy)ethy-
l]piperazine
[1000] 204
[1001] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(72%).
[1002] Free Body:
[1003] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H),
1.73-1.83 (m, 1H), 2.00-2.11 (m, 1H), 2.11-2.20 (m, 1H), 2.27-2.33
(m, 2H), 2.33-2.51 (m, 4H), 2.51-2.70 (m, 4H), 2.86 (t, J=5.8 Hz,
2H), 4.17 (t, J=5.8 Hz, 2H), 6.89-6.97 (m, 2H), 7.09-7.12 (m, 1H),
7.20-7.30 (m, 2H).
[1004] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1005] ESI-Mass; 455 (MH.sup.+)
Example 89
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(2-cyano-4-fluorophenoxy)ethy-
l]piperazine
[1006] 205
[1007] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(72%).
[1008] Free Body:
[1009] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.8 Hz,
3H), 1.16 (d, J=6.6 Hz, 3H), 1.16-1.20 (m, 1H), 1.50-1.66 (m, 1H),
1.76-1.86 (m, 1H), 2.01-2.13 (m, 2H), 2.24-2.33 (m, H), 2.33-2.51
(m, 4H), 2.51-2.70 (m, 4H), 2.87 (t, J=5.8 Hz, 2H), 4.17 (t, J=5.8
Hz, 2H), 6.89-6.97 (m, 2H), 7.20-7.30 (m, 3H), 7.33-7.38 (m,
1H).
[1010] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1011] ESI-Mass; 455 (MH.sup.+)
Example 90
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-cyano-2-fluorophenoxy)ethy-
l]piperazine
[1012] 206
[1013] The title compound was obtained as a colorless oil in a
similar method as in Example 84 (64%), by using
2-(4-cyano-2-fluorophenoxy)ethyl]- piperazine synthesized in the
same manner as in Reference Example 69 as a raw material.
[1014] Free Body:
[1015] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.6 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H),
1.72-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.11-2.20 (m, 1H), 2.27-2.33
(m, 2H), 2.33-2.51 (m, 4H), 2.51-2.70 (m, 4H), 2.85 (t, J=5.8 Hz,
2H), 4.20 (t, J=5.8 Hz, 2H), 6.94 (dd, J=3.7 Hz, 5.2 Hz, 1H), 7.00
(t, J=8.2 Hz, 1H), 7.10 (dd, J=1.3 Hz, 3.7 Hz, 1H), 7.24-7.27 (m,
1H), 7.35 (dd, J=1.9 Hz, 10.4 Hz, 1H), 7.38-7.42 (m, 1H).
[1016] The hydrochloride of the target compound was obtained by
treating the free body in the similar manner as in Example 84.
[1017] ESI-Mass; 455 (MH.sup.+)
Example 91
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-cyano-2-fluorophenoxy)ethy-
l]piperazine
[1018] 207
[1019] The title compound was obtained as a colorless oil according
to a similar method as in Example 84 (64%), by using
2-(4-cyano-2-fluorophenox- y)ethylpiperazine synthesized in
accordance with Reference Example 69 as a raw material,
[1020] Free Body:
[1021] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.8 Hz,
3H), 1.16 (d, J=6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H),
1.74-1.84 (m, 1H), 2.00-2.13 (m, 2H), 2.25-2.33 (m, 2H), 2.33-2.49
(m, 4H), 2.49-2.68 (m, 4H), 2.85 (t, J=5.8 Hz, 2H), 4.20 (t, J=5.8
Hz, 2H), 6.92 (dd, J=1.5 Hz, 5.1 Hz, 1H), 7.00 (t, J=8.4 Hz, 1H),
7.25-7.28 (m, 1H), 7.32-7.37 (m, 2H), 7.40 (ddd, J=1.3 Hz, 1.8 Hz,
8.4 Hz, 1H).
[1022] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1023] ESI-Mass; 455 (MH.sup.+)
Example 92
1-{4-Cyano-5-methyl-4-[(2.5-dibromo)-3-thienyl]hexyl}-4-[2-(3-cyanophenoxy-
)ethyl]piperazine
[1024] 208
[1025] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(78%).
[1026] Free Body:
[1027] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.6 Hz,
3H), 1.17 (d, J=6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H),
1.82-2.02 (m, 1H), 2.30-2.53 (m, 8H), 2.53-2.68 (m, 4H), 2.81 t,
J=5.8 Hz, 2H), 4.10 (t, J=5.8 Hz, 2H), 7.04 (s, 1H), 7.11-7.20 (m,
2H), 7.22-7.29 (m, 1H), 7.34-7.39 (m, 1H).
[1028] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1029] ESI-Mass; 593, 595, 597 (MH.sup.+)
Example 93
1-[4-Cyano-5-methyl-4-(2-bromo-5-cyano-3-thienyl)hexyl]-4-[2-(3-cyanopheno-
xy)ethyl]piperazine
[1030] 209
[1031] In a nitrogen atmosphere,
1-{4-cyano-5-methyl-4-[(2,5-dibromo)-3-th-
ienyl]hexyl}-4-[2-(3-cyanophenoxy)ethyl]piperazine (145 mg) was
dissolved in a mixed solvent of dimethylformamide (10 mL)/water
(0.1 mL) of zinc cyanide (57.3 mg) and
1,1'-bis(diphenylphosphino)ferrocene (13.5 mg).
Palladium-dibenzylidene acetone complex (8.9 mg) was added thereto,
the atmosphere of the mixture was replaced 3 times with nitrogen,
and then the solution was stirred at 120.degree. C. for 4 hours.
Water, diethyl ether and an aqueous ammonia were added thereto, to
separate the organic layer. The resulting organic layer was washed
with water and brine, dried over anhydrous magnesium sulfate. After
filtering off the drying agent, the filtrate was evaporated, and
the residue was purified by LC-MS (ODS column; acetonitrile/water
system), to give the title compound as a yellow oil (8 mg,
6.7%).
[1032] Free Body:
[1033] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.89 (d, J=6.6 Hz,
3H), 1.19 (d, J=6.6 Hz, 3H), 1.19-1.25 (m, 1H), 1.53-1.68 (m, 1H),
2.00-2.10 (m, 1H), 2.30-2.70 (m, 12H), 2.83 (t, J=5.7 Hz, 2H), 4.11
(t, J=5.7 Hz, 2H), 7.11-7.17 (m, 2H), 7.22-7.27 (m, 1H), 7.34-7.39
(m, 1H), 7.55 (s, 1H).
[1034] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1035] ESI-Mass; 540, 542 (MH.sup.+)
Example 94
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-methyltiophenoxy)ethyl]pip-
erazine
[1036] 210
[1037] The title compound was obtained as a colorless oil in
accordance with Example 45 described in JP-A 11-206862 (64%).
[1038] Free Body:
[1039] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.55-1.70 (m, 1H),
1.71-1.82 (m, 1H), 2.02-2.10 (m, 1H), 2.11-2.21 (m, 1H), 2.27-2.35
(m, 2H), 2.35-2.50 (m, 4H), 2.44 (s, 3H), 2.50-2.65 (m, 4H), 2.78
(t, J=5.9 Hz, 2H), 4.07 (t, J=5.9 Hz, 2H), 6.84 (brd, J=8.8 Hz,
2H), 6.94 (dd, J=3.7 Hz, 4.9 Hz, 1H), 7.11 (brd, J=3.7 Hz, 1H),
7.22-7.29 (m, 3H).
[1040] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1041] ESI-Mass; 456 (MH.sup.+)
Example 95
1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-methylsulfonylphenoxy)ethy-
l]piperazine
[1042] 211
[1043] The title compound was obatined as a colorless oil in
accordance with the production method described in Example 84
(85%).
[1044] Free Body:
[1045] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.22-1.38 (m, 1H), 1.55-1.71 (m, 1H),
1.71-1.82 (m, 1H), 2.02-2.10 (m, 1H), 2.11-2.21 (m, 1H), 2.27-2.35
(m, 2H), 2.35-2.50 (m, 4H), 2.50-2.65 (m, 4H), 2.83 (t, J=5.8 Hz,
2H), 3.03 (s, 3H), 4.16 (t, J=5.8 Hz, 2H), 6.84 (brd, J=8.8 Hz,
2H), 6.94 (dd, J=3.7 Hz, 4.9 Hz, 1H), 7.11 (brd, J=3.7 Hz, 1H),
7.22-7.29 (m, 3H).
[1046] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1047] ESI-Mass; 490 (MH.sup.+)
Example 96
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-acetylphenoxy)ethyl]pipera-
zine
[1048] 212
[1049] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(72%).
[1050] Free Body:
[1051] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.22-1.38 (m, 1H), 1.55-1.71 (m, 1H),
1.71-1.82 (m, 1H), 2.02-2.10 (m, 1H), 2.11-2.21 (m, 1H), 2.28-2.35
(m, 2H), 2.35-2.50 (m, 4H), 2.50-2.65 (m, 4H), 2.59 (s, 3H), 2.82
(t, J=5.8 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 6.94 (dd, J=3.5 Hz, 4.9
Hz, 1H), 7.09-7.13 (m, 2H), 7.24-7.28 (m, 1H), 7.36 (t, J=7.9 Hz,
1H), 7.47-7.50 (m, 1H), 7.54 (brd, J=7.9 Hz, 1H).
[1052] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1053] ESI-Mass; 454 (MH.sup.+)
Example 97
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-acetylphenoxy)ethyl]pipera-
zine
[1054] 213
[1055] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(60%).
[1056] Free Body:
[1057] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.6 Hz,
3H), 1.16 (d, J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H),
1.75-1.84 (m, 1H), 2.02-2.13 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.47
(m, 4H), 2.47-2.68 (m, 4H), 2.59 (s, 3H), 2.81 (t, J=5.9 Hz, 2H),
4.14 (t, J=5.9 Hz, 2H), 6.92 (dd, J=1.4 Hz, 4.9 Hz, 1H), 7.09-7.13
(in, 1H), 7.25-7.28 (m, 1H), 7.32-7.38 (m, 2H), 7.47-7.50 (m, 1H),
7.51-7.56 (m, 1H).
[1058] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1059] ESI-Mass; 454 (MH.sup.+)
Example 98
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]piperaz-
ine
[1060] 214
[1061] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(55%).
[1062] Free Body:
[1063] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.8 Hz,
3H), 1.16 (d, J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H),
1.72-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.45
(m, 4H), 2.45-2.65 (m, 4H), 2.81 (t, J=5.8 Hz, 2H), 4.12 (t, J=5.8
Hz, 2H), 6.90-6.97 (m, 3H), 7.23-7.32 (m, 1H), 7.32-7.36 (m, 1H),
7.57 (d, J=8.6 Hz, 2H).
[1064] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1065] ESI-Mass; 437 (MH.sup.+)
Example 99
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-methylthiophenoxy)ethyl]pi-
perazine
[1066] 215
[1067] The title compound was obtained as a colorless oil in
accordance with Example 45 described in JP-A 11-206862 (59%).
[1068] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.6 Hz,
3H), 1.16 (d, J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H),
1.72-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.48
(m, 4H), 2.44 (s, 3H), 2.48-2.65 (m, 4H), 2.78 (t, J=5.9 Hz, 2H),
4.06 (t, J=5.9 Hz, 2H), 6.84 (brd, J=6.6 Hz, 2H), 6.92 (dd, J=1.5
Hz, 5.1 Hz, 1H), 7.22-7.28 (m, 3H), 7.33 (dd, J=3.0 Hz, 5.1 Hz,
1H).
[1069] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1070] ESI-Mass; 456 (MH.sup.+)
Example 100
1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-methylsulfonylphenoxy)ethy-
l]piperazine
[1071] 216
[1072] The title compound was obtatined as a colorless oil in
accordance with the production method described in Example 84
(56%).
[1073] Free Body:
[1074] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=6.6 Hz,
3H), 1.16 (d, J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H),
1.74-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.48
(m, 4H), 2.48-2.65 (m, 4H), 2.82 (t, J=5.9 Hz, 2H), 3.03 (s, 3H),
4.16 (t, J=5.9 Hz, 2H), 6.92 (dd, J=1.5 Hz, 5.1 Hz, 1H), 7.02 (brd,
J=8.8 Hz, 2H), 7.24-7.29 (m, 1H), 7.33 (dd, J=3.0 Hz, 5.1 Hz, 1H),
7.86 (brd, J=8.8 Hz, 2H).
[1075] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1076] ESI-Mass; 490 (MH.sup.+)
Example 101
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperaz-
ine
[1077] 217
[1078] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(87%).
[1079] Free Body:
[1080] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.6 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.20-1.40 (m, 1H), 1.55-1.70 (m, 1H),
1.72-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.10-2.22 (m, 2H), 2.25-2.35
(m, 2H), 2.35-2.50 (m, 4H), 2.50-2.65 (m, 4H), 2.78 (t, J=5.8 Hz,
2H), 4.06 (t, J=5.8 Hz, 2H), 6.80-6.85 (m, 1H), 6.94 (brdd, J=3.5
Hz, 5.0 Hz, 1H), 7.04-7.15 (m, 4H), 7.24-7.28 (m, 1H).
[1081] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1082] ESI-Mass; 490, 492 (MH.sup.+)
Example 102
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-(2-phenoxyethyl)piperazine
[1083] 218
[1084] The title compound was obtained as a colorless oil in
accordance with the production method described in Example 84
(97%).
[1085] Free Body:
[1086] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.6 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.20-1.40 (m, 1H), 1.55-1.70 (m, 1H),
1.72-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.10-2.22 (m, 2H), 2.25-2.35
(m, 2H), 2.35-2.50 (m, 4H), 2.50-2.65 (m, 4H), 2.80 (t, J=5.8 Hz,
2H), 4.09 (t, J=5.8 Hz, 2H), 6.87-6.97 (m, 4H), 7.08-7.12 (m, 1H),
7.23-7.30 (m, 2H).
[1087] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1088] ESI-Mass; 412 (MH.sup.+)
Example 103
1-[4-Cyano-5-methyl-4-(2-bromo-5-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl-
]piperazine
[1089] 219
[1090] By using
[4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-tert-buty-
ldimethylsilane (700 mg) which was obtained in Example 114-5)
described in JP-A 11-206862,
4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexanol (371 mg, 80%) was
synthesized as a yellow oil in accordance with Example 114-8)
described in JP-A 11-206862. From 105 mg of the resulting compound
and 96 mg of 2-(3-cyanophenoxy)ethylpiperazine, the title compound
was synthesized as a colorless oil in accordance with the
production method described in Example 84 (138 mg, 62%).
[1091] Free Body:
[1092] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.20-1.40 (m, 1H), 1.55-1.70 (m, 1H),
1.90-2.05 (m, 1H), 2.05-2.20 (m, 2H), 2.30-2.38 (m, 2H), 2.38-2.50
(m, 4H), 2.50-2.65 (m, 4H), 2.81 (t, J=5.8 Hz, 2H), 4.10 (t, J=5.8
Hz, 2H), 6.90 (dd, J=3.8 Hz, 8.6 Hz, 2H), 7.10-7.17 (m, 2H),
7.22-7.30 (m, 1H), 7.33-7.40 (m, 1H).
[1093] Further, the hydrochloride of the free body (the title
compound) was obtained in accordance with the method described in
Example 84.
[1094] ESI-Mass; 515, 517 (MH.sup.+)
Example 104
1-[4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(4-methylsulfonylphen-
oxy)ethyl]piperazine
[1095] 220
[1096] From 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanol and
1-[2-(4-methylsulfonylphenoxy)ethyl]piperazine, the title compound
was synthesized as a pale yellow oil in accordance with the method
of Example 68 (39%). Further, the hydrochloride was obtained by
treating the free body (the title compound) in a conventional
method.
[1097] Free Body:
[1098] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.8 Hz, 3H), 1.21-1.31 (m, 1H), 1.60-1.72 (m, 1H),
1.78 (dt, J=4 Hz, J=13.2 Hz, 1H), 2.07 (qui, J=6.8 Hz, 1H), 2.20
(dt, J=4 Hz, J=13.2 Hz, 1H), 2.33 (t, J=7.2 Hz, 2H), 2.42 (bs, 4H),
2.59 (bs, 4H), 2.83 (t, J=5.6 Hz, 2H), 3.03 (s, 3H), 4.16 (t, J=5.6
Hz, 2H), 7.02 (d, J=8.8 Hz, 1H), 7.29 (d, J=1.2 Hz, 1H), 7.86 (d,
J=8.8 Hz, 2H), 7.90 (d, J=1.2 Hz, 1H).
[1099] Hydrochloride:
[1100] ESI-Mass; 515 (MH.sup.+)
Example 105
1-[4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-acetylphenoxy)ethy-
l]piperazine
[1101] 221
[1102] From 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanol and
1-[2-(3-acetylphenoxy)ethyl]piperazine, the title compound was
obtained as a pale yellow oil in accordance with the method of
Example 68 (yield: 38%). Further, the hydrochloride was obtained by
treating the free body (the title compound) in a conventional
method.
[1103] Free Body:
[1104] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.8 Hz, 3H), 1.21-1.32 (m, 1H), 1.60-1.74 (m, 1H),
1.78 (dt, J=4 Hz, J=13.2 Hz, 1H), 2.07 (qui, J=6.8 Hz, 1H), 2.20
(dt, J=4 Hz, J=13.2 Hz, 1H), 2.29-2.37 (m, 2H), 2.43 (bs, 4H), 2.59
(bs, 4H), 2.60 (s, 3H), 2.83 (t, J=5.6 Hz, 2H), 4.15 (t, J=5.6 Hz,
2H), 7.10-7.13 (m, 1H), 7.29 (d, J=1.2 Hz, 1H), 7.37 (t, J=8 Hz,
1H), 7.49 (dd, J=1.6 Hz, J=2.8 Hz, 1H), 7.52-7.55 (m, 1H), 7.90 (d,
J=1.2 Hz, 1H).
[1105] Hydrochloride:
[1106] ESI-Mass; 479 (MH.sup.+)
Example 106
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[{2-(5-cyanobenzofuranyl)}methyl-
]piperazine
[1107] 222
[1108] By using 1-[{2-(5-cyanobenzofuranyl)}methyl]piperazine, the
title compound was synthesized in accordance with the method of
Example 75 (yield: 100%).
[1109] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.22-1.37 (m, 1H), 1.56-1.70 (m, 1H),
1.70-1.80 (m, 1H), 2.00-2.09 (m, 1H), 2.10-2.19 (m, 1H), 2.32 (t,
J=7.2 Hz, 2H), 2.35-2.65 (m, 8H), 3.70 (s, 2H), 6.65 (brd-s, 1H),
6.93 (dd, J=3.2 Hz, 5.2 Hz, 1H), 7.10 (dd, J=1.2 Hz, 3.2 Hz, 1H),
7.24 (dd, J=1.2 Hz, 5.2 Hz, 1H), 7.52-7.54 (m, 2H), 7.85-7.87 (m,
1H)
[1110] ESI-MS; 447 (M+H).sup.+
Example 107
1-[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-(2-phenoxyethyl)piperazi-
ne
[1111] 223
[1112] By using 1-[2-phenoxyethyl]piperazine, the target compound
was synthesized in accordance with the method of Example 77 (yield:
96.5%). The physico-chemical data of the title compound was as
indicated below.
[1113] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.4 Hz, 3H), 1.20-1.32 (m, 1H), 1.60-1.72 (m, 1H),
1.72-1.82 (m, 1H), 2.00-2.12 (m, 1H), 2.17-2.27 (m, 1H), 2.33 (t,
J=7.2 Hz, 2H), 2.32-2.48 (m, 4H), 2.50-2.70 (m, 4H), 2.81 (t, J=6.0
Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 6.88-6.97 (m, 3H), 7.15 (d, J=4.0
Hz, 1H), 7.25-7.30 (m, 2H), 7.51 (d, J=4.0 Hz, 1H)
[1114] ESI-MS; 437 (M+H).sup.+
Example 108
1-[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-bromophenoxy)ethyl-
]piperazine
[1115] 224
[1116] By using 1-[2-(3-bromophenoxy)ethyl]piperazine, the title
compound was synthesized in accordance with the method of Example
77 (yield: 83.5%). The physico-chemical data of the title compound
was as indicated below.
[1117] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (d, J=6.4 Hz,
3H), 1.22 (d, J=6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.60-1.72 (m, 1H),
1.72-1.83 (m, 1H), 2.02-2.12 (m, 1H), 2.17-2.28 (m, 1H), 2.28-2.50
(m, 6H), 2.50-2.67 (m, 4H), 2.80 (t, J=6.0 Hz, 2H), 4.10 (t, J=6.0
Hz, 2H), 6.81-6.86 (m, 1H), 7.05-7.10 (m, 2H), 7.10-7.14 (m, 1H),
7.16 (d, J=3.6 Hz, 1H), 7.52 (d, J=3.6 Hz, 1H) MS(ESI)m/z; 515, 517
(M+H).sup.+
[1118] The compounds of Examples 110, 111, 112, 113, 114, 115, 116,
117, 118, 119 and 120 were synthesized in accordance with the
method of Example 1, 89 or 99 described in JP-A 11-206862, or
according to the methods.
Example 109
1-[4-Cyano-5-methyl-4-(2-bromo-5-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl-
]piperazine
[1119] 225
[1120] The title compoud was obtained as a pale brown oil in
accordance with Example 1 described in JP-A 11-206862.
[1121] Hydrochloride:
[1122] ESI-MS (m/e); 515, 517 (M+H)
Example 110
1-[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-chlorophenoxy)ethy-
l]piperazine
[1123] 226
[1124] Free Body:
[1125] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.6 Hz,
3H), 1.21 (d, J=6.6 Hz, 3H), 1.21-1.32 (m, 1H), 1.55-1.73 (m, 2H),
2.00-2.12 (m, 1H), 2.15-2.30 (m, 1H), 2.30-2.38 (m, 2H), 2.38-2.45
(m, 4H), 2.50-2.65 (m, 4H), 2.80 (t, J=5.8 Hz, 2H), 4.07 (t, J=5.8
Hz, 2H), 6.76-6.82 (m, 1H), 6.88-6.95 (m, 1H), 7.13-7.21 (m, 3H),
7.51 (d, J=3.8 Hz, 1H).
[1126] Hydrochloride:
[1127] ESI-MS (m/e); 471 (M+H)
Example 111
1-[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-iodophenoxy)ethyl]-
piperazine
[1128] 227
[1129] Free Body:
[1130] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.6 Hz,
3H), 1.21 (d, J=6.6 Hz, 3H), 1.21-1.32 (m, 1H), 1.55-1.73 (m, 2H),
2.00-2.12 (m, 1H), 2.15-2.30 (m, 1H), 2.30-2.38 (m, 2H), 2.38-2.45
(m, 4H), 2.50-2.65 (m, 4H), 2.79 (t, J=5.8 Hz, 2H), 4.06 (t, J=5.8
Hz, 2H), 6.86-6.99 (m, 1H), 6.96-7.01 (m, 1H), 7.15 (d, J=3.8 Hz,
1H), 7.25-7.30 (m, 2H), 7.51 (d, J=3.8 Hz, 1H).
[1131] Hydrochloride:
[1132] ESI-MS (m/e); 563 (M+H)
Example 112
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-}N-[(3-cyanophenyl)-N-isopropyla-
mino]ethyl}piperazine
[1133] 228
[1134] Hydrochloride:
[1135] ESI-MS (m/e); 478 (M+H)
Example 113
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{N-[(3-cyanophenyl)-N-methylamin-
o]ethyl}piperazine
[1136] 229
[1137] Free Body:
[1138] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.6 Hz,
3H), 1.18 (d, J=6.6 Hz, 3H), 1.20-1.40 (m, 1H), 1.45-1.70 (m, 1H),
1.70-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.20 (m, 1H), 2.24-2.60
(m, 12H), 3.00 (s, 3H), 3.46 (t, J=7.4 Hz, 2H), 6.84-6.98 (m, 4H),
7.11 (dd, J=3.5 Hz, 1.1 Hz, 1H), 7.23-7.33 (m, 2H)
[1139] Hydrochloride:
[1140] ESI-MS (m/e); 450 (M+H)
Example 114
Synthesis of
1-[3-cyano-4-methyl-5-(2-thienyl)pentyl]-4-[2-(3-cyanophenoxy-
)ethyl]piperazine
[1141] 230
[1142] Free Body:
[1143] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.6 Hz, 3H), 1.85-1.98 (m, 1H), 2.00-2.20 (m, 2H),
2.30-2.70 (m, 1H), 2.80 (t, J=5.9 Hz, 2H), 4.09 (t, J=5.9 Hz, 2H),
6.95 (dd, J=5. lHz, 3.7 Hz, 1H), 7.10-7.15 (m, 3H), 7.22-7.29 (m,
2H), 7.33-7.39 (m, 1H).
[1144] Hydrochloride:
[1145] ESI-MS (m/e); 423 (M+H)
Example 115
1-[3-Cyano-4-methyl-5-(2-thienyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piper-
azine
[1146] 231
[1147] Free Body:
[1148] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.85-1.98 (m, 1H), 2.00-2.20 (m, 2H),
2.30-2.70 (m, 1H), 2.78 (t, J=5.9 Hz, 2H), 4.04 (t, J=5.9 Hz, 2H),
6.80-6.85 (m, 2H), 6.92-6.99 (m, 3H), 7.10-7.13 (m, 1H), 7.26-7.30
(m, 1H).
[1149] Hydrochloride:
[1150] ESI-MS (m/e); 416 (M+H)
Example 116
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-(cyclohexylmethyl)piperazine
[1151] 232
[1152] Trifluoroacetate:
[1153] ESI-MS (m/e); 388 (M+H)
Example 117
4-[4-(4-Phenylpiperidinyl)-piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide
[1154] 233
[1155] Free Body:
[1156] Rf=0.5 (developing solvent; ethyl acetate:hexane=2:1, Fuji
Silysia Chemical Ltd., NH TLC)
[1157] Hydrochloride:
[1158] ESI-MS (m/e); 444 (M+H)
Example 118
4-[4-(4-Cyano-4-phenylpiperidinyl)-piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide
[1159] 234
[1160] Free Body:
[1161] Rf=0.4 (developing solvent; ethyl acetate:hexane=2:1, Fuji
Silysia Chemical Ltd., NH TLC)
[1162] Hydrochloride:
[1163] ESI-MS (m/e); 469 (M+H)
Example 119
4-[4-(4-Benzylpiperidinyl)-piperidinyl]-1-isopropyl-1-phenylbutyl
cyanide
[1164] 235
[1165] Free Body:
[1166] Rf=0.5 (developing solvent; ethyl acetate:hexane=2:1, Fuji
Silysia Chemical Ltd., NH TLC)
[1167] Hydrochloride:
[1168] ESI-MS (m/e); 458 (M+H)
Example 120
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{2-[N-(1,2,3,4-tetrahydro-1-quin-
olinyl)sulfamoyl]ethyl}piperazine
[1169] 236
[1170] The title compound was synthesized in accordance with the
method of Example 63 or 67 described in JP-A 11-206862, or
according to those methods.
[1171] Trifluoroacetate:
[1172] ESI-MS (m/e); 515 (M+H)
Example 121
1-[3-Cyano-4-methyl-5-(2-thienyl)pentyl]-4-{2-[N-(1,2,3,4-tetrahydro-1-qui-
nolinyl)sulfamoyl]ethyl}-piperazine
[1173] 237
[1174] The title compound was synthesized in accordance with the
method of Example 63 or 67 described in JP-A 11-206862, or
according to the methods.
[1175] Trifluoroacetate:
[1176] ESI-MS (m/e); 501 (M+H)
Example 122
1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{2-[N-(piperidinyl)sulfamoyl]eth-
yl}piperazine
[1177] 238
[1178] The title compound was synthesized in accordance with the
method of Example 63 or 67 described in JP-A 11-206862, or
according to the methods.
[1179] Hydrochloride:
[1180] ESI-MS (m/e); 467 (M+H)
Example 123
Bis-1,4-[(3-cyano-4-methyl-3-phenyl)pentyl]piperazine
[1181] 239
[1182] 3-Methyl-2-(2-oxoethyl)-2-phenylbutanenitrile (100 mg) and
anhydrous piperazine (22 mg) were dissolved in methylene chloride
(5 ml) To the mixture were added acetic acid (0.085 ml) and sodium
triacetoxyborohydride (158 mg), followed by stirring overnight at
room temperature. The organic layer was separated by adding an
aqueous saturated sodium bicarbonate and methylene chloride, and it
was washed with water, dried over anhydrous magnesium sulfate and
evaporated. The resulting residue was purified by Chromatorex NH
silica gel column chromatography (hexane/ethyl acetate system), to
give the title compound as a colorless oil (81 mg, 71%). The
hydrochloride (89 mg) of the title compound was obtained by
treating the free body in a conventional method.
[1183] Free Body:
[1184] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
6H), 1.10-1.20 (m, 2H), 1.19 (d, J=6.8 Hz, 6H), 1.50-1.60 (m, 2H),
1.90-2.15 (m, 6H), 2.00-2.45 (m, 8H), 7.25-7.42 (m, 10H).
[1185] Hydrochloride:
[1186] ESI-MS (m/e); 457 (M+H)
[1187] The title compounds of Examples 124 to 126 were synthesized
in accordance with the method of Example 123.
Example 124
Bis-1,4-[(3-cyano-4-methyl-3-phenyl)pentyl]homopiperazine
[1188] 240
[1189] Hydrochloride:
[1190] ESI-MS (m/e); 471 (M+H)
Example 125
Bis-1,4-[(3-cyano-4-methyl-3-phenyl)hexyl]homopiperazine
[1191] 241
[1192] Hydrochloride:
[1193] ESI-MS (m/e); 499 (M+H)
Example 126
Bis-1,4-[(3-cyano-4-methyl-3-(2-thienyl)pentyl]piperazine
[1194] 242
[1195] Hydrochloride:
[1196] ESI-MS (m/e); 469 (M+H)
Example 127
(S)-3-Phenyl-2-aminopropanic acid
{1-[(4-cyano-5-methyl-4-phenyl)hexyl]pip- erazinyl}amide
[1197] 243
[1198] After dissolving
1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (14 mg) and
N-(tert-butoxycarbonyl)-1-phenylalanine (10 mg) in methylene
chloride (0.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(10 mg) and triethylamine (0.015 ml) were added thereto, and the
mixture was stirred overnight at room temperature. After the
solution was purified by silica gel column chromatography (diethyl
ether), the solvent was removed by blowing of nitrogen. After
dissolving the resulting residue in methylene chloride (0.4 ml),
trifluoroacetic acid (0.2 ml) was added thereto and the mixture was
stirred at room temperature for 9 hours. The reaction solvent was
removed by standing the mixture as it was at 35.degree. C. by
blowing of nitrogen overnight, to give the hydrochloride (21 mg,
91%) of the title compound.
[1199] Hydrochloride:
[1200] ESI-MS (m/e); 433 (M+H)
[1201] The title compounds of Examples 128 and 129 were synthesized
in accordance with the method of Example 127.
Example 128
(S)-3-Phenyl-2-aminopropanic acid
{1-[(4-cyano-5-methyl-5-(2-thionyl)hexyl- ]piperazinyl}amide
[1202] 244
[1203] Hydrochloride:
[1204] ESI-MS (m/e); 439 (M+H)
Example 129
(S)-3-Phenyl-2-amino-propanic acid
{1-[(3-cyano-4-methyl-4-(2-thionyl)hexy- l]piperazinyl}amide
[1205] 245
[1206] Hydrochloride:
[1207] ESI-MS (m/e); 425 (M+H)
Example 130
5-[3-(Benzylamino)-4-hydroxytetrahydro-1H-1-pyrrolyl]-2-isopropyl-5-oxo-2--
(2-thienyl)pentane nitrile
[1208] 246
[1209] Under a nitrogen atmosphere,
5-(2,5-dihydro-1H-1-pyrrolyl]-2-isopro-
pyl-5-oxo-2-(2-thienyl)pentanenitrile (260 mg) was dissolved in a
mixed solvent of dimethyl sulfoxide (2 ml) and water (0.1 ml) at
room temperature. To the mixture was added N-bromosuccinimide (177
mg), followed by stirring overnight. The reaction solution was
partitioned between ethyl acetate and water, and the resulting
organic layer was dried over anhydrous magnesium sulfate and then
evaporated. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane system), to give a colorless
oily intermediate (140 mg). The intermediate (20 mg) was dissolved
in tetrahydrofuran (0.05 ml), a 1N aqueous sodium hydroxide (0.06
ml) was added, and the mixture was stirred at room temperature.
After stirring for 45 minutes, a benzylamine (11
mg)/tetrahydrofuran solution (0.05 ml) was added thereto, and the
mixture was stirred at 70.degree. C. overnight. The reaction
solution was cooled to room temperature and partitioned between
ethyl acetate and water. The resulting organic layer was dried over
anhydrous magnesium sulfate and then evaporated. The residue was
purified by Cromatorex NH silica gel column chromatography (ethyl
acetate/hexane system), to give the title compound as a colorless
oil (20 mg).
[1210] Hydrochloride:
[1211] ESI-MS (m/e); 412 (M+H)
[1212] The title compounds of Examples 131 to 136 were synthesized
in accordance with the method of Example 130.
Example 131
5-[3-(N-Methylbenzylamino)-4-hydroxytetrahydro-1H-1-pyrrolyl]-2-isopropyl--
5-oxo-2-(2-thienyl)pentane nitrile
[1213] 247
[1214] Hydrochloride:
[1215] ESI-MS (m/e); 426 (M+H)
Example 132
5-[3-(2-Thienylethylamino)-4-hydroxytetrahydro-1H-1-pyrrolyl]-2-isopropyl--
5-oxo-2-(2-thienyl)pentane nitrile
[1216] 248
[1217] Hydrochloride:
[1218] ESI-MS (m/e); 432 (M+H)
Example 133
5-[3-(N-Phenylpiperazino)-4-hydroxytetrahydro-1H-1-pyrrolyl]-2-isopropyl-5-
-oxo-2-(2-thienyl)pentane nitrile
[1219] 249
[1220] Trifluoroacetate:
[1221] ESI-MS (m/e); 467 (M+H)
Example 134
5-[3-[4-(2,3-Dihydro-1H-1-indolyl)piperazino]-4-hydroxytetrahydro-1H-pyrro-
lyl]-2-isopropyl-5-oxo-2-(2-thienyl)pentane nitrile
[1222] 250
[1223] Trifluoroacetate:
[1224] ESI-MS (m/e); 507 (M+H)
Example 135
5-[3-[(3-Pyridylethylamino)-4-hydroxytetrahydro-1H-pyrrolyl]-2-isopropyl-5-
-oxo-2-(2-thienyl)pentanenitrile
[1225] 251
[1226] Trifluoroacetate:
[1227] ESI-MS (m/e); 427 (M+H)
Example 136
5-[{3-[4-(1H-1-Indolyl)piperidino)-4-hydroxytetrahydro-1H-pyrrolyl}-2-isop-
ropyl-5-oxo-2-(2-thienyl)pentanenitrile
[1228] 252
[1229] Trifluoroacetate:
[1230] ESI-MS (m/e); 505 (M+H)
[1231] The title compounds of Examples 137 to 172 were synthesized
in accordance with the method of the above-mentioned Example
64.
Example 137
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(benzothiazolyl)piperazine
[1232] 253
[1233] Free Body:
[1234] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.50-1.70 (m, 1H),
1.87-1.20 (m, 1H), 2.08-2.24 (m, 2H), 2.30-2.38 (m, 1H), 2.40-2.48
(m, 4H), 3.52-3.64 (m, 4H), 7.04-7.10 (m, 1H), 7.24-7.34 (m, 2H),
7.35-7.40 (m, 4H), 7.50-7.61 (m, 2H).
[1235] Hydrochloride:
[1236] ESI-MS (m/e); 449 (M+H)
Example 138
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-methoxy)benzothiazolyl]pipera-
zine
[1237] 254
[1238] Free Body:
[1239] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.50-1.70 (m, 1H),
1.87-1.20 (m, 1H), 2.08-2.24 (m, 2H), 2.30-2.38 (m, 1H), 2.38-2.48
(m, 4H), 3.50-3.62 (m, 4H), 3.82 (s, 3H), 6.86-6.92 (m, 1H),
7.12-7.15 (m, 1H), 7.22-7.35 (m, 3H), 7.35-7.40 (m, 3H), 7.43-7.48
(m, 1H).
[1240] Hydrochloride:
[1241] ESI-MS (m/e); 419 (M+H)
Example 139
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzoxazolyl)piperazine
[1242] 255
[1243] Free Body:
[1244] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.50-1.70 (m, 1H),
1.77-1.20 (m, 1H), 2.08-2.25 (m, 2H), 2.28-2.38 (m, 1H), 2.38-2.48
(m, 4H), 3.60-3.72 (m, 4H), 6.98-7.04 (m, 1H), 7.12-7.18 (m, 1H),
7.22-7.28 (m, 1H), 7.28-7.43 (m, 5H).
[1245] Hydrochloride:
[1246] ESI-MS (m/e) ; 403 (M+H)
Example 140
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-quinolinyl)piperazine
[1247] 256
[1248] Free Body:
[1249] Rf=0.6 (developing solvent; diethyl ether, Merck silica gel
60F254 TLC)
[1250] Hydrochloride:
[1251] ESI-MS (m/e); 413 (M+H)
Example 141
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(1-quinolinyl)piperazine
[1252] 257
[1253] Free Body:
[1254] Rf=0.45 (developing solvent; diethyl ether, Merck silica gel
60F254 TLC)
[1255] Hydrochloric acid salt:
[1256] ESI-MS (m/e); 413 (M+H)
Example 142
4-[4-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl--
1-phenylbutyl cyanide
[1257] 258
[1258] Free Body:
[1259] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 0.81 (d, J=8.1 Hz, 6H), 1.08-1.30 (m, 1H), 1.20 (d, J=7.0 Hz,
3H), 1.50-1.70 (m, 1H), 1.77-1.20 (m, 2H), 2.00-2.32 (m, 4H),
2.40-2.52 (m, 2H), 2.60-2.67 (m, 2H), 2.67-2.73 (m, 2H), 3.48-3.60
(m, 4H), 3.81 (d, J=7.3 Hz, 2H), 7.07-7.18 (m, 3H), 7.25-7.42 (m,
5H), 7.51-7.56 (m, 1H).
[1260] Hydrochloride:
[1261] ESI-MS (m/e); 472 (M+H)
Example 143
4-[4-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)
-1,4-diazepan-1-yl]-1-isopropyl- -1-(2-chlorophenyl)butyl
cyanide
[1262] 259
[1263] Free Body:
[1264] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 0.81 (d, J=8.1 Hz, 6H), 1.08-1.30 (m, 1H), 1.20 (d, J=7.0 Hz,
3H), 1.50-1.70 (m, 1H), 1.77-1.20 (m, 2H), 2.00-2.32 (m, 4H),
2.40-2.52 (m, 2H), 2.60-2.67 (m, 2H), 2.67-2.73 (m, 2H), 3.48-3.60
(m, 4H), 3.81 (d, J=7.3 Hz, 2H), 7.05-7.35 (m, 5H), 7.3035-7.40 (m,
1H), 7.51-7.56 (m, 1H), 7.72-7.79 (m, 1H).
[1265] Hydrochloride:
[1266] ESI-MS (m/e); 506 (M[.sup.34Cl]+H), 508 (M[.sup.36Cl]+H)
Example 144
1-Isopropyl-4-[4-(1H-benzo[d]imidazol-2-yl)piperazino]-1-phenylbutyl
cyanide
[1267] 260
[1268] Free Body:
[1269] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.04-1.25 (m, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.70 (m, 1H),
1.87-1.99 (m, 1H), 2.05-2.23 (m, 2H), 2.25-2.40 (m, 2H), 2.40-2.47
(m, 4H), 3.42-3.58 (m, 4H), 7.00-7.40 (m, 9H).
[1270] Hydrochloride:
[1271] ESI-MS (m/e); 402 (M+H)
Example 145
1-Isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-phenylbu-
tyl cyanide
[1272] 261
[1273] Free Body:
[1274] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.50-1.70 (m, 1H),
1.92-2.03 (m, 1H), 2.08-2.25 (m, 2H), 2.28-2.45 (m, 2H), 2.45-2.56
(m, 4H), 3.25-3.35 (m, 4H), 3.59 (s, 3H), 7.02-7.62 (m, 9H).
[1275] Hydrochloride:
[1276] ESI-MS (m/e); 416 (M+H)
Example 146
1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-phenylbut-
yl cyanide
[1277] 262
[1278] Free Body:
[1279] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.10-1.30 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.44 (t, J=7.3 Hz,
3H), 1.50-1.70 (m, 1H), 1.92-2.03 (m, 1H), 2.08-2.25 (m, 2H),
2.28-2.45 (m, 2H), 2.45-2.56 (m, 4H), 3.20-3.35 (m, 4H), 4.03 (q,
J=7.3 Hz, 2H), 7.14-7.64 (m, 9H).
[1280] Hydrochloride:
[1281] ESI-MS (m/e); 430 (M+H)
Example 147
4-[4-(1-Ethyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-isopropyl-1-(2-thieny-
l)butyl cyanide
[1282] 263
[1283] Free Body:
[1284] Rf=0.35 (developing solvent; ethyl acetate:hexane=1:1, Fuji
Silysia Chemical Ltd., NH TLC)
[1285] Hydrochloride:
[1286] ESI-MS (m/e); 436 (M+H)
Example 148
4-[4-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-isopropyl-1-(2-thi-
enyl)butyl cyanide
[1287] 264
[1288] Free Body:
[1289] Rf=0.4 (evolution solvent; ethyl acetate:hexane=1:1, Fuji
Silysia Chemical Ltd., NH TLC)
[1290] Hydrochloride:
[1291] ESI-MS (m/e); 464 (M+H)
Example 149
1-Isopropyl-4-[4-(1-isopropyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-pheny-
lbutyl cyanide
[1292] 265
[1293] Free Body:
[1294] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.6 Hz,
3H), 1.10-1.25 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.50-1.68 (m, 7H),
1.90-2.04 (m, 1H), 2.05-2.24 (m, 2H), 2.25-2.45 (m, 2H), 2.45-2.53
(m, 4H), 3.15-3.25 (m, 4H), 4.56-4.68 (m, 1H), 7.09-7.19 (m, 2H),
7.25-7.33 (m, 1H), 7.34-7.42 (m, 5H), 7.60-7.64 (m, 1H).
[1295] Hydrochloride:
[1296] ESI-MS (m/e); 444 (M+H)
Example 150
4-[4-(1H-Benzo[dl
imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbu- tyl
cyanide
[1297] 266
[1298] Free Body:
[1299] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.74 (d, J=6.6 Hz,
3H), 1.00-1.15 (m, 1H), 1.14 (d, J=6.6 Hz, 3H), 1.40-1.50 (m, 1H),
1.78-1.93 (m, 3H), 2.00-2.17 (m, 2H), 2.30-2.40 (m, 2H), 2.45-2.55
(m, 2H), 2.57-2.64 (m, 2H), 3.57-3.63 (m, 4H), 6.96-7.52 (m,
9H).
[1300] Hydrochloride:
[1301] ESI-MS (m/e); 416 (M+H)
Example 151
4-[4-(1-Methyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1--
phenylbutyl cyanide
[1302] 267
[1303] Free Body:
[1304] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 1.07-1.17 (m, 1H), 1.18 (d, J=6.6 Hz, 3H), 1.45-1.60 (m, 1H),
1.76-2.25 (m, 5H) 2.40-2.50 (m, 2H), 2.60-2.67 (m, 2H), 2.68-2.76
(m, 2H), 3.53-3.63 (m, 4H), 3.57 (s, 3H), 7.08-7.54 (m, 9H).
[1305] Hydrochloride:
[1306] ESI-MS (m/e); 430 (M+H)
Example 152
4-[4-(1-Ethyl-1-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-ph-
enylbutyl cyanide
[1307] 268
[1308] Free Body:
[1309] 1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz, 3H),
1.05-1.17 (m, 1H), 1.19 (d, J=6.6 Hz, 3H), 1.40 (t, J=7.2 Hz, 3H),
1.47-1.62 (m, 1H), 1.76-2.23 (m, 5H), 2.40-2.50 (m, 2H), 2.60-2.67
(m, 2H), 2.68-2.76 (m, 2H), 3.51-3.63 (m, 4H), 4.02 (d, J=7.2 Hz,
3H), 7.06-7.54 (m, 9H).
[1310] Hydrochloride:
[1311] ESI-MS (m/e); 444 (M+H)
Example 153
1-Isopropyl-4-[4-(1-ethyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(4-fluorop-
henyl)butyl cyanide
[1312] 269
[1313] Free Body:
[1314] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 1.13-1.23 (m, 1H) 1.20 (d, J=6.8 Hz, 3H), 1.44 (t, J=7.1 Hz,
3H), 1.56-1.66 (m, 1H), 1.89-1.97 (m, 1H), 2.04-2.22 (m, 2H),
2.34-2.41 (m, 2H), 2.50-2.51 (m, 4H), 3.26-3.29 (m, 4H), 4.01-4.07
(m, 2H), 7.05-7.10 (m, 2H), 7.14-7.25 (m, 3H), 7.34-7.38 (m, 2H),
7.60-7.62 (m, 1H).
Example 154
1-Isopropyl-4-[4-(1-benzyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(4-fluoro-
phenyl)butyl cyanide
[1315] 270
[1316] Free Body:
[1317] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.6 Hz,
3H), 1.08-1.15 (m, 1H), 1.18 (d, J=6.6 Hz, 3H), 1.53-1.57 (m, 1H),
1.85-1.93 (m, 1H), 2.02-2.19 (m, 2H), 2.29-2.38 (m, 2H), 2.42 (m,
4H), 3.21-3.24 (m, 4H), 5.20 (s, 2H), 6.99-7.11 (m, 4H), 7.15-7.21
(m, 3H), 7.26-7.35 (m, 5H), 7.62-7.65 (m, 1H).
Example 155
1-Isopropyl-4-[4-(1-isobutyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(4-fluo-
rophenyl)butyl cyanide
[1318] 271
[1319] Free Body:
[1320] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.8 Hz,
3H), 0.82-0.85 (m, 6H), 1.12-1.25 (m, 1H), 1.20 (d, J=6.6 Hz, 3H),
1.57-1.63 (m, 1H), 1.90-1.98 (m, 1H), 2.04-2.12 (m, 1H), 2.14-2.42
(m, 4H), 2.48 (m, 4H), 3.23-3.25 (m, 4H), 3.81 (d, J=7.3 Hz, 2H),
7.05-7.20 (m, 2H), 7.21-7.23 (m, 3H), 7.33-7.38 (m, 2H), 7.60-7.63
(m, 1H).
Example 156
1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(3-flu-
orophenyl)butyl cyanide
[1321] 272
[1322] Free Body:
[1323] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77-0.89 (m, 9H),
1.13-1.26 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.58-1.65 (m, 1H),
1.90-1.98 (m, 1H), 2.04-2.41 (m, 5H), 2.41-2.50 (m, 4H), 3.23-3.25
(m, 4H), 3.80 (d, J=7.5 Hz, 2H), 6.98-7.03 (m, 1H), 7.08-7.23 (m,
5H), 7.33-7.39 (m, 1H), 7.60-7.63 (m, 1H).
Example 157
1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-flu-
orophenyl)butyl cyanide
[1324] 273
[1325] Free Body:
[1326] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80-0.88 (m, 9H),
1.15-1.25 (m, 1H), 1.23 (d, J=6.6 Hz, 3H), 1.58-1.64 (m; 1H),
2.04-2.16 (m, 1H), 2.25-2.51 (m, 9H), 3.22-3.25 (m, 4H), 3.80 (d,
J=7.5 Hz, 2H), 7.02-7.08 (m, 1H), 7.13-7.21 (m, 4H), 7.29-7.33 (m,
1H), 7.58-7.62 (m, 2H).
Example 158
1-Isopropyl-4-[4-(1-methyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(3-fluoro-
phenyl)butyl cyanide
[1327] 274
[1328] Free Body:
[1329] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80 (d, J=6.8 Hz,
3H), 1.15-1.27 (m, 1H), 1.22 (d, J=6.8 Hz, 3H), 1.58-1.66 (m, 1H),
1.89-1.97 (m, 1H), 2.01-2.24 (m, 2H), 2.34-2.41 (m, 2H), 2.51-2.53
(m, 4H), 3.29-3.32 (m, 4H), 3.59 (s, 3H), 6.98-7.04 (m, 1H),
7.08-7.21 (m, 5H), 7.33-7.39 (m, 1H), 7.58-7.61 (m, 1H).
Example 159
1-Isopropyl-4-[4-(1-ethyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(3-fluorop-
henyl)butyl cyanide
[1330] 275
[1331] Free Body:
[1332] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80 (d, J=6.8 Hz,
3H), 1.13-1.28 (m, 1H), 1.22 (d, J=6.8 Hz, 3H), 1.44 (t, J=7.1 Hz,
3H), 1.58-1.66 (m, 1H), 1.89-1.97 (m, 1H), 2.04-2.24 (m, 2H),
2.33-2.41 (m, 2H), 2.51-2.52 (m, 4H), 3.27-3.30 (m, 4H), 4.01-4.07
(m, 2H), 6.98-7.04 (m, 1H), 7.08-7.27 (m, 5H), 7.33-7.39 (m, 1H),
7.59-7.62 (m, 1H).
Example 160
1-Isopropyl-4-[4-(1-benzyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(3-fluoro-
phenyl)butyl cyanide
[1333] 276
[1334] Free Body:
[1335] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (d, J=6.6 Hz,
3H), 1.08-1.18 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.54-1.65 (m, 1H),
1.84-1.92 (m, 1H), 2.04-2.20 (m, 2H), 2.28-2.36 (m, 2H), 2.38-2.43
(m, 4H), 3.22-3.25 (m, 4H), 5.20 (s, 2H), 6.96-7.01 (m, 2H),
7.05-7.10 (m, 2H), 7.14-7.21 (m, 4H), 7.26-7.36 (m, 4H), 7.63-7.64
(m, 1H).
Example 161
1-Isopropyl-4-[4-(1-ethyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(2-fluorop-
henyl)butyl cyanide
[1336] 277
[1337] Free Body:
[1338] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.81 (d, J=6.8 Hz,
3H), 1.15-1.28 (m, 1H), 1.23 (d, J=6.8 Hz, 3H), 1.44(t, J=7.1 Hz,
3H), 1.59-1.68 (m, 1H), 2.04-2.16 (m, 1H), 2.25-2.54 (m, 8H),
3.27-3.30 (m, 4H), 4.00-4.06 (m, 2H), 7.02-7.08 (m, 1H), 7.13-7.24
(m, 4H), 7.29-7.34 (m, 1H), 7.58-7.63 (m, 2H).
Example 162
Synthesis of
1-isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazin-
o]-1-(2-tolyl)butyl cyanide
[1339] 278
[1340] Oxalate:
[1341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.77 (d, J=6.8
Hz, 3H), 1.07 (d, J=6.8 Hz, 3H), 1.25-1.40 (m, 1H), 1.53-1.70 (m,
1H), 1.97-2.10 (m, 1H), 2.20-2.35 (m, 1H), 2.40-2.50 (m, 1H), 2.47
(s, 3H), 3.05-3.20 (m, 2H), 3.10-3.30 (m, 4H), 3.33-3.50 (m, 4H),
3.59 (s, 3H), 7.07-7.15 (m, 2H), 7.20-7.29 (m, 3H), 7.34-7.46 (m,
3H).
Example 163
1-Isopropyl-4-[4-(1-methyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(4-fluoro-
phenyl)butyl cyanide
[1342] 279
[1343] Oxalate:
[1344] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.66 (d, J=6.4
Hz, 3H), 1.10 (d, J=6.4 Hz, 3H), 1.10-1.30 (m, 1H), 1.50-1.67 (m,
1H), 1.95-2.30 (m, 2H), 2.15-2.27 (m, 1H), 2.95-3.20 (m, 2H),
3.10-3.30 (m, 4H), 3. .sub.35-3.50 (m, 4H), 3.59 (s, 3H), 7.07-7.15
(m, 2H), 7.28 (t, J=8.8 Hz, 2H), 7.34-7.46 (m, 2H), 7.43-7.50 (m,
2H).
Example 164
1-Isopropyl-4-[4-(1-ethyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(2-chlorop-
henyl)butyl cyanide
[1345] 280
[1346] Oxalate:
[1347] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.73 (d, J=6.8
Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 1.10-1.35 (m, 1H), 1.30 (t, J=7.2
Hz, 3H), 1.50-1.68 (m, 1H), 2.00-2.15 (m, 1H), 2.50-2.70 (m, 1H),
2.78-2.90 (m, 1H), 3.00-3.20 (m, 2H), 3.05-3.30 (m, 4H), 3.25-3.45
(m, 4H), 4.06 (q, J=7.2 Hz, 2H), 7.06-7.15 (m, 2H), 7.38-7.49 (m,
4H), 7.54 (dd, J=7.6 Hz, 2.0 Hz, 1H), 7.65 (dd, J=7.6 Hz, 2.0 Hz,
1H).
Example 165
1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-chl-
orophenyl)butyl cyanide
[1348] 281
[1349] Oxalate:
[1350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.75 (d, J=6.8
Hz, 9H), 1.12 (d, J=6.4 Hz, 3H), 1.15-1.45 (m, 1H), 1.50-1.70 (m,
1H), 2.00-2.25 (m, 2H), 2.50-2.65 (m, 1H), 2.75-2.90 (m, 1H),
3.00-3.30 (m, 2H), 3.00-3.30 (m, 4H), 3.20-3.45 (m, 4H), 3.87 (d,
J=7.2 Hz, 2H), 7.00-7.18 (m, 2H), 7.38-7.48 (m, 4H), 7.54 (d, J=7.6
Hz, 1H), 7.64 (d, J=7.6 Hz, 1H).
Example 166
1-Isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-metho-
xyphenyl)butyl cyanide
[1351] 282
[1352] Oxalate:
[1353] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.68 (d, J=6.8
Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.50-1.65 (m,
1H), 1.90-2.05 (m, 1H), 2.35-2.50 (m, 1H), 2.57-2.70 (m, 1H),
2.95-3.20 (m, 2H), 3.05-3.25 (m, 4H), 3.30-3.50 (m, 4H), 3.59 (s,
3H), 3.81 (s, 3H), 6.98-7.04 (m, 1H), 7.07-7.15 (m, 3H), 7.33-7.43
(m, 4H).
Example 167
1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-methox-
yphenyl)butyl cyanide
[1354] 283
[1355] Oxalate:
[1356] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.67 (d, J=6.4
Hz, 3H), 1.08 (d, J=6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.30 (t, J=7.2
Hz, 3H), 1.45-1.60 (m, 1H), 1.90-2.05 (m, 1H), 2.35-2.50 (m, 1H),
2.58-2.70 (m, 1H), 2.90-3.10 (m, 2H), 3.00-3.20 (m, 4H), 3.25-3.45
(m, 4H), 3.81 (s, 3H), 4.06 (q, J=7.2 Hz, 2H), 7.01 (t, J=7.6 Hz,
1H), 7.06-7.14 (m, 3H), 7.36 (t, J=7.6 Hz, 1H), 7.35-7.45 (m,
3H).
Example 168
1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-met-
hoxyphenyl)butyl cyanide
[1357] 284
[1358] Oxalate:
[1359] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.67 (d, J=6.8
Hz, 3H), 0.74 (d, J=6.4 Hz, 6H), 1.09 (d, J=6.4 Hz, 3H), 1.05-1.30
(m, 1H), 1.45-1.65 (m, 1H), 1.90-2.03 (m, 1H), 2.10-2.20 (m, 1H),
2.35-2.50 (m, 1H), 2.57-2.70 (m, 1H), 3.00-3.20 (m, 2H), 3.10-3.25
(m, 4H), 3.25-3.45 (m, 4H), 3.81 (s, 3H), 3.86 (d, J=7.6 Hz, 2H),
7.01 (td, J=7.6 Hz, 2.0 Hz, 1H), 7.06-7.14 (m, 3H), 7.33-7.46 (m,
4H).
Example 169
1-Isopropyl-4-[4-(1-benzyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-metho-
xyphenyl)butyl cyanide
[1360] 285
[1361] Oxalate:
[1362] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.67 (d, J=6.8
Hz, 3H), 1.08 (d, J=6.8 Hz, 3H), 1.10-1.25 (m, 1H), 1.45-1.65 (m,
1H), 1.90-2.00 (m, 1H), 2.33-2.45 (m, 1H), 2.55-2.70 (m, 1H),
2.90-3.20 (m, 2H), 3.10-3.25 (m, 4H), 3.25-3.45 (m, 4H), 3.79 (s,
3H), 5.30 (s, 2H), 6.97-7.20 (m, 7H), 7.21-7.47 (m, 6H).
Example 170
1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-(2-methyl-
phenyl)butyl cyanide
[1363] 286
[1364] Free Body:
[1365] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (d, J=6.8 Hz,
3H) 1.19 (d, J=6.8 Hz, 3H), 1.20-1.28 (m, 1H), 1.44 (t, J=7.3 Hz,
3H), 1.55-1.70 (m, 1H), 2.06-2.20 (m, 1H), 2.25-2.45 (m, 4H),
2.45-2.58 (m, 7H), 3.25-3.35 (m, 4H), 4.04 (q, J=7.3 Hz, 2H),
7.15-7.23 (m, 6H), 7.57-7.68 (m, 1H), 7.59-7.60 (m, 1H).
[1366] Hydrochloride:
[1367] ESI-MS (m/e); 444 (M+H)
Example 171
1-Isopropyl-4-[4-(1-benzyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(2-methyl-
phenyl)butyl cyanide
[1368] 287
[1369] Free Body:
[1370] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6.8 Hz,
3H), 1.17 (d, J=6.8 Hz, 3H), 1.17-1.25 (m, 1H), 1.50-1.65 (m, 1H),
2.00-2.10 (m, 1H), 2.20-2.48 (m, 8H), 2.49 (s, 3H), 3.19-3.24 (m,
4H), 5.19 (s, 2H), 6.99-7.01 (m, 1H), 7.08-7.21 (m, 8H), 7.27-7.38
(m, 2H), 7.43-7.55 (m, 1H), 7.63-7.65 (m, 1H).
[1371] Hydrochloride:
[1372] ESI-MS (m/e); 506 (M+H)
Example 172
1-Isopropyl-4-[4-(1-isobutyl-1-benzo[d]imidazol-2-yl)piperazino]-1-(2-meth-
ylphenyl)butyl cyanide
[1373] 288
[1374] Free Body:
[1375] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (d, J=4.0 Hz,
3H), 0.85 (d, J=4.0 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H), 1.19 (d, J=6.6
Hz, 3H), 1.20-1.29 (m, 1H), 1.54-1.65 (m, 1H), 2.05-2.16 (m, 1H),
2.24-2.51 (m, 9H), 2.52 (s, 3H), 3.20-3.25 (m, 4H), 3.80 (d, J=7.5
Hz, 2H), 7.12-7.22 (m, 6H), 7.48-7.56 (m, 1H), 7.59-7.60 (m,
1H).
[1376] Hydrochloride:
[1377] ESI-MS (m/e); 472 (M+H)
Example 173
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-[N-(2-cyanoethyl)-N-
-benzylamino]pyrrolidine
[1378] 289
[1379] In dichloromethane (8 ml) was dissolved 300 mg (0.81 mmol)
of
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-[N-(2-cyanoethyl)a-
mino]pyrrolidine obtained in Reference Example 81, followed by
successively adding 98.9 mg (0.93 mmol) of benzaldehyde, 0.09 ml
(1.62 mmol) of acetic acid and 258 mg (1.22 mmol) of sodium
triacetoxyborohydride. After completion of the reaction, the
reaction solution was adjusted to basic with a 5N sodium hydroxide
and extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate and evaporated, to give a crude
product. The crude product was subjected to 25 g of Cromatorex NH
silica gel (ethyl acetate:hexane=25% of ethyl acetate), to give 220
mg (0.48 mmol, 59.1%) of the title compound as a colorless syrup.
The physico-chemical data of the compound was as below.
[1380] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.19 (d, J=6.4 Hz, 3H), 1.16-1.29 (m, 1H), 1.54-1.66 (m, 1H),
1.70-1.84 (m, 2H), 1.91-2.08 (m, 2H), 2.17-2.37 (m, 5H), 2.38-2.51
(m, 2H) 2.51-2.58 (m, 1H), 2.61-2.68 (m, 1H), 2.78-2.94 (m, 2H),
3.40-3.50 (m, 1H) 3.60 (d, J=14 Hz, 1H), 3.71 (d, J=14 Hz, 1H),
7.13 (d, J=3.6 Hz, 1H), 7.32-7.39 (m, 5H), 7.50 (d, J=3.6 Hz,
1H)
[1381] Further, the diastereomer of the title compound of Example
173 is synthesized in accordance with the production method of the
above-mentioned Example 173 from 4-cyano-4-(5-cyano-2-thienyl)
-5-methylhexanol (hereinafter, referred to as "alcohol b")
synthesized in accordance with Reference Examples 104 and 105 from
4-cyano-4-(2-thienyl) -5-methylhexanoic acid obtained from
Reference Example 103, and
(3R)-3-tert-butoxycarbonylaminopyrrolidine. Similarly, the mirror
isomer of the title compound of Example 173 is synthesized in
accordance with the production method of the above-mentioned
Example 173 from the alcohol b and
(3S)-3-tert-butoxycarbonylaminopyrrolidine.
Example 174
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-[N-(2-cyanoethyl)-N-
-(2-thienylmethyl)amino]pyrrolidine
[1382] 290
[1383] The title compound was synthesized in accordance with the
production method of Example 173 from
1-[4-cyano-4-(5-cyano-2-thienyl)-5--
methylhexyl]-(3R)-3-[N-(2-cyanoethyl)amino]pyrrolidine obtained
from Reference Example 81 and 2-thiophenecarboxyaldehyde. The
physico-chemical data of the compound was as below.
[1384] Yield: 46.7%
[1385] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.4 Hz, 3H), 1.16-1.29 (m, 1H), 1.54-1.67 (m, 1H),
1.67-1.84 (m, 2H), 1.95-2.09 (m, 2H), 2.17-2.35 (m, 3H), 2.35-2.56
(m, 5H), 2.61-2.70 (m, 1H), 2.80-2.96 (m, 2H), 3.44-3.54 (m, 1H),
3.84 (d, J=15.0 Hz, 1H), 3.92 (d, J=15.0 Hz, 1H), 6.92-7.04 (m,
2H), 7.13 (d, J=4.0 Hz, 1H), 7.23-7.31 (m, 1H), 7.51 (d, J=4.0 Hz,
1H)
Example 175
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cyanoethyl)-N-
-benzylamino]pyrrolidine
[1386] 291
[1387] The title compound could be synthesized in accordance with
the following two methods (synthetic methods A and B).
[1388] Synthetic Method A
[1389] (1) (3S)-3-[N-(2-Cyanoethyl)-N-benzylamino]pyrrolidine
292
[1390]
(3S)-3-[N-(2-Cyanoethyl)-N-benzylamino]-1-(tert-butoxycarbonyl)pyrr-
olidine was synthesized in accordance with the production methods
of Reference Example 81 and Example 173 from
(3S)-3-amino-1-(tert-butoxycarb- onyl)pyrrolidine. The title
compound was obtained by de-protecting the Boc group in accordance
with Reference Example 80 (yield; 78.2%, (3 steps)). The
physico-chemical data of the compound was as below. The
physico-chemical data of
(3S)-3-[N-(2-cyanoethyl)-N-benzylamino]-1-(tert--
butoxycarbonyl)pyrrolidine
[1391] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (s, 9H),
1.77-1.95 (m, 1H), 1.98-2.12 (m, 1H), 2.32 (t, J=6.8 Hz, 2H), 2.87
(t, J=6.8 Hz, 2H), 3.10-3.78 (m, 7H), 7.27-7.39 (m, 5H)
[1392] The Physico-Chemical Data of
(3S)-3-[N-(2-cyanoethyl)-N-benzylamino- )pyrrolidine
[1393] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.66-1.78 (m, 1H)
1.88-2.02 (m, 1H) 2.31 (t, J=6.8 Hz, 2H) 2.78-2.95 (m, 4H)
3.02-3.12 (m, 2H), 3.32-3.41 (m, 1H), 2.87 (t, J=6.8 Hz, 2H), 3.64
(d, J=14 Hz, 1H), 3.71 (d, J=14 Hz, 1H), 7.27-7.38 (m, 5 H)
[1394] (2)
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cy-
anoethyl)-N-benzylamino]pyrrolidine
[1395] Optically active body,
4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide (iodide C
(optically active body)) was synthesized from the alcohol B in
accordance with Example 77 (1). The title compound was synthesized
in accordance with Example 77(2) from the iodide C and
(3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine which was
obtained in (1). The physico-chemical data of the compound was as
below.
[1396] Yield; 90.6%.
[1397] ESI-MS; 460 (M+H).sup.+
[1398] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.19 (d, J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.56-1.68 (m, 1H),
1.70-1.81 (m, 2H), 1.93-2.10 (m, 2H), 2.21-2.44 (m, 7H), 2.57-2.67
(m, 2H), 2.80-2.95 (m, 2H), 3.39-3.48 (m, 1H), 3.62 (d, J=14 Hz,
1H), 3.69 (d, J=14 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.23-7.37 (m,
5H), 7.52 (d, J=4.0 Hz, 1H)
[1399] Synthetic Method B
[1400] The title compound was synthesized in accordance with the
production of Example 173 from the above-mentioned iodide C (or the
alcohol B) and (3S)-3-tert-butoxycarbonylaminopyrrolidine.
Example 176
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cyanoethyl)-N-benzyla-
mino]pyrrolidine
[1401] 293
[1402] Optically active body, 4-cyano-4-(2-thienyl)-5-methylhexyl
iodide (iodide D (optically active body)) was synthesized from the
alcohol A in accordance with Example 77(1). The title compound was
synthesized in accordance with Example 75 from the iodide D and
(3S)-3-[N-(2-cyanoethyl)- -N-benzylamino]pyrrolidine of "Synthetic
method A" (1) (1) of Example 175. The physico-chemical data of the
title compound was as below.
[1403] Yield; 97%.
[1404] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.17 (d, J=6.4 Hz, 3H), 1.20-1.35 (m, 1H), 1.55-1.68 (m, 1H),
1.69-1.82 (m, 2H), 1.92-2.10 (m, 2H), 2.17-2.43 (m, 7H), 2.54-2.66
(m, 2H), 2.87 (t, J=6.8 Hz, 2H), 3.37-3.46 (m, 1H), 3.62 (d, J=14
Hz, 1H), 3.68 (d, J=14 Hz, 1H), 6.95 (dd, J=3.6 Hz, 5.2 Hz, 1H),
7.15 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.23-7.39 (m, 6H),
Example 177
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cyanoethyl)-N-(3-cyan-
obenzyl)amino]pyrrolidine
[1405] 294
[1406] The title compound was synthesized in accordance with
Example 75 from the iodide D and
(3S)-3-[N-(2-cyanoethyl)-N-(3-cyanobenzyl)amino]pyr- rolidine
synthesized in accordance with the production method of "Synthetic
method A" (1) of Example 175. The physico-chemical data of the
compound was as below.
[1407] Yield; 82%.
[1408] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.16 (d, J=6.8 Hz, 3H), 1.22-1.34 (m, 1H), 1.54-1.67 (m, 1H),
1.67-1.80 (m, 2H), 1.93-2.09 (m, 2H), 2.16-2.27 (m, 2H), 2.27-2.43
(m, 5H), 2.59-2.72 (m, 2H), 2.88 (t, J=6.8 Hz, 2H), 3.34-3.43 (m,
1H), 3.68 (d, J=15 Hz, 1H), 3.74 (d, J=15 Hz, 1H), 6.96 (dd, J=3.6
Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.27 (dd, J=1.2
Hz, 5.2 Hz, 1H), 7.41-7.48 (m, 1H), 7.54-7.58 (m, 1H), 7.62-7.66
(m, 2H)
Example 178
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[{3-methoxy-(2R)-2-(2-pyridyloxy-
)}propyl]piperazine
[1409] 295
[1410] The title compound was synthesized in accordance with
Example 75 from the iodide D and
1-[{3-methoxy-(2R)-2-(2-pyridyloxy)}propyl]piperazi- ne. The
physico-chemical data of the target compound obtained is indicated
below. The values of the physical properties of the title compound
obtained are indeicated below.
[1411] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.89 (d, J=6.8 Hz,
3H), 1.17 (d, J=6.4 Hz, 3H), 1.21-1.35 (m, 1H), 1.55-1.69 (m, 1H),
1.70-1.80 (m, 1H), 2.00-2.18 (m, 2H), 2.20-2.62 (m, 1H), 2.62-2.72
(m, 2H), 3.38 (s, 3H), 3.60-3.70 (m, 2H), 5.47-5.55 (m, 1H),
6.71-6.78 (m, 1H), 6.81-6.87 (m, 1H), 6.94 (dd, J=3.6 Hz, 5.2 Hz,
1H), 7.10 (dd, J=1.6 Hz, 3.6 Hz, 1H), 7.25 (dd, J=1.6 Hz, 5.2 Hz,
1H), 7.50-7.58 (m, 1H), 8.09-8.13 (m, 1H)
Example 179
1-(6-Bromo-2-pyridyl)-(3R)-3-{N-[4-cyano-4-(2-thienyl)-5-methylhexyl]amino-
}pyrrolidine
[1412] 296
[1413] The title compound was synthesized in accordance with
Example 75 from the iodide C (optically active compound) and
(3R)-3-{N-[4-cyano-4-(2- -thienyl)-5-methylhexyl]amino}pyrrolidine.
The physico-chemical data of the compound was as below.
[1414] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.23-1.36 (m, 1H), 1.57-1.70 (m, 1H),
1.73-1.83 (m, 2H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.56-2.71
(m, 2H), 3.14-3.22 (m, 1H), 3.34-3.44 (m, 2H), 3.49-3.58 (m, 1H ),
3.59-3.66 (m, 1H ), 6.21 (d, J=8.0 Hz, 1H), 6.65 (d, J=7.2 Hz, 1H),
6.94 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H),
7.22 (dd, J=7.2 Hz, 8.0 Hz, 1H), 7.26 (dd, J=1.2 Hz, 5.2 Hz,
1H)
Example 180
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-[2-(5-chlorobenzoxazoyl)-
methyl]piperazine
[1415] 297
[1416] The title compound was synthesized in accordance with
Example 77 from
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]piperazine and
2-chloromethyl-5-chlorobenzoxazole synthesized in accordance with
Example 83. The physico-chemical data of the compound was as
below.
[1417] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.58-1.71 (m, 1H),
1.71-1.81 (m, 1H), 2.00-2.10 (m, 1H), 2.16-2.26 (m, 1H), 2.34 (t,
J=6.8 Hz, 2H), 2.37-2.54 (m, 4H), 2.54-2.73 (m, 4H), 3.86 (s, 2H),
7.14 (d, J=4.0 Hz, 1H), 7.31 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.45 (d,
J=8.4 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H)
Example 181
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-[2-(5-methylbenzoxazoyl)-
methyl]piperazine
[1418] 298
[1419] According to Example 180, from
1-[4-cyano-4-(5-cyano-2-thienyl)-5-m- ethylhexyl]piperazine and
2-chloromethyl-5-methylbenzoxazole synthesized in accordance with
Example 83, the title compound was synthesized in accordance with
Example 77. The physico-chemical data of the compound was as
below.
[1420] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (d, J=6.8 Hz,
3H), 1.20 (d, J=6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.58-1.70 (m, 1H),
1.70-1.81 (m, 1H), 2.00-2.10 (m, 1H), 2.16-2.26 (m, 1H), 2.33 (t,
J=6.8 Hz, 2H), 2.46 (s, 3H), 2.37-2.54 (m, 4H), 2.55-2.73 (m, 4H),
3.85 (s, 2H), 7.12-7.16 (m, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.39 (d,
J=8.4 Hz, 1H), 7.47-7.49 (m, 1H), 7.51 (d, J=4.0 Hz, 1H)
Example 182
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-[2-benzothiazoylmethyl]p-
iperazine
[1421] 299
[1422] According to Example 180, the title compound was synthesized
in accordance with Example 77 from
1-[4-cyano-4-(5-cyano-2-thienyl)-5-methyl- hexyl]piperazine in
accordance with Example 180 and 2-chloromethylbenzothiazole which
was synthesized in accordance with Example 83. The physico-chemical
data of the compound was as below.
[1423] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.8 Hz,
3H), 1.21 (d, J=6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.59-1.72 (m, 1H),
1.72-1.83 (m, 1H), 2.01-2.10 (m, 1H), 2.18-2.28 (m, 1H), 2.35 (t,
J=7.4 Hz, 2H), 2.35-2.52 (m, 4H), 2.54-2.74 (m, 4H), 3.95 (s, 2H),
7.14 (d, J=3.6 Hz, 1H), 7.33-7.39 (m, 1H), 7.42-7.48 (m, 1H), 7.51
(d, J=3.6 Hz, 1H), 7.84-7.88 (m, 1H), 7.94-7.99 (m, 1H)
Example 183
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(5-trifluoromethyl-2-pyridylo-
xy)ethyl]piperazine
[1424] 300
[1425] The target compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl]iodide and
1-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine. The
physico-chemical data of the compound was as below.
[1426] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.20-1.38 (m, 1H), 1.55-1.70 (m, 1H),
1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.20 (m, 1H), 2.31 (t,
J=7.4 Hz, 2H), 2.30-2.48 (m, 4H), 2.48-2.65 (m, 4H), 2.78 (t, J=6.0
Hz, 2H), 4.48 (t, J=6.0 Hz, 2H), 6.83 (d, J=8.8 Hz, 1H), 6.94 (dd,
J=3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.75 (dd,
J=2.4 Hz, 8.8 Hz, 1H), 8.39-8.44 (m, 1H)
Example 184
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-[2-(5-trifluoromethyl-2--
pyridyloxy)ethyl]piperazine
[1427] 301
[1428] The title compound was synthesized in accordance with
Example 77 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide
and 1-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine. The
physico-chemical data of the compound was as below.
[1429] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.21 (d, J=6.4 Hz, 3H), 1.20-1.31 (m, 1H), 1.60-1.82 (m, 2H),
2.00-2.10 (m, 1H), 2.17-2.28 (m, 1H), 2.28-2.48 (m, 6H), 2.48-2.65
(m, 4H), 2.79 (t, J=6.0 Hz, 2H), 4.49 (t, J=6.0 Hz, 2H), 6.83 (d,
J=8.8 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.76
(dd, J=2.4 Hz, 8.8 Hz, 1H), 8.40-8.44 (m, 1H)
Example 185
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(5-chloro-3-pyridyloxy)ethyl]-
piperazine
[1430] 302
[1431] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. The physico-chemical
data of the compound was as below.
[1432] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.20-1.37 (m, 1H), 1.55-1.71 (m, 1H),
1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.25-2.49
(m, 6H), 2.49-2.65 (m, 4H), 2.80 (t, J=5.6 Hz, 2H), 4.12 (t, J=5.6
Hz, 2H), 6.94 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6
Hz, 1H), 7.22 (t, J=2.0 Hz, 1H), 7.24-7.28 (m, 1H), 8.18 (d, J=2.0
Hz, 1H), 8.20 (d, J=2.0 Hz, 1H)
Example 186
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-[2-(5-chloro-3-pyridylox-
y)ethyl]piperazine
[1433] 303
[1434] The title compound was synthesized in accordance with
Example 77 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide
and 1-[2-(5-chloro-3-pyridyloxy)ethyl)piperazine. The
physico-chemical data of the compound was as below.
[1435] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.92 (d, J=6.4 Hz,
3H), 1.21 (d, J=6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.60-1.72 (m, 1H),
1.72-1.82 (m, 1H), 2.00-2.11 (m, 1H), 2.17-2.28 (m, 1H), 2.28-2.48
(m, 6H), 2.49-2.65 (m, 4H), 2.81 (t, J=5.6 Hz, 2H), 4.13 (t, J=5.6
Hz, 2H), 7.15 (d, J=4.0 Hz, 1H), 7.21-7.23 (m, 1H), 7.51 (d, J=4.0
Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 8.20 (d, J=2.8 Hz, 1H)
Example 187
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(5-chloro-3-pyridyloxy)ethyl]-
piperidine
[1436] 304
[1437] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
4-[2-(5-chloro-3-pyridyloxy)ethyl]piperidine. The physico-chemical
data of the compound was as below.
[1438] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.20-1.38 (m, 2H), 1.40-1.56 (m, 1H),
1.60-1.93 (m, 9H), 2.00-2.20 (m, 2H) 2.25-2.35 (m, 2H), 2.77-2.87
(m, 2H), 4.02(t, J=6.4 Hz, 2H), 6.95 (dd, J=3.6 Hz, 5.2 Hz, 1H),
7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.17-7.20 (m, 1H), 7.24-7.28 (m,
1H), 8.16-8.20 (m, 2H)
Example 188
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-(3-pyridylamino)piperidine
[1439] 305
[1440] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
4-(3-pyridylamino)piperidine. The physico-chemical data of the
compound was as below.
[1441] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.18 (d, J=6.8 Hz, 3H), 1.24-1.38 (m, 1H), 1.38-1.50 (m, 2H),
1.58-1.71 (m, 1H), 1.73-1.83 (m, 1H), 1.95-2.21 (m, 5H), 2.29-2.36
(m, 2H), 2.72-2.81 (m, 2H), 3.20-3.31 (m, 1H), 3.48-3.56 (m, 1H),
6.81-6.86 (m, 2H), 6.94 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.05 (dd, J=4.8
Hz, 12.8 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6 Hz, 1H), 7.26 (dd, J=1.2
Hz, 5.2 Hz, 1H), 7.92 (dd, J=1.6 Hz, 4.8 Hz, 1H), 7.99 (d, J=2.1
Hz, 1H)
Example 189
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-{N-isopropyl-N-(2-pyridyl)ami-
no]ethyl]piperazine
[1442] 306
[1443] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-{N-isopropyl-N-(2-pyridyl)amino}ethyl]piperazine. The
physico-chemical data of the compound was as below.
[1444] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.8 Hz,
3H), 1.14-1.21 (m, 9H), 1.24-1.38 (m, 1H), 1.58-1.70 (m, 1H),
1.72-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.28-2.66
(m, 12H), 3.41 (t, J=8.0 Hz, 2H), 4.74-4.84 (m, 1H), 6.47-6.53 (m,
2H), 6.94 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 3.6 Hz,
1H), 7.24-7.29 (m, 1H), 7.37-7.44 (m, 1H), 8.12-8.16 (m, 1H)
Example 190
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(6-methoxymethyl-2-pyridyloxy-
)ethyl]-piperazine
[1445] 307
[1446] The titile compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(6-methoxymethyl-2-pyridyloxy)ethyl]piperazine. The
physico-chemical data of the compound was as below.
[1447] ESI-MS; 457 (M+H).sup.+
Example 191
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(6-fluoromethyl-2-pyridyloxy)-
ethyl]piperazine
[1448] 308
[1449] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(6-fluoromethyl-2-pyridyloxy)ethyl]piperazine. The
physico-chemical data of the compound was as below.
[1450] The values of the physical properties of the target compound
obtained are indicated below.
[1451] ESI-MS; 445 (M+H).sup.+
Example 192
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(6-bromo-2-pyridyloxy)ethyl]p-
iperazine
[1452] 309
[1453] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(6-bromo-2-pyridyloxy)ethyl]piperazine. The physico-chemical
data of the compound was as below.
[1454] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (d, J=6.4 Hz,
3H), 1.18 (d, J=6.4 Hz, 3H), 1.22-1.38 (m, 1H), 1.58-1.70 (m, 1H),
1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.20 (m, 1H), 2.25-2.65
(m, 1H), 2.76 (t, J=6.0 Hz, 2H), 4.42 (t, J=6.0 Hz, 2H), 6.69 (d,
J=8.0 Hz, 1H), 6.94 (dd, J=3.6 Hz, 5.2 Hz, 1H), 7.04 (d, J=8.0 Hz,
1H), 7.11 (dd, J=1.6 Hz, 3.6 Hz, 1H), 7.24-7.28 (m, 1H), 7.40 (t,
J=8.0 Hz, 1H)
Example 193
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(6-fluoro-2-pyridyloxy)ethyl]-
piperazine
[1455] 310
[1456] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(6-fluoro-2-pyridyloxy)ethyl]piperazine. The physico-chemical
data of the compound was as below.
[1457] ESI-MS; 431 (M+H).sup.+
Example 194
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(2-pyridyloxy)ethyl]piperazin-
e
[1458] 311
[1459] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(2-pyridyloxy)ethyl]piperazine. The physico-chemical data of
the compound was as below.
[1460] ESI-MS; 413 (M+H).sup.+
Example 195
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(6-methyl-2-pyridyloxy)ethyl]-
piperazine
[1461] 312
[1462] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(6-methyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical
data of the compound was as below.
[1463] .sup.1H-NMR (400 MHz, CDC1) .delta. 0.90 (d, J=6.8 Hz, 3H),
1.18 (d, J=6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.58-1.70 (m, 1H),
1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.27-2.70
(m, 1H), 2.42 (s, 3H), 2.77 (t, J=6.0 Hz, 2H), 4.41 (t, J=6.0 Hz,
2H), 6.51-6.55 (m, 1H), 6.67-6.72 (m, 1H), 6.94 (dd, J=3.6 Hz, 5.2
Hz, 1H), 7.11 (dd, J=1.6 Hz, 3.6 Hz, 1H), 7.25 (dd, J=1.6 Hz, 5.2
Hz, 1H), 7.43 (dd, J=7.2 Hz, 8.4 Hz, 1H)
Example 196
1-[4-Cyano-4-(2-thienyl)-5-methylhexyl]-4-[2-(6-cyano-2-pyridyloxy)ethyl]p-
iperazine
[1464] 313
[1465] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and
1-[2-(6-cyano-2-pyridyloxy)ethyl]piperazine. The physico-chemical
data of the compound was as below.
[1466] ESI-MS; 438 (M+H).sup.+
Example 197
1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-4-[2-(6-cyano-2-pyridyloxy-
)ethyl]piperazine
[1467] 314
[1468] The title compound was synthesized in accordance with
Example 75 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide
and 1-[2-(6-cyano-2-pyridyloxy)ethyl]piperazine. The
physico-chemical data of the compound was as below.
[1469] ESI-MS; 463 (M+H).sup.+
Example 198
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[N-[2-(4-fluorophenoxy)ethyl]-N-2-c-
yanoethyl]aminopiperidine
[1470] 315
[1471] The title compound was synthesized in accordance with the
production method of Example 35.
[1472] Hydrochloride: ESI-Mass; 491 (MH.sup.+)
Example 199
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxybenzyl)piperazine
[1473] 316
[1474] The title compound was obtained in accordance with the
production method of Example 3.
[1475] Hydrochloride: ESI-Mass; 406 (MH.sup.+)
Example 200
1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[3-[1-(4-fluorophenyl)cyclohex-
yl]propyl]piperazine
[1476] 317
[1477] The title compound was obtained in accordance with the
production method of Example 70 by using the above-mentioned
4-[3-[1-(4-fluorophenyl- )cyclohexyl]propyl]piperazine.
[1478] Hydrochloride: ESI-Mass; 510 (MH.sup.+)
Example 201
1-[[4-Cyano-5-methyl-4-(3-benzothienyl)]hexyl]-4-[2-(3-cyanophenoxy)ethyl]-
piperazine
[1479] 318
[1480] The title compound was obtained in accordance with the
production method of Example 70.
[1481] Hydrochloride: ESI-Mass; 487 (MH.sup.+)
Example 202
1-[[4-Cyano-5-methyl-4-(3-benzothienyl)]hexyl]-4-benzylpiperazine
[1482] 319
[1483] The title compound was obtained in accordance with the
production method of Example 70.
[1484] Hydrochloride: ESI-Mass; 432 (MH.sup.+)
Example 203
1-[4-Cyano-5-methyl-4-(3-benzothienyl)]hexyl]-4-(3-cyanobenzyl)piperazine
[1485] 320
[1486] The title compound was obtained in accordance with the
production method of Example 3.
[1487] Hydrochloride: ESI-Mass; 457 (MH.sup.+)
Example 204
1-[[4-Cyano-5-methyl-4-(3-benzothienyl)]hexyl]-4-[(2-thienyl)methyl]pipera-
zine
[1488] 321
[1489] The title compound was obtained in accordance with the
production method of Example 3.
[1490] Hydrochloride: ESI-Mass; 438 (MH.sup.+)
Example 205
1-[[4-Cyano-5-methyl-4-(3-benzothienyl)]hexyl]-4-[(4-cyano-2-t-
hienyl)methyl]piperazine
[1491] 322
[1492] The title compound was obtained in accordance with the
production method of Example 3.
[1493] Hydrochloride: ESI-Mass; 463 (MH.sup.+)
Example 206
1-[[4-Cyano-5-methyl-4-(3-benzothienyl)]hexyl]-4-(6-methyl-2-picolyl)piper-
azine
[1494] 323
[1495] The title compound was obtained in accordance with the
production method of Example 3.
[1496] Hydrochloride: ESI-Mass; 447 (MH.sup.+)
Example 207
1-[[4-Cyano-5-methyl-4-(1-methyl-2-pyrrolyl)]hexyl]-4-[2-(3-cyanophenoxy)e-
thyl]piperazine
[1497] 324
[1498] The title compound was obtained-in accordance with the
production method of Example 70.
[1499] Oxalate: ESI-Mass; 434 (MH.sup.+)
Example 208
1-[[4-Cyano-5-methyl-4-(5-methyl-2-thienyl)]hexyl]-4-[N-[2-(4-fluorophenox-
y)ethyl]-N-2-cyanoethyl]aminopiperidine
[1500] 325
[1501] The title compound was obtained in accordance with the
production method of Example 35.
[1502] Hydrochloride: ESI-Mass; 522 (MH.sup.+)
Example 209
1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[N-[2-(4-fluorophenoxy)ethyl]--
N-2-cyanoethyl]aminopiperidine
[1503] 326
[1504] The title compound was obtained in accordance with the
production method of Example 35.
[1505] Hydrochloride: ESI-Mass; 497 (MH.sup.+)
Example 210
1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[(2-benzoxazolyl)amino]piperid-
ine
[1506] 327
[1507] The title compound was obtained in accordance with the
production method of Example 17.
[1508] Hydrochloride: ESI-Mass; 423 (MH.sup.+)
Example 211
1-[[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)]hexyl]-4-[(2-benzoxazolyl)amino-
]piperidine
[1509] 328
[1510] The title compound was obtained in accordance with the
production method of Example 17.
[1511] Hydrochloride: ESI-Mass; 448 (MH.sup.+)
Example 212
1-[[4-Cyano-5-methyl-4-(2-furyl)]hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperaz-
ine
[1512] 329
[1513] The title compound was obtained in accordance with the
production method of Example 70.
[1514] Hydrochloride: ESI-Mass; 421 (MH.sup.+)
Example 213
1-[[4-Cyano-5-methyl-4-(2-furyl)]hexyl]-4-[(2-benzoxazolyl)amino]piperidin-
e
[1515] 330
[1516] The title compound was obtained in accordance with the
production method of Example 17.
[1517] Oxalate: ESI-Mass; 407 (MH.sup.+)
Example 214
1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[N-(2-benzoxazolyl)-N-(2-cyano-
ethyl)amino]piperidine
[1518] 331
[1519] The title compound was obtained in accordance with the
production method of Example 35.
[1520] Hydrochloride: ESI-Mass; 476 (MH.sup.+)
Example 215
1-[[4-Cyano-5-methyl-4-(2-furyl)]hexyl]-4-[N-(2-benzoxazolyl)-N-(2-cyanoet-
hyl)amino]piperidine
[1521] 332
[1522] The title compound was obtained in accordance with the
production method of Example 35.
[1523] Oxalate: ESI-Mass; 460 (MH.sup.+)
Example 216
1-[[(4-Cyano-5-methyl-4-phenyl)]hexyl]-4-(2-pyridyl)piperazine
[1524] 333
[1525] The title compound was obtained in accordance with the
production method of Example 70.
[1526] Hydrochloride: ESI-Mass; 363 (MH.sup.+)
Example 217
1-[[(4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-(2-pyridyl)piperazine
[1527] 334
[1528] The title compound was obtained in accordance with the
production method of Example 70.
[1529] Hydrochloride: ESI-Mass; 369 (MH.sup.+)
Example 218
1-[(2-Oxo-1,2-dihydro-3-quinolyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hex-
yl]piperazine
[1530] 335
[1531] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1532] Oxalate:
[1533] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.64 (d, J=6.8
Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.40-1.60 (m,
1H), 1.95-2.15 (m, 1H), 2.10-2.25 (m, 1H), 2.60-3.05 (m, 1H), 3.59
(s, 2H), 7.17 (t, J=7.2 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.30-7.38
(m, 1H), 7.35-7.50 (m, 5H), 7.62 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.89
(s, 1H), 11.88 (s, 1H).
Example 219
1-[(2-Oxo-1,2-dihydro-3-quinolyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hex-
yl]piperidine
[1534] 336
[1535] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1536] Oxalate:
[1537] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.63 (d, J=6.8
Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.45 (m, 6H), 1.09 (d, J=6.8 Hz,
3H), 1.60 (br d, J=12.8 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m,
1H), 2.75-2.95 (m, 2H), 3.20-3.35 (m, 2H), 4.08 (s, 2H), 7.19-7.25
(m, 1H), 7.28-7.44 (m, 6H), 7.53-7.58 (m, 1H), 7.65-7.70 (m, 1H),
8.13 (s, 1H), 12.13 (s, 1H).
Example 220
1-[(2-Oxo-1,2-dihydro-3-pryridinyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)h-
exyl]piperidine
[1538] 337
[1539] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1540] Oxalate:
[1541] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.63 (d, J=6.8
Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.45 (m, 6H), 1.09 (d, J=6.8 Hz,
3H), 1.59 (br d, J=13.2 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m,
1H), 2.73-2.95 (m, 2H), 3.15-3.33 (m, 2H), 3.98 (s, 2H), 2.26 (d,
J=6.8 Hz, 1H), 7.28-7.35 (m, 1H), 7.36-7.44 (m, 4H), 7.50 (dd,
J=6.4 Hz, 2.0 Hz, 1H), 7.62-7.68 (m, 1H).
Example 221
1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(4-cyano-5-methyl-4-p-
henyl)hexyl]piperidine
[1542] 338
[1543] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1544] Oxalate:
[1545] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.63 (d, J=6.8
Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.40 (m, 6H), 1.09 (d, J=6.4 Hz,
3H), 1.53 (br d, J=13.2 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m,
1H), 2.40-2.60 (m, 2H), 3.04 (br d, J=11.6 Hz, 2H), 3.68 (s, 2H),
7.25-7.35 (m, 1H), 7.36-7.44 (m, 4H), 7.59 (d, J=2.8 Hz, 1H), 7.66
(d, J=2.4 Hz, 1H).
Example 222
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfonylamino)phenyl]me-
thyl]piperazine
[1546] 339
[1547] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1548] Oxalate:
[1549] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.64 (d, J=6.4
Hz, 3H), 0.80-1.20 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 1.40-1.60 (m,
1H), 1.90-2.15 (m, 1H), 2.10-2.25 (m, 1H), 2.60-3.10 (m, 1H), 3.03
(s, 3H), 3.65 (s, 2H), 7.13 (t, J=7.2 Hz, 1H). 7.26-7.47 (m,
8H).
Example 223
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(p-toluenesulfonylamino)phenyl]-
methyl}piperazine
[1550] 340
[1551] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1552] Oxalate:
[1553] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.65 (d, J=6.4
Hz, 3H), 0.80-1.20 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 1.45-1.60 (m,
1H), 1.95-2.15 (m, 1H), 2.10-2.25 (m, 1H), 2.33 (s, 3H), 2.60-3.05
(m, 1H), 3.34 (s, 2H), 7.05-7.12 (m, 2H), 7.16-7.24 (m, 2H), 7.32
(d, J=7.6 Hz, 2H), 7.29-7.37 (m, 1H), 7.37-7.46 (m, 4H), 7.58 (d,
J=8.0 Hz, 2H).
Example 224
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-}[2-(methanesulfonylamino)phenyl]me-
thyl}piperidine
[1554] 341
[1555] The title compound was obtained as a colorless oil in
accordance with Example 3.
[1556] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80 (d, J=6.8 Hz,
3H), 0.85-1.05 (m, 1H), 1.05-1.45 (m, 6H), 1.22 (d, J=6.4 Hz, 3H),
1.50-1.68 (m, 2H), 1.73-1.88 (m, 1H), 1.90-2.05 (m, 2H), 2.00-2.20
(m, 2H), 2.75-2.90 (m, 2H), 3.04 (s, 3H), 3.60 (s, 2H), 6.96-7.11
(m, 2H), 7.24-7.36 (m, 2H), 7.34-7.44 (m, 4H), 7.46-7.52 (m,
1H).
Example 225
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(p-toluenesulfonylamino)phenyl]-
methyl}piperidine
[1557] 342
[1558] The title compound was obtained as a colorless oil in
accordance with Example 3.
[1559] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.85-1.02 (m, 1H), 1.08-1.30 (m, 5H), 1.25-1.44 (m, 1H), 1.19
(d, J=6.4 Hz, 3H), 1.57 (br t, J=13.6 Hz, 2H), 1.76-1.90 (m, 3H),
2.06-2.16 (m, 2H), 2.37 (s, 3H), 2.68 (br d, J=11.2 Hz, 2H), 3.13
(s, 2H), 6.91 (d, J=7.2 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 7.19 (d,
J=8.4 Hz, 2H), 7.16-7.22 (m, 1H), 7.26-7.41 (m, 5H), 7.46 (d, J=8.0
Hz, 1H), 7.63 (d, J=8.4 Hz, 2H).
Example 226
1-[4-Cyano-5-methyl-4-(2-chlorophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethylpi-
perazine
[1560] 343
[1561] The oxalate of the. title compound was obtained as a
colorless solid in accordance with Example 48.
[1562] Oxalate:
[1563] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.72 (d, J=6.8
Hz, 3H), 1.10 (d, J=6.8 Hz, 3H), 1.00-1.25 (m, 1H), 1.42-1.60 (m,
1H), 1.95-2.10 (m, 1H), 2.45-2.65 (m, 1H), 2.60-3.10 (m, 13H), 4.09
(t, J=5.2 Hz, 2H), 6.89-6.99 (m, 2H), 7.10 (t, J=8.8 Hz, 2H),
7.37-7.46 (m, 2H), 7.51 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.62 (dd, J=7.6
Hz, 1.6 Hz, 1H).
Example 227
1-[4-Cyano-5-methyl-4-(0-tolyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazi-
ne
[1564] 344
[1565] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 48.
[1566] Oxalate:
[1567] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.76 (d, J=6.4
Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 1.10-1.30 (m, 1H), 1.43-1.60 (m,
1H), 1.93-2.07 (m, 1H), 2.15-2.30 (m, 1H), 2.38-2.53 (m, 1H), 2.45
(s, 3H), 2.65-3.05 (m, 12H), 4.07 (t, J=5.2 Hz, 2H), 6.89-6.96 (m,
2H), 7.10 (t, J=8.0 Hz, 2H), 7.18-7.27 (m, 3H), 7.38-7.44 (m,
1H).
Example 228
1-[4-Cyano-5-methyl-4-(2-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]-
piperazine
[1568] 345
[1569] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 48.
[1570] Oxalate:
[1571] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.66 (d, J=6.8
Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.40-1.55 (m,
1H), 1.85-2.00 (m, 1H), 2.30-2.43 (m, 1H), 2.55-2.70 (m, 1H),
2.60-3.05 (m, 12H), 3.79 (s, 3H), 4.07 (t, J=5.2 Hz, 2H), 6.88-6.96
(m, 2H), 6.99 (t, J=7.6 Hz, 1H), 7.05-7.14 (m, 3H), 7.32-7.42 (m,
2H).
Example 229
N-{1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperidine-4-yl}p-toluenesulfonamid-
e
[1572] 346
[1573] The title compound was obtained as a pale brown oil in
accordance with Example 15.
[1574] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.8 Hz,
3H), 0.95-1.15 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.30-1.45 (m, 2H),
1.35-1.55 (m, 1H), 1.63-1.75 (m, 2H), 1.75-1.95 (m, 5H), 2.00-2.15
(m, 2H), 2.15-2.25 (m, 2H), 2.45-2.65 (m, 2H), 3.00-3.15 (m, 1H),
7.29 (d, J=8.0 Hz, 2H), 7.31-7.40 (m, 5H), 7.75 (d, J=7.6 Hz,
2H).
Example 230
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-1-(4-fluorophenoxy)propa-
ne-2-yl]piperazine
[1575] 347
[1576] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 15.
[1577] Oxalate:
[1578] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.64 (d, J=6.8
Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.00-1.40 (m, 1H), 1.43-1.60 (m,
1H), 1.93-2.15 (m, 2H), 2.10-2.25 (m, 1H), 2.60-3.20 (m, 1H),
3.45-3.60 (m, 2H), 4.04 (d, J=5.6 Hz, 2H), 6.88-6.96 (m, 3H), 7.26
(t, J=7.6 Hz, 1H), 7.30-7.38 (m, 1H), 7.36-7.46 (m, 4H).
Example 231
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(3-cyanobenzyloxy)piperidine
[1579] 348
[1580] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 15.
[1581] Oxalate:
[1582] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.64 (d, J=6.8
Hz, 3H), 1.11 (d, J=6.4 Hz, 3H), 1.63-1.80 (m, 2H), 1.85-2.00 (m,
2H), 2.13-2.27 (m, 1H), 2.30-2.45 (m, 1H), 2.35-2.55 (m, 1H),
2.75-3.00 (m, 4H), 3.00-3.20 (m, 2H), 3.50-3.60 (m, 1H), 4.52 (s,
2H), 7.33-7.40 (m, 1H), 7.40-7.48 (m, 4H), 7.54 (t, J=8.0 Hz, 1H),
7.66 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.77 (m, 1H).
Example 232
4-[(3-Cyano-4-methyl-3-phenyl)pentyl]-1-[2-[3-(p-toluenesulfonylamino)phen-
oxylethyl]piperazine
[1583] 349
[1584] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 3.
[1585] Oxalate:
[1586] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.64 (d, J=6.8
Hz, 3H), 1.11 (d, J=6.4 Hz, 3H), 2.13-2.50 (m, 1H), 2.20-2.50 (m,
2H), 2.37 (s, 3H), 2.45-2.50 (m, 2H), 2.50-2.60 (m, 2H), 2.60-2.80
(m, 4H), 2.70-3.00 (m, 4H), 3.63 (t, J=6.4 Hz, 2H), 6.41 (dd, J=8.0
Hz, 2.0 Hz, 1H), 6.47 (d, J=2.0 Hz, 1H), 6.70 (dd, J=8.0 Hz, 2.4
Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.32-7.40
(m, 1H), 7.38-7.48 (m, 4H), 7.46 (d, J=8.0 Hz, 2H).
Example 233
4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{2-[3-(p-toluenesulfonylamino)pheno-
xy]ethyl}piperazine
[1587] 350
[1588] The oxalate of the title compound was obtained as a pale
brown solid in accordance with Example 15.
[1589] Oxalate:
[1590] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.64 (d, J=6.4
Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.43-1.60 (m,
1H), 1.90-2.13 (m, 2H), 2.15-2.25 (m, 1H), 2.37 (s, 3H), 2.25-2.50
(m, 4H), 2.80-3.00 (m, 8H), 3.57 (t, J=6.8 Hz, 2H), 6.38-6.43 (m,
1H), 6.46 (s, 1H), 6.68 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.08 (t, J=7.6
Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.30-7.40 (m, 1H), 7.36-7.48 (m,
4H), 7.45 (d, J=8.4 Hz, 2H).
Example 234
1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{[3-(p-toluenesulfonylamino)phenoxy-
]methyl}piperidine
[1591] 351
[1592] The title compound was obtained as yellow amorphous in
accordance with Example 15.
[1593] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.75 (d, J=6.8 Hz,
3H), 1.15 (d, J=6.4 Hz, 3H), 1.05-1.30 (m, 3H), 1.30-1.45 (m, 1H),
1.45-1.65 (m, 1H), 1.65 (br d, J=12.4 Hz, 2H), 1.65-1.80 (m, 1H),
1.75-1.95 (m, 2H), 2.00-2.18 (m, 2H), 2.26 (t, J=7.2 Hz, 2H), 2.40
(s, 3H), 2.67-2.80 (m, 2H), 3.31 (d, J=7.6 Hz, 2H), 6.43 (d, J=8.0
Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.67-6.76 (m, 1H), 7.08 (t, J=8.0
Hz, 1H), 7.22 (d, J=6.8 Hz, 2H), 7.20-7.40 (m, 5H), 7.45 (d, J=8.0
Hz, 2H).
Example 235
1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-{[3-(p-toluenesulfonylamino)phenox-
y]methyl}piperidine
[1594] 352
[1595] The title compound was obtained as pale brown amorphous in
accordance with Example 3.
[1596] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.73 (d, J=6.8 Hz,
3H), 1.14 (d, J=6.4 Hz, 3H), 1.15-1.30 (m, 2H), 1.35-1.52 (m, 1H),
1.68 (br d, J=12.4 Hz, 2H), 1.73-2.05 (m, 3H), 2.00-2.18 (m, 2H),
2.30-2.43 (m, 2H), 2.40 (s, 3H), 2.70-2.90 (m, 2H), 3.20-3.38 (m,
2H), 6.38 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.58 (d, J=1.6 Hz, 1H), 7.00
(dd, J=8.0 Hz, 2.0 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.6
Hz, 2H), 7.25-7.40 (m, 5H), 7.43 (d, J=8.4 Hz, 2H).
Example 236
1-(3-Cyanobenzyl)-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine
[1597] 353
[1598] The oxalate of the title compound was obtained as a
colorless solid in accordance with Example 48.
[1599] Oxalate:
[1600] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.63 (d, J=6.8
Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.30 (m, 5H), 1.08 (d, J=6.4 Hz,
3H), 1.20-1.35 (m, 1H), 1.58 (br d, J=12.8 Hz, 2H), 1.87-2.08 (m,
2H), 2.10-2.23 (m, 1H), 2.61 (br t, J=11.2 Hz, 2H), 3.11 (br d,
J=10.8 Hz, 2H), 4.10 (s, 2H), 7.28-7.33 (m, 1H), 7.34-7.44 (m, 4H),
7.61 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.84-7.90 (m,
2H).
Example 237
1-[(5-Phenyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(4-cyano-5-methyl-4--
phenyl)hexyl]piperidine
[1601] 354
[1602] The title compound was obtained as a pale yellow oil in
accordance with Example 3.
[1603] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 0.85-1.00 (m, 1H), 1.10-1.45 (m, 4H), 1.19 (d, J=6.8 Hz, 3H),
1.50-1.65 (m, 2H), 1.60-2.20 (m, 5H), 2.80-3.00 (m, 2H), 3.54 (s,
2H), 7.24-7.48 (m, 1H), 7.64-7.70 (m, 1H), 7.78-7.84 (m, 1H).
Example 238
Ethyl
1-benzyl-4-(4-cyano-5-methyl-4-phenylhexyl)-2-piperazinecarboxylate
[1604] 355
[1605] The title compound was synthesized by using
1-benzyl-2-(ethoxycarbo- nyl)piperazine (Synthesis 318, 1991) in
accordance with Example 15.
[1606] Free Body:
[1607] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.6 Hz,
3H), 1.05-1.10 (m, 1H), 1.18-1.31 (m, 6H), 1.50-1.63 (m, 1H),
1.86-1.94 (m, 1H), 2.04-2.15 (m, 2H), 2.21-2.54 (m, 7H), 2.96 (m,
1H), 3.22-3.27 (m, 1H), 3.51 (m, 1H), 3.86-3.90 (m, 1H), 4.12-4.23
(m, 2H), 7.21-7.37 (m, 1H).
Example 239
Ethyl
4-(4-cyano-5-methyl-4-phenylhexyl)-1-[2-(4-fluorophenoxy)ethyl]-2-pi-
perazinecarboxylate
[1608] 356
[1609] The title compound was synthesized by using ethyl
4-(4-cyano-5-methyl-4-phenylhexyl)-2-piperazinecarboxylate in
accordance with Example 48.
[1610] Free Body:
[1611] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.06-1.11 (m, 1H), 1.17-1.29 (m, 6H), 1.51-1.62 (m, 1H),
1.86-1.91 (m, 1H), 2.05-2.11 (m, 2H), 2.22-2.36 (m, 4H), 2.52-2.55
(m, 3H), 2.94-3.01 (m, 2H), 3.13-3.16 (m, 1H), 3.38-3.39 (m, 1H),
4.01-4.03 (m, 2H), 4.14-4.22 (m, 2H), 6.78-6.82 (m, 2H), 6.92-6.97
(m, 2H), 7.26-7.31 (m, 1H), 7.36-7.37 (m, 4H).
Example 240
1-(4-Cyano-5-methyl-4-phenylhexyl)-3-hydroxymethyl-4-[2-(4-fluorophenoxy)e-
thyl]piperazine
[1612] 357
[1613] Into a diethyl ether solution (5.0 ml) of lithium aluminum
hydride (20 mg) was added dropwise a diethyl ether solution (3.0
ml) of 213 mg of ethyl
4-(4-cyano-5-methyl-4-phenylhexyl)-1-[2-(4-fluorophenoxy)ethyl]-2-p-
iperazinecarboxylate under ice-cooling. After stirring under
ice-cooling for one hour, water (0.1 ml), a 1N aqueous sodium
hydroxide (0.1 ml) and water (0.2 ml) were successively added to
the reaction solution. Anhydrous magnesium sulfate was added to the
reaction solution, and the unnecessary product was filtered. The
solvent was evaporated, to give the title compound (194 mg).
[1614] Free Body:
[1615] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.6 Hz,
3H), 1.09-1.16 (m, 1H), 1.20 (dd, J=6.8 Hz, 1.8 Hz, 3H), 1.53-1.60
(m, 1H), 1.86-1.91 (m, 1H), 2.04-2.27 (m, 5H), 2.35-2.61 (m, 5H),
2.74-2.78 (m, 1H), 3.02-3.06 (m, 1H), 3.12-3.18 (m, 1H), 3.51-3.54
(m, 1H), 3.97-4.02 (m, 3H), 6.80-6.85 (m, 2H), 6.94-6.98 (m, 2H),
7.26-7.33 (m, 1H), 7.35-7.39 (m, 4H).
Example 241
Ethyl
1-benzyl-4-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate
[1616] 358
[1617] The title compound was synthesized by using
1-benzyl-2-(ethoxycarbo- nyl)piperazine (Synthesis 318, 1991) in
accordance with Example 48.
[1618] Free Body:
[1619] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24-1.28 (m, 3H),
2.36-2.12 (m, 1H), 2.54-2.61 (m, 2H), 2.71-2.83 (m, 4H), 3.02 (m,
1H), 3.31-3.34 (m, 1H), 3.53-3.56 (m, 1H), 3.89-3.92 (d, J=16.6 Hz,
1H), 3.99-4.05 (m, 2H), 4.11-4.24 (m, 2H), 6.79-6.83 (m, 2H),
6.93-6.98 (m, 2H), 7.23-7.34 (m, 5H).
Example 242
Ethyl
1-(4-cyano-5-methyl-4-phenylhexyl)-4-[2-(4-fluorophenoxy)ethyl]-2-pi-
perazinecarboxylate
[1620] 359
[1621] The title compound was synthesized by using ethyl
4-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate in accordance
with Example 15.
[1622] Free Body:
[1623] ESI-MS (m/e); 496 (M+H)
[1624] The ethyl
4-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate: 360
[1625] was obtained as a crude product (752 mg, 100%) by dissolving
ethyl 1-benzyl-4-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate
(977 mg) synthesized in accordance with Example 241 in ethanol (15
ml), adding 210 mg of 10% Pd--C thereto, replacing the atmosphere
of the reaction solution with hydrogen, stirring it, and
evaporating it after completion of the reaction.
[1626] Free Body:
[1627] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24-1.28 (m, 3H),
2.33-2.34 (m, 1H), 2.48-2.50 (m, 1H), 2.72-2.91 (m, 4H), 3.04-3.10
(m, 2H), 3.56-3.59 (m, 1H), 4.04-4.08 (m, 2H), 4.16-4.22 (m, 2H),
6.82-6.86 (m, 2H), 6.94-6.99 (m, 2H).
Example 243
1-(4-Cyano-5-methyl-4-phenylhexyl)-2-hydroxymethyl-4-[2-(4-fluorophenoxy)e-
thyl]piperazine
[1628] 361
[1629] By using ethyl
1-(4-cyano-5-methyl-4-phenylhexyl)-4-[2-(4-fluorophe-
noxy)ethyl]-2-piperazinecarboxylate, the title compound was
synthesized in accordance with Example 240.
[1630] Free Body:
[1631] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.8 Hz,
3H), 1.07-1.14 (m, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.43-1.56 (m, 1H),
1.79-1.90 (m, 1H), 2.04-2.83 (m, 13H), 3.47-3.51 (m, 1H), 3.83-3.91
(m, 1H), 4.01-4.10 (m, 2H), 6.80-6.84 (m, 2H), 6.94-6.98 (m, 2H),
7.26-7.40 (m, 5H).
TEST EXAMPLES
[1632] The calcium inhibitory action (Test Example 1) in vitro was
evaluated for the compound according to the present invention, and
the shrinking action of infarction nidus (Test Example 2) in rat
middle cerebral artery emphraxis model in vivo and the analgesic
action (Test Example 3) in a formalin test using a mouse were
evaluated. The respective test methods and results are as described
below.
Test Example 1
1 Measurement of Potential Dependent Calcium Channel Activity Using
Fluorescent Dye (fura2)
[1633] The most importance is attached to a "glutamic acid-Ca
assumption" as the mechanism of brain infarction (neural cell death
by ischemia). Namely, when cerebral blood flow is lowered,
anaerobic glycolysis is carried out, and the ATP of brain tissue is
exhausted. Ion concentration gradient in the inside and outside of
the cell is not kept by this energy exhaustion, and depolarization
occurs. The potential dependent calcium channel is activated by
depolarization in pre synapse, and the excess release of glutamic
acid is induced. In post synapse, the potential dependent calcium
channel is activated by depolarization to increase the Ca.sup.2+
concentration in the cell, and glutamic acid which was excessively
released stimulates a glutamic acid receptor and increases the
Ca.sup.2+ concentration in the cell. As a result of these, various
kinds of enzymes, such as carpaine and phospholipase, depending on
the Ca.sup.2+ concentration are activated, and induce neural cell
death. The present experiment system can evaluate the Ca.sup.2+
influx in the pre synapse among these flow charts.
[1634] Further, it is known that 10 .mu.M of nifedipine being an
L-type inhibitor, 1 .mu.M of n-conotoxin GVIA being an N-type
inhibitor and 1 .mu.M of w-Agatoxin-IVA being a P/Q type inhibitor
exhibit inhibitions of 16%, 18% and 64% against the Ca.sup.2+
influx, respectively (refer to the following reference literature).
Accordingly, it is considered that the system is suitable for
evaluating the N-type and P/Q type inhibitions.
[1635] Reference Literature:
[1636] D. Bowman, S. Alexander and D. Lodge, Pharmacological
characterization of the calcium channels coupled to the plateau
phase of KCl-induced intracellular free Ca.sup.2+ elevation in
chicken and rat synaptosomes, Neuropharmacology, 32 (11) 1195-1202
(1993)
[1637] (1) Preparation of Cerebral Cortex Synaptosome:
[1638] Cerebral cortex synaptosome was prepared as described below
in accordance with the method described in "Neuropharmacology,
32(11), 1195-1202, 1993". Namely, cerebral cortex was taken out
from a rat decapitated brain, and crushed with scissor scoarsely.
It was charged in a homogenizer, homogenized in 3 M sucrose, and
centrifuged (1,500 g.times.10 min.) at 4.degree. C. The supernatant
obtained was further centrifuged (10,000 g.times.20 min.) at
4.degree. C. 0.3 M of sucrose was added to the precipitate obtained
and the mixture was suspended. The suspension was stratified in 0.8
M sucrose, and centrifuged (10,000 g.times.30 min.). The
precipitate obtained was suspended in a "solution A" (118 mM-NaCl,
4.6 mM-KCl, 1 mM-CaCl.sub.2, 1 mM-MgCl.sub.2, 1.2
mM-Na.sub.2HPO.sub.4, 10 mM-D-glucose, 20 mM-HEPES-NaOH, pH 7.4,
0.1%-BSA), to prepare cerebral cortex synaptosome.
[1639] (2) Calcium Channel Inhibiting Action:
[1640] 4 mM-fura2/AM (Doujin) was suspended in the fore-mentioned
solution A to prepare a solution for loading. The solution for
loading in an equal amount was added to the synaptosome solution
prepared according to the method described above, and the mixture
was incubated for 40 minutes at a room temperature. After
completion of the incubation, the solution for loading was removed
by centrifuge, and further washed 2 times with the solution A. The
solution A containing the present compound was added to this
solution, and the mixture was incubated for 10 minutes at a room
temperature. The calcium channel was stimulated by adding 1/10
volume of a "solution B" (122.6mM-KCl, 1 mM-CaCl.sub.2, 1
mM-MgCl.sub.2, 1.2 mM-Na.sub.2HPO.sub.4, 10 mM-D-glucose, 20
mM-HEPES-NaOH, pH 7.4, 0.1%-BSA) to this solution. The calcium ion
concentration in the cell was measured according to specific
measurement by two wave lengths of 340 nm and 380 nm with
ARUGUS-FDSS (HAMAMATSU PHOTONICS Co.), and IC.sub.50 values of the
respective test compounds were determined. Further, verapamil
hydrochloride was used as a control compound for comparison.
[1641] Result:
1 TABLE 1 Ex. No. IC.sub.50 (.mu.M) 1 8.4 3 5.4 5 7.6 6 9 7 5.8 8
6.8 9 4.5 11 5.1 12 8.2 13 6.6 14 6.5 17 8 18 5.6 22 8.7 24 3 25
4.9 26 5.2 30 7.7 31 4.5 32 5.1 33 2.6 34 4.4 37 8.3 38 5.8 39 6.2
40 3.5 45 7.4 46 4.9 48 3.5 49 5.9 50 4.8 51 5.2 52 5.1 53 2.8 55
3.5 56 3.7 57 5.5 58 5.6 59 8.2 60 7.4 61 7.7 62 5.3 64 6.2 65 2.7
66 4.4 67 7.1 70 13 75 9 76 13 78 8.9 85 10 92 3.1 93 6.9 94 0.7 95
< 96 1.9 97 2.1 98 < 99 0.8 100 < 101 0.8 102 1.9 104 <
105 < 106 1.3 107 1.6 108 0.6 109 0.5 110 5.6 112 5.9 113 4.2
114 10 115 8.2 116 9.4 117 11 118 12 119 5.4 121 14 123 8.5 124 3.6
125 5.0 126 8.4 127 11 128 5.2 136 19 137 19 138 19 139 32< 140
11 141 15 142 8.9 143 9.8 144 12 145 15 146 7.4 147 13 148 14 149
10 150 11 151 9 152 6.1 153 7.4 154 9.8 155 7.9 156 10 157 9.9 158
14 159 12 160 8.0 161 12 162 20 163 14 164 21 165 24 166 16 167 13
168 20 169 15 170 10 171 12 172 10 173 7.2 174 9.3 175 3.9 176 2.8
177 3.4 178 5.2 179 19 180 9.3 181 8.6 182 7.8 183 5.5 184 5.4 185
13 186 18 187 6.9 189 5.8 190 11 191 6.4 193 11 195 10 196 12 197
9.8 200 3.7 201 8.1 202 7.2 203 9.2 204 14 205 11 206 14 207 16 208
6.3 209 5.2 210 4.6 211 7.8 212 7.3 213 17 214 11 215 13 218 18 219
9.8 220 32< 221 16 222 16 223 19 224 10 225 16 226 9.4 227 10
228 9.3 229 14 230 14 232 18 233 15 234 12 236 8.7 237 6.6 238 20
239 11 240 9.0 242 12 243 9.9 Control >16 -- -- Control:
verapamil hydrochloride
Test Example 2
Shrinking Effect of Infarction Nidus in Rat Middle Cerebral Artery
Emphraxis Model (I)
[1642] A calcium ion in the cell plays an important role in the
expression of various cell functions. But when the calcium ion
concentration in the cell rises excessively, cell affection is
induced (refer to literatures 1) and 2), hereinafter, the same as
this.). For example, neural cell affection induced by excitatory
amino-acid occurring in the case of cerebral ischemia provokes
excessive rise of the calcium ion concentration in the cell (3) and
4)). The maintenance mechanism of membrane potential fails by
excitatory amino-acid which rose in the case of local cerebral
ischemia (3)), the depolarization of membrane is induced (5)), and
the influx of the calcium ion into the cell through the potential
dependent calcium channel is increased (6) and 7)). In light of
these fact, it is suggested that an assumption that neural cell
death is based on excitation toxicity by excitatory amino-acid is
correlated with an assumption that neural cell death is based on
the rise of the calcium ion concentration in the cell, and that the
activation of potential dependent calcium channel contributes to
the induction of neural cell death (8)). The potential dependent
calcium channels existing in the neural cell are classified in 6
kinds of sub-types based on the electro-physiological and
pharmacological investigation (T, L, N, P, Q and R types) (9)).
Among these, N, P and Q types play an important role in the
liberation of glutamic acid from rat cerebral cortex synaptosome
(10) and 11)). Therefore, the protection effect for neural cell
affection induced after local cerebral ischemia and possessed by
the typical examples of the present compound in rat middle cerebral
artery emphraxis model was evaluated.
[1643] (1) Preparation of Specimen
[1644] The compound represented by the above formula (I) according
to the present invention was dissolved in a physiological saline,
and appropriately prepared so as to be in doses of 1.5, 5 and 15
mg/kg/h. The concentration of the specimen was calculated based on
the average body weight of an animal. Further, the average body
weight was calculated by measuring the body weight of all animals
which are intended to be used for experiment. For example, in the
case of 5 mg/kg/h, it was calculated as: concentration of
specimen=5 mg.times.average body weight (kg)/administration volume
(0.616 ml) per hour.
[1645] (2) Manufacture of Nylon Embolus
[1646] The embolus made from nylon stitch (Ethicon, Inc.,
Somerville, N.J., USA) of 4-0 monofilament was used for emphraxis
of middle cerebral artery. As the nylon embolus, that prepared by
previously rounding its tip with flame, fragmenting it in a length
of 25 mm, and marking at a position of 17 mm from the tip with an
oily felt pen was used.
[1647] (3) Implantation of Catheter for Intravenous
Administration
[1648] The implantation of catheter for intravenous administration
(Atom Vein Catheter 3Fr, manufactured by ATOM MEDICAL Co., Ltd.,
Tokyo) was carried out under 70% laughing gas-2% halothane
anaesthesia. Catheter which was filled up with a physiological
saline solution was inserted from the femoral vein of left
foot.
[1649] (4) Emphraxis of Middle Cerebral Artery
[1650] The emphraxis of middle cerebral artery was carried out in
accordance with the method of Longa et al (12)). The operation was
carried out under 70% laughing gas-2% halothane anaesthesia just
after implanting the catheter. A rat was laid in facing upward
under the stereoscopic microscope for operation, the neck was cut
open, and the portion where the whole carotid arteries of the right
side are diverged to the external carotid artery and the internal
carotid artery was confirmed. The external carotid artery was cut
off at the periphery side, and the nylon embolus was inserted from
the terminal of the external carotid artery which was cut off into
the internal carotid artery. The embolus was inserted up to the
position where the position of 17 mm from the tip of the embolus is
duplicated with a branch point of the external carotid artery and
the internal carotid artery, and was fixed. The nylon embolus was
pulled back after 2 hours from the emphraxis of middle cerebral
artery, in order to restart blood flow.
[1651] (5) Selection of Animals which Exhibit Ischemia Symptom
[1652] The rat was caught and lifted with the cauda after 30
minutes from the emphraxis of middle cerebral artery, an indivisual
which expresses clearly the one side paralysis of a fore-leg (the
paralysis of a fore-leg of the opponent side which loaded infarct)
was provided for experiment as an example in which middle cerebral
artery was occluded and was able to make an ischemia condition.
[1653] (6) Administration of Medium and Specimen
[1654] A rat which expressed the one side paralysis after 30
minutes from middle cerebral artery emphraxis was put in a cage of
a body temperature control apparatus, and a probe for monitoring a
body temperature was fixed in the rectum. Then, a syringe in which
a medium or a specimen was charged was put in the catheter for
intravenous administration, and the intravenous administration of
the half amount (0.34 ml) of the dose which would be infused for 1
hour was carried out for one minute. Then, administration was
carried out at a rate of 0.682 ml/h for 24 hours using a syringe
pump for infusion (Razel Scientific Instruments, Inc., Stamford,
Conn., USA). During the administration and for 2 hours after the
administration, the temperature of the rectal was controlled in a
range of from 37.0.degree. C. to 38.5.degree. C. under the body
temperature control system.
[1655] (7) Measurement of Infarction Nidus Size (TTC Staining of
Vrain Slice)
[1656] After 24 hours from the emphraxis of middle cerebral artery,
the rat was decapitated, the brain was taken out, and the blood
attached was rinsed with physiological saline solution which was
ice-cooled. Using the brain from which olfactory bulb was removed,
it was sliced at an interval of 2 mm from the tip (6 slices in
total), and they were immersed in a 2%-TTC solution so that the
rear face of the brain is faced upward. The TTC was appropriately
dissolved in physiological saline solution. After being left as it
was at room temperature for one hour or more in the TTC solution,
it was used for area determination of infarction nidus.
[1657] (8) Calculation of Infarction Nidus Volume
[1658] The top of each slice (the rear face of brain) was used for
calculation of infarction nidus area. As for the brain slices,
images were taken in a computer (PM7500/100, Apple Japan, Tokyo)
using an image taking device (CCD Color Camera, SANKEI Inc.,
Tokyo). The areas of infarction nidus of brain cortex in the images
were measured using an image analysis software (NIH image ver.1.60,
National Institutes of Health, USA). The volume of the infarction
nidus of one individual was calculated as the total sum
(unit=mm.sup.3) of 6 slices by multiplying the area (unit=mm.sup.2)
of the infarction nidus of the respective slices measured, by 2
(unit=mm) which is the thickness of the slice.
[1659] (9) Data Analysis Method
[1660] The volume (unit=mm.sup.3) of the infarction nidus of brain
cortex was indicated by average value .+-. standard error.
Statistical significance between the medium control group and the
respective specimen groups was analyzed by multiplex comparative
assay of Dunnett, and the level of significance was defined as 5%
of both sides. Dose reactivity was analyzed by regression analysis,
and the level of significance was defined as 5% of one side.
[1661] (10) Result:
[1662] After the middle cerebral artery was occluded by the nylon
embolus for 2 hours, blood flow was restarted by removing the nylon
embolus, and the volume of the infarction nidus was measured after
24 hours from the emphraxis of middle cerebral artery. As a result,
the compound according to the present invention significantly
suppressed the volume of the infarction nidus of cerebral cortex,
and the dose dependency was confirmed in the shrinking effect of
the infarction nidus by the compound according to the present
invention as a result of regression analysis. For example, the
compound of Example 70 reduced the volume of the infarction nidus
of cerebral cortex by 4% (128.9.+-.12.5 mm.sup.3, n=16), 20%
(108.0.+-.14.9 mm.sup.3, n=15) and 44% (75.7.+-.11.2 mm.sup.3,
n=12: p<0.01), respectively, by carrying out intravenous
administration in doses of 1.5, 5 and 15 mg/kg/h after 30 minutes
from the emphraxis of middle cerebral artery, as compared with the
volume of the infarction nidus of cerebral cortex of 134.3.+-.12.3
mm.sup.3 (n=19) for a control group. Further, the compound of
Example 75 reduced the volume of the infarction nidus of cerebral
cortex by 26% (119.9.+-.12.6 mm.sup.3, n=16), 37% (102.01.+-.14.1
mm.sup.3, n=14: p<0.01) and 49% (83.7.+-.21.3 mm.sup.3, n=11:
p<0.001), respectively, by carrying out intravenous
administration in doses of 1.5, 5and 15 mg/kg/h after 30 minutes
from the emphraxis of middle cerebral artery, as compared with the
volume of the infarction nidus of cerebral cortex of 162.9.+-.8.4
mm.sup.3 (n=15) for control group.
[1663] Namely, the compound according to the present invention
inhibits the calcium ion influx into rat cerebral cortex
synaptosome which is induced by high concentration of KCl, and
inhibits the disengagement of glutamic acid from rat cerebral
cortex slice. Further, the present compound has a protecting action
for neural cell affection caused by local cerebral ischemia in the
present experiment, and exhibits a significant shrinking effect of
the infarction nidus by administration carried after 30 minutes
from ischemia development. Accordingly, the compound according to
the present invention can exhibit the effectiveness by post
administration even in apoplectic ictus of human.
[1664] Further, these results are supported by reports in which
SNX-111 (CAS Registration No. 107452-89-1) being an N-type calcium
channel inhibiting peptide protected the liberation of glutamic
acid from cerebral cortex and subsequent neural cell affection in
rat local cerebral ischemia model (13) and 14)), and also a report
in which .omega.-agatoxin IVA being P/Q type channel inhibiting
peptide exhibited a protective action for neural cell in rat local
cerebral ischemia model (15)).
[1665] Reference Literature:
[1666] 1) -Schanne, F. A. X., Kane, A. B., Young, E. E., Farber, J.
L. Calcium dependence of toxic cell death: a final common pathway.
Science 206: 700-702 (1979).
[1667] 2) Kristian, T., Siesjo, B. K. Calcium in ischemic cell
death. Stroke 29: 705-718 (1998).
[1668] 3) Graham, S. H., Shiraisi, K., Panter, S. S., Simon, R. P.,
Faden, A. I. Changes in extracellular amino acid neurotransmitters
produced by focal cerebral ischemia. Neurosci. Lett. 110: 124-130
(1990).
[1669] 4) Rothman, S. M., Olney, J. W. Glutamate and the
pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19:
105-111(1986).
[1670] 5) Siesjo, B. K., Bengtsson, F. Calcium influxes, calcium
antagonists, and calcium-related pathology in brain ischemia,
hypoglycemia, and spreading depression: A unifying hypothesis. J.
Cereb. Blood Flow Metab. 9: 127-140 (1989).
[1671] 6) Mayer, M. L., Miller, R. J. Excitatory amino acid
receptors, second messengers and regulation of intracellular Ca2+
in mammalian neurons. Trends Pharmacol. Sci. 11: 254-260
(1990).
[1672] 7) Osuga, H., Hakim, A. M. Relationship between
extracellular glutamate concentration and voltage-sensitive calcium
channel function in focal cerebral ischemia in the rat. J. Cereb.
Blood Flow Metab. 16: 629-636 (1996).
[1673] 8) Choi, D. W. Calcium-mediatedneurotoxicity: Relationship
to specific channel types and role in ischemic damage. Trends
Neurosci. 11: 465-469 (1988).
[1674] 9) Randall, A. D., Tsien, R. W. Pharmacological dessection
of multiple types of Ca.sup.2+ channel currents in rat cerebellar
granule neurons. J. Neurosci. 15: 2995-3012 (1995).
[1675] 10) Turner, T. J., Dunlap, K. Pharmacological
characterization of presynaptic calcium channels using subsecond
biochemical measurements of synaptosomal neurosecretion.
Neuropharmacology 34: 1469-1478 (1995).
[1676] 11) Maubecin, V. A., Sanchez, V. N., RosatoSiri, M. D.,
Cherksey, B. D., Sugimori, K., Llinas, R., Uchitel, O. D.
Pharmacological characterization of the voltage-dependent Ca2+
channels present in synaptosomes from rat and chicken central
nervous system. J. Neurochem. 64: 2544-2551 (1995).
[1677] 12) Longa, E. Z., Weinstein, P. R., Carlson, S., Cummins, R.
Reversible middle cerebral artery occlusion without craniectomy in
rats. Stroke 20: 84-91 (1989).
[1678] 13) Bowersox, S. S., Singh, T., Luther, R. R. Selective
blockade of N-type voltage-sensitive calcium channels protects
against brain injury after transient focal ischemia in rats, Brain
Res. 747: 343-347 (1997).
[1679] 14) Takizawa, S., Matsushima, K., Fujita, H., Nanri, K.,
Ogawa, S., Shinohara, Y. A selective N-type calcium channel
antagonist reduces extracellular glutamate release and infarct
volume in focal cerebral ischemia. J. Cereb. Blood flow Metab. 15:
611-618 (1995).
[1680] 15) Asakura, K., Matsuo, Y., Kanemasa, T., Ninomiya, M.
P/Q-type Ca.sup.2+ channel blocker .omega.-agatoxin IVA protect
against brain injury after focal ischemia in rats. Brain Res. 7760:
140-145 (1997).
Test Example 3
Analgesic Effect (I) in Formalin Test Using Mouse
[1681] N-type calcium channel which is one of neuron specific
calcium channels is selectively inhibited by SNX-111 of a low
molecular polypeptide. Further, it is reported that SNX-111
exhibits an analgesic action by administration in spinal cord, in
the formalin test which is one of analgesic tests (1) and 2)).
Therefore, the analgesic effect obtained in the case where the
intravenous administration of the present compound was carried out
was studied in the formalin test (3)) using a mouse.
[1682] (1) Experimental Animal
[1683] Ddy mice (male, 4 to 7 weeks age) purchased from Japan SLC
Co. were used for experiment. Preliminary feeding of 4 days or more
was carried out for mice (breeding condition: a room temperature
23.+-.1.degree. C., air humidity 55.+-.5%, lighting cycle of every
12 hours). The mice were accommodated by a group of approximately
20 in a cage made of polycarbonate for 20 mice in which floor cloth
(White Flake, Charles River Co., Ltd., Tokyo) was spread, and were
bred. At the morning of the day tested, they were moved to a
laboratory. They were freely fed MF (Oriental Yeast Co., Tokyo) as
a feed. Further, they drunk city water freely.
[1684] (2) Test Compound
[1685] Examples 7, 20, 47, 49, 58, 63, 64, 198, 199, 209, 189, 123,
124, 219 and 221 were used as test compounds. Further, as known
analgesics, the morphine which is a narcotic strong analgesic and
an indomethacin which is an antiphlogistic analgesic were used, and
these were used as control drugs.
[1686] (3) Preparation of Test Compound
[1687] The compound according to the present invention was
dissolved in 5.28% Mannitol so as to be 1 mg/ml (10 mg/kg). The
test compounds were weighed on the experimental day to be prepared.
On the other hand, morphine was dissolved in physiological saline
so as to be 3 mg/ml (30 mg/kg), and the indomethacin was suspended
in 0.5% methyl cellulose so as to be 1 mg/ml (10 mg/kg). The test
compounds were weighed on the experimental day to be prepared.
[1688] (4) Preparation of Reagent
[1689] 30 .mu.L of a commercially available 35.0-38.0% formaldehyde
solution was sampled and added to 970 .mu.a physiological saline.
This was used as 3% formalin. Further, formalin is a 37%
formaldehyde solution, and since the purity of the formaldehyde
solution used is indicated as 35.0-38.0%, the 3% formalin which is
prepared for the experiment to be used is accurately 2.84-3.08%
formalin.
[1690] (5) Dose, Administration Route, Number of Examples
[1691] 10 mg/kg of the present compound was intravenously
administered (0.1 ml of 1 mg/ml solution was administered per a
body weight of 10 g). 30 mg/kg of morphine was orally administered
(0.1 ml of 3 mg/ml solution was administered per a body weight of
10 g). 10 mg/kg of indomethacin was orally administered (0.1 ml of
1 mg/ml suspension solution was administered per a body weight of
10 g). 0.1 ml of the respective solvents were intravenously or
orally administered per a body weight of 10 g as controls. Five
examples for every group were tested.
[1692] (6) Test Method
[1693] 10 mg/kg of the present compound was intravenously
administered via tail vein, 30 mg/kg of morphine was orally
administered and 10 mg/kg of indomethacin was orally administered.
After 5, 30 and 90 minutes of the respective administrations, 20
.mu.L of 3% formalin was subcutaneously administered to the planta
of the mouse left hind leg, and the mouse was stored in an
observation cage made of a transparent plastic. Just after the
administration of formalin, the licking time of an action in which
a mouse licked his left hind leg was measured for 5 minutes, and it
was made as an index of pain. The respective solvents were
similarly administered as the control. Setting the licking time of
the control as 100%, the suppression rate (%) of the present
compound was calculated by the following calculation formula.
[1694] Formula:
Depression rate (%)=(licking time of control-licking time of test
compound)/(licking time of control).times.100
[1695] (7) Result:
[1696] The compound according to the present invention
statistically and significantly suppressed the licking time as
compared with the control group, and the suppression rate was
within a range of 33 to 88%. In particular, Example 189 showed the
analgesic action by a suppression rate of 59%. On the other hand,
the morphine showed the analgesic action by a suppression rate of
54%, and the suppression rate of indomethacin was -38% and no
analgesic action was confirmed.
[1697] Namely, as a neuron specific calcium channel inhibitor, the
compound according to the present invention exhibits the analgesic
action similar as SNX-111 which is an N-type calcium channel
inhibitor, exhibits the similar analgesic action as the morphine
which is a narcotic strong analgesic even in comparison with known
analgesics, and further exhibits more superior analgesic action to
indomethacin which is an antiphlogistic analgesic. Accordingly, the
compound according to the present invention is extremely useful for
therapy and amelioration of a pain.
[1698] Reference literature:
[1699] 1) Annika B. Malmberg, and Tony L. Yaksh (1994)
Voltage-Sensitive Calcium Channels in Spinal Nociceptive
Processing: Blockade of N- and P-Type Channels Inhibits
Formalin-Induced Nociception. The Journal of Neuroscience 14(8):
4882-4890.
[1700] 2) S. Scott Bowersox, Theresa Gadbois, Tejinder Singh, Mark
Pettus, Yong-Xiang Wang and Robert R. Luther (1996) Selective
N-type Neuronal Voltage-Sensitive Calcium Channel Blocker, SNX-111,
Produces Spinal Antinociception in Rat Models of Acute, Persistent
and Neuropathic Pain. The Journal of pharmacology and Experimental
Therapeutics 279(3): 1243-1249.
[1701] 3) Hunskaar S, Fasmer O B and Hole K (1985) Formalin test in
mice, a useful technique for evaluating mild analgesics. Journal of
Neuroscience Methods 14(1): 69-76.
* * * * *