COMPOSES DE PHENYLETHANOLAMINE UTILES EN TANT QUE .BETA.3 AGONISTES, LEURS PROCEDE ET INTERMEDIAIRES DE PRODUCTION

PHENYLETHANOLAMINE COMPOUNDS USEFUL AS .BETA.3 AGONIST, PROCESS FOR PRODUCING THE SAME, AND INTERMEDIATES IN THE PRODUCTION OF THE SAME

Abrégé français

L'invention concerne des composés de phényléthanolamine représentés par la formule générale (I) et leurs sels acceptables sur le plan pharmacologique. Ces composés sont des stimulateurs très puissants et très spécifiques des récepteurs beta 3-adrénergiques. Dans cette formule, R1 représente un hydrogène ou un halogéno; R2 représente un hydrogène, hydroxy, alcoxy inférieur, alcoxy inférieur substitué par un ou deux groupes alcoxycarbonyle inférieur ou carboxy, alcoxy inférieur substitué par un alkylaminocarbonyle inférieur, éventuellement substitués par un alcoxy inférieur, un alcoxy inférieur substitué par un aminocarbonyle cyclique en C4-6, alcoxycarbonyle inférieur ou carboxy; R3 représente un hydrogène, hydroxy, alcoxy inférieur ou alcoxy inférieur substitué par un ou deux groupes alcoxycarbonyle inférieurs ou carboxy, ou R2 et R3 peuvent être liés ensemble pour former un groupe méthylènedioxy substitué par un carboxy ou un alcoxycarbonyle inférieur; m et n représentent chacun 0 ou 1.

Abrégé anglais

Phenylethanolamine compounds represented by general formula (I) and
pharmacologically acceptable salts thereof which have a
potent effect of stimulating .beta.3 adrenaline receptors and a high
selectivity for .beta.3 adrenaline receptors, wherein R1 represents hydrogen
or
halogeno; R2 represents hydrogen, hydroxy, lower alkoxy, lower alkoxy
substituted by one or two lower alkoxycarbonyl or carboxy
groups, lower alkoxy substituted by lower alkylaminocarbonyl optionally
substituted by lower alkoxy, lower alkoxy substituted by cyclic
C4-6 aminocarbonyl, lower alkoxycarbonyl, or carboxy; R3 represents hydrogen,
hydroxy, lower alkoxy, or lower alkoxy substituted by
one or two lower alkoxycarbonyl or carboxy groups, or R2 and R3 may be bonded
to each other to thereby form methylenedioxy
substituted by carboxy or lower alkoxycarbonyl; and m and n are each 0 or 1.

Revendications

CLAIMS
1. A phenylethanolamine compound represented by general
formula [I]:
<IMG>
where R1 represents hydrogen or halogen; R2 represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with
one or two lower alkoxycarbonyl or carboxy groups, lower alkoxy
substituted with lower alkylaminocarbonyl which may be
substituted with lower alkoxy, lower alkoxy substituted with
cyclic aminocarbonyl of 4 to 6 carbon atoms, lower
alkoxycarbonyl or carboxy; R3 represents hydrogen, hydroxy,
lower alkoxy or lower alkoxy substituted with one or two lower
alkoxycarbonyl or carboxy groups; R2 and R3 may be bonded to
each other to form methylenedioxy substituted with carboxy or
lower alkoxycarbonyl; and m and n are 0 or 1 ,
or a pharmacologically acceptable salt thereof.
2. A compound according to claim 1, wherein R1 is a chlorine
atom, R2 represents hydroxy, lower alkoxy, methoxy substituted
with one or two lower alkoxycarbonyl or carboxy groups, methoxy
103

substituted with lower alkylaminocarbonyl which may be
substituted with lower alkoxy, or methoxy substituted with
cyclic aminocarbonyl of 4 to 8 carbon atoms; R3 represents
hydrogen, hydroxy, lower alkoxy or methoxy substituted with
one or two lower alkoxycarbonyl or carboxy groups: R2 and R3
may be bonded to each other to form methylenedioxy substituted
with carboxy or lower alkoxycarbonyl; m is 0 and n is 1.
3. A compound according to claim 2, wherein R1 is a chlorine
atom, R2 is methoxy substituted with carboxy or lower alkoxy
carbonyl, m is 0 and n is 1.
4. A compound wherein the asymmetrical carbon to which the
primary hydroxyl group of the 1-phenyl-2-(3-
phenylcyclohexylamino) ethanol according to claim 2 is
attached has the absolute configuration (R).
5. (1R)-1-(3-chlorophenyl)-2-[(1R),(3R)-3-(3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol, (1R)-
1-(3-chlorophenyl)-2-[(1S),(3S)-3-(3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol, (1R)-
1-(3-chlorophenyl)-2-[(1R),(3R)-3-(3-carboxymethoxyphenyl)
cyclohexylamino]ethanol, (1R)-1-(3-chlorophenyl)-2-
[(1S),(3S)-3-(3-carboxymethoxyphenyl)cyclohexylamino]
ethanol, or a pharmacologically acceptable salt thereof.
6. A process for producing a phenylethanolamine compound
104

represented by general formula [I]:
<IMG>
where R1 represents hydrogen or halogen; R2 represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with
one or two lower alkoxycarbonyl or carboxy groups, lower alkoxy
substituted with lower alkylaminocarbonyl which may be
substituted with lower alkoxy, lower alkoxy substituted with
cyclic aminocarbonyl of 4 to 6 carbon atoms, lower
alkoxycarbonyl or carboxy; R3 represents hydrogen, hydroxy,
lower alkoxy or lower alkoxy substituted with one or two lower
alkoxycarbonyl or carboxy groups: R2 and R3 may be bonded to
each other to form methylenedioxy substituted with carboxy or
lower alkoxycarbonyl; and m and n are 0 or 1 ,
or a pharmacologically acceptable salt thereof, which process
involves reacting a compound of formula [II]
<IMG>
where R1 represents hydrogen or a halogen,
with a compound of formula [III] or its salt,
105

<IMG>
where R2, R3, and n are as defined in claim 1 to produce a
compound of formula [I], or a pharmacologically acceptable
salt thereof.
7. A production process wherein a compound of formula
[IV]
<IMG>
where R1 represents hydrogen or halogen
is reacted with a compound of formula [III'] , or its
salt,
<IMG>
where R4 and R5 each represents hydrogen, hydroxy, or lower
alkoxy; and m and n are 0 or 1, or its salt,
to produce a compound of formula [V],
<IMG>
or its salt,
where R1, m and n are as defined in claim 1, and R4 and R5 each
represents hydrogen, hydroxy, or lower alkoxy, and then reducing
the amide group of the compound of formula [V] to
106

produce a compound of formula [VI]
<IMG>
where R1 represents hydrogen or halogen, and R4 and R5 each
represents hydrogen, hydroxy or lower alkoxy.
8. A production process wherein a compound of formula
[IV]
<IMG>
where R1 represents hydrogen or halogen
is reacted with a compound of formula [III'], or its
salt,
<IMG>
where R4 and R5 each represents hydrogen, hydroxy, or lower
alkoxy; and m and n are 0 or 1,
to produce a compound of formula [V],
<IMG>
or its salt,
where R1, m and n are as defined in claim 1, and R4 and R5
each represents hydrogen, hydroxy, or lower alkoxy.
107

9. A production process which comprises reducing the
amine group of formula [V]
<IMG>
or its salt,
where R1, m, and n have the same definition as in claim 7, and
R4 and R5 each represents hydrogen, hydroxy, or lower alkoxy to
produce a compound of formula [VI]
<IMG>
where R1, m, and n are as defined in claim 1, and R4,and R5
each represents hydrogen, hydroxy, or lower alkoxy, or a
pharmacologically acceptable salt thereof.
10. A production process wherein the amino group of a
compound of formula [VII] is protected with a suitable
protecting group,
<IMG>
where R1 represents hydrogen or a halogen; R6 represents
hydrogen or hydroxy; and m and n are 0 or 1, to make a
compound of formula [VIII]
<IMG>
108

where R1 is a hydrogen or a halogen, R6 is a hydrogen or
hydroxy, m and n are 0 or 1;
and P represents a temporary N-protecting group,
and then reacting it with a compound of formula [IX] or
formula [IX'],
<IMG>
where R7 represents lower alkyl substituted with one or two
lower alkoxycarbonyl groups; R8 represents lower alkoxy
carbonyl; X represents an acid residue, and
subsequently removing the N-protecting group to produce
a compound of formula [X]
<IMG>
where R1, m, and n are as defined in claim 1;
R9 represents lower alkoxy substituted with one or two
lower alkoxycarbonyl groups; R10 represents hydrogen or
lower alkoxy substituted with one or two lower
alkoxycarbonyl groups; R9 and R10 may be bonded to each
other to form methylenedioxy substituted with lower
alkoxycarbonyl, and X represents an acid residue,
or a pharmacologically acceptable salt thereof.
109

11. A production process which comprises subjecting a
compound of formula [X]
<IMG>
where R1 represents hydrogen or halogen; R9 represents
lower alkoxy substituted with one or two lower alkoxy
carbonyl groups; R10 represents hydrogen or lower alkoxy
substituted with one or two lower alkoxy carbonyl groups;
R9 and R10 may be bonded to each other to form
methylenedioxy substituted with lower alkoxycarbonyl, and
m and n are 0 or 1, or its salt,
to de-esterification reaction to produce a compound
of formula [XI]
<IMG>
where R1, m and n are as defined in claim 1; R11 represents
lower alkoxy substituted with one or two carboxy groups; R12
represents hydrogen or lower alkoxy substituted with one or
two carboxy groups, and R11 and R12 may be bonded to each other
to form methylenedioxy substituted with carboxy, or a
pharmacologically acceptable salt thereof.
12. A production process wherein a compound of formula
[X]
<IMG>
110

where R1 represents hydrogen or halogen, R9 represents
lower alkoxy substituted with one or two lower alkoxy
carbonyl groups; R10 represents hydrogen, and m and n are 0
or 1, or its salts, or formula [XI]
<IMG>
where R1 represents hydrogen or halogen, m and n are 0 or
1, R11 represents lower alkoxy substituted with one or two
carboxy groups, and R12 represents hydrogen, or its salts,
with a lower alkyl amine which may be substituted with
lower alkoxy, or a cyclic amine of 4 to 6 carbon atoms,
to produce a compound of formula [XII]
<IMG>
where R1 represents hydrogen or halogen, m and n are 0 or
1, R13 represents lower alkoxy substituted with a lower
alkylaminocarbonyl group which may be substituted with
one or two lower alkoxy groups or lower alkoxy
substituted with a cyclic aminocarbonyl group of 4 to 6
carbon atoms, and R14 represents hydrogen, or a
pharmacologically acceptable salt thereof.
13. A production process wherein a compound of formula
[XV]
<IMG>
111

where R1 represents hydrogen or halogen; R2 represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted
with one or two lower alkoxy carbonyl or carboxy groups,
lower alkoxy substituted with lower alkyl amino carbonyl
which may be substituted with lower alkoxy, lower alkoxy
substituted with cyclic amino carbonyl of 4 to 6
carbon atoms, lower alkoxy carbonyl or carboxy; R3
represents hydrogen, hydroxy, lower alkoxy,
or lower alkoxy substituted with one or two lower alkoxy
carbonyl or carboxy groups; R2 and R3 may be bonded with
each other to form methylene dioxy sustituted with
carboxy or lower alkoxy carbonyl; and n is 0 or 1, is
produced from a compound of formula [XIII]
<IMG>
where R1 represents hydrogen or halogen,
and a compound of formula [XIV]
<IMG>
where R2 represents hydrogen, hydroxy, lower alkoxy, lower
alkoxy substituted with one or two lower alkoxy carbonyl
or carboxy groups, lower alkoxy substituted with lower
alkyl amino carbonyl which may be substituted with lower
alkoxy, lower alkoxy substituted with cyclic amino
carbonyl of 4 to 6 carbon atoms, lower alkoxy carbonyl or
carboxy; R3 represents hydrogen, hydroxy, lower alkoxy,
or lower alkoxy substituted with one or two
lower alkoxy carbonyl or carboxy groups; R2 and R3 may be
bonded with each other to form methylene dioxy sustituted
112

with carboxy or lower alkoxy carbonyl; and n is 0 or 1,
or its salt, and then reducing the resulting imino group
of formula [XV] to produce a compound of formula [I]
<IMG>
wherein R1, R2, R3, and n are as defined in claim 1, and m
is 0, or a pharmacologically acceptable salt thereof.
14. A production process wherein a compound of formula
[XV]
<IMG>
where R1 represents hydrogen or halogen; R2 represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted
with one or two lower alkoxy carbonyl or carboxy groups,
lower alkoxy substituted with lower alkyl amino carbonyl
which may be substituted with lower alkoxy, lower alkoxy
substituted with cyclic amino carbonyl of 4 to 6
carbon atoms, lower alkoxy carbonyl or carboxy; R3
represents hydrogen, hydroxy, lower alkoxy,
or lower alkoxy substituted with one or two lower alkoxy
carbonyl or carboxy groups; R2 and R3 may be bonded with
each other to form methylene dioxy sustituted with
carboxy or lower alkoxy carbonyl; and n is 0 or 1, by
reacting a compound of formula [XIII]
<IMG>
113

where R1 represents hydrogen or halogen,
with a compound of formula [XIV]
<IMG>
where R2 represents hydrogen, hydroxy, lower alkoxy, lower
alkoxy substituted with one or two lower alkoxy carbonyl
or carboxy groups, lower alkoxy substituted with lower
alkyl amino carbonyl which may be substituted with lower
alkoxy, lower alkoxy substituted with cyclic amino
carbonyl of 4 to 6 carbon atoms, lower alkoxy carbonyl or
carboxy; R3 represents hydrogen, hydroxy, lower alkoxy,
or lower alkoxy substituted with one or two
lower alkoxy carbonyl or carboxy groups; R2 and R3 may be
bonded with each other to form methylene dioxy sustituted
with carboxy or lower alkoxy carbonyl; and n is 0 or 1,
or its salt.
15. A production process which comprises producing a
compound of formula [I]
<IMG>
wherein R1, R2, R3, and n are as defined in claim 1, and m
is 0,or a pharmacologically acceptable salt thereof, by
reducing the imino group of the compound of formula [XV]
<IMG>
114

or its salt,
where R2 and R3 and n are as defined in claim 12.
16. A production process wherein a compound of
formula [I]
<IMG>
where R1 represents hydrogen or halogen; R2 represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted
with one or two lower alkoxy carbonyl or carboxy groups,
lower alkoxy substituted with lower alkyl amino carbonyl
which may be substituted with lower alkoxy, lower alkoxy
substituted with cyclic amino carbonyl of 4 to 6
carbon atoms, lower alkoxy carbonyl or carboxy; R3
represents hydrogen, hydroxy, lower alkoxy,
or lower alkoxy substituted with one or two lower alkoxy
carbonyl or carboxy groups; R2 and R3 may be bonded with
each other to form methylene dioxy sustituted with
carboxy or lower alkoxy carbonyl; m is 0; and n is 0 or
1, or a pharmacologically acceptable salt thereof, is
produced from a compound of formula [XIII]
<IMG>
where R1 represents hydrogen or halogen; and a compound of
formula [XIV]
<IMG>
115

wherein R2, R3 and n are as defined in claim 13, by direct
catalytic hydrogen reduction reaction.
17. A production process which comprises subjecting a
compound of formula [XVI]
<IMG>
where R4 and R5 each represents hydrogen, hydroxy or lower
alkoxy; and n is 1,
is subjected to catalytic reduction in the presence of a
compound of formula [XVII]
R15 - NH2
[XVII]
where R15 represents lower alkyl substituted with aryl
and Raney nickel, to predominantly obtain a
compound of formula [XVIII]
<IMG>
where R4 and R5 each represents hydrogen, hydroxy or lower
alkoxy; R15 represents lower alkyl substituted with aryl,
and n is 1, or its salt, having the amino group and phenyl
group in a trans configuration and then subjecting it to
catalytic hydrogen reduction in the presence of a reducing
116

agent to obtain a compound of formula [XIX]
<IMG>
where R4 and R5, each represents hydrogen, hydroxy or
lower alkoxy; and n is 1.
18. A production process which comprises subjecting a
compound of formula [XVI]
<IMG>
where R4 and R5 each represents hydrogen, hydroxy or lower
alkoxy; and n is 1,
is subjected to catalytic reduction in the presence of a
compound of formula [XVII]
R15 - NH2
[XVII]
where R15 represents lower alkyl substituted with aryl
and Raney nickel, to predominantly obtain a
compound of formula [XVIII]
<IMG>
117

where R4 and R5 each represents hydrogen, hydroxy or lower
alkoxy; R15 represents lower alkyl substituted with aryl,
and n is 1, or its salt, having the amino group and phenyl
group in a trans configuration.
19. A production process which comprises subjecting the
compound of formula [XVIII]
<IMG>
to a catalytic hydrogen reduction in the presence of a
reducing agent to obtain a compound of formula [XIX]
<IMG>
where R4, R5 and n each represents hydrogen, hydroxy or
lower alkoxy; and n is 1;
or its salt.
20. A compound of formula [V]
<IMG>
118

where R1 represents hydrogen or halogen; R4 and R5 each
represents hydrogen, hydroxy, or lower alkoxy; and m and
n are 0 or 1.
21. A compound of formula [VIII]
<IMG>
where R1 represents hydrogen or halogen; R6 represents
hydrogen or hydroxy; P represents an N-protecting group;
and m and n are 0 or 1.
22. A compound of formula [XV]
<IMG>
where R1 represents hydrogen or halogen; R2 represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted
with one or two lower alkoxy carbonyl or carboxy groups,
lower alkoxy substituted with lower alkyl amino carbonyl
which may be substituted with lower alkoxy, lower alkoxy
substituted with cyclic amino carbonyl of 4 to 6
carbon atoms, lower alkoxy carbonyl or carboxy; R3
represents hydrogen, hydroxy, lower alkoxy or lower
alkoxy substituted with one or two lower alkoxy carbonyl
or carboxy groups; R2 and R3 may be bonded with each other
to form methylene dioxy sustituted with carboxy or lower
alkoxy carbonyl; and n is 0 or 1.
119

23. A compound of formula [XVIII]
<IMG>
where R4 and R5 each represents hydrogen, halogen, or
lower alkoxy; R15 represents lower alkyl substituted aryl;
and n is 1, or its salt.
24. A compound of formula [XIX]
<IMG>
where R4 and R5 each represents hydrogen, halogen, or
lower alkoxy; and n is 1, or its salt.
25. A pharmaceutical composition containing a compound
according to claim 1 as active component, together
With an innocuous carrier or excipient.
26. Use of a compound according to claim 1 for the
treatment and/or prevention of accelerated or spasmodic
gastrointestinal motility in a human or animal.
27. Use of a compound according to claim 1 in the
manufacture of a medicament for the treatment and/or
prevention of accelerated or spasmodic gastrointestinal
motility.
28. Use of a compound according to claim 1 for the
treatment and/or prevention of pollakisuria in a human or
animal.
120

29. Use of a compound according to claim 1 in the
manufacture of a medicament for the treatment and/or
prevention of pollakisuria in a human or animal.
30. Use of a compound according to claim 1 for treating
and/or preventing urinary incontinence in a human or
animal.
31. Use of a compound according to claim 1 in the
manufacture of a medicament for treating and/or
preventing urinary incontinence in a human or animal.
32. Use of a compound according to claim 1 for the
treatment and/or prevention of obesity and diabetes in a
human or animal.
33. Use of a compound according to claim 1 in the
manufacture of a medicament for the treatment and/or
prevention of obesity and diabetes in a human or animal.
121

Description

CA 02235840 1998-04-24
Specifications
PHENYLETHANOLAMINE COMPOUNDS USEFUL AS /3 3 AGONISTS,
PROCESS FOR PRODUCING THE SAME,
AND INTERMEDIATES IN THE PRODUCTION OF THE SAME
Technical Field of the Invention
The present invention relates to novel phenylethanolamine
compounds with a S 3 adrenergic receptor stimulating effect
which are useful as drugs, and to their pharmacologically
acceptable salts.
Prior Art
Sympathetic nerve /3 receptors include the subtypes (3 1, (3
2 and (3 3, among which it is believed that the S 1 receptors
are present mainly in the heart, and the ~ 2 receptors are
present in the trachea, uterus, bladder and vascular smooth
muscle. Also, the /3 3 receptors are believed to be present on
the cell surfaces of brown adipocytes and white adipocytes and
in the enteric canal (Land, A.M. et al.: Nature, 214, 597-
598 (1967). Emorine, L.J. et al.: Science, 245, 1118-1121
(1989) ) .
Current clinical applications of (3 1 adrenergic receptor
agonists include their use as cardiac function promoters or
1

CA 02235840 1998-04-24
vasopressors, and those of Q 2 adrenergic receptor agonists
include their use as bronchial dilators, prophylactics against
impending premature birth, or therapies for urinary
incontinence. In addition, (3 3 adrenergic receptor agonists
have been reported useful as antiobestic and antidiabetic drugs
because they promote fat decomposition and energy consumption,
and as therapies for accelerated gastorointenstional motility
because they suppress it (J. Med. Chem. 35, 3081-3084 (1992) .
Br. J. Pharmacol. 100, 831-839 (1990)).
Drugs which are known to act selectively on (3 3 adrenergic
receptors include 2-amino-1-phenylethanol compounds, such as
BRL35135 [ (R*R* ) - ( ~ ) - [ 4- [2- [2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]propyl]phenoxy]acetic acid methyl ester
hydrobromide salt: Japanese Patent Publication No. 26744 of
1988 and European Patent Publication No. 23385], and SR58611A
[(RS)-N-(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-
2-yl)-2-(3-chlorophenyl)-2-hydroxyethanamine
hydrochloride: Japanese Laid-open Patent Publication No.
66152 of 1989 and European Laid-open Patent Publication No.
255415].
It has been reported that BRL35135 has a lypolytic and
hypoglycemic effect while SR58611A has a potent suppressing
effect on spontaneous locomotion of rat colon (Drugs of the
2

CA 02235840 2004-08-09
Future, 28, 529-549 (1993)).
The ~ 2 adrenergic receptor agonist clenbuterol
hydrochloride acts directly on bladder detrusor muscle S 2
receptors, having a relaxing effect on the bladder detrusor
muscle (The autonomic nervous system, ~, 380-38'~ (1989) ) , and
therefore finds clinical use as a therapy for urinary
incontinence. However, there axe problems associated with
this treatment for urinary incontinence, because of side-
effects including finger tremor and palpitation.
It is an object of the present invention to provide novel
phenylethanolamine compounds and their pharmacologically
acceptable salts, which have a strong S 3 adrenergic
stimulating effect and high S 3 receptor selectivity, andwhich
can be used as prophylactics and/or treatments for accelerated
or spasmodic gastrointestinal motility; as well as obesity and
diabetes, and pollakisuria,urinary incontinence and other
forms of dysuria.
It is another obj ect of the invention to provide a process
for producing such phenylethanolamine compounds and their
pharmacologically acceptable salts.
It is a further object of the invention to provide
pharmaceutical compositions containing such
phenylethanolamine compounds and their pharmacologically
3

CA 02235840 1998-04-24
acceptable salts as active components thereof.
The present inventors have carried out diligent research
aimed at discovering compounds which differ in chemical
structure from the widely known S 3 adrenergic agonists and
which have a potent ~ 3-selective a 3 adrenergic receptor
stimulating effect. As a result it was found that newly
synthesized novel phenylethanolamine compounds satisfy these
conditions . It was further found that these compounds of the
invention have a potent relaxing effect on rat bladder detrusor
muscle, and the present invention was thus completed.
Disclosure of the Invention
The phenylethanolamine compounds of the invention are
represented by general formula [I):
OH
CH -CH2-NH -(CHZ)m
~n
Rf C t J
(where R1 represents hydrogen or halogen; RZ represents
hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with
one or two lower alkoxycarbonyl or carboxy groups, lower alkoxy
substituted with lower alkylaminocarbonyl which may be
4

CA 02235840 1998-04-24
substituted with lower alkoxy, lower alkoxy substituted with
cyclic aminocarbonyl of 4 to 6 carbon atoms, lower
alkoxycarbonyl or carboxy; R3 represents hydrogen, hydroxy,
lower alkoxy or lower alkoxy substituted with one or two lower
alkoxycarbonyl or carboxy groups: R2 and R3 may be bonded to
each other to form methylenedioxy substituted with carboxy or
lower alkoxycarbonyl; and m and n are 0 or 1.)
In general formula [I) above, R1 is preferably a halogen,
such as fluorine, bromine, chlorine or iodine, and is most
preferably chlorine. Rz is preferably lower alkoxy
substituted with one or two lower alkoxycarbonyl or carboxy
groups, lower alkoxy substituted with a lower
alkylaminocarbonyl group which may be substituted with lower
alkoxy, or lower alkoxy substituted with a cyclic aminocarbonyl
group of 4 to 6 carbon atoms, but it is most preferably methoxy
substituted with one or two lower alkoxycarbonyl groups. As
lower alkoxy groups for lower alkoxycarbonyl there may be
mentioned methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy
and tert-butoxy, among which are preferred methoxy and ethoxy,
especially ethoxy. R3 is preferably hydrogen, and 1-
phenyl-2-(3-phenylcyclohexylamino) ethanol compounds wherein
m is 0 and n is 1 are particularly preferred.
Also, particularly preferred are compounds wherein the

CA 02235840 1998-04-24
asymmetrical carbon atom to which the hydroxyl group is
attached in the phenylethanolamine compound represented by
general formula [I] has an absolute configuration (R) rather
than compounds wherein it has an absolute configuration (S).
As mentioned above, the compounds of the invention represented
by general formula [I] also include their pharmacologically
acceptable salts. Because the compounds of the invention [I]
have 3 asymmetrical carbon atoms, they exist as 8 optical
isomers. Mixtures of any two to all eight isomers in any
proportion, as well as optically pure isomers, are all within
the scope of the present invention. Furthermore, compounds
wherein the hydroxyl-attached asymmetrical carbon atom has an
absolute configuration (R) are particularly preferred, and in
the case of 3-arylcyclohexylamines, the steric configuration
of the asymmetrical carbon atom is preferably trans (R*R*).
Salts of the compounds of the invention [I] are not
particularly restricted so long as they are pharmacologically
acceptable salts, and examples thereof include salts with
inorganic acids such as hydrochloric acid, nitric acid,
sulfuric acid, hydrobromic acid, hydroiodic acid and
phosphoric acid; salts with organic acids such as acetic acid,
tartaric acid, fumaric acid, malefic acid, malic acid,
methanesulfonic acid, ethanesulfonic acid, camphor-sulfonic
6

CA 02235840 1998-04-24
acid, benzenesulfonic acid and toluenesulfonic acid; and salts
with alkali metal or alkaline earth metal such as sodium,
potassium and calcium. The present invention encompasses the
compounds of the invention [I] as well as their
pharmacologically acceptable salts and hydrates.
As particularly suitable compounds there may be mentioned
the following and their pharmacologically acceptable salts.
(1R) -1- (3-chlorophenyl) -2- [ (1R) , (3R) -3- (3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol,(1R)-
1-(3-chlorophenyl)-2-((1S),(3S)-3-(3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol,(1R)-
1-(3-chlorophenyl)-2-[(1R),(3R)-3-(3-carboxymethoxyphenyl)
cyclohexylamino] ethanol, (1R) -1- (3-chlorophenyl) -2-
[(1S),(3S)-3-(3-carboxymethoxyphenyl)cyclohexylamino]
ethanol.
Brief Description of the Drawings
Fig. 1 is an illustration of the bladder relaxing effect
of test compounds in anesthetized rats, and Fig. 2 is an
illustration of the contraction-suppressing effect of test
compounds against bladder contraction caused by peripheral
electrical stimulation of anesthetized rat pelvic plexus.
7

CA 02235840 1998-04-24
- -~-.~~> >.--..~ ~, . :_a ~_r-r~ z. - ~~_. ° _.: -.-..~ :. x-~-.~----
:: ._~.-~-~~--4- -~ ~_~- _-.n
,v...~~.o.~.:.~.~....~. ,.
Best Mode for Carrying Out the Invention
Compounds of the invention [I] maybe produced, for example,
by the following processes.
Production process (a)
\ ~ R2
+ HZN -(CH2)m R3
)n
OH /1
\ ~ R2
CH-CHZ-NH-(CHz)m " R3
)n
R~
An addition reaction is carried out between a compound of
formula [II] (where R1 represents hydrogen or a halogen) and
a compound of formula [III] (where RZ represents hydrogen,
hydroxy, lower alkoxy, lower alkoxy substituted with one or
two lower alkoxycarbonyl or carboxy groups, lower alkoxy
substituted with lower alkylaminocarbonyl which may be
substituted with lower alkoxy, lower alkoxy substituted with
cyclic aminocarbonyl of 4 to 6 carbon atoms, lower
alkoxycarbonyl or carboxy; R3 represents hydrogen, hydroxy,
8

._..~_T_-_-__-______--~r_ _~_ .__a_.- n____. CA 022.35840 _1998-04-24_~ _ ~~-_-
._~-.~«rrs .~-.r__..
lower alkoxy or lower alkoxy substituted with one or two lower
alkoxycarbonyl or carboxy groups; Rz and R3 may be bonded to
each other to form methylenedioxy substituted with carboxy or
lower alkoxycarbonyl; and m and n are 0 or 1), either in an
appropriate solvent or without a solvent.
The solvent used may be an alcohol such as methanol, ethanol
or isopropyl alcohol; a ketone such as acetone or methyl ethyl
ketone; an ether such as diethyl ether, tetrahydrofuran or
dioxane; a halogenated hydrocarbon such as methylene chloride
or chloroform; an aromatic hydrocarbon such as benzene or
toluene; or ethyl acetate, dimethylsulfoxide (abbreviated as
DMSO) , N,N-dimethylformamide (abbreviated as DMF) , etc., with
no particular restrictions and optionally in mixtures of 2 or
more.
The reaction temperature is normally about 10 to 150°C, but
is preferably about 50 to 100°C. The compounds of formula [III]
can also be used in the form of acid addition salts, which acid
addition salts may be inorganic acid salts such as
hydrochlorides, hydrobromides, etc. or organic acid salts such
as maleates, fumarates, etc. When an acid addition salt is
used, the reaction is carried out in the presence of an alkali
carbonate such as sodium carbonate or potassium carbonate, an
alkali bicarbonate such as~sodium bicarbonate or potassium
9

CA 02235840 1998-04-24
bicarbonate, or an organic base such as triethylamine or
N-methylmorpholine.
In this production process, when the starting compound has
an asymmetrical carbon atom, the steric configuration with
respect to the asymmetrical carbon atom is preserved in the
compound of formula [I]. For example, a compound [II] with
absolute configuration (R) and a compound [III] with (RR) will
give a compound of the invention [I] (RRR) with the same steric
configuration.
The RR form which is the optically active form of compound
[III] can be obtained by optical resolution of the trans
compound which is a mixture of 2 different diastereomers
(mixture of RR and SS), using optically active mandelic acid
or the like.
Production process (b)
.A compound of formula [V] (where R1, m and n have the same
definitions given above, and R9 and RS represent hydrogen,
hydroxy or lower alkoxy) can be produced by reacting a compound
of formula [IV] with a compound of formula [III'] in the
presence of a condensation agent, an organic base and a solvent .

CA 02235840 1998-04-24
.=.-r .:__.. . --,-.__: . __.;. _F-,s:~, r f~~- ,~-.- .-- _~-->.:~ . z---~-
~__:_, ~._~,:_~r. ~v~=~:~-~-..~ _:~~-y -.-..
~. ~r
iH
CH -COOH
+ H2N -(CH2)m Rs
' )n
(IVj
[111'1
.", /1
\ ' R4
Amidation -(CHZ)m - Rs
~~ n
OH
\
Reduction ~"CH2"NH-(CHZ)m
-"---~ ~ ) n
[ vl j.
R~
This reaction is carried out using any of various
condensation agents in the presence of an organic base such
as triethylamine, tributylamine or N-methyl morpholine and
solvent. The condensation agent used may be one such as
dicyclohexylcarbodiimide (hereunder abbreviated as DCC) or
benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium
hexafluorophosphate (hereunder abbreviated as BOP), and the
reaction solvent used may be methylene chloride, ethyl acetate
or the like, with no particular restrictions.
The reaction temperature: is -10 to 70°C, and preferably 20
11

CA 02235840 1998-04-24
to 50°C. In this production process, when the mandelic acid
compound of formula [IVJ, which is an (R) compound, is reacted
with the amino compound of formula [III'], which is a trans
compound (R*R*), the resulting amide compound of formula [V]
is an (RR*R* ) compound, so that the steric configuration with
respect to the asymmetrical carbon atom is preserved. The
(RR*R*) compound represents a mixture of the (RRR) compound
and (RSS~) compound, and each stereoisomer can be isolated and
purified by common methods such as silica gel column
chromatography and recrystallization.
The reaction for reduction of the amide compound of formula
[V] is carried out under reducing conditions for the amide group,
to allow production of a compound of formula [VI] (where Rl,
R9, R5, m and n have the same definitions given above). The
reducing agent used may be lithium aluminum hydride (LiAlHq)
or diborane (B2H6) , and is preferably a borane-dimethylsulfide
complex. The reaction solvent used may be a cyclic ether or
linear ether, with the reaction preferably conducted in the
presence of an aprotic solvent such as anhydrous
tetrahydrofuran or dioxane, without any particular
restrictions.
The reaction is carried out at room temperature (10 to 35°C)
or under reflux.
12

CA 02235840 1998-04-24
Production process (c)
A compound of formula [VI] (where R1, m and n have the same
definitions given above, and RQ and RS represent hydrogen or
methoxy) is treated with a demethylating agent such as boron
tribromide (BBr3) , to produce a compound of formula (VII ] (where
Rl, m and n have the same definitions given above, and R6
represents hydrogen or hydroxy). The reaction solvent used
may be a halogen-based solvent such as methylene chloride or
chloroform. The reaction is preferably conducted at a
temperature of -70 to 30°C, and especially -30 to 20°C.
After preparing a compound of formula [VIII] (where R1, R6,
m and n have the same definitions given above, and P represents
a suitable N-protecting group) by protecting the amino group
of formula [VII] with an appropriate protecting group, it is
reacted with a compound of formula [IX] or formula [IX' ] (where
R-, represents lower alkyl substituted with one or two lower
alkoxycarbonyl groups, Re represents lower alkoxycarbonyl, and
X represents an acid residue) for 0-alkylation of the phenolic
hydroxyl group of formula [VIII], after which deprotection
produces a compound of formula [X] (where R1, m and n have the
same definitions given above, R9 represents lower alkoxy
substituted with one or two lower alkoxycarbonyl groups, Rlo
represents hydrogen or lower alkoxy substituted with one or
13

CA 02235840 1998-04-24
_,..r .r.._.~ ~sii~,~inoona~ .
-~' i~se -~'~' -.-- ,~ ss~rr<r '~ ii~ari~c
two lower alkoxycarbonyl groups, and R9 and Rlo may be bonded
to each other to form methylenedioxy substituted with lower
alkoxycarbonyl).
OH ~ ~ off
CH-CHZ-NH-(CH2)m \ ~R8
)n
[VII]
R' OH P / ~ OH
I I
N-protection CH-CHZ-N -(CH2)m - Rs
-~ ~ ~n
[ Vill j
R~
X- R~ X~ Re
or X Re
tixl tixl
i
OH ~ Ro
CH-CH2-NH-(CH2)m \R~o
~n
[X]
Ri
As suitable N-protecting groups there may be mentioned
tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) and benzyl
or trityl groups which may be substituted with p-methoxy groups,
but there are no particular restrictions. The alkylation is
carried out in the presence of an alkali metal carbonate such
as anhydrous potassium carbonate as the base, for example at
14

CA 02235840 1998-04-24
a temperature in the range of 0 to 120°C. The reaction solvent
used may be acetone, methyl ethyl ketone, DMF or the like, with
no particular restrictions. As suitable acid residues there
may be mentioned halogens, mesyl and arenesulfonyloxy (for
example, benzenesulfonyloxy, tosyloxy, etc.), but halogens
(chlorine, bromine, iodine) are particularly preferred. The
N-protecting group is removed by mild acid hydrolysis, using
any method described in the publicly known literature. In
particular, Boc groups can be easily removed off under acidic
conditions by the action of trifluoroacetic acid or hydrogen
chloride in an organic solvent, to produce compounds of formula
Production process (d)

CA 02235840 1998-04-24
OH / ~ R~
CH-CHZ-NH-(CH2)m Rio
In
R~
/~
OH ~ '~ R»
Hydro 1 ys i s CH-CHZ-NH -(CH2)m R~2
)n
[ xy
R~
/1
OH ~ \ Rt3
Amine CH-CH2-NH-(CHZ)m - R~4
1---~ ~ ) n
[X11)
R~
A compound of formula [X] (where R1, R9, Rlo, m and n have
the same definitions given above) can be hydrolyzed in hydrous
alcohol using sodium hydroxide or potassium hydroxide to
produce a compound of formula [XI] (where R1, m and n have the
same definitions given above, Rll represents lower alkoxy
substituted with one or two carboxy groups, R12 represents
hydrogen or lower alkoxy substituted with one or two carboxy
groups, and Rll and R12 may be bonded to each other to form
methylenedioxy substituted with carboxy).
Also, when a lower alkylainine or cyclic amine of 4 to 6 carbon
16

CA 02235840 1998-04-24
atoms substituted with lower alkoxy is added to a compound of
formula [X] (where Rl, m and n have the same definitions given
above, R9 represents lower alkoxy substituted with one or two
lower alkoxycarbonyl groups, and Rlo represents hydrogen) for
reaction, there may be produced a compound of formula [XII]
(where R1, m and n have the same definitions given above, Rls
represents lower alkoxy substituted with a lower
alkylaminocarbonyl group which may be substituted with one or
two lower alkoxy groups or lower alkoxy substituted with a
cyclic aminocarbonyl group of 4 to 6 carbon atoms, and R1Q
represents hydrogen) in which the ester is converted to an amide.
The reaction may be carried out using chloroform, ethyl acetate,
methylene chloride, DMF or the like, or it may be conducted
in the absence of solvents, with addition of an excess of the
amine. The reaction temperature is not particularly
restricted, and may be room temperature or heating from 40 to
8 0°C .
A compound of formula [XII] can also be produced by reacting
a compound of formula [XI] with an amine in the presence of
any of various condensation agents. DCC or BOP may be used
as the condensation agent and methylene chloride or ethyl
acetate may be used as the reaction solvent, but there are no
particular restrictions. The reaction temperature is -10 to
17

CA 02235840 1998-04-24
70°C, but is preferably 20 to 50°C.
Production process (e)
A compound of formula [ I ] (where R1, R2, R3 and n have the
same definitions given above, and m is 0) may be produced by
first producing a compound of formula [XV] from a compound of
formula [XIII] and a compound of formula [XIV], and then
reacting the product under reducing conditions.
To produce a compound of formula [XV] , a catalytic amount
of p-toluenesulfonic acid is added in an aromatic hydrocarbon
solvent such as benzene or toluene, and the reaction is
conducted using a Dean-Stark like apparatus, while removing
the generated water. The reaction temperature is normally
from about 80 to 130°C.
18

CA 02235840 1998-04-24
IH / J ~
/ CH-CH2 -NH2 + D ' 'R
3
)n [XIV]
[ xnl ]
R1 CH
\~ Rz
CH-CH2-N =
- ~ ~ )n
[XVJ
R1
/1
IH \~ R2
CH-CHZ-NH-(CH~m - R3
-"~ ~ ) n
Ill
R~
The reaction for reduction of the compound of formula [XV]
is carried out under reducing conditions which can reduce the
imine portion. Reducing conditions according to the present
invention means in the presence of a reducing agent which can
reduce the imine portion without affecting the carbonyl group,
or catalytic hydrogen reducing conditions. Examples of
reducing agents which can reduce imine portions include sodium
cyanoborohydride and sodium borohydride. The reaction is
carried out in an appropriate solvent, and the solvent used
may be an alcohol such as methanol, ethanol or isopropyl alcohol .
The reaction temperature is normally about 0 to 100°C, and
19

CA 02235840 1998-04-24
preferably 10 to 30°C.
When this production process is conducted under catalytic
hydrogen reducing conditions, palladium-carbon, Raney nickel,
platinum oxide or the like may be used as the catalyst . The
solvent used may be an alcohol such as methanol, ethanol or
isopropyl alcohol, or acetic acid or a mixed solvent of alcohol
and acetic acid, and the reaction temperature is normally 0
to 100°C, preferably 30 to 60°C. A compound of formula [I] may
also be directly produced by catalytic hydrogen reduction
reaction from a compound of formula [XIII] and a compound of
formula [XIV]. The reducing conditions used for this
production process may be the same as the reduction conditions
described above.
(Production process for intermediate 3-phenylcyclohexylamino
compound)
O RISHN
Raney N1
y
n 'Rs Rya - NHZ n
[ ~1 ~ [ XVII ] [ 7(VIII
HZN
n
XIX ~

CA 02235840 1998-04-24
A compound of formula [XVI] may be subjected to catalytic
hydrogen reduction in the presence of a compound of formula
[XVII] and Raney nickel, to produce a compound of formula
[XVI I I ] (where each RQ and RS in the above formula have the s ame
definitions given previously, R15 represents lower alkyl
substituted with an aryl group, and n is 1 ) or a salt thereof .
This reducing alkylation reaction is carried out in an
alcohol such as methanol, ethanol, isopropyl alcohol or 1-
butanol, with hydrogen addition under normal pressure or
pressurization, and the reaction temperature is normally 0 to
100°C, and preferably 30 to 60°C.
If the reducing alkylation reaction is carried out under
normal pressure or pressurization, it is possible to produce
a compound of formula [XVIII] or its salt in the form of a
trans-cis mixture, but hydrogen addition in the presence of
Raney nickel gives predominantly the trans form.
As lower alkylamines substituted with aryl groups there may
be mentioned diphenylmethylamine, phenylethylamine and
naphthylethylamine, among which optically active
phenylethylamine is preferred.
A compound of formula [XVIII] may be again subjected to
hydrogen addition in the presence of a reducing agent to produce
a compound of formula [XIX] or its pharmacologically acceptable
21

CA 02235840 1998-04-24
._-....-.__.a.,.. ,. r~.-~ .-.~_~-_-~:..: -_-~~.-~A.».a.__._.o-;s.w~~.=_:~~~-~
:_. ...m -~-.-~--.. _~ ._ ~.---~. . __- . ~~ : -,.._. 3 -:-.-_ : :.,_. .
_.._.:
salt. The reducing agent catalyst used may be palladium-
carbon, platinum oxide or the like, with no particular
restrictions.
The solvent used may be an alcohol such as methanol, ethanol
or isopropyl alcohol, or acetic acid or a mixed solvent of
alcohol and acetic acid, and the reaction temperature is
normally 0 to 100°C, preferably 10 to 60°C .
The amine of formula [ II I ] obtained in racemic form can be
easily separated into its optically active forms by forming
diastereomeric salts according to common methods and
techniques, using appropriately selected optically active
acids.
An optical isomer separating column may also be used for
their separation. Even with compounds of formula [I], it is
possible to separate all 8 optical isomers using an optical
isomer separating column.
The characteristic effects of compounds of the invention
will now be explained, referring to pharmacological test
results for the compounds of the invention and known ~3
adrenergic receptor agonists.
[Pharmacological Effects]
[Test 1] ~ 3 adrenergic receptor stimulating effect
Isolated rat colon strips were used to examine the
22

CA 02235840 1998-04-24
~i~"'.:_ - i~ii~i'~''~srirrii~~ ~ -... , . ... ~ si~~i~c
suppressing effect on spontaneous locomotion. Rat colons
(about 3 cm downward from the ileocecum) were removed to prepare
the strips. The strips were mounted in an organ bath filled
with a nutrient medium (Krebs buffer, containing 0.03 mm
ascorbic acid, 0.03 mM EDTA, 10,u M phentolamine) maintained
at 37°C, gassed with 95 o OZ and 5 o C02, and maintained at an
initial tension of 0.5g, the resulting spontaneous locomotion
was recorded. Each test compound was added cumulatively to
the organ bath at intervals of 10 minutes, and the ECSO value
was calculated based on the area under the curve (AUC) for 10
minutes of spontaneous locomotion (Table 1).
(Table 1)Spontaneous locomotion-suppressing effect on isolated rat
colon
Compound (Example No . ) ECSO (nM)
Compound 1 (Example 15) 1.4
Compound 2 (Example 11) 3.7
Compound 3 (Example 45) 3.3
Compound 4 (Example 43) 3.8
Compound 5 (Example 32) 12
Compound 6 ( Exampl a 2 8 ) 15
Compound 7 (Example 60) 42
Compound 8 (Example 69) 90
23

_T~r_:_f ~>~«_ .~:~ - ___ ~-- : _ _ ----:~~-~CA- X22-35840 1998-04-24..___
_____ __-< .__. ___ . .._.__ -_: . __
SR 58611A 7.7
[Test 2] ~ 3 adrenergic receptor stimulating effect
Isolated rat fat was used to examine the effect on fat
decomposition. Fat was removed from around the testicles of
rats (male SD rats) , and shaken for 30 minutes in a nutrient
medium (Krebs-Henseleit bicarbonate buffer, containing BSA,
crude bacterial collagenase) maintained at 37°C, gassed with
95 o OZ and 5 o COZ . The shaken suspension was filtered with gauze,
and the filtrate was centrifuged at 700 rpm for one minute,
after which all but the upper adipocyte layer was suctioned
out and discarded. More nutrient medium was added thereto,
and washing was repeated 3 times. Finally, an appropriate
amount of nutrient medium was added to make a suspension
(adipocyte suspension preparation method).
A vehicle or test compound was added to the above-mentioned
suspension. Reaction was carried out by 30 minutes of shaking
at 30°C gassed with 95% 02 and 5o CO2. The reaction was
terminated by addition of trichloroacetic acid, and after
centrifugation at 3000 rpm for 15 minutes, the supernatant was
collected. The pH was adjusted with a buffer solution, and
then an oxidizing agent and coloring reagent were added, the
OD value for 3-5-diacetyl-1,4-dihydrolutidine which
24

_.___ m~ T~ ~ _~ _~:_~: , CA 0223_5840"1998-0.4 240 __ _ . _ _ __ ______
hasmaximum absorption at 410 nm was measured, to assay the
glycerol content generated. As a result, the lypolytic
activity (ECSO value) of test compound 1 (Embodiment 15) was
21 nM, compared to the activity (ECso value) for isoproterenol
of 10 nM.
[Test 3] ~ 2 adrenergic receptor stimulating effect
Isolated guinea pig tracheal muscle strips were used to
examine the relaxing effect. The strips were isolated by
removing guinea pig tracheal muscle by a common method. Each
of the strips were mounted in an organ bath filled with a
nutrient medium (Tyrode's buffer) maintained at 37°C, gassed
with 95 0 02 and 5 o COZ, and then mounted under an initial tension
of 1 . Og. Each test compound was added cumulatively to the organ
bath at intervals of 10 minutes, and the change in relaxation
of the tracheal muscle due to addition of the test compound
was recorded with a recorder. The tracheal muscle-relaxing
effect was represented as the molar concentration of the test
compound at which 50~ relaxation occurred with respect to
maximum relaxation with isoproterenol (ECSO value) (Table 2) .

_.__. ~~-. _ ___ ._ _ ___~__~~ _ _=9CA U223_5840_.. 1998-04-24._= ._~~~-~~ _:~-
-~ar:_ :- _
(Table 2)Relaxing effect on isolated guinea pig tracheal muscle
Compound (Example No. ) ECSO (nM)
Compound 1 (Example 15) 4,200
Compound 2 (Example 11) 790
Compound 3 (Example 45) 890
Compound 4 (Example 43) 820
Compound 5 (Example 32) 15,000
Compound 6 (Example 28) 1,100
Compound 7 (Example 69) 820
SR 58611A 14,000
[Test 4] (3 1 adrenergic receptor stimulating effect
Isolated guinea pig right atrium strips were used to examine
the heart beat increasing effect. Guinea pig right atriums
were isolated by a common method, mounted in an organ bath
filled with a nutrient medium (Krebs' buffer, 0.03 mM ascorbic
acid, 0.03 mM EDTA, 10 ,u M phenanthramine) maintained at 37°C,
gassed with 95o OZ and 5~ C02, and maintained at an initial
tension of 0.5g, after which the cardiac contractile force and
heart beats were recorded with a recorder. Each test compound
was cumulatively added to the organ bath at intervals of 2.5
minutes, and the loo augmentation value of the heart beats
26

_ ._- -s. _~__- _ ____ ____.e _ ._~~p.._ ~y_ CA 02235840 _1998-04-24 _: --_ _~-
._ _. __ : :.~--~_-----~--- , --__
before and after administration (EClo value) was determined
(Table 3).
(Table 3)Heart effect on isolated
beat increasing guinea pig right
atr ium
Compound (Example No. EClo (nM)
)
Compound (Example 15) > 30, 000
1
Compound (Example 11) > 30, 000
2
Compound (Example 45) > 30, 000
3
Compound (Example 43) > 30,000
4
Compound (Example 32) , > 30, 000
Compound (Example 69) > 30,000
7
SR 58611A > 30, 000
[Test 5] Examination of relaxing effect on isolated rat
bladder detrusor muscle (smooth muscle)
Rat bladders were isolated by a common method for
preparation of strips. The isolated bladder strips were
mounted in an organ bath filled with Krebs' solution kept at
37°C, under mixed gas aeration (950 02 + 5~ COZ) and subjected
to an initial tension of l.Og. Each test compound was
cumulatively added to the organ bath at intervals of 10 minutes .
The activity of each test compound was represented as the
27

__. _ _ _ _.... . _- ~ __.. __ _~ . _ _ - CA 02235840-_1998-04-24-:.- ____ -
:. :-_ _._ ._, -_: . _.._. _:._.
relative relaxation rate, with 100 defined as the relaxation
with addition of 1,~ M isoproterenol, and the ECSO value was
calculated (Table 4).
(Table 4)Relaxing effect on isolated rat bladder detrusor muscle
Compound (Example No. ) ECSO (nM)
Compound 1 (Example l5) 16
Clenbuterol 31
Isoproterenol 10
[Test 6] Examination of suppressing effect on rat colon
spontaneous locomotion (in vivo test)
The abdomens of urethane-anesthetized rats (male Wistar
rats) were cut open and stitched (using suturing stitch with
sterilized needle, 5-0, Nichiyo Kogyo) to a force transducer
(F-081S, Star Medical) so as to allow recording of circular
muscle contraction of the proximal colon (about 3 cm from the
ileocecum) at the sternellum side. The lead wire of the force
transducer was connected to a multipurpose preamp through a
bridge box (FB-O1, Star Medical), and the spontaneous
locomotion of the colon was recorded with a Thermal Array
Recorder (Nihon Koden), upon which the total degrees of
28

g~r'~ 4J~20~ y=~4R',~~~:~~C~°,rr''~,f~~Fh ~'~~JJr/DA ~ 03529h0082;7~
3/
CA 02235840 1998-04-24
contraction over 10 minutes were compared before and after
bolus administration.
Each test compound was administered by polyethylene tube
(0.05 ml/100g b.w.) inserted into the femoral vein, and
cumulative administration was carried out while confirming
recovery of spontaneous locomotion. The spontaneous
locomotion was recorded with a Magmate (Medical Research
Equipment) , and the ECso value was calculated based on the area
under the curve for 10 minutes (Table 5).
(Table 5) Suppressing effect on spontaneous Locomotion of anesthetized
rat colon (iv administration)
Compound (Example No. ) EDSo (mg/kg, iv)
Compound 1 (Example 15) 0.27
Compound 2 (Example 11) 0.23
.SR.,..58,611A~~,- 1 12
[Test 7], Examination of suppressing effect on diarrhea
using rat confinement stress-induced diarrhea models
Each of the test compounds were orally administered to rats
(male Wistar rats) which had been starved from 5:00 p.m_ to
7:00 p.m. the previous day, and after one hour the rats were
placed in a water immersed stress cage positioned vertically
29

____ -. _-_ . ___. -. _..-,~-_~-~::- _ x-~.__CA x.2235840 1998-04~ 24_ __ _ _
_:_:- ~.__, _ .. ; _.:_._.
on an experiment stage, and the openings were capped for forced
confinement. The nature of the feces excreted over a total
of 3 hours was observed every 30 minutes, and the results were
recorded as the diarrhea coefficient (0: no fecal excretion,
1: solid feces, 2: soft feces, 3: milddiarrhea, 4: muddy feces) .
Here, cases with a diarrhea coefficient score of 3 or higher,
i.e. from feces which left a stain on filter paper to muddy
feces, were judged as diarrhea, and the rate of diarrhea
suppression was calculated (Table 6).
Effect of diarrhea suppression in rat confinement
(Table 6) stress-induced diarrhea models (diarrhea suppression rate %)
po administration
Compound Dose
(Example No.) 1.0 mg/kg
Compound (Example 15) 60
1
Compound (Example 11) 50
2
Compound (Example 45) 30
3
Compound (Example 43) 50
4
SR 58611A 20
[Test 8] Examination of relaxing effect on anesthetized
rat bladder

a-- __ ._._ :__.. _ ._.: . _ ~Tr_~~CA 02235840 1998-04-24_-- __- __:- --: __:.
___._._: - r;_
The abdomens of urethane-anesthetized rats (male Wistar
rats) were cut open and small incisions were made in the top
of bladder while avoiding the vessels for insertion, through
a 3-way cock, of a pressure transducer, a balloon connected
to a physiological saline injection syringe and a urine
catheter, after which the incision was tied up with stitch,
and the intravesical pressure was maintained at about 100 mm
H20. Each test compound was administered through a
polyethylene tube inserted into the femoral vein. The
decrease of intravesical pressure after administration of each
test compound was measured as an indicator of the effect of
each test compound (Fig. 1).
[Test 9] Effect on bladder contraction induced by
electrical stimulation of peripheral end of pelvic nerve in
anesthetized rat
After median incision in the abdomen of rats anesthetized
with urethane and a-chloralose, the ureters on both sides were
ligated and cut on the kidney side, and pledgets were placed
on the cut sections to absorb the urine. Next, the hypogastric
nerves on both sides were transected and the base of the penis
were ligated at close the urethra. A small hole was opened
in the top of bladder and, after inserting one end of a
polyethylene tube, ligated.' The other end of the polyethylene
31

i~i~~~~ ~ ~ 1 iwl: -~ - ~ -. _-_. _.. .... ..__ _.., ....... _... _ __._..:__.
-CA 02235840 1998-04-24---
tube was connected to a pressure transducer (TP 400, Nihon
Koden) to measure the intravesical pressure.
Physiological saline was inj ected into the bladder to obtain
intravesical pressure at a 100 mm H20. The change of the
intervesical pressure was recorded with a heat recorder (WT
6856, Nihon Koden) . After ablating the left pelvic nerves from
the fatty tissue around the bladder and cutting the central
section, a platinum electrode was implanted at the peripheral
end of the pelvic nerves. An electrical stimulation apparatus
(SEN-3301, Nihon Koden) was used for generating a rectangular
wave electrical stimulation (20 Hz, 0.3 msec, 5V) for 5 seconds
every 5 minutes . During the experiment, the abdomen was filled
with liquid paraffin kept at 37°C to prevent drying of the
nerves and organs.
After confirming a nearly consistent reaction by the
electrical stimulation, physiological saline (0.05 ml/100g
rat weight) was administered over a period of about one minute
through the polyethylene tube inserted in the femoral vein,
and then after 20 minutes the test compounds were administered.
As a result, compound 1 suppressed bladder contraction at
a lower dose than Clenbuterol hydrochloride (Fig. 2).
As these experimental results clearly demonstrate, the
compounds of the invention~have a strong ~ 3 adrenergic
32

. r:.--~._.= i. _____.__. ___._.__ ___;.._____:__.___ A 02235840 1998-04-24 -
_:. ~ ...__.... _ ___ _._._.,.__.::--
receptor-stimulating action, and selectivity for S 3
adrenergic receptor was high.
No particularly serious toxicity was found even with oral
administration of 1000 mg/kg of the compounds of the invention
to male rats (300-350g body weight) , showing the compounds to
be highly safe.
The compounds of the invention are normally to be
administered in the form of pharmaceutical preparations in
admixture with pharmaceutical carriers. Pharmaceutical
carriers are commonly used in the field of medicinal
preparations, and substances which do not react with the
compounds of the invention should be used.
As examples there may be mentioned lactose, glucose, mannit,
dextrin, starch, white sugar, magnesium aluminate
metasilicate, , synthetic aluminum silicate, crystalline
cellulose, carboxymethyl cellulose calcium, microcrystalline
cellulose, dry corn starch, methyl cellulose, gum Arabic,
gelatin, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, polyvinyl pyrrolidone, polyvinyl alcohol,
magnesium stearate, talc, carboxyvinyl polymer, titanium
oxide, sodium lauryl sulfate, glycerin, fatty acid glycerin
esters, purified lanolin, polysorbate, macrogol, vegetable
oil, wax, non-ionic surfactants, propylene glycol and water,
33

_.___.: _..___.-__:__,.._ . _ . _ __._________:CA 02235840 1998-04-24.__-____.
__..___ __. ._ _.._, _ _.-_____-_-__
etc.
The preparation may be in the form of tablets, capsules,
granules, powder, syrup, suspension, suppository, gel,
injection or the like. These pharmaceutical preparations may
be prepared by conventional methods.
The preparations may contain the compounds of the invention
in a proportion of 0. 01 o or greater, and preferably from 0.1
to 500. They may also contain other therapeutically effective
components.
When a compound of the invention or its pharmacologically
acceptable salt is used as a ~i 3 adrenergic receptor agonist
it may be administered either orally or parenterally, but oral
administration ispreferred. The dosage will differ depending
on the mode of administration, the symptoms and age of the
patient and the kind of procedural measure (therapy or
prevention) , but administration will normally be 0. O1 to 1000
mg/individual, preferably 0.1 to 100 mg/individual, and more
preferably 0.1 to 50 mg/individual, given from 1 to 4 times
per day.
Reference examples and examples of production processes for
compounds of the present invention will now be explained, with
the understanding that the invention is in no way limited to
these examples. The structures of the compounds were
34

_ . -.__ __._ _ ______ ___ _ ~:__.. .~wCA 02235840 1998-04-24-_=_ __ ___.____
_._ . _.__ _. _.._.. .____ ._. _.
determined by 1H-NMR or MS spectrometry.
(Reference Example 1)
3-Iodoanisole (75g), 2-cyclohexen-1-of (15g), potassium
bicarbonate (45g), tetrabutylammonium chloride (45g) and
palladium acetate ( 1 . 8g) were heated and stirred for 80 hours
at an external temperature of 60°C and under an argon air flow,
using acetonitrile (300 ml) as the solvent. After
concentrating the reaction solution under reduced pressure,
an aqueous ammonium chloride solution was added and extraction
was performed with diethyl ether. After washing the organic
layer with saturated saline, it was dried with anhydrous
magnesium sulfate. The crude product obtained from distilling
off the solvent under reduced pressure was separated and
purified by silica gel chromatography (n-hexane: ethyl
acetate=20:1) to give 6.1g of 3-(3-methoxyphenyl)
cyclohexanone (19.6 yield).
1H-NMR(CDC13) 8 ppm:1.65-2.18(4H,m),2.25-2.61(4H,rn),
2.90-3. 00 (lH,m) , 3.79 (3H, s) , 6.76-6.82 (3H,m) , 7.20-
7.26(lH,m) .
(Reference Example 2)
3-(3-Methoxyphenyl)cyclohexanone (l3.lg), benzylamine
(6.88g) and p-toluenesulfonic acid (1.22g) were refluxed for
1.5 hours in benzene (200 ml) using a Dean-Stark apparatus while

_. 04 24-. _. _.._.. _.._. ... _ _._..__ . _ __
. __._~_ . __ ..___ . _.. _ . . CA 02235840 1998- - _ _ . _.:
removing the water generated. After concentrating the
reaction solution under reduced pressure, methanol (200 ml)
was added and upon adding sodium borohydride (2 . 43g) gradually
under ice cooling, the mixture was stirred at room temperature
for an hour. After concentrating the reaction solution under
reduced pressure, water was added and extraction was performed
with chloroform. The organic layer was washed with saturated
aqueous solution of sodium bicarbonate and saturated saline,
and then dried with anhydrous magnesium sulfate. The crude
product obtained from distilling off the solvent under reduced
pressure was separated and purified by silica gel column
chromatography (n-hexane: ethyl acetate=5:1 to 1:1) to give
15 . 8g of N-benzyl-N- [ 3- ( 3-methoxyphenyl ) cyclohexyl ] amine as
a diastereomeric mixture ( 83 . 4 o yield) . Repeated silica gel
column chromatography (n-hexane: ethyl acetate=5:1) allowed
separation of the two diastereomers, with the trans form
obtained from the earlier eluted fraction and the cis form
obtained from the later eluted fraction.
trans form (R*R* ) 1H-NMR (CDC13) 8 ppm: 1. 40-2 . 00 ( 9H, m) ,
2. 90-3. 09 (2H,m) , 3. 80 (3H, s) , 3. 81 (2H, s) , 6. 68-6. 83 (3H,m) ,
7.20-7.40(6H,m).
cis form(R*S*) 1H-NMR(CDC13) 8 ppm:1.06-1.58 (5H,m), 1.76-
2.20 ( 4H,m) , 2.45-2.72 (2H,m) , 3.78 (3H, s) , 3. 80 (2H, s) , 6. 68-
36

CA 02235840 1998-04-24
6. 85 (3H,m) , 7. 15-7.35 (5H,m) .
(Reference Example 3)
(trans)-N-Benzyl-N-[3-(3-methoxyphenyl) cyclohexyl]amine
(6.59g) was dissolved in ethyl acetate (20 ml), and then 4 N
HC1-ethyl acetate solution (20 ml) was added while cooling on
ice, and the mixture was stirred at room temperature for 30
minutes. After concentrating the reaction solution under
reduced pressure, 10% palladium-carbon (1.3g) and acetic acid
(60 ml) were added for hydrogen addition at an external
temperature of 80°C for 8 hours. After filtering off the
solvent from the reaction solution, the solvent was
concentrated under reduced pressure (repeated azeotropy with
ethanol and toluene) to give 5.408 of (trans)-3-(3-
methoxyphenyl)cyclohexylamine hydrochloride (quantitative
yield) .
1H-NMR (CDC13) 8 ppm: (free compound) 1.40-1 .93 (lOH,m) ,
2.84-3. 00 (lH,m) , 3.30-3.35 (lH,m), 3.80 (3H, s) , 6. 68-
6.85(3H,m), 7.16-7.26(lH, m) .
Debenzylation of the cis form by the same method gave
(cis)-3-(3-methoxyphenyl) cyclohexylamine hydrochloride.
1H-NMR (CD30D) 8 ppm: 1. 34-1. 65 ( 4H, m) , 1. 82-2 . 22 ( 4H, m) ,
2.60-2.72(lH,m),3.17-3.30(lH,m),3.78(3H,s);6.71-6.85
( 3H, m) , 7 . 19-7 . 25 ( 1H, m) .
37

__ .___._ ____._ _ _.____- .___.._ _ _ ._.:_____CA 02235840 1998-04-24__-___.-
.._______. _.... ._-_. ..___.__________-__
The following compounds were synthesized according to the
method of Reference Examples 1 to 3.
(Reference Example 4)
3-(4-Methoxyphenyl)cyclohexanone
1H-NMR (CDC13) 8 ppm:1.76-1.84 (2H,m) , 2.03-2. 15 (2H,m) ,
2. 35-2.57 (4H,m) , 2.90-3. 03 (lH,m) , 3.80 (3H, s) , 6. 87 (2H, d, J=
6. 7lHz) , 7 . 14 (2H, d, J=6. 7lHz) .
(Reference Example 5) (trans)-N-Benzyl-N-[3-(4-
methoxyphenyl)cyclohexyl)amine hydrochloride
1H-NMR ( CDC13) b ppm: l . 25-2 . 30 ( 8H, m) , 3 .19 ( 1H, broad s ) ,
3.35(lH,m),3.75(3H,s),4.12(2H,broads),6.75(2H,d,J=8.55Hz),
7 .13 (2H, d, J=8.55Hz) , 7. 33-7.38 (3H,m) , 7. 66-7 . 69 (2H,m) ,
9 . 92 (2H, broad s ) .
(cis)-N-Benzyl-N-[3-(4-methoxyphenyl) cyclohexyl]amine
hydrochloride
1H-NMR (CDC13) 8 ppm:1.19-1.27 (2H,m) , 1.58-1. 94 (4H,m) ,
2 .19-2 . 4 2 ( 3H, m) , 2 . 8 8 ( 1H, broad s ) , 3 . 75 ( 3H, s ) , 3 . 98 (
2H, broad
s ) , 6 . 7 8 ( 2H, d, J=8 . 55Hz ) , 7 . 08 ( 2H, d, J=8 . 55Hz ) , 7 . 35-7
. 38 ( 3H, m) ,
7.61-7. 64 (2H,m) , 9.88 (2H,broad s) .
(Reference Example 6) (trans)-3-(4-methoxyphenyl)
cyclohexylamine hydrochloride
38

CA 02235840 1998-04-24
1H-NMR (CDC13+CD30D) ~ ppm: 1 . 53-2 .16 ( 8H, m) , 2 . 88-3 _ 00,
( 1H, m) , 3 . 53-3 . 62 ( 1H, m) , 3 . 8 0 ( 3H, s ) , 6 . 8 6 ( 2H, d, J=8 .
55Hz ) ,
7 .17 ( 2H, d, J=8 . 55Hz ) .
(cis)-3-(4-Methoxyphenyl)cyclohexylamine hydrochloride
1H-NMR (CDC13+CD30D) 8 ppm: 1 . 34-1. 61 ( 4H, m) , 1. 84-2 . 04 (2H, m) ,
2.09-2.26(2H,m),2.53-2.65(lH,m),3.12-3.25(lH,m),3.80(3H,s),
6 . 8 5 ( 2H, d, J=8 . 55Hz ) , 7 . 13 ( 2H, d, J=8 . 55Hz ) .
(Reference Example 7)
3-(2-Methoxyphenyl)cyclohexanone
1H-NMR (CDC13) 8 ppm: 1 .70-2.00 (2H,m) , 2. 00-2.22 (2H,m) ,
2.25-2 . 63 (4H,m) , 3.30-3.49 (lH,m) , 3. 82 (3H, s) , 6. 80-7. 00 (2H,m) ,
7 .15-7 .24 (2H, m) .
(Reference Example 8) (trans)-3-(2-Methoxyphenyl)
cyclohexylamine hydrochloride
1H-NMR (CDC13) 8 ppm: 1.50-2.32 (BH,m) , 3. 40-3.55 (lH,m) ,
3.71-3.80 (lH,m) , 3.73 (3H, s) , 6.71-6.90 (2H,m) , 7 .10-7.20
(2H,m) .
(cis)-3-(2-Methoxyphenyl)cyclohexylamine hydrochloride
1H-NMR (CDC13) ~ ppm: 1.35-2. 00 (6H,m) , 2.20-2. 30 (2H,m) ,
2 . 91-3.10 (lH,m) , 3.22-3. 35 (lH,m) , 3. 79 (3H, s) , 6. 80-6. 92 (2H, m) ,
7.13-7.20(2H,m).
(Reference Example 9)
3, 4-Dimethoxybenzaldehyde (30.1g) was dissolved in acetone
39

.___.-________ --~-__ __ _______-- _______- CA 02235840 1998-04-24..-___~ -__
__- -._.___ ____ ._._ _._-.._--_-_____-
(900 ml), and then piperidine (23.2 ml) and acetic acid (13.4
ml) were added prior to reflux for 4 hours. After distilling
off the reaction solvent under reduced pressure, it was
dissolved in 600 ml of ethyl acetate and washed with saturated
sodium bicarbonate water and saturated saline. After drying
with anhydrous magnesium sulfate, the solvent was distilled
off under reduced pressure producing yellow crystals which were
then washed in isopropyl ether to give 2l.Og of 4-(3,4-
dimethoxyphenyl)-3-buten-2-one (56.40).
1H-NMR (CDC13) ~ ppm: 2 . 38 (3H, s ) , 3 . 92 ( 6H, s ) , 6. 61
( 1H, d, J=15 . 9Hz ) , 6 . 8 8 ( 1H, d, J=7 . 94Hz ) , 7 . 08 ( 1H, s ) , 7
.13 ( 1H, d,
J=7.94Hz),7.47(lH,d,J=15.9Hz).
(Reference Example 10)
Diethyl malonate (73.7g) was dissolved in ethanol (700 ml) ,
and then potassium tert-butoxide (51.6g) was gradually added
thereto. A solution of 4-(3,4-dimethoxyphenyl)-3-buten-2-
one (79.1g) in ethanol (500 ml) was added dropwise, and the
mixture was refluxed for 1.5 hours. After distilling off the
reaction solvent under reduced pressure, ice water was poured
over it and it was adjusted to pH4 with concentrated
hydrochloric acid. The deposited crystals were filtered by
suction, washed with water and then air-dried to give 1228 of
ethyl 2-(3,4-dimethoxyphenyl)-4,6-dioxocyclohexane

__-. _ __--__.__ -___-_ _ -___.-__ ___-_CA 0 2 2 3 5 8 4 0 19 9 8 - _
_.. _. . 04 24--_____-_-____ -._-_--_.___.__ _____.__
carboxylate (99.60).
1H-NMR (CDC13) 8 ppm: 1 .05-1 .25 (3H,m) , 2.40-2.98 (3H,m) ,
3 . 44-3 . 65 (2H,m) , 3.86 ( 6H, s) , 4 . 04-4 . 31 (2H,m) , 6.71-6. 84
(2H,m) ,
7.26 (1H, s) .
(Reference Example 11)
loo Aqueous solution of potassium hydroxide (760 ml) was
added to ethyl 2-(3,4-dimethoxyphenyl)-4,6-dioxocyclohexane
carboxylate (122g) , and the mixture was refluxed for 3 .5 hours .
After cooling the reaction solution on ice, it was adjusted
to pHl with concentrated hydrochloric acid, and stirred at 50°C
for an hour. After allowing the reaction solution to cool,
the deposited crystals were filtered by suction and washed with
purified water and isopropyl ether to give 85.88 of 5-
(3,4-dimethoxyphenyl)cyclohexane-1,3-dione (90.50).
1H-NMR (DMSO-d6) 8 ppm:2.40-2.77 (4H,m) , 3.59-3. 63 (2H,m) ,
3.75(3H,s),3.76(3H,s),5.36(lH,s),6.84(2H,s),6.97(lH,s).
(Reference Example 12)
5-(3,4-Dimethoxyphenyl)cyclohexan-1,3-dione (31.8g) was
suspended in ethanol (500 ml), and concentrated hydrochloric
acid (20 ml) was added prior to reflux for 3 hours. After the
reaction solvent was concentrated under reduced pressure, it
was dissolved in chloroform and washed with saturated sodium
bicarbonate water. After~drying with anhydrous magnesium
41

_ _ - _ -_:_ ._-_____-_________ ______ ___._-__CA 0 2 2 3 5 8 4 0 19 9 8 - - _
---_-.--,- _ . 0 4 2 4-_-_--_____-__-_-_.. ___ __ ._____
sulfate, the solvent was concentrated under reduced pressure
producing crude crystals which were then washed with diethyl
ether to give 10.38 of 5-(3,4-dirnethoxyphenyl)-3-ethoxy-2-
cyclohexen-1-one (29.1x).
1H-NMR (CDC13) ~ ppm: 1 .38 (3H, t, J=7.32Hz) , 2 . 48-2.70 (4H,m) ,
3.26-3.38 (lH,m),3.87-3.99(8H,m),5.43(lH,s),6.76-
6.86(3H,m).
(Reference Example 13)
5-(3,4-Dimethoxyphenyl)-3-ethoxy-2-cyclohexen-1-one
(16.7g) was dissolved in ethanol (260 ml), and then sodium
borohydride (6.88g) was gradually added and the mixture was
stirred at 60°C for 1.5 hours. After distilling off the
reaction solvent under reduced pressure, and subsequent
pouring over of ice water, extraction with ethyl acetate and
drying with anhydrous magnesium sulfate, the solvent was
concentrated under reduced pressure to produce a yellow oily
substance. The oily substance was dissolved in ethyl acetate
( 2 0 ml ) , 4 N HC1-ethyl acetate solution ( 50 ml ) was added and
the mixture was stirred at room temperature for 13 hours . The
reaction solution was washed withsaturated sodium bicarbonate
water and saturated saline and dried with anhydrous magnesium
sulfate, after which the solvent was distilled off under
reduced pressure to produce a yellow oily substance which was
42

-_-___._-______---__ ______-___CA 02235840 1998-04-24_ ___ __--__ _____-____-
___-__
then purified by silica gel column chromatography (n-
hexane: ethyl acetate=2:1). The resulting crystals were
washed with diethyl ether to give 6.76g of 5-(3,4-
dimethoxyphenyl)-2-cyclohexen-1-one (48.1g).
1H-NMR (CDC13) b ppm:2.46-2.76 (4H,m) , 3.24-3.37 (lH,m) ,
3. 87 (3H, s ) , 3. 88 (3H, s) , 6. 13 (1H, d, J=10.4Hz) , 6.76-6. 87 (3H,m) ,
7 . 02-7 . 09 ( 1H, m) .
(Reference Example 14)
5-(3,4-Dimethoxyphenyl)-2-cyclohexen-1-one (6.76g) was
dissolved in ethanol (100 ml), and 10°s palladium-carbon (684
mg) was added thereto. After substituting the reaction vessel
with hydrogen gas, hydrogen addition was effected for 30
minutes at normal pressure and room temperature. After the
reaction, the catalyst was filtered off and the solvent was
distilled off under reduced pressure to produce an oily
substance which was dissolved in ethyl acetate (50 ml), and
then 4 N HC1-ethyl acetate solution (2 ml) was added and the
mixture was stirred at room temperature for 20 minutes. The
solvent was distilled off under reduced pressure to produce
crude crystals which were then washed with n-hexane to give
6.72g of 3-(3,4-dimethoxyphenyl)cyclohexanone (98.5x).
1H-NMR (CDC13) 8 ppm:1.74-1. 91 (2H,m) , 2. 07-2 .16 (2H,m) ,
2 . 37-2 . 62 ( 4H, m) , 2 . 91-3 . 03 ( 1H, m) , 3 . 87 (3H, s ) , 3 . 89 (
3H, s ) ,
43

CA 02235840 1998-04-24
6.74-6.85 (3H,m) .
(Reference Example 15)
3-(3,4-Dimethoxyphenyl)cyclohexanone (6.90g) and
benzylamine (3 .16g) were refluxed for 1 . 5 hours in benzene ( 150
ml) in the presence of para-toluenesulfonic acid (630 mg),
using a Dean-Stark apparatus while removing the water generated.
After distilling off the benzene under reduced pressure, it
was dissolved in methanol (120 ml) while cooling on ice, sodium
borohydride (1.12g) was gradually added and the mixture was
stirred at room temperature for an hour. After concentrating
the reaction solution, water was added, extraction was
performed with chloroform, and the solution was washed with
saturated sodium bicarbonate water and saturated saline.
After drying with anhydrous magnesium sulfate, the solvent was
distilled off under reduced pressure to produce a light yellow
oily substance which was then separated and purified by silica
gel column chromatography (n-hexane:ethyl acetate=5:1 ~ 1:1
1:2), to give 3.168 of (trans)-N-benzyl-N-[3-(3,4-
dimethoxyphenyl) cyclohexyl]amine (33.2% yield) and 3.098 of
(cis)-N-benzyl-N-[3-(3,4-dimethoxyphenyl) cyclohexyl]amine
(32.4% yield) .
1H-NMR (CDC13) b ppm: (trans) 1.43-1.95 (9H,m) , 2.89-2.98,
(lH,m),3.07(lH,brs),3.80(2H,s),3.84(3H,s),3.86(3H,s),
44

CA 02235840 1998-04-24
6.73-6. 81 (3H,m) , 7.24-7.37 (5H,m) . 1H-NMR (CDC13) 8 ppm:
(cis) 1 .14-1.53 (5H,m) , 1.80-2.18 (4H,m) , 2.47-2. 55 (lH,m) ,
2.55-2.70 (lH,m),3.84(2H,s),3.86(3H,s),3.87(3H,s),6.74-6.83
(3H,m) , 7. 24-7. 33 (SH,m)
(Reference Example 16)
N-Benzyl-N-[3-(3,4-dimethoxyphenyl)cyclohexyl]amine
(3.16g) was dissolved in ethyl acetate, 4 N HC1-ethyl acetate
solution was added, and the mixture was stirred at room
temperature for 30 minutes. After concentrating the solvent
under reduced pressure, it was dissolved in acetic acid (100
ml), and loo palladium-carbon (640 mg) was added thereto.
After substituting the reaction vessel with hydrogen gas,
hydrogen addition was effected for 3 hours at normal pressure,
at 80°C. After the reaction, the catalyst was filtered off and
the solvent was distilled off under reduced pressure to produce
crude crystals which were then washed with diethyl ether to
give 2.80g of 3-(3,4-dimethoxyphenyl)cyclohexylamine
hydrochloride (quantitative yield).
1H-NMR (CDC13) 8 ppm: (trans) 1 .48-2.28 (8H,m) , 3. 13-3.20
(lH,m) , 3. 71-3. 93 (7H,m) , 6. 69-6.79 (3H,m) . 1H-NMR(CD30D) ~ ppm:
(cis)1.39-1.59(4H,m),1.87-2.17(4H,m),2.59-2.68(lH,m),3.18-
3 . 32 ( 1H, m) , 3 . 82 ( 3H, m) , 3 . 84 ( 3H, s ) , 6. 77-6 . 90 ( 3H, m) .
(Reference Example 17)

CA 02235840 1998-04-24
Grignard reagent was prepared from magnesium (2.8g) and
3-bromoanisole (22.Og) in tetrahydrofuran (50 ml) in the
presence of iodine, and a catalytic amount of copper (I) bromide
(CuBr, 0.83g) was added thereto. A tetrahydrofuran (10 ml)
solution containing 2-cyclohexen-1-one (9.6g) was also added
dropwise while stirring on ice. After stirring at room
temperature for 3 hours, hydrochloric acid was added, and
extraction was performed with ethyl acetate. After drying
with anhydrous magnesium sulfate, the solvent was distilled
off under reduced pressure to produce a light yellow oily
substance which was then separated and purified by silica gel
column chromatography (n-hexane: ethyl acetate=5:1) to give
9.7g of 3-(3-methoxyphenyl)cyclohexanone (47.60 yield).
(Reference Example 18)
Raney nickel (0.5g) was added to a solution of 3-(3-
methoxyphenyl)cyclohexanone (2.05g) and (S)-1-
phenylethylamine (1.22g) in ethanol (20 ml) prior to room
temperature stirring and hydrogen addition. After the
starting materials were consumed, the catalyst was filtered
off, and the filtrate was distilled off under reduced pressure
to produce a light yellow oily substance which was then
separated and purified by silica gel column chromatography
(chloroform:methanol=50:1) to give 1.628 of N-[3-(3-
46

--CA 02235840 1998-04-24--
methoxyphenyl) cyclohexyl]-N-(1-phenylethyl)amine (a mixture
of trans-H form and trans-L form) (52.50 yield). The
proportion of trans form to cis form with this reaction was
about 12 to 1 (confirmed by HPLC). Repeated column
chromatography enabled separation of trans-H and trans-L.
(Trans-H) Synthesis material for compound of Example 11
(optically active compound)
1H-NMR (CDC13) 8 ppm: 1. 34-1 . 87 (llH,m) , 2 . 82-2 .90 (2H,m) , 3 . 77
(3H, s) , 3. 82-3.90 (lH,m) , 6.73-6.83 (3H,m) , 7.13-7.37 (6H,m) .
(Trans-L) synthesis material for compound of Example 12
(optically active compound)
1H-NMR (CD30D) 8 ppm: 1.36-1 .97 (llH,m) , 2.87-2.92 (2H,m) , 3 .80
(3H, s) , 3. 84-3.91 (lH,m) , 6.71-6.83 (3H,m) , 7. 18-7.32 (6H,m) .
(Reference Example 19)
The compound of Reference Example 18 (mixture of trans-H
and trans-L) was subj ected to hydrogen addition in ethanol in
the presence of 10~ palladium-carbon while heating at 50°C,
to give 3-(3-methoxyphenyl)cyclohexylamine (a mixture of
trans-H and trans-L). Reduction reaction from trans-H and
trans-L in the same manner gave optically active 3-(3-
methoxyphenyl) cyclohexylamine.
(Optical resolution)
3-(3-Methoxyphenyl) cyclohexylamine (a mixture of trans-H
47

-CA 02235840 1998-04-24
and trans-L) (35.7g) was dissolved in ethanol (20 ml), a
solution of (S) -mandelic acid (26.5g) in ethanol (50 ml) was
added, and the mixture was stirred for 30 minutes on ice. The
deposited crystals were filtered by suction and air-dried to
give 24.Og of 3-(3-methoxyphenyl) cyclohexylamine~ (S)-
mandelate (yield: 38.60, 78.5% ee) (crystal 1) . Crystal 1 was
suspended in ethanol (48 ml), refluxed for 30 minutes and
allowed to cool to room temperature, and then stirred while
cooling on ice. The crystals were filtered by suction and
air-dried to give l9.lg of salt (yield: 79.6, 98.Oo ee)
(crystal 2) . The same procedure was carried out once more to
give 18.4g of salt (yield: 96.Oo, 99.60 ee) (crystal 3) . The
optical purity of crystal 1 and 2 was measured by HPLC after
preparing free compounds. For crystal 3, it was measured by
HPLC upon acetylation of the primary amino group, by the method
described in the next reference example. After adding water
(150 ml) to crystal 3 and rendering them alkaline with
concentrated ammonia water, extraction was performed with
ethyl acetate. After washing with saturated sodium
bicarbonate water and saturated saline and drying with
anhydrous magnesium sulfate, the solvent was distilled off
under reduced pressure to give l4.Og of optically active
(trans)-3-(3-methoxyphenyl)cyclohexylamine (quantitative
48

-CA 02235840 1998-04-24
yield) .
1H-NMR(CDC13) 8 ppm:1.42-2.04(lOH,m),2.90-3.01(lH,m),
3.38 (lH,br s) , 3.79 (3H, s) , 6.71-6.84 (3H,m) , 7. 16-7.23 (lH,m) .
(hydrochloride)mp.123.5-125.0°C, [ a ]p=-13.9°
(c=1.OO,CHC13),MS (m/z) :206 (M+1) . ( (S)-mandelate)mp.181 .0-
182 . 5°C, [ a ] D=+32 . 6° (c=1 . 00, CH30H) .
(Reference Example 20)
Acetic anhydride (1 ml) and pyridine (0.5 ml) were added
to (trans)-3-(3-methoxyphenyl) cyclohexylamine (10 mg} and
the mixture was stirred at 50°C for 2 hours. The reaction
solution was poured into glacial sodium bicarbonate water and
extracted with ethyl acetate. The organic layer was washed
with 1 N hydrochloric acid, saturated sodium bicarbonate water
and saturated saline and dried with anhydrous magnesium sulfate,
and then the solvent was distilled off under reduced pressure
to give 8 mg of N-acetyl-N-[3-(3-methoxyphenyl)cyclohexyl]
amine ( 53 . 30 .
1H-NMR(CDC13) b ppm:1.25-1.99(8H,m),2.03(3H,s),2.55-2.70
(lH,m),3.80(3H,s),4.28-4.32(lH,m),5.76(lH,br s),6.72-6.82
( 3H, m) , 7 . 19-7 . 2 5 ( 1H, m) .
(Reference Example 21)
47o Hydrobromic acid (140 ml) was gradually added to
(trans)-3-(3-methoxyphenyl) cyclohexylamine (l4.Og) and the
49

A 02235840 1998-04-24
mixture was refluxed for an hour. After adjusting the reaction
solution to pH7 with sodium bicarbonate (powder), it was
adjusted to pH9 with concentrated ammonia water. After
filtering the deposited crystals by suction and washing with
water, they were dried by ventilation at 45°C for 5 hours to
give 8.588 of (trans)-3-(3-aminocyclohexyl)phenol (65.80
yield) .
1H-NMR (CD30D) 8 ppm: 1. 49-1 .84 (BH,m) , 2.79-2. 87 (lH,m) ,
3 . 23 ( 1H, br s ) , 6 . 58 ( 1H, dd, J=1 . 22, 7 . 93Hz ) , 6 . 67-6 . 68 (
2H, m) ,
7 . 07 ( 1H, t, J=7 . 93Hz ) .
(Reference Example 22)
(trans)-3-(3-Aminocyclohexyl)phenol (7.39g) was dissolved
in DMF (50 ml), and after adding a solution of di-tert-
butylcarbonate (8.43g) in DMF (20 ml) and triethylamine (11.7g) ,
the mixture was stirred at room temperature for 2 hours . Ethyl
acetate was added to the reaction solution, and after washing
3 times with water and once with saturated saline, it was dried
with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure to produce a crude product which
was then separated and purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1) to give 10.18 of
(trans)-3-[3-(N-tert-butoxycarbonylaminocyclohexyl)]phenol
(89.58 yield) .

A 02235840 1998-04-24-
1H-NMR ( CDC13) 8 ppm: 1. 47-1 . 96 ( 17H, m) , 2 . 63-2 . 71 ( 1H, m) ,
3 . 99 ( 1H, br s ) , 4 . 81 ( 1H, br s ) , 6 . 65-6 . 78 ( 3H, m) , 7 . 15
(1H, t, J=7 . 32Hz) .
(Reference Example 23)
(trans)-3-[3-(N-tert-Butoxycarbonylaminocyclohexyl)]
phenol (l0.lg) was dissolved in acetone (50 ml) , and upon adding
potassium carbonate (9.55g) and ethyl bromoacetate (5.76g) the
mixture was refluxed for 3.5 hours. After the reaction, the
precipitated salt was filtered off and the solvent was
distilled off under reduced pressure. The resulting crude
product was separated and purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1) to give 12.88 of
ethyl[3-[3-(N-tert-butoxycarbonylaminocyclohexyl)phenoxy]]
acetate (98.4 yield).
1H-NMR (CDC13) 8 ppm: 1 .30 (3H, t, J=7.32Hz) , 1.46-1 . 99 (l7H,m) ,
2 . 55-2 . 7 0 ( 1H, m) , 4 . 00 ( 1H, br s ) , 4 .27 ( 2H, q, J= 7 . 32Hz ) ,
4. 61 (2H, s ) , 4.80 (lH,br s) , 6.71 (1H, dd, J=2.44, 7. 94Hz) , 6.73-
6 . 8 6 ( 2H, m ) , 7 . 21 ( 1H, t, J=7 . 94Hz ) .
(Reference Example 24)
Ethyl [3-[3-(N-tert-butoxycarbonylaminocyclohexyl)
phenoxy]]acetate (12.8g) was dissolved in ethyl acetate (15
ml), and upon adding 4 N HC1-ethyl acetate solution (25 ml)
the mixture was stirred for 25 hours at room temperature . After
51

A 02235840 1998-04-24
adding water to the reaction solution, it was rendered weakly
alkaline with concentrated ammonia water and extraction was
performed with ethyl acetate. After washing the organic layer
with saturated sodium bicarbonate water and saturated saline,
it was dried with anhydrous magnesium sulfate and the solvent
was distilled off under reduced pressure to give 8.478 of ethyl
3-(3-aminocyclohexyl) phenoxyacetate as an oily substance
(89.70 yield).
1H-NMR (CDC13) b ppm: 1.30 (3H, t, J=7.32Hz) , 1. 44-1 . 87 (8H,m) ,
2 . 15 (2H, br s ) , 2 . 94-2 . 98 ( 1H, m) , 3 . 36-3 . 39 ( 1H, m) ,
4.27 (2H, q, J=7.32Hz) , 4. 60 (2H, s) , 6.70 (1H, dd, J=2.44, 7. 94Hz) ,
6.82-6.88(2H,m),7.20(lH,t,J=7.94Hz).
[ a ] 0=-13. 1° (c=1.09,Me0H) .
(fumaric acid salt) mp. 148.0 - 149.5°C, [ a ]D=-10.3° (c=1.00,
MeOH) . Elemental analysis: (as CZOHz~NO-,)
Calculated: C; 61.06, H; 6.92, N; 3.56
Found: C; 60.93, H; 6.93, N; 3.40
(Reference Example 25)
After adding potassium tert-butoxide to a solution of ethyl
acetoacetate (25.7g) in benzene (420 ml) while cooling on ice,
4-methoxyphenacyl bromide (24.8g) was gradually added and the
mixture was refluxed for an hour. After allowing the reaction
solution to cool, it was washed with 5o sodium hydroxide and
52

~A 02235840 1998-04-24
purified water, and dried with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to give
26.28 of ethyl 2-[2-(4-methoxyphenyl) -2-oxoethyl]-4-
oxopentanoate (87.0% yield).
1H-NMR (CDC13) 8 ppm: 1 .29 (3H, t, J=7.32Hz) , 2. 44 (3H, s) ,
3. 47 ( 1H, dd, J=5. 49, 18.3Hz) , 3 . 67 (1H, dd, J=8.54, 18 .3Hz) , 3. 87
(3H, s) , 4.22 (3H,m) , 6.93 (2H, d, J=8.55Hz) , 7.96 (2H,d, J=8.55Hz) .
(Reference Example 26)
To ethyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]-4-
oxopentanoate (26.2g) there was added 1000 ml of 1% aqueous
potassium hydroxide solution, and the mixture was refluxed for
an hour. Next, potassium hydroxide was added so that the
aqueous potassium hydroxide solution reached a concentration
of 10% (adding a solution of 146g of potassium hydroxide in
200 ml of water), and the mixture was further refluxed for 2
hours. After allowing the reaction solution to cool,
extraction was performed with ethyl acetate and water washing
was then followed by drying with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to produce
crude crystals which were then washed with diethyl ether to
give 11.48 of 3-(4-methoxyphenyl)-2-cyclopenten-1-one (64.4%
yield) .
1H-NMR (CDC13) 8 ppm:2.56-2.59 (2H,m) , 3.01-3. 04 (2H,m) , 3.87
53

A 02235840 1998-04-24
(3H, s) , 6. 48 (1H, s) , 6.96 (2H, d, J=8.55Hz) , 7. 63 (2H, d, J=8.55Hz) .
(Reference Example 27)
3-(4-Methoxyphenyl)-2-cyclopenten-1-one (11.2g) was
dissolved in ethanol, and 10 o palladium-carbon (1. lg) was added
thereto. After substituting the reaction vessel with hydrogen
gas, hydrogen addition was carried out at normal pressure, 40°C
for 4 hours. After the reaction, the catalyst was filtered
off and the solvent was distilled off under reduced pressure
to produce a light yellow oily substance which was then purified
by silica gel column chromatography (n-hexane: ethyl
acetate=5:1) to give 5.908 of 3-(4-methoxyphenyl)
cyclopentanone (52.20 yield).
1H-NMR (CDC13) 8 ppm: 1.91-2. 03 (lH,m) , 2.24-2.51 (4H,m) ,
2 . 65 ( 1H, dd, J=7 . 32, 17 . 7Hz ) , 3 . 34-3 . 4 0 ( 1H, m) , 3 . 80 ( 3H,
s ) ,
6. 88 (2H, d, J=8 . 55Hz) , 7.18 (2H, d, J=8.55Hz) .
(Reference Example 28)
3-(4-Methoxyphenyl) cyclopentanone (7.37g) and
benzylamine (4.15g) were refluxed for 1.25 hours in benzene
(150 ml) in the presence of p-toluenesulfonic acid (820 mg)
using a Dean-Stark apparatus while removing the water generated.
After distilling off the benzene under reduced pressure, it
was dissolved in methanol (150 ml) while cooling on ice, sodium
borohydride ( 1. 63g) was gradually added and the mixture was
54

A 02235840 1998-04-24
stirred at room temperature for 12.5 hours. After
concentrating the reaction solution, water was added, and
extraction with chloroform was followed by washing with
saturated sodium bicarbonate water and saturated saline.
After drying with anhydrous magnesium sulfate, the solvent was
distilled off under reduced pressure to produce a light yellow
oily substance, which was then purified by silica gel column
chromatography (n-hexane:ethyl acetate=2:1) to give lO.Og of
N-benzyl-N-[3-(4-methoxyphenyl) cyclopentyl]amine (91.7$
yield) .
1H-NMR (CDC13) 8 ppm: 1.51-2.43 (6H,m) , 3. 00-3.20 (lH,m) ,
3.37-3. 47 (lH,m) , 3. 84-3. 89 (SH,m) , 6. 94 (2H, d, J=7. 94Hz) , 7.24-
7.44 (7H,m) .
(Reference Example 29)
N-Benzyl-N-[3-(4-methoxyphenyl)cyclopentyl]amine (lO.Og)
was dissolved in ethanol (120 ml), 55 ml of 1 N hydrochloric
acid was added, and the mixture was stirred at 40°C for 3 hours .
The crystals (hydrochloride) obtained by concentrating the
reaction solution were dissolved in acetic acid (130 ml) , and
l0opalladium-carbon (1.3g) was added. Aftersubstituting the
reaction vessel with hydrogen gas, hydrogen addition was
carried out at normal pressure, 80°C for 5 hours. After the
reaction, the catalyst was filtered off and the solvent was

~'A 02235840 1998-04-24
distilled off under reduced pressure to produce light yellow
crystals which were then washed with diethyl ether to give 4 . 55g
of 3-(4-methoxyphenyl) cyclopentylamine hydrochloride
(99.80) .
1H-NMR(CDC13) 8 ppm:(a mixture of cis and trans)1.59-1.62
( 1H, m) , 1. 81-2 . 2 6 ( l OH, m) , 2 . 50-2 . 55 ( 1H, m) , 2 . 85-3 . 05 (
1H, m) ,
3. 30-3.50 (lH,m) , 3.70-3. 80 (8H,m) , 6.75 (4H, d, J= 7.94Hz) ,
7 . 05 (2H, d, J=7 . 94Hz) , 7.15 (2H, d, J=7 . 94Hz) .
(Reference Example 30)
3-(4-Methoxyphenyl)cyclopentanone (8.51g) and
methoxymethyltriphenylphosphonium chloride (16.9g) were
dissolved in tetrahydrofuran (200 ml) . After gradually adding
potassium tert-butoxide (6.70g) while maintaining an internal
temperature of 10°C or below, the mixture was stirred at room
temperature for 2 . 5 hours . The reaction solution was poured
into water, and extraction with ethyl acetate was followed by
washing with water. After drying with anhydrous magnesium
sulfate, the solvent was distilled off under reduced pressure
to produce a brown oily substance which was then purified by
silica gel column chromatography (n-hexane: ethyl
acetate=20:1) to give 4.738 of 1-methoxy-4-(3-
methoxymethylenecyclopentyl) benzene (48.4 yield).
1H-NMR (CDC13) ~ ppm: (a mixture of E form and Z form) 1 . 55-1 . 76
56

A 02235840 1998-04-24
( 1H, m) , 2 . 04-2 . 83 ( 5H, m) , 2 . 94-3 .10 ( 1H, m) , 3 . 58 ( 3H, s ) ,
3 . 7 8 ( 3H, s ) , 5 . 93-5 . 95 ( 1H, m) , 6 . 84 ( 2H, d, J=8 . 55Hz ) , 7
.16
( 1H, d, J=8 . 55Hz ) , 7 . 17, ( 1H, d, J=8 . 55Hz ) .
(Reference Example 31)
1-Methoxy-4-(3-methoxymethylenecyclopentyl) benzene
(4. 73g) was dissolved in ethyl acetate (100 ml) , 4 N HC1-ethyl
acetate solution (10 ml) was added and the mixture was stirred
at room temperature for 3 minuets. After washing the reaction
,,
solution with saturated sodium bicarbonate water and purified
water, it was dried with anhydrous magnesium sulfate and the
solvent was distilled off under reduced pressure to give 4. 30g
of 3-(4-methoxyphenyl) cyclopentane carboaldehyde (97.3%).
1H-NMR (CDC13) 8 ppm: (a mixture of cis and trans) 1 .56-2 .43
( 12H, m) , 2 . 94-3 . 12 ( 4H, m) , 3 . 7 9 ( 6H, s ) , 6 . 85 ( 4H, d, J=8 .
55Hz ) ,
7 . 15 ( 2H, d, J=8 . 55Hz ) , 7 . 17 ( 2H, d, J=8 . 55Hz ) , 9 . 69 ( 1H, s )
,
9.70(lH,s).
(Reference Example 32)
3-(4-Methoxyphenyl)cyclopentane carboaldehyde (4.30g) and
benzylamine (2.49g) were refluxed for 3 hours in benzene (100
ml) in the presence of p-toluenesulfonic acid (452 rng) using
a Dean-Stark appara~u.s while removing the water generated.
After distilling off the benzene under reduced pressure, it
was dissolved in methanol (100 ml) while cooling on ice, sodium
57

-CA 02235840 1998-04-24
borohydride (890 mg) was gradually added and the mixture was
stirred at room temperature for 18 hours. After concentrating
the reaction solution, water was added, and extraction with
chloroform was followed by washing with saturated sodium
bicarbonate water and saturated saline. After drying with
anhydrous magnesium sulfate, the solvent was distilled off
under reduced pressure to produce a light yellow oily substance
which was then purified by silica gel.column chromatography
(n-hexane : ethyl acetate=2 : 1 -~ 1: 1 -~ 1 : 2 ) to give 5 . 60g of
N-benzyl-3-(4-methoxyphenyl)cyclopentylrnethylamine (96.10
yield) .
1H-NMR(CDC13)8 ppm:(a mixture of cis and trans)1.21-2.34
(7H, m) , 2. 58-2. 64 (2H,m) , 2.98-3. O1 (lH,m) , 3.75 (3H, s) ,
3.79 (2H, s ) , 6. 81 (2H, d, J=7. 94Hz) , 7. 12 (2H, d, J=7 . 94Hz) , 7.24-
7 . 32 ( 5H, m) .
N-Benzyl-N-[3-(4-methoxyphenyl)cyclopentylmethyl) amine
(free compound, 5. 60g) was dissolved in ethyl acetate (100 ml) ,
4 N HCl-ethyl acetate solution ( 10 ml ) was added, and the
mixture was stirred at room temperature for 2 hours. The
deposited crystals were filtered and air-dried to give 6.30g
of N-benzyl-N-[3-(4-methoxyphenyl)cyclopentylmethyl)amine
hydrochloride (quantitative yield).
(Reference Example 33)
58

-CA 02235840 1998-04-24
N-Benzyl-N-[3-(4-methoxyphenyl)cyclopentylmethyl]amine
hydrochloride (6.30g) was dissolved in acetic acid (130 ml),
and loo palladium-carbon (l.lg) was added. After substituting
the reaction vessel with hydrogen gas, hydrogen addition was
carried out at normal pressure, 80°C for 2 hours. After the
reaction, the catalyst was filtered off and the solvent was
distilled off under reduced pressure to produce light yellow
crystals which were then washed with diethyl ether to give 4 . 31g
of 3-(4-methoxyphenyl) cyclopentylmethylamine hydrochloride
(94.0%) .
1H-NMR (CD30D) b ppm: (mixture of cis and trans) 1 . 19-2.49
(7H,m) , 2. 94-3.10 (3H,m) , 3.76 (3H, s) , 6. 83 (2H, d, J=8.55Hz) ,
7 . 16 ( 2H, d, J=8 . 55Hz ) .
(Reference Example 34)
2-Cyclopenten-1-one (25.9g) and cerium chloride
heptahydrate (118g) were dissolved in methanol (400 ml).
After gradually adding sodium borohydride (12.6g) while
cooling on ice, the mixture was stirred at room temperature
for 1 . 5 hours. The reaction solution was poured into ice water,
and after extraction with ether and drying with anhydrous
magnesium sulfate, the solvent was distilled off under reduced
pressure to give 7.lOg of 2-cyclopenten-1-of (26.7°x).
1H-NMR (CD30D) 8 ppm: 1.56-1. 73 (2H,m) , 2 .18-2. 35 (2H,m) ,
59

CA 02235840 1998-04-24-
2. 45-2.56 (lH,m) , 5.82-5. 85 (lH,m), 5.98-6.00 (lH,m) .
(Reference Example 35)
Palladium acetate (1.21g), potassium acetate (31.7g) and
n-tetrabutylammonium chloride (31.2g) were dissolved in
acetonitrile (100 ml) under an argon air flow. After adding
a solution of 2-cyclopenten-1-of (9.03g) in acetonitrile (80
ml) and a solution of ethyl 4-iodobenzoate (59.3g) in
acetonitrile (70,m1) in that order, the mixture was stirred
at 60°C for 28 hours. After adding a saturated aqueous
solution of ammonium chloride, the mixture was filtered with
cerite, extracted with diethyl ether and washed with saturated
saline. After drying with anhydrous magnesium sulfate, the
solvent was distilled off under reduced pressure to produce
an oily substance which was then purified by silica gel column
chromatography (n-hexane:ethyl acetate=20:1) to give 7.29g of
ethyl 4-(3-oxocyclopentyl) benzoate (29.3 yield).
1H-NMR (CDC13) 8 ppm: 1 .39 (3H, t, J=7. 32Hz) , 1 . 91-2. 06 (lH,m) ,
2 . 2 3-2 . 51 ( 4H, m) , 2 . 67 ( 1H, dd, J=7 . 33,17 . 7Hz ) , 3 . 41-3 . 50
( 1H, m) ,
4 . 3 6 ( 2H, q, J=7 . 32Hz ) , 7 . 33 ( 2H, d, J=8 . 55Hz ) , 8 . 02 ( 2H, d,
J=8 . 55Hz ) .
(Reference Example 36)
3- ( 3-methoxyphenyl ) cyclopentanone was obtained from ethyl
acetoacetate and 3-methoxyphenasyl bromide according to the
methods of Reference Examples 25 to 27.

CA 02235840 1998-04-24
1H-NMR (CDC13) 8 ppm: 1. 90-2 . 06 ( 1H, m) , 2 . 22-2 . 51 ( 4H, m) ,
2.66(lH,dd,J=7.32,18.3Hz),3.33-3.46(lH,m),3.81(3H,s),
6.78-6.86 (3H,m) , 7.26 (lH,m) .
The following compounds were obtained by the methods in
Reference Examples 28 to 29.
(Reference Example 37)
N-Benzyl-N-[3-(3-methoxyphenyl)cyclopentyl]amine
1H-NMR(CDC13) 8 ppm:(a mixture of cis and trans)1.42-2.16
(l3H,m) , 2 .30-2. 40 (lH,m) , 2. 92-3. 05 (lH,m) , 3. 19-3.36 (3H,m) ,
3 . 74 ( 6H, s ) , 3 . 77 ( 4H, s ) , 6 . 69-6 . 85 ( 6H, m) , 7 . 15-7 . 31 (
12H, m) .
(Reference Example 38)
3-(3-Methoxyphenyl)cyclopentylamine hydrochloride
1H-NMR (CD30D) 8 ppm: (a mixture of cis and trans) 1.70-2.37,
(llH,m) , 2 .48-2.58 (lH,m) , 3.00-3.20 (lH,m) , 3.31-3.38 (lH,m) ,
3.71-3.85 (4H,m) , 6.74=6.88 (6H,m) , 7.20 (2H, t, J=7. 94Hz) .
[Example 1]
To a solution of (2R)-2-(3-chlorophenyl)-2-hydroxy-N-
[3-(3-methoxyphenyl) cyclohexyl]acetamide:diastereomer A
(trans-H) and diastereomer B (trans-L)
(trans)-3-(3-Methoxyphenyl) cyclohexylamine hydrochloride
(5. 40g) in methylene chloride there were added (R) - (-) -m-
chloromandelic acid (4.17g), BOP reagent (9.88g) and
triethylamine ( 6. 78g) , and the mixture was stirred overnight.
61

A 02235840 1998-04-24
After terminating the reaction by addition of saturated
saline to the reaction solution, extraction was performed with
ethyl acetate, and after a series of washing with to
hydrochloric acid, saturated sodium bicarbonate and saturated
saline, the solution was dried with anhydrous magnesium sulfate .
The solvent was distilled off under reduced pressure to produce
a crude product which was then separated and purified by silica
gel column chromatography (n-hexane:ethyl acetate=4:1) to
give 5.718 of (2R)-2-(3-chlorophenyl)-2-hydroxy-N-[3-(3-
methoxyphenyl) cyclohexyl)acetamide as a diastereomeric
mixture (68.40 yield). Repeated silica gel column
chromatography (n-hexane: ethyl acetate=4:1) allowed
separation of thetwo diastereomers. Diastereomer A (trans-H)
was obtained from the earlier eluted fraction and the
diastereomer B (trans-L) was obtained from the later eluted
fraction.
Diastereomer A(trans-H) 1H-NMR(CDC13) 8 ppm: 1.45-
2.00(8H,m), 2.40-2.49(lH,m),3.79(3H,s),4.20-
4.26(lH,m),5.01(lH,s), 6.60-6.75(4H,m),7.17-
7 . 31 ( 4H, m) , 7 . 44 ( 1H, s ) . Diastereomer B (trans-L) 1H-
NMR (CDC13) 8 ppm: 1.34-1. 96 (8H,m) , 2.49-2. 64
(lH,m) , 3.79 (3H, s) , 4.18-4.29 (lH,m) , 5. 02 (1H, s) , 6. 64-6.77
(4H,m) , 7 . 18-7.31 (4H,m) , 7.45~(1H, s) .
62

A 02235840 1998-04-24
[Example 2]
( 2R) -2- ( 3-Chlorophenyl ) -2-hydroxy-N- [ 3- ( 3-
methoxyphenyl)cyclohexyl]acetamide:Diastereomer C(cis-
H) and, Diastereomer D(cis-L)
Diastereomer C (cis-H) and diastereomer D (cis-L) were
obtained from (cis)-3-(3-methoxyphenyl) cyclohexylamine
hydrochloride and (R) - (-) -m-chloromandelic acid, according to
the method of Example 1.
Diastereomer C (cis-H) 1H-NMR (CDC13) 8 ppm: 1 . 00-1. 62 (4H,m) ,
1.70-2. 18 (4H,m) , 2.53-2.74 (lH,m) , 3. 79 (3H, s) , 4.00-4.25 (lH,m) ,
4.94 (1H, s) , 6.23 (lH,broad s) , 6.70-6.78 (3H,m) , 7.20-7.38 (4H,
m) , 7. 40 ( 1H, s) . Diastereomer D (cis-L) 1H-NMR (CDC13) 8 ppm:
1. 05-2 . 11 ( 8H, m) , 2 . 55-2 . 65 ( 1H, m) , 3 . 7 8 ( 3H, s ) , 3 . 7 0-4
. 02 ( 1H, m) ,
4.93(lH,s),6.31(lH,d,amide NH),6.70-6.78(3H,m),7.16-7.27
( 4H, m) , 7 . 38 ( 1H, s ) .
[Example 3]
To a solution of diastereomer A obtained in Example l,
((2R)-2-(3-chlorophenyl)-2-hydroxy-N-[3-(3-methoxyphenyl)
cyclohexyl]acetamide) (2.79g) in anhydrous tetrahydrofuran
(85 ml) there was added dropwise at room temperature a
tetrahydrofuran solution (11.5 ml) containing 2 M borane-
dimethyl sulfide complex, and the mixture was refluxed for 2
hours. After adding methanol (10 ml) to the reaction solution
63

CA 02235840 1998-04-24
to suspend the reaction and stirring for 30 minutes, 4 N
HC1-ethyl acetate solution (5 ml) was added and stirring was
continued for 30 minutes.
After concentrating the solvent under reduced pressure, it
was dissolved in ethyl acetate and washed successively with
a saturated aqueous sodium bicarbonate solution and saturated
saline, and then dried with anhydrous magnesium sulfate. The
solvent was distilled off under reduced pressure to produce
a crude product which was then separated and purified by silica
gel column chromatography (n-hexane:ethyl acetate=2:1) to
give 2.15g of (1R)-1-(3-chlorophenyl)-2-[3-(3-methoxyphenyl)
cyclohexylamino]ethanol (trans-H) (79.90 yield).
1H-NMR (CDC13) 8 ppm: 1.41-1 .95 (BH,m) , 2.50-3. 08 (4H,m) ,
3 . 80 (3H, s ) , 4 . 66 (1H, dd, J=3. 05, 9. l6Hz) , 6. 70-6. 85 (3H,m) ,
7.18-7.28 (4H,m) , 7.39 (1H, s) .
Elemental analysis : as C2lHzsC1N02
Calculated: C; 70.08, H; 7.28, N; 3.89
Found: C; 69. 87, H; 7.33, N; 3.81 mp. 60 - 62°C, [ a ]D=-29.5°
(c=1. O1, CH30H) .
After dissolving 320 mg of free bases in diethyl ether (10
ml) and adding 4 N HC1-ethyl acetate solution (5 ml), the
mixture was stirred for 1. 5 hours . The solvent was distilled
off under reduced pressure to give 175 mg of (1R)-1-(3-
64

A 02235840 1998-04-24-
chlorophenyl ) -2- [ 3- ( 3-methoxyphenyl )
cyclohexylamino]ethanol hydrochloride as colorless crystals
(49. 7 o yield) .
1H-NMR (CDC13) 8 ppm: 1.48-2.20 (7H,m) , 2.25-2 .46 (lH,m) ,
2.85-3.10 (lH,m),3.20-3:60(3H,m),3.73(3H,s),5.40(lH,d,J=
9.77Hz),5.70(lH,broad s),6.62(lH,dd,J=2.44,7.93Hz),6.77
(lH,dd,J=2.44,7.93Hz),7.02-7.24(4H,m),7.35(lH,s),
8 . 17 ( 1H, broad s, ) , 10 . 2 ( 1H, broad s ) .
Elemental analysis : as C21H2-,C12N02
Calculated: C; 63.64, H; 6.87, N; 3.53
Found: C; 63 . 73, H; 7 . 04, N; 3 . 48 mp. 158 - 159°C, [ a ] D=-45 .
2 °
(c=1.00, CH30H) .
The compounds for Example 4 to 6 were synthesized according
to the method of Example 3.
[Example 4]
(1R)-1-(3-chlorophenyl)-2-[3-(3-methoxyphenyl)
cyclohexylamino]ethanol hydrochloride (trans-Z) was obtained
from diastereomer B obtained in Example 1.
1H-NMR (CDC13) b ppm: 1.37-2. 12 (8H,m) , 2. 60-3.08 (4H,m) ,
3 . 8 0 ( 3H, s ) , 4 . 65 ( 1H, dd, J=3 . 6 6, 9 . 16H z ) , 6 . 7 0- 6 . 8 3
( 3H, m) ,
7.18-7.25 (4H,m) , 7.39 (1H, s) .
[Example 5]
(1R)-1-(3-Chlorophenyl)-2-[3-(3-methoxyphenyl)

-CA 02235840 1998-04-24
cyclohexylamino]ethanol (cis-H) was obtained from
diastereomer C obtained in Example 2.
1H-NMR (CDC13) 8 ppm: 0. 92-1 .52 (4H,m) , 1.76-2 . 14 (4H,m) ,
2 . 4 6-2 . 6 9 ( 3H, m) , 3 . O 1 ( 1H, dd, J=3 . 66, 12 . 2Hz ) , 3 . 8 0 (
3H, s ) ,
4 . 60 ( 1H, dd, J=3 . 66, 9 . l6Hz ) , 6 . 68-6 . 84 ( 3H, m) , 7 . 14-7 . 30
( 4H, m) ,
7 . 37 ( 1H, s ) .
[Example 6]
(1R)-1-(3-Chlorophenyl)-2-[3-(3-methoxyphenyl)
cyclohexylamino]ethanol (cis-L) was obtained from
diastereomer D obtained in Example 2.
1H-NMR (CDC13) 8 ppm: 0 . 99-1. 53 ( 4H, m) , 1. 77-2 .16 ( 4H, m) ,
2. 45-2 .70 (3H,m) , 3. 00 (1H, dd, J=3.66, 12.2Hz) , 3. 80 (3H, s) ,
4 . 61 ( 1H, dd, J=3 . 66, 8 . 55Hz ) , 6 . 69-6 . 81 ( 3H, m) , 7 . 16-7 . 28
( 4H, m) ,
7.37(lH,s).
[Example 7]
A solution of the (1R)-1-(3-chlorophenyl)-2-[3-(3-
methoxyphenyl) cyclohexylamino]ethanol (trans-H) obtained in
Example 3 (2.21g) in methylene chloride (100 ml) was cooled
to -10°C. After slowly adding dropwise a solution of 1 M boron
tribromide in methylene chloride thereto, the mixture was
stirred for 2 hours while gradually heating it to room
temperature. The reaction solution was poured a portion at
a time into an aqueous sodium bicarbonate solution while
66

~~~~ ~ ~- A 02235840 1998-04-24
cooling on ice in order to terminate the reaction, and the
extraction was performed with a mixed solvent of
chloroform: ethanol=5:1. After washing the organic layer with
saturated saline, it was dried with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to produce
a crude product which was then separated and purified by silica
gel column chromatography (chloroform-chloroform: methanol=
2 0 : 1 ) to give 1. 72 g o f ( 1R) -1- ( 3-chlorophenyl ) -2- [ 3- ( 3-
hydroxyphenyl)cyclohexylamino] ethanol (traps-H) (Sl.lo
yield) .
1H-NMR(CDC13) ~ ppm:1.35-1.96(8H,m),2.60-3.03(4H,m),4.73
( 1H, dd, J=3 . 66, 9 . l6Hz ) , 6 . 59-6 . 7 9 ( 3H, m) , 7 . 07-7 . 28 ( 4H,
m) ,
7.35(1H,5) .
The compounds for Embodiments 8 to 10 were synthesized
according to the method of Embodiment 7.
[Example 8]
(1R)-1-(3-Chlorophenyl)-2-[3-(3-hydroxyphenyl)
cyclohexylamino]ethanol (traps-L) was obtained from the
traps-L obtained in Example 4.
1H-NMR (CDC13) 8 ppm: 1 .40-1.90 (BH,m) , 2. 61-3. 00 (4H,m) ,
4 . 74 ( 1H, dd, J=3 . 05, 9 . l5Hz ) , 6 . 64-6 . 74 ( 3H, m) , 7 . 10-7 . 25
( 4H, m) ,
7.32(lH,s) .
[Example 9]
67

~A 02235840 1998-04-24-
(1R)-1-(3-Chlorophenyl)-2-[3-(3-hydroxyphenyl)
cyclohexylamino]ethanol (cis-H) was obtained from the cis-
H obtained in Example 5.
1H-NMR (CDC13) 8 ppm: 1. O1-1 .49 (4H, m) , 1 .75-2 . 13 (4H, m) ,
2 . 44-2 . 74 ( 3H, m) , 2 . 96 ( 1H, dd, J=3 . 66, 12 . 2Hz ) , 4 . 68 ( 1H,
dd, J=
3 . 66, 9. l6Hz) , 6. 61-6.76 (3H,m) , 7. 10-7.28 (4H,m) ; 7.34 (1H, s) .
[Example 10]
(1R)-1-(3-Chlorophenyl)-2-[3-(3-hydroxyphenyl)
cyclohexylamino]ethanol hydrochloride (cis-L) was obtained
from the cis-L obtained in Embodiment 6.
1H-NMR (CDC13+CD30D) 8 ppm: 1. 30-2 . 60 ( 9H,m) , 2. 85-3 . 30
( 3H, m) , 5 . 14-5 . 22 ( 1H, m) , 6 . 65-6 . 71 ( 3H, m) , 7 . 08-7 . 16 (
1H, m) ,
7.28(3H,t),7.36(lH,s),7.44(lH,s).
[Example 11]
(1R)-1-(3-Chlorophenyl)-2-[3-(3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
hydrochloride (trans-H)
(Boc addition)
To a solution of the (1R)-1-(3-chlorophenyl)-2-[3-(3-
hydroxyphenyl) cyclohexylamino]ethanol obtained in Example 7
(1.50g) in dimethylformamide (30 ml) there were added a
solution of 1 M di-tert-butylcarbonate in dimethylformamide
(4.35 ml) and triethylamine (1.32g), and the mixture was
68

-CA 02235840 1998-04-24
stirred overnight. Water was added to the reaction solution
and extraction was performed with ethyl acetate. After
washing the organic layer 3 times with water and once with
saturated saline, it was dried with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to produce
a crude product which was then separated and purified by silica
gel chromatography (n-hexane: ethyl acetate=4:1) to give 1.28g
of (2R)-3-[3-[[2-(3-chlorophenyl)-2-hydroxy-N-tert-
butoxycarbonyl]ethylamino]cyclohexyl]phenol (trans-H)
(66.40 yield) .
(Alkylation)
To a solution of the (2R)-3-[3-[[2-(3-chlorophenyl)-2-
hydroxy-N-tert-butoxycarbonyl]ethylamino]cyclohexyl]phenol
(1 .28g) in acetone (50 ml) there were added anhydrous potassium
carbonate (1.99g) and ethyl bromoacetate (965 mg), and the
mixture was refluxed for 2 hours. After the reaction, the
deposited salt was filtered off and the solvent was
concentrated under reduced pressure. The resulting crude
product was separated and purified by silica gel column
chromatography (n-hexane: ethyl acetate=3:1 to 1:1) to give
1.49g of (2R)-ethyl[3-[3-[[2-(3-chlorophenyl)-2-hydroxy-N-
tert-butoxycarbonyl]ethylamino]cyclohexyl]phenoxy]acetate
(trans-H) (97.40 yield).
69

CA 02235840 1998-04-24
(Boc removal)
After dissolving (2R)-ethyl[3-[3-[[2-(3-chlorophenyl)-
2-hydroxy-N-tert-butoxycarbonyl]ethylamino]cyclohexyl]
phenoxy] acetate ( 1 . 4 9g) in ethyl acetate ( 5 ml ) , 4 N HC1-ethyl
acetate solution (20 ml) was added and the mixture was stirred
for 2.5 hours at room temperature. The reaction solution was
rendered alkaline with a saturated aqueous sodium bicarbonate
solution and extracted with ethyl acetate. The organic layer
was washed with saturated saline and then dried with anhydrous
magnesium sulfate. After distilling off the solvent under
reduced pressure, it was dissolved in diethyl ether (5 ml) and
ethyl acetate (5 ml), 4 N HC1-ethyl acetate solution (10 ml)
was added, and the mixture was stirred overnight at room
temperature. The reaction solution was concentrated under
reduced pressure to produce crude crystals which were then
washed with isopropyl ether to give 1.05g of (1R)-1-(3-
chlorophenyl)-2-[3-(3-ethoxycarbonylmethoxyphenyl)
cyclohexylamino]ethanol hydrochloride (trans-H) (79.90
yield) .
1H-NMR (CDC13) 8 ppm (free compound ) : 1.30 (3H, t, J=7.32Hz) ,
1 . 37-1. 98 ( 8H, m) , 2 . 61-3 . 11 ( 6H, m) , 4 . 27 ( 2H, q, J=7 . 32Hz )
,
4 . 60 (2H, s ) , 4 . 71 (1H, dd, J=3. 66, 9. l6Hz) , 6. 67-6. 72 ( lH,m) ,
6.81-6.87 (2H,m) , 7.20-7.26~(4H,m), 7.40 (1H, s) .

--CA 02235840 1998-04-24-
Elemental analysis : as CZ9H31C12NO9
Calculated:C;61.54,H;6.67,N;2.99.
Found: C; 61. 34, H; 6. 68, N; 2 . 72 . mp. 137-138°C,
[ a ] p=-2 9 . 1° , ( c=1. O 1, CHC13 ) .
The compounds for Example 12 to 14 were synthesized
according to the method of Example 11.
[Example 12 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol(trans-
L)
1H-NMR (CDC13) 8 ppm: 1 .29 (3H, t, J=6.70Hz) , 1.36-1 .97 (8H,m) ,
2 .59-3.02 ( 6H, m) , 4.27 (2H, q, J=6.70Hz) , 4. 60 (2H, s) , 4. 67
(1H, dd, J=3. 66, 9. l6Hz) , 6. 65-6.72 (lH,m) , 6. 80-6.86 (2H,m) ,
7.10-7.27(4H,m),7.38(lH, s).
[Example 13] (1R)-1-(3-Chlorophenyl)-2-[3-(3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol(cis-H)
1H-NMR (CDC13) 8 ppm:0.98-1 .47 (4H,m) , 1 .28 (3H, t, J=7.30Hz) ,
1.80-2.13 (4H,m) , 2.45-3.00 (6H,m) , 4.26 (2H, q, J=7.30Hz) ,
4.59 (2H, s ) , 4.58-4.68 (lH,m) , 6. 69-6.83 (3H,m) , 7.15-7.28 (4H,m) ,
7.36(lH,s) .
[Example 14 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol(cis-L)
1H-NMR (CDC13) 8 ppm: 0. 98-1 .51 (4H,m) , 1.30 (3H, t, J=7.30Hz) ,
1.78-2.18(4H,m),2.43-3.01(6H,m),4.27(2H,q,J=7.30Hz),
71

-.-CA 02235840 1998-04-24
4 . 60 (2H, s ) , 4 . 58-4 . 68 ( 1H, m) , 6 . 68-6 . 80 (2H, m) , 6 . 83 (
1H, d, J=
7.30Hz), 7.17-7.26(4H,m),7.36(lH, s).
[Example 15]
Sodium ( 2R) - [ 3- [ 3- [ 2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]cyclohexyl]phenoxy]acetate (trans-H)
To a solution of the trans-H obtained to the method of Example
11, ( 1R) -1- ( 3-chlorophenyl ) -2- [ 3- ( 3-
ethoxycarbonylmethoxyphenyl) cyclohexylamino] ethanol (free
base) (527 mg) in methanol (15 ml) there was added 1 N sodium
hydroxide solution (1.16 ml), and the mixture was stirred at
room temperature for 2 hours. After concentrating the
reaction solution under reduced pressure (repeated azeotropy
with toluene), it was washed with diethyl ether to give 351
mg of sodium (2R)-[3-[3-[2-(3-chlorophenyl)-2-
hydroxyethylamino] cyclohexyl] phenoxy] acetate (trans-H) as a
pale yellow powder (67.50 yield).
1H-NMR(CD30D) 8 ppm:1.47-1.98(8H,m),2.68-2.88(3H,m),3.00
(lH,broad s) , 4.37 (2H, s) , 4.75-4.77 (lH,m) , 6. 68-6.84 (3H,m) ,
7 .10-7.38 (4H,m) , 7.42 (1H, s) .
The following compounds were synthesized according to the
methods of Examples 1 to 15.
[Example 16]
( 2R) -2- ( 3-Chlorophenyl ) -2-hydroxy-N- [ 3- ( 4-
72

_ _ -_ _._ _._._-_--____ --_-.._ -
CA 02235840 1998 04 24-
methoxyphenyl)cyclohexyl]acetamide (trans-H)
1H-NMR (CDC13) 8 ppm: 1 . 34-1 . 96 ( 8H, m) , 2 . 31-2 . 43 ( 1H, m) ,
3.75(lH,d,J=4.27Hz),3.78(3H,s),4.23-4.26(lH,m),5.03
( 1H, d, J=4 . 27Hz ) , 6 . 47 ( 1H, broad d, J=7 . 32Hz ) , 6 . 82 ( 2H, d,
J=
8 . 55Hz ) , 7 . 03 ( 2H, d, J=8 . 55Hz ) , 7 . 32-7 . 33 ( 3H, m) , 7 . 45 (
1H, s ) .
[Example 17]
(2R)-2-(3-Chlorophenyl)-2-hydroxy-N-[3-(4-
methoxyphenyl)cyclohexyl]acetamide (trans-L)
1H-NMR(CDC13)8 ppm:1.31-1.96(8H,m),2.50-2.61(lH,m),
3.70-3. 71 (lH,m) , 3. 78 (3H, s) , 4.22-4.27 (lH,m) , 5. 03 (1H, d, J=
3 . 66Hz ) , 6 . 60 ( 1H, broad d, J=7 . 32Hz ) , 6 . 83 ( 2H, d, J=8 . 55Hz )
,
7 . 08 ( 2H, d, J=8 . 55Hz ) , 7 . 31-7 . 32 ( 3H, m) , 7 . 4 6 ( 1H, s ) .
[Example 18] (2R)-2-(3-Chlorophenyl)-2-hydroxy-N-
[3-(4-methoxyphenyl)cyclohexyl]acetamide(cis-H)
1H-NMR (CDC13) S ppm: 1 .09-1.57 (4H,m) , 1.77-2 .10 (4H,m) ,
2 . 54-2 . 63 ( 1H, m) , 3 . 62 ( 1H, d, J=4 . 27Hz ) , 3 . 7 8 ( 3H, s ) , 3
. 81-3 . 97
( 1H, m) , 4 . 96 ( 1H, d, J=3 . 66Hz ) , 6 . O1 ( 1H, broad d, J=7 . 94Hz ) ,
6 . 82 ( 2H, d, J=8 . 55Hz ) , 7 . 08 ( 2H, d, J=8 . 55Hz ) , 7 . 27-7 . 2 8 (
3H, m) ,
7.39 (1H, s) .
[Example 19] (2R)-2-(3-Chlorophenyl)-2-hydroxy-N-
[3-(4-methoxyphenyl)cyclohexyl]acetamide(cis-L)
1H-NMR (CDC13) 8 ppm: 1 .06-1 . 60 (4H,rn) , 1 .79-2 . 14 (4H,m) ,
2.54-2.66(lH,m),3.54-3.56(lH,m),3.78(3H,s),3.81-3.98
73

-=CA 02235840 1998-04-24
( 1H, m) , 4 . 97 ( 1H, d, J=3 . 66Hz ) , 6 . 07 ( 1H, broad d, J=3 . 05Hz ) ,
6. 82 (2H, d, J=8.55Hz) , 7. 09 (2H, d, J=8.55Hz) , 7.27-7.28 (3H,m) ,
7.39(lH,s) .
[Example 2 0 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 4-
methoxyphenyl)cyclohexylamino]ethanol(trans-H),
1H-NMR (CDC13) 8 ppm: 1 . 37-1. 91 (8H,m) , 2. 62 (1H, dd, J=
8 . 55, 12 . 2Hz ) , 2 . 77-2 . 90 ( 1H, m) , 2 . 96 ( 1H, dd, J=3 . 66, 12 .
2Hz ) ,
3 . 02-3 . 05 ( 1H, m) , 3 . 7 9 ( 3H, s ) , 4 . 64 ( 1H, dd, J=3 . 6 6, 8 .
55Hz ) ,
6. 84 (2H, d, J=9. l6Hz) , 7 .14 (2H, d, J=9. l6Hz) , 7.25-7 .26 (3H, m) ,
7.40(lH,s).
[Example 21] (1R)-1-(3-Chlorophenyl)-2-[3-(4-
methoxyphenyl)cyclohexylamino]ethanol(trans-h)
1H-NMR (CDC13) 8 ppm: 1 .36-1. 93 (8H,m) , 2. 62 (1H, dd, J=
8.55,12.2Hz),2.73-2.87(lH,m),2.97(lH,dd,J=3.66,12.2Hz),
3 . 02-3 . 05 ( 1H, m) , 3 . 7 9 ( 3H, s ) , 4 . 65 ( 1H, dd, J=3 . 6 6, 8 .
55Hz ) ,
6 . 8 5 ( 2H, d, J=8 . 55Hz ) , 7 .13 ( 2H, d, J=8 . 55Hz ) , 7 . 2 5-7 . 2 6
( 3H, m) ,
7.40(lH,s) .
[Example 22 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 4-
methoxyphenyl)cyclohexylamino]ethanol(cis-H)
1H-NMR (CDC13) 8 ppm: 0.98-1. 51 (4H,m) , 1 .79-2.16 (4H,m) ,
2.46-2 .70 (3H,m) , 3.02 (1H, dd, J=3.66, 12 .2Hz) , 3. 79 (3H, s) ,
4 . 61 ( 1H, dd, J=3 . 6 6, 8 . 55Hz ) , 6 . 84 ( 2H, d, J=8 . 55Hz ) , 7 .11
( 2H, d, J=
8.55Hz),7.23-7.25(3H,m),7.37(lH,s) .
74

--CA 02235840 1998-04-24-
[Example 23 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 4-
methoxyphenyl) cyclohexylamino]ethanol (cis-L)
1H-NMR (CDC13) 8 ppm: 1 .00-1 . 51 (4H,m) , 1 .78-2. 17 (4H,m) ,
2. 44-2.71 (3H,m) , 3. 00 (1H, dd, J=3. 66, 12.2Hz) , 3. 79 (3H, s) ,
4. 61 (1H, dd, J=3. 66, 8.54Hz) , 6.84 (2H, d, J=8.55Hz) , 7. 12 (2H, d, J=
8.55Hz),7.21-7.25(3H,m),7.37(lH,s) .
[Example 24 ] ( 1R) -1- (3-Chlorophenyl) -2- [3- ( 4-
hydroxyphenyl)cyclohexylamino]ethanol(trans-H)
1H-NMR (CDC13) 8 ppm: 1.37-1 . 91 (8H,m) , 2 . 66 (1H, dd, J=
9. 16, 12.2Hz) , 2.74-2. 88 (lH,m) , 2. 94 (1H, dd, J=3. 66, 12.2Hz) ,
3 . 00-3 . 07 ( 1H, m) , 3 . 30 ( 3H, broad s ) , 4 . 68 ( 1H, dd, J=3 . 66, 9
. l6Hz ) ,
6. 75 (2H, d, J=8.55Hz) , 7. 06 (2H, d, J=8.55Hz) , 7.23-7.25 (3H,m) ,
7.39(lH,s).
[Example 25] (1R)-1-(3-Chlorophenyl)-2-[3-(4-
hydroxyphenyl)cyclohexylamino]ethanol(trans-L)
1H-NMR (CDC13) 8 ppm: 1.36-1 . 93 (BH,m) , 2 . 65 (1H, dd, J=
8 . 55, 12 . 2Hz ) , 2 . 71-2 . 84 ( 1H, m) , 2 . 96 ( 1H, dd, J=3 . 66, 12 .
2Hz ) ,
3 . 00-3 . 06 ( 1H, m) , 3 . 30 ( 3H, broad s ) , 4 . 67 ( 1H, dd, J=3 . 66, 8
. 55Hz ) ,
6. 75 (2H, d, J=8 .55Hz) , 7. 06 (2H, d, J=8 .55Hz) , 7 .23-7.25 (3H,m) ,
7.38(lH,s) .
[Example 2 6 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- ( 3- ( 4-
hydroxyphenyl)cyclohexylamino]ethanol(cis-H)
1H-NMR (CDC13) 8 ppm: 1.04=1.51 (4H,m) , 1.69-2. 10 (4H,m) ,
?5

CA 02235840 1998-04-24
2.33-3. 02 (4H,m) , 3. 90 (3H,broad s) , 4.79 (1H, dd, J=2.44, 9. l6Hz) ,
6 . 73 ( 2H, d, J=8 . 54Hz ) , 6 . 93 ( 2H, d, J=8 . 54Hz ) , 7 .13-7 . 23 (
3H, m) ,
7 . 34 ( 1H, s ) .
[Example 27] (1R)-1-(3-Chlorophenyl)-2-[3-(4-
hydroxyphenyl)cyclohexylamino]ethanol(cis-L)
1H-NMR (CDC13+CD30D) b ppm: 1. 00-1.54 (4H,m) , 1 .76-2 .14,
(4H,m) , 2. 40-2.96 (4H,m) , 4.66-4.75 (lH,m) , 6.74-6.77 (2H,m) ,
7.00-7. 05 (2H,m) , 7.25 (3H,broad s) , 7.37 (1H, s) .
[Example 28] (1R)-1-(3-Chlorophenyl)-2-[3-(4-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
hydrochloride (trans-H)
1H-NMR (CD30D) 8 ppm: 1 .27 (3H, t, J=7 . 32Hz) , 1. 68-1. 96 ( 6H,m) ,
2.00-2.24(2H,m),2.96-3.06(lH,m),3.10(lH,dd,J=10.4;12.8Hz),
3.25-3.26 (lH,m) , 3.50-3.59 (lH,m) , 4.23 (2H, q, J=7.32Hz) ,
4 . 66 (2H, s ) , 5. 00 (1H, dd, J=3.05, 10.4Hz) , 6. 88 (2H, d, J=9. l6Hz) ,
7 .23 (2H, d, J=9.16Hz) , 7.33-7.39 (3H,m) , 7.50 (1H, s) .
[Example 29] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- (4-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
hydrochloride(trans-L)
1H-NMR (CD30D) 8 ppm: 1.27 (3H, t, J=7 . 32Hz) , 1 . 68-1. 95 ( 6H,m) ,
2.03-2.23(2H,m),2.95-3.05(lH,m),3.10(lH,dd,J=10.4,12.2Hz),
3 . 22-3 . 30 ( 1H, m) , 3 . 4 9-3 . 58 ( 1H, m) , 4 . 23 ( 2H, q, J=7 . 32Hz
) ,
4 . 66 (2H, s) , 4.98 (1H, dd, J=3.05, 10.4Hz) , 6.88 (2H, d, J=8.55Hz) ,
76

A 02235840 1998-04-24 -
7.23 (2H, d, J=8 .55Hz) , 7.33-7.39 (3H,m) , 7.50 (1H, s) .
[Example 30 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 4-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol (cis-
H)
1H-NMR (CDC13) b ppm: 1. 10-1 . 50 (4H, m) , 1 . 32 ( 3H, t, J=6. 72Hz ) ,
1 . 7 6-2 . 22 ( 4H, m) , 2 . 41-2 . 58 ( 1H, m) , 2 . 67-2 . 83 ( 2H, m) , 2
. 8 3-3 . 20
( 3H, m) , 4 . 27 ( 2H, q, J=6 . 72Hz ) , 4 . 58 (2H, s ) , 4 . 81 ( 1H, dd,
J=3 . 06,
9. l6Hz) , 6 . 82 (2H, d, J=8 . 55Hz) , 7 . 09 (2H, d, J=8 .55Hz) , 7 .20-7.30
(3H,m),7.38(lH,s) .
[Example 31] (1R)-1-(3-Chlorophenyl)-2-[3-(4-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol(cis-L)
1H-NMR (CDC13) b ppm: 1. 05-1 . 53 ( 4H, m) , 1 . 30 ( 3H, t, J=7 . 33Hz ) ,
1 . 77-2 . 75 ( 9H, m) , 2 . 99-3 . 08 ( 1H, m) , 4 . 27 ( 2H, q, J=7 . 33Hz )
,
4 . 5 9 ( 2H, s ) , 4 . 7 0 ( 1H, dd, J=3 . 05, 9 . 15Hz ) , 6 . 8 3 ( 2H, d,
J=6 . 7 2Hz ) ,
7 . 11 (2H, d, J=6.72Hz) , 7.18-7.30 (3H,m) , 7.37 (1H; s) .
[Example 32] Sodium (2R) - (4- [3- [2- (3-chlorophenyl) -
2-hydroxyethylamino]cyclohexyl]phenoxy) acetate (trans-H)
[Example 33] (1R)-1-(3-Chlorophenyl)-2-[3-(2-
methoxyphenyl) cyclohexylamino]ethanol (trans-H)
1H-NMR (CDC13) ~ ppm: 1.39-2 . 06 (BH,m) , 2.55-2 . 75 ( lH,m) ,
2.98-3 .15 (2H,m) , 3.25-3.45 (lH,m) , 3. 82 (3H, s) , 4. 61-4.78 (lH,m) ,
6. 80-7 .O1 (2H,m) , 7.13-7.38 (5H,m) , 7.42 (1H, s) .
[Example 34 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 2-
77

A 02235840 1998-04-24
methoxyphenyl) cyclohexylamino]ethanol (traps-L)
1H-NMR (CDC13) 8 ppm: 1 . 40-2 . 08 ( 8H, m) , 2 . 60-2 . 80 ( 1H, m) ,
2 . 94-3 . 16 ( 2H, m) , 3 . 24-3 . 43 ( 1H, m) , 3 . 82 ( 3H, s ) , 4 . 61-4
. 78 ( 1H, m) ,
6.80-7.03 (2H,m),7.11-7.36(SH,m),7.42 (lH,s) .
[Example 35]
(1R)-1-(3-Chlorophenyl)-2-[3-(2-methoxyphenyl)
cyclohexylamino]ethanol hydrochloride (cis-H)
1H-NMR (CDC13) -8 ppm: 1 .33-1.50 (2H,m) , 1.57-1 .98 (6H,m) ,
2.22-2.41 (2H,m),2.88-3.34(4H,m),3.78(3H,s),5.36(lH,dlike),
6.74-6. 84 (2H,m) , 7. 05-7.29 (5H,m) ,7.42 (1H, s) , 8.56 (lH,br s) ,
. 02 ( 1H, br s ) .
[Example 36] (1R)-1-(3-Chlorophenyl)-2-[3-(2-
methoxyphenyl)cyclohexylamino]ethanol hydrochloride(cis-L)
1H-NMR (CDC13) 8 ppm: 1.40-1.71 (4H,m) , 1.80-1 .91 (lH,m) ,
1 . 96-2 . 0 8 ( 1H, m) , 2 . 20-2 . 35 ( 1H, m) , 2 . 90-3 . 31 ( 4H, m) , 3
. 82 ( 3H, s ) ,
5.20(lH,dd,J=10.38,2.44Hz),6.83-6.96(2H,m),7.13-7.33(SH,m),
7.44(lH,s) .
[Example 37] (1R)-1-(3-Chlorophenyl)-2-[3-(2-
hydroxyphenyl) cyclohexylamino)ethanol (traps-H)
1H-NMR (CDC13) 8 ppm: 1. 40-2.10 (9H,m) , 2.78 (1H, dd, J=
12 . 21, 9 . 1 6Hz ) , 2 . 91 ( 1H, dd, J=12 . 21, 3 . 05Hz ) , 3 . 03-3 . 11
( 1H, m) ,
3 .20-3.35 (lH,m) , 4. 80 (1H, dd, J=9. 16, 3. 66Hz) , 6. 68-6.75 (lH,m) ,
6 . 80-6 . 91 ( 1H, m) , 7 . 00-7 . 28 (5H, m) , 7 . 35 ( 1H, s ) .
78

CA 02235840 1998-04-24
[Example 38] (1R)-1-(3-Chlorophenyl)-2-[3-(2-
hydroxyphenyl) cyclohexylamino]ethanol (trans-L)
1H-NMR ( CDC13 ) b ppm: 1. 4 0-2 . 10 ( 8H, m) , 2 . 69-3 .10 ( 4H, m) ,
2.75 (1H, dd, J=12.21, 9.77Hz) , 2. 88 (1H, dd, J=15.29, 3. 66Hz) ,
3.15-3. 33 ( lH,m) , 4 . 72 (1H, dd, J=9.46, 3. 66Hz) , 6. 79
(1H, dd, J=7 . 93, 1.22Hz) , 6. 83-6. 90 (lH,m) , 7 . 04 (1H, dd, J=
7.93, 1. 83Hz) , 7.10-7.18 (lH,m) , 7.20-7.33 (3H,m) , 7.39 (1H, s) .
[Example 39] (1R) -1- (3-Chlorophenyl) -2- [3- (2-
hydroxyphenyl)cyclohexylamino]ethanol(cis-H)
1H-NMR (CDC13) 8 ppm:1.09-1.54 (4H,m) , 1.75-2.20 (4H,m) ,
2. 64-3. 05 ( 4H,m) , 4 .74 (1H, dd, J=9. 63, 3. 66Hz) , 6. 73-6. 88 (2H, m) ,
6.98-7.05(lH,m),7.09-7.16(lH,m),7.20-7.30(3H,m),7.37
(1H, s) .
[Example 40] (1R)-1-(3-Chlorophenyl)-2-[3-(2-
hydroxyphenyl)cyclohexylamino]ethanol(cis-L)
1H-NMR (CDC13) 8 ppm: 1 .20-1.53 (4H,m) , 1. 64-1 .93 (2H,m) ,
2.00-2.14(lH,m),2.23-2.36(lH,m),2.70-3.14(4H,m),5.14,
(1H, d like) , 6.73-6. 88 (2H,m) , 6. 93-7.03 (2H,m) , 7. 13-7.26
(3H,m) , 7. 38 (1H, s) .
[Example 41] (1R) -1- (3-Chlorophenyl) -2- [3- (2-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
( trans-H )
1H-NMR (CDC13) b ppm: 1 .25 (3H, t, J=7.32Hz) , 1 . 57-1. 83 (4H,m) ,
79

CA 02235840 1998-04-24
1.93-2.25(3H,m),2.40-2.55(lH,m),2.87-3.00(lH,m),3.43-3.73
( 3H, m) , 4 . 07-4 . 23 ( 2H, m) , 4 . 53 ( 1H, d, J=16. 4 8Hz ) , 4 . 84 (
1H, d, J=
16.48Hz),5.59(lH,d like),5.94(lH,br s),6.63(lH,d,J=7.93Hz),
6. 91 (1H, t, J=7.32Hz) , 7.03-7.33 (SH,m) , 7.45 (1H, s) , 8.42 (lH,br
s) , 9.84 (lH,br s) .
[ a ] p=-13. 5° (c=0. 30, CHC13)
[Example 42 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 2-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol(trans-L)
1H-NMR (CDC13) b ppm: 1.27 (3H, t, J=7.32Hz) , 1 . 57-2.55 (8H,m) ,
3 .18-3 . 63 ( 4H, m) , 4 . 18 ( 2H, q, J=7 . 32Hz ) , 4 . 64 ( 1H, d, J=16 .
48Hz ) ,
4.81(lH,d,J=16.48Hz),5.56(lH,br s),6.00(lH,br s),
6 . 66 ( 1H, d, J=7 . 93Hz ) , 6 . 93 ( 1H, t, J=7 . 93Hz ) , 7 . 07-7 . 35 (
5H, m) ,
7.46(lH,s),8.02(lH,br s),10.28(lH,br s) .
[ a ] D=-6. 8° (c=0. 31, CHC13)
[Example 43 ] ( 1R) - ( 3-Chlorophenyl ) -2- [ 3- ( 2-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
hydrochloride (cis-H)
1H-NMR (CDC13) b ppm: 1. 00-1. 60 (4H,m) , 1.28 (3H, t, J=7 . 32Hz) ,
1 .80-2.25 (4H,m) , 2.40-2.80 (2H,m) ,2.96-3.18, (2H,m) ,
4.24 (2H, q, J=7.32Hz) , 4.56-4.73 (3H,m) , 6. 65-6.76, (lH,m) ,
6 . 90-7 . 00 ( 1H, m) , 7 . 08-7 . 33 ( 5H, m) , 7 . 37 ( 1H, s ) .
[ a ] D=-2 4 . 5° ( c=0 . 2 5, CHC13 )
[Example 44 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 2-

A 02235840 1998-04-24
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
hydrochloride (cis-L)
1H-NMR (CDC13) 8 ppm: 1 .24 (3H, t, J=7 .32Hz) , 1. 38-2. 00, ( 6H, m) ,
2.27-2.50(2H,m),2.97-3.37(4H,m),4.05-4.23,
(2H,m),4.58(2H,s), 5.38(lH,m),5.57(lH,br s),6.67(lH,d,J=
7 . 93Hz ) , 6 . 89 ( 1H, t, J=7 . 93Hz) , 7 . 05-7 . 30 ( 5H, m) ,
7 . 43 ( 1H, s ) , 8 . 52 ( 1H, br s ) , 10 . 02 ( 1H, br s ) . [ a ] D=-I-9 .
4°
(c=0.11, CHC13)
[Example 45] Sodium (2R) - (2- [3- [2- (3-chlorophenyl) -
2-hydroxyethylamino]cyclohexyl]phenoxy)acetate (trans-H)
1H-NMR (CD30D) 8 ppm: 1 . 10-1 ..64 (4H,m) , 1.75-2 .20 (4H,m) ,
2.72-3.00 (3H,m) , 3.24 (lH,m) , 4 . 39 (2H, s) , 4 .43 (1H, dd, J=
9.76, 3. 66Hz) , 6.74-6. 90 (2H,m) , 7.00-7.36 (SH,m) , 7 .41 (1H, s) .
[Example 46] To a solution of the trans-H compound,
( 1R) -1- ( 3-chlorophenyl ) -2- [ 3- ( 3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
(hydrochloride), obtained in Example 11 (220 mg) in ethanol
( 10 ml ) there was added 1 N sodium hydroxide solution ( 2 . 5 ml ) ,
and the mixture was stirred at room temperature for 2 hours .
After concentrating the reaction solution under reduced
pressure, water (2 ml) was added, and after adding 1 N aqueous
solution of hydrochloric acid (2.03 ml) while stirring and
cooling on ice, the deposited crystals were filtered off and
81

A 02235840 1998-04-24-
dried to give 153 mg of (2R) - (3- [3- [2- (3-chlorophenyl) -2-
hydroxyethylamino]cyclohexyl]phenoxy) acetic acid (trans-H)
as a white crystalline powder (81a yield).
[Example 47]
2-Methoxyethylamine (320 mg) was added to the (1R)-1-
(3-chlorophenyl)-2-[3-(4-ethoxycarbonylmethoxyphenyl)
cyclohexylamino)ethanol hydrochloride (trans-H) obtained in
Example 28 (100 mg), and the mixture was stirred at room
temperature for 71 hours. The reaction solution was separated
and purified by silica gel column chromatography
(chloroform:methanol=10:1) to obtain 97 mg of (2R)-2-[4-
[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]
phenoxy]-N-(2-methoxyethyl) acetamide (90~ yield).
1H-NMR (CDC13) 8 ppm: 1 .36-1.90 (8H,m) , 2.58 (2H,broad s) ,
2 . 64 ( 1H, dd; J=9 . 16, 12 . 2Hz ) , 2 . 7 8-2 . 90 ( 1H, m) , 2 . 93 ( 1H,
dd, J=
3 . 66, 12 . 2Hz ) , 2 . 99-3 . 13 ( 1H, m) , 3 . 36 ( 3H, s ) , 3 . 42-3 . 58
( 4H, m) ,
4.46(2H,s),4.66(lH,dd,J=3.66,9.16Hz),6.85(2H,d,J=8.55Hz),
6 . 97 ( 1H, broad s ) , 7 .15 ( 2H, d, J=8 . 55Hz ) , 7 . 23-7 . 27 ( 3H, m)
,
7.40(lH,s) .
[Example 48]
(2R)-2-[4-[3-[2-(3-Chlorophenyl)-2-hydroxyethylamino]
cyclohexyl]phenoxy]-N-ethylacetamide was obtained from the
compound of Example 28 and ethyl amine, according to the method
82

CA 02235840 1998-04-24
of Example 47.
1H-NMR(CDC13)8 ppm:1.19(3H,t,J=7.32Hz),1.39-2.16(BH,m),
2.78 (1H, dd, J=9. 77, 12.2Hz) , 2. 96-3. 15 (lH,m) , 3 .24 (lH,broad s) ,
3.40(2H,q,J=7.32Hz),4.40(2H,s),4.47(lH,broad s),4.58
( 1H, broad s ) , 4 . 97 ( 1H, dd, J=3 . 05, 9 . 7 7Hz ) , 6 . 61 ( 1H, broad
s ) ,
6. 78 (2H, d, J=8 . 55Hz) , 7.14 (2H, d, J=8 . 55Hz) , 7.23-7 .27 (3H, m) ,
7.37(lH,s).
[Example 49]
(2R)-2-[4-[3-[2-(3-Chlorophenyl)-2-hydroxyethylamino]
cyclohexyl]phenoxy]-1-piperidin-1-yl ethanone was obtained
from the compound of Example 28 and piperidine, according to
the method of Example 47.
1H-NMR (CDC13) ~ ppm: 1.36-1. 90 (l4H,m) , 2. 62 (1H, dd, J=
9.16,12.2Hz),2.66(2H,broad s),2.75-2.88(lH,m),
2 . 93 ( 1H, dd, J=3 . 66, 12 . 2Hz ) , 2 . 98-3 . 0 8 ( 1H, m) , 3 . 4 8-3 .
56 ( 4H, m) ,
4 . 63 ( 2H, s ) , 4 . 67 ( 1H, d, J=3 . 66Hz ) , 6. 77 ( 2H, d, J=8 . 55Hz )
, 7 . 12
(2H, d, J=8 .55Hz) , 7.25-7.27 (3H,m) , 7.40 (1H, s) .
[Example 50]
(2R)-2-[4-[3-[2-(3-Chlorophenyl)-2-hydroxyethylamino]
cyclohexyl]phenoxy]-N-(2-methoxyethyl) acetamide was
obtained from the compound of Example 30, (1R)-1-(3-
chlorophenyl)-2-[3-(4-ethoxycarbonylmethoxyphenyl)
cyclohexylamino]ethanol (cis-H) and 2-methoxyethylamine,
83

CA 02235840 1998-04-24
according to the method of Example 47.
1H-NMR (CDC13) b ppm: 1.00-1 .52 (4H,m) , 1 .76-2 . 40 (6H,m) ,
2.40-2.73(3H,m),3.01(lH,dd,J=3.66,12.2Hz),3.34(3H,s),3.41-
3 . 60 (4H,m) ; 4 . 47 (2H, s) , 4. 63 (1H, dd, J=3. 66, 9.15Hz) , 6. 85 (2H,
d,
J=8 . 55Hz ) , 6 . 94 ( 1H, broad s ) , 7 . 13 ( 2H, d, J=8 . 55Hz ) , 7 . 19-
7 . 28
(3H,m) , 7. 37 (1H, s) .
[Example 51]
( 2R) -Ethyl [ 4- [ 3- [ 2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]cyclohexyl)phenoxy]malonate was obtained
from the compound of Example 26 according to the method of
Example 11, using ethyl bromomalonate as the alkylating agent.
1H-NMR (CDC13) b ppm:1.23-1. 94 (l3H,m) , 2.15-2 .34 (2H, m) ,
2.42-2.58(lH,m),2.90-3.22(2H,m),4.27-4.36(4H,m),
. 08 ( 2H, broad s ) , 5 . 13 ( 1H, s ) , 5 . 22 ( 1H, d, J=6 . l OHz ) ,
6 . 83 ( 1H, d, J=8 . 55Hz ) , 7 . 04-7 . 08 ( 3H, m) , 7 . 23-7 . 27 ( 3H, m)
,
7.41(lH,s).
[Example 52]
Acetic acid ( 1 ml ) and Pt02 ( 160 mg) were added to a solution
of (R)-2-amino-1-(3-chlorophenyl) ethanol (600 mg) and 4-
phenylcyclohexanone (610 mg) in methanol (30 ml) , and hydrogen
addition was carried out at room temperature. After
consumption of the starting materials, the catalyst was
filtered off and the filtrate was concentrated under reduced
84

--CA 02235840 1998-04-24
pressure. Separation and purification by silica gel column
chromatography (chloroform:methanol=30:1) gave 43 mg of
(1R)-1-(3-chlorophenyl)-2-(4-phenylcyclohexylamino)
ethanol (4.Oo yield).
1H-NMR (CDC13) 8 ppm: 1 .04-1 . 56 (4H,m) , 1 . 80-2. 05 (4H,m) ,
2 . 37-3 . 95 ( 4H, m) , 4 . 69 ( 1H, dd) , 7 .11-7 . 30 ( 8H, m) , 7 . 39 (
1H, s ) .
Also obtained was 65 mg of the dechlorinated form, (1R)-1-
phenyl-2-(4-phenylcyclohexylamino)ethanol (6.3o yield).
1H-NMR ( CDC13 ) 8 ppm: 1. 57-1. 90 ( 8H, m) , 2 . 50-2 . 73 ( 3H, m) ,
2.90-3. 00 (2H,m) , 4. 70 (1H, dd) , 7. 12-7.22 (lOH,m) .
[Example 53J
To a solution of (R)-2-amino-1-(3-chlorophenyl)ethanol
(686 mg) and 3-(3-ethoxycarbonylmethoxyphenyl)cyclohexanone
(l.lg) in methanol (35 ml) there were added sodium
cyanoborohydride (377 mg) and acetic acid (1.2 ml) at room
temperature, and the mixture was stirred overnight. To this
solution there was then added concentrated hydrochloric acid
(2 ml) while stirring on ice. After 2 hours of stirring, water
and ammonia water were added, and once alkalinity was reached
extraction was performed with ethyl acetate. After drying the
organic layer with anhydrous magnesium sulfate, the solvent
was distilled off under reduced pressure. The residue was
separated and purified by silica gel column chromatography

CA 02235840 1998-04-24
(ethyl acetate:hexane=5:1) to give 1.238 of (1R)-1-(3-
chlorophenyl)-2-[3-(3-ethoxycarbonylmethoxyphenyl)
cyclohexylamino]ethanol as a colorless oily substance (710
yield) .
1H-NMR ( CDC13) 8 ppm: 1. 30 ( 3H, t, J=7 . 32Hz ) , 1. 37-1 . 98 ( 8H, m) ,
2. 61-3.11 ( 6H, m) , 4.27 (2H, q, J=7.32Hz) , 4. 60 (2H, s) , 4. 71
(1H, dd, J=3. 66, 9.16Hz) , 6. 67-6.72 (lH,m) , 6. 81-6.87 (2H,m) ,
7.20-7.26 (4H,m) , 7.40 (1H, s) .
[Example 54]
To a solution of (2R)-(3-[3-[2-(3-chlorophenyl)-2-
hydroxyethylamino]cyclohexyl]phenoxy)acetic acid (trans-H)
obtained in Example 46 (l.Og) in methanol (10 ml) there was
added an excess of diazomethane in ether solution, and the
mixture was stirred at room temperature for 30 minutes. After
distilling off the solvent under reduced pressure, separation
and purification by silica gel column chromatography (ethyl
acetate: hexane=5:1) gave 0.91g of (1R)-1-(3-chlorophenyl)-
2-[3-(3-methoxycarbonylmethoxyphenyl)cyclohexylamino]
ethanol ( 88 o yield) .
The following compounds were produced according to the
methods of Examples 1 to 3.
[Example 55]
The following compound was obtained from the trans amino
86

CA 02235840 1998-04-24
compound obtained in Reference Example 16 and (R)-(-)-m-
chloromandelic acid.
(1R) -1- (3-Chlorophenyl) -2- (3- (3, 4-dimethoxyphenyl)
cyclohexyl]aminoethanol hydrochloride
1H-NMR (CDC13) 8 ppm: (free compound) 1.45-1 . 88 (BH,m) , 2 .49-
3 . 06 ( 4H, m) , 3 . 35-3 . 63 ( 2H, br
s),3.84(3H,s),3.86(3H,s),4.72(lH,br s),6.74-
6.81(3H,m),7.19-7.26(3H,m),7.39(lH,s) .
[Example 56]
The following compound was obtained from the cis amino
compound obtained in Reference Example 16 and (R)-(-)-m-
chloromandelic acid.
(1R)-1-(3-Chlorophenyl)-2-[3-(3,4-dimethoxyphenyl)
cyclohexyl]aminoethanol
1H-NMR(CDC13) ~ ppm:1.15-1.42(4H,m),1.85-2.13(4H,m),2.43-
2 . 4 8 ( 1H, m) , 2 . 65-2 . 73 ( 2H, m) , 2 . 94-2 . 98 ( 1H, m) , 3 . 8 4 (
3H, s ) ,
3 . 85 ( 3H, s ) , 3 . 84-3 . 85 ( 2H, br s ) , 4 .72 ( 1H, d, J=7 . 32Hz ) ,
6 . 71-
6.80 (3H,m) , 7.21-7.27 (3H,m) , 7.36 (1H, s) .
[Example 57 ]
The following compound was synthesized from the compound
in Example 55, according to the method of Example 7.
(2R)-4-[3-[2-(3-Chlorophenyl)-2-hydroxyethylamino]
cyclohexyl]benzene-1,2-diol hydrochloride
87

CA 02235840 1998-04-24
1H-NMR (CD30D) ~ ppm: ( free compound) 1 . 74-2 . 07 ( 8H, m) , 2 . 94-
3. 08 (2H,m) , 3.17-3.22 (lH,m) , 3.44-3.47 (lH,m) , 4.99-
5. 03 (lH,m) , 6. 62 (1H, d, J=7. 94Hz) , 6.72-6.75 (2H,m) , 7. 31-
7. 37 (3H,m) , 7.48 (1H, s) .
[Example 58]
The following compound was synthesized from,the compound
in Example 56, according to the method of Example 7.
(2R) -4- [3- [2- (3-Chlorophenyl) -2-hydroxyethylamino]
cyclohexyl]benzene-1,2-diol hydrochloride
1H-NMR (CD30D) 8 ppm: (free compound) 1.28-2. 48 (8H,m) , 3. 04-
3. 21 (4H, m) , 6.54 (1H, d, J=7. 93Hz) , 6.71-6. 74 (3H,m) , 7.30-
7 . 34 (3H,m) , 7.46 (1H, s) .
[Example 59]
The following compound was synthesized from the compound
of Example 57, according to the method of Example 11.
(2R)-Ethyl (4-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]
cyclohexyl]-2-ethoxycarbonylmethoxyphenoxy)acetate
1H-NMR ( CDC13 ) b ppm: ( free compound) 1. 53 ( 3H, t, J=7 . 32Hz ) ,
1 .54 (3H, t, J=7.32Hz) , 1 . 39-1. 83 (8H, m) , 2.59-3. 03 ( 6H,m) ,
4.25 (4H, q, J=7.32Hz) , 4 . 67 (2H, s) , 4. 71 (2H, s) , 4. 65-4 .71 (lH,m) ,
6.77-6.84(3H,m),7.20-7.30(3H,m),7.39(lH, s).
[Example 60]
(2R)-Diethyl 5-[3-[2-(3-chlorophenyl)-2-
88

~A 02235840 1998-04-24
hydroxyethylamino]cyclohexyl]benzo-1,3-dioxol-2,2-
dicarboxylate
1H-NMR (CDC13) b ppm: (free compound) 1 .34 (6H, t, J=7.32Hz) ,
1 . 41-1 . 84 ( 8H, m) , 2 . 59-3 . 04 ( 6H, m) , 4 . 36 (2H, q, J=7 . 32Hz )
,
4. 67 (1H, dd, J=3.05, 9. l6Hz) , 6.72-6. 86 (3H,m) , 7 .25-7.27 (3H,m) ,
7.39 (1H, s) .
[Example 61]
The following compound was synthesized from the compound
of Example 58, according to the method of Example 11.
(2R)-Diethyl 5-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]
cyclohexyl]benzo-1,3-dioxol-2,2-dicarboxylate
1H-NMR (CDC13) 8 ppm: (free compound) 1. 34 ( 6H, t, J=7. 32Hz) ,
1.10-1 . 36 (2H,m) , 1 . 79-3.08 (l2H,m), 4.36 (4H, q, J=7.32Hz) ,
4. 77 (1H, dd, J=3. 05, 9.16Hz) , 6. 69-6. 85 (3H,m) , 7.22-7.29 (3H,m) ,
7.38(lH,s).
[Example 62 ]
The following compound was synthesized from the compound
of Example 60, according to the method of Example 15. Sodium
(2R)-5-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino)
cyclohexyl]benzo-1,3-dioxol-2,2-dicarboxylate
1H-NMR ( DMSO-d6) 8 ppm: 1. 06-1 . 72 ( 8H, m) , 2 . 57-2 . 94 (4H, m) ,
3.38-3.56 (2H,m) , 4. 69 (lH,br d, J=5.49Hz) , 6.52-6. 67 (3H,m) ,
7.23-7.39 (4H,m) .
89

CA 02235840 1998-04-24
[Example 63]
The following compound was synthesized from the compound
of Example 61, according to the method of Example 15. Sodium
(2R)-5-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]
cyclohexyl)benzo-1,3-dioxol-2,2-dicarboxylate
1H-NMR (DMSO-d6) ~ ppm: 1. 07-1.37 (4H,m) , 1.73-1. 96 (4H,m) ,
2 . 43-2 . 81 ( 4H, m) , 4 . 67-4 . 69 ( 1H, m) , 6. 54-6 . 68 ( 3H, m) , 7 .
25-
7 . 38 ( 4H, m) .
[Example 64)
Ethyl 3-(3-aminocyclohexyl)phenoxyacetate (8.47g) was
dissolved in ethanol (50 ml), and (R)-3-chlorostyrene oxide
(4.72g) was added prior to heating to reflux for 7.5 hours.
After allowing the mixture to cool, the solvent was
concentrated under reduced pressure to obtain an oily substance
which was then separated and purified by silica gel column
chromatography (n-hexane : ethyl acetate=1 : 5) , to give 8 . 15g of
( 1R) -1- ( 3-chlorophenyl ) -2- [ 3- ( 3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
(trans-H) (compound of Example 11) as an oily substance (61.8
yield) .
After dissolving (1R)-1-(3-chlorophenyl)-2-[3-(3-
ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol
(trans-H) (free base) (S.Og) in ethanol (60 ml), malefic acid

--CA 02235840 1998-04-24
(1.37g) was added, and the mixture was stirred at room
temperature for 3 hours. The deposited crystals were filtered
off and dried to give 2.928 of a malefic acid salt as a white
crystalline powder (51%). (malefic acid salt)
1H-NMR (CD30D) b ppm: 1.29 (3H, t, J=7.32Hz) , 1 . 70-2.22 (8H,m) ,
3.06-3.15 (2H,m) , 3.25-3.26 (lH,m) , 3.53-3.57 (lH,m) , 4 .24
(2H, q, J=7 . 32Hz) , 4. 69 (2H, s) , 4. 97-5.02 (lH,m) , 6.26 (2H, s) ,
6.76 (1H, d, J=7.94Hz) , 6.90-6.96 (2H,m) , 7.25 (1H, t, J=7 .94Hz) ,
7.35-7. 37 (3H,m) , 7. 50 (1H, s) .
mp.157.5-160.0°C(decomp.)
Elemental analysis : as C28H39C1N08
Calculated: C; 61.37, H; 6.25, N; 2.56
Found: C: 61.52, H; 6.38, N; 2.45
[Example 65]
The following compound was obtained from the compound of
Reference Example 29 and (R)-(-)-m-chloromandelic acid,
according to the method of Examples 1 to 4.
(1R)-1-(3-Chlorophenyl)-2-[3-(4-methoxyphenyl)
cyclopentyl]aminoethanol hydrochloride
1H-NMR (CDC13) 8 ppm: (free compound) 1.38-2 .36 ( 6H,rn) , 2. 65-
2.73 (lH,m),2.87(lH,dd,J=3.66,12.2Hz),2.99(lH,m),3.23-
3.79(3H,m), 3.79(3H,s),4.70(lH,dd,J=3.66,9.16Hz),6.85
(2H,d,J=8.55Hz),7.14(2H,m),7.25(3H,s),7.40(lH,s) .
91

A 02235840 1998-04-24
The following compounds were obtained according to the
method of Example 7.
[Example 66] (2R) -4- [3- [2- (3-Chlorophenyl) -2-
hydroxyethylamino]cyclopentyl]phenol (amine of starting
material: trans-H form)
1H-NMR (CDC13) 8 ppm:1.40-2 .04 (6H,m) , 2.32-2 .37 (lH,m) ,
2.68-2. 84 (2H,m),, 2. 98 (lH,m) , 4. 73 (1H, dd, J=3. 66, 9. l6Hz) , 6.76
(2H,d,J=8.55Hz),7.08(2H,d,J=8.55Hz),7.26(3H,s),7.39(lH,s) .
[Example 67] (2R) -4- [3- [2- (3-Chlorophenyl) -2-
hydroxyethylamino]cyclopentyl]phenol (amine of starting
material: trans-L form)
1H-NMR (CDC13) 8 ppm: 1.17-2. 31 (7H,m) , 2. 67-2. 83 (2H,m) ,
3. 12-3. 31 (2H,m) , 4 . 73 (1H, dd, J=3. 66, 9. l6Hz) , 6. 74 (2H, d, J=
7.93Hz),7.02(2H,m),7.24(3H,s),7.36(lH,s) .
[Example 68 ] (2R) -4- [3- [2- (3-Chlorophenyl) -2-
hydroxyethylamino]cyclopentyl]phenol (amine of starting
material: cis form - a mixture of cis-H and cis-L)
1H-NMR (CDC13) 8 ppm: (free compound, diastereomeric
mixture)
1 . 34-2 . 2 6 ( 7H, m) , 2 . 64-3 . 2 9 ( 4H, m) , 4 . 73 ( 1H, d, J=8 . 55Hz
) , 6 . 73
(2H, d, J=8. 55Hz) , 6. 89, 6. 99 (each 2H, d, J=8. 88, 7 . 94Hz) ,
7.21(3H,m),7.33(lH,s) .
[Example 69]
92

CA 02235840 1998-04-24
The following compound was obtained using the compound of
Example 66, according to the method of Example 11.
(2R) -Ethyl ( 4- [ 3- [ 2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]cyclopentyl]phenoxy)acetate
1H-NMR (CD30D) 8 ppm: (HC1 salt) 1.29 (3H, t, J=7. 32Hz) , 1. 68-
2. 53 (7H, m) , 3. 06-3.32 (3H,m) , 3.74-3.82 (lH,m) ,
4 . 24 (2H, q, J=7 . 32Hz) , 4. 66 (2H, s) , 4 . 98 (1H, d, J=9.77Hz) , 6. 87
(2H,
d, J=7.32Hz) , 7.20 (2H,m) , 7.37 (3H, s) , 7.50 (1H, s) .
[Example 70]
The following compound was obtained using the compound of
Example 67, according to the method of Example 11.
(2R) -Ethyl ( 4- ( 3- [ 2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]cyclopentyl]phenoxy)acetate
1H-NMR (CD30D) 8 ppm: (HC1 salt) 1.29 (3H, t, J=7 . 32Hz) , 1 . 76-
2 . 53 ( 7H, m) , 3 . 0 6-3 . 32 ( 3H, m) , 3 . 74 ( 1H, m) , 4 . 24 ( 2H, q,
J=7 . 32Hz ) ,
4 . 66 (2H, s) , 4. 98 (1H, d, J=9.77Hz) , 6.87 (2H, d, J=9.16Hz) ; 7.19
(2H,d,J=9.16Hz),7.24(3H,s),7.37(lH,s) .
The following compounds were obtained according to the
methods of Examples 65 to 69.
[Example 71 ] ( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 4-
methoxyphenyl)cyclopentyl]aminoethanol
1H-NMR (CDC13) b ppm: (free compound, diastereomer mixture)
1 . 44-2 . 15 ( 12H, m) , 2 . 35 ( 1H, mY) , 2 . 68-2 . 87 ( 4H, m) , 3 . 00 (
1H, m) ,
93

A 02235840 1998-04-24
3 .22-3. 37 (4H,m) , 3. 78 ( 6H, s) , 4. 77 (2H, dd, J=3. 66, 5. 49Hz) , 6. 84
(4H, d, J=8.55Hz) , 7. 14 (4H, d, J=7. 94Hz) , 7.26 (6H, s) , 7.39 (2H, s) .
[Example 72) The diastereomeric compound of Example
73, ( 2R) -ethyl ( 4- [ 3- [ 2- ( 3-chlorophenyl ) -2-
hydroxyethylamino)cyclopentyl]phenoxy)acetate
1H-NMR (CDC13) b ppm: (free compound) 1.30 (3H, t, J=7. 32Hz) ,
1. 33-2 . 34 ( 6H, m) , 2 . 61-3 . 35 ( 6H, m) , 4 . 27 ( 2H, q, J=7 . 32Hz )
,
4.59 (2H, s) ; 4. 66 (lH,dd, J=3. 66, 8.54Hz) , 6.83 (2H, d, J=8.54Hz),
7.13(2H,d,J=8.54Hz),7.17(3H,s),7.39(lH,s) .
[Example 73) The diastereomeric compound of Example
72, (2R) -ethyl ( 4- [3- [2- [3-chlorophenyl) -2-
hydroxyethylamino] cyclopentyl)phenoxy)acetate
1H-NMR (CDC13) ~ ppm: (free compound) 1 .30 (3H, t, J=7.32Hz) ,
1 . 3 6-2 . 37 ( 6H, m) , 2 . 61-3 . 25 ( 6H, m) , 4 . 27 ( 2H, q, J=7 . 32Hz
) ,
4.59(2H,s),4.68(lH,dd,J=3.66,5.49Hz),6.83(2H,d,J=8.54Hz),
7.11(2H,d,J=8.54Hz),7.25(3H,s),7.38(lH,s).
[Example 74]
The following compound was obtained using the compound of
Example 68, according to the method of Example 11.
( 2R) -Diethyl ( 4- [ 3- [2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]cyclopentyl]phenoxy) malonate
1H-NMR (CDC13) b ppm: ( free compound) 1. 30 ( 6H, t, J=7 . 32Hz) ,
1. 39-2 . 33 ( 7H, m) , 2 . 62-2 . 72 ( 3H, m) , 2 . 92-3 . 45 ( 3H, m) , 4 .
31
94

A 02235840 1998-04-24-
(4H, q, J=7. 32Hz) , 4. 68 (1H, d, J=5.49Hz) , 5. 16 (1H, s) , 6. 89
(2H,d,J=8.54Hz),7.13(2H,m),7.25(3H,s),7.38(lH,s) .
(Example 75]
The following compound was obtained according to the method
of Example 47.
( 2R) -2 - [ 4- [ 3- [ 2- ( 3-Chlorophenyl ) -2-hydroxyethylamino ]
cyclopentyl]phenoxy]-N-(2-methoxyethyl)acetamide
1H-NMR (CDC13) 8 ppm: (free compound) 1 .36-2. 33 (7H,m) , 2. 69-
2 . 94 (5H, m) , 3.26-3. 36 (lH,m) , 3. 34 (3H, s) , 3 . 48-3.52 (4H,m) ,
4 . 4 6 ( 2H, m) , 4 . 68 ( 1H, d, J=5 . 65Hz ) , 6 . 85 ( 2H, d, J=8 . 55Hz )
, 6 . 94
(lH,br s),7.13-7.25(SH,m),7.38(lH,s).
[Example 76]
The following compounds were obtained from the compound of
Reference Example 38 and (R)-(-)-m-chloromandelic acid,
according to the method of Examples 1 to 4.
(1R)-1-(3-Chlorophenyl)-2-[3-(3-methoxyphenyl)
cyclopentyl]aminoethanol hydrochloride (diastereomer A)
1H-NMR (CDC13) b ppm: (free compound) 1.46-1 . 62 (2H,m) , 1.79-
2 . 38 ( 4H, m) , 2 . 65-2 . 72 ( 1H, m) , 2 . 8 7-3 . 3 4 ( 3H, m) , 3 . 67 (
2H, br
s),3.78 (3H,s),4.74(lH,dd,J=3.05,9.16Hz),6.71-
6.83(3H,m),7.16-7.24 (4H,m),7.38(lH,s).
(1R)-1-(3-chlorophenyl)-2-[3-(3-methoxyphenyl)
cyclopentyl]aminoethanol hydrochloride (diastereomer B)

A 02235840 1998-04-24
1H-NMR (CDC13) ~ ppm: (free compound) 1 .46-1 . 62 (2H,m) , 1. 79-
2. 38 (4H,m) , 2. 67-2.70 (lH,m) , 2. 87-3.34 (3H,m) , 3.49 (2H,brs) ,
3.78 (3H, s) , 4 .73 (1H, d, J=6.lOHz) , 6.70-6. 83 (3H,m) , 7. 16-7.23
( 4H, m) , 7 . 37 ( 1H, s ) .
[Example 77]
The following compounds were obtained from the compound of
Example 76, according to the method of Example 7.
(2R) -3- [3- [2- (3-Chlorophenyl)-2-hydroxyethylamino]
cyclopentyl]phenol (diastereomer A)
1H-NMR(CD30D)~ ppm:l.72-2.44(6H,m),2.94-3.32(3H.m),
3.60-3. 69 (lH,m) , 5. 00 (1H, s) , 6. 62-6.74 (3H,m) , 7. 06-7.12 (lH,m) ,
7.31-7.36 (3H,m) , 7.49 (1H, s) .
(2R)-3-[3-[2-(3-Chlorophenyl)-2-hydroxyethylamino]
cyclopentyl]phenol (diastereomer B)
1H-NMR (CD30D) ~ ppm: 1. 52-2 . 44 ( 6H, m) , 2 . 82-3 . 27 ( 3H, m) ,
3.45-3.52 (lH,m) , 4 .89 (1H, d, J=9.16Hz) , 6. 61-6.72 (3H,m) , 7. 06
7.11 (lH,m) , 7.29-7.31 (3H,m), 7.45 (1H, s) .
[Example 78]
The following compounds were obtained from the compound of
Example 77, according to the method of Example 11.
( 2R) -Ethyl ( 3- [ 3- [ 2- ( 3-Chlorophenyl ) -2-
hydroxyethylamino]cyclopentyl]phenoxy)acetate
hydrochloride (diastereomer A)
96

A 02235840 1998-04-24
1H-NMR (CDC13) 8 ppm: (free compound) 1.29 (3H, t, J=7. 32Hz) ,
1.50-2.37(7H,m),2.68-2.76(lH,m), 2.90-3.29(3H,m),3.95
(2H,brs),4.26(2H,q,J=7.32Hz),4.58(2H,s),4.78(lH,d,J=
6.lOHz) , 6. 69 (1H, d, J=7.93Hz) , 6.78-6. 88 (2H,m) , 7.15-7.26
(4H,m) , 7.38 (1H, s) .
( 2R) -Ethyl ( 3- [ 3- [ 2- ( 3-chlorophenyl ) -2-
hydroxyethylamino]cyclopentyl]phenoxy)acetate
(diastereomer B)
1H-NMR (CDC13) 8 ppm: (free compound) 1.30 (3H, t, J=7.32Hz) ,
1.43-2.37(7H,m),2.67-2.75(lH,m),2.94-3.28(SH,m),
4. 27 (2H, q, J=7. 32Hz) , 4. 60 (2H, s) , 4 .75 (1H, d, J=5 . 49Hz) , 6. 70
(1H, d, J=7 .93Hz) , 6.68-6.89 (2H,m) , 7.17-7.26 (4H,m) , 7.39
(1H, s) .
The following compounds were obtained from the compound of
Reference Example 33 and (R)-(-)-m-chloromandelic acid,
according to the methods of Examples 1 to 4.
[Example 79]
( 1R) -1- ( 3-Chlorophenyl ) -2- [ 3- ( 4-methoxyphenyl )
cyclopentylmethyl]aminoethanol
1H-NMR (CDC13) 8 ppm: (free compound) 1 .20-2. 30 (7H,m) , 2 .58-
3.06
( 7H, m) , 3 . 7 8 ( 3H, s ) , 4 . 67 ( 1H, dd, J=3 . 66, 8 . 55Hz ) , 6 . 8 3
( 2H, d, J=
8 .55Hz) , 7 . 14 (2H, d, J=8.55Hz) , 7.24 (3H,m) , 7.38 (1H, s) .
9?

-CA 02235840 1998-04-24
[Example 80]
The following compound was obtained from the compound of
Example 79, according to the method of Example 7.
(2R) -4- [3- [2- (3-Chlorophenyl) -2-
hydroxyethylaminomethyl]cyclopentyl]phenol
1H-NMR (DMSO-d6) ~ ppm: 1.18-2.33 (8H,m) , 2. 70-3. 00 (SH,m) ,
4 . 79 (1H, dd, J=3. 05, 8. 55Hz) , 6. 66 (2H, d, J=8.55Hz) , 7. 01 (2H, d, J=
8 . 55Hz ) , 7 . 33 ( 3H, m) , 7 . 42 ( 1H, s ) .
[Example 81]
The following compound was obtained from the compound of
Example 80, according to the method of Example 11.
(2R) -Ethyl (4- [3- [2- (3-chlorophenyl) -2-
hydroxyethylaminomethyl]cyclopentyl)phenoxy)acetate
hydrochloride
1H-NMR (CDC13) 8 ppm: (free compound) 1.28-2.30 (7H,m) , 2. 65-
2 . 73 ( 3H, m) , 2 . 93-
3 . O1 (2H, m) , 3. 64 (2H, brs) , 4 . 25 (2H, q, J=7 . 32Hz) ,
4 . 57 ( 2H, s ) , 4 . 75 ( 1H, d, J=6 .1 OHz ) , 6. 82 ( 2H, d, J=8 . 55Hz )
, 7 .12 ( 2H,
d,J=8.55Hz),7.22(3H,m),7.37(lH,s) .
[Example 82]
(2R) -Diethyl [4- [3- [2- (3-chlorophenyl) -2-
hydroxyethylaminomethyl]cyclopentyl]phenoxy]malonate
hydrochloride
98

CA 02235840 1998-04-24_--
1H-NMR (CDC13) ~ ppm: (free compound) 1 .29 ( 6H, t, J=7. 32Hz) ,
1 . 32-2 . 61 ( 7H, m) , 2 . 67-2 . 75 (3H, m) , 2 . 90-2 . 96 (2H, m) ,
3.62(2H,brs), 4.30(4H,q,J=7.32Hz), 4.76(lH,d,J=6.lOHz),
5. 16 (1H, s) , 6. 88 (2H, d, J=7. 94Hz) , 7.13 (2H, d, J=7. 94Hz) , 7.23 (3H,
s),7.38(lH,s).
[Example 83]
The following compound was obtained from the compound of
Example 81, according to the method of Example 47.
( 2R) -2- [ 4- [ 3- [2- ( 3-Chlorophenyl ) -2-
hydroxyethylaminomethyl]cyclopentyl]phenoxy]-N-(2-
methoxyethyl)acetamide
1H-NMR (CDC13) 8 ppm: (free compound) 1 .19-2.31 (7H,m) , 2. 58-
2 . 72 (3H, m) , 2 . 83-3. 06 (4H,m) , 3. 33 (3H, s) , 3. 47-3. 52 (4H,m) ,
4 . 45 (2H, s ) , 4 . 68 (1H, dd, J=3. 66, 9. l6Hz) , 6. 83 (2H, d, J=8. 55Hz)
,
6.99 (lH,brs), 7.15 (2H,d, J=8.55Hz), 7.23 (3H, s), 7.38 (lH,s) .
[Example 84]
(R) -2-Amino-1- (3-chlorophenyl) ethanol (770 mg) and ethyl
4-(3-oxocyclopentyl) benzoate (1.15g) were dissolved in
ethanol (60 ml), and platinum oxide (80 mg) and acetic acid
(2.8 ml) were added thereto. After substituting the reaction
vessel with hydrogen gas, reducing amination reaction was
carried out for 30 minutes at normal pressure and room
temperature. After the reaction, the catalyst was filtered
99

-_CA 02235840 1998-04-24
off and the solvent was distilled off under reduced pressure
to produce an oily substance, and upon addition of saturated
bicarbonate water to achieve alkalinity, extraction was
performed with ethyl acetate.
After washing the organic layer with water and drying with
anhydrous magnesium sulfate, the solvent was distilled off
under reduced pressure to produce orange crystals which were
then purified by silica gel column chromatography (chloroform
--~chloroform:ethanol=20:1). The resulting crystals were
further washed with n-hexane: ethyl acetate=2: 1 to give 314 mg
of ethyl (2R)-4-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino)
cyclohexyl]benzoate (16.40).
1H-NMR (CDC13) 8 ppm: 1 .38 (3H, t, J=7.32Hz) , 1 .45-2.20 (7H,m) ,
2. 37-2 . 46 (lH,m) , 2 . 65-2. 73 (lH,m) , 2 . 93-3.23 (3H,m) ; 4.36
( 2H, q, J=7 . 32Hz ) , 4 . 68 ( 1H, dd, J=3 . 05, 8 . 54Hz ) , 7 . 2 6-7 . 31
( 5H, m) ,
7.39(lH,s),7.79(2H,d,J=8.55Hz) .
The following are preparation examples for the compounds
of the invention.
Tablets : The compound of Example 11 (5 mg) , microcrystalline
cellulose (40 mg) , dry corn starch (40 mg) , lactose (100 mg)
and magnesium stearate (5 mg) are combined according to a common
method and formed into granules, which are then compression
molded to make tablets containing 5 mg of the active substance .
100

A 02235840 1998-04-24
Capsules: The compound of Example 15 (10 mg) and lactose
( 120 mg) are combined, and the mixture is filled into common
hard gelatin capsules to prepare capsules containing 10 mg of
the active substance.
Industrial Applicability
As explained above, the compounds of the present invention
have a potent S 3 adrenergic stimulating effect and high (3 3
adrenergic receptor selectivity, which not only render them
effective as prophylactics and/or treatments for
gastrointestinal diseases accompanying smooth muscle
hypersthenia (for example, irritable bowel syndrome, acute and
chronic diarrhea, etc.) as well as improvement of symptoms
associated with gastric ulcer, duodenal ulcer, gastritis,
enteritis, cholecystitis and the like, such as abdominal pain,
nausea, vomiting and epigastric discomfort, but also allow
their use as therapeutic agents for diseases for which
stimulation of ~ 3 adrenergic receptors is believed to be
advantageous, for example as antiobestic drugs, antidiabetic
drugs or antidepressive drugs.
In addition, because they exhibit a stronger relaxing effect
on the bladder detrusor muscle (smooth muscle) than the S 2
adrenergic agonist clenbuterol hydrochloride, the compounds
101

CA 02235840 2004-08-09
of the present invention are useful as selective ~ 3 adrenergic
receptor agonists, for the prevention and/or treatment of
pollakisuria,and urinary incontinence, including nervous
pollakisuria, neurogenic bladder dysfunction, bladder
instability and abdominal pressure anischuria.
Furthermore, because the compounds of the present invention
have a weak stimulating effect on S 1 and ~ 2 adrenergic
receptors, they have an advantage of few side effects caused
by S 1 and S 2 action (for example, increased cardiac rate or
tremor).
102

Dessin représentatif