U.S. patent application number 11/820218 was filed with the patent office on 2008-10-16 for benzylamine analogues.
This patent application is currently assigned to BTG INTERNATIONAL LIMITED. Invention is credited to Hiroshi Kogen, Kazuo Koyama, Shinji Marumoto, Keiko Suzuki, Narihiro Toda.
Application Number | 20080255095 11/820218 |
Document ID | / |
Family ID | 32300480 |
Filed Date | 2008-10-16 |
United States Patent
Application |
20080255095 |
Kind Code |
A1 |
Koyama; Kazuo ; et
al. |
October 16, 2008 |
Benzylamine analogues
Abstract
A compound of the formula (I): ##STR00001## wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl, amino, (C.sub.1-C.sub.6 alkyl)amino,
di(C.sub.1-C.sub.6 alkyl)amino or a nitrogen-containing saturated
heterocyclic; R.sup.2 and R.sup.3 are hydrogen or C.sub.1-C.sub.6
alkyl; Arom is phenyl, idenyl, napthyl, phenanthrenyl, furyl,
thiolyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, 1,2,3 oxadiazolyl, pyranyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or quinolyl; A is
C.sub.1-C.sub.6 alkylene; R.sup.a is hydrogen, C.sub.1-C.sub.6
alkyl or C.sub.2-C.sub.6 alkenyl; E is a single bond, oxygen,
sulfur or --NR.sup.4--, wherein R.sup.4 is hydrogen or
C.sub.1-C.sub.7 alkanoyl; X.sup.1 and X.sup.2 are oxygen or sulfur;
or a pharmacologically acceptable salt or ester thereof.
Inventors: |
Koyama; Kazuo;
(Kawaguchi-shi, JP) ; Marumoto; Shinji; (Tokyo,
JP) ; Toda; Narihiro; (Tokyo, JP) ; Kogen;
Hiroshi; (Tokyo, JP) ; Suzuki; Keiko; (Tokyo,
JP) |
Correspondence
Address: |
FRISHAUF, HOLTZ, GOODMAN & CHICK, PC
220 Fifth Avenue, 16TH Floor
NEW YORK
NY
10001-7708
US
|
Assignee: |
BTG INTERNATIONAL LIMITED
London
GB
|
Family ID: |
32300480 |
Appl. No.: |
11/820218 |
Filed: |
June 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11583499 |
Oct 19, 2006 |
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11820218 |
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10629108 |
Jul 28, 2003 |
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11583499 |
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PCT/JP02/00400 |
Jan 22, 2002 |
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10629108 |
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Current U.S.
Class: |
514/217.12 ;
514/247; 514/255.06; 514/256; 514/313; 514/357; 514/364; 514/365;
514/372; 514/374; 514/396; 514/406; 514/408; 514/447; 514/471;
514/478; 540/600; 544/224; 544/329; 544/406; 546/169; 546/336;
548/125; 548/200; 548/206; 548/236; 548/240; 548/335.5; 548/561;
549/76 |
Current CPC
Class: |
A61P 25/14 20180101;
C07D 333/38 20130101; C07C 271/44 20130101; A61P 25/18 20180101;
C07C 323/20 20130101; C07D 215/20 20130101; A61P 25/24 20180101;
A61P 25/22 20180101; A61P 43/00 20180101; C07C 333/04 20130101;
C07C 323/25 20130101; A61P 25/00 20180101; C07D 213/64 20130101;
C07D 213/68 20130101; C07D 317/58 20130101; C07C 219/30 20130101;
A61P 25/28 20180101 |
Class at
Publication: |
514/217.12 ;
514/247; 514/255.06; 514/256; 514/313; 514/357; 514/364; 514/365;
514/372; 514/374; 514/396; 514/406; 514/408; 514/447; 514/471;
514/478; 540/600; 544/224; 544/329; 544/406; 546/169; 546/336;
548/125; 548/200; 548/206; 548/236; 548/240; 548/335.5; 548/561;
549/76 |
International
Class: |
A61K 31/55 20060101
A61K031/55; C07D 333/22 20060101 C07D333/22; C07D 215/38 20060101
C07D215/38; C07D 263/34 20060101 C07D263/34; A61K 31/50 20060101
A61K031/50; A61P 25/28 20060101 A61P025/28; A61K 31/4965 20060101
A61K031/4965; C07D 261/02 20060101 C07D261/02; C07D 277/00 20060101
C07D277/00; C07D 275/02 20060101 C07D275/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 24, 2002 |
JP |
202-15136 |
Jan 25, 2002 |
TW |
91101231 |
Jul 23, 2003 |
JP |
2003-200434 |
Claims
1. A compound of the formula (I): ##STR00018## wherein R.sup.1 is a
C.sub.1-C.sub.6 alkyl group, an amino group, a (C.sub.1-C.sub.6
alkyl)amino group, a di(C.sub.1-C.sub.6 alkyl)amino group or a
nitrogen-containing saturated heterocyclic group; R.sup.2 and
R.sup.3 are the same or different and are a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group; Arom is an unsubstituted aryl group, a
substituted aryl group which is substituted at 1 to 5 positions, an
unsubstituted heteroaryl group or a substituted heteroaryl group
which is substituted at 1 to 3 positions; wherein the unsubstituted
or substituted aryl group of Arom is selected from the group
consisting of phenyl, indenyl, naphthyl, phenanthrenyl and
anthracenyl; wherein the unsubstituted or substituted heteroaryl
group of Arom is selected from the group consisting of furyl,
thiolyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, 1,2,3 oxadiazolyl, pyranyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and quinolyl; wherein
the substituents of the substituted aryl group and of the
substituted heteroaryl group are independently selected from the
group consisting of a halogen atom, a C.sub.1-C.sub.6 alkyl group,
a halogeno C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy
group, a C.sub.1-C.sub.6 alkylthio group, a C.sub.1-C.sub.3
alkylenedioxy group, a C.sub.1-C.sub.7 alkanoyl group, a
C.sub.2-C.sub.7 alkyloxycarbonyl group, an amino group, a
C.sub.1-C.sub.7 alkanoylamino group, a hydroxyl group, a mercapto
group, a cyano group, a nitro group and a carboxyl group; A is an
C.sub.1-C.sub.6 alkylene group; R.sup.a is a hydrogen atom, a
C.sub.1-C.sub.6 alkyl group or a C.sub.2-C.sub.6 alkenyl group; E
is a single bond, an oxygen atom, a sulfur atom or a group of the
formula: --NR.sup.4--, wherein R.sup.4 represents a hydrogen atom
or a C.sub.1-C.sub.7 alkanoyl group; and X.sup.1 and X.sup.2 are
the same or different and are an oxygen atom or a sulfur atom; or a
pharmacologically acceptable salt or ester thereof.
2. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein the group of the formula:
##STR00019## is a carbamoyl group, a (C.sub.1-C.sub.4
alkyl)carbamoyl group, a di(C.sub.1-C.sub.4 alkyl)carbamoyl group,
a thiocarbamoyl group, a (C.sub.1-C.sub.4 alkyl)thiocarbamoyl group
or a di(C.sub.1-C.sub.4 alkyl)thiocarbamoyl group.
3. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein the group of the formula:
##STR00020## is a (C.sub.1-C.sub.4 alkyl)carbamoyl group, a
di(C.sub.1-C.sub.4 alkyl)carbamoyl group, a (C.sub.1-C.sub.4
alkyl)thiocarbamoyl group or a di(C.sub.1-C.sub.4
alkyl)thiocarbamoyl group.
4. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein the group of the formula:
##STR00021## is a (C.sub.1-C.sub.4 alkyl)carbamoyl group or a
di(C.sub.1-C.sub.4 alkyl)carbamoyl group.
5. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein the group of the formula:
##STR00022## a di(C.sub.1-C.sub.4 alkyl)carbamoyl group.
6. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein the group of the formula:
##STR00023## is a dimethylcarbamoyl group or an
ethylmethylcarbamoyl group.
7. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein the group of the formula:
##STR00024## is a dimethylcarbamoyl group,
8. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.3 is a C.sub.1-C.sub.6
alkyl group.
9. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.3 is a methyl group or
an ethyl group.
10. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.3 is a methyl
group.
11. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.2 is a hydrogen atom, a
methyl group or an ethyl group.
12. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.2 is a hydrogen atom or
a methyl group.
13. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.a is a hydrogen atom or
a methyl group.
14. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.a is a hydrogen
atom.
15. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein Arom is an unsubstituted or
substituted phenyl group or an unsubstituted or substituted pyridyl
group; and wherein the phenyl group is substituted at from 1 to 3
positions and the pyridyl group is substituted at one position; and
wherein the substituents of the phenyl group and the pyridyl group
are independently selected from the group consisting of a halogen
atom, a C.sub.1-C.sub.6 alkyl group, a halogeno C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.1-C.sub.6
alkylthio group, a C.sub.1-C.sub.3 alkylenedioxy group, a
C.sub.1-C.sub.7 alkanoyl group, a C.sub.2-C.sub.7 alkyloxycarbonyl
group, an amino, C.sub.1-C.sub.7 alkanoylamino group, a hydroxyl
group, a mercapto group, a cyano group, a nitro group and a carboxy
group.
16. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein Arom is an unsubstituted
phenyl group or a phenyl group substituted at from 1 to 3 positions
by substituent(s), which are independently selected from the group
consisting of a halogen atom, a C.sub.1-C.sub.6 alkyl group, a
halogeno C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy
group, a C.sub.1-C.sub.6 alkylthio group, a C.sub.1-C.sub.3
alkylenedioxy group, a C.sub.1-C.sub.7 alkanoyl group, a
C.sub.2-C.sub.7 alkyloxycarbonyl group, an amino group, a
C.sub.1-C.sub.7 alkanoylamino group, a hydroxyl group, a mercapto
group, a cyano group, a nitro group and a carboxyl group.
17. The compound or the pharmacologically acceptable salt thereof
according to claim 1, wherein Arom is a phenyl group substituted at
three positions by halogen atoms or is a phenyl group substituted
at one or two positions by substituent(s) which are independently
selected from the group consisting of a halogen group, a
C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 alkyl group
substituted by from 1 to 3 fluorine atoms, a C.sub.1-C.sub.4 alkoxy
group, a C.sub.1-C.sub.4 alkylthio group, a methylenedioxy group,
an ethylenedioxy group, a C.sub.1-C.sub.4 alkanoyl group, a cyano
group and a nitro group.
18. The compound or the pharmacologically acceptable salt thereof
according to claim 1, wherein Arom is a phenyl group substituted at
three positions by a fluorine atom or a chlorine atom or is a
phenyl group substituted at one or two positions by substituent(s)
which are independently selected from the group consisting of
fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio,
acetyl, cyano and nitro.
19. The compound or the pharmacologically acceptable salt thereof
according to claim 1, wherein Arom is a phenyl group substituted at
three positions by fluorine atoms or is a phenyl group substituted
at one or two positions by substituent(s) which are independently
selected from the group consisting of a fluorine atom, a chlorine
atom, a methylthio group, an acetyl group, a cyano group and a
nitro group.
20. The compound or the pharmacologically acceptable salt thereof
according to claim 1, wherein Arom is a phenyl group substituted at
three positions by fluorine atoms or is a phenyl group substituted
at one or two positions by substituent(s), which are independently
selected from the group consisting of a fluorine atom, a chlorine
atom, a methylthio group and a nitro group.
21. The compound or the pharmacologically acceptable salt thereof
according to claim 1, wherein Arom is a phenyl group substituted at
one position by a fluorine atom, a chlorine atom or a nitro group
or a phenyl group substituted at two positions by fluorine
atoms.
22. The compound or the pharmacologically acceptable salt thereof
according to claim 1, wherein Arom is a 4-fluorophenyl group, a
4-chlorophenyl group, a 4-nitrophenyl group or a 3,4-difluorophenyl
group.
23. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein A is a C.sub.1-C.sub.4
alkylene group.
24. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein A is an ethylene group.
25. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein E is an oxygen atom or a
single bond.
26. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein E is an oxygen atom.
27. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein X.sup.1 is an oxygen
atom.
28. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein X.sup.2 is an oxygen
atom.
29. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.1 is an amino group, a
(C.sub.1-C.sub.6 alkyl)amino group or a di(C.sub.1-C.sub.6
alkyl)amino group.
30. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.1 is an amino group, a
(C.sub.1-C.sub.4 alkyl)amino group or a di(C.sub.1-C.sub.4
alkyl)amino group.
31. The compound or the pharmacologically acceptable salt or ester
thereof according to claim 1, wherein R.sup.1 is a (C.sub.1-C.sub.4
alkyl)amino group or a di(C.sub.1-C.sub.4 alkyl)amino group.
32. A pharmaceutical composition containing a pharmaceutically
effective amount of a compound or a pharmacologically acceptable
salt or ester thereof according to claim 1.
33. A method of treating or preventing Alzheimer's disease,
depression, Huntington's chorea, Pick's disease, tardive
dyskinesia, compulsive disorders or panic disorders in a mammal
comprising administering to a mammal a pharmaceutically effective
amount of a compound or a pharmacologically acceptable salt or
ester thereof according to claim 1.
34. The method according to claim 33 for treating or preventing
Alzheimer's disease.
35. A method according to claim 33, wherein the mammal is a
human.
36. The method according to claim 34, wherein the mammal is a
human.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of application
Ser. No. 11/583,499 filed Oct. 19, 2006, which is a divisional
application of application Ser. No. 10/629,108 filed Jul. 28, 2003,
which is a continuation-in-part application of International
Application PCT/JP02/00400 filed Jan. 22, 2002, the entire contents
of which are hereby incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The present invention relates to benzylamine analogues,
pharmacologically acceptable salts or esters thereof and
pharmaceutical compositions containing the same that have superior
acetylcholinesterase inhibitory action and selective serotonin
reuptake inhibitory action, and which are useful as therapeutic or
prophylactic drugs for Alzheimer's disease, depression,
Huntington's chorea, Pick's disease, tardive dyskinesia, compulsive
disorders or panic disorders.
[0004] 2. Background Art
[0005] Given the rapid growth of the elderly population, there is
an urgent desire for the establishment of a treatment method for
senile dementia as typified by Alzheimer's disease, and research
and development is being conducted on therapeutic drugs for
Alzheimer's disease from various perspectives. Since decreased
acetylcholine concentration in the brain and decreased cholinergic
function are observed in Alzheimer's disease patients, studies have
been conducted on the treatment of Alzheimer's disease using
acetylcholine precursor compounds, acetylcholinesterase inhibitors
and acetylcholine agonists for the purpose of activating
cholinergic function. Activation of the central cholinergic nervous
system has been demonstrated to be effective for the treatment of
mild to moderate cases of Alzheimer's disease by clinical
application of acetylcholinesterase inhibitors (Rev. Contemp.
Pharmacother., 6, 335 (1995)). Serious adverse side effects, namely
liver toxicity, which were observed with early acetylcholinesterase
inhibitors, have been improved considerably by ensuring inhibitory
action specificity of the compounds to acetylcholinesterase and
butylcholinesterase, and second generation acetylcholinesterase
inhibitors are currently being developed (Neurology, 50, 136
(1998)).
[0006] Depression is frequently reported as a peripheral symptom in
early Alzheimer's disease patients. Treatment using antidepressants
has been tried, based on the idea that while impairment of
cognitive function is still mild, core symptoms such as cognitive
function can be expected to be improved by alleviating the
depression (Ann. N.Y. Acad. Sci., 695, 254 (1993)). At present, the
brain's serotonin system is widely recognized to be involved in
depression. Research is being conducted on drugs that act on
serotonin receptors or serotonin reuptake inhibitors, and selective
serotonin reuptake inhibitors have been reported to be
antidepressants having minimal adverse side effects (Drugs, 32, 481
(1986)). Drugs that are provided with both acetylcholinesterase
inhibitory action and selective serotonin reuptake inhibitor action
are expected to be able to alleviate depression and improve
cognitive function, which are the core symptoms of Alzheimer's
disease, and are thought to be more effective therapeutic drugs for
Alzheimer's disease than compounds only having acetylcholinesterase
inhibitory action. However, compounds having a similar chemical
structure to the compounds of the present invention that also have
both acetylcholinesterase inhibitory action and selective serotonin
reuptake inhibitory action have heretofore not been known.
SUMMARY OF THE INVENTION
[0007] As a result of seeking to develop compounds having both
superior acetylcholinesterase inhibitory action and selective
serotonin reuptake inhibitory action, and conducting earnest
research over an extended period of time on the synthesis of
various benzene derivatives and their pharmacological activity, the
inventors of the present invention found that benzylamine analogues
having an amine at the benzyl position have both superior
acetylcholinesterase inhibitory action and selective serotonin
reuptake inhibitory action, and are useful as therapeutic or
prophylactic drugs (particularly therapeutic drugs) for Alzheimer's
disease, depression, Huntington's chorea, Pick's disease, tardive
dyskinesia, compulsive disorders or panic disorders (and
particularly Alzheimer's disease), thereby leading to completion of
the present invention.
[0008] The novel benzylamine analogues of the present invention are
compounds of formula (I):
##STR00002##
[wherein R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, an amino
group, a (C.sub.1-C.sub.6 alkyl)amino group, a di(C.sub.1-C.sub.6
alkyl)amino group or a nitrogen-containing saturated heterocyclic
group;
[0009] R.sup.2 and R.sup.3 are the same or different and represent
a hydrogen atom or a C.sub.1-C.sub.6 alkyl group;
[0010] Arom represents an aryl group, an aryl group substituted at
from 1 to 5 positions by substituent(s) which are the same or
different selected from the substituent group .alpha., a heteroaryl
group, or a heteroaryl group substituted at from 1 to 3 positions
by substituent(s) which are the same or different selected from the
substituent group .alpha.;
[0011] A represents a C.sub.1-C.sub.6 alkylene group;
[0012] R.sup.a represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group or a C.sub.2-C.sub.6 alkenyl group or, together with R.sup.2,
represents a C.sub.1-C.sub.3 alkylene group (in the case of
C.sub.2-C.sub.3, it may contain a double bond);
[0013] E represents a single bond, an oxygen atom, a sulfur atom or
a group of the formula: --NR.sup.4-- (wherein R.sup.4 represents a
hydrogen atom or a C.sub.1-C.sub.7 alkanoyl group);
[0014] X.sup.1 and X.sup.2 are the same or different and represent
an oxygen atom or a sulfur atom]
or a pharmacologically acceptable salt or ester thereof.
<Substituent Group .alpha.>
[0015] halogen atom, C.sub.1-C.sub.6 alkyl group, halogeno
C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6 alkoxy group,
C.sub.1-C.sub.6 alkylthio group, C.sub.1-C.sub.3 alkylenedioxy
group, C.sub.1-C.sub.7 alkanoyl group, C.sub.2-C.sub.7
alkyloxycarbonyl group, amino group, C.sub.1-C.sub.7 alkanoylamino
group, hydroxyl group, mercapto group, cyano group, nitro group and
carboxyl group.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The compound of the above formula (I) or the
pharmacologically acceptable salt or ester is preferably
[0017] (1) a compound or pharmacologically acceptable salt or ester
thereof in which the group of formula: R.sup.1--C(.dbd.X.sup.1)--
is a carbamoyl group, a (C.sub.1-C.sub.4 alkyl)carbamoyl group, a
di(C.sub.1-C.sub.4 alkyl)carbamoyl group, a thiocarbamoyl group, a
(C.sub.1-C.sub.4 alkyl)thiocarbamoyl group or a di(C.sub.1-C.sub.4
alkyl)thiocarbamoyl group,
[0018] (2) a compound or pharmacologically acceptable salt or ester
thereof in which the group of formula: R.sup.1--C(.dbd.X.sup.1)--
is a (C.sub.1-C.sub.4 alkyl)carbamoyl group, a di(C.sub.1-C.sub.4
alkyl)carbamoyl group, a (C.sub.1-C.sub.4 alkyl)thiocarbamoyl group
or a di(C.sub.1-C.sub.4 alkyl)thiocarbamoyl group,
[0019] (3) a compound or pharmacologically acceptable salt or ester
thereof in which the group of formula: R.sup.1--C(.dbd.X.sup.1)--
is a (C.sub.1-C.sub.4 alkyl)carbamoyl group or a di(C.sub.1-C.sub.4
alkyl)carbamoyl group,
[0020] (4) a compound or pharmacologically acceptable salt or ester
thereof in which the group of formula: R.sup.1--C(.dbd.X.sup.1)--
is a di(C.sub.1-C.sub.4 alkyl)carbamoyl group,
[0021] (5) a compound or pharmacologically acceptable salt or ester
thereof in which the group of formula: R.sup.1--C(.dbd.X.sup.1)--
is a dimethylcarbamoyl group or an ethylmethylcarbamoyl group,
[0022] (6) a compound or pharmacologically acceptable salt or ester
thereof in which the group of formula: R.sup.1--C(.dbd.X.sup.1)--
is a dimethylcarbamoyl group,
[0023] (7) a compound or pharmacologically acceptable salt or ester
thereof in which R.sup.3 is a C.sub.1-C.sub.6 alkyl group,
[0024] (8) a compound or pharmacologically acceptable salt or ester
thereof in which R.sup.3 is a methyl group or an ethyl group,
[0025] (9) a compound or pharmacologically acceptable salt or ester
thereof in which R.sup.3 is a methyl group,
[0026] (10) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.2 is a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group,
[0027] (11) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.2 is a hydrogen atom, a methyl group
or an ethyl group,
[0028] (12) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.2 is a hydrogen atom or a methyl
group,
[0029] (13) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.a, together with R.sup.2, is a
C.sub.1-C.sub.3 alkylene group which may contain a double bond,
[0030] (14) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.a, together with R.sup.2, is a
C.sub.2-C.sub.3 alkylene group which may contain a double bond,
[0031] (15) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.a, together with R.sup.2, is a C.sub.3
alkylene group which contains a double bond,
[0032] (16) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.a is a hydrogen atom or a methyl
group,
[0033] (17) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.a is a hydrogen atom,
[0034] (18) a compound or pharmacologically acceptable salt or
ester thereof in which Arom is a phenyl group, a phenyl group
substituted at from 1 to 3 positions by substituent(s) which may be
the same or different selected from the substituent group .alpha.,
a pyridyl group, or a pyridyl group substituted at one position by
a substituent selected from the substituent group .alpha.,
[0035] (19) a compound or pharmacologically acceptable salt or
ester thereof in which Arom is a phenyl group or a phenyl group
substituted at from 1 to 3 positions by substituent(s) which may be
the same or different selected from the substituent group
.alpha.,
[0036] (20) a compound or pharmacologically acceptable salt thereof
in which Arom is a phenyl group substituted at one or two positions
by substituent(s) which may be the same or different selected from
the substituent group .alpha.1, or a phenyl group substituted at
three positions by halogen atoms,
[0037] (21) a compound or pharmacologically acceptable salt thereof
in which Arom is a phenyl group substituted at one or two positions
by substituent(s) which may be the same or different selected from
the substituent group .alpha.2, or a phenyl group substituted at
three positions by fluorine atoms or chlorine atoms,
[0038] (22) a compound or pharmacologically acceptable salt thereof
in which Arom is a phenyl group substituted at one or two positions
by substituent(s) which may be the same or different selected from
the substituent group .alpha.3, or a phenyl group substituted at
three positions by fluorine atoms,
[0039] (23) a compound or pharmacologically acceptable salt thereof
in which Arom is a phenyl group substituted at one or two positions
by substituent(s) which may be the same or different selected from
the substituent group (X.sup.4, or a phenyl group substituted at
three positions by fluorine atoms,
[0040] (24) a compound or pharmacologically acceptable salt thereof
in which Arom is a phenyl group substituted at one position by a
fluorine atom, a chlorine atom or a nitro group, or a phenyl group
substituted at two positions by fluorine atoms,
[0041] (25) a compound or pharmacologically acceptable salt thereof
in which Arom is a 4-fluorophenyl group, a 4-chlorophenyl group, a
4-nitrophenyl group or a 3,4-difluorophenyl group,
[0042] (26) a compound or pharmacologically acceptable salt or
ester thereof in which A is a C.sub.1-C.sub.4 alkylene group,
[0043] (27) a compound or pharmacologically acceptable salt or
ester thereof in which A is a methylene group or an ethylene
group,
[0044] (28) a compound or pharmacologically acceptable salt or
ester thereof in which A is an ethylene group,
[0045] (29) a compound or pharmacologically acceptable salt or
ester thereof in which E is an oxygen atom or a single bond,
[0046] (30) a compound or pharmacologically acceptable salt or
ester thereof in which E is an oxygen atom,
[0047] (31) a compound or pharmacologically acceptable salt or
ester thereof in which X.sup.2 is an oxygen atom,
[0048] (32) a compound or pharmacologically acceptable salt or
ester thereof in which the group of formula:
R.sup.1--C(.dbd.X.sup.1)--X.sup.2-- is attached at the
para-position,
[0049] (33) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.1 is an amino group, a
(C.sub.1-C.sub.6 alkyl)amino group or a di(C.sub.1-C.sub.6
alkyl)amino group,
[0050] (34) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.1 is an amino group, a
(C.sub.1-C.sub.4 alkyl)amino group or a di(C.sub.1-C.sub.4
alkyl)amino group,
[0051] (35) a compound or pharmacologically acceptable salt or
ester thereof in which R.sup.1 is a (C.sub.1-C.sub.4 alkyl)amino
group or a di(C.sub.1-C.sub.4 alkyl)amino group,
[0052] (36) a compound or pharmacologically acceptable salt or
ester thereof in which X.sup.1 is an oxygen atom,
<Substituent Group .alpha.1>
[0053] halogen atom, C.sub.1-C.sub.4 alkyl group, C.sub.1-C.sub.4
alkyl group substituted by from 1 to 3 fluorine atoms,
C.sub.1-C.sub.4 alkoxy group, C.sub.1-C.sub.4 alkylthio group,
methylenedioxy group, ethylenedioxy group, C.sub.1-C.sub.4 alkanoyl
group, cyano group and nitro group,
<Substituent Group .alpha.2>
[0054] fluorine atom, chlorine atom, methyl group, trifluoromethyl
group, methoxy group, methylthio group, acetyl group, cyano group
and nitro group,
<Substituent Group .alpha.3>
[0055] fluorine atom, chlorine atom, methylthio group, acetyl
group, cyano group and nitro group,
<Substituent Group .alpha.4>
[0056] fluorine atom, chlorine atom, methylthio group and nitro
group.
[0057] The pharmaceutical compositions of the present invention
contain a compound of the above formula (I) or a pharmacologically
acceptable salt or ester thereof as an active ingredient.
[0058] The inhibitors of acetylcholineesterase and selective
serotonin reuptake of the present invention contain a compound of
the above formula (I) or a pharmacologically acceptable salt or
ester thereof.
[0059] The therapeutic or prophylactic drugs for Alzheimer's
disease, depression, Huntington's chorea, Pick's disease, tardive
dyskinesia, compulsive disorders or panic disorders (preferably
Alzheimer's disease) of the present invention contain a compound of
the above formula (I) or a pharmacologically acceptable salt or
ester thereof.
[0060] The "C.sub.1-C.sub.6 alkyl group" in R.sup.1 to R.sup.3 and
<substituent group .alpha.> in formula (I) may be a straight
or branched chain alkyl group having from 1 to 6 carbon atoms such
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,
t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl, and is
preferably a straight or branched chain alkyl group having from 1
to 4 carbon atoms, more preferably a methyl group.
[0061] The "(C.sub.1-C.sub.6 alkyl)amino group" in R.sup.1 in
formula (I) may be a straight or branched chain alkylamino group
having from 1 to 6 carbon atoms such as methylamino, ethylamino,
propylamino, isopropylamino, butylamino, isobutylamino,
s-butylamino, t-butylamino, pentylamino, isopentylamino,
2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino,
isohexylamino, 4-methylpentylamino, 3-methylpentylamino,
2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino,
2,2-dimethylbutylamino, 1,1-dimethylbutylamino,
1,2-dimethylbutylamino, 1,3-dimethylbutylamino,
2,3-dimethylbutylamino and 2-ethylbutylamino, and is preferably a
methylamino group.
[0062] The "di(C.sub.1-C.sub.6 alkyl)amino group" in R.sup.1 in the
above formula (I) may be a straight or branched chain dialkylamino
group having from 2 to 12 carbon atoms such as dimethylamino,
diethylamino, ethylmethylamino, dipropylamino, diisopropylamino,
dibutylamino, diisobutylamino, di-s-butylamino, di-tert-butylamino,
dipentylamino, diisopentylamino, dineopentylamino,
di-1-ethylpropylamino, dihexylamino and diisohexylamino, and is
preferably dimethylamino or ethylmethylamino, more preferably a
dimethylamino group.
[0063] The "nitrogen-containing saturated heterocyclic group" in
R.sup.1 in the above formula (I) may be a 5 to 7-membered saturated
heterocyclic group containing one nitrogen atom and from 0 to 3
sulfur atoms, oxygen atoms or/and nitrogen atoms such as
morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl,
pyrazolidinyl, piperidinyl and piperazinyl, and is preferably a
morpholinyl group.
[0064] Preferred groups for R.sup.1 in the above formula (I) are
(C.sub.1-C.sub.6 alkyl)amino groups or di(C.sub.1-C.sub.6
alkyl)amino groups, more preferably di(C.sub.1-C.sub.6 alkyl)amino
groups.
[0065] The "aryl group" and the "aryl group" of the "aryl group
substituted at from 1 to 5 positions by substituent(s) which are
the same or different selected from the substituent group .alpha."
in Arom in the above formula (I) may be an aromatic hydrocarbon
group having from 5 to 14 carbon atoms such as phenyl, indenyl,
naphthyl, phenanthrenyl and anthracenyl, and is preferably a phenyl
group.
[0066] The "heteroaryl group" and the "heteroaryl group" of the
"heteroaryl group substituted at from 1 to 3 positions by
substituent(s) selected from the substituent group .alpha." in Arom
in the above formula (I) may be a 5 to 10-membered aromatic
heterocyclic group containing from 1 to 3 sulfur atoms, oxygen
atoms and/or nitrogen atoms such as furyl, thienyl, pyrrolyl,
azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyranyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and quinolyl, and is
preferably a pyridyl group.
[0067] The "C.sub.1-C.sub.6 alkylene group" in A in the above
formula (I) may be a straight alkylene group having from 1 to 6
carbon atoms such as methylene, ethylene, propylene, trimethylene,
tetramethylene, pentamethylene and hexamethylene, and is preferably
a straight alkylene group having from 1 to 4 carbon atoms, more
preferably a methylene or ethylene, further more preferably an
ethylene group.
[0068] The "C.sub.1-C.sub.7 alkanoyl group" in R.sup.4 and
<substituent group .alpha.> in the above formula (I) may be
an alkylcarbonyl group having from 1 to 7 carbon atoms such as
formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and
hexanoyl, and is preferably an acetyl group.
[0069] The preferred group for X.sup.1 in the above formula (I) is
an oxygen atom.
[0070] The "halogen atom" in <substituent group .alpha.> in
the above formula (I) is a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom, and is preferably a fluorine atom
or a chlorine atom.
[0071] The "halogeno C.sub.1-C.sub.6 alkyl group" in
<substituent group .alpha.> in the above formula (I) means a
group in which the "C.sub.1-C.sub.6 alkyl group" is substituted by
halogen atom(s) and may be a trifluoromethyl, trichloromethyl,
difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl,
2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl,
2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl,
4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl, and is preferably a
trifluoromethyl group.
[0072] The "C.sub.1-C.sub.6 alkoxy group" in <substituent group
.alpha.> in the above formula (I) indicates a group in which the
above "C.sub.1-C.sub.6 alkyl group" is bonded to an oxygen atom and
is a straight or branched chain alkoxy group having from 1 to 6
carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy,
2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy,
3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy,
2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,
1,3-dimethylbutoxy and 2,3-dimethylbutoxy, and is preferably a
methoxy group.
[0073] The "C.sub.1-C.sub.6 alkylthio group" in R.sup.a and
<substituent group .alpha.> in the above formula (I)
indicates a group in which the above "C.sub.1-C.sub.6 alkyl group"
is bonded to a sulfur atom and is a straight or branched chain
alkylthio group having from 1 to 6 carbon atoms such as methylthio,
ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio,
s-butylthio, tert-butylthio, n-pentylthio, isopentylthio,
2-methylbutylthio, neopentylthio, 1-ethylpropylthio, n-hexylthio,
isohexylthio, 4-methylpentylthio, 3-methylpentylthio,
2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio,
2,2-dimethylbutylthio, 1,1-dimethylbutylthio,
1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio
and 2-ethylbutylthio, and is preferably a methylthio group.
[0074] The "C.sub.1-C.sub.3 alkylene group which may contain a
double bond" for R.sup.a and R.sup.2 in the above formula (I)
indicates a straight or branched chain alkylene group having from 1
to 3 carbon atoms which may contain a double bond such as
methylene, methylmethylene, ethylene, propylene, trimethylene,
vinylene or propynylene, and is preferably a straight or branched
chain alkylene group having 2 or 3 carbon atoms which may contain a
double bond, more preferably a propynylene group.
[0075] The "C.sub.1-C.sub.3 alkylenedioxy group" in <substituent
group .alpha.> in the above formula (I) indicates
methylenedioxy, ethylenedioxy or propylenedioxy, and is preferably
a methylenedioxy group.
[0076] The "C.sub.2-C.sub.7 alkyloxycarbonyl group" in
<substituent group a> in the above formula (I) may be an
alkyloxycarbonyl group having from 2 to 7 carbon atoms such as
methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and
isobutoxycarbonyl, and is preferably a methoxycarbonyl group.
[0077] The "C.sub.1-C.sub.7 alkanoylamino group" in <substituent
group .alpha.> in the above formula (I) indicates a group in
which the "C.sub.1-C.sub.7 alkanoyl group" is substituted by an
amino group and may be an alkylcarbonylamino group having from 1 to
7 carbon atoms such as formylamino, acetylamino, propionylamino,
butyrylamino, isobutyrylamino and pentanoylamino, and is preferably
an, acetylamino group.
[0078] In the above, the "ester thereof" indicates an ester, since
the compounds of the present invention can be made into esters, and
this ester indicates an "ester of a hydroxyl group" and an "ester
of a carboxyl group" and means an ester in which the ester residue
is a "general protecting group" or a "protecting group which is
cleavable by chemical or enzymatic hydrolysis in vivo".
[0079] The "general protecting group" is a protecting group which
is cleavable by a chemical process such as hydrogenolysis,
hydrolysis, electrolysis and photolysis. The "general protecting
group" relating to the "ester of a hydroxyl group" may be an
"aliphatic acyl group" such as an alkylcarbonyl group, e.g.,
formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl,
3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,
3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,
tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,
14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl,
15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl,
nonadecanoyl, eicosanoyl and heneicosanoyl; a carboxylated
alkylcarbonyl group, e.g., succinoyl, glutaroyl and adipoyl; a
lower alkylcarbonyl group substituted by one or more halogen atoms,
e.g., chloroacetyl, dichloroacetyl, trichloroacetyl and
trifluoroacetyl; a saturated cyclic hydrocarbon-carbonyl group,
e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,
cyclohexylcarbonyl, cycloheptylcarbonyl and cyclooctylcarbonyl; a
lower alkoxy lower alkylcarbonyl group, e.g., methoxyacetyl; or an
unsaturated alkylcarbonyl group, e.g., (E)-2-methyl-2-butenoyl; an
"aromatic acyl group" such as an arylcarbonyl group e.g., benzoyl,
naphthoyl, pyridoyl, thienoyl and furoyl; an arylcarbonyl group
substituted by one or more halogen atoms, e.g., 2-bromobenzoyl and
4-chlorobenzoyl; a lower alkylated arylcarbonyl group, e.g.,
2,4,6-trimethylbenzoyl and 4-toluoyl; a lower alkoxylated
arylcarbonyl group, e.g., 4-anisoyl; a carboxylated arylcarbonyl
group, e.g., 2-carboxybenzoyl, 3-carboxybenzoyl and
4-carboxybenzoyl; a nitrated arylcarbonyl group, e.g.,
4-nitrobenzoyl and 2-nitrobenzoyl; a lower alkoxycarbonylated
arylcarbonyl group, e.g., 2-(methoxycarbonyl)benzoyl; or an
arylated arylcarbonyl group, e.g., 4-phenylbenzoyl; an
"aralkylcarbonyl group" such as a lower alkylcarbonyl group
substituted with from 1 to 3 aryl groups, e.g., phenylacetyl,
.alpha.-naphthylpropionyl, .beta.-naphthylbutyryl,
diphenylisobutyryl, triphenylacetyl,
.alpha.-naphthyldiphenylisobutyryl and 9-anthrylpentanoyl; or a
lower alkylcarbonyl group which is substituted with from 1 to 3
aryl groups in which said aryl moiety is substituted with lower
alkyl group(s), lower alkoxy group(s), nitro group(s), halogen
atom(s) and/or cyano group(s), e.g., 4-methylphenylacetyl,
2,4,6-trimethylphenylformyl, 3,4,5-trimethylphenylbutyryl,
4-methoxyphenylisobutyryl, 4-methoxyphenyldiphenylpivaloyl,
2-nitrophenylacetyl, 4-nitrophenylpropionyl, 4-chlorophenylbutyryl,
4-bromophenylacetyl and 4-cyanophenylpentanoyl; a
"tetrahydropyranyl or tetrahydrothiopyranyl group" such as
tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,
4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, and
4-methoxytetrahydrothiopyran-4-yl; a "tetrahydrofuranyl or
tetrahydrothiofuranyl group" such as tetrahydrofuran-2-yl and
tetrahydrothiofuran-2-yl; a "silyl group" such as a tri(lower
alkyl)silyl group e.g., trimethylsilyl, triethylsilyl,
isopropyldimethylsilyl, t-butyldimethylsilyl,
methyldiisopropylsilyl, methyl di-t-butylsilyl and
triisopropylsilyl; or a tri(lower alkyl)silyl group which is
substituted with one or two aryl groups, e.g., diphenylmethylsilyl,
diphenylbutylsilyl, diphenylisopropylsilyl and
phenyldiisopropylsilyl; an "alkoxymethyl group" such as a lower
alkoxymethyl group, e.g., methoxymethyl,
1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl,
isopropoxymethyl, butoxymethyl and t-butoxymethyl; a lower
alkoxylated lower alkoxymethyl group, e.g., 2-methoxyethoxymethyl;
or a lower alkoxymethyl group which is substituted with one or more
halogen atoms, e.g., 2,2,2-trichloroethoxymethyl and
bis(2-chloroethoxy)methyl; a "substituted ethyl group" such as a
lower alkoxylated ethyl group, e.g.,
1-ethoxyethyl-1-(isopropoxy)ethyl; or a halogenated ethyl group,
e.g., 2,2,2-trichloroethyl; an "aralkyl group" such as a lower
alkyl group which is substituted with from 1 to 3 aryl groups,
e.g., benzyl, .alpha.-naphthylmethyl, .beta.-naphthylmethyl,
diphenylmethyl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl and
9-anthrylmethyl; or a lower alkyl group which is substituted with
from 1 to 3 aryl groups in which said aryl moiety is substituted
with lower alkyl group(s), lower alkoxy group(s), nitro group(s),
halogen atom(s) and/or cyano group(s), e.g., 4-methylbenzyl,
2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl,
4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl,
4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; an "alkoxycarbonyl
group" such as a lower alkoxycarbonyl group, e.g., methoxycarbonyl,
ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl; or a lower
alkoxycarbonyl group which is substituted with halogen atom(s)
and/or tri(lower alkyl)silyl group(s), e.g.,
2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;
an "alkenyloxycarbonyl group" such as
vinyloxycarbonylallyloxycarbonyl; or an "aralkyloxycarbonyl group"
in which the aryl moiety may be substituted with one or two lower
alkoxy groups and/or nitro groups such as benzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
[0080] On the other hand, the "general protecting group" relating
to the "ester of a carboxyl group" may preferably be a "lower alkyl
group" such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl; an "alkenyl
group" such as ethenyl, 1-propenyl, 2-propenyl,
1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,
2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl,
1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl,
1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl,
2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl,
1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl,
1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,
1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl and 5-hexenyl; an "alkynyl group" such as
ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl,
2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl,
2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl,
1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl,
2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl,
1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,
1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,
4-hexynyl and 5-hexynyl; a "lower alkyl group which is substituted
with one or more halogen atoms" such as trifluoromethyl,
trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,
fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,
2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl,
3-chloropropyl, 4-fluorobutyl, 6-iodohexyl and 2,2-dibromoethyl; a
"hydroxy lower alkyl group" such as 2-hydroxyethyl,
2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and
4-hydroxybutyl; an "aliphatic acyl"-"lower alkyl group" such as
acetylmethyl; an "aralkyl group" such as a lower alkyl group which
is substituted with from 1 to 3 aryl groups e.g., benzyl,
phenethyl, 3-phenylpropyl, .alpha.-naphthylmethyl,
.beta.-naphthylmethyl, diphenylmethyl, triphenylmethyl,
6-phenylhexyl, .alpha.-naphthyldiphenylmethyl and 9-anthrylmethyl;
or a lower alkyl group which is substituted with from 1 to 3 aryl
groups in which said aryl moiety is substituted with lower alkyl
group(s), lower alkoxy group(s), nitro group(s), halogen atom(s),
cyano group(s) and/or alkoxycarbonyl group(s), e.g.,
4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl,
4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl,
4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,
4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piperonyl
and 4-methoxycarbonylbenzyl; or a "silyl group" such as
trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,
t-butyldimethylsilyl, methyldiisopropylsilyl, methyl
di-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl,
isopropyldiphenylsilyl, butyldiphenylsilyl and
phenyldiisopropylsilyl.
[0081] The "protecting group which is cleavable by chemical or
enzymatic hydrolysis in vivo" means a protecting group which is
cleavable by a biological method such as hydrolysis in the human
body to produce a free acid or a salt thereof. The suitability of
such a derivative can be determined by administering it to an
experimental animal such as a rat or a mouse by an intravenous
injection, measuring a body fluid of the animal thereafter and
detecting the original compound or a pharmacologically acceptable
salt thereof.
[0082] The "protecting group which is cleavable by chemical or
enzymatic hydrolysis in vivo, relating to the "ester of a hydroxyl
group" may be a 1-(acyloxy) "lower alkyl group" such as a
1-("aliphatic acyl"oxy) "lower alkyl group", e.g., formyloxymethyl,
acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl,
butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl,
isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl,
1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl,
1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl,
1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl,
1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl,
1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl,
1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl,
1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl,
1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl; a
1-("aliphatic acyl"thio) "lower alkyl group", e.g.,
formylthiomethyl, acetylthiomethyl, dimethylaminoacetylthiomethyl,
propionylthiomethyl, butyrylthiomethyl, pivaloylthiomethyl,
valerylthiomethyl, isovalerylthiomethyl, hexanoylthiomethyl,
1-formylthioethyl, 1-acetylthioethyl, 1-propionylthioethyl,
1-butyrylthioethyl, 1-pivaloylthioethyl, 1-valerylthioethyl,
1-isovalerylthioethyl, 1-hexanoylthioethyl, 1-formylthiopropyl,
1-acetylthiopropyl, 1-propionylthiopropyl, 1-butyrylthiopropyl,
1-pivaloylthiopropyl, 1-valerylthiopropyl, 1-isovalerylthiopropyl,
1-hexanoylthiopropyl, 1-acetylthiobutyl, 1-propionylthiobutyl,
1-butyrylthiobutyl, 1-pivaloylthiobutyl, 1-acetylthiopentyl,
1-propionylthiopentyl, 1-butyrylthiopentyl, 1-pivaloylthiopentyl
and 1-pivaloylthiohexyl; a 1-("cycloalkyl"carbonyloxy) "lower alkyl
group", e.g., cyclopentylcarbonyloxymethyl,
cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl,
1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl,
1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and
1-cyclohexylcarbonyloxybutyl; or a 1-("aromatic acyl"oxy) "lower
alkyl group" such as benzoyloxymethyl; an (alkoxycarbonyloxy)alkyl
group such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,
propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,
butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl,
pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl,
cyclohexyloxycarbonyloxymethyl,
cyclohexyloxycarbonyloxy(cyclohexyl)methyl,
1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,
1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl,
1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl,
1-(t-butoxycarbonyloxy)ethyl), 1-(pentyloxycarbonyloxy)ethyl,
1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,
1-(cyclopentyloxycarbonyloxy)propyl,
1-(cyclohexyloxycarbonyloxy)propyl,
1-(cyclopentyloxycarbonyloxy)butyl,
1-(cyclohexyloxycarbonyloxy)butyl,
1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl,
2-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl,
2-(propoxycarbonyloxy)ethyl, 2-(isopropoxycarbonyloxy)ethyl,
2-(butoxycarbonyloxy)ethyl, 2-(isobutoxycarbonyloxy)ethyl,
2-(pentyloxycarbonyloxy)ethyl, 2-(hexyloxycarbonyloxy)ethyl,
1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl,
1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl,
1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl,
1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl,
1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl,
1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl,
1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl,
1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl,
1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl; a
"phthalidyl group" such as phthalidyl, dimethylphthalidyl and
dimethoxyphthalidyl; a "carbonyloxyalkyl group" such as an
oxodioxolenylmethyl group, e.g.,
(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,
[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-chlorophenyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(2-oxo-1,3-dioxolen-4-yl)methyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and
(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; the above "aliphatic acyl
group"; the above "aromatic acyl group" a "half ester salt residual
group of succinic acid"; a "phosphoric acid ester salt residual
group"; an "ester forming residual group such as an amino acid"; a
carbamoyl group; a carbamoyl group substituted by one or two lower
alkyl groups; a carboxy "lower alkyl" dithioethyl group such as
2-carboxyethyldithioethyl, 3-carboxypropyldithioethyl,
4-carboxybutyldithioethyl, 5-carboxypentyldithioethyl and
6-carboxyhexyldithioethyl; or a "lower alkyl group" dithioethyl
group such as methyldithioethyl, ethyldithioethyl,
propyldithioethyl, butyldithioethyl, pentyldithioethyl and
hexyldithioethyl.
[0083] On the other hand, the "protecting group which is cleavable
by chemical or enzymatic hydrolysis in vivo" relating to the "ester
of a carboxyl group" may specifically be an "alkoxy lower alkyl
group" such as a lower alkoxy lower alkyl group, e.g.,
methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl,
1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl,
1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl,
isopropoxymethyl, butoxymethyl and t-butoxymethyl; a lower
alkoxylated lower alkoxy lower alkyl group, e.g.
2-methoxyethoxymethyl; an "aryl group" oxy "lower alkyl group",
e.g., phenoxymethyl; or a halogenated lower alkoxy lower alkyl
group, e.g., 2,2,2-trichloroethoxymethyl and
bis(2-chloroethoxy)methyl; a "lower alkoxy" carbonyl "lower alkyl
group" such as methoxycarbonylmethyl; a cyano "lower alkyl group"
such as cyanomethyl and 2-cyanoethyl; a "lower alkyl group"
thiomethyl group such as methylthiomethyl and ethylthiomethyl; an
"aryl group" thiomethyl group such as phenylthiomethyl and
naphthylthiomethyl; a "lower alkyl group" sulfonyl "lower alkyl
group" which may be substituted by halogen atom(s) such as
2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl; an
"aryl group" sulfonyl "lower alkyl group" such as
2-benzenesulfonylethyl and 2-toluenesulfonylethyl; an acyloxy
"lower alkyl group" such as an "aliphatic acyl" oxy "lower alkyl
group", e.g., formyloxymethyl, acetoxymethyl, propionyloxymethyl,
butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl,
isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl,
1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl,
1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl,
1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl,
2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl,
2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl,
1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl,
1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl,
1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl,
1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl,
1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl,
1-pivaloyloxypentyl and 1-pivaloyloxyhexyl; a "cycloalkyl"
carbonyloxy "lower alkyl group", e.g.,
cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl,
1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl,
1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl,
1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl; or
an "aromatic acyl" oxy "lower alkyl group", e.g., benzoyloxymethyl;
an (alkoxycarbonyloxy)alkyl group such as methoxycarbonyloxymethyl,
ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,
isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,
isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl,
hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl,
cyclohexyloxycarbonyloxy(cyclohexyl)methyl,
1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,
1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl,
1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl,
1-(t-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl,
1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,
1-(cyclopentyloxycarbonyloxy)propyl,
1-(cyclohexyloxycarbonyloxy)propyl,
1-(cyclopentyloxycarbonyloxy)butyl,
1-(cyclohexyloxycarbonyloxy)butyl,
1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl,
2-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl,
2-(propoxycarbonyloxy)ethyl, 2-(isopropoxycarbonyloxy)ethyl,
2-(butoxycarbonyloxy)ethyl, 2-(isobutoxycarbonyloxy)ethyl,
2-(pentyloxycarbonyloxy)ethyl, 2-(hexyloxycarbonyloxy)ethyl,
1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl,
1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl,
1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl,
1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl,
1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl,
1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl,
1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl,
1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl,
1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl,
1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl; a
"carbonyloxyalkyl group" such as an oxodioxolenylmethyl group,
e.g., (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,
[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
(2-oxo-1,3-dioxolen-4-yl)methyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and
(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; a "phthalidyl group" such
as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; an "aryl
group" such as phenyl and indanyl; the above "lower alkyl group";
the above "alkylthio group"; a "carboxy group alkyl group" such as
carboxyl group methyl; or an "amide forming residual group of an
amino acid" such as phenylalanine.
[0084] In the compound (1) of the present invention, while optical
isomers (including diastereomers) based on asymmetrical carbon
atom(s) in the molecule exist, and geometric isomers based on a
ring structure sometimes exist, these respective isomers are
included in the present invention.
[0085] The "pharmacologically acceptable salt thereof" means a salt
since the compound (1) of the present invention can be converted
into salts, and these salts may preferably be a metal salt such as
an alkali metal salt, e.g., a sodium salt, a potassium salt and a
lithium salt; a alkaline earth metal salt, e.g., a calcium salt and
a magnesium salt; an aluminum salt; an iron salt; a zinc salt; a
copper salt; a nickel salt; or a cobalt salt; an amine salt such as
an inorganic salt, e.g., an ammonium salt; or an organic salt,
e.g., a t-octylamine salt, a dibenzylamine salt, a morpholine salt,
a glucosamine salt, a phenylglycinealkyl ester salt, an
ethylenediamine salt, a N-methylglucamine salt, a guanidine salt, a
diethylamine salt, a triethylamine salt, a dicyclohexylamine salt,
a N,N'-dibenzylethylenediamine salt, a chloroprocaine salt, a
procaine salt, a diethanolamine salt, a N-benzyl-phenethylamine
salt, a piperazine salt, a tetramethylammonium salt and a
tris(hydroxymethyl)aminomethane salt; an inorganic acid salt such
as a hydrogen halide salt, e.g., hydrofluoride, hydrochloride,
hydrobromide and hydroiodide; nitrate; perchlorate; sulfate; or
phosphate; an organic acid salt such as a lower alkanesulfonate,
e.g., methanesulfonate, trifluoromethanesulfonate and
ethanesulfonate; a arylsulfonate, e.g., benzenesulfonate and
p-toluenesulfonate; acetate; malate; fumarate; succinate; citrate;
tartrate; oxalate; or maleate; an amino acid salt such as glycine
salt, lysine salt, arginine salt, ornithine salt, glutamate and
aspartate; and are more preferably an inorganic acid salt.
[0086] The compound (1) of the present invention can also exist as
a hydrate.
[0087] Compounds shown in the following Table 1 to Table 5 are
specifically illustrated as preferred compounds of formula (I).
However, the compound of the present invention is not limited to
these.
[0088] The meaning of the abbreviations in the following Table 1 to
Table 5 is shown below. That is,
Ac represents an acetyl group, tBu represents a t-butyl group, Car
represents a carbamoyl group, diMeCar represents a
N,N-dimethylcarbamoyl group, diMeTcr represents a
N,N-dimethylthiocarbamoyl group, diEtCar represents a
N,N-diethylcarbamoyl group, diPrCar represents a
N,N-diisopropylcarbamoyl group, MeEtCar represents a
N-methyl-N-ethylcarbamoyl group, Et represents an ethyl group, Me
represents a methyl group, diMeN represents a dimethylamino group,
MeEtN represents a methylethylamino group, MeOCO represents a
methoxycarbonyl group, Mor represents a morpholino group, Mtdo
represents a methylenedioxy group, pentaFPH represents a
pentafluorophenyl group, Ph represents a phenyl group, Pr
represents a propyl group, iPr represents an isopropyl group,
Py-2-yl represents a pyridin-2-yl group, Py-3-yl represents a
pyridin-3-yl group, Py-4-yl represents a pyridin-4-yl group, and
Thi-3-yl represents a thiophen-3-yl group.
TABLE-US-00001 TABLE 1 (Ia) ##STR00003## Compound No.
R.sup.1--(C.dbd.X.sup.1) R.sup.2R.sup.3N A E Arom 1-1 diMeCar MeNH
(CH.sub.2).sub.2 -- 4-F-Ph 1-2 EtCAr MeNH (CH.sub.2).sub.2 --
4-F-Ph 1-3 EtCAr MeNH (CH.sub.2).sub.2 -- 4-MeO-Ph 1-4 Ac MeNH
(CH.sub.2).sub.2 -- 4-F-Ph 1-5 tBu-(C.dbd.O) MeNH (CH.sub.2).sub.2
-- 4-F-Ph 1-6 diEtCar MeNH (CH.sub.2).sub.2 -- 4-F-Ph 1-7 diEtCar
MeNH (CH.sub.2).sub.2 O 4-Cl-Ph 1-8 diEtCar MeNH (CH.sub.2).sub.2 O
3-Cl-Ph 1-9 diPrCAr MeNH (CH.sub.2).sub.2 -- 4-F-Ph 1-10 MeEtCar
MeNH (CH.sub.2).sub.2 O 4-Cl-Ph 1-11 Mor-(C.dbd.O) MeNH
(CH.sub.2).sub.2 -- 4-F-Ph 1-12 diMeTcr MeNH (CH.sub.2).sub.2 --
4-F-Ph 1-13 diMeCar MeNH (CH.sub.2).sub.2 -- 4-Cl-Ph 1-14 diMeCar
MeNH (CH.sub.2).sub.2 -- 4-CF.sub.3-Ph 1-15 diMeCar MeNH
(CH.sub.2).sub.2 -- 4-MeO-Ph 1-16 diMeCar diMeN (CH.sub.2).sub.2 --
4-MeO-Ph 1-17 diMeCar MeNH (CH.sub.2).sub.2 -- 3-MeO-4-MeO-Ph 1-18
diMeCar MeNH (CH.sub.2).sub.2 -- 3,4-Mtdo-Ph 1-19 diMeCar MeNH
(CH.sub.2).sub.2 -- 4-NO.sub.2-Ph 1-20 diMeCar MeNH
(CH.sub.2).sub.2 -- 3-F-4-F-Ph 1-21 diMeCar diMeN (CH.sub.2).sub.2
-- 4-F-Ph 1-22 diMeCar diMeN (CH.sub.2).sub.2 -- 4-Cl-Ph 1-23
diMeCar diMeN (CH.sub.2).sub.2 -- 4-NO.sub.2-Ph 1-24 diMeCar diMeN
(CH.sub.2).sub.2 -- 3-F-4-F-Ph 1-25 diMeCar MeNH (CH.sub.2).sub.3
-- 4-F-Ph 1-26 diMeCar MeNH (CH.sub.2).sub.3 -- 4-Cl-Ph 1-27
diMeCar MeNH (CH.sub.2).sub.3 -- 4-NO.sub.2-Ph 1-28 diMeCar MeNH
(CH.sub.2).sub.3 -- 3-F-4-F-Ph 1-29 diMeCar diMeN (CH.sub.2).sub.3
-- 4-F-Ph 1-30 diMeCar diMeN (CH.sub.2).sub.3 -- 4-Cl-Ph 1-31
diMeCar diMeN (CH.sub.2).sub.3 -- 4-NO.sub.2-Ph 1-32 diMeCar diMeN
(CH.sub.2).sub.3 -- 3-F-4-F-Ph 1-33 diMeCar MeNH CH.sub.2 O 4-F-Ph
1-34 diMeCar MeNH CH.sub.2 O 4-Cl-Ph 1-35 diMeCar MeNH CH.sub.2 O
4-NO.sub.2-Ph 1-36 diMeCar MeNH CH.sub.2 O 3-F-4-F-Ph 1-37 diMeCar
diMeN CH.sub.2 O 4-F-Ph 1-38 diMeCar diMeN CH.sub.2 O 4-Cl-Ph 1-39
diMeCar diMeN CH.sub.2 O 4-NO.sub.2-Ph 1-40 diMeCar diMeN CH.sub.2
O 3-F-4-F-Ph 1-41 diMeCar MeNH (CH.sub.2).sub.2 S 4-F-Ph 1-42
diMeCar MeNH (CH.sub.2).sub.2 S 4-Cl-Ph 1-43 diMeCar MeNH
(CH.sub.2).sub.2 S 4-NO.sub.2-Ph 1-44 diMeCar MeNH (CH.sub.2).sub.2
S 3-F-4-F-Ph 1-45 diMeCar diMeN (CH.sub.2).sub.2 S 4-F-Ph 1-46
diMeCar diMeN (CH.sub.2).sub.2 S 4-Cl-Ph 1-47 diMeCar diMeN
(CH.sub.2).sub.2 S 4-NO.sub.2-Ph 1-48 diMeCar diMeN
(CH.sub.2).sub.2 S 3-F-4-F-Ph 1-49 diMeCar MeNH (CH.sub.2).sub.2 NH
4-F-Ph 1-50 diMeCar MeNH (CH.sub.2).sub.2 NH 4-Cl-Ph 1-51 diMeCar
MeNH (CH.sub.2).sub.2 NH 3-F-Ph 1-52 diMeCar MeNH (CH.sub.2).sub.2
NH 3-Cl-Ph 1-53 diMeCar MeNH (CH.sub.2).sub.2 NH 4-NO.sub.2-Ph 1-54
diMeCar MeNH (CH.sub.2).sub.2 NH 3-F-4-F-Ph 1-55 diMeCar diMeN
(CH.sub.2).sub.2 NH 4-F-Ph 1-56 diMeCar diMeN (CH.sub.2).sub.2 NH
4-Cl-Ph 1-57 diMeCar diMeN (CH.sub.2).sub.2 NH 4-NO.sub.2-Ph 1-58
diMeCar diMeN (CH.sub.2).sub.2 NH 3-F-4-F-Ph 1-59 diMeCar MeNH
(CH.sub.2).sub.2 NAc 4-Cl-Ph 1-60 diMeCar MeNH (CH.sub.2).sub.2 NAc
3-F-Ph 1-61 diMeCar MeNH (CH.sub.2).sub.2 NAc 4-NO.sub.2-Ph 1-62
diMeCar diMeN (CH.sub.2).sub.2 NAc 4-Cl-Ph 1-63 diMeCar diMeN
(CH.sub.2).sub.2 NAc 3-F-Ph 1-64 diMeCar diMeN (CH.sub.2).sub.2 NAc
4-NO.sub.2-Ph 1-65 diMeCar NH.sub.2 (CH.sub.2).sub.2 O 4-F-Ph 1-66
diMeCar NH.sub.2 (CH.sub.2).sub.2 O 4-NO.sub.2-Ph 1-67 diMeCar EtNH
(CH.sub.2).sub.2 O 4-F-Ph 1-68 diMeCar EtNH (CH.sub.2).sub.2 O
3-F-Ph 1-69 diMeCar EtNH (CH.sub.2).sub.2 O 4-Cl-Ph 1-70 diMeCar
EtNH (CH.sub.2).sub.2 O 3-NO.sub.2-Ph 1-71 diMeCar EtNH
(CH.sub.2).sub.2 O 4-NO.sub.2-Ph 1-72 diMeCar EtNH (CH.sub.2).sub.2
O 3-F-4-F-Ph 1-73 diMeCar PrNH (CH.sub.2).sub.2 O 4-F-Ph 1-74
diMeCar MeNH (CH.sub.2).sub.2 O Ph 1-75 diMeCar MeNH
(CH.sub.2).sub.2 O 4-F-Ph 1-76 diMeCar MeNH (CH.sub.2).sub.2 O
3-F-Ph 1-77 diMeCar MeNH (CH.sub.2).sub.2 O 2-F-Ph 1-78 diMeCar
MeNH (CH.sub.2).sub.2 O 4-Cl-Ph 1-79 diMeCar MeNH (CH.sub.2).sub.2
O 3-Cl-Ph 1-80 diMeCar MeNH (CH.sub.2).sub.2 O 2-Cl-Ph 1-81 diMeCar
MeNH (CH.sub.2).sub.2 O 4-Br-Ph 1-82 diMeCar MeNH (CH.sub.2).sub.2
O 4-Me-Ph 1-83 diMeCar MeNH (CH.sub.2).sub.2 O 3-Me-Ph 1-84 diMeCar
MeNH (CH.sub.2).sub.2 O 2-Me-Ph 1-85 diMeCar MeNH (CH.sub.2).sub.2
O 4-CF.sub.3-Ph 1-86 diMeCar MeNH (CH.sub.2).sub.2 O 4-MeO-Ph 1-87
diMeCar MeNH (CH.sub.2).sub.2 O 3-MeO-Ph 1-88 diMeCar MeNH
(CH.sub.2).sub.2 O 2-MeO-Ph 1-89 diMeCar MeNH (CH.sub.2).sub.2 O
4-Ac-Ph 1-90 diMeCar MeNH (CH.sub.2).sub.2 O 3-Ac-Ph 1-91 diMeCar
MeNH (CH.sub.2).sub.2 O 4-CN-Ph 1-92 diMeCar MeNH (CH.sub.2).sub.2
O 4-NO.sub.2-Ph 1-93 diMeCar MeNH (CH.sub.2).sub.2 O 2-NO.sub.2-Ph
1-94 diMeCar MeNH (CH.sub.2).sub.2 O 3-NO.sub.2-Ph 1-95 diMeCar
MeNH (CH.sub.2).sub.2 O 4-NH.sub.2-Ph 1-96 diMeCar MeNH
(CH.sub.2).sub.2 O 3-NH.sub.2-Ph 1-97 diMeCar MeNH (CH.sub.2).sub.2
O 4-AcNH-Ph 1-98 diMeCar MeNH (CH.sub.2).sub.2 O 3-AcNH-Ph 1-99
diMeCar MeNH (CH.sub.2).sub.2 O 4-COOH-Ph 1-100 diMeCar MeNH
(CH.sub.2).sub.2 O 3,4-Mtdo-Ph 1-101 diMeCar MeNH (CH.sub.2).sub.2
O 2-F-4-F-Ph 1-102 diMeCar MeNH (CH.sub.2).sub.2 O 3-F-4-F-Ph 1-103
diMeCar MeNH (CH.sub.2).sub.2 O 3-F-5-F-Ph 1-104 diMeCar MeNH
(CH.sub.2).sub.2 O 3-F-4-Cl-Ph 1-105 diMeCar MeNH (CH.sub.2).sub.2
O 2-F-4-NO.sub.2-Ph 1-106 diMeCar MeNH (CH.sub.2).sub.2 O
2-Cl-4-F-Ph 1-107 diMeCar MeNH (CH.sub.2).sub.2 O 2-Cl-4-Cl-Ph
1-108 diMeCar MeNH (CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2-Ph 1-109
diMeCar MeNH (CH.sub.2).sub.2 O 3-Cl-4-F-Ph 1-110 diMeCar MeNH
(CH.sub.2).sub.2 O 3-Cl-4-Cl-Ph 1-111 diMeCar MeNH (CH.sub.2).sub.2
O 2-Me-4-F-Ph 1-112 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me-4-Cl-Ph
1-113 diMeCar MeNH (CH.sub.2).sub.2 O 3-Me-4-Cl-Ph 1-114 diMeCar
MeNH (CH.sub.2).sub.2 O 3-Me-4-Me-Ph 1-115 diMeCar MeNH
(CH.sub.2).sub.2 O 3-Me-4-NO.sub.2-Ph 1-116 diMeCar MeNH
(CH.sub.2).sub.2 O 3-NO.sub.2-4-Cl-Ph 1-117 diMeCar MeNH
(CH.sub.2).sub.2 O 3-F-4-F-5-F-Ph 1-118 diMeCar MeNH
(CH.sub.2).sub.2 O 2-F-3-F-5-F-Ph 1-119 diMeCar MeNH
(CH.sub.2).sub.2 O Py-3-yl 1-120 diMeCar MeNH (CH.sub.2).sub.2 O
5-Cl-Py-3-yl 1-121 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me-Py-3-yl
1-122 diMeCar MeNH (CH.sub.2).sub.2 O 6-Me-Py-3-yl 1-123 diMeCar
MeNH (CH.sub.2).sub.2 O Py-2-yl 1-124 diMeCar MeNH (CH.sub.2).sub.2
O 6-Cl-Py-2-yl 1-125 diMeCar MeNH (CH.sub.2).sub.2 O
6-CF.sub.3-Py-2-yl 1-126 diMeCar MeNH (CH.sub.2).sub.2 O
6-NO.sub.2-Py-2-yl 1-127 diMeCar MeNH (CH.sub.2).sub.2 O Py-4-yl
1-128 diMeCar MeNH (CH.sub.2).sub.2 O 2-NO.sub.2Py-4-yl 1-129
diMeCar MeNH (CH.sub.2).sub.2 O Thi-3-yl 1-130 diMeCar MeNH
(CH.sub.2).sub.2 O 2-MeOCO-Thi-3-yl 1-131 diMeCar diMeN
(CH.sub.2).sub.2 O Ph 1-132 diMeCar diMeN (CH.sub.2).sub.2 O 4-F-Ph
1-133 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-Ph 1-134 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-Ph 1-135 diMeCar diMeN (CH.sub.2).sub.2 O
4-Cl-Ph 1-136 diMeCar diMeN (CH.sub.2).sub.2 O 3-Cl-Ph 1-137
diMeCar diMeN (CH.sub.2).sub.2 O 2-Cl-Ph 1-138 diMeCar diMeN
(CH.sub.2).sub.2 O 4-Br-Ph 1-139 diMeCar diMeN (CH.sub.2).sub.2 O
4-Me-Ph 1-140 diMeCar diMeN (CH.sub.2).sub.2 O 3-Me-Ph 1-141
diMeCar diMeN (CH.sub.2).sub.2 O 2-Me-Ph 1-142 diMeCar diMeN
(CH.sub.2).sub.2 O 4-CF.sub.3-Ph 1-143 diMeCar diMeN
(CH.sub.2).sub.2 O 4-MeO-Ph 1-144 diMeCar diMeN (CH.sub.2).sub.2 O
3-MeO-Ph 1-145 diMeCar diMeN (CH.sub.2).sub.2 O 2-MeO-Ph 1-146
diMeCar diMeN (CH.sub.2).sub.2 O 4-Ac-Ph 1-147 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Ac-Ph 1-148 diMeCar diMeN (CH.sub.2).sub.2 O
4-CN-Ph 1-149 diMeCar diMeN (CH.sub.2).sub.2 O 4-NO.sub.2-Ph 1-150
diMeCar diMeN (CH.sub.2).sub.2 O 2-NO.sub.2-Ph 1-151 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NO.sub.2-Ph 1-152 diMeCar diMeN
(CH.sub.2).sub.2 O 4-NH.sub.2-Ph 1-153 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NH.sub.2-Ph 1-154 diMeCar diMeN
(CH.sub.2).sub.2 O 4-AcNH-Ph 1-155 diMeCar diMeN (CH.sub.2).sub.2 O
3-AcNH-Ph 1-156 diMeCar diMeN (CH.sub.2).sub.2 O 4-COOH-Ph 1-157
diMeCar diMeN (CH.sub.2).sub.2 O 3,4-Mtdo-Ph 1-158 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-4-F-Ph 1-159 diMeCar diMeN (CH.sub.2).sub.2
O 3-F-4-F-Ph 1-160 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-5-F-Ph
1-161 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-4-Cl-Ph 1-162 diMeCar
diMeN (CH.sub.2).sub.2 O 2-F-4-NO.sub.2-Ph 1-163 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Cl-4-F-Ph 1-164 diMeCar diMeN (CH.sub.2).sub.2
O 2-Cl-4-Cl-Ph 1-165 diMeCar diMeN (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2-Ph 1-166 diMeCar diMeN (CH.sub.2).sub.2 O
3-Cl-4-F-Ph 1-167 diMeCar diMeN (CH.sub.2).sub.2 O 3-Cl-4-Cl-Ph
1-168 diMeCar diMeN (CH.sub.2).sub.2 O 2-Me-4-F-Ph 1-169 diMeCar
diMeN (CH.sub.2).sub.2 O 2-Me-4-Cl-Ph 1-170 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-Cl-Ph 1-171 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-Me-Ph 1-172 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-NO.sub.2Ph 1-173 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NO.sub.2-4-Cl-Ph 1-174 diMeCar diMeN
(CH.sub.2).sub.2 O 3-F-4-F-5-F-Ph 1-175 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-3-F-5-F-Ph 1-176 diMeCar diMeN
(CH.sub.2).sub.2 O Py-3-yl 1-177 diMeCar diMeN (CH.sub.2).sub.2 O
5-Cl-Py-3-yl 1-178 diMeCar diMeN (CH.sub.2).sub.2 O 2-Me-Py-3-yl
1-179 diMeCar diMeN (CH.sub.2).sub.2 O 6-Me-Py-3-yl 1-180 diMeCar
diMeN (CH.sub.2).sub.2 O Py-2-yl 1-181 diMeCar diMeN
(CH.sub.2).sub.2 O 6-Cl-Py-2-yl 1-182 diMeCar diMeN
(CH.sub.2).sub.2 O 6-CF.sub.3-Py-2-yl 1-183 diMeCar diMeN
(CH.sub.2).sub.2 O 6-NO.sub.2-Py-2-yl 1-184 diMeCar diMeN
(CH.sub.2).sub.2 O Py-4-yl 1-185 diMeCar diMeN (CH.sub.2).sub.2 O
2-NO.sub.2Py-4-yl 1-186 diMeCar diMeN (CH.sub.2).sub.2 O Thi-3-yl
1-187 diMeCar diMeN (CH.sub.2).sub.2 O 2-MeOCO-Thi-3-yl 1-188
diMeCar MeEtN (CH.sub.2).sub.2 O 4-F-Ph 1-189 diMeCar MeEtN
(CH.sub.2).sub.2 O 4-NO.sub.2-Ph 1-190 diMeCar MeEtN
(CH.sub.2).sub.2 O 4-Cl-Ph 1-191 diMeCar MeEtN (CH.sub.2).sub.2 O
3-F-4-F-Ph 1-192 diMeCar MeHN (CH.sub.2).sub.3 O 4-F-Ph 1-193
diMeCar MeHN (CH.sub.2).sub.3 O 4-Cl-Ph 1-194 diMeCar MeHN
(CH.sub.2).sub.3 O 4-NO.sub.2-Ph 1-195 diMeCar MeHN
(CH.sub.2).sub.2 O 2-F-4-NO.sub.2-Ph 1-196 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-4-NO.sub.2-Ph 1-197 diMeCar MeHN
(CH.sub.2).sub.2 S 2-F-4-NO.sub.2-Ph 1-198 diMeCar diMeN
(CH.sub.2).sub.2 S 2-F-4-NO.sub.2-Ph 1-199 diMeCar MeHN
(CH.sub.2).sub.2 O 4-MeS-Ph 1-200 diMeCar diMeN (CH.sub.2).sub.2 O
4-MeS-Ph 1-201 diMeCar MeHN (CH.sub.2).sub.2 S 4-MeS-Ph 1-202
diMeCar diMeN (CH.sub.2).sub.2 S 4-MeS-Ph 1-203 diMeCar MeHN
(CH.sub.2).sub.2 O pentaFPh 1-204 diMeCar diMeN (CH.sub.2).sub.2 O
pentaFPh 1-205 diMeCar MeHN (CH.sub.2).sub.2 O naphtalene-1-yl
1-206 diMeCar MeHN (CH.sub.2).sub.2 O quinoline-6-yl 1-207 diMeCar
MeHN (CH.sub.2).sub.2 O naphtalene-2-yl
TABLE-US-00002 TABLE 2 (Ib) ##STR00004## Compound No.
R.sup.1--(C.dbd.X.sup.1) R.sup.2R.sup.3N A E Arom 2-1 diMeCar MeNH
(CH.sub.2).sub.2 -- 4-F-Ph 2-2 EtCar MeNH (CH.sub.2).sub.2 O 4-F-Ph
2-3 EtCar MeNH (CH.sub.2).sub.2 -- 4-MeO-Ph 2-4 Ac MeNH
(CH.sub.2).sub.2 O 4-F-Ph 2-5 tBu-(C.dbd.O) MeNH (CH.sub.2).sub.2 O
4-F-Ph 2-6 diEtCar MeNH (CH.sub.2).sub.2 O 4-F-Ph 2-7 diEtCar MeNH
(CH.sub.2).sub.2 -- 4-Cl-Ph 2-8 diEtCar MeNH (CH.sub.2).sub.2 --
3-Cl-Ph 2-9 diPrCar MeNH (CH.sub.2).sub.2 O 4-F-Ph 2-10 MeEtCar
MeNH (CH.sub.2).sub.2 -- 4-Cl-Ph 2-11 Mor-(C.dbd.O) MeNH
(CH.sub.2).sub.2 O 4-F-Ph 2-12 diMeTcr MeNH (CH.sub.2).sub.2 O
4-F-Ph 2-13 diMeCar MeNH (CH.sub.2).sub.2 -- 4-Cl-Ph 2-14 diMeCar
MeNH (CH.sub.2).sub.2 -- 4-CF.sub.3-Ph 2-15 diMeCar MeNH
(CH.sub.2).sub.2 -- 4-MeO-Ph 2-16 diMeCar diMeN (CH.sub.2).sub.2 --
4-MeO-Ph 2-17 diMeCar MeNH (CH.sub.2).sub.2 -- 3-MeO-4-MeO-Ph 2-18
diMeCar MeNH (CH.sub.2).sub.2 -- 3,4-Mtdo-Ph 2-19 diMeCar MeNH
(CH.sub.2).sub.2 -- 4-NO.sub.2-Ph 2-20 diMeCar MeNH
(CH.sub.2).sub.2 -- 3-F-4-F-Ph 2-21 diMeCar diMeN (CH.sub.2).sub.2
-- 4-F-Ph 2-22 diMeCar diMeN (CH.sub.2).sub.2 -- 4-Cl-Ph 2-23
diMeCar diMeN (CH.sub.2).sub.2 -- 4-NO.sub.2-Ph 2-24 diMeCar diMeN
(CH.sub.2).sub.2 -- 3-F-4-F-Ph 2-25 diMeCar MeNH (CH.sub.2).sub.3
-- 4-F-Ph 2-26 diMeCar MeNH (CH.sub.2).sub.3 -- 4-Cl-Ph 2-27
diMeCar MeNH (CH.sub.2).sub.3 -- 4-NO.sub.2-Ph 2-28 diMeCar MeNH
(CH.sub.2).sub.3 -- 3-F-4-F-Ph 2-29 diMeCar diMeN (CH.sub.2).sub.3
-- 4-F-Ph 2-30 diMeCar diMeN (CH.sub.2).sub.3 -- 4-Cl-Ph 2-31
diMeCar diMeN (CH.sub.2).sub.3 -- 4-NO.sub.2-Ph 2-32 diMeCar diMeN
(CH.sub.2).sub.3 -- 3-F-4-F-Ph 2-33 diMeCar MeNH CH.sub.2 O 4-F-Ph
2-34 diMeCar MeNH CH.sub.2 O 4-Cl-Ph 2-35 diMeCar MeNH CH.sub.2 O
4-NO.sub.2-Ph 2-36 diMeCar MeNH CH.sub.2 O 3-F-4-F-Ph 2-37 diMeCar
diMeN CH.sub.2 O 4-F-Ph 2-38 diMeCar diMeN CH.sub.2 O 4-Cl-Ph 2-39
diMeCar diMeN CH.sub.2 O 4-NO.sub.2-Ph 2-40 diMeCar diMeN CH.sub.2
O 3-F-4-F-Ph 2-41 diMeCar MeNH (CH.sub.2).sub.2 S 4-F-Ph 2-42
diMeCar MeNH (CH.sub.2).sub.2 S 4-Cl-Ph 2-43 diMeCar MeNH
(CH.sub.2).sub.2 S 4-NO.sub.2-Ph 2-44 diMeCar MeNH (CH.sub.2).sub.2
S 3-F-4-F-Ph 2-45 diMeCar diMeN (CH.sub.2).sub.2 S 4-F-Ph 2-46
diMeCar diMeN (CH.sub.2).sub.2 S 4-Cl-Ph 2-47 diMeCar diMeN
(CH.sub.2).sub.2 S 4-NO.sub.2-Ph 2-48 diMeCar diMeN
(CH.sub.2).sub.2 S 3-F-4-F-Ph 2-49 diMeCar MeNH (CH.sub.2).sub.2 NH
4-F-Ph 2-50 diMeCar MeNH (CH.sub.2).sub.2 NH 4-Cl-Ph 2-51 diMeCar
MeNH (CH.sub.2).sub.2 NH 3-F-Ph 2-52 diMeCar MeNH (CH.sub.2).sub.2
NH 3-Cl-Ph 2-53 diMeCar MeNH (CH.sub.2).sub.2 NH 4-NO.sub.2-Ph 2-54
diMeCar MeNH (CH.sub.2).sub.2 NH 3-F-4-F-Ph 2-55 diMeCar diMeN
(CH.sub.2).sub.2 NH 4-F-Ph 2-56 diMeCar diMeN (CH.sub.2).sub.2 NH
4-Cl-Ph 2-57 diMeCar diMeN (CH.sub.2).sub.2 NH 4-NO.sub.2-Ph 2-58
diMeCar diMeN (CH.sub.2).sub.2 NH 3-F-4-F-Ph 2-59 diMeCar MeNH
(CH.sub.2).sub.2 NAc 4-Cl-Ph 2-60 diMeCar MeNH (CH.sub.2).sub.2 NAc
3-F-Ph 2-61 diMeCar MeNH (CH.sub.2).sub.2 NAc 4-NO.sub.2-Ph 2-62
diMeCar diMeN (CH.sub.2).sub.2 NAc 4-Cl-Ph 2-63 diMeCar diMeN
(CH.sub.2).sub.2 NAc 3-F-Ph 2-64 diMeCar diMeN (CH.sub.2).sub.2 NAc
4-NO.sub.2-Ph 2-65 diMeCar NH.sub.2 (CH.sub.2).sub.2 O 4-F-Ph 2-66
diMeCar NH.sub.2 (CH.sub.2).sub.2 O 4-NO.sub.2-Ph 2-67 diMeCar EtNH
(CH.sub.2).sub.2 O 4-F-Ph 2-68 diMeCar EtNH (CH.sub.2).sub.2 O
3-F-Ph 2-69 diMeCar EtNH (CH.sub.2).sub.2 O 4-Cl-Ph 2-70 diMeCar
EtNH (CH.sub.2).sub.2 O 3-NO.sub.2-Ph 2-71 diMeCar EtNH
(CH.sub.2).sub.2 O 4-NO.sub.2-Ph 2-72 diMeCar EtNH (CH.sub.2).sub.2
O 3-F-4-F-Ph 2-73 diMeCar PrNH (CH.sub.2).sub.2 O 4-F-Ph 2-74
diMeCar MeNH (CH.sub.2).sub.2 O Ph 2-75 diMeCar MeNH
(CH.sub.2).sub.2 O 4-F-Ph 2-76 diMeCar MeNH (CH.sub.2).sub.2 O
3-F-Ph 2-77 diMeCar MeNH (CH.sub.2).sub.2 O 2-F-Ph 2-78 diMeCar
MeNH (CH.sub.2).sub.2 O 4-Cl-Ph 2-79 diMeCar MeNH (CH.sub.2).sub.2
O 3-Cl-Ph 2-80 diMeCar MeNH (CH.sub.2).sub.2 O 2-Cl-Ph 2-81 diMeCar
MeNH (CH.sub.2).sub.2 O 4-Br-Ph 2-82 diMeCar MeNH (CH.sub.2).sub.2
O 4-Me-Ph 2-83 diMeCar MeNH (CH.sub.2).sub.2 O 3-Me-Ph 2-84 diMeCar
MeNH (CH.sub.2).sub.2 O 2-Me-Ph 2-85 diMeCar MeNH (CH.sub.2).sub.2
O 4-CF.sub.3-Ph 2-86 diMeCar MeNH (CH.sub.2).sub.2 O 4-MeO-Ph 2-87
diMeCar MeNH (CH.sub.2).sub.2 O 3-MeO-Ph 2-88 diMeCar MeNH
(CH.sub.2).sub.2 O 2-MeO-Ph 2-89 diMeCar MeNH (CH.sub.2).sub.2 O
4-Ac-Ph 2-90 diMeCar MeNH (CH.sub.2).sub.2 O 3-Ac-Ph 2-91 diMeCar
MeNH (CH.sub.2).sub.2 O 4-CN-Ph 2-92 diMeCar MeNH (CH.sub.2).sub.2
O 4-NO.sub.2-Ph 2-93 diMeCar MeNH (CH.sub.2).sub.2 O 2-NO.sub.2-Ph
2-94 diMeCar MeNH (CH.sub.2).sub.2 O 3-NO.sub.2-Ph 2-95 diMeCar
MeNH (CH.sub.2).sub.2 O 4-NH.sub.2-Ph 2-96 diMeCar MeNH
(CH.sub.2).sub.2 O 3-NH.sub.2-Ph 2-97 diMeCar MeNH (CH.sub.2).sub.2
O 4-AcNH-Ph 2-98 diMeCar MeNH (CH.sub.2).sub.2 O 3-AcNH-Ph 2-99
diMeCar MeNH (CH.sub.2).sub.2 O 4-COOH-Ph 2-100 diMeCar MeNH
(CH.sub.2).sub.2 O 3,4-Mtdo-Ph 2-101 diMeCar MeNH (CH.sub.2).sub.2
O 2-F-4-F-Ph 2-102 diMeCar MeNH (CH.sub.2).sub.2 O 3-F-4-F-Ph 2-103
diMeCar MeNH (CH.sub.2).sub.2 O 3-F-5-F-Ph 2-104 diMeCar MeNH
(CH.sub.2).sub.2 O 3-F-4-Cl-Ph 2-105 diMeCar MeNH (CH.sub.2).sub.2
O 2-F-4-NO.sub.2-Ph 2-106 diMeCar MeNH (CH.sub.2).sub.2 O
2-Cl-4-F-Ph 2-107 diMeCar MeNH (CH.sub.2).sub.2 O 2-Cl-4-Cl-Ph
2-108 diMeCar MeNH (CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2-Ph 2-109
diMeCar MeNH (CH.sub.2).sub.2 O 3-Cl-4-F-Ph 2-110 diMeCar MeNH
(CH.sub.2).sub.2 O 3-Cl-4-Cl-Ph 2-111 diMeCar MeNH (CH.sub.2).sub.2
O 2-Me-4-F-Ph 2-112 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me-4-Cl-Ph
2-113 diMeCar MeNH (CH.sub.2).sub.2 O 3-Me-4-Cl-Ph 2-114 diMeCar
MeNH (CH.sub.2).sub.2 O 3-Me-4-Me-Ph 2-115 diMeCar MeNH
(CH.sub.2).sub.2 O 3-Me-4-NO.sub.2-Ph 2-116 diMeCar MeNH
(CH.sub.2).sub.2 O 3-NO.sub.2-4-Cl-Ph 2-117 diMeCar MeNH
(CH.sub.2).sub.2 O 3-F-4-F-5-F-Ph 2-118 diMeCar MeNH
(CH.sub.2).sub.2 O 2-F-3-F-5-F-Ph 2-119 diMeCar MeNH
(CH.sub.2).sub.2 O Py-3-yl 2-120 diMeCar MeNH (CH.sub.2).sub.2 O
5-Cl-Py-3-yl 2-121 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me-Py-3-yl
2-122 diMeCar MeNH (CH.sub.2).sub.2 O 6-Me-Py-3-yl 2-123 diMeCar
MeNH (CH.sub.2).sub.2 O Py-2-yl 2-124 diMeCar MeNH (CH.sub.2).sub.2
O 6-Cl-Py-2-yl 2-125 diMeCar MeNH (CH.sub.2).sub.2 O
6-CF.sub.3-Py-2-yl 2-126 diMeCar MeNH (CH.sub.2).sub.2 O
6-NO.sub.2-Py-2-yl 2-127 diMeCar MeNH (CH.sub.2).sub.2 O Py-4-yl
2-128 diMeCar MeNH (CH.sub.2).sub.2 O 2-NO.sub.2Py-4-yl 2-129
diMeCar MeNH (CH.sub.2).sub.2 O Thi-3-yl 2-130 diMeCar MeNH
(CH.sub.2).sub.2 O 2-MeOCO-Thi-3-yl 2-131 diMeCar diMeN
(CH.sub.2).sub.2 O Ph 2-132 diMeCar diMeN (CH.sub.2).sub.2 O 4-F-Ph
2-133 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-Ph 2-134 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-Ph 2-135 diMeCar diMeN (CH.sub.2).sub.2 O
4-Cl-Ph 2-136 diMeCar diMeN (CH.sub.2).sub.2 O 3-Cl-Ph 2-137
diMeCar diMeN (CH.sub.2).sub.2 O 2-Cl-Ph 2-138 diMeCar diMeN
(CH.sub.2).sub.2 O 4-Br-Ph 2-139 diMeCar diMeN (CH.sub.2).sub.2 O
4-Me-Ph 2-140 diMeCar diMeN (CH.sub.2).sub.2 O 3-Me-Ph 2-141
diMeCar diMeN (CH.sub.2).sub.2 O 2-Me-Ph 2-142 diMeCar diMeN
(CH.sub.2).sub.2 O 4-CF.sub.3-Ph 2-143 diMeCar diMeN
(CH.sub.2).sub.2 O 4-MeO-Ph 2-144 diMeCar diMeN (CH.sub.2).sub.2 O
3-MeO-Ph 2-145 diMeCar diMeN (CH.sub.2).sub.2 O 2-MeO-Ph 2-146
diMeCar diMeN (CH.sub.2).sub.2 O 4-Ac-Ph 2-147 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Ac-Ph 2-148 diMeCar diMeN (CH.sub.2).sub.2 O
4-CN-Ph 2-149 diMeCar diMeN (CH.sub.2).sub.2 O 4-NO.sub.2-Ph 2-150
diMeCar diMeN (CH.sub.2).sub.2 O 2-NO.sub.2-Ph 2-151 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NO.sub.2-Ph 2-152 diMeCar diMeN
(CH.sub.2).sub.2 O 4-NH.sub.2-Ph 2-153 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NH.sub.2-Ph 2-154 diMeCar diMeN
(CH.sub.2).sub.2 O 4-AcNH-Ph 2-155 diMeCar diMeN (CH.sub.2).sub.2 O
3-AcNH-Ph 2-156 diMeCar diMeN (CH.sub.2).sub.2 O 4-COOH-Ph 2-157
diMeCar diMeN (CH.sub.2).sub.2 O 3,4-Mtdo-Ph 2-158 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-4-F-Ph 2-159 diMeCar diMeN (CH.sub.2).sub.2
O 3-F-4-F-Ph 2-160 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-5-F-Ph
2-161 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-4-Cl-Ph 2-162 diMeCar
diMeN (CH.sub.2).sub.2 O 2-F-4-NO.sub.2-Ph 2-163 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Cl-4-F-Ph 2-164 diMeCar diMeN (CH.sub.2).sub.2
O 2-Cl-4-Cl-Ph 2-165 diMeCar diMeN (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2-Ph 2-166 diMeCar diMeN (CH.sub.2).sub.2 O
3-Cl-4-F-Ph 2-167 diMeCar diMeN (CH.sub.2).sub.2 O 3-Cl-4-Cl-Ph
2-168 diMeCar diMeN (CH.sub.2).sub.2 O 2-Me-4-F-Ph 2-169 diMeCar
diMeN (CH.sub.2).sub.2 O 2-Me-4-Cl-Ph 2-170 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-Cl-Ph 2-171 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-Me-Ph 2-172 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-NO.sub.2-Ph 2-173 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NO.sub.2-4-Cl-Ph 2-174 diMeCar diMeN
(CH.sub.2).sub.2 O 3-F-4-F-5-F-Ph 2-175 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-3-F-5-F-Ph 2-176 diMeCar diMeN
(CH.sub.2).sub.2 O Py-3-yl 2-177 diMeCar diMeN (CH.sub.2).sub.2 O
5-Cl-Py-3-yl 2-178 diMeCar diMeN (CH.sub.2).sub.2 O 2-Me-Py-3-yl
2-179 diMeCar diMeN (CH.sub.2).sub.2 O 6-Me-Py-3-yl 2-180 diMeCar
diMeN (CH.sub.2).sub.2 O Py-2-yl 2-181 diMeCar diMeN
(CH.sub.2).sub.2 O 6-Cl-Py-2-yl 2-182 diMeCar diMeN
(CH.sub.2).sub.2 O 6-CF.sub.3-Py-2-yl 2-183 diMeCar diMeN
(CH.sub.2).sub.2 O 6-NO.sub.2-Py-2-yl 2-184 diMeCar diMeN
(CH.sub.2).sub.2 O Py-4-yl 2-185 diMeCar diMeN (CH.sub.2).sub.2 O
2-NO.sub.2Py-4-yl 2-186 diMeCar diMeN (CH.sub.2).sub.2 O Thi-3-yl
2-187 diMeCar diMeN (CH.sub.2).sub.2 O 2-MeOCO-Thi-3-yl 2-188
diMeCar MeEtN (CH.sub.2).sub.2 O 4-F-Ph 2-189 diMeCar MeEtN
(CH.sub.2).sub.2 O 4-NO.sub.2-Ph 2-190 diMeCar MeEtN
(CH.sub.2).sub.2 O 4-Cl-Ph 2-191 diMeCar MeEtN (CH.sub.2).sub.2 O
3-F-4-F-Ph 2-192 diMeCar MeHN (CH.sub.2).sub.3 O 4-F-Ph 2-193
diMeCar MeHN (CH.sub.2).sub.3 O 4-Cl-Ph 2-194 diMeCar MeHN
(CH.sub.2).sub.3 O 4-NO.sub.2-Ph 2-195 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-4-NO.sub.2-Ph 2-196 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-4-NO.sub.2-Ph 2-197 diMeCar MeHN
(CH.sub.2).sub.2 S 2-F-4-NO.sub.2-Ph 2-198 diMeCar diMeN
(CH.sub.2).sub.2 S 2-F-4-NO.sub.2-Ph 2-199 diMeCar MeHN
(CH.sub.2).sub.2 O 4-MeS-Ph 2-200 diMeCar diMeN (CH.sub.2).sub.2 O
4-MeS-Ph 2-201 diMeCar MeHN (CH.sub.2).sub.2 S 4-MeS-Ph 2-202
diMeCar diMeN (CH.sub.2).sub.2 S 4-MeS-Ph 2-203 diMeCar MeHN
(CH.sub.2).sub.2 O pentaFPh 2-204 diMeCar diMeN (CH.sub.2).sub.2 O
pentaFPh 2-205 diMeCar MeHN (CH.sub.2).sub.2 O naphtalene-1-yl
2-206 diMeCar MeHN (CH.sub.2).sub.2 O quinoline-6-yl 2-207 diMeCar
MeHN (CH.sub.2).sub.2 O naphtalene-2-yl 2-64 diMeCar diMeN
(CH.sub.2).sub.2 NAc 4-NO.sub.2-Ph 2-65 diMeCar NH.sub.2
(CH.sub.2).sub.2 O 4-F-Ph 2-66 diMeCar NH.sub.2 (CH.sub.2).sub.2 O
4-NO.sub.2-Ph 2-67 diMeCar EtNH (CH.sub.2).sub.2 O 4-F-Ph 2-68
diMeCar EtNH (CH.sub.2).sub.2 O 3-F-Ph 2-69 diMeCar EtNH
(CH.sub.2).sub.2 O 4-Cl-Ph 2-70 diMeCar EtNH (CH.sub.2).sub.2 O
3-NO.sub.2-Ph 2-71 diMeCar EtNH (CH.sub.2).sub.2 O 4-NO.sub.2-Ph
2-72 diMeCar EtNH (CH.sub.2).sub.2 O 3-F-4-F-Ph 2-73 diMeCar PrNH
(CH.sub.2).sub.2 O 4-F-Ph 2-74 diMeCar MeNH (CH.sub.2).sub.2 O Ph
2-75 diMeCar MeNH (CH.sub.2).sub.2 O 4-F-Ph 2-76 diMeCar MeNH
(CH.sub.2).sub.2 O 3-F-Ph 2-77 diMeCar MeNH (CH.sub.2).sub.2 O
2-F-Ph 2-78 diMeCar MeNH (CH.sub.2).sub.2 O 4-Cl-Ph 2-79 diMeCar
MeNH (CH.sub.2).sub.2 O 3-Cl-Ph 2-80 diMeCar MeNH (CH.sub.2).sub.2
O 2-Cl-Ph 2-81 diMeCar MeNH (CH.sub.2).sub.2 O 4-Br-Ph 2-82 diMeCar
MeNH (CH.sub.2).sub.2 O 4-Me-Ph 2-83 diMeCar MeNH (CH.sub.2).sub.2
O 3-Me-Ph 2-84 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me-Ph 2-85 diMeCar
MeNH (CH.sub.2).sub.2 O 4-CF.sub.3-Ph 2-86 diMeCar MeNH
(CH.sub.2).sub.2 O 4-MeO-Ph 2-87 diMeCar MeNH (CH.sub.2).sub.2 O
3-MeO-Ph 2-88 diMeCar MeNH (CH.sub.2).sub.2 O 2-MeO-Ph 2-89 diMeCar
MeNH (CH.sub.2).sub.2 O 4-Ac-Ph 2-90 diMeCar MeNH (CH.sub.2).sub.2
O 3-Ac-Ph 2-91 diMeCar MeNH (CH.sub.2).sub.2 O 4-CN-Ph 2-92 diMeCar
MeNH (CH.sub.2).sub.2 O 4-NO.sub.2-Ph 2-93 diMeCar MeNH
(CH.sub.2).sub.2 O 2-NO.sub.2-Ph 2-94 diMeCar MeNH (CH.sub.2).sub.2
O 3-NO.sub.2-Ph 2-95 diMeCar MeNH (CH.sub.2).sub.2 O 4-NH.sub.2-Ph
2-96 diMeCar MeNH (CH.sub.2).sub.2 O 3-NH.sub.2-Ph 2-97 diMeCar
MeNH (CH.sub.2).sub.2 O 4-AcNH-Ph 2-98 diMeCar MeNH
(CH.sub.2).sub.2 O 3-AcNH-Ph
2-99 diMeCar MeNH (CH.sub.2).sub.2 O 4-COOH-Ph
TABLE-US-00003 TABLE 3 (Ic) ##STR00005## Compound No.
R.sup.1--(C.dbd.X.sup.1) R.sup.2R.sup.3N A E Arom 3-1 diMeCar
NH.sub.2 (CH.sub.2).sub.2 O 4-F--Ph 3-2 diMeCar NH.sub.2
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 3-3 diMeCar EtNH (CH.sub.2).sub.2
O 4-F--Ph 3-4 diMeCar EtNH (CH.sub.2).sub.2 O 3-F--Ph 3-5 diMeCar
EtNH (CH.sub.2).sub.2 O 4-Cl--Ph 3-6 diMeCar EtNH (CH.sub.2).sub.2
O 3-NO.sub.2--Ph 3-7 diMeCar EtNH (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
3-8 diMeCar EtNH (CH.sub.2).sub.2 O 3-F-4-F--Ph 3-9 diMeCar PrNH
(CH.sub.2).sub.2 O 4-F--Ph 3-10 diMeCar MeNH (CH.sub.2).sub.2 O Ph
3-11 diMeCar MeNH (CH.sub.2).sub.2 O 4-F--Ph 3-12 diMeCar MeNH
(CH.sub.2).sub.2 O 3-F--Ph 3-13 diMeCar MeNH (CH.sub.2).sub.2 O
2-F--Ph 3-14 diMeCar MeNH (CH.sub.2).sub.2 O 4-Cl--Ph 3-15 diMeCar
MeNH (CH.sub.2).sub.2 O 3-Cl--Ph 3-16 diMeCar MeNH (CH.sub.2).sub.2
O 2-Cl--Ph 3-17 diMeCar MeNH (CH.sub.2).sub.2 O 4-Br--Ph 3-18
diMeCar MeNH (CH.sub.2).sub.2 O 4-Me--Ph 3-19 diMeCar MeNH
(CH.sub.2).sub.2 O 3-Me--Ph 3-20 diMeCar MeNH (CH.sub.2).sub.2 O
2-Me--Ph 3-21 diMeCar MeNH (CH.sub.2).sub.2 O 4-CF.sub.3--Ph 3-22
diMeCar MeNH (CH.sub.2).sub.2 O 4-MeO--Ph 3-23 diMeCar MeNH
(CH.sub.2).sub.2 O 3-MeO--Ph 3-24 diMeCar MeNH (CH.sub.2).sub.2 O
2-MeO--Ph 3-25 diMeCar MeNH (CH.sub.2).sub.2 O 4-Ac--Ph 3-26
diMeCar MeNH (CH.sub.2).sub.2 O 3-Ac--Ph 3-27 diMeCar MeNH
(CH.sub.2).sub.2 O 4-CN--Ph 3-28 diMeCar MeNH (CH.sub.2).sub.2 O
4-NO.sub.2--Ph 3-29 diMeCar MeNH (CH.sub.2).sub.2 O 2-NO.sub.2--Ph
3-30 diMeCar MeNH (CH.sub.2).sub.2 O 3-NO.sub.2--Ph 3-31 diMeCar
MeNH (CH.sub.2).sub.2 O 4-NH.sub.2--Ph 3-32 diMeCar MeNH
(CH.sub.2).sub.2 O 3-NH.sub.2--Ph 3-33 diMeCar MeNH
(CH.sub.2).sub.2 O 4-AcNH--Ph 3-34 diMeCar MeNH (CH.sub.2).sub.2 O
3-AcNH--Ph 3-35 diMeCar MeNH (CH.sub.2).sub.2 O 4-COOH--Ph 3-36
diMeCar MeNH (CH.sub.2).sub.2 O 3,4-Mtdo-Ph 3-37 diMeCar MeNH
(CH.sub.2).sub.2 O 2-F-4-F--Ph 3-38 diMeCar MeNH (CH.sub.2).sub.2 O
3-F-4-F--Ph 3-39 diMeCar MeNH (CH.sub.2).sub.2 O 3-F-5-F--Ph 3-40
diMeCar MeNH (CH.sub.2).sub.2 O 3-F-4-Cl--Ph 3-41 diMeCar MeNH
(CH.sub.2).sub.2 O 2-F-4-NO.sub.2--Ph 3-42 diMeCar MeNH
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 3-43 diMeCar MeNH (CH.sub.2).sub.2
O 2-Cl-4-Cl--Ph 3-44 diMeCar MeNH (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 3-45 diMeCar MeNH (CH.sub.2).sub.2 O
3-Cl-4-F--Ph 3-46 diMeCar MeNH (CH.sub.2).sub.2 O 3-Cl-4-Cl--Ph
3-47 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me-4-F--Ph 3-48 diMeCar MeNH
(CH.sub.2).sub.2 O 2-Me-4-Cl--Ph 3-49 diMeCar MeNH (CH.sub.2).sub.2
O 3-Me-4-Cl--Ph 3-50 diMeCar MeNH (CH.sub.2).sub.2 O 3-Me-4-Me--Ph
3-51 diMeCar MeNH (CH.sub.2).sub.2 O 3-Me-4-NO.sub.2--Ph 3-52
diMeCar MeNH (CH.sub.2).sub.2 O 3-NO.sub.2-4-Cl--Ph 3-53 diMeCar
MeNH (CH.sub.2).sub.2 O 3-F-4-F-5-F--Ph 3-54 diMeCar MeNH
(CH.sub.2).sub.2 O 2-F-3-F-5-F--Ph 3-55 diMeCar MeNH
(CH.sub.2).sub.2 O Py-3-yl 3-56 diMeCar MeNH (CH.sub.2).sub.2 O
5-Cl--Py-3-yl 3-57 diMeCar MeNH (CH.sub.2).sub.2 O 2-Me--Py-3-yl
3-58 diMeCar MeNH (CH.sub.2).sub.2 O 6-Me--Py-3-yl 3-59 diMeCar
MeNH (CH.sub.2).sub.2 O Py-2-yl 3-60 diMeCar MeNH (CH.sub.2).sub.2
O 6-Cl--Py-2-yl 3-61 diMeCar MeNH (CH.sub.2).sub.2 O
6-CF.sub.3--Py-2-yl 3-62 diMeCar MeNH (CH.sub.2).sub.2 O
6-NO.sub.2--Py-2-yl 3-63 diMeCar MeNH (CH.sub.2).sub.2 O Py-4-yl
3-64 diMeCar MeNH (CH.sub.2).sub.2 O 2-NO.sub.2--Py-4-yl 3-65
diMeCar MeNH (CH.sub.2).sub.2 O Thi-3-yl 3-66 diMeCar MeNH
(CH.sub.2).sub.2 O 2-MeOCO-Thi-3-yl 3-67 diMeCar diMeN
(CH.sub.2).sub.2 O Ph 3-68 diMeCar diMeN (CH.sub.2).sub.2 O 4-F--Ph
3-69 diMeCar diMeN (CH.sub.2).sub.2 O 3-F--Ph 3-70 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F--Ph 3-71 diMeCar diMeN (CH.sub.2).sub.2 O
4-Cl--Ph 3-72 diMeCar diMeN (CH.sub.2).sub.2 O 3-Cl--Ph 3-73
diMeCar diMeN (CH.sub.2).sub.2 O 2-Cl--Ph 3-74 diMeCar diMeN
(CH.sub.2).sub.2 O 4-Br--Ph 3-75 diMeCar diMeN (CH.sub.2).sub.2 O
4-Me--Ph 3-76 diMeCar diMeN (CH.sub.2).sub.2 O 3-Me--Ph 3-77
diMeCar diMeN (CH.sub.2).sub.2 O 2-Me--Ph 3-78 diMeCar diMeN
(CH.sub.2).sub.2 O 4-CF.sub.3--Ph 3-79 diMeCar diMeN
(CH.sub.2).sub.2 O 4-MeO--Ph 3-80 diMeCar diMeN (CH.sub.2).sub.2 O
3-MeO--Ph 3-81 diMeCar diMeN (CH.sub.2).sub.2 O 2-MeO--Ph 3-82
diMeCar diMeN (CH.sub.2).sub.2 O 4-Ac--Ph 3-83 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Ac--Ph 3-84 diMeCar diMeN (CH.sub.2).sub.2 O
4-CN--Ph 3-85 diMeCar diMeN (CH.sub.2).sub.2 O 4-NO.sub.2--Ph 3-86
diMeCar diMeN (CH.sub.2).sub.2 O 2-NO.sub.2--Ph 3-87 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NO.sub.2--Ph 3-88 diMeCar diMeN
(CH.sub.2).sub.2 O 4-NH.sub.2--Ph 3-89 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NH.sub.2--Ph 3-90 diMeCar diMeN
(CH.sub.2).sub.2 O 4-AcNH--Ph 3-91 diMeCar diMeN (CH.sub.2).sub.2 O
3-AcNH--Ph 3-92 diMeCar diMeN (CH.sub.2).sub.2 O 4-COOH--Ph 3-93
diMeCar diMeN (CH.sub.2).sub.2 O 3,4-Mtdo-Ph 3-94 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-4-F--Ph 3-95 diMeCar diMeN (CH.sub.2).sub.2
O 3-F-4-F--Ph 3-96 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-5-F--Ph
3-97 diMeCar diMeN (CH.sub.2).sub.2 O 3-F-4-Cl--Ph 3-98 diMeCar
diMeN (CH.sub.2).sub.2 O 2-F-4-NO.sub.2--Ph 3-99 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 3-100 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Cl-4-Cl--Ph 3-101 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 3-102 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Cl-4-F--Ph 3-103 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Cl-4-Cl--Ph 3-104 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Me-4-F--Ph 3-105 diMeCar diMeN
(CH.sub.2).sub.2 O 2-Me-4-Cl--Ph 3-106 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 3-107 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-Me--Ph 3-108 diMeCar diMeN
(CH.sub.2).sub.2 O 3-Me-4-NO.sub.2--Ph 3-109 diMeCar diMeN
(CH.sub.2).sub.2 O 3-NO.sub.2-4-Cl--Ph 3-110 diMeCar diMeN
(CH.sub.2).sub.2 O 3-F-4-F-5-F--Ph 3-111 diMeCar diMeN
(CH.sub.2).sub.2 O 2-F-3-F-5-F--Ph 3-112 diMeCar diMeN
(CH.sub.2).sub.2 O Py-3-yl 3-113 diMeCar diMeN (CH.sub.2).sub.2 O
5-Cl--Py-3-yl 3-114 diMeCar diMeN (CH.sub.2).sub.2 O 2-Me--Py-3-yl
3-115 diMeCar diMeN (CH.sub.2).sub.2 O 6-Me--Py-3-yl 3-116 diMeCar
diMeN (CH.sub.2).sub.2 O Py-2-yl 3-117 diMeCar diMeN
(CH.sub.2).sub.2 O 6-Cl--Py-2-yl 3-118 diMeCar diMeN
(CH.sub.2).sub.2 O 6-CF.sub.3--Py-2-yl 3-119 diMeCar diMeN
(CH.sub.2).sub.2 O 6-NO.sub.2--Py-2-yl 3-120 diMeCar diMeN
(CH.sub.2).sub.2 O Py-4-yl 3-121 diMeCar diMeN (CH.sub.2).sub.2 O
2-NO.sub.2--Py-4-yl 3-122 diMeCar diMeN (CH.sub.2).sub.2 O Thi-3-yl
3-123 diMeCar diMeN (CH.sub.2).sub.2 O 2-MeOCO-Thi-3-yl
TABLE-US-00004 TABLE 4 (Id) ##STR00006## Compound No. R.sup.a
R.sup.2 R.sup.3 A E Arom 4-1 .alpha.-Me H Me (CH.sub.2).sub.2 O
4-F-Ph 4-2 .alpha.-Me H Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph 4-3
.alpha.-Me H Me (CH.sub.2).sub.2 O 4-Cl--Ph 4-4 .alpha.-Me H Me
(CH.sub.2).sub.2 O 3-F--Ph 4-5 .alpha.-Me H Me (CH.sub.2).sub.2 O
3-Cl--Ph 4-6 .alpha.-Me H Me (CH.sub.2).sub.2 O 4-SMe--Ph 4-7
.alpha.-Me H Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-8 .alpha.-Me H
Me (CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-9 .alpha.-Me H Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-10 .alpha.-Me H Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-11 .beta.-Me H Me
(CH.sub.2).sub.2 O 4-F--Ph 4-12 .beta.-Me H Me (CH.sub.2).sub.2 O
4-NO.sub.2--Ph 4-13 .beta.-Me H Me (CH.sub.2).sub.2 O 4-Cl--Ph 4-14
.beta.-Me H Me (CH.sub.2).sub.2 O 3-F--Ph 4-15 .beta.-Me H Me
(CH.sub.2).sub.2 O 3-Cl--Ph 4-16 .beta.-Me H Me (CH.sub.2).sub.2 O
4-SMe--Ph 4-17 .beta.-Me H Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-18
.beta.-Me H Me (CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-19
.beta.-Me H Me (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-20 .beta.-Me H Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-21 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-F--Ph 4-22 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 4-23 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-Cl--Ph 4-24 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-F--Ph 4-25 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 4-26 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 4-27 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-28 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-29 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-30 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-31 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-F--Ph 4-32 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 4-33 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-Cl--Ph 4-34 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-F--Ph 4-35 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-Cl--Ph 4-36 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-SMe--Ph 4-37 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-38 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-39 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-40 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-41 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-F--Ph 4-42 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 4-43 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-Cl--Ph 4-44 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 3-F--Ph 4-45 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 4-46 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 4-47 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-48 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-49
.alpha.-(CH.sub.2).sub.2-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-50
.alpha.-(CH.sub.2).sub.2-- H (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-51
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-F--Ph 4-52
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
4-53 .alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-Cl--Ph 4-54
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 3-F--Ph 4-55
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 3-Cl--Ph 4-56
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-SMe--Ph 4-57
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-58
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 4-59 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-60 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-61 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-F--Ph 4-62 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-NO.sub.2--Ph 4-63 .alpha.-(CH.sub.2).sub.2--
Me (CH.sub.2).sub.2 S 4-Cl--Ph 4-64 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 3-F--Ph 4-65 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 3-Cl--Ph 4-66 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-SMe--Ph 4-67 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-3-Me--Ph 4-68 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 4-69
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph 4-70
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 S 3-Me-4-Cl--Ph 4-71
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-F--Ph 4-72
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-NO.sub.2--Ph
4-73 .alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-Cl--Ph 4-74
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 3-F--Ph 4-75
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 3-Cl--Ph 4-76
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-SMe--Ph 4-77
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 2-Cl-3-Me--Ph 4-78
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O
2-Cl-4-NO.sub.2--Ph 4-79 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 4-80 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 4-81 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-F--Ph 4-82 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 4-83 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-Cl--Ph 4-84 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 3-F--Ph 4-85 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 4-86 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 4-87 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-88 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-89
.alpha.-(CH.sub.2).sub.3-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-90
.alpha.-(CH.sub.2).sub.3-- H (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-91
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-F--Ph 4-92
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
4-93 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-Cl--Ph 4-94
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 3-F--Ph 4-95
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 3-Cl--Ph 4-96
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-SMe--Ph 4-97
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 4-98
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 4-99 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-100 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-101 .alpha.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 4-F--Ph 4-102 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 4-NO.sub.2--Ph 4-103 .alpha.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 4-Cl--Ph 4-104 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 3-F--Ph 4-105 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 3-Cl--Ph 4-106 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 4-SMe--Ph 4-107 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 2-Cl-3-Me--Ph 4-108 .alpha.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 4-109
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph 4-110
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 S 3-Me-4-Cl--Ph
4-111 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O 4-F--Ph
4-112 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
4-NO.sub.2--Ph 4-113 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3
O 4-Cl--Ph 4-114 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
3-F--Ph 4-115 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
3-Cl--Ph 4-116 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
4-SMe--Ph 4-117 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
2-Cl-3-Me--Ph 4-118 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3
O 2-Cl-4-NO.sub.2--Ph 4-119 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 4-120 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 4-121
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-F--Ph 4-122
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
4-123 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-Cl--Ph
4-124 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 3-F--Ph
4-125 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 3-Cl--Ph
4-126 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-SMe--Ph
4-127 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O
2-Cl-3-Me--Ph 4-128 .alpha.-CH.dbd.CH--CH.sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 4-129
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph
4-130 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O
3-Me-4-Cl--Ph 4-131 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 4-F--Ph 4-132 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 4-133
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 4-Cl--Ph 4-134
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 3-F--Ph 4-135
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 3-Cl--Ph 4-136
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 4-SMe--Ph 4-137
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph
4-138 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 4-139 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 4-140 .alpha.-CH.dbd.CH--CH.sub.2--
Me (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 4-141
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-F--Ph 4-142
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-NO.sub.2--Ph
4-143 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-Cl--Ph
4-144 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 3-F--Ph
4-145 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 3-Cl--Ph
4-146 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-SMe--Ph
4-147 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S
2-Cl-3-Me--Ph 4-148 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 4-149
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph
4-150 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S
3-Me-4-Cl--Ph 4-151 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 4-F--Ph 4-152 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 4-NO.sub.2--Ph 4-153
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 4-Cl--Ph 4-154
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 3-F--Ph 4-155
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 3-Cl--Ph 4-156
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 4-SMe--Ph 4-157
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 2-Cl-3-Me--Ph
4-158 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O
2-Cl-4-NO.sub.2--Ph 4-159 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 4-160 .alpha.-CH.dbd.CH--CH.sub.2--
Me (CH.sub.2).sub.3 O 3-Me-4-Cl--Ph
TABLE-US-00005 TABLE 5 (Ie) ##STR00007## Compound No. R.sup.a
R.sup.2 R.sup.3 A E Arom 5-1 .alpha.-Me H Me (CH.sub.2).sub.2 O
4-F-Ph 5-2 .alpha.-Me H Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-3
.alpha.-Me H Me (CH.sub.2).sub.2 O 4-Cl--Ph 5-4 .alpha.-Me H Me
(CH.sub.2).sub.2 O 3-F--Ph 5-5 .alpha.-Me H Me (CH.sub.2).sub.2 O
3-Cl--Ph 5-6 .alpha.-Me H Me (CH.sub.2).sub.2 O 4-SMe--Ph 5-7
.alpha.-Me H Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-8 .alpha.-Me H
Me (CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-9 .alpha.-Me H Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-10 .alpha.-Me H Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-11 .beta.-Me H Me
(CH.sub.2).sub.2 O 4-F--Ph 5-12 .beta.-Me H Me (CH.sub.2).sub.2 O
4-NO.sub.2--Ph 5-13 .beta.-Me H Me (CH.sub.2).sub.2 O 4-Cl--Ph 5-14
.beta.-Me H Me (CH.sub.2).sub.2 O 3-F--Ph 5-15 .beta.-Me H Me
(CH.sub.2).sub.2 O 3-Cl--Ph 5-16 .beta.-Me H Me (CH.sub.2).sub.2 O
4-SMe--Ph 5-17 .beta.-Me H Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-18
.beta.-Me H Me (CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-19
.beta.-Me H Me (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-20 .beta.-Me H Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-21 .gamma.-Me H Me
(CH.sub.2).sub.2 O 4-F--Ph 5-22 .gamma.-Me H Me (CH.sub.2).sub.2 O
4-NO.sub.2--Ph 5-23 .gamma.-Me H Me (CH.sub.2).sub.2 O 4-Cl--Ph
5-24 .gamma.-Me H Me (CH.sub.2).sub.2 O 3-F--Ph 5-25 .gamma.-Me H
Me (CH.sub.2).sub.2 O 3-Cl--Ph 5-26 .gamma.-Me H Me
(CH.sub.2).sub.2 O 4-SMe--Ph 5-27 .gamma.-Me H Me (CH.sub.2).sub.2
O 2-Cl-3-Me--Ph 5-28 .gamma.-Me H Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 5-29 .gamma.-Me H Me (CH.sub.2).sub.2 O
2-Cl-4-F--Ph 5-30 .gamma.-Me H Me (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph
5-31 .delta.-Me H Me (CH.sub.2).sub.2 O 4-F--Ph 5-32 .delta.-Me H
Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-33 .delta.-Me H Me
(CH.sub.2).sub.2 O 4-Cl--Ph 5-34 .delta.-Me H Me (CH.sub.2).sub.2 O
3-F--Ph 5-35 .delta.-Me H Me (CH.sub.2).sub.2 O 3-Cl--Ph 5-36
.delta.-Me H Me (CH.sub.2).sub.2 O 4-SMe--Ph 5-37 .delta.-Me H Me
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-38 .delta.-Me H Me
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-39 .delta.-Me H Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-40 .delta.-Me H Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-41 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-F--Ph 5-42 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-43 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-Cl--Ph 5-44 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-F--Ph 5-45 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 5-46 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 5-47 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-48 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-49 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-50 .alpha.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-51 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-F--Ph 5-52 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-53 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-Cl--Ph 5-54 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-F--Ph 5-55 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-Cl--Ph 5-56 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-SMe--Ph 5-57 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-58 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-59 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-60 .alpha.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-61 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-F--Ph 5-62 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-63 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-Cl--Ph 5-64 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 3-F--Ph 5-65 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 5-66 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 5-67 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-68 .alpha.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-69
.alpha.-(CH.sub.2).sub.2-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-70
.alpha.-(CH.sub.2).sub.2-- H (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-71
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-F--Ph 5-72
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
5-73 .alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-Cl--Ph 5-74
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 3-F--Ph 5-75
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 3-Cl--Ph 5-76
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-SMe--Ph 5-77
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-78
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 5-79 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-80 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-81 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-F--Ph 5-82 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-NO.sub.2--Ph 5-83 .alpha.-(CH.sub.2).sub.2--
Me (CH.sub.2).sub.2 S 4-Cl--Ph 5-84 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 3-F--Ph 5-85 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 3-Cl--Ph 5-86 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-SMe--Ph 5-87 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-3-Me--Ph 5-88 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 5-89
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph 5-90
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 S 3-Me-4-Cl--Ph 5-91
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-F--Ph 5-92
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-NO.sub.2--Ph
5-93 .alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-Cl--Ph 5-94
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 3-F--Ph 5-95
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 3-Cl--Ph 5-96
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-SMe--Ph 5-97
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 2-Cl-3-Me--Ph 5-98
.alpha.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O
2-Cl-4-NO.sub.2--Ph 5-99 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 5-100 .alpha.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 5-101 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-F--Ph 5-102 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-103 .alpha.-(CH.sub.2).sub.3--
H (CH.sub.2).sub.2 O 4-Cl--Ph 5-104 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 3-F--Ph 5-105 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 5-106 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 5-107 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-108 .alpha.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-109
.alpha.-(CH.sub.2).sub.3-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-110
.alpha.-(CH.sub.2).sub.3-- H (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-111
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-F--Ph 5-112
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
5-113 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-Cl--Ph
5-114 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 3-F--Ph
5-115 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 3-Cl--Ph
5-116 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-SMe--Ph
5-117 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O
2-Cl-3-Me--Ph 5-118 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2
O 2-Cl-4-NO.sub.2--Ph 5-119 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-120 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-121 .alpha.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 4-F--Ph 5-122 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 4-NO.sub.2--Ph 5-123 .alpha.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 4-Cl--Ph 5-124 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 3-F--Ph 5-125 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 3-Cl--Ph 5-126 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 4-SMe--Ph 5-127 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 2-Cl-3-Me--Ph 5-128 .alpha.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 5-129
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph 5-130
.alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 S 3-Me-4-Cl--Ph
5-131 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O 4-F--Ph
5-132 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
4-NO.sub.2--Ph 5-133 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3
O 4-Cl--Ph 5-134 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
3-F--Ph 5-135 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
3-Cl--Ph 5-136 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
4-SMe--Ph 5-137 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
2-Cl-3-Me--Ph 5-138 .alpha.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3
O 2-Cl-4-NO.sub.2--Ph 5-139 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 5-140 .alpha.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 5-141
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-F--Ph 5-142
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
5-143 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-Cl--Ph
5-144 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 3-F--Ph
5-145 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 3-Cl--Ph
5-146 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-SMe--Ph
5-147 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O
2-Cl-3-Me--Ph 5-148 .alpha.-CH.dbd.CH--CH.sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-149
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph
5-150 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O
3-Me-4-Cl--Ph 5-151 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 4-F--Ph 5-152 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-153
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 4-Cl--Ph 5-154
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 3-F--Ph 5-155
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 3-Cl--Ph 5-156
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 4-SMe--Ph 5-157
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph
5-158 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 5-159 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-160 .alpha.-CH.dbd.CH--CH.sub.2--
Me (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-161
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-F--Ph 5-162
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-NO.sub.2--Ph
5-163 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-Cl--Ph
5-164 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 3-F--Ph
5-165 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 3-Cl--Ph
5-166 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-SMe--Ph
5-167 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S
2-Cl-3-Me--Ph 5-168 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 5-169
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph
5-170 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S
3-Me-4-Cl--Ph 5-171 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 4-F--Ph 5-172 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 4-NO.sub.2--Ph 5-173
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 4-Cl--Ph 5-174
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 3-F--Ph 5-175
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 3-Cl--Ph 5-176
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 4-SMe--Ph 5-177
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 2-Cl-3-Me--Ph
5-178 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O
2-Cl-4-NO.sub.2--Ph 5-179 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 5-180 .alpha.-CH.dbd.CH--CH.sub.2--
Me (CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 5-181 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-F--Ph 5-182 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-183 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-Cl--Ph 5-184 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-F--Ph 5-185 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 5-186 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 5-187 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-188 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-189 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-190 .delta.-(CH.sub.2)-- H
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-191 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-F--Ph 5-192 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-193 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-Cl--Ph 5-194 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-F--Ph 5-195 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-Cl--Ph 5-196 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 4-SMe--Ph 5-197 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-198 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-199 .delta.-(CH.sub.2)--
Me (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-200 .delta.-(CH.sub.2)-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-201 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-F--Ph 5-202 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-203 .delta.-(CH.sub.2).sub.2--
H (CH.sub.2).sub.2 O 4-Cl--Ph 5-204 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 3-F--Ph 5-205 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 5-206 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 5-207 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-208 .delta.-(CH.sub.2).sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-209
.delta.-(CH.sub.2).sub.2-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-210
.delta.-(CH.sub.2).sub.2-- H (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-211
.delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-F--Ph 5-212
.delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
5-213 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-Cl--Ph
5-214 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 3-F--Ph
5-215 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 3-Cl--Ph
5-216 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O 4-SMe--Ph
5-217 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 O
2-Cl-3-Me--Ph 5-218 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2
O 2-Cl-4-NO.sub.2--Ph 5-219 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-220 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-221 .delta.-(CH.sub.2).sub.2--
Me (CH.sub.2).sub.2 S 4-F--Ph 5-222 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-NO.sub.2--Ph 5-223 .delta.-(CH.sub.2).sub.2--
Me (CH.sub.2).sub.2 S 4-Cl--Ph 5-224 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 3-F--Ph 5-225 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 3-Cl--Ph 5-226 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 4-SMe--Ph 5-227 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-3-Me--Ph 5-228 .delta.-(CH.sub.2).sub.2--
Me (CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 5-229
.delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph 5-230
.delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.2 S 3-Me-4-Cl--Ph
5-231 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-F--Ph
5-232 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O
4-NO.sub.2--Ph 5-233 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3
O 4-Cl--Ph
5-234 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 3-F--Ph
5-235 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 3-Cl--Ph
5-236 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O 4-SMe--Ph
5-237 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3 O
2-Cl-3-Me--Ph 5-238 .delta.-(CH.sub.2).sub.2-- Me (CH.sub.2).sub.3
O 2-Cl-4-NO.sub.2--Ph 5-239 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 5-240 .delta.-(CH.sub.2).sub.2-- Me
(CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 5-241 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-F--Ph 5-242 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-243 .delta.-(CH.sub.2).sub.3--
H (CH.sub.2).sub.2 O 4-Cl--Ph 5-244 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 3-F--Ph 5-245 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 3-Cl--Ph 5-246 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 4-SMe--Ph 5-247 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 2-Cl-3-Me--Ph 5-248 .delta.-(CH.sub.2).sub.3-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-249
.delta.-(CH.sub.2).sub.3-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-250
.delta.-(CH.sub.2).sub.3-- H (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-251
.delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-F--Ph 5-252
.delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
5-253 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-Cl--Ph
5-254 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 3-F--Ph
5-255 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 3-Cl--Ph
5-256 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O 4-SMe--Ph
5-257 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 O
2-Cl-3-Me--Ph 5-258 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2
O 2-Cl-4-NO.sub.2--Ph 5-259 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-260 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-261 .delta.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 4-F--Ph 5-262 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 4-NO.sub.2--Ph 5-263 .delta.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 4-Cl--Ph 5-264 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 3-F--Ph 5-265 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 3-Cl--Ph 5-266 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 4-SMe--Ph 5-267 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.2 S 2-Cl-3-Me--Ph 5-268 .delta.-(CH.sub.2).sub.3--
Me (CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 5-269
.delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph 5-270
.delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.2 S 3-Me-4-Cl--Ph
5-271 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O 4-F--Ph
5-272 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
4-NO.sub.2--Ph 5-273 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3
O 4-Cl--Ph 5-274 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
3-F--Ph 5-275 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
3-Cl--Ph 5-276 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
4-SMe--Ph 5-277 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3 O
2-Cl-3-Me--Ph 5-278 .delta.-(CH.sub.2).sub.3-- Me (CH.sub.2).sub.3
O 2-Cl-4-NO.sub.2--Ph 5-279 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 5-280 .delta.-(CH.sub.2).sub.3-- Me
(CH.sub.2).sub.3 O 3-Me-4-Cl--Ph 5-281
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-F--Ph 5-282
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-NO.sub.2--Ph
5-283 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-Cl--Ph
5-284 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 3-F--Ph
5-285 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 3-Cl--Ph
5-286 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 4-SMe--Ph
5-287 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O
2-Cl-3-Me--Ph 5-288 .alpha.-CH.dbd.CH--CH.sub.2-- H
(CH.sub.2).sub.2 O 2-Cl-4-NO.sub.2--Ph 5-289
.alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O 2-Cl-4-F--Ph
5-290 .alpha.-CH.dbd.CH--CH.sub.2-- H (CH.sub.2).sub.2 O
3-Me-4-Cl--Ph 5-291 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 4-F--Ph 5-292 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 4-NO.sub.2--Ph 5-293
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 4-Cl--Ph 5-294
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 3-F--Ph 5-295
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 3-Cl--Ph 5-296
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 4-SMe--Ph 5-297
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O 2-Cl-3-Me--Ph
5-298 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 O
2-Cl-4-NO.sub.2--Ph 5-299 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 O 2-Cl-4-F--Ph 5-300 .alpha.-CH.dbd.CH--CH.sub.2--
Me (CH.sub.2).sub.2 O 3-Me-4-Cl--Ph 5-301
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-F--Ph 5-302
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-NO.sub.2--Ph
5-303 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-Cl--Ph
5-304 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 3-F--Ph
5-305 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 3-Cl--Ph
5-306 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 4-Sme--Ph
5-307 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S
2-Cl-3-Me--Ph 5-308 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.2 S 2-Cl-4-NO.sub.2--Ph 5-309
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S 2-Cl-4-F--Ph
5-310 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.2 S
3-Me-4-Cl--Ph 5-311 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 4-F--Ph 5-312 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 4-NO.sub.2--Ph 5-313
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 4-Cl--Ph 5-314
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 3-F--Ph 5-315
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 3-Cl--Ph 5-316
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 4-Sme--Ph 5-317
.alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O 2-Cl-3-Me--Ph
5-318 .alpha.-CH.dbd.CH--CH.sub.2-- Me (CH.sub.2).sub.3 O
2-Cl-4-NO.sub.2--Ph 5-319 .alpha.-CH.dbd.CH--CH.sub.2-- Me
(CH.sub.2).sub.3 O 2-Cl-4-F--Ph 5-320 .alpha.-CH.dbd.CH--CH.sub.2--
Me (CH.sub.2).sub.3 O 3-Me-4-Cl--Ph
[0089] Among the exemplary compounds, preferred are Compound No.
1-1, 1-7, 1-8, 1-10, 1-13, 1-19, 1-23, 1-26, 1-33, 1-34, 1-35,
1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-45, 1-46, 1-47,
1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58,
1-59, 1-60, 1-61, 1-65, 1-66, 1-67, 1-68, 1-70, 1-71, 1-72, 1-74,
1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-81, 1-82, 1-83, 1-84, 1-85,
1-86, 1-87, 1-88, 1-89, 1-90, 1-91, 1-92, 1-93, 1-94, 1-95, 1-96,
1-97, 1-98, 1-99, 1-100, 1-101, 1-102, 1-103, 1-104, 1-105, 1-106,
1-107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-113, 1-114, 1-115,
1-116, 1-117, 1-118, 1-119, 1-120, 1-121, 1-122, 1-123, 1-124,
1-125, 1-126, 1-128, 1-129, 1-132, 1-133, 1-134, 1-135, 1-136,
1-137, 1-138, 1-142, 1-143, 1-144, 1-145, 1-146, 1-148, 1-149,
1-150, 1-151, 1-152, 1-153, 1-154, 1-155, 1-156, 1-157, 1-158,
1-160, 1-161, 1-162, 1-163, 1-165, 1-174, 1-180, 1-181, 1-182,
1-183, 1-187, 1-188, 1-189, 1-190, 1-191, 1-192, 1-193, 1-194,
1-195, 1-196, 1-199, 1-200, 1-203, 1-204, 1-205, 1-206, 2-1, 2-2,
2-3, 2-4, 2-5, 2-6, 2-9, 2-11, 2-12, 2-13, 2-14, 2-15, 2-16, 2-17,
2-18, 2-19, 2-22, 2-24, 2-25, 2-26, 2-27, 2-41, 2-42, 2-43, 2-49,
2-51, 2-53, 2-65, 2-67, 2-73, 2-75, 2-76, 2-77, 2-78, 2-79, 2-80,
2-81, 2-82, 2-85, 2-86, 2-87, 2-88, 2-89, 2-90, 2-91, 2-92, 2-93,
2-94, 2-95, 2-96, 2-97, 2-98, 2-100, 2-101, 2-102, 2-103, 2-104,
2-105, 2-106, 2-107, 2-108, 2-109, 2-132, 2-133, 2-134, 2-135,
2-136, 2-137, 2-138, 2-142, 2-143, 2-144, 2-145, 2-146, 2-147,
2-148, 2-149, 2-150, 2-151, 2-152, 2-154, 2-155, 2-157, 2-158,
2-159, 2-160, 2-161, 2-167, 2-173, 2-192, 2-193, 2-194, 2-199,
2-200, 3-11, 3-12, 3-14, 3-15, 3-17, 3-21, 3-25, 3-26, 3-27, 3-28,
3-29, 3-30, 3-68, 3-69, 3-71, 3-72, 3-74, 3-78, 3-82, 3-83, 3-84,
3-85, 3-87, 3-88, 3-89, 3-90, 3-91, 4-2, 4-3, 4-6, 4-12, 4-13,
4-16, 4-52, 4-58, 4-60, 4-98, 4-132, 4-136, 4-139, 4-140, 5-73,
5-160 and 5-300, more preferred are Compound No. 1-1, 1-7, 1-8,
1-10, 1-13, 1-19, 1-23, 1-26, 1-34, 1-39, 1-41, 1-42, 1-43, 1-45,
1-46, 1-47, 1-49, 1-50, 1-51, 1-52, 1-53, 1-59, 1-60, 1-61, 1-66,
1-67, 1-68, 1-70, 1-71, 1-72, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79,
1-80, 1-81, 1-82, 1-84, 1-85, 1-86, 1-87, 1-88, 1-89, 1-90, 1-91,
1-92, 1-93, 1-94, 1-95, 1-96, 1-97, 1-98, 1-99, 1-101, 1-102,
1-103, 1-104, 1-105, 1-106, 1-107, 1-108, 1-109, 1-110, 1-111,
1-112, 1-113, 1-114, 1-115, 1-116, 1-117, 1-118, 1-119, 1-120,
1-121, 1-122, 1-123, 1-124, 1-125, 1-126, 1-128, 1-129, 1-132,
1-133, 1-134, 1-135, 1-136, 1-137, 1-142, 1-146, 1-149, 1-151,
1-156, 1-158, 1-159, 1-160, 1-165, 1-174, 1-180, 1-181, 1-182,
1-183, 1-187, 1-188, 1-189, 1-190, 1-191, 1-192, 1-193, 1-194,
1-195, 1-199, 1-200, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-9, 2-11, 2-12,
2-13, 2-14, 2-15, 2-16, 2-17, 2-18, 2-22, 2-25, 2-26, 2-65, 2-67,
2-73, 2-75, 2-78, 2-79, 2-82, 2-86, 2-88, 2-92, 2-94, 2-104, 2-109,
2-132, 2-135, 2-136, 2-142, 2-149, 2-161, 2-167, 2-194, 2-199,
2-200, 4-2, 4-12, 4-60, 4-132 and 4-139, further more preferred are
the compounds given below; Compound No. 1-75:
4-[3-(4-fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
Compound No. 1-76:
4-[3-(3-fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
Compound No. 1-78:
4-[3-(4-chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
Compound No. 1-79:
4-[3-(3-chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
Compound No. 1-92: 4-[3-(4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-102:
4-[3-(3,4-difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-104:
4-[3-(4-chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-108:
4-[3-(2-chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-132:
4-[1-dimethylamino-3-(4-fluorophenoxy)propyl]phenyl
dimethylcarbamate Compound No. 1-133:
4-[1-dimethylamino-3-(3-fluorophenoxy)propyl]phenyl
dimethylcarbamate Compound No. 1-135:
4-[3-(4-chlorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-136:
4-[3-(3-chlorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-149:
4-[1-dimethylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate Compound No. 1-159:
4-[3-(3,4-difluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate Compound No. 1-165:
4-[3-(2-chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate Compound No. 2-92:
3-[1-methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
Compound No. 2-149:
3-[1-dimethylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate and Compound No. 4-132:
2-methyl-1-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl
dimethylcarbamate
MODE FOR CARRYING OUT THE INVENTION
[0090] The compound (1) of the present invention can be obtained by
Process A to Process C described below.
##STR00008##
##STR00009##
##STR00010##
[0091] In the above, R.sup.1 to R.sup.3, R.sup.a, A, Arom, E,
X.sup.1 and X.sup.2 have the same meanings as defined above;
R.sup.2a has the same meaning as the above R.sup.2, or represents
an allyl group or a protecting group for an amino group; R.sup.3a
has the same meaning as the above R.sup.3 or represents a
protecting group for an amino group; R.sup.5 represents a hydrogen
atom, a protecting group for a hydroxyl group or a group of the
formula: R.sup.1--C(.dbd.X.sup.1)-- (wherein R.sup.1 and X.sup.1
have the same meanings as defined above); R.sup.b has the same
meaning as the above R.sup.a, or represents a hydroxyl group, a
hydroxyl group substituted by a leaving group or a vinyl group;
Arom.sup.a has the same meaning as the above Arom or represents a
group in which a carboxyl group, a hydroxyl group or an amino group
on Arom is protected, if necessary, by a protecting group for the
respective functional group(s); Ea represents an oxygen atom, a
sulfur atom, an --NH-- group or an --NQ- group (wherein Q
represents a protecting group for an amino group); Eb has the same
meaning as the above E, except that it cannot represent a single
bond; E.sup.c represents a single bond, an oxygen atom, a sulfur
atom, an --NH-- group or an --NQ- group (wherein Q represents a
protecting group for an amino group); G represents a
C.sub.1-C.sub.5 alkylene group; and L represents a hydroxyl group
or a leaving group.
[0092] The protecting group for the hydroxyl group in R.sup.5 and
Arom.sup.a is not particularly limited so long as it can stably
protect the hydroxyl group during the reaction, and specifically
means a protecting group which is cleavable by a chemical method
such as hydrogenolysis, hydrolysis, electrolysis and photolysis,
and may include the above "aliphatic acyl group"; the above
"aromatic acyl group"; the above "tetrahydropyranyl or
tetrahydrothiopyranyl group"; the above "silyl group"; the above
"alkoxymethyl group"; the above "substituted ethyl group"; the
above "aralkyl group"; the above "alkoxycarbonyl group"; the above
"alkenyloxycarbonyl group"; the above "aralkyloxycarbonyl
group".
[0093] The protecting group for the amino group in R.sup.2a,
R.sup.3a, Arom.sup.a and Q is not particularly limited so long as
it can stably protect the amino group during the reaction, and
specifically means a protecting group which is cleavable by a
chemical method such as hydrogenolysis, hydrolysis, electrolysis
and photolysis, and may include the above "aliphatic acyl group";
the above "aromatic acyl group"; the above "alkoxycarbonyl group";
the above "aralkyloxycarbonyl group"; the above "silyl group"; the
above "aralkyl group"; a "substituted methylene group" forming a
Schiff base such as N,N-dimethylaminomethylene, benzylidene,
4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene,
5-chlorosalicylidene, diphenylmethylene or
(5-chloro-2-hydroxyphenyl)phenylmethylene; an "aromatic sulfonyl
group" such as an arylsulfonyl group, e.g., benzenesulfonyl, or an
arylsulfonyl group substituted by lower alkyl or lower alkoxy,
e.g., p-toluenesulfonyl, pentamethylbenzenesulfonyl,
p-methoxybenzenesulfonyl, 2,4,6-trimethoxybenzenesulfonyl or
3-methoxy-4-t-butylbenzenesulfonyl; or an "aliphatic sulfonyl
group" such as an alkylsulfonyl group, e.g., methanesulfonyl or
t-butylsulfonyl, or an alkylsulfonyl group substituted by a halogen
atom, a silyl group or an aryl group, e.g.,
trifluoromethylsulfonyl, trisilylethanesulfonyl or
benzylsulfonyl.
[0094] The protecting group in Arom.sup.a is not particularly
limited so long as it can stably protect the carboxyl group during
the reaction, and specifically means a protecting group which is
cleavable by a chemical method such as hydrogenolysis, hydrolysis,
electrolysis and photolysis, and may include the above "lower alkyl
group"; the above "alkenyl group"; the above "alkynyl group"; the
above "lower alkyl group"; an "aliphatic acyl"-"lower alkyl group"
such as acetylmethyl; the above "aralkyl group"; or the above
"silyl group".
[0095] The leaving group in R.sup.b and L is not particularly
limited so long as it is a functional group which can react with a
nucleophilic reagent to carry out a substitution reaction, and the
group may include the above "halogen atom"; a "lower
alkylsulfonyloxy group" such as methanesulfonyloxy or
ethanesulfonyloxy; a "halogen-substituted lower alkylsulfonyloxy
group" such as trifluoromethanesulfonyloxy; an "aromatic
sulfonyloxy group" such as an arylsulfonyloxy group, e.g.,
benzenesulfonyloxy; a lower alkylated arylsulfonyloxy group, e.g.,
p-toluenesulfonyloxy; or a halogen-substituted arylsulfonyloxy
group, e.g., para-chlorobenzenesulfonyloxy.
[0096] In the following, the respective steps of Process A to
Process C are described in detail.
(Process A)
(Step A-1)
[0097] This step is to prepare a compound (IV) by reacting a
compound (II) which is obtained by Process D, Process E, Process H,
Process I or Process J described later, or publicly known, or
easily obtainable from publicly known compounds, with a compound
(III) which is publicly known, or easily obtainable from publicly
known compounds, in the presence of a base.
[0098] This step is carried out by a reaction (reaction A-1a) in
which the compound (II) and the compound (III) form an ether in the
case where Ea is an oxygen or sulfur atom, or a reaction (reaction
A-1b) in which the compound (II) and the compound (III) form an
amine in the case where Ea is an amino group.
(Reaction A-1a)
[0099] This reaction is accomplished by <Method 1> in which
after (.alpha.) an alkyl or arylsulfonyl halide (preferably
methanesulfonyl chloride) is reacted with the hydroxyl group of the
compound (III), (.beta.) it is condensed with the compound (II) in
the presence of a base; or <Method 2> in which the compound
(III) and the compound (II) are condensed by a Mitsunobu reaction
described in Bull. Chem. Soc. Jap., 40, 2380 (1967).
<Method 1>
(.alpha.) Reaction of Hydroxyl Group and Sulfonyl Halide
[0100] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an aromatic
hydrocarbon such as benzene; or an ether such as diethyl ether,
tetrahydrofuran, dioxane or dimethoxyethane, and is preferably an
ether (particularly tetrahydrofuran).
[0101] The base to be employed here may be an organic base such as
triethylamine, diisopropylamine, isopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline or N,N-diethylaniline, and is preferably
triethylamine.
[0102] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from -20 to
50.degree. C., preferably from 0 to 25.degree. C.
[0103] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 5 minutes to 10 hours, preferably from 10 minutes to 3
hours.
[0104] After the reaction, the desired compound of the present step
is collected from the reaction mixture by conventional methods. For
example, after the reaction, the desired compound is extracted by
adding water to the reaction mixture and adding a solvent
immiscible with water (for example, benzene, ether, ethyl acetate,
etc.), the extracted organic layer is washed with water and is then
dried using anhydrous magnesium sulfate, etc. Thereafter, the
solvent is evaporated to obtain the desired compound. The thus
obtained desired compound can be further purified, if necessary, by
conventional methods, for example, recrystallization,
reprecipitation and chromatography. The desired compound of the
present step can be used for the subsequent step without purifying
it.
(.beta.) Condensation with the Compound (II)
[0105] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting materials to some extent, and may preferably be an ether
such as tetrahydrofuran, dioxane or dimethoxyethane; a nitrile such
as acetonitrile or isobutyronitrile; an amide such as formamide,
dimethylformamide, dimethylacetamide or hexamethylphosphoric
triamide; or a sulfoxide such as dimethyl sulfoxide or sulfolane,
and is preferably an amide (particularly dimethylformamide).
[0106] The base to be employed here may be an alkali metal
hydroxide such as lithium hydroxide, sodium hydroxide or potassium
hydroxide; an alkali metal hydride such as lithium hydride, sodium
hydride or potassium hydride; an alkyl lithium such as methyl
lithium, ethyl lithium or butyl lithium; or a lithium alkylamide
such as lithium diisopropylamide, lithium dicyclohexylamide or
lithium bis(trimethylsilyl)amide, and is preferably a metal hydride
(particularly sodium hydride).
[0107] The reaction temperature varies depending on the solvent,
starting material, reagent, etc. but it is usually from 0 to
180.degree. C., preferably from 0 to 50.degree. C.
[0108] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 1 to 24 hours, preferably from 2 to 12 hours.
[0109] After the reaction, the desired compound of the present step
is collected from the reaction mixture by conventional methods. For
example, after completion of the reaction, the desired compound is
extracted by adding water to the reaction mixture and adding a
solvent immiscible with water (for example, benzene, ether, ethyl
acetate, etc.), the extracted organic layer is washed with water
and is dried using anhydrous magnesium sulfate, etc. and thereafter
the solvent is evaporated to obtain the desired compound. The thus
obtained desired compound can be further purified, if necessary, by
conventional methods, for example, recrystallization,
reprecipitation and chromatography.
<Method 2>
[0110] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting materials to some extent, and may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or
an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether, and
is preferably an aliphatic hydrocarbon, aromatic hydrocarbon or
ether, more preferably an ether (particularly tetrahydrofuran).
[0111] The phosphine to be employed here may be a
tri-C.sub.1-C.sub.6 alkylphosphine such as trimethylphosphine,
triethylphosphine, tripropylphosphine, tributylphosphine,
tripentylphosphine or trihexylphosphine; a tri-C.sub.6-C.sub.10
arylphosphine such as triphenylphosphine, triindenylphosphine or
trinaphthylphosphine; or a tri-C.sub.6-C.sub.10 arylphosphine which
may have C.sub.1-C.sub.4 alkyl as a substituent group such as
tolyldiphenylphosphine, tritolylphosphine, trimesitylphosphine,
tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine, and is
preferably a tri-C.sub.1-C.sub.6 alkylphosphin (particularly
trimethylphosphine, triethylphosphine, tripropylphosphine or
tributylphosphine) or a tri-C.sub.6-C.sub.10 arylphosphine
(particularly triphenylphosphine, triindenylphosphine or
trinaphthylphosphine), more preferably a tri-C.sub.6-C.sub.10
arylphosphine (particularly triphenylphosphine).
[0112] The azo compound to be employed here may be a
di-C.sub.1-C.sub.4 alkyl azodicarboxylate such as dimethyl
azodicarboxylate, diethyl azodicarboxylate, dipropyl
azodicarboxylate or dibutyl azodicarboxylate, and is preferably
diethyl azodicarboxylate.
[0113] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -10.degree. C. to
100.degree. C., preferably from 0.degree. C. to 50.degree. C.
[0114] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 5 minutes
to 24 hours, preferably from 10 minutes to 12 hours.
[0115] After the reaction, the desired compound of the present step
is collected from the reaction mixture according to conventional
methods. For example, the desired compound is obtained by removing
insolubles by filtration in the case where they exist and
evaporating the solvent. The obtained desired compound can be
further purified, if necessary; by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(Reaction A-1b)
[0116] This reaction is carried out similarly to <Method 1>
of the (Reaction A-1a).
(Step A-2)
[0117] This step is to prepare the compound (1), if necessary, by
carrying out a deprotection reaction (Reaction A-2a) of a
protecting group, an N-alkylation reaction (Reaction A-2b) of the
amine, a carbamoylation reaction (Reaction A-2c) of the hydroxyl
group and a cyclization reaction (Reaction A-2d) on the compound
(IV) obtained in step A-1.
(Reaction A-2a)
[0118] The removal of the protecting group of the amino group
varies depending on the kind thereof but it is generally carried
out according to well known methods in the technology of synthetic
organic chemistry as follows.
[0119] In the case where the protecting group of the amino group is
a t-butoxycarbonyl group, a 2-trimethylsilylethoxycarbonyl group or
a p-methoxybenzyloxycarbonyl group, it can be eliminated by
treating it with an acid in an inert solvent or an aqueous solvent.
At that time, the desired compound can be also obtained as a
salt.
[0120] The acid to be employed here can be, for example,
hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid
or trifluoroacetic acid, and is preferably hydrochloric acid,
sulfuric acid, hydrobromic acid or trifluoroacetic acid.
[0121] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting materials to some extent, and may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; an
ester such as methyl acetate or ethyl acetate; an alcohol such as
methanol, ethanol, propanol, isopropanol or butanol; an amide such
as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or
hexamethylphosphoric triamide; a sulfoxide such as dimethyl
sulfoxide or sulfolane; an aliphatic acid such as formic acid or
acetic acid; or water or a mixture of water and the above solvents,
and is preferably a halogenated hydrocarbon, ether, alcohol,
aliphatic acid or a mixture of water and the above solvents, more
preferably an ester (particularly ethyl acetate), or an ether
(particularly tetrahydrofuran or dioxane).
[0122] The reaction temperature varies depending on the starting
compound, solvent and acid used, but it is usually from -20.degree.
C. to 100.degree. C., preferably from 0.degree. C. to 80.degree.
C.
[0123] The reaction time varies depending on the starting compound,
solvent and acid used, but it is usually from 5 minutes to 20
hours, preferably from one hour to 10 hours.
[0124] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by collecting the desired compound precipitated in the reaction
solution or appropriately neutralizing the reaction solution,
evaporating the solvent, pouring water into the reaction mixture,
adding a solvent immiscible with water (for example, benzene,
ether, ethyl acetate, etc.) to perform an extraction and washing
the organic layer containing the desired compound with water,
followed by drying with anhydrous magnesium sulfate, etc. and
evaporating off the solvent. The thus obtained desired compound can
be further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
[0125] In the case where the protecting group of the amino group is
a t-butoxycarbonyl group, it can also be eliminated by treating it
with a silyl compound or Lewis acid, particularly in an inert
solvent.
[0126] The silyl compound to be employed here is, for example,
trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyl
trifluoromethanesulfonate, and the Lewis acid to be employed here
is, for example, aluminum chloride.
[0127] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be a halogenated
hydrocarbon such as dichloromethane, chloroform or carbon
tetrachloride; an ether such as diethyl ether, tetrahydrofuran or
dioxane; or a nitrile such as acetonitrile, and is preferably a
halogenated hydrocarbon (particularly dichloromethane or
chloroform) or a nitrile (particularly acetonitrile).
[0128] The reaction temperature varies depending on the starting
compound, reagent and solvent, but it is usually from -20.degree.
to 100.degree. C., preferably from 0.degree. C. to 50.degree.
C.
[0129] The reaction time varies depending on the starting compound,
reagent, solvent and reaction temperature, but it is usually from
10 minutes to 10 hours, preferably from 30 minutes to 3 hours.
[0130] After the reaction, the desired compound of the present step
is collected from the reaction mixture according to conventional
methods. For example, the desired compound is obtained by
evaporating the solvent, adding water to the reaction mixture and
making the aqueous layer alkaline to collect the precipitated
substance by filtration, or adding a solvent immiscible with water
(for example, benzene, ether, ethyl acetate, etc.) to perform an
extraction and washing the organic layer containing the desired
compound with water, followed by drying with anhydrous magnesium
sulfate, etc. and evaporating off the solvent. The thus obtained
desired compound can be further purified, if necessary, by
conventional methods, for example, recrystallization,
reprecipitation and chromatography.
[0131] In the case where the protecting group of the amino group is
an allyloxycarbonyl group, it can be usually eliminated by reacting
it with tetrakis(triphenylphosphine)palladium or
bis(triphenylphosphine)palladium chloride in the presence of from 1
to 3 equivalents of potassium 2-ethylhexanoate, methyl malonate,
dimedone or tributyl tin hydride in an inert solvent.
[0132] The solvent to be employed here is not particularly limited
so long as it does not affect the present reaction, and may be a
halogenated hydrocarbon such as dichloromethane, chloroform or
carbon tetrachloride; an ether such as diethyl ether,
tetrahydrofuran or dioxane; or an ester such as ethyl acetate or
propyl acetate, and is preferably a halogenated hydrocarbon
(particularly dichloromethane), an ether (particularly
tetrahydrofuran) or an ester (particularly ethyl acetate).
[0133] The reaction temperature varies depending on the starting
compound, solvent and reducing agent used, but it is usually from
-10.degree. to 80.degree. C., preferably from 0.degree. C. to
50.degree. C.
[0134] The reaction time varies depending on the starting compound,
solvent, reducing agent used, and the reaction temperature, but it
is usually from 30 minutes to 24 hours, preferably from one hour to
8 hours.
[0135] After the reaction, the desired compound of the present step
is collected from the reaction mixture according to conventional
methods. For example, the desired compound is obtained by removing
the palladium catalyst by filtration and then evaporating the
solvent, pouring water into the reaction mixture and making the
aqueous layer alkaline to collect the precipitated substance by
filtration, or adding a solvent immiscible with water (for example,
benzene, ether, ethyl acetate, etc.) to perform an extraction and
washing the organic layer containing the desired compound with
water, followed by drying with anhydrous magnesium sulfate, etc.
and evaporating off the solvent. The obtained desired compound can
be further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
[0136] The removal of the protecting group of the hydroxyl group
varies depending on the kind thereof but it is generally carried
out according to well known methods in the technology of synthetic
organic chemistry as follows.
[0137] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, cyclohexane, heptane, ligroin or
petroleum ether; an aromatic hydrocarbon such as benzene, toluene
or xylene; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol
dimethyl ether; an ester such as methyl acetate or ethyl acetate;
an alcohol such as methanol, ethanol, propanol, isopropanol,
butanol or isobutanol; or a mixture obtained by arbitrarily mixing
the above solvents and water, and is preferably an alcohol
(particularly methanol) or a mixture of an alcohol and water.
[0138] The catalyst to be employed here is not particularly limited
so long as it is usually used for catalytic reduction reactions,
and may be palladium black, palladium-carbon, palladium hydroxide,
palladium hydroxide-carbon, Raney nickel, rhodium-aluminum oxide,
palladium-barium sulfate, platinum oxide or platinum black, and is
preferably palladium-carbon or palladium hydroxide-carbon.
[0139] An acid can be added to effectively carry out the reaction
in the present step. The acid to be employed here may be a mineral
acid such as hydrochloric acid or hydrobromic acid; or an organic
acid such as picric acid, formic acid, acetic acid, propionic acid,
trifluoroacetic acid, benzenesulfonic acid, 4-toluenesulfonic acid
or camphorsulfonic acid, and is preferably acetic acid.
[0140] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -100 to 100.degree.
C., preferably from 0.degree. C. to 50.degree. C.
[0141] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 10 minutes
to 48 hours, preferably from 30 minutes to 24 hours.
[0142] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after the reaction, the desired compound is obtained by
removing the catalyst by filtration and evaporating the filtrate.
The obtained desired compound can be further purified, if
necessary, by conventional methods, for example, recrystallization,
reprecipitation or chromatography.
[0143] The removal of the protecting group of the carboxyl group
varies depending on the kind thereof but it is generally carried
out according to well known methods in the technology of synthetic
organic chemistry as follows.
[0144] In the case where a lower alkyl group or an aryl group is
used as the protecting group of the carboxyl group, it can be
removed by treatment with an acid or a base.
[0145] As the acid, hydrochloric acid, sulfuric acid, phosphoric
acid or hydrobromic acid are used, and the base is not particularly
limited so long as it does not affect other portions of the
compound, and may preferably be an alkali metal carbonate such as
sodium carbonate or potassium carbonate; an alkali metal hydroxide
such as sodium hydroxide or potassium hydroxide; or a concentrated
ammonia-methanol solution.
[0146] Isomerization sometimes occurs during hydrolysis by a
base.
[0147] The solvent to be employed here is not particularly limited
so long as it is usually used for hydrolysis reactions and does not
inhibit the reaction, and may preferably be water; or a mixture of
an organic solvent such as an alcohol, e.g., methanol, ethanol and
n-propanol or an ether, e.g., tetrahydrofuran and dioxane, and
water.
[0148] The reaction temperature and the reaction time vary
depending on the starting material, solvent, reagent used, etc. and
are not particularly limited, but the reaction is usually carried
out at from 0.degree. to 150.degree. C. for from 1 to 10 hours.
[0149] In the case where the protecting group of the carboxyl group
is a diaryl-substituted methyl group such as diphenylmethyl, it is
usually eliminated by treating it with an acid in an inert
solvent.
[0150] The solvent to be employed here is preferably an aromatic
hydrocarbon such as anisole, and as the acid, a fluorinated organic
acid such as trifluoroacetic acid is used.
[0151] The reaction temperature and the reaction time vary
depending on the starting material, solvent, acid used, etc., but
the reaction is usually carried out at room temperature for 30
minutes to 10 hours.
[0152] In the case where the protecting group of the carboxyl group
is an aralkyl group or a halogeno-lower alkyl group, it is usually
eliminated by reduction in a solvent.
[0153] As the reduction method, in the case where the protecting
group of the carboxyl group is a halogeno-lower alkyl group, a
method employing chemical reduction such as zinc-acetic acid is
preferably used, and in the case where it is an aralkyl group, a
method employing catalytic reduction using a catalyst such as
palladium-carbon or platinum is carried out, or a method employing
chemical reduction using an alkali metal sulfide such as potassium
sulfide or sodium sulfide is carried out.
[0154] The solvent to be employed here is not particularly limited
so long as it does not affect the present reaction, and may
preferably be an alcohol such as methanol or ethanol; an ether such
as tetrahydrofuran or dioxane; an aliphatic acid such as acetic
acid; or a mixture of these organic solvents and water.
[0155] The reaction temperature and the reaction time vary
depending on the starting material, solvent and reduction method,
but the reaction is usually carried out at from 0.degree. C. to
approximately room temperature for from 5 minutes to 12 hours.
[0156] In the case where the protecting group of the carboxyl group
is an alkoxymethyl group, it is usually eliminated by treating it
with an acid in a solvent.
[0157] The acid to be employed here is not particularly limited so
long as it is usually used as Bronsted acid, and may preferably be
an inorganic acid such as hydrochloric acid or sulfuric acid, or an
organic acid such as acetic acid or para-toluenesulfonic acid.
[0158] The solvent to be employed here is not particularly limited
so long as it does not affect the present reaction, and may
preferably be an alcohol such as methanol or ethanol; an ether such
as tetrahydrofuran or dioxane; or a mixture of these organic
solvents and water.
[0159] The reaction temperature and the reaction time vary
depending on the starting material, solvent and acid used, but the
reaction is usually carried out at from 0.degree. C. to 50.degree.
C. for from 10 minutes to 18 hours.
[0160] If the elimination of the protecting group of the carboxyl
group is carried out by treatment with ammonia according to
conventional methods, the carboxyl group can be also amidated.
[0161] An alkali metal salt can be prepared, if desired, by
dissolving the thus produced carboxylic acid in a mixture of water
and an organic solvent immiscible with water such as ethyl acetate,
adding an aqueous solution of an alkali metal carbonate or
hydrogencarbonate such as aqueous sodium hydrogencarbonate solution
or aqueous potassium carbonate solution at from 0.degree. C. to
room temperature, followed by adjusting the pH of the mixture to
approximately 7 and collecting the precipitate by filtration.
[0162] The thus prepared salt or the above carboxylic acid can be
reacted with 2 equivalents of base (preferably an organic base such
as triethylamine or dicyclohexylamine; an alkali metal salt hydride
such as sodium hydride; or an alkali metal carbonate or
hydrogencarbonate such as sodium hydrogencarbonate, sodium
carbonate or potassium carbonate) in a solvent (preferably an ether
such as tetrahydrofuran; or a polar solvent such as
N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide or triethylphosphate), followed by reaction with an
aliphatic acyloxymethyl halide such as acetoxymethyl chloride or
propionyloxymethyl bromide, a 1-lower alkoxycarbonyloxyethyl halide
such as 1-methoxycarbonyloxyethyl chloride or
1-ethoxycarbonyloxyethyl iodide, a phthalidyl halide, or a
(2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl halide, to prepare an
ester product protected by a protecting group of the carboxyl group
which is easily hydrolyzed in a living body.
[0163] The reaction temperature and the reaction time vary
depending on the starting material, solvent and the kind of
reaction reagent, but the reaction is usually carried out at from
0.degree. C. to 100.degree. C. for from 0.5 to 10 hours.
(Reaction A-2b)
[0164] The N-alkylation of the amine is accomplished by <Method
1>: a combination of an alkylcarbonyl compound and a reducing
agent or <Method 2>: reaction with an alkyl halide in the
presence of a base.
<Method 1>
[0165] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be water; a halogenated
hydrocarbon such as methylene chloride, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a
nitrile such as acetonitrile or isobutyronitrile; an amide such as
formamide, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide; a sulfoxide such as dimethyl
sulfoxide or sulfolane; or an organic base such as
N-methylmorpholine, triethylamine, tripropylamine, tributylamine,
diisopropylethylamine dicyclohexylamine, N-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline or N,N-diethylaniline; and is
preferably an alcohol. The reaction can be also carried out, if
necessary, without using a solvent.
[0166] The reducing agent to be employed here may be a metal
borohydride such as sodium borohydride or sodium cyanoborohydride;
a combination of hydrogen gas and a catalyst such as
palladium-carbon, platinum or Raney nickel; or a combination of
zinc and hydrochloric acid, and is preferably a metal borohydride.
In the case where the alkylating agent is formaldehyde, formic acid
can be also used.
[0167] The reaction temperature varies depending on the starting
compound, reagent and solvent, but it is usually from -20.degree.
C. to 200.degree. C., preferably from 0.degree. C. to 100.degree.
C.
[0168] The reaction time varies depending mainly on the reaction
temperature, starting compound, and the kind of solvent used, but
it is usually from 10 minutes to 24 hours, preferably from one hour
to 12 hours.
[0169] After the reaction, the desired compound of the present
reaction is obtained, for example, by concentrating the reaction
mixture, adding an organic solvent immiscible with water such as
ethyl acetate, washing with water, separating the organic layer
containing the desired compound, drying with anhydrous magnesium
sulfate and evaporating the solvent.
<Method 2>
[0170] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane, chlorobenzene or
dichlorobenzene; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol
dimethyl ether; a nitrile such as acetonitrile or isobutyronitrile;
an amide such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidone
or hexamethylphosphoric triamide; a sulfoxide such as dimethyl
sulfoxide or sulfolane; or an organic base such as
N-methylmorpholine, triethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline or N,N-diethylaniline, and is
preferably an amide, particularly preferably
N,N-dimethylacetamide.
[0171] The base to be employed here may be an alkali metal
carbonate such as sodium carbonate, potassium carbonate or lithium
carbonate; an alkali metal hydrogencarbonate such as sodium
hydrogencarbonate, potassium hydrogencarbonate or lithium
hydrogencarbonate; or an organic base such as N-methylmorpholine,
triethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO) or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably an
alkali metal carbonate, particularly preferably potassium
carbonate.
[0172] Sodium iodide may be also added in order to effectively
carry out the reaction.
[0173] The reaction temperature varies depending on the starting
compound, reagent and solvent, but it is usually from 0.degree. C.
to 200.degree. C., preferably from 20.degree. C. to 100.degree.
C.
[0174] The reaction time varies mainly depending on the reaction
temperature, starting compound, and the kind of solvent used, but
it is usually from 10 minutes to 24 hours, preferably from one hour
to 12 hours.
[0175] After the reaction, the desired compound of the present
reaction is obtained, for example, by concentrating the reaction
mixture, adding an organic solvent immiscible with water such as
ethyl acetate, washing with water, separating the organic layer
containing the desired compound, drying with anhydrous magnesium
sulfate and evaporating the solvent.
(Reaction A-2c)
[0176] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such
as benzene, toluene or xylene; a halogenated hydrocarbon such as
dichloromethane, chloroform, carbon tetrachloride, dichloroethane,
chlorobenzene or dichlorobenzene; an ester such as ethyl formate,
ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate;
an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a
nitrile such as acetonitrile or isobutyronitrile; or an amide such
as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably a halogenated
hydrocarbon (particularly dichloromethane), an ether (particularly
tetrahydrofuran) or an amide (particularly
N,N-dimethylformamide).
[0177] The base to be employed here may be an alkali metal
carbonate such as sodium carbonate, potassium carbonate or lithium
carbonate; an alkali metal hydride such as lithium hydride, sodium
hydride or potassium hydride; or an organic amine such as
triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane
(DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is
preferably an alkali metal carbonate (particularly potassium
carbonate) or an organic amine (particularly triethylamine).
[0178] The reaction temperature varies depending on the starting
compound, solvent and base used, but it is usually from
.about.20.degree. C. to 100.degree. C., preferably from 0.degree.
C. to 50.degree. C.
[0179] The reaction time varies depending on the starting compound,
solvent and base used, but it is usually from 5 minutes to 48
hours, preferably from one hour to 10 hours.
[0180] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound
precipitated in the reaction solution is obtained by collecting
through filtration, or appropriately neutralizing the reaction
solution, evaporating the solvent, pouring water into the reaction
mixture and adding a solvent immiscible with water (for example,
benzene, ether, ethyl acetate, etc.) to perform an extraction,
washing the organic layer containing the desired compound with
water, drying with anhydrous magnesium sulfate and evaporating the
solvent. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
(Reaction A-2d)
[0181] This reaction is accomplished by vinylating the phenyl group
(.alpha.) and allylating the amino group (.beta.), followed by
cyclization of the vinyl group and the allyl group by olefin
metathesis (.gamma.). Either the vinylation (.alpha.) or the
allylation (.beta.) may be carried out first.
(.beta.)
[0182] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such
as benzene, toluene oxylene; an ether such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or
diethylene glycol dimethyl ether; a nitrile such as acetonitrile or
isobutyronitrile; or an amide such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably an ether
(particularly tetrahydrofuran or dioxane) or an amide (particularly
N,N-dimethylformamide).
[0183] Lithium chloride can be added for the purpose of promoting
the reaction.
[0184] The catalyst to be employed here is not particularly limited
so long as it can vinylate the hydroxyl group of the phenol, and is
preferably a palladium catalyst, that is, a catalyst containing 0
valent- or 2 valent-palladium metal which is used in organic
synthesis, and may be palladium metal, palladium-carbon, palladium
hydroxide, palladium chloride, palladium (II) acetate,
tris(dibenzylideneacetone)dipalladium-chloroform, allyl palladium
chloride, [1,2-bis(diphenylphosphino)ethane]palladium dichloride,
bis(tri-o-toluoylphosphine)palladium dichloride,
bis(triphenylphosphine)palladium dichloride,
tetrakis(triphenylphosphine)palladium,
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, or a
catalyst produced in solution by adding a ligand into the reaction
solution of these. The ligand added into the reaction solution may
be a phosphoric ligand such as
1,1'-bis(diphenylphosphino)ferrocene,
bis(2-diphenylphosphinophenyl)ether,
2,2'-bis(diphenylphosphino)-1,1'-binaphthol,
1,3-bis(diphenylphosphino)propane,
1,4-bis(diphenylphosphino)butane, tri-o-toluoylphosphine,
2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl or
2,2-bis(diphenylphosphino)-1,1-binaphthyl. The above palladium
catalyst is preferably palladium acetate,
tris(dibenzylideneacetone)dipalladium-chloroform, a combination of
palladium acetate and the ligand
bis(2-diphenylphosphinophenyl)ether, or a combination of
tris(dibenzylideneacetone)dipalladium-chloroform and the ligand
1,1'-bis(diphenylphosphino)ferrocene, more preferably a combination
of palladium acetate and the ligand
bis(2-diphenylphosphinophenyl)ether, or a combination of
tris(dibenzylideneacetone)dipalladium-chloroform and the ligand
1,1'-bis(diphenylphosphino)ferrocene.
[0185] The reagent to be employed in the present reaction is not
particularly limited so long as it is used for Stille coupling and
produces a vinyl group, and is preferably tributylvinyl tin.
[0186] The reaction temperature varies depending on the starting
compound, solvent and base used, but it is usually from -20.degree.
C. to 50.degree. C., preferably from 0.degree. C. to 25.degree.
C.
[0187] The reaction time varies depending on the starting compound,
solvent and base used, but it is usually from 5 minutes to 24
hours, preferably from 30 minutes to 12 hours.
[0188] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by collecting the desired compound precipitated in the reaction
solution by filtration, or adding a saturated aqueous potassium
fluoride solution, filtering the solvent to evaporate the solvent
in the filtrate, adding water and a solvent immiscible with water
(for example, benzene, ether, ethyl acetate, etc.) to perform an
extraction, washing the organic layer containing the desired
compound with water, drying with anhydrous magnesium sulfate and
evaporating the solvent. The obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(.beta.)
[0189] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such
as benzene, toluene or xylene; an ether such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or
diethylene glycol dimethyl ether; a nitrile such as acetonitrile or
isobutyronitrile; or an amide such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably an amide
(particularly N,N-dimethylformamide).
[0190] The allylating reagent to be employed here is on allyl
halide, preferably allyl bromide or allyl iodide, more preferably
allyl bromide.
[0191] The base to be employed here may be an alkali metal
carbonate such as sodium carbonate, potassium carbonate or lithium
carbonate; an alkali metal hydride such as lithium hydride, sodium
hydride or potassium hydride; an alkali metal alkoxide such as
sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, potassium t-butoxide or lithium methoxide; or an organic
base such as N-methylmorpholine, triethylamine, tripropylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine,
N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO) or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably an
alkali metal hydride (particularly sodium hydride).
[0192] The reaction temperature varies depending on the starting
compound, solvent and base used, but it is usually from 0.degree.
C. to 200.degree. C., preferably from 20.degree. C. to 100.degree.
C.
[0193] The reaction time varies depending on the starting compound,
solvent and base used, but it is usually from 5 minutes to 48
hours, preferably from 1 hour to 12 hours.
[0194] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by collecting the desired compound precipitated in the reaction
solution, or neutralizing appropriately the reaction mixture,
pouring water into the reaction mixture, adding a solvent
immiscible with water (for example, benzene, ether, ethyl acetate,
etc.) to perform an extraction, washing the organic layer
containing the desired compound with water, followed by drying with
anhydrous magnesium sulfate, and evaporating the solvent. The thus
obtained desired compound can be further purified, if necessary, by
conventional methods, for example, recrystallization,
reprecipitation or chromatography.
(.gamma.)
[0195] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aromatic
hydrocarbon such as benzene, toluene or xylene; a halogenated
hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or
an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether, and
is preferably an aromatic hydrocarbon or a halogenated hydrocarbon,
more preferably toluene or dichloromethane.
[0196] The catalyst to be employed here is not particularly limited
so long as it can be used for olefin metathesis, and is preferably
Grubbs catalyst in which two phosphine ligands are coordinated to
benzylidene dihalogenated ruthenium, and this catalyst may be
benzylidenebis(tricyclohexylphosphine)dichlororuthenium,
benzylidenebis(triphenylphosphine)dichlororuthenium, or
benzylidenedichloro(1,3-dimesityl-2-imidazolidinylidene)(tricyclohexylpho-
sphine)ruthenium.
[0197] The reaction temperature varies depending on the starting
compound, solvent and base used, but it is usually from 0.degree.
C. to 120.degree. C., preferably from 25.degree. C. to 40.degree.
C.
[0198] The reaction time varies depending on the starting compound,
solvent and base used, but it is usually from 1 hour to 24 hours,
preferably from 2 hours to 12 hours.
[0199] After completion of the reaction, the desired compound of
the present reaction is collected from the reaction mixture
according to conventional methods. For example, the desired
compound is obtained by collecting the desired compound
precipitated in the reaction solution, or evaporating the solvent.
The thus obtained desired compound can be further purified, if
necessary, by conventional methods, for example, recrystallization,
reprecipitation or chromatography.
[0200] In the present step, any of the deprotection reactions of
the protecting groups, the N-alkylation reaction of the amine, the
carbonylation reaction of the hydroxyl group, and the cyclization
reaction, may be carried out first depending on the structure of
the desired compound. In the case where the conditions are common
to them, the reactions may be carried out consecutively without
purification.
(Process B)
(Step B-1)
[0201] This step is to prepare a compound (V) by oxidizing the
hydroxyl group of the compound (IIa) obtained by Process D, Process
E, Process H, Process I or Process J described later, or which is
publicly known or easily obtainable from known compounds, to a
formyl group (Reaction B-1a), carrying out a Wittig reaction on the
formyl group (Reaction B-1b), and reducing the obtained compound
(Reaction B-1c).
(Reaction B-1a)
[0202] The oxidizing agent to be employed here is not particularly
limited so long as it is usually used for oxidation reactions and
may preferably be a manganese oxide such as manganese dioxide; a
chromic acid compound such as chromic anhydride-pyridine complex; a
reagent used for Swern oxidation (a combination of dimethyl
sulfoxide and an activating agent (dicyclohexylcarbodiimide,
dicyclohexylcarbodiimide and pyridine-trifluoroacetic acid, oxalyl
chloride, acetic anhydride, phosphorus pentoxide, pyridine-sulfuric
anhydride, sulfur trioxide-pyridine, mercury acetate, chlorine or
N-chlorosuccinimide)); a transition metal oxidizing agent such as
tetrapropylammonium perruthenate; or a high valence iodine
oxidizing agent such as
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, and is more
preferably a chromic acid compound.
[0203] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an aromatic
hydrocarbon such as benzene, toluene or xylene; a halogenated
hydrocarbon such as dichloromethane, chloroform or dichloroethane;
an ester such as ethyl acetate; an ether such as tetrahydrofuran,
dioxane or dimethoxyethane; a ketone such as acetone or methyl
ethyl ketone; or a nitrile such as acetonitrile or
isobutyronitrile, and is more preferably a halogenated hydrocarbon
(particularly dichloromethane).
[0204] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from
-60.degree. C. to 50.degree. C.
[0205] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc. but it is usually
from one to 16 hours.
[0206] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by appropriately neutralizing the reaction mixture, or in the case
where insolubles exist, removing them by filtration, adding an
organic solvent immiscible with water such as ethyl acetate,
washing with water, separating the organic layer containing the
desired compound, drying with anhydrous magnesium sulfate and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(Reaction B-1b)
[0207] The reaction is carried out in the presence of a base. The
base to be employed here may be an alkyl lithium such as methyl
lithium or butyl lithium; an alkali metal hydride such as sodium
hydride or potassium hydride; an alkali metal amide such as lithium
amide, sodium amide or potassium amide; an alkali metal alkoxide
such as sodium methoxide, sodium ethoxide, potassium propoxide,
sodium butoxide, potassium-t-butoxide or sodium-t-pentoxide; or an
alkali metal disilazide such as lithium hexamethyldisilazide,
sodium hexamethyldisilazide or potassium hexamethyldisiliazide; and
is preferably an alkali metal hydride, alkali metal alkoxide or
alkali metal disilazide, more preferably sodium hydride, potassium
hydride, potassium-t-butoxide, sodium hexamethyldisilazide,
potassium hexamethyldisilazide or lithium hexamethyldisilazide,
particularly preferably sodium hydride or potassium hydride.
[0208] The Wittig reagent to be employed here is preferably a
combination of a triphenylphosphorane such as
benzylidenetriphenylphosphorane, and the corresponding benzyl
halide compound, or a phosphonium salt obtained by the
combination.
[0209] The solvent to be employed here is preferably an ether such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane or diethylene glycol dimethyl ether (particularly
tetrahydrofuran).
[0210] The present reaction is preferably carried out under an
inert gas stream such as nitrogen, helium or argon.
[0211] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is preferably from
-78.degree. C. to room temperature.
[0212] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc., but it is preferably
from 10 minutes to 5 hours.
[0213] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by pouring the reaction
mixture into an aqueous ammonium chloride solution, extracting the
mixture with a solvent immiscible with water, for example, benzene,
ether or ethyl acetate, and evaporating the solvent from the
extract. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
(Reaction B-1c)
[0214] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, cyclohexane, heptane, ligroin or
petroleum ether; an aromatic hydrocarbon such as benzene, toluene
or xylene; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol
dimethyl ether; an ester such as methyl acetate or ethyl acetate;
or an alcohol such as methanol, ethanol, propanol, isopropanol,
butanol or isobutanol, and is preferably an ester (particularly
ethyl acetate) or an alcohol (particularly methanol).
[0215] The catalytic reduction catalyst to be employed here is not
particularly limited so long as it is used for usual catalytic
reduction reactions, and may be palladium black, palladium-carbon,
palladium hydroxide, palladium hydroxide-carbon, Raney nickel,
rhodium-aluminum oxide, palladium-barium sulfate, platinum oxide or
platinum black, and is preferably palladium-carbon.
[0216] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -10.degree. C. to
100.degree. C., preferably from 0.degree. C. to 50.degree. C.
[0217] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 10 minutes
to 48 hours, preferably from 30 minutes to 24 hours.
[0218] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after completion of the reaction, the desired compound is
obtained by removing the catalyst by filtration and evaporating the
filtrate. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
(Step B-2)
[0219] This step is to prepare the compound (1) by carrying out, if
necessary, a deprotection reaction of the protecting group, an
N-alkylation reaction of the amine, and a carbamoylation reaction
of the hydroxyl group of the compound (V) obtained in Step B-1.
[0220] The present step is carried out similarly to Step A-2.
(Process C)
(Step C-1a)
[0221] This step is to prepare the compound (VII) by reducing the
carbonyl group of the compound (VI) obtained by Process F or
Process G described later (Reaction C-1a), further halogenating the
obtained hydroxyl group (Reaction C-1b) and thereafter aminating it
(Reaction C-1c)
(Reaction C-1a)
[0222] The reducing agent to be employed here is preferably a
hydride compound such as lithium aluminum hydride, sodium
borohydride or diisobutyl aluminum hydride, more preferably sodium
borohydride.
[0223] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an ether
such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane;
or an alcohol such as methanol or ethanol, and is preferably an
ether (particularly tetrahydrofuran) or an alcohol (particularly
methanol).
[0224] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from
-78.degree. C. to 100.degree. C., preferably from -78.degree. C. to
room temperature.
[0225] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 10 minutes to 24 hours, preferably from one to 10 hours.
[0226] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by appropriately neutralizing the reaction mixture, or, in the case
where insolubles exist, removing them by filtration, adding an
organic solvent immiscible with water such as ethyl acetate,
washing with water, separating the organic layer containing the
desired compound, drying with anhydrous magnesium sulfate, and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(Reaction C-1b)
[0227] The phosphine to be employed here may be a
tri-C.sub.1-C.sub.6 alkylphosphine such as trimethylphosphine,
triethylphosphine, tripropylphosphine, tributylphosphine,
tripentylphosphine or trihexylphosphine; a tri-C.sub.6-C.sub.10
arylphosphine such as triphenylphosphine, triindenylphosphine or
trinaphthylphosphine; or a tri-C.sub.6-C.sub.10 arylphosphine which
may have a C.sub.1-C.sub.4 alkyl substituent, such as
tolyldiphenylphosphine, tritolylphosphine, trimesitylphosphine,
tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine, and is
preferably a tri-C.sub.1-C.sub.6 alkylphosphine (particularly
trimethylphosphine, triethylphosphine, tripropylphosphine or
tributylphosphine) or a tri-C.sub.6-C.sub.10 arylphosphine
(particularly triphenylphosphine, triindenylphosphine or
trinaphthylphosphine), more preferably a tri-C.sub.6-C.sub.10
arylphosphine (particularly triphenylphosphine).
[0228] The halogenating agent to be employed is a carbon
tetrahalide such as carbon tetrabromide.
[0229] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a
nitrile such as acetonitrile; an amide such as formamide,
dimethylformamide dimethylacetamide, hexamethylphosphoramide (HMPA)
or hexamethylphosphorus triamide (HMPT); or a sulfoxide such as
dimethyl sulfoxide or sulfolane, and is preferably a halogenated
hydrocarbon.
[0230] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -10.degree. C. to
100.degree. C., preferably from 0.degree. C. to 50.degree. C.
[0231] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 5 minutes
to 10 hours, preferably from 10 minutes to 3 hours.
[0232] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by appropriately neutralizing the reaction mixture, and, in the
case where insolubles exist, removing them by filtration, adding an
organic solvent immiscible with water such as ethyl acetate,
washing with water, separating the organic layer containing the
desired compound, drying with anhydrous magnesium sulfate or the
like and evaporating the solvent. The thus obtained desired
compound can be further purified, if necessary, by conventional
methods, for example, recrystallization, reprecipitation or
chromatography.
(Reaction C-1c)
[0233] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; an ether
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane or diethylene glycol dimethyl ether; an alcohol
such as methanol or ethanol; a nitrile such as acetonitrile; an
amide such as formamide, dimethylformamide, dimethylacetamide,
hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide
(HMPT); or a sulfoxide such as dimethyl sulfoxide or sulfolane, and
is preferably an alcohol.
[0234] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from 0.degree. C. to
150.degree. C., preferably from 0.degree. C. to 50.degree. C.
[0235] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 5 minutes
to 24 hours, preferably from one hour to 24 hours.
[0236] After the reaction, the desired compound of the present step
is collected from the reaction mixture according to conventional
methods. For example, the desired compound is obtained by adding
water to the reaction mixture, adding a solvent immiscible with
water (for example, benzene, ether, ethyl acetate, etc.) to extract
the desired compound, washing the extracted organic layer with
water, drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(Step C-2)
[0237] This step is to prepare the compound (1) by carrying out, if
necessary, a deprotection reaction of the protecting group, an
N-alkylation reaction of the amine, and a carbamoylation reaction
of the hydroxyl group of the compound (VII) obtained in Step
C-1.
[0238] The present step is carried out similarly to Step A-2.
[0239] The compound (II) used in the above Process A and Process B
can be obtained by the following Process D, Process E, Process H,
Process I or Process J, and the compound (VI) used in Process C can
be obtained by the following Process F or Process G.
##STR00011##
##STR00012##
##STR00013##
##STR00014##
##STR00015##
##STR00016##
##STR00017##
[0240] In the above schemes, R.sup.5, R.sup.2a, R.sup.3a, R.sup.b,
A, Arom.sup.a, E.sup.c, L and X.sup.2 have the same meanings as
defined above, Alk represents a C.sub.1-C.sub.6 alkyl group, Hal
represents a halogen atom, L.sup.a indicates the above L or a
protected hydroxyl group, n represents an integer of from 0 to 4, m
represents an integer of from 1 to 6 and p represents an integer of
from 1 to 3.
[0241] The protecting group for the hydroxyl group in L.sup.a is
not particularly limited so long as it can stably protect the
hydroxyl group during the reaction, and specifically means a
protecting group which is cleavable by a chemical method such as
hydrogenolysis, hydrolysis, electrolysis and photolysis, and may
include the above "aliphatic acyl group"; the above "aromatic acyl
group"; the above "tetrahydropyranyl or tetrahydrothiopyranyl
group"; the above "silyl group" the above "alkoxymethyl group"; the
above "substituted ethyl group"; the above "aralkyl group"; the
above "alkoxycarbonyl group"; the above "alkenyloxycarbonyl group";
and the above "aralkyloxycarbonyl group".
[0242] In the following, Process D to Process J are described in
detail.
(Process D)
(Step D-1)
[0243] This step is to prepare the compound (X) by reacting the
compound (VIII) which is publicly known or easily obtainable from
publicly known compounds, the compound (IX) and malonic acid.
[0244] The present step is accomplished by reacting the compounds
according to the method described in Helv. Chim. Acta, 68, 403
(1985).
[0245] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, cyclohexane, heptane, ligroin or
petroleum ether; an aromatic hydrocarbon such as benzene, toluene
or xylene; a halogenated hydrocarbon such as dichloromethane,
chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene
or dichlorobenzene; an ether such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene
glycol dimethyl ether; an ester such as methyl acetate or ethyl
acetate; or an alcohol such as methanol, ethanol, propanol,
isopropanol, butanol or isobutanol, and is preferably an alcohol
(particularly ethanol or propanol).
[0246] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from 0.degree. C. to
150.degree. C., preferably from 50.degree. C. to 100.degree. C.
[0247] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 30 minutes
to 24 hours, preferably from one hour to 12 hours.
[0248] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after completion of the reaction, the desired compound is
obtained by collecting by filtration. The desired compound of the
present step can be used for the subsequent step without
purification.
[0249] In the desired compound of the present reaction, if
necessary, a protecting group can be introduced onto the hydroxyl
group and the amino group according to known methods (for example,
the methods described in "Protective Groups in Organic Synthesis"
(written by Theodora W. Geene, Peter G. M. Wuts, 1999 published by
A Wiley-Interscience Publication)). The reaction for introducing
the protecting group may be carried out in an arbitrary step other
than the present step, and a person skilled in the art, when
introducing the protecting group, can easily select an appropriate
step depending on the desired compound.
[0250] Namely, in the case where a protecting group is introduced
onto the hydroxyl group, for example, the step is carried out as
follows.
[0251] The compound employed for protecting the hydroxyl group may
be an aralkyl halide compound such as benzyl chloride, benzyl
bromide, 4-nitrobenzyl bromide or 4-methoxybenzyl bromide; an
alkoxy-, alkylthio- or aralkyloxy-substituted alkyl halide compound
such as methoxymethyl chloride, methylthiomethyl chloride,
ethoxyethyl chloride or benzyloxymethyl chloride; an unsaturated
ether such as methylvinyl ether or ethylvinyl ether; or a silyl
compound such as hexamethyldisilazane, trimethylsilyl chloride,
tri-n-propylsilyl chloride, t-butyldimethylsilyl chloride or
diphenyl-t-butylsilyl chloride, as the preferred compounds.
[0252] The reagent employed here may be an organic base such as
triethylamine, pyridine, 4-N,N-dimethylaminopyridine, imidazole or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); or an inorganic base such
as sodium hydroxide, potassium hydroxide or potassium carbonate. In
the case where an unsaturated ether is used, the reaction is
carried out in the presence of a small amount of an acid, for
example, a mineral acid such as hydrochloric acid or hydrobromic
acid, or an organic acid such as picric acid, trifluoroacetic acid;
benzenesulfonic acid, 4-toluenesulfonic acid or camphorsulfonic
acid in the presence or absence of an inert solvent. The solvent to
be employed here is not particularly limited so long as it does not
inhibit the reaction and dissolves the starting material to some
extent, and may be an ether such as ether, tetrahydrofuran or
dioxane; an amide such as formamide, dimethylformamide or
dimethylacetamide; a halogenated hydrocarbon such as
dichloromethane, chloroform or carbon tetrachloride; or an aromatic
hydrocarbon such as benzene, toluene or xylene, and is preferably
an amide (particularly dimethylformamide) or a halogenated
hydrocarbon. The reaction can also be carried out by using an
excess amount of vinyl ether compound to act also as the solvent in
the absence of an inert solvent.
[0253] The reaction temperature varies depending on the solvent,
starting material, reagent, reaction temperature, etc., but it is
usually from 0.degree. C. to 50.degree. C.
[0254] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc. but it is usually
from 30 minutes to 3 hours.
[0255] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by appropriately neutralizing the reaction mixture, and, in the
case where insolubles exist, removing them by filtration, adding an
organic solvent immiscible with water such as ethyl acetate,
washing with water, separating the organic layer containing the
desired compound, drying with anhydrous magnesium sulfate or the
like and evaporating the solvent. The thus obtained desired
compound can be further purified, if necessary, by conventional
methods, for example, recrystallization, reprecipitation or
chromatography.
[0256] In the case where a protecting group is introduced onto the
amino group, the step is, for example, carried out as follows.
[0257] The introduction of the protecting group is accomplished by
<Method 1> in which the compound is reacted with from 1 to 4
equivalents (preferably from 2 to 3 equivalents) of a compound of
formula: P.sup.1-LG or a compound of formula: P.sup.1--O--P.sup.1
(in the case where P.sup.1 is an acyl group) in the presence or
absence of a base (preferably in the absence of a base) in an inert
solvent; or <Method 2> in which the compound is reacted with
a compound of formula: P.sup.1--OH (in the case where P.sup.1 is an
acyl group) in the presence of a condensing agent and in the
presence or absence of a catalytic amount of base (preferably in
the presence of both) in an inert solvent; or <Method 3> in
which the compound is reacted with a compound of formula:
P.sup.1--OH (in the case where P.sup.1 is an acyl group) in the
presence of a halogenated phosphoric acid dialkyl ester (preferably
diethyl chlorophosphate) and a base in an inert solvent.
[0258] In the above, the leaving group LG may be a group similar to
those described above.
[0259] The compound of formula: P.sup.1-LG used in the above
<Method 1> may be t-butoxycarbonyl chloride, t-butoxycarbonyl
bromide, 2-trimethylsilylethoxycarbonyl chloride,
2-trimethylsilylethoxycarbonyl bromide, p-methoxybenzyloxycarbonyl
chloride, p-methoxybenzyloxycarbonyl bromide, allyloxycarbonyl
chloride or allyloxycarbonyl bromide, and is preferably
t-butoxycarbonyl chloride.
[0260] The compound of formula: P.sup.1--O--P.sup.1 used in
<Method 1> may be di-t-butyl dicarbonate,
2-trimethylsilylethoxycarboxylic anhydride,
p-methoxybenzyloxycarboxylic acid or allyloxycarboxylic anhydride,
and is preferably di-t-butyl dicarbonate.
[0261] The solvent employed in <Method 1> is not particularly
limited so long as it does not inhibit the reaction and dissolves
the starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such
as benzene, toluene or xylene; a halogenated hydrocarbon such as
dichloromethane, chloroform, carbon tetrachloride, dichloroethane,
chlorobenzene or dichlorobenzene; an ester such as ethyl formate,
ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate;
an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a
nitrile such as acetonitrile or isobutyronitrile; or an amide such
as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably an ether
(particularly diethyl ether or tetrahydrofuran) or a halogenated
hydrocarbon (particularly dichloromethane).
[0262] The base employed in <Method 1> may be an organic
amine such as N-methylmorpholine, triethylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine,
imidazole, quinoline, N,N-dimethylaniline or N,N-diethylaniline,
and is preferably triethylamine or
4-(N,N-dimethylamino)pyridine.
[0263] A catalytic amount of 4-(N,N-dimethylamino)pyridine or
4-pyrrolidinopyridine can be also used in combination with other
bases, and a quaternary ammonium salt such as
benzyltriethylammonium chloride or tetrabutylammonium chloride or a
crown ether such as dibenzo-18-crown-6 can be also added in order
to effectively carry out the reaction.
[0264] The reaction temperature in <Method 1> is usually from
-20.degree. C. to 100.degree. C., preferably from -10.degree. C. to
50.degree. C.
[0265] The reaction time in <Method 1> mainly varies
depending on the reaction temperature, starting compound, base used
and kind of solvent used, but it is usually from 10 minutes to one
day, preferably from 30 minutes to 12 hours.
[0266] The compound of formula: P.sup.1--OH employed in the
above
<Method 2> and <Method 3> may be t-butoxycarboxylic
acid, 2-trimethylsilylethoxycarboxylic acid,
p-methoxybenzyloxycarboxylic acid or allyloxycarboxylic acid, and
is preferably pivalic acid.
[0267] The solvent employed in the above <Method 2> is not
particularly limited so long as it does not inhibit the reaction
and dissolves the starting material to some extent, and may be an
aliphatic hydrocarbon such as hexane or heptane; an aromatic
hydrocarbon such as benzene, toluene or xylene; a halogenated
hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ester such as ethyl formate, ethyl acetate, propyl acetate, butyl
acetate or diethyl carbonate; an ether such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or
diethylene glycol dimethyl ether; a nitrile such as acetonitrile or
isobutyronitrile; or an amide such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably a halogenated
hydrocarbon (dichloromethane or carbon tetrachloride) or an ether
(particularly diethyl ether, tetrahydrofuran or dioxane).
[0268] The condensing agent employed in <Method 2> may be
dicyclohexylcarbodiimide, carbonyldimidazole or
1-methyl-2-chloro-pyridinium iodide-triethylamine, and is
preferably dicyclohexylcarbodiimide.
[0269] The base employed in <Method 2> can be one which is
similar to the base employed in the above <Method 1>,
preferably triethylamine or 4-(N,N-dimethylamino)pyridine.
[0270] The reaction temperature in <Method 2> is usually from
-20.degree. C. to 80.degree. C., preferably from 0.degree. C. to
30.degree. C.
[0271] The reaction time in <Method 2> varies depending
mainly on the reaction temperature, starting compound, reaction
reagent and kind of solvent used, but it is usually from 10 minutes
to 3 days, preferably from 30 minutes to one day.
[0272] The solvent employed in the above <Method 3> is not
particularly limited so long as it does not inhibit the reaction
and dissolves the starting material to some extent, and may be an
aliphatic hydrocarbon such as hexane or heptane; an aromatic
hydrocarbon such as benzene, toluene or xylene; a halogenated
hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ester such as ethyl formate, ethyl acetate, propyl acetate, butyl
acetate or diethyl carbonate; an ether such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or
diethylene glycol dimethyl ether; a nitrile such as acetonitrile or
isobutyronitrile; or an amide such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably an ether (diethyl
ether or tetrahydrofuran) or an amide (N,N-dimethylformamide or
N,N-dimethylacetamide).
[0273] The base employed in <Method 3> can be, for example,
one which is similar to the base employed in the above <Method
1>, preferably triethylamine or
4-(N,N-dimethylamino)pyridine.
[0274] The reaction temperature in <Method 3> is from
0.degree. C. to the reflux temperature of the solvent used,
preferably from 20.degree. C. to 50.degree. C.
[0275] The reaction time in <Method 3> varies depending
mainly on the reaction temperature, starting compound, reaction
reagent and kind of solvent used, but it is usually from 10 minutes
to 3 days, preferably from 30 minutes to one day.
[0276] After the reaction, the desired compound obtained by the
above method is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by evaporating the
solvent or by pouring water onto the residue after the solvent is
evaporated, adding a solvent immiscible with water (for example,
benzene, ether, ethyl acetate, etc.) to extract the desired
compound, washing the extracted organic layer with water, followed
by drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, according to conventional methods,
for example, recrystallization, reprecipitation or
chromatography.
(Step D-2)
[0277] This step is to prepare the compound (XI) by esterifying the
carboxyl group of the compound (X) obtained in Step D-1.
[0278] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be water; an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane, chlorobenzene or
dichlorobenzene; an ester such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate or diethyl carbonate; an ether such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane or diethylene glycol dimethyl ether; a nitro
compound such as nitroethane or nitrobenzene; a nitrile such as
acetonitrile or isobutyronitrile; an amide such as formamide,
dimethylformamide, dimethylacetamide or hexamethylphosphoric
triamide; or a sulfoxide such as dimethyl sulfoxide or sulfolane.
In the present reaction, an esterifying agent such as ethanol can
be used as the solvent.
[0279] The esterifying reagent to be employed here may be a
combination of an alcohol such as methanol or ethanol and an
inorganic acid such as sulfuric acid; an alkylated inorganic acid
such as dimethylsulfuric acid; or an alkyldiazo compound such as
diazomethane.
[0280] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from 0.degree. C. to
150.degree. C., preferably from 20.degree. C. to 100.degree. C.
[0281] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 30 minutes
to 24 hours, preferably from one hour to 12 hours.
[0282] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after completion of the reaction, the desired compound is
obtained by collecting through filtration. Or, for example, after
completion of the reaction, the desired compound is obtained by
adding water to the reaction solution, adding a solvent immiscible
with water (for example, benzene, ether, ethyl acetate, etc.) to
extract the desired compound, washing the extracted organic layer
with water, drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(Step D-3)
[0283] This step is to prepare the compound (II) by reducing the
ester of the compound (X.sup.1) obtained in Step D-2.
[0284] The reducing agent to be employed here is preferably a
hydride compound such as lithium aluminum hydride, sodium
borohydride, lithium borohydride or diisobutyl aluminum hydride,
more preferably lithium aluminum hydride.
[0285] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an ether such as
diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, and is
preferably an ether (particularly tetrahydrofuran).
[0286] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from
-78.degree. C. to 100.degree. C., preferably from -78.degree. C. to
room temperature.
[0287] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 10 minutes to 24 hours, preferably from one hour to 10
hours.
[0288] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by appropriately neutralizing the reaction mixture and, in the case
where insolubles exist, removing them by filtration, adding an
organic solvent immiscible with water such ethyl acetate, washing
with water, separating the organic layer containing the desired
compound, drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography.
[0289] In the case where A of the desired compound is a group other
than a methylene group, after the hydroxyl group moiety is further
substituted for a cyano group (Reaction D-3a) and converted into a
formyl group by reduction (Reaction D-3b), it is further reduced to
a hydroxyl group (Reaction D-3c). Thereby, it can be converted into
an ethylene group in which the number of carbons is increased by
one, and the desired compound (II) can be prepared by repeating
this step a plurality of times.
[0290] Further, in the case where the desired compound is cyclized,
the desired compound (II) can be prepared by carrying out a
cyclization reaction (D-3d).
(Reaction D-3a)
[0291] The present reaction is accomplished by (.alpha.) reacting
an alkyl or arylsulfonyl halide (preferably methanesulfonyl
chloride) with the hydroxyl group of the compound and (.beta.)
reacting the product with an alkyl metal cyanide (preferably sodium
cyanide or potassium cyanide).
(.alpha.) Reaction of Hydroxyl Group with a Sulfonyl Halide
[0292] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an aromatic
hydrocarbon such as benzene; a halogenated hydrocarbon such as
dichloromethane or chloroform; or an ether such as diethyl ether,
tetrahydrofuran, dioxane or dimethoxyethane, and is preferably an
ether (particularly tetrahydrofuran).
[0293] The base to be employed here may be an organic base such as
triethylamine, diisopropylamine, isopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline or N,N-diethylaniline, and is preferably
triethylamine.
[0294] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from -20 to
50.degree. C., preferably from 0 to 25.degree. C.
[0295] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 5 minutes to 10 hours, preferably from 10 minutes to 3
hours.
[0296] After the reaction, the desired compound of the present step
is collected from the reaction mixture according to conventional
methods. For example, after completion of the reaction, the desired
compound is obtained by adding water to the reaction solution,
adding a solvent immiscible with water (for example, benzene,
ether, ethyl acetate, etc.) to extract the desired compound,
washing the extracted organic layer with water, drying with
anhydrous magnesium sulfate or the like and evaporating the
solvent. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography. The desired
compound of the present step can be used for the subsequent step
without purification.
(.beta.) Reaction with Cyanide
[0297] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an ether such as
tetrahydrofuran, dioxane or dimethoxyethane; a nitrile such as
acetonitrile or isobutyronitrile; an amide such as formamide,
dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; or a sulfoxide such as dimethyl sulfoxide or sulfolane,
and is preferably an amide (particularly dimethylformamide).
[0298] In the present reaction, crown ether compound can be added.
The crown ether compound employed here may be 12-crown-4,
15-crown-5, 18-crown-6, 1-aza-12-crown-4,1-aza-15-crown-5,
1-aza-18-crown-6, benzo-15-crown-5,4'-nitrobenzo-15-crown-5,
benzo-18-crown-6, dibenzo-18-crown-6, dibenzo-24-crown-8,
dicyclohexano-18-crown-6 or dicyclohexano-24-crown-8, and is
preferably 15-crown-5, 18-crown-6,
1-aza-15-crown-5,1-aza-18-crown-6,
benzo-15-crown-5,4'-nitrobenzo-15-crown-5, benzo-18-crown-6,
dibenzo-18-crown-6 or dicyclohexano-18-crown-6, more preferably
15-crown-5, 18-crown-6, 1-aza-18-crown-6, benzo-18-crown-6,
dibenzo-18-crown-6 or dicyclohexano-18-crown-6, particularly
preferably 15-crown-5 or 18-crown-6.
[0299] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from 0 to
180.degree. C., preferably from 0 to 50.degree. C.
[0300] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc. but it is usually
from 1 to 24 hours, preferably from 2 to 12 hours.
[0301] After the reaction, the desired compound of the present step
is collected from the reaction mixture according to conventional
methods. For example, after completion of the reaction, the desired
compound is obtained by adding water to the reaction solution,
adding a solvent immiscible with water (for example, benzene,
ether, ethyl acetate, etc.) to extract the desired compound,
washing the extracted organic layer with water, drying with
anhydrous magnesium sulfate or the like and evaporating the
solvent. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
(Reaction D-3b)
[0302] The reducing agent employed here is preferably diisobutyl
aluminum hydride.
[0303] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an ether
such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane;
a halogenated hydrocarbon such as dichloromethane, chloroform or
dichloroethane; an aromatic hydrocarbon such as benzene, toluene or
xylene; or an aliphatic hydrocarbon such as pentane or hexane, and
is more preferably a halogenated hydrocarbon such as
dichloromethane.
[0304] The present step is preferably carried out under an inert
gas stream such as nitrogen, helium or argon.
[0305] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from
-78.degree. C. to 50.degree. C., preferably from -20.degree. C. to
room temperature.
[0306] The reaction time varies depending on the solvent, starting
material reagent, reaction temperature, etc., but it is usually
from 10 minutes to 24 hours, preferably from one to 5 hours.
[0307] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by appropriately neutralizing the reaction mixture and, in the case
where insolubles exist, removing them by filtration, adding a
solvent immiscible with water such as ethyl acetate, washing with
water, separating the organic layer containing the desired
compound, drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, by conventional methods, for
example, recrystallization, reprecipitation or chromatography. The
desired compound of the present step can be used for the subsequent
step without purification.
(Reaction D-3c)
[0308] The reducing agent to be employed here is preferably a
hydride compound such as lithium aluminum hydride, sodium
borohydride or diisobutyl aluminum hydride, more preferably sodium
borohydride.
[0309] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an ether
such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane;
or an alcohol such as methanol or ethanol, and is preferably an
ether (particularly tetrahydrofuran) or an alcohol (particularly
methanol).
[0310] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from
-78.degree. C. to 100.degree. C., preferably from -78.degree. C. to
room temperature.
[0311] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 10 minutes to 24 hours, preferably from one to 10 hours.
[0312] After completion of the reaction, the desired compound of
the present reaction is collected from the reaction mixture
according to conventional methods. For example, the desired
compound is obtained by appropriately neutralizing the reaction
mixture and, in the case where insolubles exist, removing them by
filtration, adding an organic solvent immiscible with water such as
ethyl acetate, washing with water, separating the organic layer
containing the desired compound, drying with anhydrous magnesium
sulfate or the like and evaporating the solvent. The thus obtained
desired compound can be further purified, if necessary, by
conventional methods, for example, recrystallization,
reprecipitation or chromatography.
[0313] A leaving group can be introduced, if necessary, to the
desired compound of the present reaction by known methods.
[0314] Namely, in the case where the leaving group is a halogen
atom, the desired compound can be obtained according to the process
of (Reaction C-1b), and in the case where the leaving group is a
sulfonyloxy group, the desired compound can be obtained according
to the method of (Reaction D-3a) (.alpha.).
(Reaction D-3d)
[0315] This reaction is carried out similarly to (Reaction
A-2d).
[0316] The present reaction may be carried out at any stage of the
reduction reaction of the ester or (Reaction D-3a) to (Reaction
D-3c), depending on the desired compound.
(Process E)
(Step E-1)
[0317] This step is to prepare the compound (XII) by enolating an
acetate derivative with a base, followed by reacting with the
compound (VIII), which is publicly known or easily obtainable from
known compounds.
[0318] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, cyclohexane, heptane, ligroin or
petroleum ether; an aromatic hydrocarbon such as benzene, toluene
or xylene; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol
dimethyl ether; an amide such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; or a sulfoxide
such as dimethyl sulfoxide or sulfolane, and is preferably an
alcohol (particularly methanol or ethanol).
[0319] The base may be an alkali metal hydroxide such as lithium
hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal
hydride such as lithium hydride, sodium hydride or potassium
hydride; an alkyl lithium such as methyl lithium, ethyl lithium or
butyl lithium; or a lithium alkylamide such as lithium
diisopropylamide, lithium dicyclohexylamide or lithium
bis(trimethylsilyl)amide, and is preferably an alkali metal
hydroxide (particularly potassium hydroxide).
[0320] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -100.degree. C. to
50.degree. C., preferably from 0.degree. C. to room
temperature.
[0321] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 5 minutes
to 24 hours, preferably from one hour to 12 hours.
[0322] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after completion of the reaction, the desired compound is
obtained by adding water to the reaction solution, adding a solvent
immiscible with water (for example, benzene, ether, ethyl acetate,
etc.) to extract the desired compound, washing the extracted
organic layer with water, drying with anhydrous magnesium sulfate
or the like and evaporating the solvent. The thus obtained desired
compound can be further purified, if necessary, by conventional
methods, for example, recrystallization, reprecipitation or
chromatography. A plurality of compounds can sometimes be obtained
in the present step but it can be easily judged by a person skilled
in the art which compound is the desired compound by using the
usual means (for example, measurement of a coupling constant in NMR
spectrum, etc.) and the desired compound can be obtained.
(E-2)
[0323] The Present Step is to Prepare the Compound (XI) by carrying
out a Michael addition using a metal amide on the compound
(XII).
[0324] The present step can be accomplished by the addition
reaction of the metal amide derived from benzylphenylethylamine
described in Tetrahedron; Asymmetry, 2, 183 (1991).
[0325] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic
hydrocarbon such as hexane, cyclohexane, heptane, ligroin or
petroleum ether; an aromatic hydrocarbon such as benzene, toluene
or xylene; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol
dimethyl ether; or an amide such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone or
hexamethylphosphoric triamide, and is preferably an ether
(particularly tetrahydrofuran).
[0326] The reaction is carried out in the presence of a base. The
base to be employed here may be an alkyl lithium such as methyl
lithium or butyl lithium; an alkali metal disilazide such as
lithium hexamethyldisilazide, sodium hexamethyldisilazide or
potassium hexamethyldisilazide; or a lithium amide such as lithium
diisopropylamide or lithium dicyclohexylamide, and is preferably an
alkyl lithium (particularly butyl lithium).
[0327] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -78.degree. C. to
40.degree. C., preferably from -78.degree. C. to 0.degree. C.
[0328] The reaction time varies depending on the starting compound,
reagent, and reaction temperature, but it is usually from 10
minutes to 24 hours, preferably from 10 minutes to 4 hours.
[0329] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after completion of the reaction, the desired compound is
obtained by removing the catalyst by filtration and evaporating the
filtrate. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
(Step E-3)
[0330] This step is to prepare the compound (II) by reducing the
ester of the compound (X.sup.1) obtained in Step E-2.
[0331] The present step is carried out similarly to Step D-3
(Process F)
(Step F-1)
[0332] This step is to prepare the compound (XIV) by enolating the
compound (XII), which is publicly known or easily obtainable from
publicly known compounds, with a base, followed by reacting with an
aldehyde.
[0333] The present reaction is carried out similarly to Step
E-1.
(Step F-2)
[0334] This step is to prepare the compound (VI) by reducing the
compound (XIV) obtained in Step F-1.
[0335] The present step is carried out similarly to (Reaction
B-1c).
(Process G)
(Step G-1)
[0336] This step is to prepare the compound (XIV) by reacting the
compound (XV), which is publicly known or easily obtainable from
publicly known compounds, with a compound of the formula:
R.sup.3-E.sup.c-H (wherein R.sup.3 and E.sup.c have the same
meanings as defined above) in the presence of a base.
[0337] The present step is carried out similarly to Step A-1.
(Step G-2)
[0338] This step is a step in which the ester of the compound (XVI)
obtained in G-1 is hydrolyzed (Reaction G-2a) and is then amidated
(Reaction G-2b).
(Reaction G-2a)
[0339] The base may preferably be an alkali metal carbonate such as
sodium carbonate or potassium carbonate; an alkali metal hydroxide
such as sodium hydroxide or potassium hydroxide; or a concentrated
ammonia-methanol solution.
[0340] The solvent to be employed here may preferably be water; or
a mixture of an organic solvent such as an alcohol, e.g., methanol,
ethanol or n-propanol, or an ether, e.g., tetrahydrofuran or
dioxane, and water.
[0341] The reaction temperature and the reaction time vary
depending on the starting material, solvent and reagent used, but
the reaction is usually carried out at from 0.degree. C. to
150.degree. C. for from one to 10 hours in order to inhibit side
reactions.
[0342] After the reaction, the desired compound is collected from
the reaction mixture according to conventional methods. For
example, after completion of the reaction, the desired compound is
obtained by evaporating the filtrate. The thus obtained desired
compound can be further purified, if necessary, by conventional
methods, for example, recrystallization, reprecipitation or
chromatography.
(Reaction G-2b)
[0343] The reaction is carried out according to conventional
methods in peptide synthesis, for example, by an activated ester
method, a mixed acid anhydride method, or a condensation
method.
1) The activated ester method is carried out by reacting the
compound with an active esterifying agent in an inert solvent to
prepare an active ester and reacting it with
N,O-dimethylhydroxylamine in an inert solvent.
[0344] The active esterifying agent employed here may be an
N-hydroxy compound such as N-hydroxysuccinimide,
1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide;
or a disulfide compound such as dipyridyl disulfide. Furthermore,
the active esterification reaction is preferably carried out in the
presence of a condensing agent such as dicyclohexylcarbodiimide,
carbonyldiimidazole or triphenylphosphine.
[0345] The solvent to be employed in both reactions is not
particularly limited so long as it does not inhibit the reaction
and dissolves the starting material to some extent, and may be a
halogenated hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a
nitrile such as acetonitrile or isobutyronitrile; or an amide such
as formamide, dimethylformamide, dimethylacetamide,
hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide
(HMPT), and is preferably an ether (particularly tetrahydrofuran),
a nitrile (particularly acetonitrile) or an amide (particularly
dimethylformamide).
[0346] The reaction temperature varies depending on the starting
compound, reagent, etc., but it is usually from -20.degree. C. to
100.degree. C. for the active esterification reaction, preferably
from 0.degree. C. to 50.degree. C. For the reaction with the active
ester compound, it is from -20.degree. C. to 100.degree. C.,
preferably from 0.degree. C. to 50.degree. C.
[0347] The reaction time varies depending on the starting compound,
reagent and reaction temperature, but it is usually from 30 minutes
to 24 hours in both reactions, preferably from 1 to 12 hours.
[0348] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by evaporating the
solvent, or pouring water onto the residue from which the solvent
has been evaporated, adding a solvent immiscible with water (for
example, benzene, ether, ethyl acetate, etc.) to extract the
desired compound, washing the extracted organic layer with water,
drying with anhydrous magnesium sulfate or the like and evaporating
the solvent. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
2) Next, the mixed acid anhydride method is carried out by reacting
the compound with a mixed acid anhydride forming agent in the
presence or absence of a base (preferably in the presence of a
base) in an inert solvent to prepare a mixed acid anhydride, and
reacting the mixed acid anhydride with N,O-dimethylhydroxylamine in
an inert solvent.
[0349] The mixed acid anhydride forming agent employed here may be
an oxalyl halide such as oxalyl chloride; a chloroformic acid C1-C8
ester such as ethyl chloroformate or isobutyl chloroformate; a
C1-C5 alkanoyl halide such as pivaloyl chloride; or a C1-C4 alkyl
or di-C6-C14 arylcyanophosphoric acid such as
diethylcyanophosphoric acid or diphenylcyanophosphoric acid, and is
preferably an oxalyl halide (particularly oxalyl chloride).
[0350] The reaction is carried out in the presence or absence of a
base, but it is preferably carried out in the presence of a base.
The base employed here may be an alkali metal carbonate such as
sodium carbonate, potassium carbonate or lithium carbonate; or an
organic amine such as triethylamine, tributylamine,
diisopropylethylamine, N-methylmorpholine, pyridine,
4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline,
N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene,
1,4-diazabicyclo[2.2.2]octane (DABCO), or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably an
organic amine (particularly triethylamine).
[0351] The reaction to prepare the mixed acid anhydride is
preferably carried out in the presence of a solvent. The solvent to
be employed here is not particularly limited so long as it
dissolves the starting material to some extent, and may be a
halogenated hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or an
amide such as formamide, dimethylformamide, dimethylacetamide,
hexamethylphosphoramide (HMPA), or hexamethylphosphorus triamide
(HMPT), and is preferably a halogenated hydrocarbon (particularly
dichloromethane).
[0352] The reaction temperature for the reaction to prepare the
mixed acid anhydride varies depending on the starting compound,
reagent, etc., but it is usually from -50.degree. C. to 100.degree.
C., preferably from -10.degree. C. to 50.degree. C.
[0353] The reaction time for the reaction to prepare the mixed acid
anhydride varies depending on the starting compound, reagent and
reaction temperature, but it is usually from 5 minutes to 20 hours,
preferably from 10 minutes to 10 hours.
[0354] Next, the solvent to be employed for the reaction of the
mixed acid anhydride and N,O-dimethylhydroxylamine is not
particularly limited so long as it does not inhibit the reaction
and dissolves the starting material to some extent, and may be an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or an
amide such as formamide, dimethylformamide, dimethylacetamide,
hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide
(HMPT), and is preferably an amide (particularly
dimethylformamide).
[0355] The reaction temperature for the reaction with the mixed
acid anhydride varies depending on the starting compound, reagent,
etc., but it is usually from -30.degree. C. to 100.degree. C.,
preferably from 0.degree. C. to 80.degree. C.
[0356] The reaction time for the reaction with the mixed acid
anhydride varies depending on the starting compound, reagent and
reaction temperature, but it is usually from 5 minutes to 24 hours,
preferably from 10 minutes to 12 hours.
[0357] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by evaporating the
solvent, or pouring water onto the residue from which the solvent
has been evaporated, adding a solvent immiscible with water (for
example, benzene, ether, ethyl acetate, etc.) to extract the
desired compound, washing the extracted organic layer with water,
drying with anhydrous magnesium sulfate or the like and evaporating
the solvent. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
3) Next, the condensation method is carried out by reacting the
compound with N,O-dimethylhydroxylamine in an inert solvent using a
condensing agent and a base.
[0358] The condensing agent employed here may be an azodicarboxylic
acid di-lower alkyl ester-triphenylphosphine such as diethyl
azodicarboxylate-triphenylphosphine; an
N,N'-dicycloalkylcarbodiimide such as N,N'-dicyclohexylcarbodiimide
(DCC); a 2-halo-1-lower alkyl pyridinium halide such as
2-chloro-1-methylpyridinium iodide; a diarylphosphorylazide such as
diphenylphosphorylazide (DPPA); a chloroformate such as ethyl
chloroformate or isobutyl chloroformate; a phosphoryl chloride such
as diethyl phosphoryl chloride; an imidazole derivative such as
N,N'-carbodiimidazole (CDI); a carbodiimide derivative such as
1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (EDAPC);
or a sulfonyl chloride derivative such as
2,4,6-triisopropylbenzenesulfonyl chloride, and is preferably DDC,
CDI, 2-chloro-1-methylpyridinium iodide, isobutyl chloroformate or
diethylphosphoryl chloride.
[0359] The base employed here may be an organic base such as
triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
4-pyrrolidinopyridine, N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane
(DABCO), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is
preferably triethylamine, diisopropylethylamine, pyridine or
4-pyrrolidinopyridine.
[0360] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may preferably be an aromatic
hydrocarbon such as benzene, toluene or xylene; a halogenated
hydrocarbon such as dichloromethane, chloroform or dichloroethane;
an ester such as ethyl acetate or propyl acetate; an ether such as
diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or
diethylene glycol dimethyl ether; a ketone such as acetone or
methyl ethyl ketone; a nitro compound such as nitromethane; a
nitrile such as acetonitrile or isobutyronitrile; or an amide such
as dimethylformamide, dimethylacetamide or hexamethylphosphoric
triamide, and is more preferably a nitrile (particularly
acetonitrile), an aromatic hydrocarbon (particularly benzene), a
halogenated hydrocarbon (particularly dichloromethane), or an ether
(particularly tetrahydrofuran).
[0361] The reaction temperature varies depending on the solvent,
starting material, reagent, etc., but it is usually from 0.degree.
C. to 150.degree. C., preferably from 25.degree. C. to 120.degree.
C.
[0362] The reaction time varies depending on the solvent, starting
material, reagent, reaction temperature, etc., but it is usually
from 10 minutes to 48 hours, preferably from one to 24 hours.
[0363] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by adding an organic solvent immiscible with water such as ethyl
acetate to the reaction mixture, washing with water, separating the
organic layer containing the desired compound, drying with
anhydrous magnesium sulfate or the like and evaporating the
solvent. The thus obtained desired compound can be further
purified, if necessary, according to conventional methods, for
example, recrystallization, reprecipitation or chromatography.
(Step G-3)
[0364] This step is to prepare the compound (VI) by reacting the
carbanion obtained by treatment of the compound (XVIII) with a
base, with the compound (XVII) obtained in Step G-2.
[0365] When the compound (XVIII) is treated with a base, the base
employed may be an alkyl lithium such as methyl lithium, butyl
lithium, s-butyl lithium or t-butyl lithium, and is preferably
butyl lithium, s-butyl lithium or t-butyl lithium, more preferably
butyl lithium.
[0366] The solvent to be employed here is not particularly limited
so long as it does not inhibit the reaction and dissolves the
starting material to some extent, and may be an aliphatic or
alicyclic hydrocarbon such as hexane or cyclohexane; an aromatic
hydrocarbon such as benzene, toluene or xylene; or an ether such as
diethyl ether, tetrahydrofuran or dioxane, and is preferably an
aromatic hydrocarbon or an ether, more preferably an ether
(particularly tetrahydrofuran).
[0367] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from
-78.degree. C. to 0.degree. C., preferably from -78.degree. C. to
-20.degree. C.
[0368] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc. but it is usually
from 10 minutes to 24 hours, preferably from 10 minutes to 6
hours.
[0369] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by pouring the reaction
mixture into an aqueous solution such as a cooled saturated aqueous
ammonium chloride solution, adding a solvent immiscible with water
(for example, benzene, ether, ethyl acetate, etc.) to extract the
desired compound, washing the extracted organic layer with water,
drying with anhydrous magnesium sulfate or the like and evaporating
the solvent. The thus obtained desired compound can be further
purified, if necessary, by conventional methods, for example,
recrystallization, reprecipitation or chromatography.
(Process H)
(Step H-1)
[0370] This step is one in which after an aldol condensation
reaction is carried out on the compound (VIII), which is publicly
known or easily obtainable from publicly known compounds (Reaction
H-1a), the ester is reduced (Reaction H-1b) and the produced
primary alcohol is protected, if necessary (Reaction H-1c).
(Reaction H-1a)
[0371] The present reaction is carried out by firstly treating the
reagent with a base to prepare an organic anionic reagent and
adding the compound (VIII) thereto.
[0372] The solvent to be employed here may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane, chlorobenzene or
dichlorobenzene; or an ether such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene
glycol dimethyl ether, and is preferably an ether (particularly
tetrahydrofuran).
[0373] The reagent employed in the present reaction is not
particularly limited so long as it can be used for aldol
condensations, but it is preferably ethyl acetate.
[0374] The base employed here may be an alkali metal hydride such
as lithium hydride, sodium hydride or potassium hydride; an alkali
metal hydroxide such as sodium hydroxide, potassium hydroxide,
barium hydroxide or lithium hydroxide; or an organometal base such
as butyl lithium, lithium diisopropylamide or lithium
bis(trimethylsilyl)amide, and is preferably an organometal base
(particularly lithium bis(trimethylsilyl)amide).
[0375] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from
-100.degree. C. to 50.degree. C., preferably from -78.degree. C. to
0.degree. C.
[0376] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc. but it is usually
from 5 minutes to 12 hours, preferably from 30 minutes to 10
hours.
[0377] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by collecting the desired compound precipitated in the reaction
solution by filtration, or appropriately neutralizing the reaction
solution, evaporating the solvent, pouring water into the reaction
solution, adding a solvent immiscible with water (for example,
benzene, ether, ethyl acetate, etc.) to carry out an extraction,
washing the organic layer containing the desired compound with
water, drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, according to conventional methods,
for example, recrystallization, reprecipitation or
chromatography.
(Reaction H-1b)
[0378] This reaction is carried out similarly to the reduction
reaction of the ester in Step D-3.
(Reaction H-1c)
[0379] This reaction is carried out similarly to the protection
reaction of the hydroxyl group in Step D-2.
[0380] In the present step, the desired R.sup.b can be obtained by
carrying out a similar reaction to (a) in (Reaction A-2d), if
necessary.
(Step H-2)
[0381] This step is to prepare the compound (II) by reacting the
compound (IX) with the compound (XIV) obtained in Step H-1
(Reaction H-2a); and then carrying out similar reactions (Reaction
H-2b) to those in (Reaction D-3a) to (Reaction D-3d).
(Reaction H-2a)
[0382] This step is accomplished by carrying a reaction similar to
<Method 1> of (Reaction A-1a), or carrying out a reaction
similar to (.beta.) of <Method 1> of (Reaction A-1a), after
carrying out a reaction similar to (Reaction C-1b).
(Reaction H-2b)
[0383] This reaction is carried out similarly to (Reaction D-3a) to
(Reaction D-3d).
(Process I)
(Step I-1)
[0384] This step is to prepare the compound (IIa) by carrying out
an acylation reaction (Reaction I-1a) on the compound (XV), which
is publicly known or easily obtainable from publicly known
compounds, followed by carrying out a Bischler-Napieralski reaction
(Reaction I-1b), and by reducing the thus obtained compound
(Reaction I-1c).
(Reaction I-1a)
[0385] The solvent to be employed here may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; a
halogenated hydrocarbon such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane, chlorobenzene or
dichlorobenzene; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxy ethane or diethylene glycol
dimethyl ether; an amide such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone or hexamethylphosphoric triamide; or a
sulfoxide such as dimethyl sulfoxide or sulfolane, and is
preferably an amide (particularly dimethylformamide) or a
halogenated hydrocarbon (particularly dichloromethane).
[0386] The acylating agent employed here is not particularly
limited so long as the produced amide becomes an amide appropriate
for the Bischler-Napieralski reaction, and is preferably
ethylmalonyl chloride.
[0387] The base employed here may be an alkali metal carbonate such
as sodium carbonate, potassium carbonate or lithium carbonate; or
an organic base such as N-methylmorpholine, triethylamine,
tripropylamine, tributylamine, diisopropylethylamine,
dicyclohexylamine, N-methylpiperidine, pyridine,
4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine,
2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,
N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicylo[2.2.2]octane (DABCO) or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably
potassium carbonate or triethylamine.
[0388] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from
-100.degree. C. to 50.degree. C., preferably from -78.degree. C. to
0.degree. C.
[0389] The reaction time varies depending on the solvent, starting
compound, reagent, the reaction temperature, etc., but it is
usually from 5 minutes to 12 hours, preferably from 30 minutes to
10 hours.
[0390] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by collecting the desired compound precipitated in the reaction
solution by filtration, or appropriately neutralizing the reaction
solution, evaporating the solvent, pouring water into the reaction
solution, adding a solvent immiscible with water (for example,
benzene, ether, ethyl acetate, etc.) to perform an extraction,
washing the organic layer containing the desired compound with
water, drying with anhydrous magnesium sulfate or the like and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, according to conventional methods,
for example, recrystallization, reprecipitation or
chromatography.
(Reaction I-1b)
[0391] This reaction is carried out in phosphorus oxychloride.
[0392] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from 25.degree.
C. to 120.degree. C., preferably from 50.degree. C. to 100.degree.
C.
[0393] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc., but it is usually
from 5 minutes to 48 hours, preferably from one hour to 12
hours.
[0394] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods.
[0395] For example the desired compound may be obtained by
filtration of the desired compound precipitated in the reaction
solution or by evaporation of the resulting organic layer after
appropriately neutralizing the reaction solution, filtering,
evaporating the solvent, pouring water into the reaction solution,
adding a solvent immiscible with water (for example, benzene,
ether, ethyl acetate, etc.) to perform an extraction, washing the
organic layer containing the desired compound with water and then
drying with anhydrous magnesium sulfate or the like. The thus
obtained desired compound can be further purified, if necessary, by
conventional methods, for example, recrystallization,
reprecipitation or chromatography.
(Reaction I-1c)
[0396] In this reaction, after a similar reaction to the catalytic
reduction in (Reaction A-2a) is carried out, a reaction is carried
out similar to (Step D-3).
(Process J)
(Step J-1)
[0397] This step is to prepare the compound (IIa) in optically
active form by introducing a chiral auxiliary group to the compound
(XVI), which is publicly known or easily obtainable from publicly
known compounds (Reaction J-1a), introducing a side chain thereto
(Reaction J-1b), and removing the chiral auxiliary group (Reaction
J-1c).
(Reaction J-1a)
[0398] The solvent to be employed here may be an aromatic
hydrocarbon such as benzene, toluene or xylene; or an ether such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane or diethylene glycol dimethyl ether, and is
preferably an aromatic hydrocarbon (particularly toluene).
[0399] The group to introduce the chiral auxiliary group employed
here is not particularly limited so long as it is usually used, and
may be
N,N-dimethyl-N'-[(S/R)-2-(3,3-dimethyl-1-methoxybutyl)]formamidine,
N,N-dimethyl-N'-[(S/R)-2-(3-methyl-1-methoxybutyl)]formamidine or
N,N-dimethyl-N'-[(S/R)-2-(3-methyl-1-methoxypentyl)]formamidine,
and is preferably
N,N-dimethyl-N'-[(S)-2-(3,3-dimethyl-1-methoxybutyl)]formamidine or
N,N-dimethyl-N'-[(R)-2-(3,3-dimethyl-1-methoxybutyl)]formamidine.
[0400] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from 50.degree.
C. to 200.degree. C., preferably from 100.degree. C. to 150.degree.
C.
[0401] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc., but it is usually
from one hour to 72 hours, preferably from 12 hours to 48
hours.
[0402] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by pouring the reaction
mixture into an aqueous solution such as a cooled saturated aqueous
ammonium chloride solution, adding a solvent immiscible with water
(for example, benzene, ether, ethyl acetate, etc.) to extract the
desired compound, washing the extracted organic layer with water,
drying with anhydrous magnesium sulfate or the like, and
evaporating the solvent. The thus obtained desired compound can be
further purified, if necessary, according to conventional methods,
for example, recrystallization, reprecipitation or
chromatography.
(Reaction J-1b)
[0403] The solvent to be employed here may be an aliphatic
hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an
aromatic hydrocarbon such as benzene, toluene or xylene; or an
ether such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane or diethylene glycol dimethyl ether, and
is preferably an ether (particularly the tetrahydrofuran).
[0404] The reagent employed here is a 2-halogeno-1-hydroxyethyl
silyl ether, preferably 2-bromo-1-hydroxyethyl-t-butyldimethylsilyl
ether.
[0405] The base employed here may be an organometal base such as
butyl lithium, lithium diisopropylamide or lithium
bis(trimethylsilyl)amide, and is preferably butyl lithium.
[0406] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from
-90.degree. C. to 0.degree. C., preferably from -78.degree. C. to
-20.degree. C.
[0407] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc., but it is usually
from 5 minutes to 12 hours, preferably from 30 minutes to 3
hours.
[0408] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, the desired compound is obtained
by adding methanol and then evaporating the solvent. The thus
obtained desired compound can be further purified, if necessary,
according to conventional methods, for example, recrystallization,
reprecipitation or chromatography.
(Reaction J-1c)
[0409] The solvent to be employed here may be an ether such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane or diethylene glycol dimethyl ether; or an alcohol
such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,
glycerine, octanol, cyclohexanol or methyl cellosolve, and is
preferably an alcohol (particularly ethanol).
[0410] The acid to be employed here is not particularly limited so
long as it is used in usual reactions as an acid catalyst, and may
preferably be an organic acid such as acetic acid, formic acid,
oxalic acid, methanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, trifluoroacetic acid or
trifluoromethanesulfonic acid, and is preferably acetic acid.
[0411] The reagent employed here is hydrazine, preferably hydrazine
monohydrate.
[0412] The reaction temperature varies depending on the solvent,
starting compound, reagent, etc., but it is usually from
-20.degree. C. to 50.degree. C., preferably from 0.degree. C. to
25.degree. C.
[0413] The reaction time varies depending on the solvent, starting
compound, reagent, reaction temperature, etc., but it is usually
from 30 minutes to 24 hours, preferably from one hour to 12
hours.
[0414] After the reaction, the desired compound of the present
reaction is collected from the reaction mixture according to
conventional methods. For example, after completion of the
reaction, the desired compound is obtained by pouring the reaction
mixture into an aqueous solution such as a cooled saturated aqueous
ammonium chloride solution, adding a solvent immiscible with water
(for example, benzene, ether, ethyl acetate, etc.) to extract the
desired compound, washing the extracted organic layer with water,
drying with anhydrous magnesium sulfate or the like and evaporating
the solvent. The thus obtained desired compound can be further
purified, if necessary, according to conventional methods, for
example, recrystallization, reprecipitation or chromatography.
[0415] The optical purity of the desired compound can be measured
by conventional methods, for example, analysis by chiral HPLC or
the like.
[0416] The compounds of the present invention (I) or
pharmacologically acceptable salts thereof exert both
acetylcholinesterase inhibitory activity and serotonin re-uptake
inhibitory activity. In addition, the compounds of the present
invention (I) exhibit excellent pharmacodynamics, such as
absorption, distribution, and elimination half-life from the blood
stream, and their toxicity to organs such as the liver and kidney
are low. Thus the compounds of the present invention (I) are useful
as remedies and particularly they are useful as prophylactic or
therapeutic agents for various neurological disorders.
[0417] In cases where the compounds of the present invention are
used as prophylactic or therapeutic agents for the disorders
described above, the compounds expressed by the general formula (I)
described above or pharmacologically acceptable salts or esters
thereof may be orally administered in formulations such as tablets,
capsules, granules, powders, or syrups, or non-orally administered
in formulations such as injections, suppositories, patches, or
formulations for external application, by optionally mixing with a
pharmacologically acceptable diluent and excipient, i.e., carrier,
etc.
[0418] Preparations are prepared by conventionally known methods
using additives such as excipients (for instance, organic
excipients including sugar derivatives such as lactose, sucrose,
glucose, mannitol and sorbitol; starch derivatives such as corn
starch, potato starch, .alpha.-starch and dextrin; cellulose
derivatives such as crystalline cellulose; gum Arabic; dextran;
pullulan; and inorganic excipients including silicate derivatives
such as light anhydrous silicic acid, synthetic aluminum silicate,
calcium silicate and magnesium aluminometasilicate; phosphates such
as calcium hydrogenphosphate; carbonates such as calcium carbonate;
and sulfates such as calcium sulfate), lubricants (for instance,
stearic acid, metal salts of stearic acid such as calcium stearate
and magnesium stearate; talc; colloidal silica; waxes such as
beeswax and spermaceti; boric acid; adipic acid; sulfates such as
sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine;
laurylsulphates such as sodium lauryl sulfate and magnesium lauryl
sulfate; silicates such as silicic anhydride and silicic hydrate;
and starch derivatives described above can be listed), binders (for
instance, hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyvinylpyrrolidone, Macrogol and similar excipients described
above), disintegrants (for instance, cellulose derivatives such as
low-substituted hydroxypropylcellulose, carboxymethylcellulose,
calcium carboxymethylcellulose and internally crosslinked-sodium
carboxymethylcellulose; chemically modified starch/cellulose
derivatives such as carboxymethylstarch, sodium
carboxymethylstarch, crosslinked polyvinylpyrrolidone), emulsifiers
(for instance, colloidal clay such as bentonite and veegum; metal
hydrates such as magnesium hydroxide and aluminum hydroxide;
anionic surfactants such as sodium lauryl sulfate and calcium
stearate; cationic surfactants such as benzalkonium chloride; and
non-ionic surfactants such as polyoxyethylenealkyl ethers,
polyoxyethylene sorbitan fatty acid esters, and sucrose esters of
fatty acids), stabilizers (for instance, para-oxy benzoates such as
methylparaben and propylparaben; alcohols such as chlorobutanol,
benzylalcohol and phenylethylalcohol; benzalkonium chloride;
phenols such as phenol and cresol; thimerosal; dehydroacetic acid;
and sorbic acid), flavors (for instance, conventionally employed
sweeteners, acidifiers and flavors), and diluents, etc.
[0419] The dosage varies depending on the symptoms, age, etc. of
the patient (human). For example, in the case of oral
administration, it is desirable to administer 1 mg (preferably 30
mg) as a lower limit and 2000 mg (preferably 1500 mg) as an upper
limit per one time for an adult (human) and one to six times a day
depending on the symptoms. In the case of intravenous
administration, it is desirable to administer 0.5 mg (preferably 5
mg) as a lower limit and 500 mg (preferably 250 mg) as an upper
limit per one time for an adult (human) and one to six times a day
depending on the symptoms.
[0420] The above dosage ranges are based on a human adult. The
dosage range for mammals who differ in weight from a human adult
would be proportional to the respective average weight of a human
adult and a non-human mammal.
BEST MODE FOR CARRYING OUT THE INVENTION
Example 1
3-[1-Methylamino-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-14)
(a) 3-Acetylphenyl dimethylcarbamate
[0421] Tetrahydrofuran (100 ml) was added to sodium hydride (1.94
g, 45 mmol) under an atmosphere of nitrogen. To the suspension was
added a tetrahydrofuran solution of 1-(3-hydroxyphenyl)ethanone
(5.05 g, 37 mmol) in an ice bath. After stirring the mixture for 15
minutes dimethylcarbamyl chloride (1.7 ml, 19 mmol) was added
dropwise into the mixture and the resulting mixture was stirred at
room temperature for 4 hours. Saturated aqueous sodium chloride
solution was added to the reaction mixture. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with
water and saturated sodium chloride solution, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by chromatography on a silica gel column to
afford the desired compound (6.54 g).
[0422] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, s),
3.03 (3H, s), 3.12 (3H, s), 7.34 (1H, d, J=7.9 Hz), 7.46 (1H, t,
J=7.9 Hz), 7.70 (1H, s), 7.79 (1H, d, J=7.9 Hz).
(b) 3-[3-(4-Trifluoromethyl)phenyl]acryloyl]phenyl
dimethylcarbamate
[0423] 3-Acetylphenyl dimethylcarbamate (1.30 g, 6.3 mmol) obtained
from Example 1a and 4-(trifluoromethyl)benzaldehyde (1.25 g, 6.9
mmol) were dissolved in ethanol (35 ml). To the ethanol solution
was added potassium hydroxide (42 mg, 0.63 mmol) and the resulting
mixture was stirred at room temperature for 3 hours. Water was
added to the reaction mixture and the aqueous layer was extracted
with ether. The organic layer was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column to afford the
desired compound (1.74 g).
[0424] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 3.04 (3H, s),
3.14 (3H, s), 7.38 (1H, dd, J=8.1 Hz, 1.4 Hz), 7.49-7.57 (2H, m),
7.68 (2H, d, J=8.5 Hz), 7.73-7.77 (3H, m), 7.82 (1H, d, J=13.8 Hz),
7.86 (1H, d, J=7.2 Hz).
(c) 3-[3-[(4-Trifluoromethyl)phenyl]propionyl]phenyl
dimethylcarbamate
[0425] 3-[3-(4-Trifluoromethyl)phenyl]acryloyl]phenyl
dimethylcarbamate (1.71 g, 5.2 mmol) obtained from Example 1b was
dissolved in ethyl acetate (50 ml). To the solution was added 5%
palladium on charcoal (40 mg) and the resulting mixture was stirred
under an atmosphere of hydrogen at room temperature for 2 hours.
The catalyst was removed by filtration and the filtrate was
concentrated under reduced pressure to afford the crude desired
product which was used in next step reaction without
purification.
(d) 3-[1-Hydroxy-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate
[0426] The crude product of
3-[3-[(4-trifluoromethyl)phenyl]propionyl]phenyl dimethylcarbamate
obtained from Example 1c was dissolved in methanol (60 ml). To the
solution was slowly added sodium borohydride (216 mg, 5.7 mmol) in
an ice bath and the resulting mixture was stirred for 1 hour. Water
was added to the reaction mixture and the methanol was evaporated
under reduced pressure and the aqueous residue was extracted with
ethyl acetate. The organic layer was washed with water and
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by chromatography on a silica gel column to
afford the desired compound (1.63 g).
[0427] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.96-2.15
(2H, m), 2.62-2.84 (2H, m), 3.00 (3H, s), 3.10 (3H, s), 4.65 (1H,
dd, J=7.5 Hz, 5.4 Hz), 7.02 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.15
(1H, d, J=7.7 Hz), 7.26-7.35 (3H, m), 7.52 (1H, d, J=8.1 Hz).
(e) 3-[1-Bromo-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate
[0428] 3-[1-Hydroxy-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate (372 mg, 1.1 mmol) obtained from Example 1d and
triphenylphosphine (349 mg, 1.3 mmol) were dissolved in
dichloromethane under an atmosphere of nitrogen. To the solution
was added carbon tetrabromide (441 mg, 1.3 mmol) in an ice bath and
the mixture was stirred for 20 minutes. The reaction mixture was
concentrated under reduced pressure to afford the crude desired
product which was used in next step reaction without
purification.
(f) 3-[1-Methylamino-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate hydrochloride
[0429] A 40% ethylamine solution in methanol (5 ml) was added to
the crude product of
3-(1-bromo-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate obtained from Example 1d and the mixture was
stirred overnight. The reaction mixture was concentrated under
reduced pressure and the residue was partitioned between saturated
aqueous sodium hydrogencarbonate solution and ethyl acetate. The
organic layer was washed with water and saturated aqueous sodium
chloride solution, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column to give
3-[1-methylamino-3-[(4-trifluoromethyl)phenyl]propyl]phenyl
dimethylcarbamate (209 mg). The product was treated with 1N
hydrogen chloride/ethyl acetate solution to afford the title
compound as an amorphous solid.
[0430] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.39 (3H, s),
2.51-2.61 (3H, m), 2.78-2.81 (1H, m), 3.02 (3H, s), 3.12 (3H, s),
3.85 (1H, br s), 7.19-7.24 (4H, m), 7.45-7.49 (4H, m), 9.90 (1H, br
s), 10.30 (1H, br s).
Example 2
3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-15)
[0431] 4-Methoxybenzaldehyde was treated using similar procedures
to those described in Example 1 to afford the title compound as an
amorphous solid.
[0432] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.39 (3H, s),
2.34-2.52 (3H, m), 2.70-2.76 (1H, m), 3.02 (3H, s), 3.12 (3H, s),
3.74 (3H, s), 3.84 (1H, br s), 6.77 (2H, d, J=8.6 Hz), 7.03 (2H, d,
J=8.6 Hz), 7.21 (1H, dd, J=6.4 Hz, 2.5 Hz), 7.23 (1H, s), 7.43-7.48
(2H, m), 9.83 (1H, br s), 10.20 (1H, br s).
Example 3
3-[1-Dimethylamino-3-(4-methoxyphenyl)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-16)
[0433] Formic acid (10 ml) and 35% aqueous formaldehyde solution
(10 ml) were added to
3-[3-(4-methoxyphenyl)-1-methylaminopropyl]phenyl dimethylcarbamate
(500 mg, 1.4 mmol) obtained from Example 2 and the mixture was
stirred at 90.degree. C. for 2 hours. After cooling the reaction
mixture to room temperature the mixture was neutralized with 1N
aqueous sodium hydroxide solution. The neutralized mixture was
extracted with ether and the organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by chromatography on a silica gel column using ethyl
acetate:methanol=80:20 as the eluent to give
3-[1-dimethylamino-3-(4-methoxyphenyl)propyl]phenyl
dimethylcarbamate. The product was treated with 1N hydrogen
chloride/ethyl acetate solution to afford the title compound as an
amorphous solid.
[0434] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.33-2.39
(1H, m), 2.44-2.57 (2H, m), 2.60 (3H, br s), 2.66 (3H, br s),
2.74-2.81 (1H, m), 3.03 (3H, s), 3.14 (3H, s), 3.78 (3H, s),
3.95-3.99 (1H, m), 6.81 (2H, d, J=8.6 Hz), 7.02 (2H, d, J=8.6 Hz),
7.21 (1H, s), 7.25-7.31 (2H, m), 7.50 (2H, t, J=7.9 Hz).
Example 4
3-[3-(3,4-Dimethoxyphenyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-17)
[0435] 3,4-Dimethoxybenzaldehyde was treated using similar
procedures to those described in Example 1 to afford the title
compound as an amorphous solid.
[0436] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.39 (3H, s),
2.33-2.60 (3H, m), 2.78-2.83 (1H, m), 3.01 (3H, s), 3.11 (3H, s),
3.82 (3H, s), 3.83 (1H, br s), 3.85 (3H, s), 6.65-6.76 (3H, m),
7.20-7.22 (2H, m), 7.45-7.47 (2H, m), 9.88 (1H, br s), 10.20 (1H,
br s).
Example 5
3-(3-Benzo[1,3]dioxol-5-yl-1-methylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-18)
[0437] Benzo[1,3]dioxol-5-carboaldehyde was treated using similar
procedures to those described in Example 1 to afford the title
compound as an amorphous solid.
[0438] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.40 (3H, s),
2.32-2.50 (3H, m), 2.67-2.71 (1H, m), 3.06 (3H, s), 3.12 (3H, s),
3.87 (1H, br s), 5.87 (2H, s), 6.55 (1H, d, J=7.9 Hz), 6.61 (1H,
s), 6.66 (1H, d, J=7.9 Hz), 7.19-7.25 (1H, m), 7.29 (1H, s),
7.44-7.48 (2H, m), 9.84 (1H, br s), 10.18 (1H, br s).
Example 6
3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyl ethylcarbamate
hydrochloride (Exemplification compound number 2-3)
(a) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methyl-
carbamate
[0439] 3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyl
dimethylcarbamate (342 mg, 1.0 mmol) obtained from Example 2 was
dissolved in tetrahydrofuran (5 ml) under an atmosphere of nitrogen
and di-tert-butyl dicarbonate (262 mg, 1.2 mmol) was added to the
solution. The mixture was stirred at room temperature overnight.
After evaporation of the solvent of the reaction mixture under
reduced pressure, the residue was purified by chromatography on a
silica gel column using hexane:ethyl acetate=80:20 as the eluent to
afford the desired compound (420 mg).
[0440] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.54 (9H, s),
2.11-2.26 (2H, m), 2.66 (5H, br s), 3.05 (3H, s), 3.14 (3H, s),
3.85 (3H, s), 5.26 (0.5H, br s), 5.55 (0.5H, br s), 6.89 (2H, d,
J=8.6 Hz), 7.06-7.15 (2H, m), 7.18 (2H, d, J=8.6 Hz), 7.36 (1H, t,
J=8.1 Hz).
(b) t-Butyl
N-[1-(3-hydroxyphenyl)-3-(4-methoxyphenyl)propyl]-N-methylcarbamate
[0441] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methyl-
carbamate (300 mg, 0.68 mmol) obtained from Example 2a was
dissolved in methanol (3 ml) and 1N aqueous lithium hydroxide
solution (3 ml) was added to the solution. The mixture was stirred
at room temperature for 3 hours. The reaction mixture was
partitioned between water and ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column using hexane:ethyl acetate=80:20 as the eluent to afford
the desired compound (2.45 mg).
[0442] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.50 (9H, s),
2.10-2.22 (2H, m), 2.64 (5H, br s), 3.80 (3H, s), 5.23 (0.5H, br
s), 5.50 (0.5H, br s), 6.83 (2H, d, J=8.6 Hz), 7.01-7.12 (2H, m),
7.15 (2H, d, J=8.6 Hz), 7.31 (1H, t, J=8.0 Hz).
(c) t-Butyl
N-[1-[(3-ethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methylcar-
bamate
[0443] t-Butyl
N-[1-(3-hydroxyphenyl)-3-(4-methoxyphenyl)propyl]-N-methylcarbamate
(250 mg, 0.67 mmol) obtained from Example 6b was dissolved in
tetrahydrofuran (2 ml) under an atmosphere of nitrogen, and
triethylamine (0.16 ml, 1.3 mmol) and ethyl isocyanate (0.11 ml,
1.3 mmol) were sequentially added to the solution. The resulting
mixture was stirred at room temperature for 1 hour and concentrated
under reduced pressure. The residue was purified by chromatography
on a silica gel column using hexane:ethyl acetate=90:10 as the
eluent to give the desired compound (198 mg).
[0444] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.21 (3H, t,
J=7.3 Hz), 1.48 (9H, s), 2.06-2.19 (2H, m), 2.60 (5H, br s),
3.27-3.38 (2H, m), 3.79 (3H, s), 5.00 (1H, br s), 5.20 (0.5H, br
s), 5.45 (0.5H, br s), 6.84 (2H, d, J=8.6 Hz), 7.02-7.11 (2H, m),
7.13 (2H, d, J=8.6 Hz), 7.30 (1H, t, J=8.0 Hz).
(d) 3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyl
ethylcarbamate hydrochloride
[0445] t-Butyl
N-[1-[(3-ethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methylcar-
bamate (198 mg, 0.45 mmol) obtained from Example 6c was dissolved
in ethyl acetate (3 ml) and 4N hydrogen chloride/ethyl acetate
solution (1 ml) was added to the solution. The mixture was stirred
at room temperature overnight and concentrated under reduced
pressure. The residue was partitioned between saturated aqueous
sodium hydrogencarbonate solution and ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by chromatography
on a silica gel column using ethyl acetate:methanol=80:20 as the
eluent to give 3-[3-(4-methoxyphenyl)-1-methylaminopropyl]phenyl
ethylcarbamate (133 mg). The product was treated with 1N hydrogen
chloride/ethyl acetate solution to afford the title compound as an
amorphous solid.
[0446] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.23 (3H, t,
J=7.3 Hz), 2.38 (3H, s), 2.33-2.52 (3H, m), 2.70-2.75 (1H, m),
3.28-3.36 (2H, m), 3.74 (3H, s), 3.84 (1H, br s), 5.16 (1H, t,
J=5.7 Hz), 6.77 (2H, d, J=8.6 Hz), 7.02 (2H, d, J=8.6 Hz), 7.23
(1H, d, J=8.1 Hz), 7.26 (1H, s), 7.39-7.47 (2H, m), 9.80 (1H, br
s), 10.17 (1H, br s).
Example 7
3-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-85)
(a) 3-(3-Hydroxyphenyl)-3-methylaminopropionic acid
[0447] 3-Hydroxybenzaldehyde (25.7 g, 210 mmol) was dissolved in
ethanol (70 ml), and malonic acid (25.7 g) and the acetic acid salt
of methylamine (38.6 g) were added to the solution. The resulting
mixture was heated under reflux for 3 hours. Crystals which
precipitated in the reaction mixture were collected by filtration
to afford the desired compound (24.1 g).
[0448] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 2.23 (3H, s),
2.30 (1H, dd, J=15.5, 4.1 Hz), 2.42-2.48 (1H, m), 3.89-3.92 (1H,
m), 6.70 (1H, dd, J=7.8, 1.7 Hz), 6.78-6.81 (2H, m), 7.15 (1H, t,
J=7.8 Hz), 9.50 (1H, brs).
(b) Ethyl 3-(3-hydroxyphenyl)-3-methylaminopropionate
[0449] 3-(3-Hydroxyphenyl)-3-methylaminopropionic acid (24.1 g)
obtained from Example 7a was dissolved in ethanol (200 ml), and
concentrated sulfuric acid (10 ml) was added dropwise to the
solution. The resulting mixture was heated under reflux for 8
hours. The reaction mixture was neutralized with saturated aqueous
sodium hydrogencarbonate solution and the solvent was removed under
reduced pressure. The residual aqueous solution was extracted with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to afford the
desired compound which was used in next step reaction without
further purification.
(c) Ethyl
3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(3-hydroxyphenyl)propio-
nate
[0450] The crude product of ethyl
3-(3-hydroxyphenyl)-3-methylaminopropionate obtained from Example
7b was dissolved in tetrahydrofuran (200 ml) under an atmosphere of
nitrogen and di-tert-butyl dicarbonate (32 g, 150 mmol) was added
to the solution. The mixture was stirred at room temperature
overnight. The reaction mixture was concentrated under reduced
pressure and purified by chromatography on a silica gel column
using hexane:ethyl acetate=70:30 as the eluent to afford the
desired compound (37 g).
[0451] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.24 (3H, t,
J=7.1Hz), 1.47 (9H, s), 2.64 (3H, brs), 2.84-2.96 (2H, m),
4.10-4.16 (2H, m), 5.64 (1/2H, brs), 5.82 (1/2H, brs), 6.74-6.76
(2H, m), 6.8 (1H, d, J=7.7 Hz), 7.20 (1H, t, J=8.1 Hz).
(d) Ethyl
3-[N-(t-butoxycarbonyl)-N-methylamino]-3-[(3-dimethylcarbamoylox-
y)phenyl]propionate
[0452] Tetrahydrofuran (100 ml) was added to sodium hydride (1.01
g, 23 mmol) under an atmosphere of nitrogen and to the mixture was
added a solution of ethyl
3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(3-hydroxyphenyl)propionate
(5.00 g, 16 mmol) obtained from Example 7c in tetrahydrofuran in an
ice bath. After stirring the resulting mixture for 20 minutes,
dimethylcarbamyl chloride (1.7 ml, 19 mmol) was added dropwise and
the resulting mixture was stirred at room temperature for 1 hour.
The reaction mixture was partitioned between saturated aqueous
sodium chloride solution and ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by chromatography on a
silica gel column using hexane:ethyl acetate=60:40 to afford the
desired compound (4.85 g)
[0453] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.24 (3H, t,
J=7.1 Hz); 1.47 (9H, s), 2.67 (3H, brs), 2.90-2.93 (2H, m), 3.01
(3H, s), 3.10 (3H, s), 4.11-4.15 (2H, m), 5.67 (1/2H, brs), 5.85
(1/2H, brs), 6.99 (1H, s), 7.05 (1H, dd, J=7.9, 2.0 Hz), 7.10 (1H,
brs), 7.32 (1H, t, d=7.9 Hz).
(e) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
[0454] Tetrahydrofuran (100 ml) was added to lithium aluminum
hydride (770 mg, 20 mmol) under an atmosphere of nitrogen, and to
the mixture was added a tetrahydrofuran solution of ethyl
3-[N-(t-butoxycarbonyl)-N-methylamino]-3-[(3-dimethylcarbamoyloxy)phenyl]-
propionate (4.01 g 10 mmol) obtained from Example 7d at -78.degree.
C. After stirring the mixture for 20 minutes, the mixture was
slowly warmed to 0.degree. C. and then stirred for 30 minutes. To
the reaction mixture was added sequentially water (0.8 ml), 15%
aqueous sodium hydroxide solution (0.8 ml) and water (0.8 ml). The
resulting mixture was stirred at room temperature for 30 minutes.
After addition of anhydrous magnesium sulfate to the mixture, the
resulting mixture was filtered and the filtrate was concentrated
under reduced pressure. The residue was purified by chromatography
on a silica gel column using hexane:ethyl acetate=20:80 as the
eluent to afford the desired compound (2.40 g).
[0455] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (9H, s),
1.92-1.97 (1H, m), 2.14-2.21 (1H, m), 2.46 (3H, s), 3.02 (3H, s),
3.11 (3H, s), 3.48-3.54 (1H, m), 3.58-3.62 (1H, m), 3.75 (1H, brs),
5.57-5.60 (1H, m), 7.04-7.06 (2H, m), 7.13-7.15 (1H, m), 7.34 (1H,
t, J=8.2 Hz).
(f) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-[(4-trifluoromethyl)phenoxy]propy-
l]-N-methylcarbamate
[0456] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methyl
carbamate (200 mg, 0.56 mmol) obtained from Example 7e was
dissolved in tetrahydrofuran (2 ml) under an atmosphere of
nitrogen. Triethylamine (0.14 ml, 1.0 mmol) and methanesulfonyl
chloride (0.06 ml, 0.68 mmol) was sequentially added to the
solution in an ice bath. The mixture was stirred at room
temperature for 30 minutes. The reaction mixture was partitioned
between water and ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate and concentrated under reduced pressure to give a
methanesulfonate. On the other hand N,N-dimethylformamide (2 ml)
was added to sodium hydride (30 mg, 0.63 mmol) under an atmosphere
of nitrogen. A solution of 4-(trifluoromethyl)phenol (110 mg, 0.63
mmol) in N,N-dimethylformamide was added to the suspension of
sodium hydride in an ice bath and the mixture was stirred for 30
minutes. To this reaction mixture was added a solution of the
methanesulfonate obtained above in N,N-dimethylformamide and the
mixture was stirred at room temperature overnight. The reaction
mixture was partitioned between water and ether. The organic layer
was washed with saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column using hexane:ethyl acetate=50:50 as the eluent to afford
the desired compound (243 mg).
[0457] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.39 (9H, s),
2.34-2.47 (2H, m), 2.62 (3H, s), 3.02 (3H, s), 3.11 (3H, s), 4.07
(2H, brs), 5.57 (1H, brs), 6.95 (2H, d, J=8.6 Hz), 7.05-7.06 (2H,
m), 7.14-7.16 (1H, m), 7.34 (1H, t, J=8.1 Hz), 7.54 (2H, d, J=8.6
Hz).
(g) 3-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate hydrochloride
[0458] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-[(4-trifluoromethyl)phenoxy]propy-
l]-N-methylcarbamate obtained from Example 7f was treated using a
similar procedure to that described in Example 6d to afford the
title compound as an amorphous solid.
[0459] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.58-2.65 (1H, m), 2.98 (3H, s), 2.98-3.07 (1H, m), 3.07 (3H, s),
3.68-3.72 (1H, m), 4.01-4.05 (1H, m), 4.31-4.34 (1H, m), 6.86 (2H,
d, J=8.7 Hz), 7.18 (1H, d, J=7.4 Hz), 7.31 (1H, s), 7.42-7.50 (4H,
m).
[0460] MS (FAB) m/z: 397 (M+H).sup.+.
Example 8
3-[3-(4-Methoxyphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-86)
[0461] 4-Methoxyphenol was treated using similar procedures to
those described in Example 7f and 7g to afford the title compound
as an amorphous solid.
[0462] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.50-2.57
(1H, m), 2.53 (3H, s), 2.93-3.01 (1H, m), 2.99 (3H, s), 3.08 (3H,
s), 3.57-3.61 (1H, m), 3.73 (3H, s), 3.91-3.94 (1H, m), 4.32-4.35
(1H, m), 6.73-6.78 (4H, m), 7.18 (1H, d, J=7.8 Hz), 7.34 (1H, s),
7.41-7.49 (2H, m).
[0463] MS (EI) m/z: 358 (M).sup.+.
Example 9
3-(1-Methylamino-3-p-toluoyloxypropyl)phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-82)
[0464] 4-Methylphenol was treated using similar procedures to those
described in Example 7f and 7g to afford the title compound as an
amorphous solid.
[0465] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.24 (3H, s),
2.53 (3H, s), 2.53-2.58 (1H, m), 2.92-2.99 (1H, m), 2.99 (3H, s),
3.08 (3H, s), 3.56-3.62 (1H, m), 3.91-3.94 (1H, m), 4.32-4.36 (1H,
m), 6.69 (2H, d, J=8.4 Hz), 7.02 (2H, d, J=8.4 Hz), 7.18 (1H, d,
J=7.9 Hz), 7.34 (1H, s), 7.39-7.47 (2H, m).
[0466] MS (FAB) m/z: 343 (M+H).sup.+.
Example 10
3-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-78)
[0467] 4-Chlorophenol was treated using similar procedures to those
described in Example 7f and 7g to afford the title compound as an
amorphous solid.
[0468] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.53-2.58 (1H, m), 2.94-3.01 (1H, m), 2.99 (3H, s), 3.08 (3H, s),
3.58-3.63 (1H, m), 3.94-3.96 (1H, m), 4.30-4.33 (1H, m), 6.73 (2H,
d, J=9.0 Hz), 7.15-7.19 (3H, m), 7.31 (1H, s), 7.31-7.45 (2H,
m).
[0469] MS (FAB) m/z: 363 (M+H).sup.+.
Example 11
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-75)
(a) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methyl-
carbamate
[0470] 4-Fluorophenol was treated using a similar procedure to that
described in Example 7f to afford the desired compound.
[0471] .sup.1H-NMR 400 MHz, CDCl.sub.3) .delta.: 1.40 (9H, s),
2.30-2.42 (2H, m), 2.61 (3H, s), 3.02 (3H, s), 3.11 (3H, s),
3.94-3.98 (2H, m), 5.56 (1H, brs), 6.80-6.84 (2H, m), 6.96 (2H, t,
J=8.6 Hz), 7.04-7.05 (2H, m), 7.13-7.15 (1H, m), 7.34 (1H, t, J=8.3
Hz).
(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0472] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methyl-
carbamate obtained from Example 11a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0473] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.53-2.59 (1H, m), 2.94-3.05 (1H, m), 2.99 (3H, s), 3.08 (3H, s),
3.59-3.63 (1H, m), 3.92-3.96 (1H, m), 4.31-4.34 (1H, m), 6.73-6.78
(2H, m), 6.91 (2H, t, J=8.6 Hz), 7.18 (1H, d, J=6.7 Hz), 7.32 (1H,
s), 7.42-7.47 (2H, m).
[0474] MS (FAB) m/z: 347 (M+H).sup.+.
Example 12
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl ethylcarbamate
hydrochloride (Exemplification compound number 2-2)
(a) t-Butyl
N-[3-[(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
[0475] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methyl-
carbamate obtained from Example 11a was treated using a similar
procedure to that described in Example 6b to afford the desired
compound.
[0476] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.41 (9H, br
s), 2.30-2.43 (2H, m), 3.97 (2H, br s), 5.52 (1H, br s), 5.98
(0.5H, br s), 6.40 (0.5H, br s), 6.76-6.86 (5H, m), 6.95 (1H, t,
J=8.4 Hz), 7.21 (1H, t, J=7.8 Hz).
(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
ethylcarbamate hydrochloride
[0477] t-Butyl
N-[3-[(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
obtained from Example 12a was treated using a similar procedure to
that described in Example 6d to afford the title compound as an
amorphous solid.
[0478] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 0.88 (3H, t,
J=7.3 Hz), 2.53 (3H, s), 2.52-2.59 (1H, m), 2.90-3.00 (1H, m),
3.25-3.31 (2H, m), 3.57-3.61 (1H, m), 3.92-3.95 (1H, m), 4.30-4.34
(1H, m), 5.04-5.09 (1H, m), 6.73 (2H, dd, J=9.0 Hz, 4.3 Hz), 6.91
(2H, t, J=9.0 Hz), 7.21-7.24 (1H, m), 7.36 (1H, s), 7.41-7.44 (2H,
m), 9.88 (1H, br s), 10.22 (1H, br s).
[0479] MS (FAB) m/z: 347 (M+H).sup.+.
Example 13
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl acetate
hydrochloride (Exemplification compound number 2-4)
(a)
3-[1-(N-t-Butoxycarbonyl-N-methylamino)-3-(4-fluorophenoxy)propyl]phen-
yl acetate
[0480] t-Butyl
N-[3-[(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
(100 mg, 0.27 mmol) obtained from Example 12a was dissolved in
dichloromethane (1 ml) under an atmosphere of nitrogen, and
triethylamine (0.045 ml, 0.32 mmol) and acetic anhydride (0.030 ml,
0.32 mmol) were added to the solution. The resulting mixture was
stirred at room temperature overnight. The reaction mixture was
partitioned between water and dichloromethane. The organic layer
was washed with water and saturated aqueous sodium chloride
solution, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by chromatography on a
silica gel column using hexane:ethyl acetate=80:20 to 75:25 as the
eluent to afford the desired compound (98.7 mg).
[0481] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.40 (9H, s),
2.40 (3H, s), 2.34-2.57 (2H, m), 2.62 (3H, s), 3.97-3.99 (2H, m),
5.54-5.87 (1H, m), 6.82 (2H, dd, J=9.1 Hz, 4.3 Hz), 6.94-6.83 (3H,
m), 7.02 (1H, d, J=6.2 Hz), 7.18 (1H, d, J=7.1 Hz), 7.36 (1H, t,
J=8.1 Hz).
(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl acetate
hydrochloride
[0482]
3-[1-(N-t-Butoxycarbonyl-N-methylamino)-3-(4-fluorophenoxy)propyl]p-
henyl acetate obtained from Example 13a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0483] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.28 (3H, s),
2.53 (3H, s), 2.51-2.60 (1H, m), 2.95-3.01 (1H, m), 3.56-3.61 (1H,
m), 3.92-3.96 (1H, m), 4.35 (1H, br s), 6.72 (2H, dd, J=8.8 Hz, 4.3
Hz), 6.91 (2H, t, J=8.8 Hz), 7.16 (1H, d, J=7.7 Hz), 7.34 (1H, s),
7.43-7.50 (2H, m), 9.97 (1H, br s), 10.30 (1H, br s).
[0484] MS (FAB) m/z: 318 (M+H).sup.+.
Example 14
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
2,2-dimethylpropionate hydrochloride (Exemplification compound
number 2-5)
[0485] 2,2-Dimethylpropionyl chloride was treated using similar
procedures to those described in Example 13 to afford the title
compound as an amorphous solid.
[0486] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.33 (s, 9H),
2.54 (3H, s), 2.48-2.57 (1H, m), 2.96-3.01 (1H, m), 3.55-3.59 (1H,
m), 3.91-3.96 (1H, m), 4.32-4.36 (1H, m), 6.73 (2H, dd, J=9.1 Hz,
4.3 Hz), 6.91 (2H, t, J=9.1 Hz), 7.11 (1H, d, J=7.1 Hz), 7.30 (1H,
s), 7.43-7.50 (2H, m), 9.98 (1H, br s), 10.38 (1H, br s).
[0487] MS (FAB) m/z: 360 (M+H).sup.+.
Example 15
3-[3-(4-Chlorophenyl)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-13)
[0488] 4-Chlorobenzaldehyde was treated using similar procedures to
those described in Example 1 to afford the title compound as an
amorphous solid.
[0489] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.39 (3H, s),
2.39-2.56 (3H, m), 2.75 (1H, br s), 3.02 (3H, s), 3.12 (3H, s),
3.83 (1H, br s), 7.05 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3 Hz),
7.17-7.23 (2H, m), 7.40-7.49 (2H, m), 9.85 (1H, br s), 10.25 (1H,
br s).
[0490] MS (FAB) m/z: 347 (M+H).sup.+.
Example 16
4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-78)
(a) Ethyl
3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propio-
nate
[0491] 4-Hydroxybenzaldehyde was treated using similar procedures
to those described in Example from 7a to 7c to afford the desired
compound.
[0492] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (9H, s),
1.91-1.98 (1H, m), 2.13-2.20 (1H, m), 2.43 (3H, s), 3.02 (3H, s),
3.10 (3H, s), 3.48-3.58 (2H, m), 3.74 (1H, br s), 5.57-5.61 (1H,
m), 7.10 (2H, dt, J=8.6, 1.9 Hz), 7.28 (2H, d, J=8.6 Hz).
(b) t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
[0493] Ethyl
3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propionate
obtained from Example 16a was treated using similar procedures to
those described in Example 7d and 7e to afford the desired
compound.
[0494] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.40 (9H, s),
2.29-2.44 (2H, m), 2.60 (3H, s), 3.01 (3H, s), 3.10 (3H, s), 3.98
(2H, br s), 5.56 (1H, br s), 6.81 (2H, d, J=8.8 Hz), 7.10 (2H, d,
J=8.5 Hz), 7.22 (2H, d, J=8.8 Hz), 7.28-7.30 (2H, m).
(c) 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0495] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-chlorophenol were treated using
similar procedures to those described in Example 7f and 6d to
afford the title compound as amorphous solid.
[0496] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.51-2.59 (1H, m), 2.94-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.55-3.59 (1H, m), 3.91-4.13 (1H, m), 4.30-4.34 (1H, m), 6.71 (2H,
d, J=9.0Hz), 7.15-7.19 (4H, m), 7.59 (2H, d, J=8.6 Hz).
[0497] IR (KBr) .mu..sub.maxcm.sup.-1: 3430, 2942 2765, 2699,
1725.
[0498] MS (FAB) m/z: 363 ([M+H]).sup.+, 332, 273, 242, 207.
Example 17
4-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-85)
[0499] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-trifluoromethylphenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0500] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.58-2.64 (1H, m), 2.99-3.03 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.64-3.68 (1H, m), 3.99-4.03 (1H, m), 4.32-4.35 (1H, m), 6.85 (2H,
d, J=8.7 Hz), 7.19 (2H, d, J=8.6 Hz), 7.48 (2H, d, J=8.7 Hz), 7.59
(2H, d, J=8.6 Hz).
[0501] MS (FAB) m/z: 397 (M+H).sup.+.
Example 18
4-[3-[(4-Methoxyphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-86)
[0502] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-methoxyphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0503] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.51-2.54 (1H, m), 2.92-2.97 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.53-3.58 (1H, m), 3.73 (3H, s), 3.90-3.92 (1H, m), 4.34-4.36 (1H,
m), 6.72-6.81 (4H, m), 7.18 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4
Hz).
[0504] MS (FAB) m/z: 359 (M+H).sup.+.
Example 19
3-[1-Amino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-65)
(a) t-Butyl
[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]carbamate
[0505] Ammonium acetate was treated using similar procedures to
those described in from Example 7a to 7e to afford the desired
compound.
[0506] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.40 (9H, br
s) 2.22 (2H, br s), 3.00 (3H, s), 3.09 (3H, s), 3.84-3.96 (2H, m),
4.92 (1H, br s), 5.18 (1H, br s), 6.81 (2H, dd, J=8.8 Hz, 4.3 Hz),
6.95 (2H, t, J=8.8 Hz), 7.00-7.05 (2H, m), 7.21 (1H, d, J=7.8 Hz),
7.31 (1H, t, J=7.8 Hz).
(b) 3-[1-Amino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride
[0507] t-Butyl
[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]carbamate
obtained from Example 19a was treated using a similar procedure to
that described in Example 6d to afford the title compound as an
amorphous solid.
[0508] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.35-2.39
(1H, m), 2.69-2.74 (1H, m), 2.88 (3H, s), 3.04 (3H, s), 3.64-3.71
(1H, m), 3.91-3.96 (1H, m), 4.53 (1H, br s), 6.74 (2H, dd, J=8.9
Hz, 4.3 Hz), 6.90 (2H, t, J=8.9 Hz), 7.02 (1H, d, J=8.0 Hz),
7.31-7.39 (3H, m), 8.71 (3H, br s).
Example 20
3-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-67)
(a) t-Butyl
N-[1-(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-ethylca-
rbamate
[0509] N,N-Dimethylformamide (2 ml) was added to sodium hydride (12
mg, 0.28 mmol) under an atmosphere of nitrogen, and to the mixture
was added a solution of t-butyl
[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]carbamate
(100 mg, 0.23 mmol) obtained from Example 19a in
N,N-dimethylformamide in an ice bath. After stirring the resulting
mixture for 20 minutes, ethyl iodide (0.022 ml, 0.28 mmol) was
added dropwise thereto and this mixture was stirred at room
temperature overnight. The reaction mixture was partitioned between
water and ethyl acetate. The organic layer was washed with water
and saturated aqueous sodium chloride solution, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by chromatography on a silica gel column using
hexane:ethyl acetate=90:10 to 70:30 as the eluent to afford the
desired compound (63 mg).
[0510] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.42 (9H, br
s), 2.39-2.47 (2H, m), 3.01 (3H, s), 3.02-3.09 (2H, m), 3.10 (3H,
s), 3.96-4.05 (2H, m), 5.44 (1H, br s), 6.82 (2H, dd, J=8.9 Hz, 4.3
Hz), 6.96 (2H, t, J=8.9 Hz), 7.04 (1H, t, J=7.9 Hz), 7.09 (1H, s),
7.18 (1H, d, J=7.9 Hz), 6.32 (1H, t, J=7.9 Hz).
(b) 3-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride
[0511] t-Butyl
N-[1-(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-ethylca-
rbamate obtained from Example 20a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0512] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.46 (3H, t,
J=7.2 Hz), 2.60-2.65 (1H, m), 2.83-3.00 (2H, m), 2.99 (3H, s), 3.08
(3H, s), 3.06-3.11 (1H, m), 3.52-3.57 (1H, m), 3.86-3.90 (1H, m),
4.40 (1H, br s), 6.71 (2H, dd, J=9.0 Hz, 4.3 Hz), 6.90 (2H, t,
J=9.0 Hz), 7.18 (1H, d, J=7.8 Hz), 7.37 (1H, s), 7.43 (1H, t, J=7.8
Hz), 7.51 (1H, d, J=7.8 Hz), 9.97 (1H, br s), 10.34 (1H, br s)
Example 21
3-[3-(4-Fluorophenoxy)-1-propylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-73)
[0513] 1-Iodopropane was treated using similar procedures to those
described in Example 20 to afford the title compound as an
amorphous solid.
[0514] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 0.90 (3H, t,
J=7.4 Hz), 1.90-2.01 (2H, m), 2.60-2.67 (1H, m), 2.72 (2H, t, J=8.1
Hz) 3.00 (3H, s), 3.08 (3H, s), 3.07-3.15 (1H, m), 3.52-3.57 (1H,
m), 3.83-3.89 (1H, m), 4.36-4.40 (1H, m), 6.70 (2H, dd, J=8.9 Hz,
4.3 Hz), 6.90 (2H, t, J=8.9 Hz), 7.19 (1H, d, J=7.9 Hz), 7.37 (1H,
s), 7.43 (1H, t, J=7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 9.88 (1H, br
s), 10.27 (1H, br s).
Example 22
3-[4-(4-Fluorophenyl)-1-methylaminobutyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-25)
(a) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-oxo-propyl]-N-methylcarbamate
[0515] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
(200 mg, 0.57 mmol) was dissolved in dichloromethane (3 ml) under
an atmosphere of nitrogen and pyridinium dichromate (320 mg, 0.85
mmol) was added to the solution. The resulting mixture was stirred
at room temperature overnight. After addition of ether to the
reaction mixture, the crystals was collected by filtration and the
filtrate was concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column using
hexane:ethyl acetate=80:20 to 60:40 as the eluent to afford the
desired compound (148 mg).
[0516] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.48 (9H, s),
2.59 (3H, br s), 2.95-3.01 (2H, m), 3.02 (3H, s), 3.11 (3H, s),
6.02 (1H, br s), 6.99 (1H, s), 7.05-7.08 (2H, m), 7.35 (1H, t,
J=7.9 Hz), 9.80 (1H, s).
(b) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)-3-butenyl]-N-met-
hylcarbamate
[0517] Tetrahydrofuran (1 ml) was added to sodium hydride (14 mg,
0.31 mmol) under an atmosphere of nitrogen and a solution of
(4-fluorobenzyl)triphenylphosphonium bromide (110 mg, 0.27 mmol) in
tetrahydrofuran was added to the sodium hydride. The resulting
mixture was stirred for 2 hours and then t-butyl
N-methyl-N-[1-(3-nitrophenyl)-3-oxopropyl]carbamate (72 mg, 0.21
mmol) obtained from Example 22a was added thereto. The resulting
mixture was stirred at room temperature for 3 hours. The reaction
mixture was partitioned between saturated aqueous sodium chloride
solution and ethyl acetate. The organic layer was washed with water
and saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column using hexane:ethyl acetate=90:10 to 70:30 to afford the
desired compound (80 mg).
[0518] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.41 (4.5H,
s), 1.48 (4.5H, s), 2.47-2.90 (5H, m), 3.01 (1.5H, s), 3.02 (1.5H,
s), 3.10 (1.5 H, s), 3.11 (1.5H, s), 5.61-6.51 (3H, m), 6.96-7.36
(8H, m).
(c) t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)butyl]-N-methylca-
rbamate
[0519] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)-3-butenyl]-N-met-
hylcarbamate (42 mg, 1.3 mmol) obtained from Example 22b was
dissolved in methanol (1 ml) and to the solution was added 5%
palladium on charcoal (10 mg). The mixture was stirred under an
atmosphere of hydrogen at room temperature for 1 hour and the
reaction mixture was filtered in order to remove the catalyst. The
filtrate was concentrated under reduced pressure and the residue
was purified by chromatography on a silica gel column using
hexane:ethyl acetate=90:10 to 75:25 as the eluent to afford the
desired compound (40 mg).
[0520] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.48 (9H, s),
1.60-1.69 (2H, m), 2.53 (3H, br s), 2.59-2.65 (1H, m), 2.69-2.75
(1H, m), 3.01 (3H, s), 3.10 (3H, s), 5.23 (0.5H, br s), 5.44 (0.5H,
br s), 6.94-7.15 (7H, m), 7.30 (1H, t, J=7.9 Hz).
(d) 3-[4-(4-Fluorophenyl)-1-methylaminobutyl]phenyl
dimethylcarbamate hydrochloride
[0521] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)butyl]-N-methylca-
rbamate obtained from Example 22c was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0522] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.39-1.47
(1H, m), 1.52-1.60 (1H, m), 2.18-2.27 (1H, m), 2.41 (3H, s),
2.40-2.62 (3H, m), 3.01 (3H, s), 3.11 (3H, s), 3.90 (1H, dd, J=10.5
Hz, 4.4 Hz), 6.90 (2H, t, J=8.6 Hz), 7.02 (2H, dd, J=8.6 Hz, 50.5
Hz), 7.19 (1H, d, J=7.3 Hz), 7.22 (1H, s), 7.41-7.48 (2H, m), 9.83
(1H, br s), 10.16 (1H, br s).
Example 23
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl diethylcarbamate
hydrochloride (Exemplification compound number 2-6)
(a) t-Butyl
N-[1-[(3-diethylcarbamoyloxy)phenyl)-3-(4-fluorophenoxy)propyl]-N-methylc-
arbamate
[0523] N,N-Dimethylformamide (1 ml) was added to sodium hydride (14
mg, 0.32 mmol) under an atmosphere of nitrogen and to the sodium
hydride was added a solution of t-butyl
N-[3-(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
(100 mg, 0.27 mmol) obtained from Example 12a in
N,N-dimethylformamide in an ice bath. The mixture was stirred for
30 minutes and to this mixture was added diethylcarbamyl chloride
(0.041 ml, 0.32 mmol). The resulting mixture was stirred for 1 hour
and the reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with water and saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column using
methylenechloride:ethyl acetate=10:90 as the eluent to afford the
desired compound (108 mg).
[0524] .sup.1H-NMR (400 MHz, CDCl.sub.3) (400 MHz, CDCl.sub.3)
.delta. ppm: 1.19-1.28 (6H, m), 1.40 (9H, s), 2.31-2.44 (2H, m),
2.62 (3H, s), 3.37-3.47 (4H, m), 3.97-3.99 (2H, m), 5.56 (1H, brs),
6.81-6.84 (2H, m), 6.96 (2H, t, J=8.6 Hz), 7.05-7.11 (2H, m),
7.12-7.16 (1H, m), 7.34 (1H, t, J=8.2 Hz).
(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
diethylcarbamate hydrochloride
[0525] t-Butyl
N-[1-[(3-diethylcarbamoyloxy)phenyl)-3-(4-fluorophenoxy)propyl)-N-methylc-
arbamate obtained from Example 23a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0526] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.20-1.29
(6H, m), 2.55 (3H, s), 2.55-2.62 (1H, m), 2.98-3.04 (1H, m),
3.36-3.45 (4H, m), 3.59-3.64 (1H, m), 3.94-3.98 (1H, m), 4.33-4.36
(1H, m), 6.74-6.78 (2H, m), 6.92 (2H, t, J=8.6 Hz), 7.21 (1H, d,
J=7.5 Hz), 7.34 (1H, s), 7.43-7.50 (2H, m).
[0527] MS (FAB) m/z: 375 (M+H).sup.+.
Example 24
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
diisopropylcarbamate hydrochloride (Exemplification compound number
2-9)
[0528] Diisopropylcarbamyl chloride was treated using similar
procedures to those described in Example 23 to afford the title
compound as an amorphous solid.
[0529] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.28 (12H,
brs), 2.54 (3H, s), 2.54-2.59 (1H, m), 2.95-3.02 (1H, m), 3.57-3.62
(1H, m), 3.92-3.99 (2H, m), 4.05 (1H, brs), 4.32-4.35 (1H, m),
6.76-6.78 (2H, m), 6.90 (2H, t, J=8.6 Hz), 7.19 (1H, dd, J=7.9 Hz,
1.0 Hz), 7.28 (1H, d, J=1.0 Hz), 7.42 (1H, t, J=7.9 Hz), 7.49 (1H,
d, J=7.9 Hz).
[0530] MS (FAB) m/z: 403 (M+H).sup.+.
Example 25
3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
morpholin-4-carboxylate hydrochloride (Exemplification compound
number 2-11)
[0531] Morpholin-4-carbonyl chloride was treated using similar
procedures to those described in Example 23 to afford the title
compound as an amorphous solid.
[0532] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.53-2.59 (1H, m), 2.96-2.99 (1H, m), 3.54-3.64 (5H, m), 3.74 (4H,
d, J=4.7 Hz), 3.93-3.95 (1H, m), 4.31-4.35 (1H, m), 6.72-6.75 (2H,
m), 6.91 (2H, t, J=8.7 Hz), 7.19 (1H, d, J=6.9 Hz), 7.35 (1H, s),
7.42-7.46 (2H, m).
[0533] MS (FAB) m/z: 389 (M+H).sup.+.
Example 26
O-[3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl]dimethylthiocarbamate
hydrochloride (Exemplification compound number 2-12)
[0534] Dimethylthiocarbamyl chloride was treated using similar
procedures to those described in Example 23 to afford the title
compound as an amorphous solid.
[0535] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.55 (3H, s),
2.55-2.63 (1H, m), 2.99-3.02 (1H, m), 3.33 (3H, s), 3.43 (3H, s),
3.62-3.68 (1H, m), 3.91-3.95 (1H, m), 4.33-4.37 (1H, m), 6.72-6.75
(2H, m), 6.90 (2H, t, J=8.7 Hz), 7.11 (1H, d, J=7.8 Hz), 7.26 (1H,
s), 7.47 (1H, t, J=7.8 Hz), 7.53 (1H, t, J=7.8 Hz).
[0536] MS (FAB) m/z: 363 (M+H).sup.+.
Example 27
3-[1-Dimethylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-142)
[0537] 3-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate obtained from Example 7g was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0538] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.64 (3H, s),
2.64-2.74 (1H, m), 2.87 (3H, s), 2.95-3.05 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.64-3.70 (1H, m), 4.04-4.13 (1H, m), 4.29-4.31 (1H,
m), 6.81 (2H, d, J=8.5 Hz), 7.22 (1H, m), 7.30 (1H, s), 7.38 (1H,
d, J=7.7 Hz), 7.43-7.50 (3H, m).
[0539] MS (FAB) m/z: 411 (M+H).sup.+.
Example 28
3-[1-Dimethylamino-3-(4-fluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-132)
[0540] 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained from Example 11b was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0541] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.63-2.68
(4H, m), 2.87 (3H, s), 2.92-3.01 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.54-3.60 (1H, m), 3.95-4.13 (1H, m), 4.28-4.30 (1H, m),
6.67-6.70 (2H, m), 6.91 (2H, t, J=8.6 Hz), 7.23 (1H, d, J=7.8 Hz),
7.32 (1H, s), 7.39 (1H, d, J=7.8 Hz), 7.45 (1H, t, J=7.8 Hz).
[0542] MS (FAB) m/z 361 (M+H).sup.+.
Example 29
4-[1-Dimethylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-142)
[0543] 4-[1-Methylamino-3-(4-trifluoromethyl)phenoxy]propyl]phenyl
dimethylcarbamate obtained from Example 17 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0544] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H, s),
2.72-2.75 (1H, m), 2.91 (3H, s), 2.96-3.02 (1H, m), 3.02 (3H, s),
3.10 (3H, s), 3.58-3.63 (1H, m), 4.03-4.06 (1H, m), 4.27-4.31 (1H,
m), 6.81 (2H, d, J=8.5 Hz), 7.23 (2H, d, J=8.2 Hz), 7.49 (2H, d,
J=8.5 Hz), 7.57 (2H, d, J=8.2 Hz).
[0545] MS (FAB) m/z: 411 (M+H).sup.+.
Example 30
4-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-75)
[0546] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-fluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0547] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.46-2.60
(1H, m), 2.51 (3H, s), 2.92-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H,
s), 3.53-3.59 (1H, m), 3.90-3.94 (1H, m), 4.33-4.34 (1H, m),
6.70-6.73 (2H, m), 6.91 (2H, t, J=8.7 Hz), 7.18 (2H, d, J=8.6 Hz),
7.60 (2H, d, J=8.6 Hz).
[0548] MS (FAB) m/z: 347 (M+H).sup.+.
Example 31
4-[1-Dimethylamino-3-(4-trifluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-132)
[0549] 4-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained from Example 30 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0550] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54-2.69
(1H, m), 2.60 (3H, d, J=4.0 Hz), 2.85-2.96 (1H, m), 2.91 (3H, d,
J=4.0 Hz), 3.02 (3H, s), 3.11 (3H, s), 3.47-3.52 (1H, m), 3.94-3.96
(1H, m), 4.27-4.30 (1H, m), 6.66-6.70 (2H, m), 6.92 (2H, t, J=8.6
Hz), 7.23 (2H, d, J=8.1 Hz), 7.58 (2H, d, J=8.1 Hz).
[0551] MS (FAB) m/z: 361 (M+H).sup.+.
Example 32
3-[3-(4-Fluorophenyl)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-1)
[0552] 4-Fluorobenzaldehyde was treated using similar procedures to
those described in Example 1 to afford the title compound as an
amorphous solid.
[0553] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.39 (3H, s),
2.34-2.54 (3H, m), 2.70-2.78 (1H, m), 3.02 (3H, s), 3.12 (3H, s),
3.80-3.87 (1H, m), 6.91 (2H, t, J=8.4 Hz), 7.07 (2H, dd, J=8.4 Hz,
5.6 Hz), 7.17-7.24 (2H, m), 7.40-7.49 (2H, m).
[0554] MS (EI) m/z: 331 (M+H).sup.+.
Example 33
4-[3-(4-Fluorophenyl)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-1)
[0555] 4-Acetylphenol and 4-fluorobenzaldehyde were treated using
similar procedures to those described in Example 1 to afford the
title compound as an amorphous solid.
[0556] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.37 (3H, s),
2.33-2.54 (3H, m), 2.69-2.78 (1H, m), 3.03 (3H, s), 3.12 (3H, s),
3.85 (1H, br s), 6.88-6.96 (2H, m), 7.01-7.08 (2H, m), 7.22 (2H, d,
J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz), 9.79 (1H, br s), 10.12 (1H, br
s).
[0557] MS (FAB) m/z: 331 (M+H).sup.+.
Example 34
3-[4-(4-Chlorophenyl)-1-methylaminobutyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-26)
[0558] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-oxopropyl]-N-methylcarbamate
obtained from Example 22a and (4-chlorobenzyl)triphenylphosphonium
chloride were treated using similar procedures to those described
in Example from 22b to 22d to afford the title compound as an
amorphous solid.
[0559] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.40-1.48
(1H, m), 1.58-1.66 (1H, m), 2.20-2.28 (1H, m), 2.42 (3H, s),
2.40-2.57 (3H, m), 3.01 (3H, s), 3.11 (3H, s), 3.94 (1H, br s),
6.99-7.28 (6H, m), 7.44-7.52 (2H, m), 9.77 (1H, br s), 10.15 (1H,
br s).
Example 35
4-[4-(4-Chlorophenyl)-1-methylaminobutyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-26)
[0560] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b, 3-methoxyphenol and
(4-chlorobenzyl)triphenylphosphonium chloride were treated using
similar procedures to those described in Example 22 to afford the
title compound as an amorphous solid.
[0561] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.38-1.58
(2H, m), 2.20-2.26 (1H, m), 2.39 (3H, s), 2.38-2.62 (3H, m), 3.01
(3H, s), 3.10 (3H, s), 3.90 (1H, br s), 6.99 (1H, d, J=8.4 Hz),
7.06 (1H, d, J=6.9 Hz), 7.11-7.24 (4H, m), 7.52 (1H, d, J=8.4 Hz),
9.77 (1H, br s), 10.15 (1H, br s).
Example 36
4-[3-(3-Methoxyphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-87)
[0562] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-methoxyphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0563] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.52-2.58 (1H, m), 2.92-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.55-3.60 (1H, m), 3.75 (3H, s), 3.91-3.96 (1H, m), 4.32-4.36 (1H,
m), 6.36-6.38 (2H, m), 6.47 (1H, dd, J=8.9 Hz, 1.9 Hz), 7.11 (1H,
t, J=8.9 Hz), 7.18 (2H, d, J=8.6 Hz), 7.60 (2H, d, J=8.6 Hz).
[0564] MS (FAB) m/z: 359 (M+H).sup.+.
Example 37
4-[3-(2-Methoxyphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-88)
[0565] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-methoxyphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0566] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.56 (3H, s),
2.56-2.62 (1H, m), 2.85-2.89 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.86-3.93 (1H, m), 3.90 (3H, s), 4.08-4.11 (1H, m), 4.43-4.46 (1H,
m), 6.81 (1H, d, J=7.9 Hz), 6.86-6.91 (2H, m), 6.95-6.98 (1H, m),
7.18 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz).
[0567] MS (FAB) m/z: 359 (M+H).sup.+.
Example 38
4-[3-(3-chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-79)
(a) t-Butyl
[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylca-
rbamate
[0568] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-chlorophenol were treated using a
similar procedure to that described in Example 7f to afford the
desired compound.
[0569] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.41 (9H, s),
2.30-2.41 (2H, m), 2.60 (3H, s), 3.02 (3H, s), 3.10 (3H, s), 4.00
(2H, brs), 5.54 (1H, brs), 6.77 (1H, dd, J=8.2, 2.4 Hz), 6.86-6.93
(2H, m), 7.10 (2H, d, J=8.6 Hz), 7.18 (1H, t, J=8.2 Hz), 7.28-7.30
(2H, m).
(b) 4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0570] t-Butyl
[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylca-
rbamate obtained from Example 38a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0571] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.52-2.61 (1H, m), 2.93-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.55-3.60 (1H, m), 3.92-3.97 (1H, m), 4.31-4.35 (1H, m), 6.68 (1H,
dd, J=8.1 Hz, 2.1 Hz), 6.78 (1H, t, J=2.1 Hz), 6.90 (1H, dd, J=8.1
Hz, 2.1 Hz), 7.14 (1H, t, J=8.1 Hz), 7.19 (2H, d, J=8.5 Hz), 7.60
(2H, d, J=8.5 Hz).
[0572] MS (EI) m/z: 363 (M+H).sup.+.
Example 39
4-[3-(2-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-80)
[0573] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-chlorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0574] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.55 (3H, s),
2.58-2.65 (1H, m), 2.98-3.06 (1H, m), 3.00 (3H, s), 3.08 (3H, s),
3.59-3.65 (1H, m), 4.11-4.16 (1H, m), 4.44-4.48 (1H, m), 6.75 (1H;
dd, J=8.1 Hz, 1.3 Hz), 6.87 (1H, td, J=8.1 Hz, 1.3 Hz), 7.13 (1H,
td, J=8.1 Hz, 1.6 Hz), 7.17 (2H, d, J=8.6 Hz), 7.33 (1H, dd, J=8.1
Hz, 1.6 Hz), 7.66 (2H, d, J=8.6 Hz), 9.90 (1H, br s), 10.20 (1H, br
s).
[0575] MS (EI) m/z: 363 (M+H).sup.+.
Example 40
4-(1-Methylamino-3-p-toluoyloxypropyl)phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-82)
[0576] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-methylphenol were treated using
similar procedures to those described in Example 7f and 79 to
afford the title compound as an amorphous solid.
[0577] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.24 (3H, s),
2.46-2.54 (1H, m), 2.51 (3H, s), 2.95-3.00 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.52-3.58 (1H, m), 3.90-3.94 (1H, m), 4.33-4.37 (1H,
m), 6.68 (2H, d, J=8.5 Hz), 7.01 (2H, d, J=8.5 Hz), 7.17 (2H, d,
J=8.5 Hz), 7.61 (2H, d, J=8.6 Hz).
[0578] MS (EI) m/z: 342 (M).sup.+.
Example 41
4-[3-(4-Chlorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-135)
4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
obtained from Example 16d was treated using a similar procedure to
that described in Example 3 to afford the title compound as an
amorphous solid.
[0579] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, s),
2.64-2.68 (1H, m), 2.90 (3H, s), 2.90-2.98 (1H, m), 3.02 (3H, s),
3.11 (3H, s), 3.50-3.54 (1H, m), 3.95-3.98 (1H, m), 4.26-4.28 (1H,
m), 6.67 (2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.9 Hz), 7.23 (2H, d,
J=8.5 Hz), 7.59 (2H, d, J=8.6 Hz).
[0580] MS (EI) m/z: 376 (M).sup.+.
Example 42
4-[3-(4-Chlorophenyl)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-13)
[0581] 4-Acetylphenol and 4-chlorobenzaldehyde were treated using
similar procedures to those described in Example 1 to afford the
title compound as an amorphous solid.
[0582] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.37 (3H, s),
2.31-2.53 (3H, m), 2.68-2.79 (1H, m), 3.03 (3H, s), 3.12 (3H, s),
3.84 (1H, br s), 7.03 (2H, d, J=8.2 Hz), 7.20 (2H, d, J=8.2 Hz),
7.22 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz), 9.85 (1H, br s),
10.15 (1H, br s).
[0583] MS (EI) m/z: 347 (M+H).sup.+.
Example 43
4-[3-(2,4-Difluorophenoxy)-1-methylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-101)
[0584] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2,4-difluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0585] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.50-2.61 (1H, m), 2.92-3.05 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.58-3.67 (1H, m), 4.02-4.08 (1H, m), 4.33-4.40 (1H, m), 6.67-6.85
(3H, m), 7.19 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz).
[0586] MS (FAB) m/z: 365 (M+H).sup.+.
Example 44
4-[3-(2-Chloro-4-fluorophenoxy)-1-methylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-106)
[0587] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-chloro-4-fluorophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0588] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.55-2.65 (1H, m), 2.95-3.07 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.55-3.65 (1H, m), 4.05-4.12 (1H, m), 4.38-4.45 (1H, m), 6.71 (1H,
dd, J=9.1 Hz, 4.8 Hz), 6.83-6.89 (1H, m), 7.10 (1H, dd, J=8.0 Hz,
3.0 Hz), 7.18 (2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.6 Hz).
[0589] MS (FAB) m/z: 381 (M+H).sup.+.
Example 45
4-[3-(4-Acetylphenoxy)-1-methylaminopropyl)phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-89)
[0590] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-acetylphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0591] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (6H, s),
2.52-2.66 (1H, m), 2.97-3.07 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.63-3.73 (1H, m), 4.00-4.08 (1H, m), 4.30-4.38 (1H, m), 6.82 (2H,
d, J=8.9 Hz), 7.19 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz), 7.87
(2H, d, J=8.9 Hz).
[0592] MS (FAB) m/z: 371 (M+H).sup.+.
Example 46
4-[3-(2,4-Dichlorophenoxy)-1-methylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-107)
[0593] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2,4-dichlorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0594] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.55-2.66 (1H, m), 2.95-3.07 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.55-3.65 (1H, m), 4.07-4.13 (1H, m), 4.36-4.45 (1H, m), 6.67 (1H,
d, J=8.8 Hz), 7.10 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.18 (2H, d, J=8.6
Hz), 7.33 (1H, d, J=2.5 Hz), 7.64 (2H, d, J=8.6 Hz), 10.05 (2H, br
s).
[0595] MS (FAB) m/z: 397 (M+H).sup.+.
Example 47
4-[3-(3,4-Dichlorophenoxy)-1-methylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-110)
[0596] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3,4-dichlorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0597] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.57 (1H, br s), 2.98 (1H, br s), 3.01 (3H, s), 3.10 (3H, s),
3.52-3.62 (1H, m), 3.90-3.98 (1H, m), 4.31 (1H, br s), 6.66 (1H,
dd, J=8.8 Hz, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.20 (2H, d, J=8.1
Hz), 7.27 (1H, d, J=8.8 Hz), 7.59 (2H, d, J=8.1 Hz), 9.93 (1H, br
s), 10.30 (1H, br s).
[0598] MS (FAB) m/z: 397 (M+H).sup.+.
Example 48
4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-92)
(a) t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]-N-methylc-
arbamate
[0599] Triphenylphosphine (420 mg, 1.6 mmol) was dissolved in
tetrahydrofuran (4 ml) under an atmosphere of nitrogen and 40%
solution of diethyl azodicarboxylate in toluene (0.72 ml, 1.6 mmol)
was added to the solution. After stirring the resulting mixture for
30 minutes at room temperature, 4-nitrophenol (190 mg, 1.4 mmol)
was added to the reaction mixture. After stirring this mixture for
30 minutes, t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b (400 mg, 1.1 mmol) was added and the
resulting mixture was stirred for 5 hours. The reaction mixture was
partitioned between water and ether. The organic layer was washed
with water and saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column using hexane:ethyl acetate=50:50 as the eluent to afford
the desired compound (392 mg).
[0600] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.39 (9H, s),
2.39-2.49 (2H, m), 2.60 (3H, s), 3.02 (3H, s), 3.11 (3H, s),
4.11-4.13 (2H, m), 5.60 (1H, br s), 6.95 (2H, d, J=9.1 Hz), 7.11
(2H, d, J=8.6 Hz), 7.27-7.31 (2H, m), 8.20 (2H, d, J=9.1 Hz).
(b) 4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride
[0601] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]-N-methylc-
arbamate obtained from Example 48a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0602] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.62-2.66 (1H, m), 3.01 (3H, s), 3.01-3.10 (1H, m), 3.10 (3H, s),
3.72-3.75 (1H, m), 4.07-4.11 (1H, m), 4.29-4.32 (1H, m), 6.86 (2H,
d, J=9.2 Hz), 7.20 (2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz), 8.15
(2H, d, J=9.2 Hz).
[0603] IR (KBr) .nu..sub.maxcm.sup.-1: 3430, 2941 2756, 2698, 2446,
1724.
[0604] MS m/z: 374 (M+H).sup.+.
Example 49
4-[3-(4-Aminophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
dihydrochloride (Exemplification compound number 1-95)
(a) t-Butyl
N-[3-(4-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylc-
arbamate
[0605] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]-N-methylc-
arbamate (1.13 g, 2.4 mmol) obtained from Example 48a was dissolved
in methanol (11 ml) and 5% palladium on charcoal (110 mg) was added
to the solution. The resulting mixture was stirred at room
temperature under an atmosphere of hydrogen for 1 hour. The
catalyst was filtered off and the solvent of the filtrate was
evaporated under reduced pressure. The residue was recrystallized
from a mixture of ethyl acetate and hexane to afford the desired
compound (820 mg) as crystals (mp 146-149.degree. C.).
(b) 4-[3-(4-Aminophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride
[0606] t-Butyl
N-[3-(4-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylc-
arbamate obtained from Example 49a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0607] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 2.27-2.36
(1H, m), 2.38 (3H, s), 2.60-2.62 (1H, m), 2.90 (3H, s), 3.03 (3H,
s), 3.61-3.63 (1H, m), 3.94-3.96 (1H, m), 4.38-4.41 (1H, m), 6.92
(2H, d, J=8.8 Hz), 7.19-7.25 (4H, m), 7.55 (2H, d, J=8.6 Hz).
[0608] MS (FAB) m/z: 344 (M+H).sup.+.
Example 50
4-[3-(4-Acetylaminophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-97)
(a) t-Butyl
[3-(4-acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methyl-
carbamate
[0609] t-Butyl
N-[3-(4-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylc-
arbamate (100 mg, 0.23 mmol) obtained from Example 49a was
dissolved in pyridine (1 ml) under an atmosphere of nitrogen, and
acetic anhydride (0.026 ml, 0.28 mmol) was added to the solution.
The resulting mixture was stirred at room temperature for 30
minutes. To the reaction mixture was added 0.5N aqueous
hydrochloric acid solution and the mixture was extracted with ethyl
acetate. The organic layer was washed with 0.5N aqueous
hydrochloric acid solution, water and saturated aqueous sodium
chloride solution, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column using ethyl acetate as the
eluent to afford the desired compound (106 mg).
[0610] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.43 (9H, s),
2.32-2.43 (2H, m), 2.61 (3H, s), 3.01 (3H, s), 3.10 (3H, s), 3.97
(2H, brs), 5.52 (1H, brs), 6.22 (1H, s), 6.27-6.31 (2H, m), 7.03
(1H, t, J=8.0 Hz), 7.09 (2H, d, J=8.5 Hz), 7.29 (2H, brs).
(b) 4-[3-(4-Acetylaminophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0611] t-Butyl
[3-(4-Acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methyl-
carbamate obtained from Example 50a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0612] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.13 (3H, s),
2.43-2.53 (1H, m), 2.47 (3H, s), 2.88-2.90 (1H, m), 3.01 (3H, s),
3.10 (3H, s), 3.57-3.62 (1H, m), 3.87-3.89 (1H, m), 4.32-4.34 (1H,
m), 6.71 (2H, d, J=8.7 Hz), 7.18 (2H, d, J=8.1 Hz), 7.26-7.35 (2H,
m), 7.59 (2H, d, J=8.1 Hz), 7.63 (1H, s).
[0613] MS (FAB) m/z: 386 (M+H).sup.+.
Example 51
4-[3-(3-Chlorophenoxy)-1-dimethylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-136)
4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
obtained from Example 38b was treated using a similar procedure to
that described in Example 3 to afford the title compound as an
amorphous solid.
[0614] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H,
brs), 2.60-2.71 (1H, m), 2.88-2.97 (1H, m), 3.02 (3H, s), 3.11 (3H,
s), 3.49-3.55 (1H, m), 3.96-4.00 (1H, m), 4.24-4.29 (1H, m), 6.64
(1H, ddd, J=8.4 Hz, 2.2 Hz, 0.8 Hz), 6.74 (1H, t, J=2.2 Hz), 6.92
(1H, ddd, J=8.4 Hz, 2.2 Hz, 0.8 Hz), 7.15 (1H, t, J=8.2 Hz), 7.23
(2H, d, J=8.7 Hz), 7.57 (2H, d, J=8.7 Hz).
[0615] MS (FAB) m/z: 377 (M+H).sup.+.
Example 52
4-[3-(2-Chlorophenoxy-1-dimethylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-137)
4-[3-(2-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
obtained from Example 39 was treated using a similar procedure to
that described in Example 3 to afford the title compound as an
amorphous solid.
[0616] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.58 (3H, s),
2.69-2.77 (1H, m), 2.90-3.00 (4H, m), 3.01 (3H, s), 3.09 (3H, s),
3.47-3.53 (1H, m), 4.13-4.17 (1H, m), 4.32-4.35 (1H, m), 6.73 (1H,
dd, J=7.9 Hz, 1.3 Hz), 6.89 (1H, td, J=7.9 Hz, 1.3 Hz), 7.15 (1H,
td, J=7.9 Hz, 1.6 Hz), 7.20 (2H, d, J=8.7 Hz), 7.34 (1H, dd, J=7.9
Hz, 1.6 Hz), 7.66 (2H, d, J=8.7 Hz).
[0617] MS (FAB) m/z: 377 (M+H).sup.+.
Example 53
4-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-94)
(a) t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(3-nitrophenoxy)propyl]-N-methylc-
arbamate
[0618] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-nitrophenol were treated using a
similar procedure to that described in Example 7f to afford the
desired compound.
[0619] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.40 (9H, s),
2.39-2.48 (2H, m), 2.61 (3H, s), 3.02 (3H, s), 3.11 (3H, s),
4.09-4.15 (2H, m), 5.63 (1H, brs), 7.11 (2H, d, J=8.6 Hz), 7.23
(1H, d, J=8.2 Hz), 7.31 (2H, d, J=8.6 Hz), 7.43 (1H, t, J=8.2 Hz),
7.72 (1H, s), 7.83 (1H, d, J=8.2 Hz).
(b) 4-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride
[0620] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(3-nitrophenoxy)propyl]-N-methylc-
arbamate obtained from Example 53a was treated using a similar
procedure to that described in Example 6d to afford the title
compound.
[0621] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.64-2.67 (1H, m), 2.96-3.09 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.70-3.74 (1H, m), 4.06-4.10 (1H, m), 4.32-4.36 (1H, m), 7.15 (1H,
dd, J=8.2 Hz, 2.4 Hz), 7.21 (1H, d, J=8.4 Hz), 7.39 (1H, t, J=8.2
Hz), 7.59 (1H, s), 7.60 (2H, d, J=8.4 Hz), 7.80 (1H, dd, J=8.2 Hz,
2.4 Hz).
[0622] MS (FAB) m/z: 374 (M+H).sup.+.
Example 54
4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl)phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-102)
[0623] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3,4-difluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0624] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, br
s), 2.55-2.62 (1H, m), 2.92-3.02 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.52-3.59 (1H, m), 3.89-3.95 (1H, m), 4.28-4.35 (1H, m),
6.45-6.51 (1H, m), 6.61 (1H, ddd, J=11.9 Hz, 6.6 Hz, 2.2 Hz), 7.00
(1H, q, J=9.4 Hz), 7.19 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz)
9.93 (1H, br s), 10.30 (1H, br s)
[0625] MS (FAB) m/z: 365 (M+H).sup.+.
Example 55
4-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-104)
[0626] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-chloro-3-fluorophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0627] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, br
s), 2.51-2.62 (1H, m), 2.91-3.04 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.53-3.62 (1H, m), 3.90-3.98 (1H, m), 4.27-4.34 (1H, m),
6.52-6.55 (1H, m), 6.60 (1H, dd, J=10.7 Hz, 2.7 Hz), 7.18-7.25 (3H,
m), 7.59 (2H, d, J=8.3 Hz), 9.94 (1H, br s), 10.32 (1H, br s).
[0628] MS (FAB) m/z: 381 (M+H).sup.+.
Example 56
4-[3-(4-Cyanophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-91)
[0629] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-hydroxybenzonitrile were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0630] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, br
s), 2.55-2.68 (1H, m), 2.95-3.05 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.64-3.72 (1H, m), 3.98-4.07 (1H, m), 4.25-4.35 (1H, m), 6.84
(2H, d, J=8.8 Hz), 7.19 (2H, d, J=8.3 Hz), 7.53 (2H, d, J=8.8 Hz),
7.58 (2H, d, J=8.3 Hz), 9.96 (1H, br s), 10.36 (1H, br s).
[0631] MS (EI) m/z: 354 (M+H).sup.+.
Example 57
4-[3-(4-Bromophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-81)
[0632] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-bromophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0633] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, br
s), 2.52-2.62 (1H, m), 2.92-3.03 (1H, m), 3.01 (3H, s), 3.09 (3H,
s), 3.53-3.61 (1H, m), 3.88-3.97 (1H, m), 4.28-4.38 (1H, m), 6.66
(2H, d, J=9.0 Hz), 7.18 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=9.0 Hz),
7.59 (2H, d, J=8.5 Hz), 9.91 (1H, br s), 10.22 (1H, br s).
[0634] MS (FAB) m/z: 407 (M+H).sup.+.
Example 58
4-[3-(4-Fluoro-2-methylphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-111)
[0635] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-fluoro-2-methylphenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0636] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.19 (3H, s),
2.51 (3H, br s), 2.53-2.63 (1H, m), 2.93-3.03 (1H, m), 3.01 (3H,
s), 3.09 (3H, s), 3.54-3.62 (1H, m), 3.89-3.97 (1H, m), 4.28-4.37
(1H, m), 6.53 (1H, dd, J=8.7 Hz, 4.5 Hz), 6.73 (1H, td, J=8.7 Hz,
3.0 Hz), 6.82 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.19 (2H, d, J=8.5 Hz),
7.60 (2H, d, J=8.5 Hz) 9.94 (1H, br s), 10.32 (1H, br s).
[0637] MS (FAB) m/z: 361 (M+H).sup.+.
Example 59
4-[1-Methylamino-3-m-toluoyloxypropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-83)
[0638] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-methylphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0639] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.28 (3H, s)
2.52 (3H, s), 2.48-2.60 (1H, m), 2.90-3.03 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.53-3.61 (1H, m), 3.89-3.97 (1H, m), 4.32-4.40 (1H,
m), 6.56-6.62 (2H, m), 6.73 (1H, d, J=7.6 Hz), 7.10 (1H, t, J=7.6
Hz), 7.18 (2H, d, J=8.5 Hz), 7.61 (2H, d, J=8.5 Hz), 9.93 (1H, br
s), 10.25 (1H, br s).
[0640] MS (EI) m/z: 343 (M+H).sup.+.
Example 60
4-[3-(3,4-Dimethylphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-114)
[0641] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3,4-dimethylphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0642] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.15 (3H, s),
2.18 (3H, s), 2.51 (3H, br s), 2.45-2.58 (1H, m), 2.87-3.00 (1H,
m), 3.00 (3H, s), 3.08 (3H, s), 3.48-3.57 (1H, m), 3.86-3.94 (1H,
m), 4.34 (1H, br s), 6.51 (1H, dd, J=8.2 Hz, 2.6 Hz), 6.59 (1H, d,
J=2.6 Hz), 6.95 (1H, d, J=8.2 Hz), 7.17 (2H, d, J=8.6 Hz), 7.60
(2H, d, J=8.6 Hz), 9.90 (1H, br s), 10.24 (1H, br s).
[0643] MS (FAB) m/z: 357 (M+H).sup.+.
Example 61
(R)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-79)
(a) Methyl
(R)-3-t-butoxycarbonylamino-3-(4-hydroxyphenyl)propionate
[0644] Methyl (R)-3-amino-3-(4-hydroxyphenyl)propionate, which was
synthesized according to the method described in Tetrahedron:
Asymmetry, 2, 183, (1991), was treated using a similar procedure to
that described in Example 6a to give the desired compound. The
product was recrystallized from a mixture of ethyl acetate and
hexane to afford the desired compound (mp 130-132.degree. C.),
which had greater than 99% optical purity. The optical purity was
determined by HPLC on a Chiralcel OD column (product of Daisel
Chemical Industry Co. Ltd.) using hexane:isopropyl alcohol=95:5 as
the eluent.
(b) t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
[0645] Methyl
(R)-3-t-butoxycarbonylamino-3-(4-hydroxyphenyl)propionate obtained
from Example 61a was treated using similar procedures to those
described in Example 7d and 7e to afford the desired product.
[0646] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (9H, s),
1.92-1.97 (1H, m), 2.14-2.20 (1H, m), 2.43 (1H, br), 3.01 (3H, s),
3.10 (3H, s), 3.51-3.58 (2H, m), 3.73-3.77 (1H, br), 5.57-5.59 (1H,
m), 7.10 (2H, d, J=7.7 Hz), 7.28 (2H, d, J=7.7 Hz).
(c) t-Butyl
(R)-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]carbama-
te
[0647] t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 61b and 3-chlorophenol were treated using a
similar procedure to that described in Example 7f to afford the
desired compound.
[0648] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.41 (9H, s),
2.34-2.44 (2H, m), 3.02 (3H, s), 3.11 (3H, s), 4.00 (2H, br s),
5.54 (2H, br s), 6.78 (1H, d, J=8.1 Hz), 6.89 (1H, s), 6.94 (1H, d,
J=8.1 Hz), 7.12 (2H, d, J=8.4 Hz), 7.17 (1H, t, J=8.1 Hz), 7.29
(2H, br s).
(d) t-Butyl
(R)-N-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-me-
thylcarbamate
[0649] N,N-dimethylformamide (30 ml) was added to sodium hydride
(1.75 g, 40 mmol) under an atmosphere of nitrogen, and to the
sodium hydride was added a solution of t-butyl
(R)-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]carbama-
te (7.00 g, 16 mmol) obtained from Example 61c in
N,N-dimethylformamide in an ice bath. The mixture was stirred for
30 minutes and then methyl iodide (1.9 ml, 30 mmol) was added
thereto. The resulting mixture was warmed to room temperature and
then stirred overnight. The reaction mixture was partitioned
between water and ethyl acetate. The organic layer was washed with
water and saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column using hexane:ethyl acetate=95:5 to 85:15 to afford the
desired compound (6.14 g).
[0650] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.41 (9H, s),
2.35-2.44 (3H, s), 2.60 (3H, s) 3.02 (3H, s), 3.10 (3H, s), 4.00
(2H, br), 5.54 (1H, br), 6.78 (1H, d, J=8.3 Hz), 7.10 (2H, d, J=8.4
Hz), 7.18 (1H, t, J=8.3 Hz), 7.29 (2H. m).
(e) (R)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0651] t-Butyl
(R)-N-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-me-
thylcarbamate obtained from Example 61d was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0652] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.52-2.61 (1H, m), 2.93-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.55-3.60 (1H, m), 3.92-3.97 (1H, m), 4.31-4.35 (1H, m), 6.68 (1H,
dd, J=8.1 Hz, 2.1 Hz), 6.78 (1H, t, J=2.1 Hz), 6.90 (1H, dd, J=8.1
Hz, 2.1 Hz), 7.14 (1H, t, J=8.1 Hz), 7.19 (2H, d, J=8.5 Hz), 7.60
(2H, d, J=8.5 Hz).
[0653] MS (EI) m/z: 363 (M+H).sup.+
Example 62
(R)-4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-78)
[0654] t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 61b and 4-chlorophenol were treated using
similar procedures to those described in Example from 61c to 61e to
afford the title compound.
[0655] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.51-2.59 (1H, m), 2.94-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.55-3.59 (1H, m), 3.91-4.13 (1H, m), 4.30-4.34 (1H, m), 6.71 (2H,
d, J=9.0 Hz), 7.15-7.19 (4H, m), 7.59 (2H, d, J=8.6 Hz).
[0656] [.alpha.].sub.D.sup.22 +72 (c 0.37, CHCl.sub.3)
Example 63
4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl diethylcarbamate
hydrochloride (Exemplification compound number 1-7)
(a) t-Butyl
N-[3-(4-chlorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
[0657] t-Butyl
[3-(4-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylca-
rbamate obtained from Example 16c was treated using a similar
procedure to that described in Example 6b to afford the desired
compound.
[0658] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.41 (9H, s),
2.29-2.39 (2H, m), 2.57 (3H, s), 3.97 (2H. br s), 5.21 (1H. br s),
5.51 (1H, br s), 6.79-6.82 (4H, m), 7.17 (2H, d, J=7.4 Hz), 7.22
(2H, d, J=8.9 Hz).
(b) 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
diethylcarbamate hydrochloride
[0659] t-Butyl
N-[3-(4-chlorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
obtained from Example 63a was treated using similar procedures to
those described in Example 23 to afford the title compound as an
amorphous solid.
[0660] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.18-1.27
(6H, m), 2.50 (3H, s), 2.49-2.58 (1H, m), 2.94-3.01 (1H, m),
3.34-3.45 (4H, m), 3.54-3.59 (1H, m), 3.90-3.96 (1H, m), 4.32 (1H,
br s), 6.71 (2H, d, J=9.2 Hz), 7.17 (2H, d, J=8.9 Hz), 7.19 (2H, d,
J=9.2 Hz), 7.59 (2H, d, J=8.9 Hz), 9.95 (1H, br s), 10.31 (1H, br
s).
[0661] MS (EI) m/z: 391
[0662] (M+H).sup.+
Example 64
4-[3-(3-Aminophenoxy)1-methylaminopropyl]phenyl dimethylcarbamate
dihydrochloride (Exemplification compound number 1-96)
(a) t-Butyl
N-[3-(3-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylc-
arbamate
[0663] t-Butyl
N-[1-[4-dimethylcarbamoyloxy]phenyl-3-(3-nitrophenoxy)propyl]-N-methylcar-
bamate obtained from Example 53a was treated in a similar procedure
to that described in Example 49a to afford the desired
compound.
[0664] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.41 (9H, s),
2.16 (3H, s), 2.28-2.33 (1H, m), 2.34-2.47 (1H, m), 2.60 (3H, s),
3.02 (3H, s), 3.11 (3H, s), 3.98-4.06 (2H, m), 5.52 (1H, brs), 6.62
(1H, d, J=6.7 Hz), 6.99 (1H, brs), 7.08-7.12 (3H, m), 7.19 (1H, t,
J=8.2 Hz), 7.27-7.33 (2H, m)
(b) 4-[3-(3-Aminophenoxy)1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride
[0665] t-Butyl
N-[3-(3-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylc-
arbamate obtained from Example 64a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0666] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 2.28-2.39
(1H, m), 2.39 (3H, t, J=5.0 Hz), 2.59-2.64 (1H, m), 2.90 (3H, s),
3.03 (3H, s), 3.56-3.63 (1H, m), 3.90-3.95 (1H, m), 4.38-4.42 (1H,
m), 6.66-6.75 (3H, m), 7.19-7.27 (3H, m), 7.56 (2H, d, J=8.4
Hz).
[0667] MS (FAB) m/z: 344 (M+H).sup.+.
Example 65
4-[3-(3-Acetylaminophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-98)
(a) t-Butyl
[3-(3-acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methyl-
carbamate
[0668] t-Butyl
N-[3-(3-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylc-
arbamate obtained from Example 64a was treated using a similar
procedure to that described in Example 50a to afford the desired
compound.
(b) 4-[3-(3-Acetylaminophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0669] t-Butyl
[3-(3-acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methyl-
carbamate obtained from Example 65a was treated using a similar
procedure to that described in Example 6d to afford the title
compound as an amorphous solid.
[0670] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.13 (3H, s),
2.48 (4H, br s), 2.86 (1H, br s), 3.03 (3H, s), 3.12 (3H, s), 3.74
(1H, br s), 3.86 (1H, br s), 4.28 (1H, br s), 6.50 (1H, d, J=5.9
Hz), 6.59 (1H, br s), 7.13-7.16 (3H, m), 7.36-7.37 (1H, m), 7.57
(2H, br s), 8.41 (1H, br s), 9.82 (1H, br s), 10.01 (1H, br s).
[0671] MS (FAB) m/z: 386 (M+H).sup.+.
Example 66
4-[1-Methylamino-3-(2-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-93)
[0672] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-nitrophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0673] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.56 (3H, s),
2.62-2.70 (1H, m), 2.95-3.03 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.75-3.81 (1H, m), 4.28-4.33 (1H, m), 4.46-4.50 (1H, m), 6.96 (1H,
dd, J=8.0 Hz, 1.0 Hz), 7.02 (1H, td, J=8.0 Hz, 1.0 Hz), 7.17 (2H,
d, J=8.6 Hz), 7.48 (1H, td, J=8.0 Hz, 1.6 Hz), 7.69 (2H, d, J=8.6
Hz), 7.87 (1H, dd, J=8.0 Hz, 1.6 Hz).
[0674] MS (EI) m/z: 374 (M+H).sup.+.
Example 67
4-[1-Methylamino-3-phenoxypropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-74)
[0675] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and phenol were treated using similar
procedures to those described in Example 7f and 7g to afford the
title compound as an amorphous solid.
[0676] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.48-2.59
(1H, m), 2.52 (3H, s), 2.93-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H,
s), 3.56-3.62 (1H, m), 3.94-3.98 (1H, m), 4.34-4.38 (1H, m), 6.79
(2H, d, J=8.5 Hz), 6.91 (1H, t, J=7.3 Hz), 7.17-7.24 (4H, m), 7.61
(2H, d, J=8.5 Hz).
[0677] MS (EI) m/z: 329 (M+H).sup.+.
Example 68
4-[3-(3-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-76)
[0678] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-fluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0679] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.52-2.61 (1H, m), 2.93-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.55-3.61 (1H, m), 3.93-3.97 (1H, m), 4.32-4.35 (1H, m), 6.50 (1H,
dt, J=10.8 Hz, 2.3 Hz), 6.57 (1H, dd, J=7.3 Hz, 2.3 Hz), 6.62 (1H,
td, J=8.3 Hz, 2.3 Hz), 7.13-7.20 (3H, m), 7.60 (2H, d, J=8.6 Hz)
9.93 (1H, br s), 10.28 (1H, br s).
[0680] MS (FAB) m/z: 347 (M+H).sup.+.
Example 69
4-[3-(2-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-77)
[0681] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-fluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0682] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.53-2.63 (1H, m), 2.97-3.09 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.61-3.67 (1H, m), 4.06-4.13 (1H, m), 4.39-4.41 (1H, m), 6.79-6.90
(2H, m), 6.96-7.06 (2H, m), 7.18 (2H, d, J=8.5 Hz), 7.65 (2H, d,
J=8.5 Hz), 9.91 (1H, br s), 10.23 (1H, br s).
[0683] MS (EI) m/z: 347 (M+H).sup.+.
Example 70
4-[1-Dimethylamino-3-(3-fluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-133)
4-[3-(3-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
obtained from Example 68 was treated using a similar procedure to
that described in Example 3 to afford the title compound as an
amorphous solid.
[0684] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, s),
2.60-2.73 (1H, m), 2.91 (3H, s), 2.91-3.02 (1H, m), 3.02 (3H, s),
3.11 (3H, s), 3.49-3.55 (1H, m), 3.96-4.00 (1H, m), 4.26-4.29 (1H,
m), 6.46 (1H, dt, J=10.7 Hz, 2.3 Hz), 6.53 (1H, dd, J=8.3 Hz, 2.3
Hz), 6.64 (1H, td, J=8.3 Hz, 2.3 Hz), 7.14-7.24 (3H, m), 7.58 (2H,
d, J=8.5 Hz).
[0685] MS (EI) m/z: 360 (M).sup.+.
Example 71
4-[1-Dimethylamino-3-(2-fluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-134)
4-[3-(2-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
obtained from Example 69 was treated using a similar procedure to
that described in Example 3 to afford the title compound as an
amorphous solid.
[0686] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.58 (3H, s),
2.68-2.73 (1H, m), 2.95 (4H, br s), 3.01 (3H, s), 3.10 (3H, s),
3.49-3.56 (1H, m), 4.09-4.15 (1H, m), 4.31 (1H, br s), 6.78 (1H, t,
J=8.3 Hz), 6.87-6.92 (1H, m), 6.97-7.08 (2H, m), 7.21 (2H, d, J=7.9
Hz), 7.64 (2H, d, J=7.9 Hz).
[0687] MS (EI) m/z: 360 (M).sup.+.
Example 72
4-[3-(3-Acetylphenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-90)
[0688] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-acetylphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0689] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.47-2.66
(1H, m), 2.53 (3H, s), 2.56 (3H, s), 2.93-3.06 (1H, m), 3.00 (3H,
s), 3.09 (3H, s), 3.61-3.70 (1H, m), 3.98-4.07 (1H, m), 4.32-4.40
(1H, m), 7.02 (1H, dd, J=7.9 Hz, 2.5 Hz), 7.18 (2H, d, J=8.5 Hz),
7.32 (1H, t, J=7.9 Hz), 7.34 (1H, br s), 7.51 (1H, d, J=7.9 Hz),
7.60 (2H, d, J=8.5 Hz), 10.10 (2H, br s).
[0690] MS (EI) m/z: 371 (M+H).sup.+.
Example 73
4-[3-(4-Chloro-3-methylphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-113)
[0691] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-chloro-3-methylphenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0692] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.28 (3H, s),
2.50-2.62 (1H, m), 2.51 (3H, br s), 2.89-3.05 (1H, m), 3.01 (3H,
s), 3.09 (3H, s), 3.50-3.59 (1H, m), 3.86-3.95 (1H, m), 4.27-4.37
(1H, m), 6.55 (1H, dd, J=8.7 Hz, 2.9 Hz), 6.65 (1H, d, J=2.9 Hz),
7.15 (1H, d, J=8.7 Hz), 7.18 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5
Hz), 9.96 (1H, br s), 10.33 (1H, br s).
[0693] MS (EI) m/z: 377 (M+H).sup.+.
Example 74
4-[3-(3-Chloro-4-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-109)
[0694] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-chloro-4-fluorophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0695] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, br
s), 2.50-2.63 (1H, m), 2.91-3.04 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.51-3.60 (1H, m), 3.88-3.97 (1H, m), 4.25-4.36 (1H, m), 6.65
(1H, dt, J=8.9 Hz, 3.0 Hz), 6.81 (1H, dd, J=6.0 Hz, 3.0 Hz), 6.99
(1H, t, J=8.9 Hz), 7.20 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz),
9.98 (1H, br s), 10.34 (1H, br s).
[0696] MS (EI) m/z: 381 (M+H).sup.+.
Example 75
4-[3-(4-Acetylphenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-146)
4-[3-(4-Acetylphenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
obtained from Example 45 was treated using a similar procedure to
that described in Example 3 to afford the title compound an
amorphous solid.
[0697] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.62 (3H, br s), 2.67-2.79 (1H, br s), 2.90 (3H, br s), 2.99 (1H,
br s), 3.02 (3H, s), 3.10 (3H, s), 3.63 (1H, br s), 4.06 (1H, br
s), 4.30 (1H, br s), 6.78 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.2
Hz), 7.57 (2H, d, J=8.2 Hz), 7.87 (2H, d, J=8.7 Hz).
[0698] MS (EI) m/z: 384 (M+H).sup.+.
Example 76
4-[3-(3,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-159)
[0699] 4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained from Example 54 was treated using a
similar procedure to that described in Example 3 to afford the
title compound an amorphous solid.
[0700] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H, br
s), 2.60-2.75 (1H, m), 2.90 (3H, br s), 2.88-3.00 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.45-3.55 (1H, m), 3.88-3.98 (1H, m),
4.22-4.31 (1H, br s), 6.40-6.47 (1H, m), 6.56 (1H, ddd, J=11.7 Hz,
6.5 Hz, 2.9 Hz), 7.01 (1H, q, J=9.4 Hz), 7.23 (2H, d, J=8.4 Hz),
7.56 (2H, d, J=8.4 Hz).
[0701] MS (EI) m/z: 378 (M+H).sup.+.
Example 77
4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl diethylcarbamate
hydrochloride (Exemplification compound number 1-8)
[0702] t-Butyl
[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylca-
rbamate obtained from Example 38a was treated using similar
procedures to those described in Example 63 to afford the title
compound as an amorphous solid.
[0703] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.18-1.28
(6H, m), 2.51 (3H, s), 2.50-2.61 (1H, m), 2.94-3.02 (1H, m),
3.36-3.44 (4H, m), 3.54-3.59 (1H, m), 3.91-3.96 (1H, m), 4.34 (1H,
br s), 6.68 (1H, d, J=8.5 Hz), 6.77 (1H, s), 6.89 (1H, d, J=8.5
Hz), 7.13 (1H, t, J=8.5 Hz), 7.20 (2H, d, J=8.2 Hz), 7.60 (2H, d,
J=8.2 Hz), 9.95 (1H, br s), 10.28 (1H, br s).
Example 78
4-[3-(4-Chloro-3-fluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-161)
4-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained from Example 55 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0704] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H, br
s), 2.62-2.75 (1H, m), 2.90 (3H, br s), 2.96 (1H, br s), 3.02 (3H,
s), 3.11 (3H, s), 3.46-3.55 (1H, m), 3.91-4.01 (1H, m), 4.26 (1H,
br s), 6.49 (1H, dd, J=8.8 Hz, 1.8 Hz), 6.55 (1H, dd, J=10.6 Hz,
2.6 Hz), 7.21 (2H, d, J=8.6 Hz), 7.23 (1H, d, J=8.8 Hz), 7.55 (2H,
d, J=8.6 Hz).
[0705] MS (EI) m/z: 394 (M+H).sup.+.
Example 79
4-[3-(3,5-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-103)
[0706] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3,5-difluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0707] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, br
s), 2.52-2.63 (1H, m), 2.91-3.03 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.52-3.61 (1H, m), 3.90-3.98 (1H, m), 4.30 (1H, br s), 6.32
(2H, dd, J=8.8 Hz, 2.1 Hz), 6.38 (1H, tt, J=9.0 Hz, 2.1 Hz), 7.20
(2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 9.99 (1H, br s), 10.38
(1H, br s).
[0708] MS (EI) m/z: 365 (M+H).sup.+.
Example 80
4-[1-Methylamino-3-(3,4,5-trifluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-117)
[0709] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3,4,5-trifluorophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0710] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, br
s), 2.52-2.63 (1H, m), 2.92-3.03 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.49-3.58 (1H, m), 3.87-3.95 (1H, m), 4.28 (1H, br s),
6.37-6.47 (2H, m), 7.20 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz),
9.99 (1H, br s), 10.34 (1H, br s).
[0711] MS (EI) m/z: 381 (M+H).sup.+.
Example 81
(S)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-79)
(a) t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
[0712] Methyl (S)-3-amino-3-(4-hydroxyphenyl)propionate, which was
synthesized according to the method described in Tetrahedron:
Asymmetry, 2, 183, (1991), was treated using similar procedures to
those described in Example 61a and 61b to afford the desired
compound.
[0713] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.42 (9H, s),
2.78-2.90 (2H, m), 3.00 (3H, s), 3.09 (3H, s), 3.62 (3H, s), 5.09
(1H, br s), 5.42 (1H, br s), 7.07 (2H, d, J=9.0 Hz), 7.28 (2H, d,
J=9.0 Hz).
(b) (S)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0714] t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 81a and 3-chlorophenol were treated using
similar procedures to those described Example 7f, 61d and 61e to
afford the title compound as an amorphous solid.
[0715] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.52-2.61 (1H, m), 2.93-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.55-3.60 (1H, m), 3.92-3.97 (1H, m), 4.31-4.35 (1H, m), 6.68 (1H,
dd, J=8.1 Hz, 2.1 Hz), 6.78 (1H, t, J=2.1 Hz), 6.90 (1H, dd, J=8.1
Hz, 2.1 Hz), 7.14 (1H, t, J=8.1 Hz), 7.19 (2H, d, J=8.5 Hz), 7.60
(2H, d, J=8.5 Hz).
Example 82
(S)-4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-78)
[0716] t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 81a and 4-chlorophenol were treated using
similar procedures to those described Example 7f, 61d and 61e to
afford the title compound as an amorphous solid.
[0717] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.51-2.59 (1H, m), 2.94-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s),
3.55-3.59 (1H, m), 3.91-4.13 (1H, m), 4.30-4.34 (1H, m), 6.71 (2H,
d, J=9.0 Hz), 7.15-7.19 (4H, m), 7.59 (2H, d, J=8.6 Hz).
Example 83
4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
N-ethyl-N-methylcarbamate hydrochloride (Exemplification compound
number 1-10)
(a) t-Butyl
N-[3-(4-chlorophenoxy)-1-[4-(N-ethyl-N-methylcarbamoyloxy)phenyl]propyl]--
N-methylcarbamate
[0718] t-Butyl
N-[3-(4-chlorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate
(200 mg, 0.51 mmol) obtained from Example 63a was dissolved in
dichloromethane (3 ml) and to the solution was added
N,N-carbonyldiimidazole (165 mg, 1.0 mmol). The mixture was stirred
at room temperature overnight and then ethylamine (0.09 ml, 1.0
mmol) was added thereto. The resulting mixture was stirred for one
day. The reaction mixture was partitioned between water and
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by chromatography on a silica gel column using
hexane:ethyl acetate=80:20 to 60:40 as the eluent to afford the
desired compound (96 mg).
[0719] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.17-1.26
(6H, m), 1.41 (9H, s), 2.33-2.57 (2H, m), 2.59 (3H, s), 2.99 (3H,
s), 3.07 (3H, s), 3.41 (2H, q, J=7.1 Hz), 3.46 (2H, q, J=7.1 Hz),
3.98 (2H, br s), 5.56 (1H, br s), 6.81 (2H, d, J=9.0 Hz), 7.10 (2H,
d, J=6.4 Hz), 7.22 (2H, d, J=9.0 Hz), 7.29 (2H, d, J=6.4 Hz).
(b) 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
N-ethyl-N-methylcarbamate hydrochloride
[0720] t-Butyl
N-[3-(4-chlorophenoxy)-1-[4-(N-ethyl-N-methylcarbamoyloxy)phenyl]propyl]--
N-methylcarbamate obtained from Example 83a was treated using a
similar procedure to that described in Example 6d to afford the
title compound as an amorphous solid.
[0721] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.19 and 1.23
(3H, t, J=7.1 Hz), 2.50 (3H, s), 2.49-2.60 (1H, m), 2.92-3.00 (1H,
m), 2.98 and 3.06 (3H, s), 3.40 and 3.46 (2H, q, J=7.1 Hz),
3.53-3.60 (1H, m), 3.89-3.96 (1H, m), 4.32 (1H, br s), 6.71 (2H, d,
J=8.9 Hz), 7.15-7.20 (4H, m), 7.59 (2H, d, J=8.4 Hz), 9.93 (1H, br
s), 10.30 (1H, br s).
Example 84
4-[3-(3,5-Difluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-160)
4-[3-(3,5-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained from Example 79 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0722] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, br
s), 2.63-2.75 (1H, m), 2.90 (3H, br s), 2.92-3.03 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.44-3.55 (1H, m), 3.92-4.00 (1H, m),
4.20-4.28 (1H, m), 6.23-6.32 (2H, m), 6.40 (1H, tt, J=8.9 Hz, 2.2
Hz), 7.24 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5 Hz).
[0723] MS (EI) m/z: 378 (M+H).sup.+.
Example 85
4-[3-(2,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-158)
4-[3-(2,4-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained from Example 43 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0724] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.59 (3H, br
s), 2.63-2.75 (1H, m), 2.94 (3H, br s), 2.90-3.01 (1H, m), 3.02
(3H, s), 3.10 (3H, s), 3.47-3.57 (1H, m), 4.02-4.08 (1H, m),
4.25-4.34 (1H, m), 6.68-6.78 (2H, m), 6.79-6.87 (1H, m), 7.23 (2H,
d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz).
[0725] MS (EI) m/z: 378 (M+H).sup.+.
Example 86
4-[1-Dimethylamino-3-(3-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-151)
4-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamate
obtained from Example 53 was treated using a similar procedure to
that described in Example 3 to afford the title compound as an
amorphous solid.
[0726] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.62 (3H, d,
J=4.7 Hz), 2.70-2.78 (1H, m), 2.89 (3H, d, J=4.7 Hz), 2.99-3.09
(1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.63-3.69 (1H, m), 4.06-4.09
(1H, m), 4.29-4.34 (1H, m), 7.10 (1H, dd, J=8.2 Hz, 2.3 Hz), 7.24
(2H, d, J=8.7 Hz), 7.40 (1H, t, J=8.2 Hz), 7.55-7.57 (3H, m), 7.81
(1H, dd, J=8.2 Hz, 2.3 Hz).
[0727] MS (EI) m/z: 387 (M).sup.+.
Example 87
4-[3-(3-Chlorophenylamino)-1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride (Exemplification compound number
1-52)
(a) t-Butyl
N-[3-[N-t-butoxycarbonyl-N-methylamino]-3-[(4-dimethylcarbamoyloxy)phenyl-
]propyl]-N-(3-chlorophenyl)carbamate
[0728] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl-3-hydroxypropyl]-N-methylcarbamate
(100 mg, 0.28 mmol) obtained from Example 16b was dissolved in
tetrahydrofuran (1.5 ml) under an atmosphere of nitrogen. To the
solution were added sequentially triethylamine (0.07 ml, 0.50 mmol)
and methanesulfonyl chloride (0.03 ml, 0.34 mmol) in an ice bath.
The resulting mixture was stirred at room temperature for 45
minutes. The reaction mixture was partitioned between water and
ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the
methanesulfonate. On the other hand N,N-dimethylformamide (1.5 ml)
was added to sodium hydride (15 mg, 0.33 mmol) and to the sodium
hydride was added a solution of t-butyl (3-chlorophenyl)carbamate
(75 mg, 0.33 mmol) in N,N-dimethylformamide in an ice bath. This
mixture was stirred for 30 minutes and then a solution of the
methanesulfonate obtained above in N,N-dimethylformamide was added
thereto. The resulting mixture was stirred at room temperature 2
days. The reaction mixture was partitioned between water and ether.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by chromatography
on a silica gel column using hexane:ethyl acetate=60:40 as the
eluent to afford the desired compound (106 mg)
[0729] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.44 (9H, s),
1.47 (9H, s), 2.10-2.18 (2H, m), 2.56 (3H, s), 3.01 (3H, s), 3.09
(3H, s), 3.67 (2H, brs), 5.44 (1H, brs), 7.06 (2H, d, J=8.6 Hz),
7.11 (1H, d, J=8.3 Hz), 7.17-7.29 (5H, m).
(b) 4-[3-(3-Chlorophenylamino)-1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride
[0730] t-Butyl
N-[3-[N-t-butoxycarbonyl-N-methylamino]-3-[(4-dimethylcarbamoyloxy)phenyl-
]propyl]-N-(3-chlorophenyl)carbamate obtained from Example 87a was
treated using a similar procedure to that described in Example 6d
to afford the title compound.
[0731] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.46 (3H, s),
2.77-2.82 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.21 (1H, t, J=10.7
Hz), 3.36 (2H, br s), 4.08 (1H, br s), 7.25 (2H, d, J=8.0 Hz), 7.33
(2H, d, J=6.7 Hz), 7.46 (1H, br s), 7.56 (1H, s), 7.63 (2H, br
s).
[0732] MS (EI) m/z: 361 (M).sup.+.
Example 88
4-[3-(3-Fluoro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-195)
[0733] 3-Fluoro-4-nitrophenol was treated using similar procedures
to those described in Example 48 to afford the title compound as an
amorphous solid.
[0734] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.62-2.68 (1H, m), 3.01 (3H, s), 3.01-3.07 (1H, m), 3.10 (3H, s),
3.72-3.76 (1H, m), 4.08-4.10 (1H, m), 4.23-4.31 (1H, m), 6.63-6.68
(2H, m), 7.21 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz), 8.05 (1H,
t, J=8.9 Hz).
[0735] MS (FAB) m/z: 392 (M+H).sup.+.
Example 89
4-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-149)
[0736] 4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate obtained from Example 48b was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0737] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.62 (3H, br
s), 2.72-2.79 (1H, m), 2.88 (3H, br s), 2.99-3.07 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.67-3.73 (1H, m), 4.08-4.13 (1H, m),
4.28-4.31 (1H, m), 6.81 (2H, d, J=9.2 Hz), 7.24 (2H, d, J=8.6 Hz),
7.55 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=9.2 Hz).
[0738] MS (EI) m/z 387 (M).sup.+.
Example 90
4-[3-(4-Chloro-3-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-116)
[0739] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-chloro-3-nitrophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0740] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.59-2.67 (1H, m), 2.97-3.10 (1H, m), 3.01 (3H, s), 3.10 (3H, s),
3.67-3.73 (1H, m), 4.02-4.07 (1H, m), 4.28-4.31 (1H, m), 6.98 (1H,
dd, J=8.9 Hz, 3.0 Hz), 7.21 (2H, d, J=8.5 Hz), 7.28 (1H, d, J=3.0
Hz), 7.39 (1H, d, J=8.9 Hz), 7.59 (2H, d, J=8.5 Hz).
[0741] MS (FAB) m/z: 408 (M+H).sup.+.
Example 91
4-[1-Methylamino-3-(2,3,5-trifluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-118)
[0742] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2,3,5-trifluorophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0743] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.62-2.68 (1H, m), 3.02 (3H, s), 3.02-3.11 (1H, m), 3.11 (3H, s),
3.62-3.66 (1H, m), 4.09-4.12 (1H, m), 4.35-4.38 (1H, m), 6.35-6.39
(1H, m), 6.49-6.54 (1H, m), 7.22 (2H, d, J=8.3 Hz), 7.65 (2H, d,
J=8.3 Hz).
[0744] MS (FAB) m/z: 383 (M+H).sup.+.
Example 92
4-[3-(3-Fluorophenylamino)-1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride (Exemplification compound number
1-51)
[0745] t-Butyl (3-fluorophenyl)carbamate was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0746] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.46 (3H, s),
2.76-2.82 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.20-3.26 (1H, m),
3.34-3.45 (2H, m), 4.07-4.13 (1H, m), 7.06-7.11 (1H, m), 7.24-7.26
(1H, m), 7.30-7.42 (4H, m), 7.64 (2H, br s).
[0747] MS (FAB) m/z: 346 (M+H).sup.+.
Example 93
4-[2-(4-Chlorophenoxy)-1-methylaminoethyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-34)
(a) 2-(4-Chlorophenoxy)-1-[(4-methoxymethoxy)phenyl]ethanone
[0748] 1-Iodo-4-methoxymethoxybenzene (1.72 g, 6.5 mmol), which was
synthesized according to the method described in Chem. Abstr., 68,
87026, (1968), was dissolved in tetrahydrofuran (40 ml) and 1.5N
solution of butyl lithium in hexane (4.3 ml, 6.5 mmol) was added
dropwise to the solution at -78.degree. C. The resulting mixture
was stirred for 30 minutes and then to the mixture was added a
solution of 2-(4-chlorophenoxy)-N-methoxy-N-methylacetamide (1.00
g, 4.4 mmol), which was synthesized according to the method
described in Tetrahedron, 54, 15861, (1998), in tetrahydrofuran.
The mixture was stirred for 2 hours and the reaction mixture was
partitioned between saturated aqueous sodium chloride solution and
ether. The organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by chromatography on a silica gel column using hexane:ethyl
acetate=95:5 to 80:20 as the eluent to afford the desired compound
(1.02 g).
[0749] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 3.49 (3H, s),
5.20 (2H, s), 5.25 (2H, s), 6.87 (2H, d, J=9.0 Hz), 7.11 (2H, d,
J=8.9 Hz), 7.23 (2H, d, J=9.0 Hz), 7.97 (2H, d, J=8.9 Hz).
(b) 2-(4-Chlorophenoxy)-1-(4-hydroxyphenyl)ethanone
[0750] 2-(4-Chlorophenoxy)-1-[(4-methoxymethoxy)phenyl]ethanone
(1.01 g, 3.3 mmol) obtained from Example 93a was dissolved in
acetone (10 ml) and to the solution was added 4N aqueous
hydrochloric acid solution (10 ml). The resulting mixture was
stirred at room temperature overnight and the reaction mixture was
neutralized with saturated aqueous sodium hydrogencarbonate
solution. The mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to afford the crude desired compound (0.85
g) which was used in next step reaction without further
purification.
[0751] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 5.34 (2H, s),
6.63 (1H, s), 6.89 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=9.1 Hz), 7.24
(2H, d, J=9.1 Hz), 7.94 (2H, d, J=8.8 Hz).
(c) 4-[2-(4-Chlorophenoxy)-1-methylaminoethyl]phenyl
dimethylcarbamate hydrochloride
[0752] 2-(4-Chlorophenoxy)-1-(4-hydroxyphenyl)ethanone obtained in
Example 93b was treated using similar procedures to those described
in Example 1a, and 1d to 1f, to afford the title compound as an
amorphous solid.
[0753] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.36 (3H, s),
3.02 (3H, s), 3.11 (3H, s), 4.27-4.36 (2H, m), 4.60 (1H, dd, J=11.3
Hz, 9.2 Hz), 6.96 (2H, d, J=8.9 Hz), 7.16 (2H, d, J=8.9 Hz), 7.21
(2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.6 Hz), 10.21 (2H, br s).
[0754] MS (FAB) m/z: 349 (M+H).sup.+
Example 94
3-[3-(3-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-76)
[0755] 3-Fluorophenol was treated using similar procedures to those
described in Example 7f and 7g to afford the title compound as an
amorphous solid.
[0756] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.41-2.61 (1H,
m), 2.53 (3H, br s), 2.90-3.02 (1H, m), 2.99 (3H, s), 3.08 (3H, s),
3.59-3.65 (1H, m), 3.94-3.99 (1H, m), 4.32 (1H, br s), 6.51 (1H,
dt, J=11.0 Hz, 2.2 Hz), 6.57-6.64 (2H, m), 7.13-7.20 (2H, m), 7.33
(1H, s), 7.41-7.47 (2H, m), 9.94 (1H, br s), 10.36 (1H, br s).
[0757] MS (FAB) m/z: 347 (M+H).sup.+.
Example 95
3-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-92)
[0758] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 7e was treated using similar procedures to
those described in Example 48 to afford the title compound as an
amorphous solid.
[0759] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.65-2.70 (1H, m), 2.98 (3H, s), 3.01-3.10 (1H, m), 3.07 (3H, s),
3.75-3.81 (1H, m), 4.08-4.13 (1H, m), 4.30 (1H, dd, J=9.9 Hz, 4.1
Hz), 6.87 (2H, d, J=9.3 Hz), 7.17-7.21 (1H, m), 7.31 (1H, s),
7.43-7.48 (2H, m), 8.15 (2H, d, J=9.3 Hz), 10.05 (1H, br s), 10.48
(1H, br s).
[0760] MS (FAB) m/z: 374 (M+H).sup.+.
Example 96
4-[3-(2-Fluoro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-105)
[0761] 2-Fluoro-4-nitrophenol was treated using similar procedures
to those described in Example 48 to afford the title compound as an
amorphous solid.
[0762] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53 (3H, s),
2.66-2.74 (1H, m), 3.01 (3H, s), 3.05-3.14 (1H, m), 3.09 (3H, s),
3.76-3.82 (1H, m), 4.21-4.26 (1H, m), 4.34-4.37 (1H, m), 6.88 (1H,
t, J=8.7 Hz), 7.21 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz),
7.95-8.00 (2H, m).
[0763] MS (FAB) m/z: 392 (M+H).sup.+.
Example 97
4-[3-(4-Fluorophenylamino)-1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride (Exemplification compound number
1-49)
[0764] t-Butyl (4-fluorophenyl)carbamate was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0765] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.46 (3H, s),
2.72-2.77 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.17-3.22 (1H, m),
3.38-3.49 (2H, m), 4.01-4.09 (1H, br s), 7.10 (2H, t, J=8.4 Hz),
7.24-4.26 (2H, m), 7.62-7.65 (4H, m).
Example 98
(S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-92)
(a) t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamat-
e
[0766] t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 81a and 4-nitrophenol were treated using a
similar procedure to that described in Example 48a to afford the
desired compound.
[0767] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.40 (9H, s),
2.17-2.40 (2H, m), 3.01 (3H, s), 3.10 (3H, s), 3.96-4.10 (2H, m),
4.90-5.01 (2H, br s), 6.91 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8
Hz), 7.27 (2H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8 Hz).
(b) (S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride
[0768] t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamat-
e obtained from Example 98a was treated using similar procedures to
those described in Example 61d and 61e to afford the title
compound.
[0769] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.62-2.66 (1H, m), 3.01 (3H, s), 3.01-3.10 (1H, m), 3.10 (3H, s),
3.72-3.75 (1H, m), 4.07-4.11 (1H, m), 4.29-4.32 (1H, m), 6.86 (2H,
d, J=9.2 Hz), 7.20 (2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz), 8.15
(2H, d, J=9.2 Hz).
[0770] [.alpha.].sub.D.sup.22 +143.6 (CHCl.sub.3, C=1.01)
[0771] MS (FAB) m/z: 374 (M+H).sup.+.
Example 99
(S)-4-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-149)
[0772] (S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate obtained from Example 98 was treated using a
similar procedure to that described in Example 3 to give the
desired product, which was recrystallized from a mixture of ethyl
acetate and hexane to afford the title compound as crystals (mp
180.5-181.5.degree. C.)
[0773] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.62 (3H, br
s), 2.72-2.79 (1H, m), 2.88 (3H, br s), 2.99-3.07 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.67-3.73 (1H, m), 4.08-4.13 (1H, m),
4.28-4.31 (1H, m), 6.81 (2H, d, J=9.2 Hz), 7.24 (2H, d, J=8.6 Hz),
7.55 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=9.2 Hz).
[0774] [.alpha.].sub.D.sup.22 +116.0 (CHCl.sub.3, C=0.94)
[0775] MS (EI) m/z: 387 (M).sup.+.
Example 100
(R)-4-[1-Amino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-66)
(a) t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamat-
e
[0776] t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 61b and 4-nitrophenol were treated using a
similar procedure to that described in Example 48a to afford the
desired compound.
[0777] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.40 (9H, s),
2.18-2.40 (2H, m), 3.01 (3H, s), 3.09 (3H, s), 3.99 (1H, dt, J=6.2,
9.6 Hz), 4.08 (1H, dt, J=6.2, 9.6 Hz), 4.85-5.03 (2H, br), 6.91
(2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz),
8.18 (2H, d, J=8.8 Hz).
(b) (R)-4-[1-Amino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride
[0778] t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamat-
e obtained from Example 10a was treated using a similar procedure
to that described in Example 6d to afford the title compound as an
amorphous solid.
[0779] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.36-2.46
(1H, m), 2.66-2.75 (1H, m), 2.95 (3H, s), 3.07 (3H, s), 3.81-3.89
(1H, m), 4.06-4.14 (1H, m), 4.46 (1H, dt, J=5.6 Hz, 3.2 Hz), 6.87
(2H, d, J=9.6 Hz), 7.06 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz),
8.14 (2H, d, J=9.6 Hz). [.alpha.].sub.D.sup.22 -110.5 (CHCl.sub.3,
C=1.04)
[0780] MS (FAB) m/z: 360 (M+H).sup.+.
Example 101
(R)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-92)
[0781] t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamat-
e obtained from Example 10a was treated using similar procedures to
those described in Example 61d and 61e to afford the title compound
as an amorphous solid.
[0782] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.62-2.66 (1H, m), 3.01 (3H, s), 3.01-3.10 (1H, m), 3.10 (3H, s),
3.72-3.75 (1H, m), 4.07-4.11 (1H, m), 4.29-4.32 (1H, m), 6.86 (2H,
d, J=9.2 Hz), 7.20 (2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz), 8.15
(2H, d, J=9.2 Hz).
[0783] [.alpha.].sub.D.sup.22- 142.1 (CHCl.sub.3, C=1.00)
[0784] MS (FAB) m/z: 374 (M+H).sup.+.
Example 102
(R)-4-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-149)
[0785] (R)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate obtained from Example 101 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0786] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.62 (3H, br
s), 2.72-2.79 (1H, m), 2.88 (3H, br s), 2.99-3.07 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.67-3.73 (1H, m), 4.08-4.13 (1H, m),
4.28-4.31 (1H, m), 6.81 (2H, d, J=9.2 Hz), 7.24 (2H, d, J=8.6 Hz),
7.55 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=9.2 Hz).
[0787] [.alpha.].sub.D.sup.22 -115.2 (CHCl.sub.3, C=0.92)
[0788] MS (EI) m/z: 387 (M+H).sup.+.
Example 103
4-[1-Methylamino-3-(pyridin-3-yloxy)propyl]phenyl dimethylcarbamate
dihydrochloride (Exemplification compound number 1-119)
[0789] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 3-hydroxypyridine were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0790] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.45-2.56
(1H, m), 2.58 (3H, s), 2.65-3.73 (1H, m), 3.07 (3H, s), 3.99-4.04
(1H, m), 4.21-4.26 (1H, m), 4.49 (1H, dd, J=10.4 Hz, 4.4 Hz), 7.19
(2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.8 Hz), 7.85-7.89 (1H, m), 8.00
(1H, d, J=7.2 Hz), 8.37 (1H, d, J=6.0 Hz), 8.39 (1H, a).
Example 104
3-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-149)
[0791] 3-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate obtained from Example 95 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0792] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.53-2.9 (7H,
m), 3.00 (3H, s), 2.98-3.12 (1H, m), 3.09 (3H, s), 3.75-3.81 (1H,
m), 4.10-4.15 (1H, m), 4.34 (1H, dd, J=11.0 Hz, 3.7 Hz), 6.82 (2H,
d, J=8.8 Hz), 7.24 (1H, d, J=7.7 Hz), 7.3 (1H, s), 7.36 (1H, d,
J=7.7 Hz), 7.46 (1H, t, J=7.7 Hz), 8.14 (2H, d, J=8.8 Hz).
[0793] MS (FAB) m/z: 38.8 (M+H).sup.+.
Example 105
4-[1-Ethylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-70)
(a) t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
[0794] 4-Hydroxybenzaldehyde and ethylamine acetate were treated
using similar procedures to those described in Example 7a to 7e to
afford the desired compound.
(b) 4-[1-Ethylamino-3-(3-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride
[0795] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
obtained from Example 105a and 3-nitrophenol were treated similar
procedures to those described in Example 7f and 7g to afford the
title compound as an amorphous solid.
[0796] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.46 (3H, t,
J=7.3 Hz), 2.67-2.75 (1H, m), 2.82-2.90 (1H, m), 2.93 (3H, s),
3.05-3.19 (1H, m), 3.09 (3H, s), 3.64-3.70 (1H, m), 4.00-4.05 (1H,
m), 4.42 (1H, dd, J=10.7 Hz, 3.4 Hz), 7.12 (1H, dd, J=8.2 Hz, 2.0
Hz), 7.19 (2H, d. J=8.6 Hz), 7.38 (1H, t, J=8.2 Hz), 7.56 (1H, t,
J=2.0 Hz), 7.65 (2H, d, J=8.6 Hz), 7.78 (1H, dd, J=8.2 Hz, 2.0 Hz),
9.95 (1H, br s), 10.28 (1H, br s).
[0797] MS (FAB) m/z: 388 (M+H).sup.+.
Example 106
4-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-67)
[0798] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
obtained from Example 105a and 4-fluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0799] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.46 (3H, t,
J=7.0 Hz), 2.56-2.66 (1H, m), 2.79-2.92 (2H, m), 3.01 (3H, s),
3.00-3.10 (1H, m), 3.09 (3H, s), 3.49-3.54 (1H, m), 3.84-3.89 (1H,
m), 4.43 (1H, d, J=8.1 Hz), 6.67-6.70 (2H, m), 6.87-6.91 (2H, m),
7.18 (2H, d, J=8.4 Hz), 7.65 (2H, d, J=8.4 Hz), 9.92 (1H, br s),
10.21 (1H, br s).
[0800] MS (FAB) m/z: 361 (M+H).sup.+.
Example 107
4-[1-Ethylamino-3-(3-fluorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-68)
[0801] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
obtained from Example 105a and 3-fluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0802] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.45 (3H, t,
J=7.3 Hz), 2.60-2.70 (1H, m), 2.83-2.93 (2H, m), 3.01 (3H, s),
3.01-3.13 (1H, m), 3.09 (3H, s), 3.50-3.56 (1H, m), 3.87-3.92 (1H,
m), 4.42 (1H, brd, J=8.1 Hz), 6.47 (1H, dt, J=11.0 Hz, 2.2 Hz),
6.54 (1H, dd, J=8.1 Hz, 2.2 Hz), 6.60 (1H, td, J=8.1 Hz, 2.2 Hz),
7.13 (1H, dd, J=8.1 Hz, 6.6 Hz), 7.18 (2H, d, J=8.4 Hz), 7.65 (2H,
d, J=8.4 Hz), 9.95 (1H, br s), 10.26 (1H, br s)
[0803] MS (FAB) m/z: 361 (M+H).sup.+.
Example 108
3-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-94)
[0804] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 7e and 3-nitrophenol were treated using
similar procedures to those described in Example 48 to afford the
title compound as an amorphous solid.
[0805] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.25 (3H, s),
2.61-2.69 (1H, m), 2.98 (3H, s), 2.97-3.10 (1H, m), 3.08 (3H, s),
3.73-3.79 (1H, m), 4.07-4.12 (1H, m), 4.35 (1H, dd, J=10.3 Hz, 4.4
Hz), 7.14-7.20 (2H, m), 7.35-7.48 (4H, m), 7.60 (1H, t, J=2.0 Hz),
7.79 (1H, dd, J=8.1 Hz, 2.2 Hz), 10.10 (2H, br)
[0806] MS (FAB) m/z: 374 (M+H).sup.+.
Example 109
4-[3-(4-Chlorophenylamino)-1-methylaminopropyl]phenyl
dimethylcarbamate dihydrochloride (Exemplification compound number
1-50)
[0807] t-Butyl (4-chlorophenyl)carbamate was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0808] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.46 (3H, s),
2.71-2.76 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.16-3.23 (1H, m),
3.38-3.49 (2H, m), 4.05-4.08 (1H, m), 7.23-7.26 (2H, m), 7.39 (2H,
d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.63 (2H, br s).
[0809] MS (FAB) m/z: 362 (M+H).sup.+.
Example 110
4-[3-[N-Acetyl-N-(3-chlorophenyl)amino]-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-60)
[0810] N-(3-Fluorophenyl)acetamide was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0811] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.94 (3H, s),
2.10-2.15 (1H, m), 2.45 (3H, s), 2.71-2.77 (1H, m), 3.02 (3H, s),
3.11 (3H, s), 3.58-3.63 (1H, m), 3.91-3.95 (1H, m), 4.13-4.18 (1H,
m), 6.99 (1H, d, J=8.1 Hz), 7.08-7.14 (2H, m), 7.20 (2H, d, J=8.0
Hz), 7.41-7.47 (1H, m), 7.69 (2H, d, J=8.0 Hz).
[0812] MS (EI) m/z: 387 (M).sup.+.
Example 111
4-[1-Methylamino-3-(3-methyl-4-nitrophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-115)
[0813] 3-Methyl-4-nitrophenol was treated using similar procedures
to those described in Example 48 to afford the title compound as an
amorphous solid.
[0814] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.58 (3H, s), 2.58-2.66 (1H, m), 3.01 (3H, s), 3.01-3.10 (1H, m),
3.10 (3H, s), 3.67-3.73 (1H, m), 4.03-4.07 (1H, m), 4.29-4.34 (1H,
m), 6.68-6.70 (2H, m), 7.20 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.3
Hz), 8.01 (1H, d, J=9.1 Hz).
[0815] MS (FAB) m/z: 388 (M+H).sup.+.
Example 112
4-(1-Methylamino-3-o-toluoyloxypropyl)phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-84)
[0816] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-methylphenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0817] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.21 (3H, s),
2.52 (3H, s), 2.57-2.63 (1H, m), 2.95-3.09 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.59-3.65 (1H, m), 3.96-4.00 (1H, m), 4.30-4.36 (1H,
m), 6.61 (1H, d, J=8.1 Hz), 6.82 (1H, t, J=8.1 Hz), 7.03-7.11 (2H,
m), 7.18 (2H, d, J=8.0 Hz), 7.61 (2H, d, J=8.0 Hz).
[0818] MS (EI) m/z 342 (M).sup.+.
Example 113
4-[3-(4-Chloro-2-methylphenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-112)
[0819] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-chloro-2-methylphenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0820] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.17 (3H, s),
2.51 (3H, t, J=2.7 Hz), 2.56-2.63 (1H, m), 2.94-3.09 (1H, m), 3.01
(3H, s), 3.09 (3H, s), 3.57-3.63 (1H, m), 3.92-3.97 (1H, m),
4.27-4.32 (1H, m), 6.52 (1H, d, J=8.7 Hz), 7.01 (1H, dd, J=8.7 Hz,
2.5 Hz), 7.07 (1H, d, J=2.5 Hz), 7.19 (2H, d, J=8.4 Hz), 7.59 (2H,
d, J=8.4 Hz).
[0821] MS (EI) m/z: 376 (M).sup.+.
Example 114
4-[1-Dimethylamino-3-(3,4,5-trifluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-174)
[0822] 4-[1-Methylamino-3-(3,4,5-trifluorophenoxy)propyl]phenyl
dimethylcarbamate obtained from Example 80 was treated using a
similar procedure to that described in Example 3 to afford the
title compound as an amorphous solid.
[0823] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, d,
J=5.0 Hz), 2.65-2.74 (1H, m), 2.88 (3H, d, J=4.7 Hz), 2.91-3.02
(1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.48 (1H, td, J=9.6 Hz, 3.6
Hz), 3.89-3.95 (1H, m), 4.21-4.28 (1H, m), 6.34-6.39 (2H, m), 7.24
(2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz).
[0824] MS (EI) m/z: 396 (M+H).sup.+
Example 115
4-[4-(4-Chlorophenoxy)-1-methylaminobutyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-193)
(a) Ethyl
3-(4-benzyloxyphenyl)-3-[N-(t-butoxycarbonyl)-N-methylamino]prop-
ionate
[0825] N,N-Dimethylformamide and benzyl bromide (2.3 ml, 19 mmol)
were added sequentially to ethyl 3-[N-(t-butoxy
carbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propionate (5.10 g, 16
mmol) obtained from Example 16a and potassium carbonate (3.27 g, 24
mmol) and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with water and saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column to afford the
desired compound (5.57 g).
[0826] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.23 (3H, t,
J=7.2 Hz), 1.48 (9H, s), 2.61 (3H. br s), 2.88-2.92 (2H, m), 4.21
(2H, q, J=7.2 Hz), 5.05 (2H, s), 5.66 (1H, br s), 6.94 (2H, d,
J=8.4 Hz), 7.18 (2H, d, J=8.4 Hz), 7.31-7.44 (5H, m).
(b) t-Butyl
N-[1-(4-benzyloxyphenyl)-3-hydroxypropyl]-N-methylcarbamate
[0827] Tetrahydrofuran (100 ml) was added to lithium aluminum
hydride (1.02 g, 27 mmol) under an atmosphere of nitrogen, and a
solution of ethyl
3-(4-benzyloxyphenyl)-3-[N-(t-butoxycarbonyl)-N-methylamino]propion-
ate (5.56 g, 13 mmol) obtained from Example 115a in tetrahydrofuran
was slowly added thereto at -78.degree. C. After stirring the
resulting mixture for 30 minutes, the temperature was gradually
raised to 0.degree. C. and then the mixture was stirred for 30
minutes. To the reaction mixture was added sequentially water (1
ml), 15% aqueous sodium hydroxide solution (1 ml) and water (3 ml)
and the resulting mixture was stirred at room temperature for 30
minutes. To the mixture was added anhydrous magnesium sulfate and
the resulting mixture was filtered. The filtrate was concentrated
under reduced pressure. The residue was purified by chromatography
on a silica gel column to afford the desired compound (4.78 g).
[0828] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (9H, s),
1.92-2.15 (2H, m), 2.42 (3H, br s), 3.50-3.74 (3H, m), 5.06 (2H,
s), 5.54 (1H, br s), 6.95 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5
Hz), 7.31-7.45 (5H, m).
(c) t-Butyl
N-[1-(4-benzyloxyphenyl)-3-cyanopropyl]-N-methylcarbamate
[0829] t-Butyl
N-[1-(4-benzyloxyphenyl)-3-hydroxypropyl]-N-methylcarbamate (1.50
g, 4.0 mmol) obtained from Example 115b was dissolved in
tetrahydrofuran (20 ml) under an atmosphere of nitrogen. To the
solution was added triethylamine (0.84 ml, 6.0 mmol) and then
methanesulfonyl chloride (0.37 ml, 4.8 mmol), in an ice bath. The
resulting mixture was stirred at room temperature for 30 minutes.
The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was dissolved in
N,N-dimethylformamide (20 ml) and to the solution was added
15-crown-5 (1.2 ml, 6.0 mmol) and then sodium cyanide (294 mg, 6.0
mmol). The resulting mixture was stirred at room temperature
overnight. The reaction mixture was partitioned between water and
ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by chromatography on a silica gel column using hexane:ethyl
acetate=80:20 to 70:30 as the eluent to afford the desired compound
(1.41 g).
[0830] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (9H, br
s), 2.20-2.28 (1H, m), 2.41 (3H, br s), 5.06 (2H, s), 5.35 (1H, br
s), 6.96 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz), 7.31-7.44 (5H,
m).
(d) t-Butyl
N-[1-(4-benzyloxyphenyl)-4-hydroxybutyl]-N-methylcarbamate
[0831] t-Butyl
N-[1-(4-benzyloxyphenyl)-3-cyanopropyl]-N-methylcarbamate (1.00 g,
2.6 mmol) obtained from Example 115c was dissolved in
dichloromethane (20 ml) under an atmosphere of nitrogen. To the
solution was added 0.95 M solution of diisobutylaluminum hydride in
hexane (5.5 ml, 5.3 mmol) at -78.degree. C. and the temperature was
slowly raised to room temperature and then the mixture was stirred
at room temperature for 2 hours. To the resulting mixture was added
sodium sulfate (2.6 g) and this mixture was stirred at room
temperature for 1 hour. The reaction mixture was filtered and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in methanol (10 ml) and to the solution was slowly added
sodium borohydride (98 mg, 2.6 mmol). The resulting mixture was
stirred at room temperature for 1 hour. Water was added to the
reaction mixture and the methanol was evaporated under reduced
pressure. The aqueous layer was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column using hexane:ethyl
acetate=70:30 to 50:50 as the eluent to afford the desired compound
(830 mg).
[0832] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.49 (9H, s),
1.59-1.65 (2H, m), 1.89-2.01 (2H, m), 2.53 (3H, br s), 3.73 (2H, t,
J=6.2 Hz), 5.05 (2H, s), 5.20 (0.5H, br s), 5.39 (0.5H, br s), 6.94
(2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 7.31-7.44 (5H, m).
(e) t-Butyl
N-[4-hydroxybutyl-1-(4-hydroxyphenyl)]-N-methylcarbamate
[0833] t-Butyl
N-[1-(4-benzyloxyphenyl)-4-hydroxybutyl]-N-methylcarbamate (278 mg,
0.72 mmol) obtained from Example 126d was dissolved in methanol (5
ml) and to the solution was added 5% palladium on charcoal (30 mg).
The mixture was stirred under an atmosphere of hydrogen at room
temperature for 2 hours. The catalyst was filtered off and the
filtrate was concentrated under reduced pressure to afford the
crude desired compound, which was used in the reaction of the next
step without further purification.
[0834] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.49 (9H, s),
1.54-1.67 (2H, m), 1.87-2.06 (2H, m), 2.54 (3H, br s), 3.01 (3H,
s), 3.10 (3H, s), 3.73 (2H, t, J=6.2 Hz), 5.22 (0.5H, br s), 5.43
(0.5H, br s), 7.07 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz).
(f) t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-4-hydroxybutyl]-N-methylcarbamate
[0835] The crude product of t-butyl
N-[4-hydroxybutyl-1-(4-hydroxyphenyl)]-N-methylcarbamate obtained
from Example 126e and potassium carbonate (150 mg, 1.1 mmol) were
dissolved in N,N-dimethylformamide (5 ml) under an atmosphere of
nitrogen. To the solution was added dimethylcarbamyl chloride
(0.079 ml, 0.86 mmol) and the resulting mixture was stirred at room
temperature overnight. The reaction mixture was partitioned between
water and ethyl acetate. The organic layer was washed with water
and saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column to afford the desired compound (220 mg).
[0836] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.48 (9H, s),
1.80-1.84 (2H, m), 1.99-2.10 (2H, m), 2.56 (3H, br s), 3.01 (3H,
s), 3.10 (3H, s), 4.00 (2H, t, J=6.1 Hz), 5.24 (0.5H, br s), 5.45
(0.5H, br s), 6.82 (2H, d, J=8.9 Hz), 7.08 (2H, d, J=8.6 Hz), 7.23
(2H, d, J=8.9 Hz), 7.28 (2H, d, J=8.6 Hz).
(g) 4-[4-(4-Chlorophenoxy)-1-methylaminobutyl]phenyl
dimethylcarbamate hydrochloride
[0837] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-4-hydroxybutyl]-N-methylcarbamate
obtained from Example 115f and 4-chlorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0838] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.52-1.76
(2H, m), 2.30-2.42 (1H, m), 2.43 (3H, s), 2.47-2.63 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.81 (2H, t, J=6.1 Hz), 4.00 (1H, dd, J=10.5
Hz, 4.3 Hz), 6.72 (2H, d, J=9.0 Hz), 7.17 (2H, d, J=9.0 Hz), 7.21
(2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.6 Hz), 9.86 (1H, br s), 10.16
(1H, br s).
[0839] MS (FAB) m/z: 377 (M+H)
Example 116
4-[1-Methylamino-4-(4-nitrophenoxy)butyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-194)
[0840] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-4-hydroxybutyl]-N-methylcarbamate
obtained from Example 115f was treated using similar procedures to
those described in Example 48 to afford the title compound as an
amorphous solid.
[0841] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.53-1.83
(2H, m), 2.32-2.45 (1H, m), 2.44 (3H, s), 2.55-2.65 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.94 (2H, t, J=6.0 Hz), 4.00 (1H, br s),
6.85 (2H, d, J=9.1 Hz), 7.21 (2H, d, J=8.4 Hz), 7.58 (2H, d, J=8.4
Hz), 8.14 (2H, d, J=9.1 Hz), 9.86 (1H, br s), 10.21 (1H, br s).
[0842] MS (FAB) m/z: 388 (M+H).sup.+
Example 117
4-[1-Methylamino-2-(4-nitrophenoxy)ethyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-39)
[0843] N-Methoxy-N-methyl-2-(4-nitrophenoxy)acetamide was treated
using similar procedures to those described in Example 93 to afford
the title compound as an amorphous solid.
[0844] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.34 (3H, s),
3.03 (3H, s), 3.12 (3H, s), 4.37 (1H, br s), 4.48 (1H, dd, J=10.0
Hz, 4.2 Hz), 4.74 (1H, dd, J=10.0 Hz, 7.9 Hz), 7.13 (2H, d, J=9.2
Hz), 7.23 (2H, d, J=8.5 Hz), 7.67 (2H, d, J=8.5 Hz), 8.13 (2H, d,
J=9.2 Hz), 10.33 (2H, br s).
[0845] MS (FAB) m/z: 360 (M+H).sup.+
Example 118
4-[3-[N-Acetyl-N-(4-chlorophenyl)amino]-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-59) N-(4-Chlorophenyl)acetamide was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0846] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.90 (3H, s),
2.12-2.18 (1H, m), 2.43 (3H, t, J=2.6 Hz), 2.66-2.73 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.61-3.67 (1H, m), 3.95-3.97 (1H, m),
4.02-4.08 (1H, m), 7.19-7.23 (4H, m), 7.42 (2H, d, J=8.6 Hz), 7.67
(2H, d, J=8.5 Hz).
[0847] MS (FAB) m/z: 404 (M+H).sup.+.
Example 119
4-[3-[N-Acetyl-N-(4-nitrophenyl)amino]-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-61)
[0848] N-(4-Nitrophenyl)acetamide was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0849] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.94 (3H, s),
2.22-2.26 (1H, m), 2.44 (3H, t, J=2.6 Hz), 2.68-2.86 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.77-3.83 (1H, m), 3.97-4.05 (2H, m), 7.20
(2H, d, J=8.6 Hz), 7.50 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.6 Hz),
8.31 (2H, d, J=8.8 Hz).
[0850] MS (FAB) m/z: 415 (M+H).sup.+.
Example 120
4-[1-Methylamino-3-(4-nitrophenylamino)propyl]phenyl
dimethylcarbamate dihydrochloride (Exemplification compound number
1-53)
[0851] t-Butyl (4-nitrophenyl)carbamate was treated using similar
procedures to those described in Example 87 to afford the title
compound as an amorphous solid.
[0852] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.47 (3H, s),
2.74 (1H, br s), 2.88 (1H, br s), 3.02 (3H, s), 3.11 (3H, s), 3.18
(1H, br s), 4.13 (1H, br s), 6.82 (2H, br s), 7.19-7.24 (2H, m),
7.57 (2H, br s), 8.10 (2H, d, J=6.8 Hz).
[0853] MS (FAB) m/z: 373 (M+H).sup.+.
Example 121
(S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate 1/2 fumarate (Exemplification compound number
1-92)
[0854] (S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl
dimethylcarbamate obtained from Example 98 was converted into the
1/2 fumarate thereof, which was recrystallized from isopropanol to
afford the title compound as crystals (mp 164-166.degree. C.)
[0855] .sup.1H-NMR (500 MHz, CD.sub.3OD) .delta. ppm: 2.32-2.39
(1H, m), 2.48 (3H, s), 2.57-2.64 (1H, m), 2.99 (3H, s), 3.11 (3H,
s), 3.88 (1H, dt, J=9.5 Hz, 5.0 Hz), 4.13 (1H, dt, J=10.5 Hz, 5.0
Hz), 4.30 (1H, dd, J=10.0 Hz, 4.0 Hz), 6.68 (1H, s), 6.99 (2H, d,
J=9.3 Hz), 7.19 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=8.8 Hz), 8.17
(2H, d, J=9.3 Hz).
[0856] IR (KBr) .mu..sub.maxcm.sup.-1: 3423, 3108, 1717, 1591,
1511, 1389, 1341, 1257, 1216, 1175, 1110, 859, 753.
[0857] Elemental analysis: Calcd for
C.sub.21H.sub.25N.sub.3O.sub.7: C, 58.46; H, 5.84; N, 9.74; O,
25.96. Found: C, 58.19; H, 5.68; N, 9.69; O, 26.20.
[.alpha.].sub.D.sup.22 +119.5 (MeOH, C=1.00)
Example 122
4-[1-Methylamino-3-(4-nitrophenyl)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-19)
[0858] 2-Nitrobenzaldehyde was treated using similar procedures to
those described in Example 1 to afford the title compound as an
amorphous solid.
[0859] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.38 (3H, s),
2.51-2.58 (3H, m), 2.80-2.84 (1H, m), 3.03 (3H, s), 3.12 (3H, s),
3.89 (1H, br s), 7.23 (2H, d, J=8.0 Hz), 7.27 (2H, d, J=8.4 Hz),
7.53 (2H, d, J=8.0 Hz), 8.08 (2H, d, J=8.4 Hz), 9.88 (1H, br s),
10.24 (1H, br s).
Example 123
(S)-4-[1-Amino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-66)
[0860] t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamat-
e obtained from Example 98a was treated using a similar procedure
to that described in Example 6d to afford the title compound as an
amorphous solid.
[0861] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.36-2.46
(1H, m), 2.66-2.75 (1H, m) 2.95 (3H, s), 3.07 (3H, s), 3.81-3.89
(1H, m), 4.06-4.14 (1H, m), 4.46 (1H, dt, J=5.6 Hz, 3.2 Hz), 6.87
(2H, d, J=9.6 Hz), 7.06 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz),
8.14 (2H, d, J=9.6 Hz). [.alpha.].sub.D.sup.22 +111.3 (CHCl.sub.3,
C=1.01)
[0862] MS (FAB) m/z: 360 (M+H).sup.+.
Example 124
4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-108)
[0863] 2-Chloro-4-nitrophenol was treated using similar procedures
to those described in Example 48 to afford the title compound as an
amorphous solid.
[0864] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.66-2.73 (1H, m), 3.00 (3H, s), 3.06-3.12 (1H, m), 3.09 (3H, s),
3.73-3.79 (1H, m), 4.26-4.30 (1H, m), 4.37-4.41 (1H, m), 6.83 (1H,
d, J=9.1 Hz), 7.19 (2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.6 Hz), 8.08
(1H, dd, J=9.1 Hz, 2.8 Hz), 8.27 (1H, d, J=2.8 Hz).
[0865] MS (FAB) m/z: 408 (M+H).sup.+.
Example 125
(S)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl
dimathylcarbamate hydrochloride (Exemplification compound number
2-92)
(a) t-Butyl
(S)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
[0866] Methyl (S)-3-amino-3-(3-hydroxyphenyl)propionate, which was
synthesized according to the method described in Tetrahedron:
Asymmetry, 2, 183, (1991), was treated using similar procedures to
those described in Example 61a and 61b to afford the desired
compound.
(b) (S)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0867] t-Butyl
(S)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 125a and 4-nitrophenol were treated using
similar procedures to those described in Example 7f, 61d and 61e to
afford the title compound as an amorphous solid.
[0868] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.67 (1H, m), 2.99 (3H, s), 3.05 (1H, m), 3.07 (3H, s), 3.78 (1H,
m), 4.11 (1H, m), 4.30 (1H, m), 6.87 (2H, d, J=9.2 Hz), 7.20 (1H,
m), 7.31 (1H, s), 7.45 (2H, m), 8.15 (2H, d, J=9.2 Hz), 9.97 (1H,
br s), 10.48 (1H, br s),
[0869] ms (FAB) m/z: 374 ((M+H).sup.+)
Example 126
(S)-3-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-149)
[0870] (S)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 125b was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0871] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.65 (3H, s),
2.74 (1H, m), 2.85 (3H, s), 3.00 (3H, s), 3.07 (1H, m), 3.09 (3H,
s), 3.77 (1H, m), 4.12 (1H, m), 4.30 (1H, m), 6.82 (2H, d, J=9.0
Hz), 7.24 (1H, m), 7.30 (1H, m), 7.36 (1H, m), 7.46 (1H, m), 8.15
(2H, d, J=9.0 Hz),
[0872] ms (FAB) m/z: 388 ((M+H).sup.+)
Example 127
(S)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-108)
[0873] t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 81a and 2-chloro-4-nitrophenol were treated
using similar procedures to those described in Example 7f, 61d and
61e to afford the title compound as an amorphous solid.
[0874] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.67-2.72 (1H, m), 3.00 (3H, s), 3.05-3.14 (1H, m), 3.09 (3H, s),
3.73-3.77 (1H, m), 4.27-4.30 (1H, m), 4.37-4.41 (1H, m), 6.83 (1H,
d, J=9.0 Hz), 7.19 (2H, d, J=9.0 Hz), 7.64 (2H, d, J=9.0 Hz), 8.08
(1H, dd, J=9.0 Hz, 3.0 Hz), 8.27 (1H, d, J=3.0 Hz).
[0875] IR (CHCl.sub.3) 2977, 2710, 1587, 1515, 1492, 1392, 1346,
1277, 1176, 1054, 1027, 1019.
[0876] [.alpha.].sub.D.sup.22 +135.1 (CHCl.sub.3, C=0.72)
Example 128
(R)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-108)
[0877] t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 61a and 2-chloro-4-nitrophenol were treated
using similar procedures to those described in Example 7f, 61d and
61e to afford the title compound as an amorphous solid.
[0878] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.67-2.72 (1H, m), 3.00 (3H, s), 3.05-3.14 (1H, m), 3.09 (3H, s),
3.73-3.77 (1H, m), 4.27-4.30 (1H, m), 4.37-4.41 (1H, m), 6.83 (1H,
d, J=9.0 Hz), 7.19 (2H, d, J=9.0 Hz), 7.64 (2H, d, J=9.0 Hz), 8.08
(1H, dd, J=9.0 Hz, 3.0 Hz), 8.27 (1H, d, J=3.0 Hz).
[0879] IR (CHCl.sub.3) 2977, 2710, 1587, 1515, 1492, 1392, 1346,
1277, 1176, 1054, 1027, 1019.
[0880] [.alpha.].sub.D.sup.22 -131.0 (CHCl.sub.3, C=0.86)
Example 129
(S)-4-[3-(2-Chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-165)
[0881]
(S)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 127 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0882] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H, d,
J=5.0 Hz), 2.80-2.89 (1H, m), 2.95 (3H, d, J=5.0 Hz), 3.01 (3H, s),
3.02-3.10 (1H, m), 3.10 (3H, s), 3.66-3.74 (1H, m), 4.23-4.30 (1H,
m), 4.31-4.37 (1H, m), 6.82 (1H, d, J=9.0 Hz), 7.22 (2H, d, J=9.0
Hz), 7.62 (2H, d, J=9.0 Hz), 8.09 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.27
(1H, d, J=2.5 Hz).
[0883] IR (CHCl.sub.3) 2970, 2317, 1725, 1587, 1517, 1492, 1467,
1392, 1346, 1277, 1176, 1054, 1029, 1018.
[0884] [.alpha.].sub.D.sup.22 +142.0 (CHCl.sub.3, C=0.96)
Example 130
(R)-4-[3-(2-Chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-165)
[0885]
(R)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 128 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0886] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H, d,
J=5.0 Hz), 2.80-2.89 (1H, m), 2.95 (3H, d, J=5.0 Hz), 3.01 (3H, s),
3.02-3.10 (1H, m), 3.10 (3H, s), 3.66-3.74 (1H, m), 4.23-4.30 (1H,
m), 4.31-4.37 (1H, m), 6.82 (1H, d, J=9.0 Hz), 7.22 (2H, d, J=9.0
Hz), 7.62 (2H, d, J=9.0 Hz), 8.09 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.27
(1H, d, J=2.5 Hz).
[0887] IR (CHCl.sub.3) 2970, 2317, 1725, 1587, 1517, 1492, 1467,
1392, 1346, 1277, 1176, 1054, 1029, 1018.
[0888] [.alpha.].sub.D.sup.22 -141.6 (CHCl.sub.3, C=1.16)
Example 131
4-[3-(2-Chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-165)
[0889] 4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 124 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0890] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H, d,
J=5.1 Hz), 2.81-2.89 (1H, m), 2.95 (3H, d. J=5.1 Hz), 3.01 (3H, s),
3.01-3.10 (1H, m), 3.10 (3H, s), 3.67-3.72 (1H, m), 4.26-4.33 (2H,
m), 6.81 (1H, d, J=9.0 Hz), 7.22 (2H, d, J=8.4 Hz), 7.61 (2H, d,
J=8.4 Hz), 8.09 (1H, dd, J=9.0, 2.7 Hz), 8.28 (1H, d, J=2.7
Hz).
[0891] IR (KBr) .nu..sub.maxcm.sup.-1: 3427, 2934, 2555, 2457,
1726, 1516.
[0892] MS m/z: 422 ([M+H].sup.+), 406, 377, 221, 204.
Example 132
4-[1-Methylamino-3-(5-chloropyridin-3-yloxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-120)
[0893] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl)-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 5-chloropyridin-3-ol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0894] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.49 (3H,
brs), 2.62 (1H, brs), 3.02 (3H, s), 3.12 (3H, s), 4.39 (2H, br s),
4.83 (1H, br s), 7.22 (2H, br s), 7.67 (2H, br s), 7.84 (1H, br s),
8.41 (1H, br s), 9.05 (1H, br s), 10.14 (1H, br s), 10.39 (1H, br
s).
[0895] IR (KBr) .nu..sub.maxcm.sup.-1: 2941, 2738, 2473, 2023,
1732, 1549.
[0896] MS m/z: 364 ([M+H].sup.+), 333, 273, 259, 242, 207.
Example 133
4-[1-Methylamino-3-(6-methylpyridin-3-yloxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-122)
[0897] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 6-methylpyridin-3-ol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0898] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.47 (3H, t,
J=5.2 Hz), 2.58 (3H, s), 2.58-2.66 (1H, m), 2.83 (3H, s), 3.02 (3H,
s), 3.02-3.11 (1H, m), 3.11 (3H, s), 4.31-4.36 (1H, m), 4.41-4.43
(1H, m), 4.56-4.61 (1H, m), 7.19 (2H, d, J=8.5 Hz), 7.53 (1H, d,
J=8.9 Hz), 7.68 (2H, d, J=8.5 Hz), 7.80 (1H, dd, J=8.9, 2.0 Hz),
8.57 (1H, d, J=2.0 Hz), 10.23 (2H, br s).
[0899] IR (KBr) .nu..sub.maxcm.sup.-1: 3427, 2937, 2682, 1739,
1555.
[0900] MS m/z: 344 ([M+H].sup.+-), 313, 273, 242, 207.
Example 134
4-[1-Methylamino-3-(2-methylpyridin-3-yloxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-121)
[0901] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 2-methylpyridin-3-ol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0902] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.47 (3H, s),
2.68 (1H, brs), 2.80 (3H, s), 3.01 (3H, s), 3.01-3.09 (1H, m), 3.11
(3H, s), 4.21 (1H, br s), 4.38 (1H, br s), 4.41 (1H, br s), 7.22
(2H, d, J=8.0 Hz), 7.68-7.69 (3H, m), 7.84 (1H, br s), 8.25 (1H, br
s), 10.19 (1H, br s), 10.26 (1H, br s).
[0903] IR (KBr) .nu..sub.maxcm.sup.-1: 3423, 2938, 2759, 2690,
1722, 1550.
[0904] MS m/z: 344 ([M+H].sup.+), 313, 273, 242, 207.
Example 135
(R)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-194)
(a) t-Butyl
(R)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
[0905] Methyl (R)-3-amino-3-(3-hydroxyphenyl)propionate, which was
synthesized according to the method described in Tetrahedron:
Asymmetry, 2, 183, (1991), was treated using similar procedures to
those described in Example 61a and 61b to afford the desired
compound.
(b) (R)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride
[0906] t-Butyl
(R)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 135a and 4-nitrophenol were treated using
similar procedures to those described in Example 7f, 61d and 61e to
afford the title compound as an amorphous solid.
[0907] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.66 (1H, m), 2.99 (3H, s), 3.05 (1H, m), 3.07 (3H, s), 3.79 (1H,
m), 4.11 (1H, m), 4.31 (1H, m), 6.87 (2H, d, J=9.2 Hz), 7.19 (1H,
m), 7.32 (1H, s), 7.45 (2H, m), 8.16 (2H, d, J=9.2 Hz),
[0908] ms (FAB) m/z: 374 ((M+H).sup.+)
Example 136
(R)-3-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-149)
[0909] (R)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 135 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0910] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.66 (3H, m),
2.73 (1H, m), 2.86 (3H, m), 3.00 (3H, s), 3.07 (1H, m), 3.09 (3H,
m), 3.78 (1H, m), 4.13 (1H, m), 4.34 (1H, m), 6.82 (2H, J=9.2 Hz),
7.24 (1H, dd, J=8.1 Hz, 1.5 Hz), 7.31 (1H, s), 7.37 (1H, d, J=8.1),
7.46 (1H, t, J=8.1), 8.14 (2H, J=9.2),
[0911] ms (FAB) m/z: 388 ((M+H).sup.+)
Example 137
4-[1-Ethylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-71)
[0912] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
obtained from Example 105a and 4-nitrophenol were treated using
similar procedures to those described in Example 48a and 48b to
afford the title compound as an amorphous solid.
[0913] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.46 (3H, t,
J=7.3 Hz), 2.71 (1H, m), 2.88 (2H, m), 3.01 (3H, s), 3.10 (3H, s),
3.14 (1H, m), 3.70 (1H, m), 4.04 (1H, m), 4.40 (1H, m), 6.83 (2H,
d, J=9.5 Hz), 7.19 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8 Hz), 8.14
(2H, d, J=9.5 Hz),
[0914] ms (FAB) m/z: 388 ((M+H).sup.+)
Example 138
4-[1-Ethylamino 3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-189)
4-[1-Ethylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride obtained from Example 143 was treated using a similar
procedure to that described in Example 3 to afford the title
compound as an amorphous solid.
[0915] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.37 (1.5H,
t, J=6.8 Hz), 1.52 (1.5H, t, J=6.8 Hz), 2.63 (3H, d, J=3.4 Hz),
2.76 (2H, m), 2.93 (3H, d, J=3.4 Hz), 3.02 (3H, s), 3.04 (1H, m),
3.11 (3H, s), 3.27 (0.5H, m), 3.39 (0.5H, m), 3.77 (0.5H, m), 3.78
(0.5H, m), 4.11 (1H, m), 4.40 (0.5H, m), 4.54 (0.5H, m), 6.81 (2H,
d, J=8.8 Hz), 7.22 (2H, m), 7.56 (1H, dd, J=8.8 Hz), 7.64 (1H, dd,
J=7.8 Hz), 8.13 (2H, d, J=8.8 Hz),
[0916] ms (FAB) m/z: 402 ((M+H).sup.+)
Example 139
4-[1-Ethylamino-3-(4-chlorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-69)
[0917] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
obtained from Example 105a and 4-chlorophenol were treated using
similar procedures to those described in Example 48a and 48b to
afford the title compound as an amorphous solid.
[0918] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.44 (3H, t,
J=7.3 Hz), 2.63 (1H, m), 2.89 (2H, m), 3.01 (3H, s), 3.08 (1H, m),
3.09 (3H, s), 3.52 (1H, m), 3.88 (1H, m), 4.43 (1H, m), 6.69 (2H,
m), 7.17 (4H, m), 7.63 (2H, m),
[0919] ms (FAB) m/z: 377 ((M+H).sup.+)
Example 140
4-[1-Ethylamino-3-(4-chlorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 1-190)
4-[1-Ethylamino-3-(4-chlorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride obtained from Example 139 was treated using a similar
procedure to that described in Example 3 to afford the title
compound as an amorphous solid.
[0920] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (1.5H,
m), 1.34 (1.5H, m), 2.58 (3H, br s), 2.93 (3H, br s), 3.02 (3H, s),
3.11 (3H, s), 3.23-2.62 (4H, m), 3.42 (0.5H, m), 3.53 (0.5H, m),
3.86 (0.5H, m), 3.95 (0.5H, m), 4.31 (0.5H, m), 4.44 (0.5H, m),
6.67 (2H, m), 7.18 (4H, m), 7.57 (1H, d, J=7.8 Hz), 7.64 (1H, d,
J=7.8 Hz)
[0921] ms (FAB) m/z: 391 ((M+H).sup.+)
Example 141
4-[1-Ethylamino-3-(3,4-difluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-72)
[0922] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate
obtained from Example 105a and 3,4-difluorophenol were treated
using similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0923] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.45 (3H, t,
J=7.3 Hz), 2.62 (1H, m), 2.87 (2H, m), 3.01 (3H, s), 3.08 (1H, m)
3.10 (3H, s), 3.52 (1H, m), 3.87 (1H, m), 4.39 (1H, m), 6.45 (1H,
m), 6.58 (1H, m), 6.99 (1H, m), 7.19 (2H, d, J=8.4 Hz), 7.63 (2H,
d, J=8.4 Hz),
[0924] ms (FAB) m/z: 379 ((M+H).sup.+)
Example 142
4-[1-Ethylmethylamino-3-(3,4-difluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-191)
[0925] 4-[1-Ethylamino-3-(3,4-difluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 141 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0926] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.34 (1.5H,
t, J=7.3 Hz), 1.52 (1.5H, t, J=7.3 Hz), 2.57 (1.5H, d, J=4.9 Hz),
2.91 (1.5H, d, J=4.9 Hz), 3.02 (3H, d, J=2.0 Hz), 3.11 (3H, d,
J=2.0 Hz), 3.56-2.65 (5H, m), 3.92 (1H, m), 4.26 (0.5H, m), 4.39
(0.5H, m), 6.43 (1H, m), 6.56 (1H, m), 7.00 (1H, m), 7.21 (1H, d,
J=8.8 Hz), 7.23 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=8.8 Hz), 7.64
(1H, d, J=8.8 Hz),
[0927] ms (FAB) m/z: 393 ((M+H).sup.+)
Example 143
4-[1-Ethylmethylamino-3-(4-fluorophenoxy)propyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-188)
4-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamate
hydrochloride obtained from Example 106 was treated using a similar
procedure to that described in Example 3 to afford the title
compound as an amorphous solid.
[0928] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.33 (1.5H,
m), 1.51 (1.5H, m), 2.09 (1.5H, s), 2.91 (1.5H, s), 3.02 (3H, s),
3.10 (3H, s), 3.53-2.66 (5H, m), 3.93 (1H, m), 4.27 (0.5H, m), 4.39
(0.5H, m), 6.68 (2H, dd, J=3.9 Hz, 8.8 Hz), 6.91 (2H, t, J=8.8 Hz),
7.21 (2H, m), 7.56 (1H, d, J=7.8 Hz), 7.66 (1H, d, J=7.8 Hz),
[0929] ms (FAB) m/z: 375 ((M+H).sup.+)
Example 144
3-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamate
hydrochloride (Exemplification compound number 2-79)
[0930] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 7e and 3-chlorophenol were treated using
similar procedures to those described in Example 48a and 48b to
afford the title compound as an amorphous solid.
[0931] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.56-2.62 (1H, m), 2.93-2.99 (1H, m), 2.99 (3H, s), 3.08 (3H, s),
3.60-3.66 (1H, m), 3.94-3.99 (1H, m), 4.29-4.33 (1H, m), 6.70 (1H,
d, J=8.1 Hz), 6.79 (1H, s), 6.90 (1H, d, J=8.1 Hz), 7.14 (1H, tri,
J=8.1 Hz), 7.17-7.20 (1H, m), 7.33 (1H, s), 7.43-7.44 (2H, m).
[0932] ms (FAB) m/z: (FAB): 363 ((M+H).sup.+)
Example 145
3-[3-(4-Chlorophenoxy)-1-dimethylmethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-135)
[0933] 3-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 10 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0934] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60-2.73
(1H, m), 2.73 (6H, br), 2.91-2.99 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.55-3.61 (1H, m), 3.96-4.00 (1H, m), 4.27-4.31 (1H, m), 6.67
(2H, d, J=9.0 Hz), 7.18 (2H, d, J=9.0 Hz), 7.22 (1H, dt, J=7.9 Hz,
1.8 Hz), 7.30 (1H, tri, J=1.8 Hz), 7.38 (1H, d, J=7.9 Hz), 7.45
(1H, tri, J=7.9 Hz)
[0935] ms (FAB) m/z: 377 ((M+H).sup.+)
Example 146
3-[3-(3-Chloro-4-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-109)
[0936] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 7e and 3-chloro-4-fluorophenol were treated
using similar procedures to those described in Example 48a and 48b
to afford the title compound as an amorphous solid.
[0937] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.56-2.62 (1H, m), 2.92-2.98 (1H, m), 3.00 (3H, s), 3.09 (3H, s),
3.56-3.64 (1H, m), 3.92-3.97 (1H, m), 4.28-4.32 (1H, m), 6.65-6.68
(1H, m), 6.82-6.84 (1H, m), 6.99 (1H, tri, J=8.8 Hz), 7.17-7.20
(1H, m), 7.31 (1H, s), 7.44 (2H, d, J=5.1 Hz).
[0938] ms (FAB) m/z: 381 ((M+H).sup.+)
Example 147
3-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-104)
[0939] t-Butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 7e and 4-chloro-3-fluorophenol were treated
using similar procedures to those described in Example 48a and 48b
to afford the title compound as an amorphous solid.
[0940] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.56-2.62 (1H, m), 2.93-2.98 (1H, m), 2.99 (3H, s), 3.08 (3H, s),
3.60-3.65 (1H, m), 3.94-3.99 (1H, m), 4.29-4.31 (1H, m), 6.56 (1H,
dd, J=2.9 Hz, 1.5 Hz), 6.62 (1H, dd, J=2.9 Hz, 1.5 Hz), 7.17-7.23
(2H, m), 7.31 (1H, m), 7.44 (2H, d, J=5.1 Hz)
[0941] ms (FAB) m/z: 381 ((M+H).sup.+)
Example 148
3-[3-(3-Chlorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-136)
[0942] 3-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 144 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0943] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 2.64 (3H, d,
J=4.8 Hz), 2.60-2.71 (1H, m), 2.88 (3H, d, J=4.8 Hz), 2.93-3.00
(1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.56-3.62 (1H, m), 3.97-4.02
(1H, m), 4.28-4.34 (1H, m), 6.64 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.74
(1H, tri, J=2.0 Hz), 6.91 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.14 (1H,
tri, J=8.1 Hz), 7.23 (1H, d J=8.0), 7.32 (1H, s), 7.38 (1H, d,
J=8.0 Hz), 7.46 (1H, tri, J=8.1 Hz)
[0944] ms (FAB) m/z: 377 ((M+H).sup.+)
Example 149
3-[3-(3-Chloro-4-fluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-166)
[0945] 3-[3-(3-Chloro-4-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 146 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0946] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60-2.70
(1H, m), 2.73 (6H, br), 2.90-3.00 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.54-3.60 (1H, m), 3.94-3.99 (1H, m), 4.26-4.29 (1H, m),
6.59-6.63 (1H, m), 6.76-6.78 (1H, m), 6.99 (1H, tri, J=8.8 Hz),
7.26 (1H, dd, J=8.1 Hz, 2.2 Hz), 7.30 (1H, d, J=2.2 Hz), 7.37 (1H,
dd, J=8.1 Hz, 2.2 Hz), 7.46 (1H, tri, J=7.7 Hz).
[0947] ms (FAB) m/z: 395 ((M+H).sup.+)
Example 150
3-[3-(4-Chloro-3-fluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-161)
[0948] 3-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate-hydrochloride obtained from Example 147 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0949] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.63-2.70
(1H, m), 2.75 (6H, br), 2.93-2.99 (1H, m), 3.01 (3H, s), 3.10 (3H,
s), 3.56-3.62 (1H, m), 3.96-4.01 (1H, m), 4.27-4.31 (1H, m),
6.48-6.57 (2H, m), 7.20 (1H, d, J=8.1 Hz), 7.23 (1H, d, J=6.6 Hz),
7.30 (1H, s), 7.37 (1H, d, J=8.1 Hz), 7.46 (1H, tri, J=8.1 Hz).
[0950] ms (FAB) m/z: 395 ((M+H).sup.+)
Example 151
(R)-4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-102)
[0951] t-Butyl
(R)-N-[1-(4'-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained from Example 61b and 3,4-difluorophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0952] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.45-2.64 (1H, m), 2.90-3.05 (1H, m), 3.01 (3H, s), 3.10 (3H, s),
3.50-3.60 (1H, m), 3.87-3.97 (1H, m), 4.27-4.36 (1H, m), 6.44-6.52
(1H, m), 6.61 (1H, ddd, J=11.7 Hz, 6.6 Hz, 2.9 Hz), 7.00 (1H, q,
J=9.5 Hz), 7.19 (2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz) 9.5-10.6
(br).
[0953] MS (FAB.sup.+): 365 (M+H).sup.+.
[0954] [.alpha.].sub.D.sup.22 -94.8 (CHCl.sub.3, C=0.92)
Example 152
(R)-4-[3-(3,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-159)
[0955] (R)-4-[3-(3-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 151 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0956] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H,
brs), 2.55-2.73 (1H, br), 2.89 (3H, brs), 2.82-2.98 (1H, br), 3.02
(3H, s), 3.11 (3H, s), 3.45-3.56 (1H, br), 3.90-4.00 (1H, br),
4.22-4.34 (1H, br), 6.40-6.49 (1H, m), 6.51-6.62 (1H, m), 7.01 (1H,
q, J=9.5 Hz), 7.23 (2H, d, J=6.6 Hz), 7.56 (2H, d, J=6.6 Hz).
[0957] MS (FAB+): 379 (M+H)+
[0958] [.alpha.].sub.D.sup.22 -88.9 (CHCl.sub.3, C=0.98)
Example 153
4-[3-(4-Nitrophenylsulfanyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-43)
[0959] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-nitrothiophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0960] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.43 (3H, s),
2.56 (1H, m), 2.82 (2H, m), 3.01 (1H, m), 3.02 (3H, s), 3.12 (3H,
s), 4.13 (1H, m), 7.23 (4H, m), 7.58 (2H, d, J=8.1 Hz), 8.09 (2H,
d, J=8.8 Hz)
[0961] ms (FAB) m/z: 390 ((M+H).sup.+)
Example 154
4-[3-(4-Nitrophenylsulfanyl)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-47)
4-[3-(4-Nitrophenylsulfanyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 153 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0962] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.59 (3H, m),
2.67 (1H, m), 2.76 (3H, m), 2.80 (1H, m), 3.01 (1H, m), 3.04 (3H,
s), 3.10 (1H, m), 3.13 (3H, s), 4.25 (1H, m), 7.25 (4H, m), 7.53
(2H, d, J=8.1 Hz), 8.12 (2H, d, J=8.8 Hz),
[0963] ms (FAB) m/z: 404 ((M+H).sup.+)
Example 155
4-[3-(4-Chlorophenylsulfanyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-42)
[0964] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-chlorothiophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0965] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.40 (3H, s),
2.46 (1H, m), 2.63 (2H, m), 2.86 (1H, m), 3.02 (3H, s), 3.11 (3H,
s), 4.17 (1H, m), 7.22 (6H, m), 7.54 (2H, d, J=8.8 Hz),
[0966] ms (FAB) m/z: 379 ((M+H).sup.+)
Example 156
4-[3-(4-Chlorophenylsulfanyl)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-46)
[0967] 4-[3-(4-Chlorophenylsulfanyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 155 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0968] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, d,
J=4.8 Hz), 2.60-2.50 (3H, m), 2.73 (3H, d, J=4.8 Hz), 2.90 (1H, m),
3.03 (3H, s), 3.12 (3H, s), 4.21 (1H, m), 7.24 (6H, m), 7.51 (2H,
d, J=8.8 Hz),
[0969] ms (FAB) m/z: 393 ((M+H).sup.+)
Example 157
4-(3-(4-Fluorophenylsulfanyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-41)
[0970] t-Butyl
N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and 4-fluorothiophenol were treated using
similar procedures to those described in Example 7f and 7g to
afford the title compound as an amorphous solid.
[0971] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.40 (3H, s),
2.43 (1H, m), 2.60 (2H, m), 2.84 (1H, m), 3.02 (3H, s), 3.11 (3H,
s), 4.19 (1H, m), 6.98 (2H, t, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz),
7.30 (2H, dd, J=8.8 Hz, 5.9 Hz), 7.54 (2H, d, J=8.8 Hz),
[0972] ms (FAB) m/z: 363 ((M+H).sup.+)
Example 158
4-[3-(4-Fluorophenylsulfanyl)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-45)
[0973] 4-[3-(4-Fluorophenylsulfanyl)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained from Example 157 was
treated using a similar procedure to that described in Example 3 to
afford the title compound as an amorphous solid.
[0974] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.63-2.42
(3H, m), 2.54 (3H, br s), 2.73 (3H, br s), 2.86 (1H, m), 3.03 (3H,
s), 3.12 (3H, s), 4.21 (1H, m), 7.01 (2H, t, J=8.8 Hz), 7.24 (2H,
d, J=7.7 Hz), 7.32 (2H, dd, J=8.8 Hz, 5.1 Hz), 7.50 (2H, d, J=7.7
Hz),
[0975] ms (FAB) m/z: 377 ((M+H).sup.+)
Example 159
4-[3-(Pyridin-2-yloxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-180)
[0976] t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained from Example 16b and pyridin-2-ol were treated using
similar procedures to those described in Example 48a, 48b and 3 to
afford the title compound as an amorphous solid.
[0977] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, d,
J=4.4 Hz), 2.95 (2H, m), 3.01 (3H, s), 3.05 (3H, d, J=4.4 Hz), 3.10
(3H, s), 4.17 (1H, br s), 4.63 (1H, br s), 4.99 (1H, br s), 7.13
(1H, br d), 7.19 (2H, d, J=7.7 Hz), 7.37 (1H, br t), 7.82 (2H, d,
J=7.7 Hz), 8.21 (1H, br t), 8.31 (1H, d, J=5.4 Hz),
[0978] ms (FAB) m/z: 344 ((M+H).sup.+)
Example 160
4-[3-(6-Chloropyridin-2-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-124)
[0979] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and 6-chloropyridine-2-ol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[0980] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.49 (1H, m),
2.98 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 4.41 (1H, br s), 4.47
(1H, br s), 4.61 (1H, br s), 7.05 (1H, m), 7.19 (2H, d, J=6.9 Hz),
7.54 (2H, br d), 7.86 (1H, br s), 8.14 (1H, br s),
[0981] ms (FAB) m/z: 364 ((M+H).sup.+)
Example 161
4-[3-(6-Chloropyridin-2-yloxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-181)
[0982] The title compound was obtained as an amorphous solid using
4-[3-(6-chloropyridin-2-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained in Example 160 in a
similar manner to that mentioned in Example 3.
[0983] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.60 (3H, d,
J=3.2 Hz), 2.70 (1H, m), 2.84 (3H, d, J=3.2 Hz), 2.97 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 3.94 (1H, m), 4.32 (2H, br s), 6.65 (1H, br
d, J=8.6 Hz), 7.22 (2H, d, J=7.9 Hz), 7.55 (3H, m), 8.02 (1H, br
s),
[0984] ms (FAB) m/z: 378 ((M+H).sup.+)
Example 162
(S)-4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-102)
[0985] The title compound was obtained as an amorphous solid using
t-butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained in step (b) of Example 81 and 3,4-difluorophenol by
conducting successively reactions similar to those mentioned in
steps (f) and (g) of Example 7.
[0986] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.51 (3H, s),
2.48-2.62 (1H, m), 2.90-3.05 (1H, m), 3.01 (3H, s), 3.10 (3H, s),
3.50-3.61 (1H, m), 3.88-3.97 (1H, m), 4.27-4.37 (1H, m), 6.45-6.55
(1H, m), 6.61 (1H, ddd, J=11.9 Hz, 6.5 Hz, 3.0 Hz), 7.00 (1H, q,
J=9.4 Hz), 7.19 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz) 9.4-10.7
(br).
[0987] MS (FAB.sup.+): 365 (M+H).sup.+.
[0988] [.alpha.].sub.D.sup.22 +94.6 (CHCl.sub.3, C=1.05)
Example 163
(S)-4-[3-(3,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-159)
[0989] The title compound was obtained as an amorphous solid using
(S)-4-[3-(3,4-difluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained in Example 162 in a
similar manner to that mentioned in Example 3.
[0990] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.61 (3H,
brs), 2.60-2.74 (1H, br), 2.90 (3H, brs), 2.84-3.00 (1H, br), 3.02
(3H, s), 3.11 (3H, s), 3.42-3.58 (1H, br), 3.88-4.00 (1H, br),
4.20-4.34 (1H, br), 6.40-6.48 (1H, m), 6.52-6.62 (1H, m), 7.01 (1H,
q, J=9.5 Hz), 7.23 (2H, d, J=6.4 Hz), 7.56 (2H, d, J=6.4 Hz).
[0991] MS (FAB+): 379 (M+H).sup.+
[0992] [.alpha.].sub.D.sup.22 +86.5 (CHCl.sub.3, C=1.06)
Example 164
(S)-4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate 1/2 fumarate salt (Exemplification compound
number 1-78)
[0993] The title compound was obtained as crystals using
(S)-4-[3-(4-chlorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained in Example 82 in a similar manner to
that mentioned in Example 121.
[0994] Melting point: 173-174.degree. C.
[0995] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.16-2.29
(1H, m), 2.39 (3H, s), 2.46-2.59 (1H, m), 2.99 (3H, s), 3.08 (3H,
s), 3.61-3.71 (1H, m), 3.84-3.94 (1H, m), 4.03-4.12 (1H, m), 6.71
(2H, d, J=8.8 Hz), 6.78 (1H, s), 7.13 (2H, d, J=8.8 Hz), 7.16 (2H,
d, J=8.8 Hz), 7.39 (2H, d, J=8.8 Hz)
[0996] MS (FAB+): 363 (M+H).sup.+
[0997] [.alpha.].sub.D.sup.22 +78.4 (CHCl.sub.3, C=1.03)
Example 165
4-[3-(4-Dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]benzoic
acid (Exemplification compound number 1-99)
(a) Benzyl
4-[3-(4-dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]benz-
oate
[0998] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and benzyl 4-hydroxybenzoate by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[0999] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.00-2.07
(1H, m), 2.22-2.29 (1H, m), 2.29 (3H, s), 3.01 (3H, s), 3.09 (3H,
s), 3.76 (1H, t, J=7.5 Hz), 3.84-3.89 (1H, m), 4.00 (1H, dt, J=5.5
Hz, 10.0 Hz), 5.33 (2H, s), 6.85 (2H, d, J=9.0 Hz), 7.07 (2H, d,
J=8.5 Hz), 7.27 (2H, d, J=8.5 Hz), 7.32-7.34 (3H, m), 7.44 (2H, d,
J=8.0 Hz), 8.00 (2H, d; J=9.0 Hz).
(b)
4-[3-(4-Dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]benzoic
acid
[1000] The crude title compound was synthesized using benzyl
4-[3-t-butoxycarbonylamino-3-(4-dimethylcarbamoyloxy)phenylpropyloxy]benz-
oate obtained in step (a) of Example 165 by conducting a reaction
similar to that mentioned in step (c) of Example 1, from which the
title compound was obtained as an amorphous solid by washing with
ether.
[1001] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.18-2.28
(1H, m), 2.38 (3H, s), 2.52-2.62 (1H, m), 3.02 (3H, s), 3.11 (3H,
s), 3.90-3.98 (1H, m), 4.13-4.22 (2H, m), 6.77 (2H, d, J=8.8 Hz),
7.17 (2H, d, J=8.8 Hz), 7.47 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.8
Hz).
[1002] IR (CHCl.sub.3) 2952, 2470, 1716, 1605, 1511, 1389, 1250,
1169, 1036, 1018, 851.
Example 166
4-[3-(4-Dimethylcarbamoyloxy)phenyl-3-dimethylaminopropyloxy]benzoic
acid (Exemplification compound number 1-156)
[1003] The title compound was obtained as an amorphous solid using
benzyl
4-[3-t-butoxycarbonylamino-3-(4-dimethylcarmoyloxy)phenylpropyloxy]benzoa-
te obtained in step (a) of Example 165 by conducting successively
reactions similar to those mentioned in Example 6 (b), 3 and 165
(b).
[1004] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.23-2.36
(1H, m), 2.41 (6H, s), 2.65-2.74 (1H, m), 3.03 (3H, s), 3.12 (3H,
s), 3.88-3.94 (1H, m), 4.08-4.14 (1H, m), 4.27 (1H, dd, J=9.4 Hz,
5.0 Hz), 6.79 (2H, d, J=8.8 Hz), 7.20 (2H, d, J=8.8 Hz), 7.38 (2H,
d, J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz).
[1005] IR (CHCl.sub.3) 2962, 1719, 1605, 1510, 1470, 1391, 1251,
1168, 1037, 1017, 851.
Example 167
4-[3-(6-Nitropyridin-2-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-126)
[1006] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and 6-nitropyridine-2-ol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1007] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.50 (3H, s),
2.68 (1H, m), 3.01 (3H, s), 3.05 (1H, m), 3.10 (3H, s), 4.14 (1H,
m), 4.25 (1H, m), 4.47 (1H, m), 6.78 (1H, d, J=8.6 Hz), 7.19 (2H,
d, J=7.8 Hz), 7.58 (2H, d, J=7.8 Hz), 8.33 (1H, dd, J=8.6 Hz, 2.9
Hz), 8.96 (1H, d, J=2.9 Hz), 9.95 (1H, br s), 10.30 (1H, br s),
[1008] ms (FAB) m/z: 375 ((M+H).sup.+)
Example 168
4-[3-(6-Nitropyridin-2-yloxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-183)
[1009] The title compound was obtained as an amorphous solid using
4-[3-(6-nitropyridin-2-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained in Example 167 in a
similar manner to that mentioned in Example 3.
[1010] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.63 (3H, d,
J=4.7 Hz), 2.75 (1H, m), 2.82 (3H, d, J=4.7 Hz), 3.01 (1H, m), 3.02
(3H, s), 3.11 (3H, s), 4.13 (1H, m), 4.33 (1H, m), 4.45 (1H, m),
6.73 (1H, d, J=9.0 Hz), 7.23 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4
Hz), 8.32 (1H, dd, J=9.0 Hz, 2.8 Hz), 8.96 (1H, d, J=2.8 Hz),
[1011] ms (FAB) m/z: 389 ((M+H).sup.+)
Example 169
4-[3-(6-Trifluoromethylpyridin-2-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-125)
[1012] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and
6-trifluoromethylpyridine-2-ol by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48.
[1013] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.50 (3H, m),
2.64 (1H, m), 2.99 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 4.06 (1H,
m), 4.19 (1H, m), 4.40 (1H, m), 6.78 (1H, d, J=8.8 Hz), 7.19 (2H,
d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.75 (1H, dd, J=8.8 Hz, 2.0
Hz), 8.83 (1H, s), 9.97 (1H, br s), 10.26 (1H, br s),
[1014] IR (KBr) cm.sup.-1: 2950, 2770, 2700, 1730, 1610, 1390,
1330, 1290, 1220, 1180, 1160, 1130
Example 170
4-[3-(6-Trifluoromethylpyridin-2-yloxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-182)
[1015] The title compound was obtained as an amorphous solid using
4-[3-(6-trifluoromethylyridin-2-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride obtained in Example 169 in a
similar manner to that mentioned in Example 3.
[1016] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.88-2.63
(7H, m), 3.00 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 4.02 (1H, m),
4.30 (1H, m), 4.38 (1H, m), 5.73 (1H, d, J=7.8 Hz), 7.22 (2H, d,
J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.74 (1H, m), 8.33 (1H, s),
[1017] IR (KBr) cm.sup.-1: 2930, 2630, 2580, 2510, 2460, 1730,
1610, 1390, 1330, 1290, 1220, 1180, 1160, 1130
Example 171
Methyl
3-[3-(4-dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]-thiophe-
necarboxylate (Exemplification compound number 1-130)
[1018] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and methyl
3-hydroxythiophenecarboxylate by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48.
[1019] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.55 (1H, m),
2.64 (3H, m), 3.01 (3H, s), 3.08 (1H, m), 3.09 (3H, s), 3.87 (3H,
s), 4.04 (1H, m), 4.30 (1H, m), 4.53 (1H, m), 6.78 (1H, d, J=4.9
Hz), 7.18 (2H, d, J=7.8 Hz), 7.48 (3H, m), 9.84 (1H, br s), 10.65
(1H, br s),
[1020] ms (FAB) m/z: 393 ((M+H).sup.+)
Example 172
Methyl
3-[3-(4-Dimethylcarbamoyloxy)phenyl-3-dimethylaminopropyloxy]-thiop-
henecarboxylate (Exemplification compound number 1-187)
[1021] The title compound was obtained as an amorphous solid using
methyl
3-[3-(4-dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]-thiophenecarb-
oxylate obtained in Example 171 in a similar manner to that
mentioned in Example 3.
[1022] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 2.58 (3H, d,
J=4.9 Hz), 2.68 (1H, m), 2.93 (1H, m), 3.00 (3H, m), 3.01 (3H, s),
3.10 (3H, s), 3.56 (1H, m), 3.86 (3H, s), 4.24 (1H, m), 4.55 (1H,
m), 6.67 (1H, d, J=5.4 Hz), 7.19 (2H, d, J=8.8 Hz), 7.36 (1H, d,
J=5.4 Hz), 7.69 (2H, d, J=8.8 Hz),
[1023] IR (film) cm.sup.-1: 3420, 3100, 3020, 2950, 2660, 2580,
2510, 2460, 1720, 1540, 1440, 1390, 1220, 1070
Example 173
4-[3-(2-Nitropyridin-4-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-128)
[1024] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and 2-nitropyridine-4-ol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1025] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. ppm: 2.39 (1H,
m), 2.50 (3H, d, J=2.0 Hz), 2.64 (1H, m), 2.88 (3H, s), 3.01 (3H,
s), 3.94 (1H, m), 4.32 (2H, m), 7.18 (2H, d, J=8.8 Hz), 7.32 (1H,
d, J=5.9 Hz), 7.51 (2H, d, J=8.8 Hz), 8.70 (1H, m), 9.01 (1H,
s),
[1026] ms (FAB) m/z: 375 ((M+H).sup.+)
Example 174
4-[3-(4-Methylthiophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-199)
[1027] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and 4-methylthiophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1028] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.41 (3H, s),
2.45-2.64 (2H, m), 2.51 (3H, s), 2.90-3.09 (2H, m), 3.00 (3H, s),
3.09 (3H, s), 3.51-3.62 (1H, m), 3.88-3.98 (1H, m), 4.28-4.42 (1H,
m), 6.72 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.4 Hz) 7.19 (2H, d,
J=8.8 Hz), 7.60 (2H, d, J=8.4 Hz), 9.7-10.2 (1H, br), 10.2-10.5
(1H, br).
[1029] MS (FAB): 375 (M+H).sup.+.
Example 175
4-[3-(4-Methylthiophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-200)
[1030] The title compound was obtained as an amorphous solid using
4-[3-(4-methylthiophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained in Example 174 in a similar manner to
that mentioned in Example 3.
[1031] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.42 (3H, s),
2.54-2.74 (1H, m), 2.59 (3H, brs), 2.85-2.99 (1H, m), 2.85-2.99
(1H, m), 2.91 (3H, brs), 3.02 (3H, s), 3.10 (3H, s), 3.46-3.56 (1H,
m), 3.92-4.01 (1H, m), 4.23-4.33 (1H, m), 6.69 (2H, d, J=8.7 Hz),
7.16-7.25 (4H, m) 7.58 (2H, d, J=8.4 Hz), 12.8 (1H, brs)
[1032] MS (FAB): 389 (M+H).sup.+.
Example 176
(S)-4-[3-(4-Methylthiophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-199)
[1033] The title compound was obtained as an amorphous solid using
t-butyl
(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained in step (a) of Example 81 and 4-methylthiophenol by
conducting successively reactions similar to those mentioned in
step (a) of Example 48 and steps (d) and (e) of Example 61.
[1034] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.41 (3H, s),
2.45-2.63 (1H, m), 2.51 (3H, s), 2.89-3.07 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.50-3.62 (1H, m), 3.86-4.00 (1H, m), 4.35 (1H, brs),
6.72 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.6 Hz), 7.19 (2H, d, J=8.8
Hz), 7.60 (2H, d, J=8.6 Hz), 9.75-10.05 (1H, br), 10.10-10.45 (1H,
br).
[1035] MS (FAB): 375 (M+H).sup.+.
Example 177
(R)-4-[3-(4-Methylthiophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-199)
[1036] The title compound was obtained using t-butyl
(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate
obtained in step (b) of Example 61 and 4-methylthiophenol by
conducting successively reactions similar to those mentioned in
steps (c), (d) and (e) of Example 61.
[1037] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.41 (3H, s),
2.45-2.63 (1H, m), 2.51 (3H, s), 2.89-3.07 (1H, m), 3.00 (3H, s),
3.09 (3H, s), 3.50-3.62 (1H, m), 3.86-4.00 (1H, m), 4.35 (1H, brs),
6.72 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.6 Hz), 7.19 (2H, d, J=8.8
Hz), 7.60 (2H, d, J=8.6 Hz), 9.75-10.05 (1H, br), 10.10-10.45 (1H,
br).
[1038] MS (FAB): 375 (M+H).sup.+.
Example 178
4-[3-(Pentafluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-203)
[1039] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and pentafluorophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1040] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.52 (3H, s),
2.40-2.63 (1H, m), 2.90-3.15 (1H, m), 3.02 (3H, s), 3.11 (3H, s),
3.69-3.85 (1H, m), 4.20-4.31 (1H, m), 4.38 (1H, brs), 7.23 (2H, d,
J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 9.95 (1H, brs), 10.34 (1H,
brs)
[1041] MS (FAB): 419 (M+H).sup.+.
Example 179
4-[3-(Naphthalen-1-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-205)
[1042] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and 1-naphthylphenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1043] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.56 (3H, s),
2.65-2.79 (1H, m), 2.99 (3H, s), 3.06 (3H, s), 3.12-3.25 (1H, m),
3.70-3.82 (1H, m), 4.06-4.14 (1H, m), 4.41-4.53 (1H, br), 6.56 (1H,
d, J=7.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.22-7.29 (1H, m), 7.37 (1H,
d, J=8.3 Hz), 7.44-7.51 (2H, m), 7.62 (2H, d, J=8.5 Hz), 7.73-7.80
(1H, m), 8.16-8.24 (1H, m), 10.03 (1H, brs), 10.41 (1H, brs).
[1044] MS (FAB): 379 (M+H).sup.+.
Example 180
4-[3-(Quinolin-6-yloxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-206)
[1045] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (b) of Example 16 and 6-hydroxyquinoline by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1046] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.54 (3H, s),
2.57-2.73 (1H, m), 2.90-3.14 (1H, m), 2.99 (3H, s), 3.07 (3H, s),
3.67-3.78 (1H, m), 4.00-4.10 (1H, m), 4.35-4.45 (1H, m), 6.89 (1H,
d, J=2.9 Hz), 7.18 (2H, d, J=8.1 Hz), 7.26-7.34 (2H, m), 7.63 (2H,
d, J=8.1 Hz), 7.96 (2H, d, J=8.8 Hz), 8.73 (1H, dd, J=4.4 Hz, 1.5
Hz).
[1047] MS (FAB): 380 (M+H).sup.+.
Example 181
4-[3-(Pentafluorophenoxy)-1-dimethylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
1-204)
[1048] The title compound was obtained as an amorphous solid using
4-[3-(pentafluorophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate obtained in Example 178 in a similar manner to
that mentioned in Example 3.
[1049] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.59 (3H, s),
2.60-2.76 (1H, m), 2.88-3.05 (1H, m), 2.93 (3H, s), 3.03 (3H, s),
3.12 (3H, s), 3.62-3.73 (1H, m), 4.18-4.29 (1H, m), 4.29-4.40 (1H,
m), 7.27 (2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz).
[1050] MS (FAB): 433 (M+H).sup.+.
Example 182
4-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride (Exemplification compound number
4-12)
(a) t-Butyl
N-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylc-
arbamate
[1051] The title compound was obtained using
2-methyl-4-hydroxybenzaldehyde by conducting successively reactions
similar to those mentioned in steps (a)-(e) of Example 7.
[1052] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 1.51 (9H, s),
1.90-2.04 (1H, m), 2.07-2.21 (1H, m), 2.21 (3H, s), 2.44 (3H, s),
3.02 (3H, s), 3.11 (3H, s), 3.50-3.60 (2H, m), 3.75 (1H, brs),
5.53-5.60 (1H, m), 7.05 (1H, d, J=7.8 Hz), 7.11-7.13 (2H, m).
(b) 4-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride
[1053] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylc-
arbamate obtained in step (a) of Example 182 and 4-nitrophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1054] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.21 (3H, s),
2.51 (3H, s), 2.62-2.67 (1H, m), 3.02 (3H, s), 2.98-3.09 (1H, m),
3.12 (3H, s), 3.75-3.78 (1H, m), 4.08-4.12 (1H, m), 4.26 (1H, d,
J=6.6 Hz), 6.86 (2H, d, J=9.1 Hz), 7.14 (1H, d, J=8.1 Hz), 7.39
(1H, d, J=8.1 Hz), 7.46 (1H, s), 8.1 5 (2H, d, J=9.1 Hz)
[1055] MS (FAB) m/z: 388 (M+H).sup.+.
Example 183
(S)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride (Exemplification compound number
4-12)
(a) t-Butyl
(S)-[1-[(4-dimethylcarbamoyloxy)-3-methylphenyl]-3-hydroxypropyl]carbamat-
e
[1056] The title compound was obtained using methyl
(S)-3-amino-3-(4-hydroxy-2-methylphenyl)propionate, which was
synthesized using 4-hydroxy-2-methylbenzaldehyde as a starting
material by the procedure described in Tetrahedron: Asymmetry, 2,
183 (1991), by conducting successively reactions similar to those
mentioned in steps (a) and (b) of Example 61.
[1057] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.44 (9H, s),
1.71-1.82 (2H, m), 2.16 (1H, br), 2.20 (3H, s), 3.02 (3H, s), 3.12
(3H, s), 3.67 (2H, br), 4.84 (1H, br), 5.00 (1H, br), 7.03 (1H, d,
J=8.2 Hz), 7.10-7.13 (2H, m).
[1058] [.alpha.].sub.D.sup.22 -46 (c 0.90, CHCl.sub.3).
(b) (S)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride
[1059] The title compound was obtained as an amorphous solid using
t-butyl
(S)-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]carbamat-
e obtained in step (a) of Example 183 and 4-nitrophenol by
conducting successively reactions similar to those mentioned in
step (a) of Example 48 and steps (d) and (e) of Example 61.
[1060] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.49 (3H, s),
2.54-2.60 (1H, m), 2.93-2.96 (1H, m), 3.02 (3H, s), 3.12 (3H, s),
3.77-3.80 (1H, m), 4.07-4.10 (1H, m), 4.20-4.23 (1H, m), 7.86 (2H,
d, J=9.2 Hz), 7.13 (1H, d, J=8.5 Hz), 7.37 (1H, d, J=8.5 Hz), 7.43
(1H, s), 8.15 (2H, d, J=9.2 Hz).
[1061] MS (FAB) m/z: 388 (M+H).sup.+.
[1062] [.alpha.].sub.D.sup.22 +189 (c 0.95, CHCl.sub.3).
Example 184
(R)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride (Exemplification compound number
4-12)
(a) t-Butyl
(R)-[1-[(4-dimethylcarbamoyloxy)-3-methylphenyl]3-hydroxypropyl]carbamate
[1063] The title compound was obtained using methyl
(R)-3-amino-3-(4-hydroxy-2-methylphenyl)propionate, which was
synthesized using 4-hydroxy-2-methylbenzaldehyde as a starting
material by the procedure described in Tetrahedron: Asymmetry, 2,
183 (1991), by conducting successively reactions similar to those
mentioned in steps (a) and (b) of Example 61.
[1064] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.44 (9H, s),
1.76-1.83 (1H, m), 2.00-2.09 (1H, m), 2.21 (3H, s), 3.02 (3H, s),
3.12 (3H, s), 3.69 (2H, brs), 4.83-4.93 (2H, m), 7.04 (1H, d, J=8.2
Hz), 7.11-7.13 (2H, m).
[1065] [.alpha.].sub.D +52.9 (c 0.90, CHCl.sub.3)
(b) (R)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride
[1066] The title compound was obtained as an amorphous solid using
t-butyl
(R)-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]carbamat-
e obtained in step (a) of Example 184 and 4-nitrophenol by
conducting successively reactions similar to those mentioned in
step (a) of Example 48 and steps (d) and (e) of Example 61.
[1067] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.21 (3H, s),
2.52 (3H, s), 2.61-2.67 (1H, m), 3.01 (3H, s), 3.01-3.12 (1H, m),
3.12 (3H, s), 3.73-3.78 (1H, m), 4.08-4.13 (1H, m), 4.26 (1H, brs),
6.86 (2H, d, J=9.1 Hz), 7.13 (1H, d, J=8.2 Hz), 7.39 (1H, d, J=8.2
Hz), 7.47 (1H, s), 8.15 (2H, d, J=9.1 Hz), 9.94 (1H, brs), 10.36
(1H, brs).
[1068] [.alpha.].sub.D -123.4 (c 0.95, CHCl.sub.3)
[1069] MS (FAB) m/z: 388 (M+H).sup.+.
Example 185
4-[3-(4-Chlorophenoxy)-1-dimethylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride (Exemplification compound number
4-13)
[1070] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylc-
arbamate obtained in step (a) of Example 182 and 4-chlorophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1071] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.21 (3H, s),
2.50 (3H, s), 2.50-2.59 (1H, m), 2.92-3.02 (1H, m), 3.02 (3H, s),
3.12 (3H, s), 3.59 (1H, td, J=9.6, 4.1 Hz), 3.90-3.95 (1H, m),
4.25-4.28 (1H, m), 6.72 (2H, d, J=9.0 Hz), 7.12 (1H, d, J=8.3 Hz),
7.17 (2H, d, J=9.0 Hz), 7.39 (1H, dd, J=8.3, 1.9 Hz), 7.46 (1H,
s).
[1072] MS (FAB) m/z: 377 (M+H).sup.+.
Example 186
4-[3-(4-Methylthiophenoxy)-1-dimethylaminopropyl]-2-methylphenyl
dimethylcarbamate hydrochloride (Exemplification compound number
4-16)
[1073] The title compound was obtained as an amorphous solid using
t-butyl
N-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylc-
arbamate obtained in step (a) of Example 182 and 4-methylthiophenol
by conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1074] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 2.21 (3H, s),
2.41 (3H, s), 2.50 (3H, s), 2.50-2.59 (1H, m), 2.91-3.01 (1H, m),
3.01 (3H, s), 3.12 (3H, s), 3.59 (1H, td, J=9.6, 4.0 Hz), 3.91-3.96
(1H, m), 4.28 (1H, dd, J=10.3, 3.9 Hz), 6.74 (2H, d, J=8.8 Hz),
7.12 (1H, d, J=8.3 Hz), 7.19 (2H, d, J=8.8 Hz), 7.39 (1H, d, J=8.3
Hz), 7.47 (1H, s).
[1075] MS (FAB) m/z: 389 (M+H).sup.+.
Example 187
2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl
dimethylcarbamate hydrochloride (Exemplification compound number
4-52)
(a) Ethyl N-[2-(3-methoxyphenyl)-ethyl]-malonate
[1076] To a solution of 2-(3-methoxy-phenyl)-ethylamine (11.0 g,
6.6 mmol) in dichloromethane (10 ml) were added potassium carbonate
(1.1 g, 8.0 mmol) and ethyl malonyl chloride (0.92 ml, 7.2 mmol) at
0.degree. C., and resulting mixture was stirred for 30 minutes at
0.degree. C. under a nitrogen atmosphere. After stirring, water (50
ml) was added, and the resulting mixture was extracted with
dichloromethane (30 ml.times.2). The organic layer was washed
successively with water (30 ml.times.1) and saturated aqueous
sodium chloride solution (30 ml.times.1), dried over anhydrous
sodium sulfate, filtered, and evaporated in vacuo to afford the
crude product. The obtained crude product was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (50:50-33:67) as the eluent to afford the
title compound (1.1 g, yield: 63%) as a colorless oil.
[1077] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 1.26 (3H, t,
J=7.5 Hz), 2.81 (2H, t, J=7.0 Hz), 3.27 (2H, s), 3.55 (2H, q, J=7.0
Hz), 3.80 (3H, s), 4.17 (2H, q, J=7.5 Hz), 6.78-6.80 (3H, m), 7.08
(1H, br s), 7.22 (1H, t, J=8.0 Hz)
(b) Ethyl
(6-methoxy-3,4-dihydro-2H-isoquinolin-1-yliden)-acetate
[1078] Ethyl N-[2-(3-methoxy-phenyl)-ethyl]-malonate (20.8 g, 78.4
mmol) synthesized in step (a) of Example 187 was dissolved in
phosphorus oxychloride (60 ml), and the resulting mixture was
stirred for 4 hours at 80.degree. C. under a nitrogen atmosphere.
After stirring, the reaction mixture was poured into ice-cold water
(300 ml), neutralized with potassium carbonate, and extracted with
ethyl acetate (300 ml.times.2). The organic layer was washed with
saturated aqueous sodium chloride solution (300 ml.times.1), dried
over anhydrous sodium sulfate, filtered, and evaporated in vacuo to
afford the crude product. The obtained crude product was purified
by chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (1:1) as the eluent to afford a yellow
oily product (7.56 g) containing the title compound as the major
product.
[1079] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.30 (3H, t,
J=7.5 Hz), 2.88 (2H, t, J=7.0 Hz), 3.43 (2H, dt, J=3.0, 7.0 Hz),
3.84 (3H, s), 4.16 (2H, q, J=7.5 Hz), 5.08 (1H, s), 6.70 (1H, d,
J=2.5 Hz), 6.80 (1H, dd, J=2.5, 9.0 Hz), 7.62 (1H, d, J=9.0 Hz),
9.04 (1H, br s)
(c) Ethyl
(6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate
[1080] To a solution of ethyl
(6-methoxy-3,4-dihydro-2H-isoquinolin-1-yliden)-acetate (7.56 g)
obtained in step (b) of Example 187 in acetic acid (50 ml) was
added platinum oxide (400 mg), and the resulting mixture was
stirred for 3 hours at room temperature under a hydrogen
atmosphere. After stirring, the reaction mixture was filtered
through celite and evaporated in vacuo. The residue obtained was
neutralized with 1N aqueous sodium hydroxide solution and potassium
carbonate, and extracted with ethyl acetate (300 ml.times.2). The
organic layer was washed with saturated aqueous sodium chloride
solution (300 ml.times.1), dried over anhydrous sodium sulfate,
filtered, and evaporated in vacuo to afford the crude product. The
crude product was purified by chromatography on a silica gel column
using a mixed solvent of ethyl acetate and methanol
[1081] (1:0-5:1) as the eluent to afford the title compound (4.88
g) as a yellow oil.
[1082] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.26 (3H, t,
J=7.2 Hz), 2.67-2.76 (2H, m), 2.80-2.87 (2H, m), 3.01 (1H, ddd,
J=5.2, 7.6, 12.4 Hz), 3.19 (1H, dt, J=5.2, 12.4 Hz), 4.17 (2H, q,
J=7.2 Hz), 4.41 (1H, dd, J=3.2, 9.6 Hz), 6.63 (1H, d, J=2.8 Hz),
6.72 (1H, dd, J=2.8, 8.8 Hz), 7.01 (1H, d, J=8.8 Hz).
(d) t-Butyl
1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylat-
e
[1083] To a solution of ethyl
(6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate (4.88 g,
19.6 mmol) synthesized in step (c) of Example 187 in
dichloromethane (30 ml) was added 1M solution of boron tribromide
in dichloromethane (30 ml) at -78.degree. C. with stirring, and the
resulting mixture was stirred for 3 hours at room temperature under
a nitrogen atmosphere. After stirring, water (10 ml) was added, and
the resulting mixture was neutralized with saturated aqueous sodium
hydrogen carbonate solution and extracted with dichloromethane (40
ml.times.2). The organic layer was dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to afford the crude
product (2.10 g). To a solution of the crude product (2.10 g) in
tetrahydrofuran (20 ml) was added di-t-butyl dicarbonate (2.84 g,
13.0 mmol), and the resulting mixture was stirred for 1 hour at
room temperature under a nitrogen atmosphere. After stirring, the
reaction mixture was evaporated in vacuo and purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (90:10-50:50) as the eluent to afford the
title compound (1.72 g, yield: 26%) as a colorless oil.
[1084] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.25 (3H, t,
J=8.0 Hz), 1.48 (9H, s), 2.59-2.90 (4H, m), 3.23-3.30 (0.5H, m),
3.32-3.42 (0.5H, m), 3.84-3.92 (0.5H, m), 4.02-4.10 (0.5H, m),
4.08-4.18 (2H, m), 5.26 (1H, br s), 5.46 (0.5H, t, J=7.0 Hz), 5.56
(0.5H, t, J=7.0 Hz), 6.60 (1H, s), 6.62-6.68 (1H, m), 7.02 (1H, d,
J=8.0 Hz).
(e) t-Butyl
6-dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-is-
oquinoline-2-carboxylate
[1085] To a solution of t-butyl
1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylat-
e (1.70 g, 5.07 mmol) synthesized in step (d) of Example 187 in
dimethylformamide (5 ml) were added potassium carbonate (1.03 g,
7.50 mmol) and N,N-dimethylcarbamoyl chloride (0.69 ml, 7.5 mmol),
and the resulting mixture was stirred for 2.5 hours at room
temperature under a nitrogen atmosphere. After stirring, water (20
ml) was added, and the resulting mixture was extracted with ethyl
acetate (20 ml.times.2). The organic layer was washed with
saturated aqueous sodium chloride solution (30 ml.times.1), dried
over anhydrous sodium sulfate, filtered, and evaporated in vacuo to
afford the crude product. The crude product was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1-1:1) as the eluent to afford the
title compound (1.97 g, yield: 95%) as a colorless oil.
[1086] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.25 (3H, t,
J=7.0 Hz), 1.47 (9H, s), 2.62-2.98 (4H, m), 3.00 (3H, s), 3.08 (3H,
s), 3.18-3.26 (0.5H, m), 3.32-3.40 (0.5H, m), 3.90-3.92 (0.5H, m),
4.10-4.18 (2.5H, m), 5.53 (0.5H, t, J=7.0 Hz), 5.64 (0.5H, t, J=7.0
Hz), 6.89 (1H, s), 6.89-6.97 (1H, m), 7.14-7.19 (1H, m).
(f) t-Butyl
6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-c-
arboxylate
[1087] To a solution of t-butyl
6-dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-is-
oquinoline-2-carboxylate (1.97 g, 4.84 mmol) synthesized in step
(e) of Example 187 in tetrahydrofuran (30 ml) was added lithium
aluminum hydride (270 mg, 7.2 mmol) at -78.degree. C., and the
resulting mixture was stirred for 20 minutes at -78.degree. C. and
for 20 minutes at 0.degree. C. successively under a nitrogen
atmosphere. After stirring, to the reaction mixture were added
water (0.3 ml), 15% aqueous sodium hydroxide solution (0.3 ml) and
water (0.9 ml) in this order with stirring, and the resulting
mixture was dried over anhydrous sodium sulfate, filtered, and
evaporated in vacuo to afford the crude product. The crude product
was purified by chromatography on a silica gel column using a mixed
solvent of hexane and ethyl acetate (1:1-0:1) as the eluent to
afford the title compound (1.38 g, yield: 78%) as a colorless
oil.
[1088] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.49 (9H, s),
1.74 (1H, t, J=12.4 Hz), 2.00-2.10 (1H, m), 2.71 (1H, dt, J=4.4,
16.0 Hz), 2.86-2.94 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.54 (1H,
t, J=11.0 Hz), 3.65 (1H, br), 4.02 (1H, dt, J=4.4, 12.4 Hz), 4.12
(0.8H, br), 4.23 (0.2H, br), 5.30 (1H, d, J=12.0 Hz), 6.89 (1H, d,
J=2.0 Hz), 6.93 (1H, dd, J=2.0, 8.0 Hz), 7.15 (1H, d, J=8.0
Hz).
(g)
2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6--
yl dimethylcarbamate hydrochloride
[1089] The title compound was obtained as an amorphous solid using
t-butyl
6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-c-
arboxylate obtained in step (f) of Example 187 and 4-nitrophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48 and Example 3.
[1090] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 2.19-2.27 (1H,
m), 2.89 (3H, d, J=5.2 Hz), 3.02 (3H, s), 3.04-3.20 (3H, m), 3.10
(3H, s), 3.32-3.40 (1H, m), 3.71-3.80 (1H, m), 4.14-4.20 (1H, m),
4.50 (1H, t, J=6.4 Hz), 4.60-4.65 (1H, m), 7.02-7.10 (5H, m), 8.23
(2H, d, J=8.8 Hz).
[1091] MS (FAB) m/z: 400 (M+H).sup.+.
Example 188
2-Methyl-1-[2-(4-chloro-3-methylphenoxy)-ethyl]-1,2,3,4-tetrahydroisoquino-
lin-6-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-60)
[1092] The title compound was obtained as an amorphous solid using
t-butyl
6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-c-
arboxylate obtained in step (f) of Example 187 and
4-chloro-3-methylphenol by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48 and
Example 3.
[1093] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 7.24 (1H, d,
J=8.8), 7.10 (1H, m), 7.03 (2H, m), 6.83 (1H, s), 6.72 (1H, d,
J=7.6), 4.53 (1H, br s), 4.35 (1H, br s), 3.98 (1H, br s), 3.75
(1H, br s), 3.35 (1H, br s), 3.15 (1H, m), 3.10 (3H, s), 3.02 (3H,
s), 2.89 (3H, s), 2.35 (3H, s), 2.16 (1H, br s), 1.72 (2H, br
s)
[1094] MS (FAB) m/z: 403 (M+H).sup.+.
Example 189
2-Methyl-1-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinol-
in-6-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-58)
[1095] The title compound was obtained as an amorphous solid using
t-butyl
6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-c-
arboxylate obtained in step (f) of Example 187 and
2-chloro-4-nitrophenol by conducting successively reactions similar
to those mentioned in steps (a) and (b) of Example 48 and Example
3.
[1096] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 2.32-2.44 (1H,
m), 2.90 (3H, s), 2.92-3.02 (1H, m), 3.02 (3H, s), 3.08-3.22 (2H,
m), 3.10 (3H, s), 3.34-3.42 (1H, m), 3.68-3.78 (1H, m), 4.26-4.34
(1H, m), 4.56-4.62 (1H, m), 4.92-5.00 (1H, m), 7.05 (1H, d, J=2.4
Hz), 7.09 (1H, dd, J=2.4, 9.0 Hz), 7.16 (1H, d, J=9.0 Hz), 7.28
(1H, d, J=9.0 Hz), 8.19 (1H, dd, J=2.4, 9.0 Hz), 8.32 (1H, d, J=2.4
Hz)
[1097] MS (FAB) m/z: 433 (M+H).sup.+.
Example 190
2-Methyl-1-(R)-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoqu-
inolin-6-yl dimethylcarbamate hydrochloride (Exemplification
compound number 4-60)
(a)
6-Methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoqui-
noline-trifluoroacetamide
[1098] To a solution of
6-methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoquinol-
ine (1.30 g, 4.05 mmol), synthesized according to the procedure
described in J. Org. Chem. 57, 4732 (1992), and pyridine (0.65 ml,
8.10 mmol) in dichloromethane (20 ml) was added dropwise
trifluoroacetic anhydride (0.69 ml, 4.86 mmol) under cooling in an
ice bath, and the resulting mixture was stirred at room
temperature. After confirming the disappearance of the starting
material by thin layer chromatography, saturated aqueous sodium
hydrogen carbonate solution was added with stirring, and the
resulting mixture was extracted with ethyl acetate. The extract was
washed successively with dilute hydrochloric acid and saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate, and evaporated in vacuo. The residue obtained was purified
by chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1) as the eluent to afford the title
compound (1.50 g, yield: 88%) as a pale yellow oil.
[1099] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.08 (1H, m),
6.79 (1H, m), 6.68 (0.25H, d, J=2.5), 6.64 (0.75H, d, J=2.5), 5.62
(0.75H, dd, J=9.0, 5.5), 5.19 (0.25H, m), 4.41 (0.25H, ddd, J=13.5,
6.5, 4.5), 4.01 (0.75H, br d), 3.79 (3H, s), 3.59 (3H, m), 3.01
(1H, m), 2.85 (1H, m), 2.13 (1H, m), 2.04 (0.75H, m), 1.92 (0.25H,
m), 0.93 (2.25H, s), 0.90 (6.75H, s), 0.03 (0.25H, s), 0.06 (2.63H,
s), 0.05 (2.63H, s) [.alpha.].sub.D.sup.25 -45.4.degree. (c 1.06
CH.sub.2Cl.sub.2)
(b)
6-Methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoro-
acetamide
[1100] To a solution of
6-methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoquinol-
ine-trifluoroacetamide (1.14 g, 2.73 mmol) obtained in step (a) of
Example 190 in acetonitrile (10 ml) was added dropwise 48% solution
of hydrofluoric acid in water (0.5 ml, 13.67 mmol) gradually with
stirring under cooling in a water bath. The resulting mixture was
further stirred at room temperature, and after confirming the
disappearance of the starting material by thin layer
chromatography, saturated aqueous sodium hydrogen carbonate
solution was added with stirring, and the resulting mixture was
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate and evaporated in vacuo. The residue obtained was purified
by chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1) as the eluent to afford the title
compound (0.65 g, yield: 79%) as a colorless oil.
[1101] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.11 (1H, d,
J=8.5), 6.82 (1H, dd, J=8.5, 2.5), 6.65 (1H, d, J=2.5), 5.60 (1H,
dd, J=10.8, 3.0), 4.09 (1H, br d), 3.79 (3H, s), 3.68 (1H, m), 3.50
(2H, m), 3.04 (1H, m), 2.84 (1H, m), 2.16 (1H, m), 1.93 (1H, m)
[.alpha.].sub.D.sup.25 -30.00 (c 0.98 CH.sub.2Cl.sub.2)
(c)
6-Methoxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroac-
etamide
[1102] To a solution of
6-methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroace-
tamide (330 mg, 1.09 mmol) obtained in step (b) of Example 190 and
carbon tetrabromide (542 mg, 1.63 mmol) in dichloromethane (5 ml)
was added gradually triphenyl phosphine (343 mg, 1.31 mmol) with
stirring under cooling in a water bath. The resulting mixture was
further stirred at room temperature, and after confirming the
disappearance of the starting material by thin layer
chromatography, the reaction mixture was evaporated in vacuo. The
residue obtained was purified by chromatography on a silica gel
column using a mixed solvent of hexane and ethyl:acetate (80:20) as
the eluent to afford the title compound (390 mg, yield: 98%) as a
colorless oil.
[1103] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.10 (1H, m),
6.80 (1H, m), 6.70 (0.15H, d, J=2.5), 6.66 (0.85H, d, J=2.5), 5.63
(0.85H, dd, J=9.3, 5.0), 5.10 (0.15H, t, J=7.5), 4.41 (0.85H, ddd,
J=13.5, 6.5, 4.5), 4.03 (0.85H, br d), 3.79 (3H, s), 3.64 (1H, m),
3.44 (1H, m), 3.30 (1H, m), 3.02 (1H, m), 2.86 (1H, m), 2.45 (1H,
m), 2.36 (1H, m) [.alpha.].sub.D.sup.25 -45.1.degree. (c 1.05
CH.sub.2Cl.sub.2)
(d)
6-Hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroac-
etamide
[1104] To a solution of
6-methoxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroaceta-
mide (390 mg, 1.07 mmol) obtained in step (c) of Example 190 in
dichloromethane (5 ml) was added 1M solution of boron tribromide in
dichloromethane (2.14 ml, 2.14 mmol) gradually at -78.degree. C.
with stirring. The resulting mixture was further stirred at
-78.degree. C., and after confirming the disappearance of the
starting material by thin layer chromatography, saturated aqueous
sodium hydrogen carbonate solution was added to the reaction
mixture, and after raising the temperature to ambient temperature,
the resulting mixture was extracted with ethyl acetate. The extract
was washed successively with dilute hydrochloric acid and saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate, and evaporated in vacuo. The residue obtained was purified
by chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1) as the eluent to afford the title
compound (280 mg, yield: 75%) as a colorless oil.
[1105] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.04 (1H, m),
6.72 (1H, m), 6.65 (0.15H, d, J=2.0), 6.62 (0.85H, d, J=2.0), 5.61
(0.85H, dd, J=9.3, 5.0), 5.10 (0.15H, t, J=7.5), 4.37 (0.15H, m),
4.02 (0.85H, br d), 3.63 (1H, m), 3.45 (1H, m), 3.33 (1H, m), 2.97
(1H, m), 2.84 (1H, m), 2.45 (1H, m), 2.35 (1H, m)
[.alpha.].sub.D.sup.25 -60.1.degree. (c 0.94 CH.sub.2Cl.sub.2)
(e)
6-Dimethylcarbamoyloxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinolin-
e-trifluoroacetamide
[1106] To a solution of
6-hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroaceta-
mide (270 mg, 0.77 mmol) obtained in step (d) of Example 190 and
potassium carbonate (268 mg, 1.94 mmol) in dimethylformamide (3 ml)
was added dimethylcarbamyl chloride (0.2 ml, 1.55 mmol) gradually
with stirring under cooling in an ice bath. Subsequently, the
resulting mixture was stirred at 40.degree. C., and after
confirming the disappearance of the starting material by thin layer
chromatography, water was added to the reaction mixture, and the
resulting mixture was extracted with ethyl acetate. The extract was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and evaporated in vacuo. The residue
obtained was purified by chromatography on a silica gel column
using a mixed solvent of hexane and ethyl acetate (80:20) as the
eluent to afford the title compound (170 mg, yield: 52%) as a
colorless oil.
[1107] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.16 (m, 1H),
6.99 (1H, d, J=8.5), 6.97 (0.15H, s), 6.93 (0.85H, s), 5.70 (0.85H,
m), 5.16 (0.15H, m), 4.44 (0.15H, m), 4.04 (0.85H, br d), 3.62 (1H,
m), 3.41 (2H, m), 3.09 (3H, s), 3.05 (1H, m), 3.01 (3H, s), 2.85
(1H, m), 2.37 (2H, m) [.alpha.].sub.D.sup.25 -49.00 (c 0.86
CH.sub.2Cl.sub.2)
(f)
6-Dimethylcarbamoyloxy-1-(R)-(2-(4-chloro-3-methylphenoxy)ethyl)-3,4-d-
ihydro-1H-isoquinoline-trifluoroacetamide
[1108] To a solution of potassium carbonate (115 mg, 0.83 mmol),
potassium iodide (catalytic amount) and 4-chloro-m-cresol (65 mg,
0.46 mmol) in dimethylformamide (2 ml) was added a solution of
6-dimethylcarbamoyloxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-t-
rifluoroacetamide (160 mg, 0.38 mmol) obtained in step (e) of
Example, 190 in dimethylformamide (2 ml) gradually with stirring
under cooling in an ice bath. Subsequently, the resulting mixture
was stirred at 100.degree. C., and after confirming the
disappearance of the starting material by thin layer
chromatography, the reaction temperature was cooled to ambient
temperature and water was added to the reaction mixture with
stirring. The resulting mixture was extracted with ethyl acetate,
and the extract was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate and evaporated in
vacuo. The residue obtained was purified by chromatography on a
silica gel column using a mixed solvent of hexane and ethyl acetate
(80:20) as the eluent to afford the title compound (154 mg, yield:
84%) as a pale yellow oil.
[1109] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.23 (0.2H,
d, J=13.5), 7.20 (0.8H, d, J=9.0), 7.15 (0.8H, d, J=8.5), 7.05
(0.2H, d, J=8.0), 6.96 (2H, m), 6.74 (1H, m), 6.64 (1H, m), 5.78
(0.8H, dd, J=9.5, 5.0), 5.29 (0.2H, t, J=7.0), 4.49 (0.2H, m), 4.02
(3H, m), 3.43 (0.2H, m), 3.09 (3H, s), 3.05 (1H, m), 3.01 (3H, s),
2.88 (1H, td, J=16.0, 3.5), 2.33 (3H, s), 2.30 (2H, m)
[.alpha.].sub.D.sup.25 -63.3.degree. (c 0.25 CH.sub.2Cl.sub.2)
(g)
1-(R)-(2-(4-Chloro-3-methylphenoxy)-ethyl)-1,2,3,4-tetrahydroisoquinol-
in-6-yl dimethylcarbamate
[1110] To a solution of
6-dimethylcarbamoyloxy-1-(R)-(2-(4-chloro-3-methylphenoxy)ethyl)-3,4-dihy-
dro-1H-isoquinoline-trifluoroacetamide (154 mg, 0.54 mmol) obtained
in step (f) of Example 190 in methanol (1 ml) was added gradually
1M aqueous solution of potassium carbonate (1 ml) with stirring
under cooling in a water-bath. The resulting mixture was stirred at
40.degree. C., and after confirming the disappearance of the
starting material by thin layer chromatography, the reaction
temperature was cooled to ambient temperature, and saturated
aqueous sodium hydrogen carbonate solution was added to the
reaction mixture with stirring. The resulting mixture was extracted
with ethyl acetate, and the extract was washed with saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate and evaporated in vacuo. The residue obtained was purified
by chromatography on a silica gel column using a mixed solvent of
ethyl acetate and methanol (2:1) as the eluent to afford the title
compound (90 mg, yield: 73%) as a pale yellow oil.
[1111] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 7.21 (1H, d,
J=8.8), 7.12 (1H, d, J=8.8), 6.90 (1H, dd, J=8.4, 2.4), 6.86 (1H,
d, J=2.4), 6.80 (1H, d, J=2.8), 6.69 (1H, dd, J=8.8, 2.8), 4.18
(2H, m), 4.06 (1H, m), 3.18 (1H, m), 3.09 (3H, s), 3.01 (3H, s),
3.00 (1H, m), 2.77 (2H, m), 2.33 (3H, s), 2.28 (1H, m), 2.14 (1H,
m)
[1112] [.alpha.].sub.D.sup.25 +4.3.degree. (c 0.65
CH.sub.2Cl.sub.2)
(h)
2-Methyl-1-(R)-[2-(4-chloro-3-methylphenoxy)-ethyl]-1,2,3,4-tetrahydro-
isoquinolin-6-yl dimethylcarbamate hydrochloride
[1113] The title compound was obtained as an amorphous solid using
1-(R)-(2-(4-chloro-3-methylphenoxy)-ethyl)-1,2,3,4-tetrahydroisoquinolin--
6-yl dimethylcarbamate obtained in step (g) of Example 190 by
conducting a reaction similar to that mentioned in Example 3.
[1114] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 7.24 (1H, d,
J=8.8), 7.10 (1H, m), 7.03 (2H, m), 6.83 (1H, s), 6.72 (1H, d,
J=7.6), 4.53 (1H, br s), 4.35 (1H, br s), 3.98 (1H, br s), 3.75
(1H, br s), 3.35 (1H, br s), 3.15 (1H, m), 3.10 (3H, s), 3.02 (3H,
s), 2.89 (3H, s), 2.35 (3H, s), 2.16 (1H, br s), 1.72 (2H, br
s)
[1115] [.alpha.].sub.D.sup.25 -54.9.degree. (c 0.67
CH.sub.2Cl.sub.2)
Example 191
2-Methyl-1-[2-(4-chlorophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl
dimethylcarbamate hydrochloride (Exemplification compound number
5-73)
(a) t-Butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-c-
arboxylate
[1116] The title compound was obtained as an oily material using
2-(4-methoxyphenyl)-ethylamine as the starting material by
conducting successively reactions similar to those mentioned in
steps (a)-(f) of Example 187.
[1117] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.49 (9H, s),
1.77 (1H, t, J=13.5 Hz), 2.02-2.11 (1H, m), 2.71 (1H, dt, J=4.0,
15.5 Hz), 2.85-2.92 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.09-3.16
(1H, m), 3.54 (1H, t, J=12.0 Hz), 3.64 (1H, br s), 4.03 (1H, dt,
J=4.0, 12.5 Hz), 4.07 (0.8H, br s), 4.25 (0.2H, br s), 5.29 (1H, d,
J=10.0 Hz), 6.92 (1H, s), 6.93 (1H, d, J=8.0 Hz), 7.09 (1H, d,
J=8.0 Hz).
(b)
2-Methyl-1-[2-(4-chlorophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-7-
-yl dimethylcarbamate hydrochloride
[1118] The title compound was obtained as an amorphous solid using
t-butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-c-
arboxylate obtained in step (f) of Example 187 and 4-chlorophenol
by conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48 and Example 3.
[1119] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 2.14-2.22 (1H,
m), 2.89 (3H, d, J=4.5 Hz), 2.97 (3H, s), 3.02 (3H, s), 3.02-3.13
(2H, m), 3.21 (1H, br d, J=15.5 Hz), 3.31-3.38 (1H, m), 3.71-3.78
(1H, m), 4.03-4.09 (1H, m), 4.37-4.42 (1H, m), 4.50 (1H, t, J=6.5
Hz), 6.86 (1H, d, J=2.0 Hz), 6.91 (2H, d, J=8.5 Hz), 7.09 (1H, dd,
J=2.0, 8.5 Hz), 7.24 (1H, d, J=8.5 Hz), 7.25 (2H, d, J=8.5 Hz).
[1120] MS (FAB) m/z: 388 (M+H).sup.+.
Example 192
2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl
dimethylcarbamate hydrochloride (Exemplification compound number
4-132)
(a) 4-Formyl-3-hydroxy-phenyl dimethylcarbamate
[1121] To a suspension of sodium hydride (5.74 g, 239 mmol), which
was prepared free from mineral oil by washing with hexane, in
dimethylformamide (100 ml) was added 2,4-dihydroxybenzaldehyde
(15.0 g, 109 mmol) at 0.degree. C. with stirring, and the resulting
mixture was stirred for 30 minutes at 0.degree. C. under a nitrogen
atmosphere. Subsequently, N,N-dimethylcarbamoyl chloride (10.1 ml,
110 mmol) was added at 0.degree. C., and the resulting mixture was
stirred for 2 hours at room temperature under a nitrogen
atmosphere. After stirring, water (300 ml) was added to the
reaction mixture, and the resulting mixture was washed with ethyl
acetate (200 ml.times.1). The aqueous layer was acidified to pH 1
with concentrated hydrochloric acid and extracted with ethyl
acetate (200 ml.times.3). The extract was washed successively with
water (300 ml.times.3) and saturated aqueous sodium chloride
solution (200 ml.times.2), dried over anhydrous sodium sulfate,
filtered, and evaporated in vacuo to afford the crude product. The
crude product was purified by chromatography on a silica gel column
using a mixed solvent of hexane and ethyl acetate (5:1-1:2) as the
eluent to afford the title compound (6.78 g, yield: 30%) as a
colorless solid.
[1122] Mp 58-60.degree. C.
[1123] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 3.02 (3H s),
3.10 (3H, s), 6.77 (1H, d, J=2.0 Hz), 6.82 (1H, dd, J=2.0, 8.0 Hz),
7.53 (1H, d, J=8.0 Hz), 9.84 (1H, s), 11.21 (1H, s).
(b) 5-Dimethylcarbamoyloxy-2-formyl-phenyl
trifluoromethanesulfonate
[1124] To a solution of 4-formyl-3-hydroxy-phenyl dimethylcarbamate
(2.60 g, 12.4 mmol) synthesized in step (a) of Example 192 in
dichloromethane (30 ml) were added pyridine (1.61 ml, 20.0 mmol)
and trifluoromethanesulfonic anhydride (2.35 ml, 14.0 mmol) at
0.degree. C. with stirring, and the resulting mixture was stirred
for 1 hour at room temperature under a nitrogen atmosphere. After
stirring, water (20 ml) was added to the reaction mixture, and the
resulting mixture was extracted with dichloromethane (20
ml.times.2). The organic layer was washed successively with 1N
hydrochloric acid (20 ml.times.1) and saturated aqueous sodium
chloride solution (20 ml.times.1), dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to afford the crude
product (4.14 g). The crude product was used for the following
reaction without further purification.
[1125] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 3.04 (3H, s),
3.12 (3H, s), 7.31 (1H, d, J=2.0 Hz), 7.35 (1H, dd, J=2.0, 9.0 Hz),
8.00 (1H, d, J=9.0 Hz), 10.21 (1H, s).
(c) 4-Formyl-3-vinyl-phenyl dimethylcarbamate
[1126] To a solution of 5-dimethylcarbamoyloxy-2-formyl-phenyl
trifluoromethanesulfonate (4.13 g, 12.1 mmol) obtained in step (b)
of Example 192 in 1,4-dioxane (15 ml) were added
tetrakis(triphenylphosphine)palladium (693 mg, 0.600 mmol),
2,6-di-t-butylphenol (5 mg), lithium chloride (1.54 g, 36.4 mmol)
and tributyl(vinyl)tin (4.23 ml, 14.5 mmol) with stirring, and the
resulting mixture was stirred for 3 hours at 100.degree. C. under a
nitrogen atmosphere. Subsequently, saturated aqueous potassium
fluoride solution (5 ml) was added to the reaction mixture, and the
resulting mixture was stirred for 2 hours at room temperature,
filtered, and evaporated in vacuo. To the residue was added water
(40 ml), and the resulting mixture was extracted with ethyl acetate
(50 ml.times.2). The organic layer was washed successively with 1N
hydrochloric acid (40 ml.times.1) and saturated aqueous sodium
chloride solution (40 ml.times.1), dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to afford the crude
product. The crude product was purified by chromatography on a
silica gel column using a mixed solvent of hexane and ethyl acetate
(10:1-1:1) as the eluent to afford the title compound (2.11 g,
yield: 79%) as a colorless oil.
[1127] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 3.04 (3H, s),
3.12 (3H, s), 5.53 (1H, dd, J=1.6, 11.2 Hz), 5.72 (1H, d, J=18.0
Hz), 7.21 (1H, dd, J=2.4, 8.0 Hz), 7.33 (1H, d, J=2.4 Hz), 7.53
(1H, dd, J=11.2, 18.0 Hz), 7.84 (1H, d, J=8.0 Hz), 10.24 (1H,
s).
(d) Ethyl
3-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-hydroxy-propionate
[1128] To a solution of diisopropylamine (1.26 g, 12.5 mmol) in
tetrahydrofuran (30 ml) was added 1.6M solution of n-butyllithium
in hexane (7.20 ml, 11.5 mmol) at -20.degree. C. with stirring, and
the resulting mixture was stirred for 20 minutes at -20.degree. C.
under a nitrogen atmosphere. Subsequently, ethyl acetate (1.07 ml,
11.0 mmol) was added at -78.degree. C., and the resulting mixture
was stirred for 20 minutes at -78.degree. C. under a nitrogen
atmosphere. Subsequently, to the reaction mixture was added a
solution of 4-formyl-3-vinyl-phenyl dimethylcarbamate (2.11 g, 9.62
mmol) obtained in step (c) of Example 192 in tetrahydrofuran at
-78.degree. C., and the resulting mixture was stirred for 30
minutes at -78.degree. C. under a nitrogen atmosphere. After
stirring, to the reaction mixture was added saturated aqueous
ammonium chloride solution (40 ml), and the resulting mixture was
extracted with ethyl acetate (40 ml.times.2). The organic layer was
washed successively with water (40 ml.times.1) and saturated
aqueous sodium chloride solution (40 ml.times.1), dried over
anhydrous sodium sulfate, filtered, and evaporated in vacuo to
afford the crude product. The crude product was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (1:1-1:2) as the eluent to afford the
title compound (2.95 g, yield: 99%) as a colorless oil.
[1129] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.28 (3H, t,
J=7.5 Hz), 2.65 (2H, d, J=6.0 Hz), 3.01 (3H, s), 3.10 (3H, s),
3.23-3.25 (1H, m), 4.19 (2H, q, J=7.5 Hz), 5.35 (1H, d, J=11.0 Hz),
5.38-5.43 (1H, m), 5.63 (1H, d, J=17.0 Hz), 6.99 (1H, dd, J=11.0,
17.0 Hz), 7.05 (1H, d, J=8.5 Hz), 7.20 (1H, s), 7.52 (1H, d, J=8.5
Hz).
(e) 4-(1,3-Dihydroxy-propyl)-3-vinyl-phenyl dimethylcarbamate
[1130] To a solution of ethyl
3-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-hydroxy-propionate
(5.28 g, 17.2 mmol) obtained in step (d) of Example 192 in
tetrahydrofuran (50 ml) was added lithium tetrahydroborate (544 mg,
25.0 mmol) at -20.degree. C. with stirring, and the reaction
temperature was raised gradually to ambient temperature over one
hour under a nitrogen atmosphere. To the reaction mixture were
added successively water (20 ml) and 1N hydrochloric acid (20 ml),
and the resulting mixture was extracted with ethyl acetate (40
ml.times.2). The organic layer was dried over anhydrous sodium
sulfate, filtered; and evaporated in vacuo to afford the crude
product. The crude product was purified by chromatography on a
silica gel column using mixed solvents of hexane and ethyl acetate
(1:1-0:1) and ethyl acetate and methanol (5:1) successively as the
eluents to afford the title compound (4.44 g, yield: 97%) as a
colorless oil.
[1131] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.78-1.90
(2H, m), 2.88 (1H, s), 3.00 (3H, s), 3.10 (3H, s), 3.44 (1H, s),
3.77 (2H, br s), 5.14-5.19 (1H, m), 5.32 (1H, d, J=11.0 Hz), 5.60
(1H, d, J=17.5 Hz), 6.96 (1H, dd, J=11.0, 17.5 Hz), 7.03 (1H, dd,
J=2.5, 8.5 Hz), 7.17 (1H, d, J=2.5 Hz), 7.51 (1H, d, J=8.5 Hz).
(f)
4-[3-(t-Butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyl
dimethylcarbamate
[1132] To a solution of 4-(1,3-dihydroxy-propyl)-3-vinyl-phenyl
dimethylcarbamate (4.44 g, 16.7 mmol) synthesized in step (e) of
Example 192 in dichloromethane (40 ml) were added triethylamine
(4.18 ml, 30.0 mmol), t-butyldimethylchlorosilane (4.67 g, 17.0
mmol) and a catalytic amount of 4-dimethylaminopyridine at
-0.degree. C. with stirring, and the resulting mixture was stirred
for 5 hours at room temperature under a nitrogen atmosphere. After
stirring, water (30 ml) was added to the reaction mixture, and the
resulting mixture was extracted with dichloromethane (40
ml.times.2). The organic layer was washed successively with 1N
hydrochloric acid (50 ml.times.1) and saturated aqueous sodium
chloride solution (50 ml.times.1), dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to afford the crude
product. The crude product was purified by chromatography on a
silica gel column using a mixed solvent of hexane and ethyl acetate
(2:1-1:1) as the eluent to afford the title compound (5.87 g,
yield: 70%) as a colorless oil.
[1133] .sup.1H NMR (CDCl.sub.3.+-.500 MHz) .delta. ppm: 1.09 (9H,
s), 1.85-1.90 (2H, m), 3.01 (3H, s), 3.10 (3H, s), 3.32 (1H, s),
3.84-3.93 (2H, m), 5.27 (1H, d, J=10.5 Hz), 5.28-5.33 (1H, br m),
5.60 (1H, d, J=17.0 Hz), 6.97 (1H, dd, J=10.5, 17.0 Hz), 7.05 (1H,
dd, J=2.5, 9.0 Hz), 7.19 (1H, d, J=2.5 Hz), 7.38-7.45 (5H, m), 7.51
(1H, d, J=9.0 Hz), 7.69 (4H, d, J=7.0 Hz).
(g)
4-[1-Bromo-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-p-
henyl dimethylcarbamate
[1134] To a solution of
4-[3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyl
dimethylcarbamate (3.00 g, 5.95 mmol) synthesized in step (f) of
Example 192 and carbon tetrabromide (3.98 g, 12.0 mmol) in
dichloromethane (20 ml) was added triphenyl phosphine (3.14 g, 12.0
mmol) at room temperature, and the resulting mixture was stirred
for 1 hour at room temperature under a nitrogen atmosphere. After
stirring, the reaction mixture was evaporated in vacuo, and the
residue was purified by chromatography on a silica gel column using
a mixed solvent of hexane and ethyl acetate (5:1-2:1) as the eluent
to afford the title compound (2.62 g, yield: 78%) as a colorless
oil.
[1135] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.05 (9H, s),
2.26-2.33 (1H, m), 2.41-2.48 (1H, m), 3.02 (3H, s), 3.10 (3H, s),
3.74 (1H, dt, J=5.0, 9.0 Hz), 3.86-3.90 (1H, m), 5.40 (1H, d,
J=10.5 Hz), 5.66 (1H, d, J=17.0 Hz), 5.70 (1H, dd, J=5.0, 9.0 Hz),
7.04 (1H, dd, J=2.0, 9.0 Hz), 7.10 (1H, dd, J=10.5, 17.0 Hz), 7.19
(1H, d, J=2.0 Hz), 7.33-7.43 (5H, m), 7.46 (1H, d, J=9.0 Hz), 7.60
(2H, d, J=7.5 Hz), 7.69 (2H, d, J=7.5 Hz).
(i)
4-[1-Allylamino-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vi-
nyl-phenyl dimethylcarbamate
[1136] To a solution of
4-[1-bromo-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phen-
yl dimethylcarbamate (2.62 g, 4.62 mmol) synthesized in step (g) of
Example 192 in acetonitrile (20 ml) was added allylamine (1.87 ml,
25.0 mmol) at room temperature, and the resulting mixture was
stirred at room temperature overnight under a nitrogen atmosphere.
After stirring, the reaction mixture was evaporated in vacuo, and
the residue was purified by chromatography on a silica gel column
using a mixed solvent of hexane and ethyl acetate (2:1-0:1) as the
eluent to afford the title compound (1.82 g, yield: 72%) as a
colorless oil.
[1137] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.06 (9H, s),
1.79-1.84 (2H, m), 3.00 (1H, dd, J=7.0, 16.0 Hz), 3.02 (3H, s),
3.07-3.12 (1H, m), 3.10 (3H, s), 3.65 (1H, dt, J=5.0, 11.0 Hz),
3.76 (1H, dt, J=5.0, 11.0 Hz), 4.32 (1H, t, J=6.0 Hz), 5.04 (1H, d,
J=11.0 Hz), 5.11 (1H, d, J=17.5 Hz), 5.24 (1H, d, J=11.0 Hz), 5.56
(1H, d, J=17.5 Hz), 5.81-5.89 (1H, m), 7.02 (1H, dd, J=3.0, 9.0
Hz), 7.15 (1H, dd, J=11.0, 17.5 Hz), 7.19 (1H, d, J=3.0 Hz),
7.26-7.44 (6H, m), 7.63-7.68 (4H, m).
(j) t-Butyl
allyl-[3-(t-butyl-diphenyl-silanyloxy)-1-(4-dimethylcarbamoyloxy-2-vinyl--
phenyl)-propyl]-carbamate
[1138] To a solution of
4-[1-allylamino-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-
-phenyl dimethylcarbamate (1.80 g, 3.31 mmol) synthesized in step
(i) of Example 192 in tetrahydrofuran (20 ml) were added
triethylamine (1.12 ml, 8.00 mmol) and di-t-butyl dicarbonate (870
mg, 4.00 mmol), and the resulting mixture was stirred for 3 hours
at 50.degree. C. under a nitrogen atmosphere. After stirring, the
reaction mixture was evaporated in vacuo, and the residue was
purified by chromatography on a silica gel column using a mixed
solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to
afford the title compound (1.90 g, yield: 89%) as a colorless
oil.
[1139] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.04 (9H, s),
1.38 (9H, s), 2.10-2.30 (2H, m), 3.02 (3H, s), 3.11 (3H, s),
3.24-3.60 (2H, br), 3.67 (1H, q, J=8.0 Hz), 3.72-3.82 (1H, m),
4.72-4.79 (0.4H, m), 4.79 (0.6H, d, J=9.6 Hz), 5.24 (1H, d, J=11.2
Hz), 5.37 (1H, br), 5.51 (1H, br), 5.55 (1H, d, J=17.6 Hz), 6.98
(1H, d, J=8.0 Hz), 7.01 (1H, dd, J=11.2, 17.6 Hz), 7.19 (1H, d,
J=8.0 Hz), 7.22 (1H, d, J=2.4 Hz), 7.32-7.43 (5H, m), 7.60 (1.6H,
br s), 7.66 (2.4H, d, J=7.2 Hz).
(k) t-Butyl
1-[2-(t-butyl-diphenyl-silanyloxy)-ethyl]-7-dimethylcarbamoyloxy-1,3-dihy-
dro-benzo[c]azepine-2-carboxylate
[1140] To a solution of t-butyl
allyl-[3-(t-butyl-diphenyl-silanyloxy)-1-(4-dimethylcarbamoyloxy-2-vinyl--
phenyl)-propyl]-carbamate (360 mg, 0.56 mmol) synthesized in step
(j) of Example 192 in dichloromethane (40 ml) was added
tricyclohexylphosphine
[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]
[benzylidene] ruthenium (IV) dichloride (47.5 mg, 0.0560 mmol), and
the resulting mixture was stirred for 3 hours at 45.degree. C.
under a nitrogen atmosphere. After stirring, the reaction mixture
was evaporated in vacuo, and the residue was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (5:1-2:1) as the eluent to afford the
title compound (330 mg, yield: 96%) as a colorless oil
[1141] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.04 (9H, s),
1.38 (9H, s), 2.10-2.30 (2H, m), 3.02 (3H, s), 3.11 (3H, s),
3.24-3.60 (2H, br), 3.67 (1H, q, J=8.0 Hz), 3.72-3.82 (1H, m),
4.72-4.79 (0.4H, m), 4.79 (0.6H, d, J=9.6 Hz), 5.24 (1H, d, J=11.2
Hz), 5.37 (1H, br), 5.51 (1H, br), 5.55 (1H, d, J=17.6 Hz), 6.98
(1H, d, J=8.0 Hz), 7.01 (1H, dd, J=11.2, 17.6 Hz), 7.19 (1H, d,
J=8.0 Hz), 7.22 (1H, d, J=2.4 Hz), 7.32-7.43 (5H, m), 7.60 (1.6H,
br s), 7.66 (2.4H, d, J=7.2 Hz).
(l) t-Butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-c-
arboxylate
[1142] To a solution of t-butyl
1-[2-(t-butyl-diphenyl-silanyloxy)-ethyl]-7-dimethylcarbamoyloxy-1,3-dihy-
dro-benzo[c]azepine-2-carboxylate (1.82 g, 2.96 mmol) synthesized
in step (k) of Example 192 in tetrahydrofuran (10 ml) was added 1M
solution of tetrabutylammonium fluoride in tetrahydrofuran (6.0 ml,
6.0 mmol) at room temperature, and the resulting mixture was
stirred for 1 hour at room temperature under a nitrogen atmosphere.
After stirring, water (30 ml) was added to the reaction mixture,
and the resulting mixture was extracted with ethyl acetate (40
ml.times.2). The organic layer was washed successively with water
(40 ml.times.1) and saturated aqueous sodium chloride solution (40
ml.times.1), dried over anhydrous sodium sulfate, filtered, and
evaporated in vacuo to afford the crude product. The crude product
was purified by chromatography on a silica gel column using a mixed
solvent of hexane and ethyl acetate (1:1-0:1) as the eluent to
afford the title compound (1.07 g, yield: 96%) as a colorless
oil.
[1143] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.30 (5H, s),
1.40 (4H, s), 1.90-2.08 (1H, m), 2.07-2.24 (1H, br), 3.00 (3H, s),
3.09 (3H, s), 3.59 (1H, br s), 3.65 (1H, br s), 3.76-3.88 (0.4H,
br), 3.98 (0.6H, d, J=19.0 Hz), 4.58 (0.6H, d, J=19.0 Hz),
4.78-5.10 (0.4H, br), 4.92-5.20 (0.4H, br), 5.31 (0.6H, br t, J=7.5
Hz), 5.77-5.83 (1H, m), 6.32 (0.6H, d, J=11.5 Hz), 6.39 (0.4H, d,
J=13.0 Hz), 6.92 (1H, dd, J=2.0, 8.0 Hz), 6.95 (1H, s), 7.13 (0.6H,
d, J=8.0 Hz), 7.25, (0.4H, d, J=8.9 Hz).
(m)
2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7--
yl dimethylcarbamate hydrochloride
[1144] The title compound was obtained as an amorphous solid using
t-butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-c-
arboxylate obtained in step (1) of Example 192 and 4-nitrophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48 and Example 3.
[1145] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.12-2.21
(1H, m), 2.60 (3H, s), 2.85-2.93 (1H, m), 3.02 (3H, s), 3.10 (3H,
s), 3.81 (1H, dd, J=4.4, 19.6 Hz), 3.85-3.90 (1H, m), 4.06 (1H, dt,
J=5.2, 9.6 Hz), 4.39 (1H, d, J=19.6 Hz), 4.77 (1H, d, J=11.6 Hz),
5.85 (1H, ddd, J=3.2, 4.4, 12.4 Hz), 6.36 (1H, d, J=12.4 Hz), 6.86
(2H, d, J=8.8 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.14 (1H, d, J=8.8
Hz), 7.21 (1H, d, J=2.4 Hz), 8.16 (2H, d, J=8.8 Hz).
[1146] MS (FAB) m/z: 412 (M+H).sup.+.
Example 193
2-Methyl-1-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,3,4,5-tetrahydro-1H-benzo-
[c]azepin-7-yl dimethylcarbamate hydrochloride (Exemplification
compound number 4-137)
(a) t-Butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3,4,5-tetrahydro-benzo[c]azep-
ine-2-carboxylate
[1147] To a solution of t-butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-c-
arboxylate (207 mg, 0.550 mmol) synthesized in step (k) of Example
192 in methanol (10 ml) was added 10% palladium carbon (27 mg), and
the resulting mixture was stirred for 1 hour at room temperature.
After stirring, the reaction mixture was filtered through celite
and evaporated in vacuo to afford the crude product. The crude
product was purified by chromatography on a silica gel column using
a mixed solvent of ethyl acetate and methanol (1:1-0:1) as the
eluent to afford the title compound (189 mg, yield: 91%) as a
colorless oil.
[1148] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.36 (5.4H,
s), 1.45 (3.6H, s), 1.68-1.84 (1H, br), 1.86-2.00 (1H, br),
1.88-2.06 (0.4H, br), 2.06-2.18 (0.6H, br), 2.22-2.44 (1H, br),
2.83 (2H, br s), 3.00 (3H, s), 3.08 (3H, s), 3.55-3.68 (1H, br),
3.67 (2H, br s), 3.75-3.90 (1H, br), 5.03-5.18 (0.4H, br),
5.38-5.52 (0.6H, br), 6.88 (2H, s), 7.15 (0.4H, br s), 7.24 (0.6H,
br s).
(b)
2-Methyl-1-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,3,4,5-tetrahydro-1H-b-
enzo[c]azepin-7-yl dimethylcarbamate hydrochloride
[1149] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.88-2.32
(2H, m), 2.42 (1H, br s), 2.60-2.80 (0.4H, br), 2.70 (3H, d, J=4.4
Hz), 2.91 (0.6H, dd, J=5.6, 15.6 Hz), 3.01 (1.8H, s), 3.02 (1.2H,
s), 3.09 (1.8H, s), 3.10 (1.2H, s), 3.15-3.40 (4H, m), 3.62 (0.4H,
t, J=13.6 Hz), 3.82 (0.6H, t, J=13.6 Hz), 4.07-4.16 (0.6H, m), 4.30
(1H, dt, J=5.6, 9.2 Hz), 4.53-4.59 (0.4H, m), 4.80 (0.4H, br s),
5.18 (0.6H, br s), 6.93-7.14 (3H, m), 7.17 (0.6H, d, J=8.8 Hz),
7.37 (0.4H, d, J=8.8 Hz), 8.10-8.16 (1H, m), 8.25 (1H, s).
[1150] MS (FAB) m/z: 448 (M+H).sup.+.
Example 194
2-Methyl-1-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]aze-
pin-7-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-140)
[1151] The title compound was obtained as an amorphous solid using
t-butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-c-
arboxylate obtained in step (1) of Example 192 and
4-chloro-3-methylphenol by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48 and
Example 3.
[1152] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.03-2.12
(1H, m), 2.30 (3H, s), 2.60 (3H, d, J=5.2 Hz), 2.77-2.85 (1H, m),
3.02 (3H, s), 3.10 (3H, s), 3.65 (1H, dt, J=4.4, 9.6 Hz), 3.78 (1H,
dd, J=4.4, 20.0 Hz), 3.85-3.90 (1H, m), 4.37 (1H, d, J=17.2 Hz),
4.79 (1H, dt, J=3.6, 12.4 Hz), 5.82 (1H, ddd, J=2.8, 4.4, 12.4 Hz),
6.55 (1H, dd, J=2.8, 8.8 Hz), 6.64 (1H, d, J=12.4 Hz), 6.68 (1H, d,
J=2.8 Hz), 7.03 (1H, dd, J=2.8, 8.8 Hz), 7.13-7.19 (3H, m).
[1153] MS (FAB) m/z: 415 (M+H).sup.+.
Example 195
2-Methyl-1-[2-(2-chloro-4-fluorophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]aze-
pin-7-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-139)
[1154] The title compound was obtained as an amorphous solid using
t-butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-c-
arboxylate obtained in step (1) of Example 192 and
2-chloro-4-fluorophenol by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48 and
Example 3.
[1155] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.07-2.09
(1H, m), 2.61 (3H, s), 2.83-2.92 (1H, m), 3.03 (3H, s), 3.11 (3H,
s), 3.74-3.82 (2H, m), 4.02-4.07 (1H, m), 4.38 (1H, d, J=19.1 Hz),
4.77-4.82 (1H, m), 5.82-5.87 (1H, m), 6.69 (1H, d, J=12.7 Hz),
6.82-6.92 (2H, m), 7.06-7.12 (2H, m), 7.18 (1H, d, J=2.3 Hz), 7.28
(1H, t, J=8.2 Hz).
[1156] MS (FAB) m/z: 419 (M+H).sup.+.
Example 196
2-Methyl-1-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-
-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-136)
[1157] The title compound was obtained as an amorphous solid using
t-butyl
7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-c-
arboxylate obtained in step (1) of Example 192 and
4-methylthiophenol by conducting successively reactions similar to
those mentioned in steps (a) and (b) of Example 48 and Example
3.
[1158] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.03-2.11
(1H, m), 2.44 (3H, s), 2.60 (3H, s), 2.83 (1H, brs), 3.03 (3H, s),
3.11 (3H, s), 3.65-3.70 (1H, m), 3.78 (1H, d, J=18.9 Hz), 3.89-3.92
(1H, m), 4.38 (1H, d, J=18.9 Hz), 4.79 (1H, d, J=10.4 Hz), 5.82
(1H, d, J=12.6 Hz), 6.65 (1H, d, J=12.6 Hz), 6.74 (2H, d, J=8.7
Hz), 7.03 (1H, d, J=7.2, 1.1 Hz), 7.16 (1H, d, J=8.3 Hz), 7.19-7.22
(3H, m).
[1159] MS (FAB) m/z: 413 (M+H).sup.+.
Example 197
2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepi-
n-7-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-136)
(a) 4-Benzyloxy-2-hydroxy-benzaldehyde
[1160] To a solution of 2,4-dihydroxybenzaldehyde (50.0 g, 362
mmol) in acetonitrile (350 ml) were added sodium hydrogen carbonate
(34.6 g, 412 mmol), potassium iodide (6.0 g, 36 mmol), and benzyl
chloride (54.0 ml, 470 mmol), and the resulting mixture was
refluxed for 24 hours under a nitrogen atmosphere. At the end of
the reaction, 1N hydrochloric acid (400 ml) was added, and the
resulting mixture was extracted with ethyl acetate (400
ml.times.2). The organic layer was washed successively with 3%
aqueous potassium carbonate solution (300 ml.times.2), water (300
ml.times.1), 1N hydrochloric acid (300 ml.times.1) and saturated
aqueous sodium chloride solution (300 ml.times.1), dried over
anhydrous sodium sulfate, filtered, and evaporated in vacuo to
afford the crude product. The crude product was recrystallized from
a mixture of t-butyl methyl ether and hexane to afford the title
compound (45.9 g, yield: 56%) as pale orange crystals.
[1161] Mp 71-72.degree. C.
[1162] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 5.11 (2H, s),
6.51 (1H, d, J=2.0 Hz), 6.62 (1H, dd, J=2.0, 8.5 Hz), 7.35-7.45
(6H, m), 9.72 (1H, s), 11.46 (1H, s).
(b) 4-Benzyloxy-2-methoxymethoxy-benzaldehyde
[1163] To a solution of 4-benzyloxy-2-hydroxy-benzaldehyde (44.9 g,
197 mmol) synthesized in step (a) of Example 197 in dichloromethane
(200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and
methoxymethyl chloride (20.5 ml, 270 mmol) at 0.degree. C. with
stirring, and the resulting mixture was stirred overnight at room
temperature under a nitrogen atmosphere. After stirring, water (200
ml) was added, and the resulting mixture was extracted with
dichloromethane (200 ml.times.2). The organic layer was washed
successively with water (300 ml.times.1) and saturated aqueous
sodium chloride solution (300 ml.times.1), dried over anhydrous
sodium sulfate, filtered, and evaporated in vacuo to afford the
crude product. The crude product was purified by chromatography on
a silica gel column using a mixed solvent of hexane and ethyl
acetate (5:1-1:1) as the eluent to afford the title compound (42.2
g, yield: 79%) as a colorless oil.
[1164] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 3.51 (3H, s),
5.11 (2H, s), 5.26 (2H, s), 6.68 (1H, dd, J=2.0, 9.0 Hz), 6.80 (1H,
d, J=9.0 Hz), 7.34-7.43 (5H, m), 7.81 (1H, d, J=9.0 Hz), 9.72 (1H,
s), 11.46 (1H, s).
(c) Ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate
[1165] To a suspension of 55% sodium hydride dispersion in mineral
oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl
diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0.degree. C. with
stirring, and the resulting mixture was stirred for 30 minutes at
0.degree. C. under a nitrogen atmosphere. Subsequently, a solution
of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol)
obtained in step (b) of Example 197 in tetrahydrofuran was added at
0.degree. C. with stirring, and the resulting mixture was stirred
for 2 hours at 0.degree. C. under a nitrogen atmosphere. After
stirring, water (200 ml) was added, and the resulting mixture was
extracted with ethyl acetate (200 ml.times.2). The organic layer
was washed successively with water (100 ml.times.1) and saturated
aqueous sodium chloride solution (100 ml.times.1), dried-over
anhydrous sodium sulfate, filtered, and evaporated in vacuo to
afford the crude product. The crude product was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (5:1-1:1) as the eluent to afford the
title compound (9.32 g, yield: 99%) as a colorless oil.
[1166] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.32 (3H, t,
J=7.2 Hz), 3.47 (3H, s), 4.24 (2H, q, J=7.2 Hz), 5.05 (2H s), 5.21
(2H, s), 6.39 (1H, d, J=16.0 Hz), 6.62 (1H, dd, J=2.0, 8.8 Hz),
6.81 (1H, d, J=2.0 Hz), 7.30-7.43 (5H, m), 7.45 (1H, d, J=8.8 Hz),
7.95 (1H, d, J=16.0 Hz).
(d) Ethyl
(3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate
acetate
[1167] To a solution of (S)-N-benzyl-1-phenylethylamine (4.24 g,
20.1 mmol) in tetrahydrofuran (40 ml) was added 1.6 M solution of
n-butyllithium in hexane (12.4 ml, 18.9 mmol) at -78.degree. C.
with stirring, and the resulting mixture was stirred for 20 minutes
at -78.degree. C. under a nitrogen atmosphere. Subsequently, a
solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate
(4.32 g, 12.6 mmol) synthesized in Example 3 in tetrahydrofuran was
added dropwise at -78.degree. C. with stirring, and the resulting
mixture was stirred for 30 minutes at -78.degree. C. under a
nitrogen atmosphere. After stirring, a saturated aqueous ammonium
chloride solution (40 ml) was added at -78.degree. C. with
stirring, and the resulting mixture was extracted with ethyl
acetate (50 ml.times.2). The organic layer was washed with
saturated aqueous sodium chloride solution (50 ml.times.1), dried
over anhydrous sodium sulfate, filtered, and evaporated in vacuo to
afford the crude product. The crude product was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (10:1-5:1) as the eluent to afford ethyl
3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)--
amino]-propionate (7.21 g) containing a small amount of
(S)--N-benzyl-1-phenylethylamine.
[1168] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 0.98 (3H, t,
J=7.0 Hz), 1.23 (3H, d, J=7.0 Hz), 2.60 (1H, dd, J=9.0, 13.5 Hz),
2.73 (1H, dd, J=7.0, 15.0 Hz), 3.47 (3H, s), 3.73 (2H, dd, J=14.5,
22.5 Hz), 3.79-3.92 (2H, m), 4.08 (1H, q, J=7.0 Hz), 4.80 (1H, dd,
J=6.0, 8.0 Hz), 5.03 (2H, s), 5.15 (2H, dd, J=7.0, 17.0 Hz), 6.61
(1H, dd, J=2.5, 8.5 Hz), 6.83 (1H, d, J=2.5 Hz), 7.13-7.44 (16H,
m).
[1169] Subsequently, to a solution of ethyl
3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)--
amino]-propionate (7.21 g) obtained above as a yellow oil in a
mixture of methanol/water/acetic acid (80 ml/8 ml/4 ml) was added
20% palladium hydroxide (1.8 g), and the resulting mixture was
stirred for 4 hours at room temperature under an atmosphere of
hydrogen. After stirring, the reaction mixture was filtered through
celite and evaporated in vacuo to afford the crude product. The
crude product was purified by chromatography on a silica gel column
using a mixed solvent of ethyl acetate and methanol (1:0-3:1) as
the eluent to afford the title compound (2.77 g, yield: 67%) as an
amorphous solid.
[1170] [.alpha.].sub.D.sup.23 -8.0 (c 0.82, MeOH)
[1171] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. ppm: 1.20 (3H, t,
J=7.6 Hz), 1.90 (3H, s), 2.93 (1H, dd, J=6.0, 16.4 Hz), 2.98 (1H,
dd, J=8.8, 16.4 Hz), 3.49 (3H, s), 4.13 (2H, q, J=7.6 Hz), 4.71
(1H, t, J=7.4 Hz), 5.24 (2H, s), 6.45 (1H, dd, J=2.4, 8.8 Hz), 6.69
(1H, d, J=2.8 Hz), 7.12 (1H, d, J=8.8 Hz).
(e) Ethyl
(3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phen-
yl)-propionate
[1172] To a solution of ethyl
(3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate
acetate (4.26 g, 12.9 mmol) obtained in step (d) of Example 197 in
methanol (20 ml) were added triethylamine (3.62 ml, 26.0 mmol) and
di-t-butyl dicarbonate (3.27 g, 15.0 mmol) with stirring, and the
resulting mixture was stirred for 30 minutes at room temperature
under a nitrogen atmosphere. After stirring, the reaction mixture
was evaporated in vacuo, and the residue obtained was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1-1:2) as the eluent to afford the
title compound (4.64 g, yield: 97%) as a colorless solid. The
optical purity of the title compound obtained was determined to be
98.8% ee by chiral liquid chromatography (Dicel Chiral cel OJ,
hexane:isopropanol=95:5, 1 ml/min, R-isomer: 20.48 min and
S-isomer: 23.68 min).
[1173] Mp 82-86.degree. C.
[1174] [.alpha.].sub.D.sup.23 +42.3 (c 0.86, CHCl.sub.3).
[1175] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.16 (3H, t,
J=7.0 Hz), 1.43 (9H, s), 2.79 (1H, dd, J=7.0, 14.5 Hz), 2.86 (1H,
dd, J=6.0, 14.5 Hz), 3.45 (3H, s), 4.05 (2H, q, J=7.0 Hz),
4.8.5-5.20 (3H, m), 5.43 (0.2H, br s), 5.81 (0.8H, d, J=8.0 Hz),
6.28 (1H, d, J=8.0 Hz), 6.50 (1H, br s), 6.57 (1H, br s), 6.98 (1H,
d, J=8.0 Hz).
(f) Ethyl
(3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methox-
ymethoxy-phenyl)-propionate
[1176] To a solution of ethyl
(3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propi-
onate (2.35 g, 6.36 mmol) synthesized in step (e) of Example 197 in
dimethylformamide (10 ml) were added potassium carbonate (1.80 g,
13.0 mmol) and N,N-dimethylcarbamoyl chloride (0.65 ml, 7.0 mmol)
with stirring, and the resulting mixture was stirred for 3 hours at
room temperature under a nitrogen atmosphere. After stirring, water
(30 ml) was added to the reaction mixture, and the resulting
mixture was extracted with ethyl acetate (40 ml.times.2). The
organic layer was washed with saturated aqueous sodium chloride
solution (40 ml.times.1), dried over anhydrous sodium sulfate,
filtered, and evaporated in vacuo to afford the crude product. The
crude product was purified by chromatography on a silica gel column
using a mixed solvent of hexane and ethyl acetate (2:1-1:2) as the
eluent to afford the title compound (2.73 g, yield: 97%) as a
colorless oil.
[1177] [.alpha.].sub.D.sup.23 +25.3 (c 1.09, CHCl.sub.3).
[1178] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.17 (3H, t,
J=7.0 Hz), 1.41 (9H, s), 2.77-2.89 (2H, m), 2.99 (3H, s), 3.07 (3H,
s), 3.49 (3H, s), 4.01-4.10 (2H, m), 5.24 (2H, dd, J=7.0, 10.0 Hz),
5.30 (1H, br s), 5.74 (1H, br d, J=9.0 Hz), 6.73 (1H, dd, J=2.0,
9.0 Hz), 6.89 (1H, d, J=2.0 Hz), 7.23 (1H, d, J=9.0 Hz).
(g) t-Butyl
[(1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-c-
arbamate
[1179] To a solution of ethyl
(3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy--
phenyl)-propionate (4.68 g, 10.6 mmol) synthesized in step (f) of
Example 197 in tetrahydrofuran (30 ml) was added lithium aluminum
hydride (524 mg, 13.8 mmol) at -50.degree. C. with stirring, and
the resulting mixture was stirred successively for 10 minutes at
-50.degree. C. and for 15 minutes at 0.degree. C. under a nitrogen
atmosphere. After stirring, to the reaction mixture were added
water (0.5 ml), 15% aqueous sodium hydroxide solution (0.5 ml) and
water (1.5 ml) at 0.degree. C. in this order, and the resulting
mixture was dried over anhydrous sodium sulfate, filtered, and
evaporated in vacuo to afford the crude product. The crude product
was purified by chromatography on a silica gel column using a mixed
solvent of hexane and ethyl acetate (2:1-0:1) as the eluent to
afford the title compound (3.48 g, yield: 82%) as a colorless
oil.
[1180] [.alpha.].sub.D.sup.23 +48.0 (c 1.09, CHCl.sub.3).
[1181] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.43 (9H, s),
1.94 (2H, dt, J=4.8, 6.0 Hz), 3.00 (3H, s), 3.08 (3H, s), 3.30 (1H,
br s), 3.49 (3H, s), 3.61-3.74 (2H, m), 5.06 (1H, q, J=5.6 Hz),
5.23 (2H, dd, J=6.4, 10.8 Hz), 5.47 (1H, d, J=9.6 Hz), 6.74 (1H,
dd, J=2.4, 8.8 Hz), 6.90 (1H, d, J=2.4 Hz), 7.19 (1H, d, J=8.8
Hz).
(h) 4-[(1R)-Amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxy-phenyl
dimethylcarbamate
[1182] To a solution of t-butyl
[(1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-c-
arbamate (1.63 g, 4.08 mmol) synthesized in step (g) of Example
197, 4-methylthiophenol (660 mg, 4.50 mmol) and triphenylphosphine
(1.60 g, 6.12 mmol) in tetrahydrofuran (15 ml), was added dropwise
40 wt % solution of diethyl azodicarboxylate in toluene (2.66 g,
6.12 mmol) at 0.degree. C. with stirring, and the resulting mixture
was stirred for 1 hour at room temperature under a nitrogen
atmosphere. After stirring, the reaction mixture was evaporated in
vacuo, and the residue obtained was purified by chromatography on a
silica gel column using a mixed solvent of hexane and ethyl acetate
(2:1-1:2) as the eluent to afford the crude product (2.74 g)
containing hydrazine dicarboxylate. Subsequently, to a solution of
the crude product (2.74 g) in methanol (18 ml) was added
concentrated hydrochloric acid (6 ml), and the resulting mixture
was stirred overnight at room temperature. After stirring, the
reaction mixture was neutralized with 15% aqueous sodium hydroxide
solution and adjusted to pH 10 with saturated aqueous sodium
hydrogen carbonate solution and then extracted with ethyl acetate
(50 ml.times.2). The organic layer was dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to afford the crude
product. The crude product was purified by chromatography on a
silica gel column using a mixed solvent of ethyl acetate and
methanol (1:0-5:1) as the eluent to afford the title compound (1.05
g, yield: 69%) as a colorless oil.
[1183] [.alpha.].sub.D.sup.23 -66.5 (c 0.77, CHCl.sub.3).
[1184] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 2.12-2.18
(1H, m), 2.21-2.28 (1H, m), 2.44 (3H, s), 2.99 (3H, s), 3.07 (3H,
s), 3.89 (1H, dt, J=4.0, 10.0 Hz), 4.00 (1H, dt, =5.0, 10.0 Hz),
4.43 (1H, t, J=7.5 Hz), 6.51 (1H, dd, J=2.5, 8.0 Hz), 6.60 (1H, d,
J=2.5 Hz), 6.82 (2H, d, J=8.5 Hz), 6.86 (1H, d, J=8.0 Hz), 7.25
(2H, d, J=8.5 Hz).
(i) t-Butyl
[(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-p-
ropyl]-carbamate
[1185] To a solution of
4-[(1R)-amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxy-phenyl
dimethylcarbamate (1.05 g, 2.80 mmol) synthesized in step (h) of
Example 197 in methanol (10 ml) were added triethylamine (0.83 ml,
6.0 mmol) and di-t-butyl dicarbonate (650 mg, 3.00 mmol), and the
resulting mixture was stirred for 1 hour at room temperature under
a nitrogen atmosphere. After stirring, the reaction mixture was
evaporated in vacuo, and the residue obtained was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1-0:1) as the eluent to afford the
title compound (1.34 g, yield: 100%) as a colorless solid.
[1186] [.alpha.].sub.D.sup.23 +14.3 (c 0.52, CHCl.sub.3)
[1187] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.40 (9H, s),
2.26-2.37 (2H, m), 2.44 (3H, s), 3.00 (3H, s), 3.07 (3H, s),
3.89-3.95 (1H, m), 3.98-4.03 (1H, m), 5.00 (1H, dd, J=8.0, 15.2
Hz), 5.25 (1H, br s), 6.63 (1H, dd, J=3.2, 8.0 Hz), 6.66 (1H, d,
J=3.2 Hz), 6.81 (2H, d, J=8.8 Hz), 7.10 (1H, d, J=8.0 Hz), 7.24
(2H, d, J=8.8 Hz).
(j) t-Butyl
[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-pro-
pyl]-carbamate
[1188] To a solution of t-butyl
[(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-p-
ropyl]-carbamate (1.34 g, 2.80 mmol) synthesized in step (i) of
Example 197 in dichloromethane (10 ml) were added pyridine (0.48
ml, 6.0 mmol) and trifluoromethanesulfonic anhydride (0.50 ml, 3.0
mmol) at 0.degree. C. with stirring, and the resulting mixture was
stirred for 1 hour at room temperature under a nitrogen atmosphere.
After stirring, water (20 ml) was added to the reaction mixture,
and the resulting mixture was extracted with dichloromethane (20
ml.times.2). The organic layer was washed successively with 0.5N
hydrochloric acid (20 ml.times.1) and saturated aqueous sodium
chloride solution (20 ml.times.1), dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to afford the crude
triflate derivative (1.48 g).
[1189] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.38 (9H, br
s), 2.17-2.34 (2H, m), 2.44 (3H, s), 3.01 (3H, s), 3.09 (3H, s),
3.97 (2H, t, J=6.0 Hz), 5.13 (1H, dd, J=8.0, 12.5 Hz), 5.44 (1H, br
s), 6.82 (2H, d, J=8.5 Hz), 7.14 (1H, d, J=8.5 Hz), 7.15 (1H, s),
7.25 (2H, d, J=8.5 Hz), 7.43 (1H, d, J=8.5 Hz).
[1190] Subsequently, to a solution of the crude triflate derivative
(1.48 g) obtained above in 1,4-dioxane (20 ml) were added
tetrakis(triphenylphosphine)palladium (647 mg, 0.560 mmol),
2,6-di-t-butylphenol (5 mg), lithium chloride (356 mg, 8.40 mmol)
and tributyl(vinyl)tin (0.88 ml, 3.0 mmol), and the resulting
mixture was stirred for 3 hours at 100.degree. C. under a nitrogen
atmosphere. Subsequently, saturated aqueous potassium fluoride
solution (10 ml) was added, and the resulting mixture was stirred
for 2 hours at room temperature and then filtered and evaporated in
vacuo. To the residue obtained was added water (40 ml), and the
resulting mixture was extracted with ethyl acetate (50 ml.times.2).
The organic layer was washed successively with 1N hydrochloric acid
(40 ml.times.1) and saturated aqueous sodium chloride solution (40
ml.times.1), dried over anhydrous sodium sulfate, filtered, and
evaporated in vacuo to afford the crude product. The crude product
was purified by chromatography on a silica gel column using a mixed
solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to
afford the title compound (1.08 g, yield: 79%) as a colorless
oil.
[1191] [.alpha.].sub.D.sup.23 -7.7 (c 0.58, CHCl.sub.3)
[1192] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.40 (9H, s),
2.18 (2H, br m), 2.44 (3H, s), 3.01 (3H, s), 3.09 (3H, s),
3.84-3.96 (2H, m), 5.23 (1H, br s), 5.31 (1H, d, J=10.8 Hz), 5.58
(1H, dd, J=1.2, 16.8 Hz), 6.80 (2H, d, J=8.0 Hz), 7.00-7.16 (1H, br
m), 7.02 (1H, dd, J=2.8, 8.8 Hz), 7.19-7.28 (4H, m).
(k) t-Butyl
allyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenox-
y)-propyl]-carbamate
[1193] To a solution of t-butyl
[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-pro-
pyl]-carbamate (1.08 g, 2.22 mmol) synthesized in step (j) of
Example 197 in dimethylformamide (10 ml) was added sodium hydride
(160 mg, 6.66 mmol), being prepared free from mineral oil by
washing with hexane, at 0.degree. C., and the resulting mixture was
stirred for 30 minutes at 0.degree. C. under a nitrogen atmosphere.
Subsequently, allyl bromide (0.57 ml, 6.7 mmol) was added at
0.degree. C., and the resulting mixture was stirred for 2 hours at
room temperature under a nitrogen atmosphere. After stirring, water
(30 ml) was added, and the resulting mixture was extracted with
ethyl acetate (30 ml.times.2). The organic layer was washed
successively with water (30 ml.times.1) and saturated aqueous
sodium chloride solution (30 ml.times.1), dried over anhydrous
sodium sulfate, filtered, and evaporated in vacuo to afford the
crude product. The crude product was purified by chromatography on
a silica gel column using a mixed solvent of hexane and ethyl
acetate (2:1-1:1) as the eluent to afford the title compound (932
mg, yield: 80%) as a colorless oil.
[1194] [.alpha.].sub.D.sup.23 +76.1 (c 0.63, CHCl.sub.3).
[1195] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.43 (9H, s),
2.29-2.42 (1H, br m), 2.40-2.52 (1H, br m), 2.43 (3H, s), 3.02 (3H,
s), 3.11 (3H, s), 3.47 (2H, br s), 3.97 (1H, dt, J=6.0, 8.0 Hz),
4.06 (1H, br q, J=8.0 Hz), 4.82 (1H, d, J=17.0 Hz), 4.84 (1H, d,
J=9.5 Hz), 5.28 (1H, d, J=10.5 Hz), 5.48 (1H, br s), 5.58 (1H, d,
J=16.5 Hz), 5.67 (1H, br s), 6.82 (2H, d, J=8.5 Hz), 7.02 (1H, dd,
J=10.5, 16.5 Hz), 7.04-7.06 (1H, m), 7.24-7.26 (3H, m), 7.34 (1H,
d, J=7.5 Hz).
(l) t-Butyl
7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1,3-dihydro-b-
enzo[c]azepine-2-carboxylate
[1196] To a solution of t-butyl
allyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenox-
y)-propyl]-carbamate (907 mg, 1.72 mmol) synthesized in step (k) of
Example 197 in dichlorometane (100 ml) was added
tricyclohexylphosphine
[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]
[benzylidene] ruthenium(IV) dichloride (146 mg, 0.172 mmol), and
the resulting mixture was stirred for 3 hours at 45.degree. C.
under a nitrogen atmosphere. After stirring, the reaction mixture
was evaporated in vacuo, and the residue was purified by
chromatography on a silica gel column using a mixed solvent of
hexane and ethyl acetate (2:1-1:1) as the eluent to afford the
title compound (796 mg, yield: 93%) as a colorless oil.
[1197] [.alpha.].sub.D.sup.23 -43.8 (c 0.71, CHCl.sub.3).
[1198] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm: 1.29 (6H, s),
1.38 (3H, s), 2.27 (1H, br s), 2.36 (1H, br s), 2.44 (3H, s), 3.00
(3H, s), 3.09 (3H, s), 3.77-4.18 (3H, br m), 4.74 (0.34H, d, J=16.0
Hz), 4.99 (0.66H, br s), 5.23 (0.66H, br s), 5.35 (0.34H, br s),
5.78 (0.34H, d, J=11.5 Hz), 5.84 (0.66H, d, J=11.5 Hz), 6.35 (1H,
d, J=11.5 Hz), 6.80 (0.68H, d, J=7.5 Hz), 6.82 (1.32H, d, J=7.5
Hz), 6.88 (1H, br s), 6.96 (1H, s), 7.08 (1H, br s), 7.20-7.26 (2H,
m).
(m)
2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]a-
zepin-7-yl dimethylcarbamate hydrochloride
[1199] The title compound was obtained as an amorphous solid using
t-butyl
7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1,3-dihydro-b-
enzo[c]azepine-2-carboxylate obtained in step (1) of Example 197 by
conducting successively reactions similar to those mentioned in
step (d) of Example 6 and Example 3.
[1200] [.alpha.].sub.D.sup.23-24.2 (c=0.73, CHCl.sub.3)
[1201] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.03-2.15
(1H, m), 2.43 (3H, s), 2.53 (3H, s), 2.64-2.76 (1H, m), 3.02 (3H,
s), 3.10 (3H, s), 3.76-3.79 (2H, m), 3.92 (1H, quintet, J=5.2 Hz),
4.19 (1H, br s), 4.63 (1H, d, J=7.6 Hz), 5.84 (1H, d, J=12.4 Hz),
6.60 (1H, d, J=12.4 Hz), 6.76 (2H, d, J=8.8 Hz), 7.00 (1H, dd,
J=2.0, 8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.15 (1H, d, J=8.0 Hz),
7.21 (2H, d, J=8.8.degree. Hz).
Example 198
2-Methyl-(1S)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepi-
n-7-yl dimethylcarbamate hydrochloride (Exemplification compound
number 4-136)
[1202] The title compound was obtained as an amorphous solid using
(R)-N-benzyl-1-phenylethylamine as the starting material instead of
(S)--N-benzyl-1-phenylethylamine, by conducting successively
reactions similar to those mentioned in Example 197.
[1203] [.alpha.].sub.D.sup.23 +19.9 (c 0.87, CHCl.sub.3)
[1204] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm 2.03-2.15 (1H,
m), 2.43 (3H, s), 2.53 (3H, s), 2.64-2.76 (1H, m), 3.02 (3H, s),
3.10 (3H, s), 3.76-3.79 (2H, m), 3.92 (1H, quintet, J=5.2 Hz), 4.19
(1H, br s), 4.63 (1H, d, J=7.6 Hz), 5.84 (1H, d, J=12.4 Hz), 6.60
(1H, d, J=12.4 Hz), 6.76 (2H, d, J=8.8 Hz), 7.00 (1H, dd, J=2.0,
8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.15 (1H, d, J=8.0 Hz), 7.21 (2H,
d, J=8.8 Hz).
Example 199
2-Methyl-(1S)-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-y-
l dimethylcarbamate hydrochloride (Exemplification compound number
4-132)
[1205] The title compound was obtained as an amorphous solid using
4-nitrophenol as the starting material instead of
4-methylthiophenol by conducting successively reactions similar to
those mentioned in Example 197.
[1206] [.alpha.].sub.D.sup.23 +30.9 (c 0.67, CHCl.sub.3)
[1207] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.12-2.21
(1H, m), 2.60 (3H, s), 2.85-2.93 (1H, m), 3.02 (3H, s), 3.10 (3H,
s), 3.81 (1H, dd, J=4.4, 19.6 Hz), 3.85-3.90 (1H, m), 4.06 (1H, dt,
J=5.2, 9.6 Hz), 4.39 (1H, d, J=19.6 Hz), 4.77 (1H, d, J=11.6 Hz),
5.85 (1H, ddd, J=3.2, 4.4, 12.4 Hz), 6.36 (1H, d, J=12.4 Hz), 6.86
(2H, d, J=8.8 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.14 (1H, d, J=8.8
Hz), 7.21 (1H, d, J=2.4 Hz), 8.16 (2H, d, J=8.8 Hz)
Example 200
2-Methyl-(1S)-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-y-
l dimethylcarbamate hydrochloride (Exemplification compound number
4-132)
[1208] The title compound was obtained as an amorphous solid using
4-nitrophenol as the starting material instead of
4-methylthiophenol by conducting successively reactions similar to
those mentioned in Example 198.
[1209] [.alpha.].sub.D.sup.23-25.0 (c 0.70, CHCl.sub.3).
[1210] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.12-2.21
(1H, m), 2.60 (3H, s), 2.85-2.93 (1H, m), 3.02 (3H, s), 3.10 (3H,
s), 3.81 (1H, dd, J=4.4, 19.6 Hz), 3.85-3.90 (1H, m), 4.06 (1H, dt,
J=5.2, 9.6 Hz), 4.39 (1H, d, J=19.6 Hz), 4.77 (1H, d, J=11.6 Hz),
5.85 (1H, ddd, J=3.2, 4.4, 12.4 Hz), 6.36 (1H, d, J=12.4 Hz), 6.86
(2H, d, J=8.8 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.14 (1H, d, J=8.8
Hz), 7.21 (1H, d, J=2.4 Hz), 8.16 (2H, d, J=8.8 Hz).
Example 201
2-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepi-
n-8-yl dimethylcarbamate hydrochloride (Exemplification compound
number 5-160)
(a) t-Butyl
8-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-ca-
rboxylate
[1211] The title compound was obtained as an amorphous solid using
2,5-dihydroxybenzaldehyde as the starting material by conducting
successively reactions similar to those mentioned in steps (a)-(l)
of Example 192.
[1212] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.29 (9H, s),
1.90-1.98 (1H, m), 2.13-2.14 (1H, m), 2.99 (3H, s), 3.12 (3H, s),
3.48-3.56 (2H, m), 3.90-4.04 (1H, m), 4.74-4.83 (1H, m), 5.11-5.19
(1H, m), 5.80 (1H, d, J=12.0 Hz), 6.43 (1H, d, J=12.0 Hz),
6.96-7.01 (2H, m), 7.24 (1H, d, J=8.9 Hz).
(b)
2-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]a-
zepin-8-yl dimethylcarbamate hydrochloride
[1213] The title compound was obtained as an amorphous solid using
t-butyl
8-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-ca-
rboxylate obtained in step (a) of Example 201 and
4-chloro-3-methylphenol by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48 and
Example 3.
[1214] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. ppm: 2.19-2.27
(1H, m), 2.31 (3H, s), 2.47-2.56 (1H, m), 2.89 (3H, s), 2.95 (3H,
s), 3.02 (3H, s), 3.66-3.72 (1H, m), 4.01-4.12 (2H, m), 4.25-4.29
(1H, m), 4.80-4.84 (1H, m), 5.82-5.87 (1H, m), 6.70 (1H, dd, J=2.9,
8.7 Hz), 6.78 (1H, d, J=12.7 Hz), 6.82 (1H, d, J=2.9 Hz), 7.02 (1H,
d, J=2.4 Hz), 7.20-7.22 (2H, m), 7.47 (1H, d, J=8.4 Hz).
[1215] MS (FAB) m/z: 415 (M+H).sup.+.
Example 202
2-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepi-
n-6-yl dimethylcarbamate hydrochloride (Exemplification compound
number 5-300)
(a) t-Butyl
6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-ca-
rboxylate
[1216] The title compound was obtained as an amorphous solid using
2,3-dihydroxybenzaldehyde as the starting material by conducting
successively reactions similar to those mentioned in steps (a)-(1)
of Example 192.
[1217] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 1.31 (5.4H,
s), 1.42 (3.2H, s), 1.88-2.28 (2H, m), 3.02 (3H, s), 3.13 (3H, s),
3.59 (1H, br s), 3.66 (1H, br s), 3.85-4.05 (0.4H, br), 3.98 (0.6H,
d, J=15.6 Hz), 4.41 (0.6H, d, J=15.6 Hz), 4.60-5.00 (0.4H, br),
5.00-5.20 (0.4H, br), 5.35 (0.6H, br t, J=7.2 Hz), 5.86-5.91 (1H,
m), 6.56 (0.6H, d, J=12.4 Hz), 6.64 (0.4H, d, J=12.4 Hz), 6.99-7.26
(3H, m)
(b)
2-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]a-
zepin-6-yl dimethylcarbamate hydrochloride
[1218] The title compound was obtained as an amorphous solid using
t-butyl
6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-ca-
rboxylate obtained in step (a) of Example 201 and
4-chloro-3-methylphenol by conducting successively reactions
similar to those mentioned in steps (a) and (b) of Example 48 and
Example 3.
[1219] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm: 2.14-2.21
(1H, m), 2.30 (3H, s), 2.64 (3H, d, J=4.8 Hz), 2.78-2.89 (1H, m),
3.04 (3H, s), 3.18 (3H, s), 3.65 (1H, dt, J=4.4, 9.6 Hz), 3.78 (1H,
d, J=19.2 Hz), 3.89 (1H, dt, J=5.2, 10.4 Hz), 4.34 (1H, dd, J=3.6,
19.2 Hz), 4.79 (1H, dt, J=3.6, 11.2 Hz), 5.91 (1H, dt, J=3.6, 12.4
Hz), 6.52 (1H, dd, J=2.8, 8.8 Hz), 6.67 (1H, d, J=2.8 Hz), 6.88
(1H, d, J=12.4 Hz), 7.04 (1H, d, J=7.2 Hz), 7.15-7.32 (3H, m).
[1220] MS (FAB) m/z: 415 (M+H).sup.+.
Example 203
3-[3-(4-Chloro-3-nitrophenoxy)-1-methylaminopropyl]phenyl
dimethylcarbamate hydrochloride (Exemplification compound number
2-116)
[1221] The title compound was obtained using t-butyl
N-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate
obtained in step (e) of Example 7 and 4-chloro-3-nitrophenol by
conducting successively reactions similar to those mentioned in
steps (a) and (b) of Example 48.
[1222] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.46 (2H, m),
7.38 (1H, d, J=9.2), 7.30 (2H, d, J=2.8), 7.19 (1H, td, J=7.2,
2.0), 6.99 (1H, dd, J=9.2, 2.4), 4.30 (1H, dd, J=10.4, 4.8), 4.06
(1H, m), 3.73 (1H, td, J=10.9, 4.4), 3.09 (s, 3H), 3.03 (m, 1H),
2.98 (s, 3H), 2.63 (1H, m), 2.53 (3H, m)
[1223] ms (FAB) m/z: 408 (M+H).sup.+.
Test Example
Test Example 1
In Vitro Study
Test Example 1a
Acetylcholinesterase Inhibitory Activity Test
[1224] Whole brains of mice were used as a source of
acetylcholinesterase. Acetylcholinesterase activity was determined
according to a previously described method (Biochem Pharmacol 7:
88, 1961). Briefly, 10 .mu.l of dimethylsulfoxide (DMSO)-dissolved
test substance was added to 3 ml of phosphate buffer solution
containing the brain homogenate [2990 .mu.l of 100 mM phosphate
buffer solution (100 mM of Na.sub.2HPO.sub.4 and 100 mM of
NaH.sub.2PO.sub.4, pH=7.4)+10 .mu.l of brain homogenate] and
preincubated for 10 min at room temperature. Then 50 .mu.l of
dithiobisnitrobenzoate (DTNB) solution (395 mg of DTNB and 150.5 mg
of NaHCO.sub.3 dissolved in 100 ml of 100 mM phosphate buffer
solution) was added to the solution which was again preincubated
for 20 min at room temperature. Fifty microliters of
acetylthiocholine iodide (ATC) solution (8.676 mg of ATC dissolved
in 1 ml of distilled water) were added to the solution to initiate
the response. Immediately and 8 min after the response was started,
absorbance (412 nm) was determined and the inhibition rate (%)
caused by the test substance was calculated. Furthermore, the
concentration of the test substance needed to inhibit
acetylcholinesterase activity by 50% (IC.sub.50) was
calculated.
Test Example 1b
Serotonin Re-Uptake Inhibitory Activity
[1225] Serotonin re-uptake inhibitory activity was determined using
synaptosome prepared from rat whole brains except the cerebellums.
Briefly, 10 .mu.l of DMSO solution-dissolved test substance
(control group; DMSO solution alone) was added to 1 ml of
synaptosome and incubated for 5 min at 37.degree. C. (in the
control, DMSO alone was added to the synaptosome and incubated at
4.degree. C.). Furthermore, 10 .mu.l of [.sup.3H]5-HT solution
(final concentration: 10 .mu.M as a total concentration of 5-HT,
100 nM as [.sup.3H]15-HT) was added and incubated for 5 min at
37.degree. C. Then 4 ml of ice-cold saline was added to stop the
response. The response solution was filtered, 4 ml of saline was
added, and the solution was once again filtered. Furthermore, 5 ml
of Pico-Fluor was added, then .sup.3H levels on filter papers were
counted by a liquid scintillation counter. Concentrations of test
compounds to inhibit serotonin re-uptake by 50% (IC.sub.50) were
calculated.
[1226] The results are summarized in Table 6.
TABLE-US-00006 TABLE 6 IC.sub.50 (nM) Acetylcholinesterase
Serotonin re-uptake Test Compound No. inhibitory activity
inhibitory activity Test Compound 16 210 493 Test Compound 30 790
594 Test Compound 31 440 323 Test Compound 38 175 199 Test Compound
41 79 507 Test Compound 54 670 166 Test Compound 55 280 60 Test
Compound 61 230 182 Test Compound 62 270 343 Test Compound 68 580
145 Test Compound 70 90 86 Test Compound 76 300 124 Test Compound
81 320 228 Test Compound 82 83 377 Test Compound 89 87 319 Test
Compound 95 52 221 Test Compound 102 170 167 Test Compound 104 53
176 Test Compound 124 64 110 Test Compound 125 19 841 Test Compound
127 40 856 Test Compound 128 15 70 Test Compound 129 64 650 Test
Compound 130 42 88 Test Compound 131 57 129 Test Compound 136 980
236 Test Compound 152 310 67 Test Compound 162 790 594 Test
Compound 174 93 85 Test Compound 175 291 380 Test Compound 176 88
56 Test Compound 177 201 120 Test Compound 179 372 86 Test Compound
180 111 104 Test Compound 181 198 44 Test Compound 182 50 44 Test
Compound 183 26 67 Test Compound 184 56 49 Test Compound 185 156
170 Test Compound 186 106 62 Test Compound 187 11 940 Test Compound
188 53 150 Test Compound 189 6 300 Test Compound 190 12 460 Test
Compound 191 265 520 Test Compound 192 66 63 Test Compound 193 24
680 Test Compound 194 103 61 Test Compound 195 50 44 Test Compound
196 48 18 Test Compound 197 19 6 Test Compound 199 14 6 Test
Compound 200 609 930 Test Compound 202 146 900 Test Compound 203 49
40
[1227] As clearly shown in Table 4, the tested compounds of the
present invention exert remarkable inhibitory activities toward
both acetylcholinesterase activity and serotonin re-uptake
activity. Thus the compounds of the present invention are useful as
safe and effective remedies.
Test Example 2
Ex Vivo Activity Test
Test Example 2a
Acetylcholinesterase Inhibiting Activity
[1228] Sixty min after oral administration of the test compound to
a mouse, the whole brain except the cerebellum was removed. The
removed brain was homogenized in phosphate buffer solution (pH:
8.0) with the volume of buffer corresponding to 1.6 times the brain
tissue weight. The homogenised solution (100 .mu.L) was mixed with
acetylthiocholine solution (60 mM, 10 .mu.L) and incubated for 60
sec at 26.degree. C. After centrifugation at 10,000 rpm for 10 min,
the supernatant (10 .mu.L) was mixed with dithionitrobenzoic acid
solution (10 mM, 200 .mu.L) and left for 20 min at room temperature
for the color to develop. Then the absorbance (415 nm) was
determined with a microplate-reader. Relative inhibitory activity
(%) of the test compound against the production level of
thiocholine in the brain homogenate of the control group (100%), in
which the test compound was not administered, was calculated.
Test example 2b
Serotonin Transporter Binding Inhibition Test
[1229] Sixty min after oral administration of the test compound to
a mouse, the whole brain except the cerebellum was removed. The
removed brain was homogenized in 50 mM Tris HCl buffer solution
(pH: 7.7) with the volume of buffer corresponding to 3 times the
brain tissue weight. The homogenised solution (250 .mu.L) was mixed
with [.sup.3H]citalopram (NEN Life Science Products: final
concentration 0.77 nM) (1) in the presence of fluvoxamine
(final-concentration: 1 mM) or (2) in the absence of fluvoxamine,
and incubated for 60 sec at 25.degree. C. After Tris HCl buffer
solution (2.5 ml) was added, the solution was centrifuged at 3,000
rpm for 6 min. The sediment was recovered. After this process was
repeated twice, the sediment was suspended in 1 mL of the buffer
solution and Pico-Fluor-40 (4 mL) added. Then the radioactivity was
determined with a liquid scintillation counter (ALOKA, LSC-3500).
Serotonin transporter protein binding level was calculated by
subtraction of the radioactivity in the presence of citalopram (2)
from that in the absence of citalopram (1).
[1230] Compounds of the present invention showed potent inhibitory
activities against both acetylcholinesterase activity and serotonin
transporter protein binding in the brains of mice following oral
administration. Thus compounds of the present invention are useful
as safe and effective remedies.
(Formulation Example)
[1231] (Formulation example 1) Hard Capsules Each capsule is
manufactured by addition of 100 mg of powder of test compound 1,
100 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium
stearate into a hard gelatin capsule. After washing, the capsule is
dried.
Formulation example 2
Soft Capsules
[1232] Test compound 2 is added into a digestible oily substance,
for example soybean oil, cottonseed oil, or olive oil, and well
mixed. The mixture is placed into a gelatin capsule with a plunger
pump and a soft capsule containing 100 mg of active compound
obtained. After washing, the soft capsule is dried.
Formulation Example 3
Tablets
[1233] According to conventional methods, the tablet is
manufactured using 100 mg of test compound 3, 0.2 mg of colloidal
silicon dioxide, 5 mg of magnesium stearate, 275 mg of crystalline
cellulose, 11 mg of starch, and 98.8 mg of lactose.
[1234] If desired, the tablet is coated.
Formulation Example 4
Suspension
[1235] A suspension is manufactured containing 100 mg of finely
powdered test compound 4, 10 mg of sodium carboxymethylcellulose, 5
mg of sodium benzoate, 1.0 g of sorbitol solution (Japanese
Pharmacopoeia), and 0.025 ml of vanillin, in 5 ml.
[1236] (Formulation example 5) Cream
[1237] A cream formulation is manufactured by addition of 100 mg of
finely powdered test compound 5 into 5 g of cream containing 40% of
white petrolatum, 3% fine crystallized wax, 10% lanolin, 5% span
20, 0.3% Tween 20, and 41.7% water.
[1238] Compounds of the present invention exert inhibitory
activities towards both acetylcholinesterase activity and selective
serotonin re-uptake, and are useful as preventative and/or
therapeutic agents for Alzheimer's disease, depression,
Huntington's chorea, Pick disease, tardive dyskinesia,
obsessive-compulsive disorder, or panic disorder.
* * * * *