U.S. patent application number 10/553120 was filed with the patent office on 2006-09-14 for preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof.
This patent application is currently assigned to TOYAMA CHEMICAL CO., LTD.. Invention is credited to Noboru Iwakami, Tatsuo Kimura, Akihito Saitoh.
Application Number | 20060205709 10/553120 |
Document ID | / |
Family ID | 33296058 |
Filed Date | 2006-09-14 |
United States Patent
Application |
20060205709 |
Kind Code |
A1 |
Kimura; Tatsuo ; et
al. |
September 14, 2006 |
Preventive/remedy for retinal nerve diseases containing alkyl ether
derivatives or salts thereof
Abstract
An alkyl ether derivative represented by the following general
formula [1] ##STR1## or its salt: wherein R.sup.1 and R.sup.2
represent each a substituent such as hydrogen, halogeno or alkyl;
R.sup.3 represents alkylamino, amino or hydroxyl; the ring A
represents a 5- or 6-membered aromatic heterocycle or a benzene
ring; m and n are each an integer of from 1 to 6; and p is an
integer of from 1 to 3; shows an effect of protecting retinal nerve
cells and, therefore, is useful as a preventive and/or a remedy for
retinal nerve diseases such as glaucoma, diabetic retinopathy,
retinal artery obstruction, retinal venous obstruction, macular
degeneration and retinopathy of prematurity.
Inventors: |
Kimura; Tatsuo; (Toyama,
JP) ; Iwakami; Noboru; (Toyama, JP) ; Saitoh;
Akihito; (Toyama, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
TOYAMA CHEMICAL CO., LTD.
TOKYO
JP
|
Family ID: |
33296058 |
Appl. No.: |
10/553120 |
Filed: |
April 15, 2004 |
PCT Filed: |
April 15, 2004 |
PCT NO: |
PCT/JP04/05355 |
371 Date: |
October 14, 2005 |
Current U.S.
Class: |
514/210.19 ;
514/319; 514/320; 514/422 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 27/02 20180101; C07D 207/12 20130101; A61P 9/00 20180101; A61P
9/10 20180101; A61K 31/4025 20130101; A61P 43/00 20180101; Y10S
514/912 20130101; A61K 31/40 20130101; C07D 405/12 20130101; A61P
27/06 20180101; A61K 31/4535 20130101; A61P 7/02 20180101; A61P
27/00 20180101; Y10S 514/913 20130101; A61K 31/4525 20130101; A61K
31/397 20130101; C07D 409/12 20130101; A61K 31/435 20130101 |
Class at
Publication: |
514/210.19 ;
514/319; 514/320; 514/422 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 31/445 20060101 A61K031/445; A61K 31/452 20060101
A61K031/452; A61K 31/453 20060101 A61K031/453; A61K 31/4025
20060101 A61K031/4025 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 17, 2003 |
JP |
2003-112539 |
Claims
1. A preventive and/or remedy for retinal nerve diseases
characterized in that it comprises an alkyl ether derivative
represented by the following general formula [1]: ##STR9## wherein
R.sup.1 and R.sup.2, which may be the same or different, each
represents one or more groups selected from a hydrogen atom, a
halogen atom, a substituted or unsubstituted alkyl, aryl, aralkyl,
alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino,
alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic group, a
protected or unprotected amino, hydroxyl or carboxyl group, a nitro
group and an oxo group; R.sup.3 represents a substituted or
unsubstituted alkylamino group, or a protected or unprotected amino
or hydroxyl group; the ring A represents a 5- or 6-membered
aromatic heterocyclic ring or a benzene ring; m and n each
represents an integer between 1 and 6; and p represents an integer
between 1 and 3; or a salt thereof.
2. The preventive and/or remedy for retinal nerve diseases
according to claim 1, wherein the portion represented by the
following formula: ##STR10## of the alkyl ether derivative
represented by the general formula [1] according to claim 1 is any
one of the following (A), (B), and (C): ##STR11##
3. The preventive and/or remedy for retinal nerve diseases
according to claim 1, wherein R.sup.1 represents a hydrogen atom;
and R.sup.2 represents a hydrogen atom, a halogen atom or an alkoxy
group.
4. The preventive and/or remedy for retinal nerve diseases
according to claim 1, wherein m represents 2; n represents an
integer of 2 or 3; and p represents an integer of 1 or 2.
5. The preventive and/or remedy for retinal nerve diseases
according to claim 2, wherein R.sup.1 represents a hydrogen atom;
and R.sup.2 represents a hydrogen atom, a halogen atom or an alkoxy
group.
6. The preventive and/or remedy for retinal nerve diseases
according to claim 2, wherein m represents 2; n represents an
integer of 2 or 3; and p represents an integer of 1 or 2.
7. The preventive and/or remedy for retinal nerve diseases
according to claim 3, wherein m represents 2; n represents an
integer of 2 or 3; and p represents an integer of 1 or 2.
Description
TECHNICAL FIELD
[0001] The present invention relates to a preventive and/or remedy
for retinal nerve diseases, which comprise a novel alkyl ether
derivative or a salt thereof as an active ingredient.
BACKGROUND ART
[0002] The retina acting as a photoreceptive tissue is located at
the inner surface of the wall of eyeball. When pathologic lesion
occurs on the retina, eyesight fails, sometimes resulting in
blindness. Such retina is broadly divided into sensory retina and
retinal pigment epithelium. Such sensory retina is divided into 9
layers, and comprises visual cells as first neuron, bipolar cells
as second neuron, ganglion cells as third neuron, and other cells
(Hyojun Ganka Gaku, 7.sup.th edition, pp. 103-107, Igaku-Shoin
Ltd., 1998).
[0003] Various retinal diseases are developed depending on the
causes of diseases or onset forms. Examples of a disease affecting
the retinal nerve may include glaucoma, diabetic retinopathy,
retinal artery obstruction, retinal venous obstruction, macular
degeneration, and retinopathy of prematurity.
[0004] It has been considered that the cell death of retinal nerve
cells is deeply associated with dysfunction of the retinal nerve.
Factors, which contribute the cell death of refinal nerve cells,
may include apoptosis, neurotoxicity caused by glutamic acid, the
absence of a neurotrophic factor, the abnormality of mitochondria,
caspase activation, nitric oxide, and autoimmunity (Atarashii
Ganka, 19(7), 903-912, 2002). For example, from the viewpoint of
suppression of the cell death with an excitatory neurotransmitter
such as glutamic acid, compounds having antagonistic action to
N-methyl-D-aspartic acid have been studied (JP-A-8-506807; Scrip
No. 2229, p. 13, 1997; Scrip No. 2307, p. 10, 1998).
[0005] As stated above, various factors are associated with the
cell death of retinal nerve cells. Other than compounds having
antagonistic action to N-methyl-D-aspartic acid, compounds useful
as remedies for diseases such as glaucoma, diabetic retinopathy,
retinal artery obstruction, retinal venous obstruction, macular
degeneration, and retinopathy of prematurity, are required.
DISCLOSURE OF THE INVENTION
[0006] The present inventors have found that an alkyl ether
derivative represented by the general formula [1] described below
or a salt thereof shows the effect of protecting retinal nerve
cells, and thus that it is useful as a preventive and/or remedy for
retinal nerve diseases, thereby completing the present invention.
##STR2##
[0007] In the formula, R.sup.1 and R.sup.2, which may be the same
or different, each represent one or more groups selected from a
hydrogen atom, a halogen atom, a substituted or unsubstituted
alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio,
alkenyl, alkenyloxy, amino, alkylsulfonyl, arylsulfonyl, carbamoyl
or heterocyclic group, a protected or unprotected amino, hydroxyl
or carboxyl group, a nitro group and an oxo group; R.sup.3
represents a substituted or unsubstituted alkylamino group or a
protected or unprotected amino or hydroxyl group; the ring A
represents a 5- or 6-membered aromatic heterocyclic ring or a
benzene ring; m and n each represent an integer between 1 and 6;
and p represents an integer between 1 and 3.
BEST MODE FOR CARRYING OUT THE INVENTION
[0008] The present invention will be described in detail below.
[0009] In the present specification, the terms have the following
means, unless otherwise specified.
[0010] The term "halogen atom" is used to mean a fluorine atom, a
chlorine atom, a bromine atom, or an iodine atom; the term "alkyl
group" is used to mean a linear or branched C.sub.1-12 alkyl group
such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl, hexyl, heptyl, or octyl group; the term "lower
alkyl group" is used to mean a linear or branched C.sub.1-6 alkyl
group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl, or hexyl group; the term "alkenyl group" is
used to mean a C.sub.2-12 alkenyl group such as a vinyl, propenyl,
butenyl, pentenyl, hexenyl, heptenyl, or octenyl group; the term
"lower alkenyl group" is used to mean a C.sub.2-6 alkenyl group
such as a vinyl, propenyl, butenyl, pentenyl, or hexenyl group; the
term "alkynyl group" is used to mean a C.sub.2-6 alkynyl group such
as an ethynyl, 2-propynyl, or 2-butynyl group; the term "cycloalkyl
group" is used to mean a cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl group; the term "alkoxy group" is used to mean a linear
or branched C.sub.1-12 alkyloxy group such as a methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy,
hexyloxy, heptyloxy, or octyloxy group; the term "lower alkoxy
group" is used to mean a linear or branched C.sub.1-6 alkyloxy
group such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, tert-butoxy, pentyloxy, or hexyloxy group; the term
"alkenyloxy group" is used to mean a C.sub.2-12 alkenyloxy group
such as a vinyloxy, propenyloxy, butenyloxy, pentenyloxy,
hexenyloxy, heptenyloxy, or octenyloxy group; the term "lower
alkenyloxy group" is used to mean a C.sub.2-6 alkenyloxy group such
as a vinyloxy, propenyloxy, butenyloxy, pentenyloxy, or hexenyloxy
group; the term "alkylthio group" is used to mean a C.sub.1-12
alkylthio group such as a methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio,
hexylthio, heptylthio, or octylthio group; the term "lower
alkylthio group" is used to mean a C.sub.1-6 alkylthio group such
as a methylthio, ethylthio, propylthio, isopropylthio, butylthio,
isobutylthio, tert-butylthio, pentylthio, or hexylthio group; the
term "aryl group" is used to mean a phenyl group, naphthyl group,
indanyl group, or indenyl group; the term "aryloxy group" is used
to mean a phenyloxy, naphthyloxy, indanyloxy, or indenyloxy group;
the term "aralkyl group" is used to mean an ar C.sub.1-6 alkyl
group such as a benzyl, diphenylmethyl, trityl, or phenethyl group;
the term "arylthio group" is used to mean a phenylthio,
naphthylthio, indanylthio, or indenylthio group; the term "acyl
group" is used to mean a formyl group, a C.sub.2-12 alkanoyl group
such as acetyl, isovaleryl, propionyl, or pivaloyl, an
aralkylcarbonyl group such as benzylcarbonyl, or an aroyl group
such as benzoyl or naphthoyl; the term "alkylsulfonyl group" is
used to mean a C.sub.1-12 alkylsulfonyl group such as
methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,
butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,
tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl,
or octylsulfonyl; the term "lower alkylsulfonyl group" is used to
mean a C.sub.1-6 alkylsulfonyl group such as methylsulfonyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, or
pentylsulfonyl; the term "arylsulfonyl group" is used to mean a
phenylsulfonyl, p-toluenesulfonyl, or naphthylsulfonyl group; the
term "lower alkylsulfonyloxy group" is used to mean a C.sub.1-6
alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy,
propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy,
isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy,
or pentylsulfonyloxy; the term "arylsulfonyloxy group" is used to
mean a phenylsulfonyloxy, p-toluenesulfonyloxy, or
naphthylsulfonyloxy group; the term "alkylamino group" is used to
mean a mono- or di-C.sub.1-6 alkylamino group such as methylamino,
ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,
diethylamino, diisopropylamino, or dibutylamino; the term
"monoalkylamino group" is used to mean a mono-C.sub.1-6 alkylamino
group such as methylamino, ethylamino, propylamino, isopropylamino,
or butylamino; the term "dialkylamino group" is used to mean a
di-C.sub.1-6 alkylamino group such as dimethylamino, diethylamino,
diisopropylamino, or dibutylamino; the term "heterocyclic group" is
used to mean a heterocyclic group including a 5- or 6-membered
ring, condensed ring, or crosslinked ring, containing at least one
heteroatom selected from a nitrogen atom, an oxygen atom, and a
sulfur atom, such as pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, quinuclidinyl,
imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,
quinolyl, quinolizinyl, thiazolyl, tetrazolyl, thiadiazolyl,
pyrrolyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl,
benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl,
benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl,
2,3-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl,
imidazo[2,3-a]pyridyl, benzo[b]piperazinyl, chromenyl,
isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl,
isoquinolyl, 1,3-benzodioxanyl, or 1,4-benzodioxanyl group; and the
term "cyclic amino group" is used to mean a cyclic amino group
including a 5-, 6-, or 7-membered ring, condensed ring, or
crosslinked ring, which contains at least one nitrogen atom as a
heteroatom that forms the above ring, and may further contain at
least one oxygen atom or sulfur atom, such as pyrrolidinyl,
piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl,
morpholinyl, thiomorpholinyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, or imidazolidinyl.
[0011] A 5- or 6-membered aromatic heterocyclic ring as the ring A
may be a heterocyclic ring containing one or more heteroatoms
selected from an oxygen atom, a nitrogen atom, and a sulfur atom as
a heteroatom forming the above ring. Examples may include 5- or
6-membered aromatic heterocyclic rings such as triazine,
pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene,
pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole,
pyrazole, or pyran.
[0012] Substituents for an alkyl group, an aryl group, an aralkyl
group, an alkoxy group, an aryloxy group, an alkylthio group, an
arylthio group, an alkenyl group, an alkenyloxy group, an amino
group, an alkylsulfonyl group, an arylsulfonyl group, a carbamoyl
group, and a heterocyclic group in R.sup.1 and R.sup.2, and an
alkylamino group in R.sup.3, may include a halogen atom, a lower
alkyl group, a cycloalkyl group, an aryl group, a lower alkoxy
group, an aryloxy group, a lower alkylthio group, an arylthio
group, a lower alkenyl group, a lower alkylsulfonyl group, an
arylsulfonyl group, an alkylamino group, an amino group that may be
protected, a hydroxyl group that may be protected, a carboxyl group
that may be protected, an acyl group, and a heterocyclic group.
[0013] Protecting groups for a carboxyl group may include all
groups that can be used as common protecting groups for a carboxyl
group. Examples of such a protecting group may include: a lower
alkyl group such as methyl, ethyl, propyl, isopropyl,
1,1-dimethylpropyl, butyl, or tert-butyl; an aryl group such as
phenyl or naphthyl; an ar lower alkyl group such as benzyl,
diphenylmethyl, trityl, 4-nitrobenzyl, 4-methoxybenzyl, or
bis(4-methoxyphenyl)methyl; an acyl-lower alkyl group such as
acetylmethyl, benzoylmethyl, 4-nitrobenzoylmethyl,
4-bromobenzoylmethyl, or 4-methanesulfonylbenzoylmethyl; an
oxygen-containing heterocyclic group such as 2-tetrahydropyranyl or
2-teterahydrofuranyl; a halogeno-lower alkyl group such as
2,2,2-trichloroethyl; a lower alkylsilyl-lower alkyl group such as
2-(trimethylsilyl)ethyl; an acyloxy-lower alkyl group such as
acetoxymethyl, propionyloxymethyl, or pivaloyloxymethyl; a
nitrogen-containing heterocyclic ring-lower alkyl group such as
phthalimidomethyl or succinimidomethyl; a cycloalkyl group such as
cyclohexyl; a lower alkoxy-lower alkyl group such as methoxymethyl,
methoxyethoxymethyl, or 2-(trimethylsilyl)ethoxymethyl; an ar-lower
alkoxy-lower alkyl group such as benzyloxymethyl; a lower
alkylthio-lower alkyl group such as methylthiomethyl or
2-methylthioethyl; an arylthio-lower alkyl group such as
phenylthiomethyl; a lower alkenyl group such as
1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, or allyl; and a
substituted silyl group such as trimethylsilyl, triethylsilyl,
triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, diphenylmethylsilyl, or
tert-butylmethoxyphenylsilyl.
[0014] Protecting groups for a hydroxyl group may include all
groups that can be used as common protecting groups for a hydroxyl
group. Examples of such a protecting group may include: alkoxy and
alkylthio-carbonyl groups such as benzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,
1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,
isobutyloxycarbonyl, diphenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl,
1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,
4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, or
S-benzylthiocarbonyl; an acyl group such as acetyl, formyl,
chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,
methoxyacetyl, phenoxyacetyl, pivaloyl, or benzoyl; a lower alkyl
group such as methyl, tert-butyl, 2,2,2-trichloroethyl, or
2-trimethylsilylethyl; a lower alkenyl group such as allyl; a lower
alkynyl group such as propargyl; an ar-lower alkyl group such as
benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, or
trityl; oxygen-containing and sulfur-containing heterocyclic groups
such as tetrahydrofuryl, tetrahydropyranyl, or
tetrahydrothiopyranyl; lower alkoxy- and lower alkylthio-lower
alkyl groups such as methoxymethyl, methylthiomethyl,
benzyloxymethyl, 2-methoxyethoxymethyl,
2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
1-ethoxyethyl, or 1-methyl-1-methoxyethyl; lower alkyl- and
aryl-sulfonyl groups such as methanesulfonyl or p-toluenesulfonyl;
and a substituted silyl group such as trimethylsilyl,
triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,
tert-butyldimethylsilyl, tert-butyldiphenylsilyl,
diphenylmethylsilyl, or tert-butylmethoxyphenylsilyl.
[0015] Protecting groups for an amino group may include all groups
that can be used as common protecting groups for an amino group.
Examples of such a protecting group may include: an alkoxycarbonyl
group such as methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
2,2,2-tribromoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,
1,1-dimethylpropoxycarbonyl, tert-butoxycarbonyl, vinyloxycarbonyl,
allyloxycarbonyl, 1-adamantyloxycarbonyl, benzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,
diphenylmethoxycarbonyl, 4-(phenylazo)benzyloxycarbonyl,
2-furfuryloxycarbonyl, or 8-quinolyloxycarbonyl; an acyl group such
as (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl,
formyl, acetyl, benzoyl, phthaloyl, succinyl, alanyl, or leucyl; an
ar lower alkyl group such as benzyl, diphenyl, methyl, or trityl;
an arylthio group such as 2-nitrophenylthio or
2,4-dinitrophenylthio; an alkyl- or aryl-sulfonyl group such as
methanesulfonyl or p-toluenesulfonyl; a di-lower alkylamino-lower
alkylidene group such as N,N-dimethylaminomethylene; an ar-lower
alkylidene group such as benzylidene, 2-hydroxybenzylidene,
2-hydroxy-5-chlorobenzylidene, or 2-hydroxy-1-naphthylmethylene; a
nitrogen-containing heterocyclic alkylidene group such as
3-hydroxy-4-pyridylmethylene; a cycloalkylidene group such as
cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,
2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, or
3,3-dimethyl-5-oxycyclohexylidene; a diaryl- or diar-lower
alkylphosphoryl group such as diphenylphosphoryl or
dibenzylphosphoryl; an oxygen-containing heterocyclic alkyl group
such as 5-methyl-2-oxo-2H-1,3-dioxole-4-yl-methyl; and a
substituted silyl group such as trimethylsilyl.
[0016] A salt of the compound represented by the general formula
[1] may include salts in commonly known basic groups such as an
amino group or acidic groups such as a hydroxyl or carboxyl
group.
[0017] Examples of such salts in basic groups may include: salts
with mineral acids such as hydrochloric acid, hydrobromic acid,
nitric acid, or sulfuric acid; salts with organic carboxylic acids
such as formic acid, acetic acid, citric acid, oxalic acid, fumaric
acid, maleic acid, succinic acid, malic acid, tartaric acid,
aspartic acid, trichloroacetic acid, or trifluoroacetic acid; and
salts with sulfonic acids such as methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic
acid, or naphthalenesulfonic acid.
[0018] Examples of salts in acidic groups may include: salts with
alkaline metals such as sodium or potassium; salts with
alkaline-earth metals such as calcium or magnesium; ammonium salts;
and salts with nitrogen-containing organic bases such as
trimethylamine, triethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
diethylamine, dicyclohexylamine, procaine, dibenzylamine,
N-benzyl-p-phenethylamine, 1-ephenamine, and
N,N'-dibenzylethylenediamine.
[0019] Among the aforementioned salts, pharmacologically acceptable
salts are preferable.
[0020] When isomers (for example, optical isomers, geometric
isomers, and tautomers) are present in the alkyl ether derivative
represented by the general formula [1] or a salt thereof, the
present invention includes all these isomers, and further includes
hydrates, solvates, and all crystal forms.
[0021] Preferred examples of the alkyl ether derivative represented
by the general formula [1] or a salt thereof of the present
invention may be compounds wherein, the following portion: ##STR3##
is any one of the following (A), (B), and (C): ##STR4## wherein,
preferably, R.sup.1 represents a hydrogen atom; and R.sup.2
represents a hydrogen atom, a halogen atom or an alkoxy group.
[0022] Moreover, the above compound wherein, in general formula
[1], m is 2 and n is an integer of 2 or 3, is preferable.
Furthermore, the above compound wherein, in the above formula, p is
an integer of 1 or 2, is more preferable.
[0023] A compound wherein, in the above (A), each of R.sup.1 and
R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydroxyl
group; m is 2; n is 3; and p is 1, is most preferable.
[0024] Next, the production method of the alkyl ether derivative
represented by the general formula [1] or a salt thereof will be
described.
[0025] The alkyl ether derivative represented by the general
formula [1] or a salt thereof can be produced by known methods or
by appropriately combining such methods. For example, it can be
produced by the following production method. ##STR5## ##STR6##
wherein R.sup.1, R.sup.2, R.sup.3, A, m, n, and p have the same
meanings as defined above; R.sup.3a represents a dialkylamino
group, a monoalkylamino group that is protected, an amino group
that is protected, or a hydroxyl group that may be protected;
R.sup.3b represents a dialkylamino group, a monoalkylamino group
that is protected, an amino group that is protected, or a hydroxyl
group that is protected; R.sup.3c represents a hydroxyl group that
is protected; R.sup.3d represents a dialkylamino group, a
monoalkylamino group, an amino group, or a hydroxyl group; and each
of X.sup.1, X.sup.2, and X.sup.3 represents a leaving group.
[0026] Examples of such a leaving group may include a halogen atom,
a lower alkylsulfonyloxy group, and an arylsulfonyloxy group.
[0027] Next, each production method will be described.
[Production Method 1]
(1-1) The compound represented by the general formula [3] is
allowed to react with the compound represented by the general
formula [2] or a reactive derivative thereof, so as to produce the
compound represented by the general formula [4].
[0028] This reaction may be carried out by known methods, for
example, by the method described in Jikken Kagaku Koza, Vol. 22,
The Chemical Society of Japan, pp. 137-173, 1992, (Maruzen), or a
method equivalent thereto.
[0029] Examples of the reactive derivative of the compound
represented by the general formula [2] may include an acid halide,
an acid anhydride, an active amide, and an active ester.
[0030] When the compound represented by the general formula [2] is
used in the form of a free acid, the reaction is preferably carried
out in the presence of a condensing agent.
[0031] Examples of such a condensing agent may include:
carbodiimides such as N,N'-dicyclohexylcarbodiimide; halogenating
agents such as thionyl chloride or oxalyl chloride; acid halides
such as ethoxycarbonyl chloride; active amidation agents such as
carbonyldiimidazole; and azidation agents such as
diphenylphosphoric azide.
[0032] A condensing agent may be used at a molar ratio to the
compound represented by the general formula [2] of 1 or greater: 1,
and more preferably between 1:1 and 5:1.
[0033] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
water; halogenated hydrocarbons such as methylene chloride or
chloroform; ethers such as tetrahydrofuran or dioxane; aromatic
hydrocarbons such as benzene, toluene, or xylene; sulfoxides such
as dimethyl sulfoxide; amides such as N,N-dimethylformamide; esters
such as ethyl acetate; ketones such as acetone or methyl ethyl
ketone; nitrites such as acetonitrile; and heteroaromatics such as
pyridine. These solvents may also be used in combination.
[0034] This reaction can be carried out in the presence of a
base.
[0035] Examples of such a base may include organic bases and
inorganic bases, such as triethylamine, diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, potassium
tert-butoxide, sodium carbonate, sodium bicarbonate, potassium
carbonate, or sodium hydroxide.
[0036] Such a base is used to the compound represented by the
general formula [2] at a molar ratio of 0.5 or greater: 1, and
preferably at a molar ratio between 1:1 and 10:1.
[0037] The compound represented by the general formula [3] is used
to the compound represented by the general formula [2] at a molar
ratio of 1 or greater 1, and preferably at a molar ratio between
1:1 and 20:1.
[0038] This reaction may be carried out generally between
-100.degree. C. and 200.degree. C., and preferably between
-60.degree. C. and 100.degree. C., for 10 minutes to 20 hours.
[0039] The obtained compound represented by the general formula [4]
may directly be used in the subsequent reaction without being
isolated.
[0040] (1-2) When R.sup.3a in the compound represented by the
general formula [4] is a hydroxyl group that is not protected, the
above compound of the general formula [4] is subjected to a common
hydroxyl group-protecting reaction, so as to induce it to the
compound represented by the general formula [4a].
[0041] This reaction may be carried out by known methods, for
example, by the method described in Protective Groups in Organic
Synthesis, pp. 10-118, 1991, Theodora W. Green, John Wiley &
Sons, Inc., or a method equivalent thereto.
[0042] Examples of a compound used in such a hydroxyl
group-protecting reaction may include: acid anhydrides such as
acetic anhydride; acid halides such as benzoyl chloride, pivaloyl
chloride, methoxycarbonyl chloride, or ethoxycarbonyl chloride;
halides such as methoxymethyl chloride, benzyloxymethyl chloride,
benzyl chloride, benzyl bromide, trityl chloride, or triethylsilyl
chloride; organic carboxylic acid compounds such as benzoic acid;
dialkoxyalkyl compounds such as dimethoxymethane; and noncyclic and
cyclic alkoxyvinyl compounds such as 2-methoxypropene or
3,4-dihydro-2H-pyran.
[0043] The compound used in a hydroxyl group-protecting reaction is
used at a molar ratio to the compound represented by the general
formula [4] of 1 or greater: 1, and preferably between 1:1 and
2:1.
[0044] A hydroxyl group-protecting reaction using an acid
anhydride, an acid halide, or a halide, is generally carried out in
the presence of a base or a dehalogenating agent. Examples of a
base used herein may include organic bases and inorganic bases,
such as triethylamine, N,N-diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,
4-dimethylaminopyridine, potassium tert-butoxide, sodium hydroxide,
potassium hydroxide, or sodium hydride. Examples of a
dehydrogenating agent may include silver compounds such as silver
oxide.
[0045] A hydroxyl group-protecting reaction using an organic
carboxylic acid compound is carried out in a dehydrating agent.
Examples of a dehydrating agent used herein may include
triphenylphosphine-diisopropyl=azodicarboxylate.
[0046] In addition, a hydroxyl group-protecting reaction using an
acid anhydride, a dialkoxyalkyl compound, or a noncyclic or cyclic
alkoxyvinyl compound, is generally carried out in the presence of
an acid catalyst. Examples of an acid used herein may include:
organic sulfonic acids such as p-toluenesulfonic acid; inorganic
acids such as hydrochloric acid or sulfuric acid; and Lewis acids
such as boron trifluoride, a boron trifluoride-diethyl ether
complex, or a boron trifluoride-tetrahydrofuran complex.
[0047] A base, a dehalogenating agent, or a dehydrating agent used
in this reaction may be used at a molar ratio to the compound used
in the hydroxyl group-protecting reaction of 1 or greater: 1, and
preferably between 1:1 and 2:1. An acid catalyst may be used at a
molar ratio to the compound represented by the general formula [4]
between 0.001:1 and 10:1, and preferably between 0.01:1 and
1:1.
[0048] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
halogenated hydrocarbons such as methylene chloride or chloroform;
ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons
such as benzene, toluene, or xylene; sulfoxides such as dimethyl
sulfoxide; amides such as N,N-dimethylformamide; esters such as
ethyl acetate; ketones such as acetone or methyl ethyl ketone;
nitrites such as acetonitrile; and heteroaromatics such as
pyridine. These solvents may also be used in combination.
[0049] This reaction may be carried out generally between
-100.degree. C. and 200.degree. C., and preferably between
-60.degree. C. and 100.degree. C., for 10 minutes to 30 hours.
[0050] Moreover, the reaction reagent or base used in each of the
aforementioned production methods may also be used as a solvent,
depending on the properties thereof.
[0051] The obtained compound represented by the general formula
[4a] may be used in the subsequent reaction without being
isolated.
(1-3) The compound represented by the general formula [4] or [4a]
is subjected to a common reduction reaction, so as to produce the
compound represented by the general formula [1].
[0052] This reduction reaction may be carried out by known methods,
for example, by the method described in Shin Jikken Kagaku Koza,
Vol. 15, [II], The Chemical Society of Japan, pp. 29-244, 1977,
(Maruzen), or a method equivalent thereto.
[0053] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
halogenated hydrocarbons such as methylene chloride or chloroform;
ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons
such as benzene, toluene, or xylene; and alcohols such as methanol,
ethanol, or isopropanol. These solvents may also be used in
combination.
[0054] Examples of a reducing agent may include: aluminum hydrides
such as lithium aluminum hydride; and boron hydrides such as
diborane, a borane-tetrahydrofuran complex, a borane-dimethyl
sulfide complex, or sodium borohydride.
[0055] When sodium borohydride is used as a reducing agent, the
reaction is preferably carried out in the presence of Lewis acid
such as boron trifluoride, a boron trifluoride-diethyl ether
complex, or a boron trifluoride-tetrahydrofuran complex.
[0056] Such a reducing agent may be used at a molar ratio to the
compound represented by the general formula [4] or [4a] of 0.2:1 or
greater, and preferably between 0.5:1 and 10:1.
[0057] Lewis acid may be used at a molar ratio to such a reducing
agent of 1 or greater: 1, and preferably between 4/3:1 and 2:1.
[0058] This reaction may be carried out generally between
-50.degree. C. and 200.degree. C., and preferably between 0.degree.
C. and 110.degree. C., for 10 minutes to 20 hours.
[Production Method 2]
[0059] The compound represented by the general formula [3] is
allowed to react with the compound represented by the general
formula [5] in the presence or absence of a base, so as to product
the compound represented by the general formula [1a].
[0060] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
water; halogenated hydrocarbons such as methylene chloride or
chloroform; aromatic hydrocarbons such as benzene, toluene, or
xylene; ethers such as tetrahydrofuran or dioxane; alcohols such as
methanol and ethanol; nitrites such as acetonitrile; amides such as
N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These
solvents may also be used in combination.
[0061] Examples of a base that is used as necessary may include
organic bases and inorganic bases, such as triethylamine,
diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
pyridine, potassium tert-butoxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, or sodium hydroxide.
[0062] Such a base may be used at a molar ratio to the compound
represented by the general formula [5] of 0.5 or greater: 1, and
preferably between 1:1 and 20:1.
[0063] Moreover, this reaction may also be carried out in the
presence of a catalyst.
[0064] Examples of a catalyst may include potassium iodide and
sodium iodide.
[0065] Such a catalyst may be used at a molar ratio to the compound
represented by the general formula [5] of between 0.01:1 and 10:1,
and preferably between 0.1:1 and 1:1.
[0066] The compound represented by the general formula [3] may be
used to the compound represented by the general formula [5] at a
molar ratio of 1 or greater: 1, and preferably at a molar ratio
between 1:1 and 20:1.
[0067] This reaction may be carried out generally between 0.degree.
C. and 200.degree. C., and preferably between 20.degree. C. and
150.degree. C., for 10 minutes to 20 hours.
[0068] Moreover, the reaction reagent or base used in each of the
aforementioned production methods may also be used as a solvent,
depending on the properties thereof.
[Production Method 3]
[0069] The compound represented by the general formula [7] is
allowed to react with the compound represented by the general
formula [6] in the presence of a base, so as to produce the
compound represented by the general formula [1b].
[0070] This reaction may be carried out by known methods, for
example, by the methods described in Tetrahedron Letters, Vol. 38,
pp. 3251-3254, 1975, and Shin Jikken Kagaku Koza, Vol. 14, [I], The
Chemical Society of Japan, pp. 567-611, 1977, (Maruzen), or methods
equivalent thereto.
[0071] Examples of a base may include sodium hydride, sodium
hydroxide, potassium hydroxide, and potassium tert-butoxide.
[0072] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
halogenated hydrocarbons such as methylene chloride or chloroform;
ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons
such as benzene, toluene, or xylene; sulfoxides such as dimethyl
sulfoxide; amides such as N,N-dimethylformamide; and water. These
solvents may also be used in combination.
[0073] This reaction can be carried out in the presence or absence
of a catalyst.
[0074] Examples of a catalyst used herein may include commonly
known phase-transfer catalysts of quaternary ammonium salts.
Preferred examples may include tetra-n-butyl ammonium hydrogen
sulfate and tetra-n-butyl ammonium bromide.
[0075] In this reaction, each of the compound represented by the
general formula [7] and a base may be used to the compound
represented by the general formula [6] at a molar ratio of 1 or
greater: 1, and preferably at a molar ratio between 1:1 and 20:1. A
catalyst is used to the above compound at a molar ratio between
0.001:1 and 1:1.
[0076] This reaction may be carried out generally between
-50.degree. C. and 200.degree. C., and preferably between 0.degree.
C. and 150.degree. C., for 10 minutes to 20 hours.
[Production Method 4]
[0077] The compound represented by the general formula [9] is
allowed to react with the compound represented by the general
formula [8] in the presence or absence of a base, so as to produce
the compound represented by the general formula [1b].
[0078] This reaction may be carried out by known methods, for
example, by the same method as Production method 3.
[Production Method 5]
(5-1) The compound represented by the general formula [1a]or the
compound represented by the general formula [1b] is subjected to a
common deprotection reaction, so as to produce the compound
represented by the general formula [1c].
[0079] This reaction may be carried out by known methods, for
example, by the method described in Protective Groups in Organic
Synthesis, pp. 10-118 and 309-405, 1991, Theodora W. Green, John
Wiley & Sons, Inc., or a method equivalent thereto.
[0080] This deprotection reaction is carried out, for example,
under conditions consisting of hydrolysis and transesterification
in the presence of an acid or base, substitution and dissociation
reaction in the presence of an acid catalyst, or hydrogenation in
the presence of a metal catalyst. Examples of a base used herein
may include inorganic bases such as sodium hydroxide, potassium
hydroxide, or sodium hydride. Examples of an acid used herein may
include: organic sulfonic acids such as p-toluenesulfonic acid;
organic carboxylic acids such as formic acid, acetic acid, or
trifluoroacetic acid; inorganic acids such as hydrochloric acid or
sulfuric acid; and Lewis acids such as boron trifluoride, a boron
trifluoride-diethyl ether complex, or a boron
trifluoride-tetrahydrofuran complex. Examples of a metal catalyst
may include transition metals such as platinum, palladium,
palladium carbon, or palladium hydroxide.
[0081] The base used in this reaction may be used at a molar ratio
to the compound represented by the general formula [1a]or [1b] of 1
or greater: 1, and preferably between 1:1 and 5:1. The acid may be
used to the compound represented by the general formula [1a]or [1b]
at a molar ratio of 1 or greater: 1, and preferably at a molar
ratio between 1.1:1 and 100:1. In addition, the metal catalyst may
be used to the compound represented by the general formula [1a]or
[1b] at a catalytic amount, and preferably at a weight ratio
between 0.01% and 30%.
[0082] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
halogenated hydrocarbons such as methylene chloride or chloroform;
ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons
such as benzene, toluene, or xylene; sulfoxides such as dimethyl
sulfoxide; amides such as N,N-dimethylformamide; esters such as
ethyl acetate; ketones such as acetone or methyl ethyl ketone;
nitrites such as acetonitrile; alcohols such as methanol or
ethanol; organic carboxylic acids such as formic acid or acetic
acid; and water. These solvents may also be used in
combination.
[0083] This reaction may be carried out generally between
-100.degree. C. and 200.degree. C., and preferably between
-60.degree. C. and 120.degree. C., for 10 minutes to 20 hours.
[0084] Moreover, the base used in each of the aforementioned
production methods may also be used as a solvent, depending on the
properties thereof.
[0085] (5-2) The compound represented by the general formula [1c]
is subjected to a common protection reaction for a hydroxyl group
and an amino group or to an alkylation reaction of an amino group,
so as to induce it to the compound represented by the general
formula [1b].
[0086] The hydroxyl group-protecting reaction may be carried out by
known methods, for example, by the method described in Protective
Groups in Organic Synthesis, pp. 10-118, 1991, Theodora W. Green,
John Wiley & Sons, Inc., or a method equivalent thereto. This
reaction may be carried out by the same method as in Example
(1-2).
[0087] The amino group-protecting reaction may be carried out by
known methods, for example, by the method described in Protective
Groups in Organic Synthesis, pp. 309-405, 1991, Theodora W. Green,
John Wiley & Sons, Inc., or a method equivalent thereto.
[0088] Examples of a compound used in the amino group-protecting
reaction may include: acid anhydrides such as acetic anhydride; and
acid halides such as acetyl chloride, benzoyl chloride,
methanesulfonyl chloride, or tosyl chloride. Such a compound may be
used at a molar ratio to the compound represented by the general
formula [1c] of 1 or greater: 1, and preferably between 1:1 and
2:1.
[0089] This reaction is generally carried out in the presence of a
base. Examples of such a base may include organic bases and
inorganic bases, such as triethylamine, diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, potassium
tert-butoxide, sodium carbonate, sodium bicarbonate, potassium
carbonate, or sodium hydroxide.
[0090] Such a base may be used at a molar ratio to the compound
represented by the general formula [1c] of 0.5 or greater: 1, and
preferably between 1:1 and 10:1.
[0091] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
halogenated hydrocarbons such as methylene chloride or chloroform;
ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons
such as benzene, toluene, or xylene; sulfoxides such as dimethyl
sulfoxide; amides such as N,N-dimethylformamide; esters such as
ethyl acetate; ketones such as acetone or methyl ethyl ketone;
nitrites such as acetonitrile; alcohols such as methanol or
ethanol; and water. These solvents may also be used in
combination.
[0092] This reaction may be carried out generally between
-100.degree. C. and 200.degree. C., and preferably between
-60.degree. C. and 100.degree. C., for 10 minutes to 20 hours.
[0093] Furthermore, an alkylation reaction of an amino group may be
carried out by known methods, for example, by the method described
in Shin Jikken Kagaku Koza, Vol. 14, [III], The Chemical Society of
Japan, pp. 1332-1399, 1977, (Maruzen), or a method equivalent
thereto.
[0094] Examples of a compound used in such an alkylation reaction
of an amino group may include carbonyl compounds such as formalin,
paraformaldehyde, acetaldehyde, or acetone.
[0095] Such a compound may be used at a molar ratio to the compound
represented by the general formula [1c] of 1 or greater: 1, and
preferably between 1:1 and 5:1.
[0096] This reaction is generally carried out in the presence of a
reducing agent. Examples of a reducing agent may include boron
hydrides such as sodium borohydride.
[0097] Such a reducing agent may be used at a molar ratio to a
carbonyl compound of 0.5 or greater: 1, and preferably between 1:1
and 10:1.
[0098] Any solvent may be used in this reaction, as long as it does
not affect the reaction. Examples of such a solvent may include:
water; halogenated hydrocarbons such as methylene chloride or
chloroform; aromatic hydrocarbons such as benzene, toluene, or
xylene; ethers such as tetrahydrofuran or dioxane; and alcohols
such as methanol or ethanol. These solvents may also be used in
combination.
[0099] This reaction may be carried out generally between
-100.degree. C. and 200.degree. C., and preferably between
0.degree. C. and 100.degree. C., for 10 minutes to 30 hours.
[0100] The reaction reagent used in each of the aforementioned
production methods may also be used as a solvent, depending on the
properties thereof.
[0101] In addition, in the aforementioned production methods, the
compounds represented by the general formulas [1a], [1b], [1c], [2]
to [9], and [4a], can also be used in the form of salts. Examples
of such salts are the same as those of the compound represented by
the general formula [1].
[0102] When isomers (for example, optical isomers, geometric
isomers, and tautomers) are present in the compounds represented by
the general formulas [1a], [1b], [1c], [2] to [9], and [4a], all
these isomers can be used. Further, hydrates, solvates, and all
crystal forms can also be used.
[0103] Furthermore, the compounds represented by the general
formulas [1a], [1b], [1c], [2] to [9], and [4a], may directly be
used in the subsequent reaction without being isolated.
[0104] When the compounds represented by the general formulas [1],
[1a], [1b], [1c], [2] to [9], and [4a], comprise a hydroxyl group,
an amino group, or a carboxyl group, such a hydroxyl group, an
amino group, or a carboxyl group has previously been protected with
a common protecting group, and after completion of the reaction,
such a protecting group can be dissociated by known methods, as
necessary. Moreover, the alkyl ether derivatives represented by the
general formulas [1], [1a], [1b], and [1c], or salts thereof are
subjected, for example, to the appropriate combined use of known
methods such as an oxidization reaction, a reduction reaction, an
alkylation reaction, a halogenation reaction, a sulfonylation
reaction, a substitution reaction, a dehydration reaction, and a
hydrolysis reaction, so as to induce them to another type of alkyl
ether derivative represented by the general formula [1] or a salt
thereof.
[0105] The thus obtained alkyl ether derivatives represented by the
general formulas [1], [1a], [1b], and [1c], or salts thereof, can
be isolated and purified by common methods such as extraction,
crystallization, distillation, or chromatography.
[0106] Next, a method for producing the compounds represented by
the general formulas [2] and [5] used as raw materials for
producing the compound of the present invention will be
described.
[0107] The compound represented by the general formula [2] can be
produced by known methods or by appropriately combining such
methods, for example, by the following production method A.
##STR7## wherein R.sup.1, R.sup.2, A, X.sup.3, m, and n have the
same meanings as defined above; R.sup.4 represents a cyano group, a
lower alkoxycarbonyl group, a dialkylaminocarbonyl group, or a
cyclic aminocarbonyl group; and X.sup.4 represents a leaving group.
(A-1) The compound represented by the general formula [10] is
allowed to react with the compound represented by the general
formula [6] in the presence of a base, so as to produce the
compound represented by the general formula [11].
[0108] This reaction may be carried out by known methods, for
example, by the method described in Shin Jikken Kagaku Koza, Vol.
14, [I], The Chemical Society of Japan, pp. 567-611, 1977,
(Maruzen), or a method equivalent thereto.
(A-2) The compound represented by the general formula [12] is
allowed to react with the compound represented by the general
formula [8] in the presence of a base, so as to produce the
compound represented by the general formula [11].
[0109] This reaction may be carried out by known methods, for
example, by the same method as Production method (A-1).
[0110] (A-3) The compound represented by the general formula [11]
is subjected to a common hydrolysis reaction of a nitrile, ester,
or amide, so as to produce the compound represented by the general
formula [2]. This reaction may be carried out by known methods, for
example, by the methods described in Shin Jikken Kagaku Koza, Vol.
14, [II], The Chemical Society of Japan, pp. 930-950, 1977,
(Maruzen), and Protective Groups in Organic Synthesis, pp. 152-192,
1981, Theodora W. Green, John Wiley & Sons. Inc., or methods
equivalent thereto.
[0111] (A-4) The compound represented by the general formula [16]
is allowed to react with the compound represented by the general
formula [6] by the Michael addition reaction in the presence of a
base, so as to produce the compound represented by the general
formula [11a]. This reaction may be carried out by known methods,
for example, by the methods described in Chemical &
Pharmaceutical Bulletin, Vol. 41, pp. 1659-1663, 1993; Shin Jikken
Kagaku Koza, Vol. 14, [I], The Chemical Society of Japan, pp.
585-587, 1977, (Maruzen); and JP-A-3-99038, or methods equivalent
thereto.
[0112] (A-5) The compound represented by the general formula [11a]
is subjected to a common hydrolysis reaction of a nitrile, ester,
or amide, so as to produce the compound represented by the general
formula [2a]. This reaction may be carried out by known methods,
for example, by the same method as that described in (A-3)
above.
[0113] The compound represented by the general formula [5] can be
produced by known methods or by appropriately combining such
methods, for example, by the following production method B.
##STR8## wherein R.sup.1, R.sup.2, X.sup.1, A, m, and n have the
same meanings as defined above; R.sup.4a represents an
alkoxycarbonyl group; R.sup.5 represents a hydroxyl-protecting
group that is stable under basic conditions; each of X.sup.5 and
X.sup.6 represents a leaving group.
[0114] Examples of a hydroxyl-protecting group that is stable under
basic conditions may include: lower alkyl groups such as
tert-butyl; lower alkenyl groups such as allyl; ar-lower alkyl
groups such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,
diphenylmethyl, or trityl; oxygen-containing and sulfur-containing
heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, or
tetrahydrothiopyranyl; lower alkoxy-lower alkyl groups such as
methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, or
1-methyl-1-methoxyehtyl; and substituted silyl groups such as
tert-butyldimethylsilyl or diphenylmethylsilyl.
[0115] (B-1) The compound represented by the general formula [13]
is allowed to react with the compound represented by the general
formula [6], so as to produce the compound represented by the
general formula [5]. This reaction may be carried out by known
methods, for example, by the methods described in Tetrahedron
Letters, Vol. 38, pp. 3251-3254, 1975, and Shin Jikken Kagaku Koza,
Vol. 14, [I], The Chemical Society of Japan, pp. 567-611, 1977,
(Maruzen), or methods equivalent thereto.
[0116] (B-2) The compound represented by the general formula [14]
is allowed to react with the compound represented by the general
formula [6], and thereafter, a protecting group is dissociated, so
as to produce the compound represented by the general formula [15].
This reaction may be carried out by known methods, for example, by
the same method as Production method 3, followed by dissociation of
a protecting group.
[0117] (B-3) The compound represented by the general formula [2] or
the compound represented by the general formula [11b] is subjected
to a common reduction reaction, so as to produce the compound
represented by the general formula [15]. This reduction reaction
may be carried out by known methods, for example, by the method
described in Shin Jikken Kagaku Koza, Vol. 15, pp. 26-244, 1977,
(Maruzen), or a method equivalent thereto.
(B-4) A halogenating agent or a sulfonylating agent is allowed to
react with the compound represented by the general formula [15] in
the presence or absence of a base, so as to produce the compound
represented by the general formula [5].
[0118] Examples of a solvent used in this reaction may include:
halogenated hydrocarbons such as methylene chloride or chloroform;
ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons
such as benzene, toluene, or xylene; sulfoxides such as dimethyl
sulfoxide; amides such as N,N-dimethylformamide; esters such as
ethyl acetate; and nitrites such as acetonitrile. These solvents
may also be used in combination.
[0119] In addition, examples of a base used in this reaction as
necessary may include organic or inorganic bases, such as
triethylamine, diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, potassium
tert-butoxide, sodium carbonate, potassium carbonate, or sodium
hydride.
[0120] Examples of a halogenating agent may include phosphorus
oxychloride, phosphorous oxybromide, phosphorus trichloride,
phosphorus pentachloride, carbon tetrabromide-triphenylphosphine,
and thionyl chloride.
[0121] Examples of a sulfonylating agent may include
methanesulfonyl chloride and p-toluenesulfonyl chloride.
[0122] Such a halogenating agent, sulfonylating agent, or base may
be used to the compound represented by the general formula [15] at
a molar ratio of 1 or greater: 1, and preferably at a molar ratio
between 1:1 and 2:1.
[0123] This reaction may be carried out generally between
-50.degree. C. and 200.degree. C., and preferably between 0.degree.
C. and 50.degree. C., for 10 minutes to 30 hours.
[0124] When the compounds represented by the general formulas [2],
[2a], [6], [8], [10] to [16], [11a], and [11b] in the production
methods A and B, comprise a hydroxyl group, an amino group, or a
carboxyl group, such a hydroxyl group, an amino group, or a
carboxyl group has previously been protected with a common
protecting group, and after completion of the reaction, such a
protecting group can be dissociated by known methods, as
necessary.
[0125] Moreover, when isomers (for example, optical isomers,
geometric isomers, and tautomers) are present in the compounds
represented by the general formulas [2], [2a], [6], [8], [10] to
[16], [11a], and [11b], all these isomers can be used. Further,
hydrates, solvates, and all crystal forms can also be used.
[0126] Furthermore, the compounds represented by the general
formulas [2], [2a], [6], [8], [10] to [16], [11a], and [11b], may
directly be used in the subsequent reaction without being
isolated.
[0127] The compound of the present invention can be formulated into
pharmaceutical preparations such as oral agents (a tablet, a
capsule, a powder, a granule, a fine granules, a pill, a
suspension, an emulsion, a syrup, etc.), injections, or eyedrops,
by adding thereto various types of pharmaceutical additives such as
an excipient, a binder, a disintegrator, a disintegration
inhibitor, an anticaking/antiadhesion agent, a lubricant, an
absorption/adsorption carrier, a solvent, an extender, an
isotonizing agent, a solubilizer, an emulsifier, a suspending
agent, a thickener, a coating agent, an absorbefacient, a
gelation/agglutination promoter, a light stabilizer, a
preservative, an anti-moisture agent, an emulsion, suspension or
dispersion stabilizer, a coloration preventing agent, a
deoxidizer/antioxidant, correctives, a coloring agent, a whipping
agent, an antifoaming agent, a soothing agent, an antistatic agent,
or a buffer/pH adjuster.
[0128] The aforementioned various types of agents are formulated by
common methods.
[0129] Oral solid preparations such as a tablet, a powder, or a
granule may be prepared according to common methods, using the
following pharmaceutical additives for such solid preparations, for
example: excipients such as lactose, saccharose, sodium chloride,
glucose, starch, calcium carbonate, kaolin, crystalline cellulose,
anhydrous dicalcium phosphate, corn starch, or alginic acid;
binders such as simple syrup, glucose solution, starch solution,
gelatin solution, polyvinyl alcohol, polyvinylpyrrolidone, shellac,
methylcellulose, ethylcellulose, sodium alginate, gum Arabic,
hydroxypropylmethylcellulose, hydroxypropylcellulose, water, or
ethanol; disintegrators such as dry starch, alginic acid, agar
powders, starch, partial .alpha. starch, crosslinked
polyvinylpyrrolidone, carboxymethylcellulose, crosslinked
carboxymethylcellulose sodium, carboxymethylcellulose calcium, or
sodium starch glycolate; disintegration inhibitors such as stearyl
alcohol, stearic acid, cacao butter, or hydrogenated oil;
anticaking/antiadhesion agents such as aluminum silicate, calcium
hydrogen phosphate, magnesium oxide, talc, or silicic acid
anhydride; lubricants such as carnauba wax, light anhydrous silicic
acid, aluminum silicate, magnesium silicate, hardened oil, hardened
vegetable oil derivative, sesame oil, white beeswax, titanium
oxide, dry aluminum hydroxide gel, stearic acid, calcium stearate,
magnesium stearate, talc, calcium hydrogen phosphate, sodium lauryl
sulfate, or polyethylene glycol; absorption promoters such as
quaternary ammonium salts, sodium lauryl sulfate, urea, or enzyme;
and absorption/adsorption carriers such as starch, lactose, kaolin,
bentonite, silicic acid anhydride, hydrous silicon dioxide,
magnesium aluminometasilicate, or colloidal silicic acid.
[0130] Moreover, as necessary, a tablet may be processed into a
tablet coated with a common coating agent, such as a sugar-coated
tablet, a gelatin-coated tablet, a gastric coated tablet, an
enteric coated tablet, and a water-soluble film coated tablet.
[0131] A capsule is prepared by mixing the present compound with
the aforementioned various types of pharmaceuticals and filling the
obtained mixture in a hard gelatin capsule or soft capsule.
[0132] Furthermore, the compound of the present invention may also
be formulated into water- or oil-type suspension, solution, syrup,
and elixir, by common methods, using the aforementioned various
types of additives for liquid preparations, such as a solvent, an
extender, an isotonizing agent, a solubilizer, an emulsifier, a
suspending agent, or a thickener.
[0133] An injection may be prepared by common methods, using
pharmaceutical additives for liquid preparations including:
diluents such as water, ethyl alcohol, Macrogol, propylene glycol,
citric acid, acetic acid, phosphoric acid, lactic acid, sodium
lactate, sulfuric acid, sodium hydroxide; pH adjusters and buffers,
such as sodium citrate, sodium acetate, or sodium phosphate;
stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic
acid, thioglycolic acid, or thiolactic acid; isotonizing agents
such as common salts, glucose, mannitol, or glycerin; solubilizers
such as carboxymethylcellulose sodium, propylene glycol, sodium
benzoate, benzyl benzoate, urethane, ethanolamine, or glycerin;
soothing agents such as calcium gluconate, chlorobutanol, glucose,
or benzyl alcohol; and local anesthetics.
[0134] An eyedrop may be prepared according to common methods by
appropriately mixing the compound of the present invention with
preservatives such as chlorobutanol, sodium dehydroacetate,
benzalkonium chloride, cetyl pyridinium chloride, phenethyl
alcohol, methyl parahydroxybenzoate, or benzethonium chloride;
buffers such as borax, boric acid, or potassium dihydrogen
phosphate; thickeners such as methylcellulose,
hydroxyethylcellulose, carboxymethylcellulose,
hydroxypropylmethylcellulose, polyvinyl alcohol,
carboxymethylcellulose sodium, or chondroitin sulfate; solubilizers
such as polysorbate 80 or polyoxyethylene hardened caster oil 60;
stabilizers such as edetate sodium or sodium bisulfite; or
isotonizing agents such as sodium chloride, potassium chloride, or
glycerin.
[0135] A method for administration of the aforementioned
preparations is not particularly limited. It is determined as
appropriate, depending on the form of a preparation, the age of a
patient, the sex thereof, and the degree of the symptoms of a
patient, and other conditions.
[0136] The dosage of the active ingredient of the preparation of
the present invention is selected as appropriate, depending on the
usage, the age of a patient, the sex thereof, the form of disease,
and other conditions. In general, the present preparation may be
administered at a dosage between 0.1 and 500 mg per adult per day,
once or divided over several administrations.
EXAMPLES
[0137] The present invention will be described in the following
test example, production examples, and formulation examples.
However, these examples are not intended to limit the scope of the
present invention. The mixing ratios of eluents in production
examples are all represented by volume ratios. The carriers used in
column chromatography are B.W. silica gel, BW-127ZH, and FL-100DX
(manufactured by Fuji Silysia Chemical Ltd.).
Test Example 1
Protecting Effect of Retinal Nerve in Rat Retinal Ischemia
Reperfusion Model
(a) Preparation of Retinal Ischemia Reperfusion Model
[0138] A rat retinal ischemia reperfusion model was prepared by a
partially modified method of Steven Roth et al. (Experimental Eye
Research, Vol. 65, pp. 771-779, 1997).
[0139] As experimental animals, SD rats (SPF, 9-week-old, male,
approximately 300 g of body weight) were used. Such rats were
anesthetized with halothane (introduction: 4%; retention: 2%; gas
composition: 70% air+30% oxygen; gas flow rate: 2 L/min). The rat
was placed on a fixing plate with the left body side upward. The
skin located between the external acoustic foramen and the external
canthus on the left side was incised, and the skin-incised portion
was held with a hook. The temporal muscle was burned out with a
bipolar coagulator (output: 4.5 W), and it was detached from the
cranial bone and the mandibular arch. Thereafter, the optic nerve
was detached under an operation microscope, and the central retinal
blood vessel with the thus obtained optic nerve was tied up with a
silk thread to such an extent that the silk thread did not damage
the optic nerve, and thereafter, the silk thread was fixed with a
vascular clip. During ischemia for 30 minutes, the incised portion
of the rat was closed, and the rat was then placed in a cage
without undergoing anesthesia, so that it was allowed to move
freely. 30 minutes later, the vascular clip and the silk thread
were removed under halothane anesthesia again, so that the blood
was allowed to flow again. Thereafter, the incised portion was
sutured. In order to prevent the operated eye (left eye) from
infection, ofloxacin eye ointment was applied thereto, and the
eyelid was sutured in order to prevent the cornea from being
dried.
(b) Administration of Test Compound
[0140] A test compound dissolved in distilled water was orally
administered at an amount of 10 mg/kg to the rat from 2 days after
retinal ischemia reperfusion, twice a day, for 14 days. In
addition, distilled water was orally administered to a control
group in the same manner described above.
(c) Electroretinogram (ERG) Measurement
[0141] ERG was measured in accordance with the method of Kawakami
et al. (Gifu-dai Iki, Vol. 48, pp. 166-175, 2000). That is to say,
after adaptation to darkness for approximately 1 hour, a mixed
solution consisting of 66 mg/kg ketamine hydrochloride and 5 mg/kg
xylazine hydrochloride was intramuscularly injected into the muscle
of thigh of the rat for anesthesia under red light. Thereafter, the
rat was held on brain stereotaxis apparatus, and it was further
anesthetized by eyedrop with 0.4% oxybuprocaine hydrochloride.
Thereafter, contact lens electrode for ERG was applied thereto. At
that time, a droplet of adjuvant used for application of special
contact lens to the cornea was added dropwise to the portion
between the electrode and the cornea, so that they were allowed to
closely contact with each other. A ground electrode was implanted
into the skin of the lower extremity. For photic stimulation,
single-shot white light discharge flashing was applied by full
light emission with a stroboscope (stimulation frequency: 0.017
Hz). Such a stroboscope was placed at a position of 10 cm from the
anterior surface of cornea of the rat. Electric signals generated
as a result of the photic stimulation were added together twice and
then averaged using reaction adding/histogram analyzing apparatus.
The obtained waveform was swept on a memory oscilloscope and then
recorded by a thermal array recorder. ERG measurement was carried
out on each eye. Since ERG was indicated with the population spike
of wave (a) and wave (b), the amplitude value of ERG was defined as
a value from the bottom of the wave (a) to the vertex of the wave
(b). Such ERG measurement was carried out also on a normal control
eye of the same individual. ERG of the ischemic eye was evaluated
as a ratio to the value of normal control eye. ERG was measured
after adaptation to darkness at 2 days after retinal ischemia
reperfusion, and at approximately 1 hour after the final
administration.
(d) Results
[0142] The ratio of the ERG amplitude value of the ischemic eye to
the normal control eye was 35% in the control group, to which
distilled water had been administered. In contrast, the same above
ratio was 65% in the group, to which
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
maleate.
Production Example 1
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol
[0143] (1) 1.20 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)acetic acid
was dissolved in 12 ml of methylene chloride. Thereafter, 2.3 ml of
triethylamine and 0.38 g of imidazole were added to the obtained
solution, and the mixture was then cooled to 5.degree. C.
Thereafter, 0.41 ml of thionyl chloride was added dropwise thereto,
and the obtained mixture was stirred at the same above temperature
for 1 hour. The reaction mixture was cooled to -60.degree. C., and
thereafter, 0.82 ml of triethylamine and 0.72 g of 3-azetidinol
hydrochloride were added thereto. The mixture was stirred at the
same above temperature for 1 hour and then at a room temperature
for 1.5 hours. Thereafter, water was added to the reaction mixture,
and the pH thereof was adjusted to pH 1.0 by addition of 6 mol/l
hydrochloric acid. Thereafter, an organic layer was separated. The
organic layer was washed with a saturated saline solution and then
dried over anhydrous magnesium sulfate. The solvent was distilled
away under a reduced pressure, so as to obtain a yellow oil
product,
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-
-ethanone.
[0144] (2) The above
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanone
was dissolved in 12 ml of tetrahydrofuran, and the obtained
solution was cooled to 5.degree. C. Thereafter, 12.7 ml of a
tetrahydrofuran solution containing a 1 mol/l
borane-tetrahydrofuran complex was added dropwise thereto, and the
obtained mixture was stirred at a room temperature for 17 hours.
Thereafter, 10 ml of acetone was added to the reaction mixture, and
the obtained mixture was then stirred for 30 minutes. Thereafter,
6.0 ml of 6 mol/l hydrochloric acid was added thereto, followed by
heating to reflux for 2 hours. The reaction solution was cooled,
and water and ethyl acetate were added to the reaction mixture. The
pH thereof was adjusted to pH 13 by addition of a 2 mol/l aqueous
sodium hydroxide solution, and an organic layer was then separated.
The organic layer was washed with a saturated saline solution and
then dried over anhydrous magnesium sulfate. The solvent was
distilled away under a reduced pressure, so as to obtain 1.13 g of
a yellow oil product,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol.
[0145] IR (neat)cm.sup.-1: 3378, 2943, 1438, 1198, 1119, 703
[0146] NMR (CDCl.sub.3).delta.ppm: 2.66 (2H, t, J=6 Hz), 2.9-3.1
(2H, m), 2.99 (2H, t, J=7 Hz), 3.46 (2H, t, J=6 Hz), 3.6-3.7 (2H,
m), 3.67 (2H, t, J=7 Hz), 4.41 (1H, qn, J=6 Hz), 7.20 (1H, dd, J=2,
8 Hz), 7.27 (1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz), 7.66 (1H, d, J=2
Hz), 7.78 (1H, d, J=8 Hz)
Production Example 2
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol
hydrochloride
[0147] 1.03 g of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol was
dissolved in 4.2 ml of ethyl acetate. Thereafter, 0.86 ml of an
ethyl acetate solution containing 4.76 mol/l dry hydrogen chloride
was added to the obtained solution, and the obtained mixture was
stirred at a room temperature for 1 hour, and then at 5.degree. C.
for 1 hour. Thereafter, precipitated crystals were collected by
filtration, washed with ethyl acetate, and then dried, so as to
obtain 0.98 g of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol
hydrochloride.
[0148] Melting point: 101.degree. C. to 102.degree. C.
[0149] IR (KBr)cm.sup.-1: 3132, 2952, 1423, 1340, 1158, 814,
701
[0150] NMR (CDCl.sub.3).delta.ppm: 2.97 (2H, t, J=7 Hz), 3.2-3.3
(2H, m), 3.69 (2H, t, J=7 Hz), 3.6-3.8 (2H, m), 3.9-4.1 (2H, m),
4.2-4.4 (2H, m), 4.6-4.8 (1H, m), 7.18 (1H, dd, J=1, 8 Hz), 7.29
(1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz), 7.65 (1H, d, J=1 Hz), 7.78
(1H, d, J=8 Hz)
Production Example 3
Production of
1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol
[0151] 1.00 g of 6-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was
dissolved in 5 ml of dimethyl sulfoxide. Thereafter, 0.86 g of
3-azetidinol hydrochloride and 1.63 g of potassium carbonate were
added to the obtained solution, and the obtained mixture was
stirred at 75.degree. C. for 2.5 hours, and then at 95.degree. C.
for 1.5 hours. Thereafter, the reaction solution was cooled, and
thereafter, water and ethyl acetate were added to the reaction
mixture. The pH of the obtained mixture was adjusted to pH 1 by
addition of 6 mol/l hydrochloric acid, and a water layer was then
separated. Ethyl acetate was added to the water layer, and the pH
of the obtained mixture was adjusted to pH 10 by addition of a 2
mol/l aqueous sodium hydroxide solution, followed by separation of
an organic layer. The organic layer was successively washed with
water and a saturated saline solution, and then dried over
anhydrous magnesium sulfate. Thereafter, the solvent was distilled
away under a reduced pressure. The residue was purified by column
chromatography (eluent; chloroform:methanol=30:1 to 5:1), so as to
obtain 0.28 g of an achromatic oil product,
1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol.
[0152] IR (neat)cm.sup.1: 3398, 2940, 2867, 1197, 1107, 820,
757
[0153] NMR (CDCl.sub.3).delta.ppm: 1.60 (2H, qn, J=7 Hz), 2.45 (2H,
t, J=7 Hz), 2.7-2.8 (2H, m), 2.99 (2H, t, J=7 Hz), 3.45 (2H, t, J=7
Hz), 3.5-3.6 (2H, m), 3.66 (2H, t, J=7 Hz), 4.37 (1H, qn, J=6 Hz),
7.23 (1H, dd, J=1, 8 Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H, d, J=5
Hz), 7.73 (1H, d, J=1 Hz), 7.74 (1H, d, J=8 Hz)
Production Example 4
Production of
1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol
hydrochloride
[0154] 0.28 g of
1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol was
dissolved in 3.0 ml of ethyl acetate. Thereafter, 0.35 ml of an
ethyl acetate solution containing 3.25 mol/l dry hydrogen chloride
was added to the obtained solution, and the obtained mixture was
stirred at a room temperature for 1 hour. Subsequently, the solvent
was distilled away under a reduced pressure, so as to obtain 0.30 g
of a light yellow oil product,
1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol
hydrochloride.
[0155] IR (neat)cm.sup.-1: 3264, 2866, 2596, 1398, 1109, 1048,
821
[0156] NMR (CDCl.sub.3).delta.ppm: 1.81 (2H, qn, J=6 Hz), 2.92 (2H,
t, J=6 Hz), 2.98 (2H, t, J=6 Hz), 3.46 (2H, t, J=6 Hz), 3.68 (2H,
t, J=6 Hz), 3.8-3.9 (2H, m), 3.8-4.0 (2H, m), 4.4-4.6 (1H, m), 7.23
(1H, dd, J=1, 8 Hz), 7.31 (1H, d, J=5 Hz), 7.39 (1H, d, J=5 Hz),
7.74 (1H, d, J=1 Hz), 7.76 (1H, d, J=8 Hz)
Production Example 5
Production of
1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol
[0157] An achromatic oil product,
1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol was
obtained in the same manner as in Production Example 3.
[0158] IR (neat)cm.sup.-1: 3366, 2942, 2856, 1458, 1436, 1113,
750
[0159] NMR (CDCl.sub.3).delta.ppm: 1.64 (2H, qn=7 Hz), 2.49 (2H, t,
J=7 Hz), 2.7-2.8 (2H, m), 3.15 (2H, t, J=7 Hz), 3.50 (2H, t, J=7
Hz), 3.5-3.7 (2H, m), 3.71 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.06
(1H, s), 7.2-7.4 (2H, m), 7.67 (1H, dd, J=1, 7 Hz), 7.77 (1H, dd,
J=1, 7 Hz)
Production Example 6
Production of
1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol
hydrochloride
[0160] A light yellow oil product,
1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol
hydrochloride was obtained in the same manner as in Production
Example 4.
[0161] IR (neat)cm.sup.-1: 3290, 2868, 1457, 1436, 1113, 751
[0162] NMR (CDCl.sub.3).delta.ppm: 1.83 (2H, qn, J=6 Hz), 2.91 (2H,
t, J=6 Hz), 3.16 (2H, t, J=6 Hz), 3.52 (2H, t, J=6 Hz), 3.74 (2H,
t, J=6 Hz), 3.7-3.8 (2H, m), 3.7-3.9 (2H, m), 4.3-4.5 (1H, m), 7.09
(1H, s), 7.27 (1H, dt, J=1, 8 Hz), 7.33 (1H, dt, J=1, 8 Hz), 7.69
(1H, dd, J=1, 8 Hz), 7.78 (1H, dd, J=1, 8 Hz)
Production Example 7
Production of
1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol
[0163] An achromatic oil product,
1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol was
obtained in the same manner as in Production Example 3.
[0164] IR (neat)cm.sup.-1: 3386, 2942, 2856, 1458, 1105, 796, 755,
700
[0165] NMR (CDCl.sub.3).delta.ppm: 1.61 (2H, qn, J=7 Hz), 2.45 (2H,
t, J=7 Hz), 2.7-2.8 (2H, m), 3.17 (2H, t, J=7 Hz), 3.48 (2H, t, J=7
Hz), 3.5-3.7 (2H, m), 3.79 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 7.20
(1H, dd, J=1, 8 Hz), 7.32 (1H, t, J=8 Hz), 7.36 (1H, d, J=5 Hz),
7.43 (1H, d, J=5 Hz), 7.70 (1H, dd, J=1, 8 Hz)
Production Example 8
Production of
1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol
hydrochloride
[0166] An achromatic crystal,
1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol
hydrochloride was obtained in the same manner as in Production
Example 2.
[0167] Melting point: 105.degree. C. to 106.degree. C.
[0168] IR (KBr)cm.sup.-1: 3252, 2806, 2620, 1398, 1130, 1106, 811,
708
[0169] NMR (CDCl.sub.3).delta.ppm: 1.82 (2H, qn, J=6 Hz), 2.8-3.0
(2H, m), 3.16 (2H, t, J=6 Hz), 3.47 (2H, t, J=6 Hz), 3.83 (2H, t,
J=6 Hz), 3.7-4.1 (4H, m), 4.5-4.7 (1H, m), 7.21 (1H, d, J=8 Hz),
7.36 (1H, t, J=8 Hz), 7.38 (1H, d, J=5 Hz), 7.46 (1H, d, J=5 Hz),
7.73 (1H, d, J=8 Hz)
Production Example 9
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
[0170] (1) 5.00 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)propionic
acid was suspended in 12.5 ml of toluene, and 0.1 ml of
N,N-dimethylformamide was then added thereto. Thereafter, 1.68 ml
of thionyl chloride was added dropwise thereto at 15.degree. C.,
and the obtained mixture was then stirred at a room temperature for
1 hour. This reaction mixture was added dropwise to 25 ml of an
aqueous solution containing 4.44 g of 3-hydroxyazetidine-1/2
tartrate and 3.76 g of sodium hydroxide at 10.degree. C., and the
mixture was then stirred at a room temperature for 1 hour.
Thereafter, ethyl acetate was added to the reaction mixture, so as
to separate an organic layer. The organic layer was successively
washed with diluted hydrochloric acid and a saturated saline
solution, and then dried over anhydrous magnesium sulfate. The
solvent was then distilled away under a reduced pressure. The
residue was purified by column chromatography (eluent;
chloroform:acetone=3:1 to 1:1), and then crystallized from
diisopropyl ether, so as to obtain 5.48 g of an achromatic crystal,
3-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-propanon-
e.
[0171] IR (KBr)cm.sup.-1: 3316, 2875, 1610, 1481, 1112, 992,
706
[0172] NMR (CDCl.sub.3).delta.ppm: 2.2-2.4 (2H, m), 2.98 (2H, t,
J=7 Hz), 3.6-3.8 (5H, m), 3.8-4.0 (1H, m), 4.1-4.3 (2H, m), 4.4-4.4
(1H, m), 7.20 (1H, dd, J=1, 8 Hz), 7.28 (1H, dd, J=1, 5 Hz), 7.41
(1H, d, J=5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J=8 Hz)
[0173] (2) 5.00 g of
3-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-propanon-
e was dissolved in 20 ml of tetrahydrofuran, and 1.09 g of sodium
borohydride was then added thereto. Thereafter, 4.25 ml of a boron
trifluoride-tetrahydrofuran complex was added dropwise thereto at
10.degree. C., and the obtained mixture was then stirred at the
same temperature for 1 hour and then at 40.degree. C. for 3 hours.
Thereafter, the reaction solution was cooled to 10.degree. C.
Thereafter, 30 ml of 6 mol/l hydrochloric acid was added dropwise
to the reaction mixture, followed by reflux for 1 hour. After
cooling, the solvent was concentrated under a reduced pressure, and
ethyl acetate was added thereto. The pH of the mixture was adjusted
to pH 9.4 by addition of a 20% aqueous sodium hydroxide solution,
and an organic layer was then separated. The organic layer was
successively washed with water and a saturated saline solution, and
then dried over anhydrous magnesium sulfate. The solvent was then
distilled away under a reduced pressure. The residue was purified
by column chromatography (eluent; chloroform:methanol=20:1 to
10:1), and then crystallized from toluene-diisopropyl ether (1:3;
14 ml), so as to obtain 2.31 g of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol.
[0174] IR (KBr)cm.sup.-1: 3095, 2944, 2769, 1361, 1191, 1098, 810,
709
[0175] NMR (CDCl.sub.3).delta.ppm: 1.61 (2H, qn, J=7 Hz), 2.45 (2H,
t, J=7 Hz), 2.7-2.9 (2H, m), 2.99 (2H, t, J=7 Hz), 3.45 (2H, t, J=7
Hz), 3.5-3.6 (2H, m), 3.66 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.22
(1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz),
7.67 (1H, d, J=1 Hz), 7.79 (1H, d, J=8 Hz)
Production Example 10
(A) Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
hydrochloride
[0176] An achromatic crystal,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
hydrochloride, was obtained in the same manner as in Production
Example 2.
[0177] Melting point: 71.degree. C. to 73.degree. C.
[0178] IR (KBr)cm.sup.-1: 3301, 2937, 2809, 2631, 1125, 1099, 818,
765, 710
[0179] NMR (CDCl.sub.3).delta.ppm: 1.8-1.9 (2H, m), 2.98 (2H, t,
J=7 Hz), 2.9-3.1 (2H, m), 3.48 (2H, t, J=6 Hz), 3.69 (2H, t, J=7
Hz), 3.6-4.4 (4H, m), 4.5-4.7 (1H, m), 7.22 (1H, dd, J=1, 8 Hz),
7.31 (1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz), 7.68 (1H, d, J=1 Hz),
7.81 (1H, d, J=8 Hz)
(B) Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol 1/2
fumarate
[0180] 5.00 g of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol was
dissolved in 10.0 ml of ethanol, and the obtained solution was then
heated to 70.degree. C. Thereafter, 0.99 g of fumaric acid was
added to the solution, and the obtained mixture was stirred for 30
minutes. Thereafter, 30.0 ml of ethyl acetate was added dropwise to
the solution, and the obtained mixture was stirred at 60.degree. C.
for 15 minutes and then cooled to 5.degree. C. over 1 hour.
Thereafter, the solution was further stirred at the same above
temperature for 1 hour. Thereafter, precipitated crystals were
collected by filtration and were then washed with ethyl acetate,
followed by drying, so as to obtain 5.83 g of an achromatic
crystal, 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
1/2 fumarate.
[0181] IR (KBr)cm.sup.-1: 3258, 2936, 2862, 1578, 1360, 1114, 1109,
707, 665
[0182] NMR (DMSO-d.sub.6).delta.ppm: 1.5-1.6 (2H, m), 2.60 (2H, t,
J=7 Hz), 2.91 (2H, t, J=7 Hz), 2.9-3.1 (2H, m), 3.39 (2H, t, J=7
Hz), 3.60 (2H, t, J=7 Hz), 3.6-3.8 (2H, m), 4.1-4.3 (1H, m), 6.50
(1H, s), 7.25 (1H, dd, J=1, 8 Hz), 7.39 (1H, d, J=5 Hz), 7.72 (1H,
d, J=5 Hz), 7.73 (1H, d, J=1 Hz), 7.89 (1H, d, J=8 Hz)
(C) Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
maleate
[0183] 8.00 g of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol was
dissolved in 56 ml of acetone. Thereafter, 3.19 g of maleic acid
was added thereto, and the obtained mixture was heated to
60.degree. C. for dissolution. The reaction mixture was gradually
cooled, and it was then stirred at 5.degree. C. for 30 minutes.
Thereafter, precipitated crystals were collected by filtration, so
as to obtain 9.89 g of an achromatic crystal,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol
maleate.
[0184] NMR (DMSO-d.sub.6).delta.ppm: 1.6-1.8 (2H, m), 2.93 (2H, t,
J=7 Hz), 3.13 (2H, t, J=7 Hz), 3.43 (2H, t, J=6 Hz), 3.63 (2H, t,
J=7 Hz), 3.7-3.9 (2H, m), 4.1-4.3 (2H, m), 4.4-4.5 (1H, m), 6.04
(2H, s), 7.26 (1H, dd, J=1, 8 Hz), 7.40 (1H, d, J=5 Hz), 7.7-7.8
(1H, m), 7.74 (1H, d, J=5 Hz), 7.92 (1H, d, J=8 Hz)
Production Example 11
Production of
1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol
[0185] An achromatic oil product,
1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol was
obtained in the same manner as in Production Example 3.
[0186] IR (neat)cm.sup.-1: 3368, 2946, 2856, 1457, 1107, 759
[0187] NMR (CDCl.sub.3).delta.ppm: 1.60 (2H, qn, J=7 Hz), 2.44 (2H,
t, J=7 Hz), 2.7-2.9 (2H, m), 3.22 (2H, t, J=7 Hz), 3.45 (2H, t, J=7
Hz), 3.5-3.6 (2H, m), 3.70 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 7.19
(1H, d, J=7 Hz), 7.28 (1H, t, J=7 Hz), 7.44 (1H, d, J=6 Hz), 7.46
(1H, d, J=6 Hz), 7.76 (1H, d, J=7 Hz)
Production Example 12
Production of
1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol
hydrochloride
[0188] A light yellow oil product,
1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol
hydrochloride was obtained in the same manner as in Production
Example 4.
[0189] IR (neat)cm.sup.-1: 3302, 2966, 2877, 2594, 1412, 1108,
766
[0190] NMR (CDCl.sub.3).delta.ppm: 1.78 (2H, qn, J=6 Hz), 2.82 (2H,
t, J=7 Hz), 3.21 (2H, t, J=6 Hz), 3.43 (2H, t, J=6 Hz), 3.73 (2H,
t, J=6 Hz), 3.7-3.9 (2H, m), 3.8-4.0 (2H, m), 4.5-4.7 (1H, m), 7.21
(1H, d, J=7 Hz), 7.30 (1H, t, J=7 Hz), 7.49 (2H, s), 7.78 (1H, d,
J=7 Hz)
Production Example 13
Production of
1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol
[0191] 1.00 g of 3-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was
dissolved in 5 ml of dimethyl sulfoxide. Thereafter, 1.10 g of
3-azetidinol trifluoroacetate and 1.63 g of potassium carbonate
were added to the obtained solution, and the mixture was then
stirred at 70.degree. C. for 2 hours. After cooling, water and
ethyl acetate were added to the reaction mixture. The pH of the
mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric
acid, and a water layer was then separated. Ethyl acetate was added
to the water layer, and the pH of the obtained mixture was adjusted
to pH 10 by addition of a 2 mol/l aqueous sodium hydroxide
solution, followed by separation of an organic layer. The organic
layer was successively washed with water and a saturated saline
solution, and then dried over anhydrous magnesium sulfate.
Thereafter, the solvent was distilled away under a reduced
pressure. The residue was purified by column chromatography
(eluent; chloroform:methanol=30:1 to 10:1), so as to obtain 0.55 g
of an achromatic oil product,
1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol.
[0192] IR (neat)cm.sup.-1: 3368, 2942, 2845, 1427, 1191, 1109,
759
[0193] NMR (CDCl.sub.3).delta.ppm: 1.62 (2H, qn, J=7 Hz), 2.47 (2H,
t, J=7 Hz), 2.7-2.9 (2H, m), 3.11 (2H, t, J=7 Hz), 3.48 (2H, t, J=6
Hz), 3.5-3.7 (2H, m), 3.74 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 7.18
(1H, s), 7.33 (1H, dt, J=1, 7 Hz), 7.39 (1H, dt, J=1, 7 Hz), 7.77
(1H, dd, J=1, 7 Hz), 7.86 (1H, dd, J=1, 7 Hz)
Production Example 14
Production of
1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol
hydrochloride
[0194] A light yellow oil product,
1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol
hydrochloride was obtained in the same manner as in Production
Example 4.
[0195] IR (neat) cm.sup.-1: 3284, 2966, 2596, 1428, 1112, 1049,
765, 734
[0196] NMR (CDCl.sub.3).delta.ppm: 1.83 (2H, qn, J=6 Hz), 2.96 (2H,
t, J=6 Hz), 3.12 (2H, t, J=6 Hz), 3.48 (2H, t, J=6 Hz), 3.76 (2H,
t, J=6 Hz), 3.8-3.9 (2H, m), 3.9-4.1 (2H, m), 4.5-4.7 (1H, m), 7.21
(1H, s), 7.35 (1H, dt, J=1, 7 Hz), 7.40 (1H, dt, J=1, 7 Hz), 7.78
(1H, dd, J=1.7 Hz), 7.86 (1H, dd, J=1, 7 Hz)
Production Example 15
Production of
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide
[0197] 0.80 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was
dissolved in 8 ml of N,N-dimethylformamide. Thereafter, 1.20 g of
N-(3-azetidinyl)acetamide was added to the obtained solution, and
the obtained mixture was stirred at 90.degree. C. for 12 hours.
After cooling, water and ethyl acetate were added to the reaction
mixture, and an organic layer was separated. The organic layer was
successively washed with water and a saturated saline solution, and
then dried over anhydrous magnesium sulfate. Thereafter, the
solvent was distilled away under a reduced pressure. The residue
was purified by column chromatography (eluent;
chloroform:methanol=7:1), so as to obtain 0.39 g of a light yellow
oil product,
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide.
[0198] IR (neat)cm.sup.-1: 3276, 2941, 2860, 1654, 1559, 1111, 756,
703
[0199] NMR (CDCl.sub.3).delta.ppm: 1.59 (2H, qn, J=7 Hz), 1.97 (3H,
s), 2.42 (2H, t, J=7 Hz), 2.7-2.9 (2H, m), 2, 98 (2H, t, J=7 Hz),
3.45 (2H, t, J=7 Hz), 3.4-3.6 (2H, m), 3.66 (2H, t, J=7 Hz),
4.4-4.5 (1H, m), 7.22 (1H, dd, J=1, 8 Hz), 7.29 (1H, d, J=5 Hz),
7.42 (1H, d, J=5 Hz), 7.67 (1H, d, J=1 Hz), 7.80 (1H, d, J=8
Hz)
Production Example 16
Production of
1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
[0200] (1) 0.74 g of 2-(2-(1-benzothiophene-6-yl)ethoxy)acetic acid
was dissolved in 7.4 ml of methylene chloride. Thereafter, 1.36 ml
of triethylamine and 0.22 g of imidazole were added to the obtained
solution. Subsequently, the mixture was cooled to 5.degree. C.
Thereafter, 0.24 ml of thionyl chloride was added dropwise thereto,
and the obtained mixture was stirred at the same above temperature
for 1 hour. After the reaction mixture was cooled to -50.degree.
C., 0.45 ml of triethylamine and 0.32 ml of 3-pyrrolidinol were
added thereto. The mixture was stirred at the same above
temperature for 1 hour and then at a room temperature for 1 hour.
Thereafter, water was added to the reaction mixture, and an organic
layer was separated. The organic layer was successively washed with
1 mol/l hydrochloric acid, then with a 2 mol/l aqueous sodium
hydroxide solution, and then with a saturated saline solution. The
resultant was then dried over anhydrous magnesium sulfate.
Subsequently, the solvent was distilled away under a reduced
pressure, so as to obtain a light yellow oil product,
2-(2-(1-benzothiophene-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethano-
ne.
[0201] IR (neat)cm.sup.-1: 3386, 2942, 1636, 1106, 758
[0202] (2) The above
2-(2-(1-benzothiophene-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethano-
ne was dissolved in 7.4 ml of tetrahydrofuran. Thereafter, 7.4 ml
of a tetrahydrofuran solution containing a 1 mol/l
borane-tetrahydrofuran complex was added dropwise to the obtained
solution while cooling on ice, and the obtained mixture was then
stirred at a room temperature for 17 hours. Thereafter, 10 ml of
acetone was added to the reaction mixture, and the obtained mixture
was then stirred for 30 minutes. Thereafter, 1.5 ml of 6 mol/l
hydrochloric acid was added thereto, and the obtained mixture was
heated to reflux for 2 hours. After the reaction mixture was
cooled, water and ethyl acetate were added thereto, and a water
layer was separated. Thereafter, ethyl acetate was added to the
water layer. The pH of the obtained mixture was adjusted to pH 9.5
by addition of a 2 mol/l aqueous sodium hydroxide solution,
followed by separation of an organic layer. The organic layer was
successively washed with water and a saturated saline solution, and
then dried over anhydrous magnesium sulfate. Thereafter, the
solvent was distilled away under a reduced pressure. The residue
was purified by column chromatography (eluent;
chloroform:methanol=30:1 to 20:1), so as to obtain 0.53 g of a
yellow oil product,
1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol.
[0203] IR (neat)cm.sup.-1: 3386, 2940, 2867, 1110, 820, 756
[0204] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.0-2.2 (1H,
m), 2.31 (1H, dt, J=7, 9 Hz), 2.53 (1H, dd, J=5, 10 Hz), 2.6-2.7
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.01 (2H, t, J=7 Hz), 3.58 (2H,
t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 4.2-4.3 (1H, m), 7.23 (1H, d, J=8
Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H, d, J=5 Hz), 7.73 (1H, d, J=8
Hz), 7.73 (1H, s)
Production Example 17
Production of
1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0205] 0.48 g of
1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol was
dissolved in 2.0 ml of ethyl acetate. Thereafter, 2.8 ml of an
ethyl acetate solution containing 0.15 g of oxalic acid was added
to the obtained solution, and the mixture was stirred at a room
temperature for 1 hour and then at 5.degree. C. for 1 hour.
Thereafter, precipitated crystals were collected by filtration and
were then washed with ethyl acetate, followed by drying, so as to
obtain 0.42 g of an achromatic crystal,
1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate.
[0206] IR (KBr)cm.sup.-1: 3384, 2862, 2687, 1717, 1636, 1400, 1200,
1114, 720
[0207] NMR (DMSO-d.sub.6).delta.ppm: 1.7-1.8 (1H, m), 1.9-2.1 (1H,
m), 2.96 (2H, t, J=7 Hz), 3.0-3.2 (1H, m), 3.1-3.4 (5H, m), 3.6-3.8
(4H, m), 4.3-4.4 (1H, m), 7.29 (1H, d, J=8 Hz), 7.41 (1H, d, J=5
Hz), 7.68 (1H, d, J=5 Hz), 7.80 (1H, d, J=8 Hz), 7.87 (1H, s)
Production Example 18
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
[0208]
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-
-ethanone was obtained in the same manner as in Production Example
16(1).
[0209] NMR (CDCl.sub.3).delta.ppm: 1.6-2.2 (2H, m), 2.9-4.0 (8H,
m), 4.0-4.2 (2H, m), 4.2-4.5 (1H, m), 7.1-7.4 (2H, m), 7.42 (1H, d,
J=5 Hz), 7.69 (1H, s), 7.79 (1H, d, J=8 Hz)
[0210] Subsequently, a light yellow oil product,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol was
obtained in the same manner as in Production Example 16(2).
[0211] IR (neat)cm.sup.-1: 3386, 2941, 2864, 1438, 1112, 755,
702
[0212] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (1H, m), 2.0-2.9 (7H,
m), 3.00 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.71 (2H, t, J=7
Hz), 4.2-4.4 (1H, m), 7.21 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz),
7.42 (1H, d, J=5 Hz), 7.67 (1H, s), 7.79 (1H, d, J=8 Hz)
Production Example 19
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0213] An achromatic crystal,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate
was obtained in the same manner as in Production Example 17.
[0214] IR (KBr) cm.sup.-1: 3347, 2943, 2687, 1719, 1404, 1119,
720
[0215] NMR (CDCl.sub.3).delta.ppm: 1.7-2.2 (2H, m), 2.9-3.8 (6H,
m), 2.94 (2H, t, J=6 Hz), 3.68 (4H, t, J=6 Hz), 4.2-4.5 (1H, m),
7.17 (1H, d, J=8 Hz), 7.26 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz),
7.62 (1H, s), 7.78 (1H, d, J=8 Hz)
Production Example 20
Production of
1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol
[0216] An oil product,
2-(2-(1-benzothiophene-4-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethano-
ne was obtained in the same manner as in Production Example
16(1).
[0217] IR (neat)cm.sup.-1: 3374, 2944, 1637, 1107, 761
[0218] Subsequently, a light yellow oil product,
1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol was
obtained in the same manner as in Production Example 16(2).
[0219] IR (neat)cm.sup.-1: 3376, 2939, 2867, 1452, 1413, 1111,
760
[0220] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.30 (1H, dt, J=6, 9 Hz), 2.53 (1H, dd, J=5, 10 Hz), 2.6-2.7
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.25 (2H, t, J=7 Hz), 3.58 (2H,
t, J=6 Hz), 3.75 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.20 (1H, d, J=7
Hz), 7.27 (1H, t, J=7 Hz), 7.44 (1H, d, J=6 Hz), 7.46 (1H, d, J=6
Hz), 7.75 (1H, d, J=7 Hz)
Production Example 21
Production of
1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride
[0221] 0.63 g of
1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol was
dissolved in 5.0 ml of ethyl acetate. Thereafter, 0.80 ml of an
ethyl acetate solution containing 3.25 mol/l dry hydrogen chloride
was added to the obtained solution. The mixture was stirred at a
room temperature for 1 hour and then at 5.degree. C. for 1 hour.
Thereafter, precipitated crystals were collected by filtration. The
precipitated crystals were washed with ethyl acetate and then
dried, so as to obtain 0.43 g of an achromatic crystal,
1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride.
[0222] IR (KBr)cm.sup.-1: 3229, 2872, 2625, 1451, 1413, 1119,
771
[0223] NMR (DMSO-d.sub.6).delta.ppm: 1.7-2.2 (2H, m), 2.9-3.6 (6H,
m), 3.22 (2H, t, J=7 Hz), 3.74 (4H, t, J=7 Hz), 4.3-4.4 (1H, m),
7.27 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.61 (1H, d, J=5 Hz),
7.77 (1H, d, J=5 Hz), 7.86 (1H, d, J=8 Hz)
Production Example 22
Production of
1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinol
[0224] An oil product,
2-(2-(1-benzothiophene-7-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethano-
ne was obtained in the same manner as in Example 16(1).
[0225] NMR (CDCl.sub.3).delta.ppm: 1.8-2.0 (2H, m), 3.1-3.3 (3H,
m), 3.3-3.6 (3H, m), 3.8-4.0 (2H, m), 4.0-4.2 (2H, m), 4.3-4.5 (1H,
m), 7.23 (1H, d, J=7 Hz), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 7.6-7.8
(1H, m)
[0226] Subsequently, an achromatic oil product,
1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinol was
obtained in the same manner as in Example 16(2).
[0227] IR (neat)cm.sup.-1: 3385, 2941, 2867, 1459, 1395, 1106, 795,
754, 701
[0228] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.30 (1H, dt, J=7, 9 Hz), 2.52 (1H, dd, J=5, 10 Hz), 2.6-2.7
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.19 (2H, t, J=7 Hz), 3.59 (2H,
t, J=6 Hz), 3.84 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.20 (1H, d, J=8
Hz), 7.32 (1H, t, J=8 Hz), 7.35 (1H, d, J=5 Hz), 7.42 (1H, d, J=5
Hz), 7.69 (1H, d, J=8 Hz)
Production Example 23
Production of
1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride
[0229] An achromatic crystal,
1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride was obtained in the same manner as in Production
Example 21.
[0230] IR (KBr)cm.sup.-1: 3283, 2938, 2706, 1395, 1358, 1125, 810,
720
[0231] NMR (DMSO-d.sub.6).delta.ppm: 1.7-2.2 (2H, m), 2.8-3.7 (6H,
m), 3.12 (2H, t, J=7 Hz), 3.7-3.8 (2H, m), 3.82 (2H, t, J=7 Hz),
4.3-4.4 (1H, m), 7.29 (1H, d, J=7 Hz), 7.36 (1H, t, J=7 Hz), 7.49
(1H, d, J=5 Hz), 7.76 (1H, d, J=5 Hz), 7.77 (1H, d, J=7 Hz)
Production Example 24
Production of
1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol
[0232]
2-(2-(1-benzothiophene-2-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-
-ethanone was obtained in the same manner as in Example 16(1).
[0233] NMR (CDCl.sub.3).delta.ppm: 1.8-2.0 (2H, m), 3.1-3.3 (3H,
m), 3.3-3.7 (3H, m), 3.8-4.0 (2H, m), 4.1-4.2 (2H, m), 4.2-4.5 (1H,
m), 7.10 (1H, s), 7.2-7.4 (2H, m), 7.6-7.7 (1H, m), 7.7-7.8 (1H,
m)
[0234] Subsequently, a light yellow oil product,
1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol was
obtained in the same manner as in Example 16(2).
[0235] IR (neat)cm.sup.-1: 3396, 2939, 1458, 1438, 1113, 747,
727
[0236] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.34 (1H, dt, J=6, 9 Hz), 2.55 (1H, dd, J=5, 10 Hz), 2.6-2.8
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.18 (2H, dt, J=1, 7 Hz), 3.62
(2H, t, J=6 Hz), 3.77 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.07 (1H,
s), 7.26 (1H, dt, J=1, 8 Hz), 7.31 (1H, dt, J=1, 8 Hz), 7.67 (1H,
dd, J=1, 8 Hz), 7.76 (1H, dd, J=1, 8 Hz)
Production Example 25
Production of
1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0237] An achromatic crystal,
1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate
was obtained in the same manner as in Production Example 17.
[0238] IR (KBr)cm.sup.-1: 3432, 2871, 1716, 1436, 1127, 827, 760,
706
[0239] NMR (DMSO-d.sub.6).delta.ppm: 1.7-1.8 (1H, m), 1.9-2.2 (1H,
m), 3.0-3.4 (8H, m), 3.73 (4H, t, J=6 Hz), 4.2-4.4 (1H, m), 7.23
(1H, s), 7.28 (1H, t, J=7 Hz), 7.33 (1H, t, J=7 Hz), 7.74 (1H, d,
J=7 Hz), 7.87 (1H, d, J=7 Hz)
Production Example 26
[0240] Production of
1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
[0241] An oil product,
2-(2-(1-benzothiophene-3-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethano-
ne was obtained in the same manner as in Example 16(1).
[0242] NMR (CDCl.sub.3).delta.ppm: 1.8-1.9 (1H, m), 1.9-2.0 (1H,
m), 3.1-3.6 (6H, m), 3.8-4.0 (2H, m), 4.09 (1H, s), 4.13 (1H, s),
4.3-4.5 (1H, m), 7.26 (1H, s), 7.3-7.4 (2H, m), 7.77 (1H, d, J=8
Hz), 7.85 (1H, d, J=8 Hz)
[0243] Subsequently, a light yellow oil product,
1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol was
obtained in the same manner as in Example 16(2).
[0244] IR (neat)cm.sup.-1: 3388, 2934, 1426, 1112, 761, 733
[0245] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.33 (1H, dt, J=6, 9 Hz), 2.56 (1H, dd, J=5, 10 Hz), 2.6-2.8
(3H, m), 2.87 (1H, dt, J=5, 9 Hz), 3.14 (2H, dt, J=1, 7 Hz), 3.61
(2H, t, J=6 Hz), 3.80 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.20 (1H,
s), 7.34 (1H, dt, J=1, 7 Hz), 7.38 (1H, dt, J=1, 7 Hz), 7.77 (1H,
dd, J=1, 7 Hz), 7.85 (1H, dd, J=1, 7 Hz)
Production Example 27
Production of
1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0246] An achromatic crystal,
1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate
was obtained in the same manner as in Production Example 17.
[0247] IR (KBr)cm.sup.-1: 3363, 2922, 2691, 1718, 1636, 1427, 1404,
1119, 767, 721
[0248] NMR (DMSO-d.sub.6).delta.ppm: 1.7-1.8 (1H, m), 2.0-2.2 (1H,
m), 3.10 (2H, t, J=7 Hz), 3.1-3.4 (6H, m), 3.72 (2H, t, J=5 Hz),
3.78 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.37 (1H, t, J=8 Hz), 7.42
(1H, t, J=8 Hz), 7.51 (1H, s), 7.85 (1H, d, J=8 Hz), 7.98 (1H, d,
J=8 Hz)
Production Example 28
Production of 1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol
[0249] A yellow oil product,
2-(2-(1-naphthyl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone
was obtained in the same manner as in Production Example 16(1).
[0250] IR (neat)cm.sup.-1: 3392, 2946, 1645, 1133, 800, 779
[0251] Subsequently, a light yellow oil product,
1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol was obtained in
the same manner as in Production Example 16(2).
[0252] IR (neat)cm.sup.-1: 3395, 2944, 1107, 778
[0253] NMR (CDCl.sub.3).delta.ppm: 1.5-1.9 (1H, m), 2.0-2.5 (3H,
m), 2.5-3.0 (4H, m), 3.37 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz),
3.80 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.4-7.6 (4H, m), 7.6-8.0
(2H, m), 8.0-8.2 (1H, m)
Production Example 29
Production of 1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0254] An achromatic crystal,
1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol oxalate was
obtained in the same manner as in Production Example 17.
[0255] IR (KBr)cm.sup.-1: 3366, 1400, 1116, 780, 720
[0256] NMR (DMSO-d.sub.6).delta.ppm: 1.6-2.3 (2H, m), 2.7-3.5 (8H,
m), 3.5-3.9 (4H, m), 4.2-4.5 (1H, m), 7.4-7.6 (4H, m), 7.7-8.0 (2H,
m), 8.0-8.2 (1H, m)
Production Example 30
Production of
(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
[0257] A light yellow oil product,
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-((3S)-3-hydroxy-1-pyrrolidinol))-1--
ethanone was obtained in the same manner as in Production Example
16(1).
[0258] Subsequently, a light yellow oil product,
(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in the same manner as in Production Example 16(2).
[0259] IR (neat)cm.sup.-1: 3386, 2936, 2867, 1438, 1111, 755,
702
[0260] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (1H, m), 2.0-3.0 (5H,
m), 2.66 (2H, t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.58 (2H, t, J=6
Hz), 3.71 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.21 (1H, d, J=8 Hz),
7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, s), 7.79 (1H,
d, J=8 Hz)
Production Example 31
Production of
(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0261] An achromatic crystal,
(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate was obtained in the same manner as in Production Example
17.
[0262] IR (KBr)cm.sup.-1: 3366, 2941, 2867, 2686, 1718, 1701, 1404,
1114, 720
[0263] NMR (DMSO-d.sub.6).delta.ppm: 1.5-2.2 (2H, m), 2.8-3.5 (8H,
m), 3.70 (4H, t, J=6 Hz), 4.2-4.5 (1H, m), 7.28 (1H, d, J=8 Hz),
7.40 (1H, d, J=5 Hz), 7.73 (1H, d, J=5 Hz), 7.76 (1H, s), 7.91 (1H,
d, J=8 Hz)
Production Example 32
Production of
(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
[0264] An achromatic crystal,
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-((3R)-3-hydroxy-1-pyrrolidinyl))-1--
ethanone was obtained in the same manner as in Production Example
16(1).
[0265] IR(KBr)cm.sup.-1: 3408, 2937, 1637, 1137, 1108, 812, 703
[0266] Subsequently, a light yellow oil product,
(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in the same manner as in Production Example 16(2).
[0267] IR (neat)cm.sup.-1: 3373, 2940, 1438, 1111, 755, 702
[0268] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (1H, m), 2.0-3.0 (5H,
m), 2.68 (2H, t, J=6 Hz), 3.01 (2H, t, J=7 Hz), 3.59 (2H, t, J=6
Hz), 3.71 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.21 (1H, d, J=8 Hz),
7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, s), 7.79 (1H,
d, J=8 Hz)
Production Example 33
Production of
(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0269] An achromatic crystal,
(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate was obtained in the same manner as in Production Example
17.
[0270] IR (KBr)cm.sup.-1: 3318, 2870, 1718, 1114, 720
[0271] NMR (DMSO-d.sub.6).delta.ppm: 1.5-2.2 (2H, m), 2.8-3.5 (8H,
m), 3.70 (4H, t, J=6 Hz), 4.2-4.5 (1H, m), 7.28 (1H, d, J=8 Hz),
7.40 (1H, d, J=5 Hz), 7.73 (1H, d, J=5 Hz), 7.76 (1H, s), 7.91 (1H,
d, J=8 Hz)
Production Example 34
Production of
(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
[0272] An achromatic oil product,
2-(2-(1-benzothiophene-6-yl)ethoxy)-1-((3S)-3-hydroxy-1-pyrrolidinyl))-1--
ethanone was obtained in the same manner as in Production Example
16(1).
[0273] IR(neat)cm.sup.-1: 3385, 2944, 1637, 1133, 820, 699
[0274] Subsequently, an achromatic oil product,
(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in the same manner as in Production Example 16(2).
[0275] IR (neat)cm.sup.-1: 3385, 2940, 2867, 1110, 820, 757
[0276] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.32 (1H, dt, J=6, 9 Hz), 2.54 (1H, dd, J=5, 10 Hz), 2.6-2.7
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.01 (2H, t, J=7 Hz), 3.58 (2H,
t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 4.2-4.3 (1H, m), 7.23 (1H, d, J=8
Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H, d, J=5 Hz), 7.73 (1H, d, J=8
Hz), 7.74 (1H, s)
Production Example 35
Production of
(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0277] An achromatic crystal,
(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate was obtained in the same manner as in Production Example
17.
[0278] IR (KBr)cm.sup.-1: 3364, 2938, 2692, 1718, 1400, 1201, 1114,
720
[0279] NMR (DMSO-d.sub.6).delta.ppm: 1.7-1.8 (1H, m), 1.9-2.1 (1H,
m), 2.96 (2H, t, J=7 Hz), 3.0-3.1 (1H, m), 3.1-3.3 (5H, m), 3.70
(4H, t, J=7 Hz), 4.2-4.3 (1H, m), 7.29 (1H, d, J=8 Hz), 7.41 (1H,
d, J=5 Hz), 7.68 (1H, d, J=5 Hz), 7.80 (1H, d, J=8 Hz), 7.87 (1H,
s)
Production Example 36
Production of
(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
[0280] An oil product,
2-(2-(1-benzothiophene-6-yl)ethoxy)-1-((3R)-3-hydroxy-1-pyrrolidinyl))-1--
ethanone was obtained in the same manner as in Production Example
16(1).
[0281] IR(neat)cm.sup.1: 3386, 2940, 1637, 1107, 820, 758
[0282] Subsequently, an achromatic oil product,
(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in the same manner as in Production Example 16(2).
[0283] IR (neat)cm.sup.-1: 3385, 2940, 2867, 1110, 820, 757
[0284] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.32 (1H, dt, J=6, 9 Hz), 2.54 (1H, dd, J=5, 10 Hz), 2.6-2.7
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.01 (2H, t, J=7 Hz), 3.58 (2H,
t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 4.2-4.3 (1H, m), 7.23 (1H, d, J=8
Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H, d, J=5 Hz), 7.73 (1H, d, J=8
Hz), 7.74 (1H, s)
Production Example 37
Production of
(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0285] An achromatic crystal,
(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol
oxalate was obtained in the same manner as in Production Example
17.
[0286] IR (KBr)cm.sup.-1: 3364, 2938, 2688, 1718, 1400, 1201, 1114,
720
[0287] NMR (DMSO-d.sub.6).delta.ppm: 1.7-1.8 (1H, m), 1.9-2.1 (1H,
m), 2.96 (2H, t, J=7 Hz), 3.0-3.1 (1H, m), 3.1-3.3 (5H, m), 3.70
(4H, t, J=7 Hz), 4.2-4.3 (1H, m), 7.29 (1H, d, J=8 Hz), 7.41 (1H,
d, J=5 Hz), 7.68 (1H, d, J=5 Hz), 7.80 (1H, d, J=8 Hz), 7.87 (1H,
s)
Production Example 38
Production of
(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
[0288]
2-(2-(1-benzothiophene-3-yl)ethoxy)-1-((3R)-3-hydroxy-1-pyrrolidin-
yl))-1-ethanone was obtained in the same manner as in Production
Example 16(1).
[0289] NMR (CDCl.sub.3).delta.ppm: 1.8-1.9 (1H, m), 1.9-2.0 (1H,
m), 3.1-3.4 (3H, m), 3.3-3.7 (3H, m), 3.8-4.0 (2H, m), 4.0-4.2 (2H,
m), 4.3-4.5 (1H, m), 7.27 (1/2H, s), 7.28 (1/2H, s), 7.3-7.5 (2H,
m), 7.7-7.8 (1H, m), 7.8-7.9 (1H, m)
[0290] Subsequently, a yellow oil product,
(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in the same manner as in Production Example 16(2).
[0291] IR (neat)cm.sup.-1: 3386, 2942, 1458, 1429, 1113, 759,
733
[0292] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H,
m), 2.34 (1H, dt, J=6, 9 Hz), 2.55 (1H, dd, J=5, 10 Hz), 2.6-2.8
(3H, m), 2.85 (1H, dt, J=5, 9 Hz), 3.14 (2H, t, J=7 Hz), 3.61 (2H,
t, J=6 Hz), 3.80 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.21 (1H, s),
7.34 (1H, dt, J=1, 7 Hz), 7.38 (1H, dt, J=1, 7 Hz), 7.76 (1H, dd,
J=1, 7 Hz), 7.85 (1H, dd, J=1, 7 Hz)
Production Example 39
Production of
(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride
[0293] 0.99 g of
(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
was dissolved in 5.0 ml of ethyl acetate. Thereafter, 1.10 ml of an
ethyl acetate solution containing 3.25 mol/l dry hydrogen chloride
was added to the obtained solution, and the obtained mixture was
then stirred at a room temperature for 1 hour. Thereafter, the
solvent was distilled away under a reduced pressure, so as to
obtain 1.05 g of a light yellow oil product,
(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride.
[0294] IR (neat)cm.sup.-1: 3368, 2946, 1560, 1430, 1121, 765,
734
[0295] NMR (CDCl.sub.3).delta.ppm: 1.9-2.1 (1H, m), 2.1-2.3 (1H,
m), 2.8-3.0 (2H, m), 3.1-3.2 (4H, m), 3.29 (1H, d, J=12 Hz),
3.3-3.5 (1H, m), 3.8-3.9 (4H, m), 4.3-4.4 (1H, m), 7.24 (1H, s),
7.35 (1H, t, J=8 Hz), 7.40 (1H, t, J=8 Hz), 7.76 (1H, d, J=8 Hz),
7.86 (1H, d, J=8 Hz)
Production Example 40
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol
[0296] An oil product,
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(4-hydroxy-1-piperidinyl)-1-ethanon-
e was obtained in the same manner as in Production Example
16(1).
[0297] Subsequently, a yellow oil product,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol was
obtained in the same manner as in Production Example 16(2).
[0298] IR (neat)cm.sup.-1: 3386, 2939, 1110, 1071, 754, 701
[0299] NMR (CDCl.sub.3).delta.ppm: 1.5-2.3 (6H, m), 2.5-3.0 (2H,
m), 2.56 (2H, t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.5-3.9 (1H, m),
3.58 (2H, t, J=6 Hz), 3.70 (2H, t, J=7 Hz), 7.19 (1H, d, J=8 Hz),
7.27 (1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz), 7.65 (1H, s), 7.78 (1H,
d, J=8 Hz)
Production Example 41
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol
hydrochloride
[0300] A light brown crystal,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol
hydrochloride was obtained in the same manner as in Production
Example 21.
[0301] IR (KBr)cm.sup.-1: 3312, 2946, 2691, 1457, 1124, 1043, 769,
712
[0302] NMR (CDCl.sub.3).delta.ppm: 1.5-2.5 (4H, m), 2.8-3.2 (6H,
m), 2.99 (2H, t, J=6 Hz), 3.76 (2H, t, J=6 Hz), 3.8-4.2 (3H, m),
7.19 (1H, d, J=8 Hz), 7.30 (1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz),
7.67 (1H, s), 7.80 (1H, d, J=8 Hz)
Production Example 42
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol
[0303] A yellow oil product,
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-piperidinyl)-1-ethanon-
e was obtained in the same manner as in Production Example
16(1).
[0304] IR(neat)cm.sup.1: 3408, 2938, 1637, 1114, 704
[0305] Subsequently, a yellow oil product,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol was
obtained in the same manner as in Production Example 16(2).
[0306] IR (neat)cm.sup.-1: 3387, 2937, 1438, 1109, 703
[0307] NMR (CDCl.sub.3).delta.ppm: 1.4-2.0 (4H, m), 2.0-2.7 (6H,
m), 2.57 (2H, t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.56 (2H, t, J=6
Hz), 3.6-3.9 (1H, m), 3.70 (2H, t, J=7 Hz), 7.20 (1H, d, J=8 Hz),
7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.66 (1H, s), 7.79 (1H,
d, J=8 Hz)
Production Example 43
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol
hydrochloride
[0308] An achromatic crystal,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol
hydrochloride was obtained in the same manner as in Production
Example 21.
[0309] IR (KBr)cm.sup.-1: 3260, 2949, 2638, 1433, 1129, 1045, 702,
668
[0310] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (4H, m), 2.1-2.8 (2H,
m), 2.99 (2H, t, J=6 Hz), 3.1-3.6 (4H, m), 3.76 (2H, t, J=6 Hz),
3.8-4.1 (3H, m), 7.20 (1H, d, J=8 Hz), 7.30 (1H, d, J=5 Hz), 7.44
(1H, d, J=5 Hz), 7.67 (1H, s), 7.80 (1H, d, J=8 Hz)
Production Example 44
Production of
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol
[0311]
2-(2-(1-benzofuran-5-yl)ethoxy)-1-(4-hydroxy-1-piperidinyl)-1-etha-
none was obtained in the same manner as in Production Example
16(1).
[0312] IR(neat)cm.sup.-1: 3406, 2931, 1636, 1110, 771, 740
[0313] Subsequently, an achromatic oil product,
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol was obtained
in the same manner as in Production Example 16(2).
[0314] IR (neat)cm.sup.-1: 3359, 2939, 1468, 1111, 1073, 882, 768,
739
[0315] NMR (CDCl.sub.3).delta.ppm: 1.5-2.3 (6H, m), 2.5-3.0 (2H,
m), 2.57 (2H, t, J=6 Hz), 2.97 (2H, t, J=7 Hz), 3.5-3.8 (1H, m),
3.58 (2H, t, J=6 Hz), 3.68 (2H, t, J=7 Hz), 6.71 (1H, dd, J=1, 2
Hz), 7.13 (1H, dd, J=2, 8 Hz), 7.40 (1H, d, J=8 Hz), 7.42 (1H, dd,
J=1, 2 Hz), 7.55 (1H, d, J=2 Hz)
Production Example 45
Production of
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol
hydrochloride
[0316] A light yellow oil product,
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol
hydrochloride was obtained in the same manner as in Production
Example 39.
[0317] IR (neat)cm.sup.-1: 3366, 2938, 2638, 1458, 1126, 776,
742
[0318] NMR (CDCl.sub.3).delta.ppm: 1.6-2.4 (4H, m), 2.8-3.2 (8H,
m), 3.71 (2H, t, J=6 Hz), 3.7-4.1 (3H, m), 6.72 (1H, dd, J=1, 2
Hz), 7.12 (1H, dd, J=2, 8 Hz), 7.44 (1H, d, J=8 Hz), 7.42 (1H, dd,
J=1, 2 Hz), 7.60 (1H, d, J=2 Hz)
Production Example 46
Production of
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol
[0319] (1) 1.28 g of 2-(2-(1-benzofuran-5-yl)ethoxy)acetic acid was
dissolved in 13.0 ml of tetrahydrofuran. The obtained solution was
cooled to 5.degree. C. Thereafter, 1.41 g of
1,1'-carbonyldiimidazole was added thereto, and the obtained
mixture was then stirred at a room temperature for 2 hours.
Thereafter, 1.22 ml of triethylamine and 0.72 ml of 3-pyrrolidinol
were added to the reaction mixture, followed by stirring at a room
temperature for 2 hours. Thereafter, water and ethyl acetate were
added to the reaction mixture. The pH of the obtained mixture was
adjusted to pH 1 by addition of 6 mol/l hydrochloric acid, and an
organic layer was then separated. The organic layer was
successively washed with a saturated sodium bicarbonate solution
and a saturated saline solution, and then dried over anhydrous
magnesium sulfate. Subsequently, the solvent was distilled away
under a reduced pressure, so as to obtain 1.39 g of an achromatic
oil product,
2-(2-(1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone.
[0320] IR(neat)cm.sup.-1: 3398, 2943, 1637, 1467, 1128, 1030, 771,
741
[0321] (2) 1.39 g of
2-(2-(1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone
was dissolved in 14.0 ml of tetrahydrofuran. Thereafter, 14.4 ml of
a tetrahydrofuran solution containing a 1 mol/l
borane-tetrahydrofuran complex was added dropwise to the obtained
solution while cooling on ice, and the obtained mixture was then
stirred at a room temperature for 17 hours. Thereafter, 8.0 ml of 6
mol/l hydrochloric acid was added to the reaction mixture, and the
obtained mixture was heated to reflux for 1 hour. After cooling,
water and ethyl acetate were added to the reaction mixture. The pH
of the obtained mixture was adjusted to pH 10 by addition of a 2
mol/l aqueous sodium hydroxide solution, and an organic layer was
separated. The organic layer was successively washed with water and
a saturated saline solution, and then dried over anhydrous
magnesium sulfate. Thereafter, the solvent was distilled away under
a reduced pressure. The residue was purified by column
chromatography (eluent; chloroform:methanol=30:1 to 10:1), so as to
obtain 0.96 g of an achromatic oil product,
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol.
[0322] IR (neat)cm.sup.1: 3386, 2941, 1468, 1261, 1110, 1030, 882,
769, 738
[0323] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (1H, m), 1.9-3.0 (5H,
m), 2.68 (2H, t, J=6 Hz), 2.98 (2H, t, J=7 Hz), 3.58 (2H, t, J=6
Hz), 3.70 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 6.71 (1H, dd, J=1, 2
Hz), 7.14 (1H, d, J=8 Hz), 7.42 (1H, d, J=8 Hz), 7.4-7.5 (1H, m),
7.59 (1H, d, J=2 Hz)
Production Example 47
Production of
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-piperidinol oxalate
[0324] An achromatic crystal,
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-piperidinol oxalate was
obtained in the same manner as in Production Example 17.
[0325] IR (KBr)cm.sup.-1: 3418, 2945, 2698, 1715, 1197, 1111, 720
NMR (DMSO-d.sub.6).delta.ppm: 1.6-2.3 (2H, m), 2.92 (2H, t, J=7
Hz), 3.0-3.5 (6H, m), 3.5-3.8 (4H, m), 4.2-4.5 (1H, m), 6.89 (1H,
dd, J=1, 2 Hz), 7.19 (1H, dd, J=1, 8 Hz), 7.50 (1H, d, J=8 Hz),
7.5-7.6 (1H, m), 7.94 (1H, d, J=2 Hz)
Production Example 48
Production of
(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinedio-
l
[0326] A yellow oil product,
2-(2-(1-benzothiophene-5-yl)ethoxy)-1-((3R*,4R*)-3,4-dihydroxy-1-pyrrolid-
inyl)-1-ethanone was obtained in the same manner as in Production
Example 46(1).
[0327] IR(neat)cm.sup.-1: 3370, 2935, 2874, 1636, 1131, 756,
701
[0328] Subsequently, a yellow oil product,
(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinedio-
l was obtained in Production Example 46(2).
[0329] IR (neat)cm.sup.-1: 3386, 2938, 2866, 1438, 1113, 756,
703
[0330] NMR (CDCl.sub.3).delta.ppm: 2.5-3.0 (5H, m), 3.00 (2H, t,
J=7 Hz), 3.2-3.7 (1H, m), 3.56 (2H, t, J=6 Hz), 3.71 (2H, t, J=7
Hz), 3.9-4.4 (2H, m), 7.20 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz),
7.43 (1H, d, J=5 Hz), 7.66 (1H, s), 7.80 (1H, d, J=8 Hz)
Production Example 49
Production of
(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinedio-
l oxalate
[0331] An achromatic crystal,
(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinedio-
l oxalate was obtained in the same manner as in Production Example
17.
[0332] IR (KBr)cm.sup.-1: 3309, 2929, 1718, 1617, 1199, 1104,
702
[0333] NMR (DMSO-d.sub.6).delta.ppm: 2.8-3.2 (6H, m), 3.2-3.8 (6H,
m), 4.1-4.4 (2H, m), 7.26 (1H, d, J=8 Hz), 7.39 (1H, d, J=5 Hz),
7.72 (1H, d, J=5 Hz), 7.75 (1H, s), 7.90 (1H, d, J=8 Hz)
Production Example 50
Production of
1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-pyrrolidinol
[0334] An achromatic oil product,
2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1--
ethanone was obtained in the same manner as in Production Example
46(1).
[0335] IR(neat)cm.sup.-1: 3394, 2941, 1637, 1465, 1197, 1131, 1015,
841, 759
[0336] Subsequently, an achromatic oil product,
1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in Production Example 46(2).
[0337] IR (neat)cm.sup.-1: 3386, 2940, 1466, 1430, 1198, 1131,
1015, 837, 762
[0338] NMR (CDCl.sub.3).delta.ppm: 1.5-2.4 (3H, m), 2.5-3.0 (5H,
m), 2.99 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.67 (2H, t, J=7
Hz), 3.85 (3H, s), 4.2-4.4 (1H, m), 6.68 (1H, d, J=2 Hz), 6.99 (1H,
s), 7.34 (1H, s), 7.54 (1H, d, J=2 Hz)
Production Example 51
Production of
1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-piperidinol
oxalate
[0339] An achromatic crystal,
1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-piperidinol
oxalate was obtained in the same manner as in Production Example
17.
[0340] IR (KBr) cm.sup.-1: 3396, 2942, 2691, 1718, 1636, 1465,
1198, 1130, 720
[0341] NMR (DMSO-d.sub.6).delta.ppm: 1.7-2.3 (2H, m), 2.8-3.6 (6H,
m), 2.91 (2H, t, J=6 Hz), 3.5-3.9 (4H, m), 3.83 (3H, s), 4.2-4.5
(1H, m), 6.86 (1H, d, J=2 Hz), 7.17 (1H, s), 7.43 (1H, s), 7.88
(1H, d, J=2 Hz)
Production Example 52
Production of
1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol
[0342] An achromatic oil product,
2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1--
ethanone was obtained in the same manner as in Production Example
46(1).
[0343] IR(neat)cm.sup.-1: 3381, 2944, 1638, 1475, 1201, 1125, 1011,
758
[0344] Subsequently, an achromatic oil product,
1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol
was obtained in Production Example 46(2).
[0345] IR (neat)cm.sup.-1: 3398, 2938, 1475, 1202, 1094, 757, 730
NMR (CDCl.sub.3).delta.ppm: 1.5-2.4 (3H, m), 2.5-3.0 (5H, m), 2.98
(2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.68 (2H, t, J=7 Hz), 3.86
(3H, s), 4.2-4.4 (1H, m), 6.65 (1H, d, J=2 Hz), 7.00 (1H, s), 7.35
(1H, s), 7.50 (1H, d, J=2 Hz)
Production Example 53
Production of
1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride
[0346] An achromatic oil product,
1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol
hydrochloride was obtained in the same manner as in Production
Example 39.
[0347] IR (neat)cm.sup.-1: 3377, 2938, 2694, 1475, 1202, 1124,
1093, 1011
[0348] NMR (CDCl.sub.3).delta.ppm: 1.7-2.2 (2H, m), 2.8-3.6 (6H,
m), 2.96 (2H, t, J=6 Hz), 3.5-4.2 (4H, m), 3.86 (3H, s), 4.3-4.6
(1H, m), 6.6-6.7 (1H, m), 7.01 (1H, s), 7.34 (1H, d, J=1 Hz), 7.51
(1H, d, J=2 Hz)
Production Example 54
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine
[0349] (1) 1.00 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)acetic acid
was dissolved in 10.0 ml of tetrahydrofuran. The obtained solution
was cooled to 5.degree. C. Thereafter, 1.03 g of
1,1'-carbonyldiimidazole was added thereto, and the obtained
mixture was then stirred at a room temperature for 1 hour. The
reaction solution was cooled to 5.degree. C. Thereafter, 0.88 ml of
triethylamine and 1.18 g of tert-butyl=3-pyrrolidinyl carbamate
were added to the reaction mixture, followed by stirring at a room
temperature for 1 hour. Thereafter, water and ethyl acetate were
added to the reaction mixture. The pH of the obtained mixture was
adjusted to pH 4 by addition of 6 mol/l hydrochloric acid, and an
organic layer was then separated. The organic layer was
successively washed with a saturated sodium bicarbonate solution
and a saturated saline solution, and then dried over anhydrous
magnesium sulfate. Subsequently, the solvent was distilled away
under a reduced pressure, so as to obtain 2.00 g of a light yellow
oil product,
tert-butyl=1-(2-(2-(1-benzothiophene-5-yl)ethoxy)acetyl)-3-pyrrolidinyl
carbamate.
[0350] (2) 2.00 g of the obtained
tert-butyl=1-(2-(2-(1-benzothiophene-5-yl)ethoxy)acetyl)-3-pyrrolidinyl
carbamate was dissolved in 2.0 ml of tetrahydrofuran. The obtained
solution was cooled to 5.degree. C. Thereafter, 10.6 ml of a
tetrahydrofuran solution containing a 1 mol/l
borane-tetrahydrofuran complex was added dropwise to the obtained
solution, and the obtained mixture was then stirred at a room
temperature for 17 hours. Thereafter, 3.5 ml of 6 mol/l
hydrochloric acid was added to the reaction mixture, and the
obtained mixture was heated to reflux for 3 hours. After the
reaction mixture was cooled, water and ethyl acetate were added
thereto. The pH of the obtained mixture was adjusted to pH 10 by
addition of a 5 mol/l aqueous sodium hydroxide solution, and an
organic layer was separated. The organic layer was washed with a
saturated saline solution and then dried over anhydrous magnesium
sulfate. Thereafter, the solvent was distilled away under a reduced
pressure. The residue was purified by column chromatography
(eluent; chloroform:methanol=30:1 to 15:1), so as to obtain 1.01 g
of a light yellow oil product,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine.
[0351] IR (neat)cm.sup.-1: 3358, 2938, 2861, 1438, 1112, 1052, 755,
703
[0352] NMR (CDCl.sub.3).delta.ppm: 1.2-1.7 (1H, m), 1.9-3.0 (7H,
m), 2.01 (2H, s), 3.00 (2H, t, J=7 Hz), 3.3-3.7 (1H, m), 3.57 (2H,
t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 7.20 (1H, d, J=8 Hz), 7.28 (1H,
d, J=5 Hz), 7.41 (1H, d, J=5 Hz), 7.66 (1H, s), 7.78 (1H, d, J=8
Hz)
Production Example 55
Production of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine
dioxalate
[0353] 0.71 g of
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine was
dissolved in 3.0 ml of ethyl acetate. Thereafter, 4.0 ml of an
ethyl acetate solution containing 0.44 g of oxalic acid was added
to the obtained solution, and the obtained mixture was stirred at a
room temperature for 1 hour and then at 5.degree. C. for 1 hour.
Thereafter, precipitated crystals were collected by filtration,
washed with ethyl acetate, and then dried, so as to obtain 1.03 g
of an achromatic crystal,
1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine
dioxalate.
[0354] IR (KBr)cm.sup.-1: 3447, 2938, 1406, 1279, 1115, 720
[0355] NMR (DMSO-d.sub.6).delta.ppm: 1.7-2.5 (2H, m), 2.8-3.5 (8H,
m), 3.5-4.0 (5H, m), 7.27 (1H, d, J=8 Hz), 7.40 (1H, d, J=5 Hz),
7.72 (1H, d, J=5 Hz), 7.75 (1H, s), 7.90 (1H, d, J=8 Hz)
Production Example 56
Production of
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine
[0356] In the same manner as in Production Example 54(1),
tert-butyl=1-(2-(2-(1-benzofuran-5-yl)ethoxy)acetyl)-3-pyrrolidinyl
carbamate was obtained.
[0357] Subsequently, a yellow oil product,
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine was
obtained in the same manner as in Production Example 54(2).
[0358] IR (neat)cm.sup.-1: 3356, 2938, 1467, 1261, 1111, 1030, 882,
769, 740
[0359] NMR (CDCl.sub.3).delta.ppm: 1.2-1.7 (1H, m), 2.02 (2H, s),
2.1-3.0 (7H, m), 2.98 (2H, t, J=7 Hz), 3.3-3.7 (1H, m), 3.57 (2H,
t, J=6 Hz), 3.69 (2H, t, J=7 Hz), 6.71 (1H, dd, J=1, 2 Hz), 7.15
(1H, dd, J=1, 7 Hz), 7.40 (1H, d, J=7 Hz), 7.4-7.5 (1H, m), 7.59
(1H, d, J=2 Hz)
Production Example 57
Production of
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine
oxalate
[0360] An achromatic crystal,
1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine oxalate
was obtained in the same manner as in Production Example 17.
[0361] IR (KBr)cm.sup.-1: 3408, 2952, 1615, 1311, 1127, 769
[0362] NMR (DMSO-d.sub.6).delta.ppm: 1.5-1.9 (1H, m), 1.8-2.4 (1H,
m), 2.1-3.0 (6H, m), 2.89 (2H, t, J=7 Hz), 3.4-3.8 (5H, m), 6.89
(1H, dd, J=1, 2 Hz), 7.18 (1H, d, J=8 Hz), 7.50 (1H, d, J=8 Hz),
7.4-7.6 (1H, m), 7.94 (1H, d, J=2 Hz)
Production Example 58
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
[0363] 1.20 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was
dissolved in 12 ml of N,N-dimethylformamide. Thereafter, 0.82 g of
3-pyrrolidinol and 1.30 g of potassium carbonate were added to the
obtained solution, and the mixture was then stirred at 85.degree.
C. for 2.5 hours. After the reaction mixture was cooled, water and
ethyl acetate were added thereto, and an organic layer was
separated. The organic layer was successively washed with water and
a saturated saline solution, and then dried over anhydrous
magnesium sulfate. Thereafter, the solvent was distilled away under
a reduced pressure. The residue was purified by column
chromatography (eluent; chloroform:methanol=20:1 to 10:1), so as to
obtain 0.78 g of an achromatic oil product,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol.
[0364] IR (neat)cm.sup.-1: 3386, 2943, 1438, 1106, 1052, 755,
701
[0365] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (3H, m), 2.0-3.0 (7H,
m), 2.98 (2H, t, J=7 Hz), 3.49 (2H, t, J=6 Hz), 3.67 (2H, t, J=7
Hz), 4.2-4.4 (1H, m), 7.1-7.3 (2H, m), 7.41 (1H, d, J=6 Hz), 7.66
(1H, s), 7.78 (1H, d, J=8 Hz)
Production Example 59
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
hydrochloride
[0366] An achromatic crystal,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
hydrochloride was obtained in the same manner as in Production
Example 21.
[0367] IR (KBr)cm.sup.-1: 3368, 2937, 2695, 1438, 1108, 821, 764,
708
[0368] NMR (CDCl.sub.3).delta.ppm: 1.8-2.3 (4H, m), 2.3-3.6 (6H,
m), 2.96 (2H, t, J=6 Hz), 3.50 (2H, t, J=6 Hz), 3.68 (2H, t, J=7
Hz), 4.3-4.7 (1H, m), 7.21 (1H, d, J=8 Hz), 7.30 (1H, d, J=5 Hz),
7.43 (1H, d, J=5 Hz), 7.67 (1H, s), 7.80 (1H, d, J=8 Hz)
Production Example 60
Production of
1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol
[0369] A light yellow oil product,
1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol was
obtained in the same manner as in Production Example 58.
[0370] IR (neat)cm.sup.-1: 3386, 2942, 1467, 1261, 1108, 1030, 883,
740
[0371] NMR (CDCl.sub.3).delta.ppm: 1.5-2.0 (3H, m), 2.0-3.0 (7H,
m), 2.95 (2H, t, J=7 Hz), 3.49 (2H, t, J=6 Hz), 3.65 (2H, t, J=7
Hz), 4.2-4.4 (1H, m), 6.71 (1H, dd, J=1, 2 Hz), 7.14 (1H, dd, J=1,
8 Hz), 7.3-7.5 (2H, m), 7.58 (1H, d, J=2 Hz)
Production Example 61
Production of
1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol
hydrochloride
[0372] A light yellow oil product,
1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol
hydrochloride was obtained in the same manner as in Production
Example 39.
IR (neat)cm.sup.-1: 3339, 2941, 2605, 1468, 1262, 1110, 773,
742
[0373] NMR (CDCl.sub.3).delta.ppm: 1.6-2.4 (4H, m), 2.4-4.0 (12H,
m), 4.4-4.8 (1H, m), 6.72 (1H, d, J=2 Hz), 7.12 (1H, d, J=8 Hz),
7.3-7.6 (2H, m), 7.59 (1H, d, J=2 Hz)
Production Example 62
Production of
1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
[0374] A yellow oil product,
1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
was obtained in the same manner as in Production Example 58.
[0375] IR (neat)cm.sup.-1: 3422, 2952, 1458, 1257, 1106, 838, 747,
711
[0376] NMR (CDCl.sub.3).delta.ppm: 1.5-3.0 (10H, m), 3.00 (2H, t,
J=7 Hz), 3.4-3.6 (2H, m), 3.68 (2H, t, J=7 Hz), 4.2-4.4 (1H, m),
7.23 (1H, d, J=5 Hz), 7.36 (1H, d, J=5 Hz), 7.51 (1H, d, J=10 Hz),
7.66 (1H, d, J=7 Hz)
Production Example 63
Production of
1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
hydrochloride
[0377] A yellow oil product,
1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol
hydrochloride was obtained in the same manner as in Production
Example 39.
[0378] IR (neat)cm.sup.-1: 3377, 2954, 2702, 1458, 1257, 1107, 750,
712
[0379] NMR (CDCl.sub.3).delta.ppm: 1.8-2.3 (4H, m), 2.8-3.6 (8H,
m), 3.53 (2H, t, J=6 Hz), 3.69 (2H, t, J=7 Hz), 4.3-4.4 (1H, m),
7.27 (1H, d, J=5 Hz), 7.39 (1H, d, J=5 Hz), 7.52 (1H, d, J=10 Hz),
7.67 (1H, d, J=7 Hz)
Production Example 64
Production of
(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediol
[0380] An achromatic oil product,
(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediol
was obtained in the same manner as in Production Example 58.
[0381] IR (neat)cm.sup.-1: 3387, 2940, 1438, 1159, 1108, 1051,
703
[0382] NMR (CDCl.sub.3).delta.ppm: 1.5-1.9 (2H, m), 2.4-2.8 (6H,
m), 2.98 (2H, t, J=7 Hz), 3.47 (2H, t, J=6 Hz), 3.67 (2H, t, J=7
Hz), 4.1-4.3 (2H, m), 7.20 (1H, dd, J=1, 8 Hz), 7.27 (1H, d, J=5
Hz), 7.42 (1H, d, J=5 Hz), 7.65 (1H, d, J=1 Hz), 7.79 (1H, d, J=8
Hz)
Production Example 65
Production of
(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediol
hydrochloride
[0383] An achromatic crystal,
(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediol
hydrochloride was obtained in the same manner as in Production
Example 21.
[0384] IR (KBr)cm.sup.-1: 3381, 2871, 2602, 1120, 808, 768, 718
[0385] NMR (DMSO-d.sub.6).delta.ppm: 1.8-2.0 (2H, m), 2.8-3.8 (12H,
m), 3.9-4.3 (2H, m), 7.25 (1H, dd, J=2, 8 Hz), 7.39 (1H, d, J=5
Hz), 7.72 (1H, d, J=5 Hz), 7.73 (1H, d, J=2 Hz), 7.90 (1H, d, J=8
Hz)
Production Example 66
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol
[0386] A light yellow oil product,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol was
obtained in the same manner as in Production Example 58.
[0387] IR (neat)cm.sup.-1: 3385, 2935, 1438, 1364, 1111, 755,
701
[0388] NMR (CDCl.sub.3).delta.ppm: 1.4-2.2 (8H, m), 2.1-2.5 (2H,
m), 2.5-3.0 (2H, m), 2.98 (2H, t, J=7 Hz), 3.48 (2H, t, J=6 Hz),
3.5-3.8 (1H, m), 3.67 (2H, t, J=7 Hz), 7.1-7.3 (2H, m), 7.42 (1H,
d, J=5 Hz), 7.66 (1H, s), 7.79 (1H, d, J=8 Hz)
Production Example 67
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol
oxalate
[0389] An achromatic crystal,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol oxalate
was obtained in the same manner as in Production Example 17.
[0390] IR (KBr)cm.sup.-1: 3420, 2866, 1718, 1616, 1190, 1120,
705
[0391] NMR (DMSO-d.sub.6).delta.ppm: 1.5-2.0 (6H, m), 2.8-3.1 (8H,
m), 3.4-3.8 (1H, m), 3.44 (2H, t, J=6 Hz), 3.64 (2H, t, J=6 Hz),
7.24 (1H, d, J=8 Hz), 7.40 (1H, d, J=5 Hz), 7.6-7.8 (2H, m), 7.91
(1H, d, J=8 Hz)
Production Example 68
Production of 1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol
[0392] 0.80 g of 2-(2-(2-naphthyl)ethoxy)ethyl)=methanesulfonate
was dissolved in 8 ml of N,N-dimethylformamide. Thereafter, 0.45 ml
of 3-pyrrolidinol and 0.75 g of potassium carbonate were added to
the obtained solution, and the mixture was stirred at 90.degree. C.
for 2 hours. After the reaction mixture was cooled, water and ethyl
acetate were added, and an organic layer was separated. The organic
layer was successively washed with water and a saturated saline
solution, and then dried over anhydrous magnesium sulfate.
Thereafter, the solvent was distilled away under a reduced
pressure. The residue was purified by column chromatography
(eluent; chloroform:methanol=8:1 to 5:1), so as to obtain 0.51 g of
an achromatic oil product,
1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol.
[0393] IR (neat)cm.sup.-1: 3422, 2938, 1112, 820, 749
[0394] NMR (CDCl.sub.3).delta.ppm: 1.5-1.9 (1H, m), 2.0-2.5 (3H,
m), 2.5-3.0 (4H, m), 3.05 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz),
3.75 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.2-7.6 (4H, m), 7.6-8.0
(3H, m)
Production Example 69
Production of 1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol
oxalate
[0395] An achromatic crystal,
1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol oxalate was
obtained in the same manner as in Production Example 17.
[0396] IR (KBr)cm.sup.-1: 3366, 2945, 1405, 1113, 820, 720
[0397] NMR (DMSO-d.sub.6).delta.ppm: 1.6-2.3 (2H, m), 2.7-3.5 (8H,
m), 3.5-3.9 (4H, m), 4.2-4.5 (1H, m), 7.4-7.6 (3H, m), 7.7-8.0 (4H,
m)
Production Example 70
Production of
(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol
[0398] 2.50 g of
2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)=methanesulfonate was
dissolved in 25 ml of N,N-dimethylformamide. Thereafter, 1.40 g of
(3R,4S)-3,4-pyrrolidinediol hydrochloride and 4.70 ml of
triethylamine were added to the obtained solution, and the mixture
was then stirred at 90.degree. C. for 1 hour. After cooling, water
and ethyl acetate were added to the reaction mixture. The pH of the
obtained mixture was adjusted to pH 10 by addition of a 2 mol/l
aqueous sodium hydroxide solution, and an organic layer was then
separated. The organic layer was successively washed with water and
a saturated saline solution, and then dried over anhydrous
magnesium sulfate. The solvent was then distilled away under a
reduced pressure. The residue was purified by column chromatography
(eluent; chloroform:methanol=8:1 to 5:1), so as to obtain 0.84 g of
a yellow oil product,
(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol.
[0399] IR (neat)cm.sup.-1: 3390, 2940, 1438, 1111, 1050, 703
[0400] NMR (CDCl.sub.3).delta.ppm: 2.5-3.0 (6H, m), 3.00 (2H, t,
J=7 Hz), 3.55 (2H, t, J=6 Hz), 3.70 (2H, t, J=7 Hz), 4.0-4.3 (2H,
m), 7.21 (1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.43 (1H, d,
J=5 Hz), 7.66 (1H, d, J=1 Hz), 7.80 (1H, d, J=8 Hz)
Production Example 71
Production of
(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol
hydrochloride
[0401] An achromatic crystal,
(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol
hydrochloride was obtained in the same manner as in Production
Example 21.
[0402] IR (KBr)cm.sup.-1: 3194, 2854, 1365, 1348, 1130, 1111, 820,
712
[0403] NMR (DMSO-d.sub.6).delta.ppm: 2.8-4.0 (12H, m), 3.9-4.3 (2H,
m), 7.2-7.5 (2H, m), 7.7-8.2 (3H, m)
Production Example 72
Production of
tert-butyl=1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl
carbamate
[0404] 0.70 g of
3-(2-(1-benzothiophene-5-yl)ethoxy)propyl=methanesulfonate was
dissolved in 7 ml of N,N-dimethylformamide. Thereafter, 1.03 g of
tert-butyl=3-pyrrolidinyl carbamate carbonate and 1.86 ml of
triethylamine were added to the obtained solution, and the mixture
was then stirred at 90.degree. C. for 2 hours. After cooling, water
and ethyl acetate were added to the reaction mixture. The pH of the
obtained mixture was adjusted to pH 10 by addition of 6 mol/l
hydrochloric acid, and an organic layer was then separated. The
organic layer was successively washed with water and a saturated
saline solution, and then dried over anhydrous magnesium sulfate.
Thereafter, the solvent was then distilled away under a reduced
pressure, so as to obtain 1.12 g of a yellow oil product,
tert-butyl=1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl
carbamate.
[0405] NMR (CDCl.sub.3).delta.ppm: 1.2-1.9 (3H, m), 1.44 (9H, s),
1.9-3.0 (7H, m), 2.99 (2H, t, J=7 Hz), 3.49 (2H, t, J=6 Hz), 3.67
(2H, t, J=7 Hz), 4.0-4.3 (1H, m), 7.19 (1H, d, J=8 Hz), 7.27 (1H,
d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.66 (1H, s), 7.79 (1H, d, J=8
Hz)
Production Example 73
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine
[0406] 1.12 g of
tert-butyl=1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl
carbamate was dissolved in 7.0 ml of ethyl acetate. Thereafter,
1.86 ml of 6 mol/l hydrochloric acid was added to the obtained
solution, and the mixture was then heated to reflux for 1 hour.
After cooling, water and ethyl acetate were added to the reaction
mixture. The pH of the obtained mixture was adjusted to pH 10 by
addition of a 2 mol/l aqueous sodium hydroxide solution, and an
organic layer was then separated. The organic layer was
successively washed with water and a saturated saline solution, and
then dried over anhydrous magnesium sulfate. The solvent was then
distilled away under a reduced pressure. The residue was purified
by column chromatography (eluent; chloroform:methanol=30:1 to
20:1), so as to obtain 0.38 g of a light yellow oil product,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine.
[0407] IR (neat)cm.sup.-1: 3357, 2937, 2861, 2796, 1146, 1108, 755,
701
[0408] NMR (CDCl.sub.3).delta.ppm: 1.2-1.9 (4H, m), 1.9-2.8 (7H,
m), 2.97 (2H, t, J=7 Hz), 3.48 (2H, t, J=6 Hz), 3.66 (2H, t, J=7
Hz), 7.19 (1H, d, J=8 Hz), 7.23 (1H, d, J=5 Hz), 7.39 (1H, d, J=5
Hz), 7.64 (1H, s), 7.77 (1H, d, J=8 Hz)
Production Example 74
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine
oxalate
[0409] An achromatic crystal,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine
oxalate was obtained in the same manner as in Production Example
17.
[0410] IR (KBr)cm.sup.-1: 3390, 2871, 1614, 1310, 1122, 766
[0411] NMR (DMSO-d.sub.6).delta.ppm: 1.5-1.9 (2H, m), 1.9-2.9 (8H,
m), 2.92 (2H, t, J=7 Hz), 3.3-3.7 (1H, m), 3.43 (2H, t, J=6 Hz),
3.62 (2H, t, J=7 Hz), 7.25 (1H, d, J=8 Hz), 7.39 (1H, d, J=5 Hz),
7.72 (1H, d, J=5 Hz), 7.73 (1H, s), 7.90 (1H, d, J=8 Hz)
Production Example 75
Production of
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamide
[0412] 0.50 g of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine was
dissolved in 5 ml of methylene chloride. The obtained solution was
cooled to -60.degree. C. Thereafter, 0.27 ml of triethylamine and
0.14 ml of acetyl chloride were added thereto, and the obtained
mixture was stirred at a room temperature for 1 hour. Thereafter,
water and ethyl acetate were added to the reaction mixture, and an
organic layer was then separated. The organic layer was washed with
a saturated saline solution and then dried over anhydrous magnesium
sulfate. The solvent was then distilled away under a reduced
pressure. The residue was purified by column chromatography
(eluent; chloroform:methanol=50:1 to 10:1), so as to obtain 0.55 g
of a yellow oil product,
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamide-
.
[0413] IR (neat)cm.sup.-1: 3292, 2946, 1654, 1560, 1110, 757,
702
[0414] NMR (CDCl.sub.3).delta.ppm: 1.5-1.7 (1H, m), 1.7-1.8 (2H,
m), 1.94 (3H, s), 2.13 (1H, q, J=9 Hz), 2.2-2.3 (1H, m), 2.4-2.5
(3H, m), 2.59 (1H, dd, J=2, 10 Hz), 2.86 (1H, dt, J=4, 9 Hz), 2.99
(2H, t, J=7 Hz), 3.49 (2H, t, J=6 Hz), 3.67 (2H, t, J=7 Hz),
4.3-4.5 (1H, m), 5.8-5.9 (1H, m), 7.22 (1H, dd, J=1, 8 Hz), 7.28
(1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, d, J=1 Hz), 7.79
(1H, d, J=8 Hz.)
Production Example 76
Production of
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamide
hydrochloride
[0415] A light brown crystal,
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamide
hydrochloride was obtained in the same manner as in Production
Example 21.
[0416] IR (KBr)cm.sup.-1: 3422, 2868, 2475, 1664, 1542, 1343, 1117,
711
[0417] NMR (CDCl.sub.3).delta.ppm: 1.9-2.1 (3H, m), 2.05 (3H, s),
2.3-2.4 (1H, m), 2.4-2.5 (1H, m), 2.6-2.7 (1H, m), 2.8-2.9 (2H, m),
2.97 (2H, t, J=6 Hz), 3.4-3.5 (1H, m), 3.51 (2H, t, J=6 Hz),
3.6-3.7 (1H, m), 3.70 (2H, t, J=6 Hz), 4.6-4.8 (1H, m), 7.22 (1H,
dd, J=1, 8 Hz), 7.31 (1H, d, J=5 Hz), 7.46 (1H, d, J=5 Hz), 7.67
(1H, s), 7.81 (1H, d, J=8 Hz)
Production Example 77
Production of
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesu-
lfonamide
[0418] A yellow oil product,
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesu-
lfonamide was obtained in the same manner as in Production Example
75.
[0419] IR (neat)cm.sup.-1: 3270, 2927, 2856, 1320, 1148, 1110,
756
[0420] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (3H, m), 2.1-2.3 (2H,
m), 2.44 (2H, t, J=7 Hz), 2.50 (1H, dd, J=6, 10 Hz), 2.60 (1H, dd,
J=3, 10 Hz), 2.77 (1H, dt, J=4, 9 Hz), 2.94 (3H, s), 2.99 (2H, t,
J=7 Hz), 3.48 (2H, t, J=6 Hz), 3.68 (2H, t, J=7 Hz), 3.9-4.0 (1H,
m), 4.6-4.8 (1H, m), 7.22 (1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5
Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, d, J=1 Hz), 7.79 (1H, d, J=8
Hz)
Production Example 78
Production of
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesu-
lfonamide oxalate
[0421] An achromatic crystal,
N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesu-
lfonamide oxalate was obtained in the same manner as in Production
Example 17.
[0422] IR (KBr)cm.sup.-1: 3250, 2868, 1718, 1314, 1165, 1119,
707
[0423] NMR (DMSO-d.sub.6).delta.ppm: 1.8-2.0 (3H, m), 2.2-2.3 (1H,
m), 2.93 (2H, t, J=7 Hz), 2.97 (3H, s), 3.0-3.1 (3H, m), 3.1-3.2
(1H, m), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.45 (2H, t, J=6 Hz),
3.63 (2H, t, J=7 Hz), 4.0-4.1 (1H, m), 7.26 (1H, dd, J=1, 8 Hz),
7.40 (1H, d, J=5 Hz), 7.4-7.6 (1H, m), 7.72 (1H, d, J=5 Hz), 7.74
(1H, d, J=1 Hz), 7.90 (1H, d, J=8 Hz)
Production Example 79
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinam-
ine
[0424] 0.43 g of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine was
dissolved in 8.6 ml of methanol. The obtained solution was cooled
to 5.degree. C. Thereafter, 0.35 ml of 37% formalin and 0.09 g of
sodium borohydride were added thereto, and the obtained mixture was
stirred at a room temperature for 17 hours. Thereafter, 2.6 ml of 2
mol/l hydrochloric acid was added to the reaction mixture under
cooling on ice, and the obtained mixture was then stirred at a room
temperature for 30 minutes. Thereafter, water and ethyl acetate
were added to the reaction mixture, and a water layer was then
separated. After ethyl acetate was added to the water layer, the pH
of the mixture was adjusted to pH 9.5 by addition of a 2 mol/l
aqueous sodium hydroxide solution, and an organic layer was
separated. The organic layer was washed with a saturated saline
solution and then dried over anhydrous magnesium sulfate. The
solvent was then distilled away under a reduced pressure. The
residue was purified by column chromatography (eluent;
chloroform:methanol=50:1 to 10:1), so as to obtain 0.39 g of a
yellow oil product,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinam-
ine.
[0425] IR (neat)cm.sup.-1: 2945, 2862, 2786, 1458, 1111, 700
[0426] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (3H, m), 1.9-2.0 (1H,
m), 2.20 (6H, s), 2.2-2.3 (1H, m), 2.3-2.5 (2H, m), 2.50 (1H, dt,
J=8, 12 Hz), 2.7-2.8 (2H, m), 2.8-2.9 (1H, m), 2.99 (2H, t, J=7
Hz), 3.49 (2H, t, J=7 Hz), 3.67 (2H, t, J=7 Hz), 7.22 (1H, dd, J=1,
8 Hz), 7.28 (1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz), 7.67 (1H, d, J=1
Hz), 7.79 (1H, d, J=8 Hz)
Production Example 80
Production of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinam-
ine dihydrochloride
[0427] 0.39 g of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinam-
ine was dissolved in 4.0 ml of ethyl acetate. Thereafter, 0.80 ml
of an ethyl acetate solution containing 3.25 mol/l dry hydrogen
chloride was added to the obtained solution, and the mixture was
stirred at a room temperature for 1 hour and then at 5.degree. C.
for 1 hour. Thereafter, precipitated crystals were collected by
filtration. The crystals were washed with ethyl acetate and then
dried, so as to obtain 0.32 g of an achromatic crystal,
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinam-
ine dihydrochloride.
[0428] IR (KBr)cm.sup.-1: 2936, 1437, 1101, 701
[0429] NMR (CDCl.sub.3).delta.ppm: 1.9-2.1 (2H, m), 2.4-2.6 (2H,
m), 2.84 (6H, s), 2.98 (2H, t, J=7 Hz), 3.1-3.2 (2H, m), 3.4-3.9
(4H, m), 3.54 (2H, t, J=5 Hz), 3.72 (2H, dt, J=3, 7 Hz), 4.2-4.3
(1H, m), 7.24 (1H, d, J=8 Hz), 7.35 (1H, d, J=5 Hz), 7.43 (1H, d,
J=5 Hz), 7.71 (1H, s), 7.84 (1H, d, J=8 Hz)
Reference Example 1
Production of 3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol
[0430] 2.2 g of 2-(1-benzothiophene-4-yl)-1-ethanol was suspended
in 2.2 ml of toluene and 8.8 ml of a 50% (W/V) aqueous sodium
hydroxide solution. Thereafter, 4.41 g of
2-(3-chloropropoxy)tetrahydro-2H-pyran and 0.42 g of tetra-n-butyl
ammonium hydrogen sulfate were added to the suspension, and the
obtained mixture was then heated to reflux for 2 hours. After
cooling, water and toluene were added to the reaction mixture, and
an organic layer was separated. The organic layer was successively
washed with water and a saturated saline solution, and then dried
over anhydrous magnesium sulfate. Subsequently, the solvent was
distilled away under a reduced pressure, so as to obtain 6.50 g of
a light brown oil mixture consisting of
2-(3-(2-(1-benzothiophene-4-yl)ethoxy)propoxy)tetrahydro-2H-pyran
and 2-(3-chloropropoxy)tetrahydro-2H-pyran.
[0431] 6.50 g of this mixture was dissolved in 8.0 ml of methanol.
Thereafter, 8.0 ml of water and 0.70 g of p-toluenesulfonic acid
monohydrate were added to the obtained solution. The obtained
mixture was then stirred at a room temperature for 12 hours.
Thereafter, ethyl acetate and a saturated sodium bicarbonate
solution were added to the reaction mixture, and an organic layer
was then separated. The organic layer was successively washed with
water and a saturated saline solution, and then dried over
anhydrous magnesium sulfate. The solvent was then distilled away
under a reduced pressure. The residue was purified by column
chromatography (eluent; toluene:ethyl acetate=4:1 to 3:1), so as to
obtain 1.42 g of an oil product,
3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol.
[0432] IR (neat)cm.sup.-1: 3394, 2943, 2867, 1413, 1110, 761
[0433] NMR (CDCl.sub.3).delta.ppm: 1.81 (2H, qn, J=6 Hz), 2.1 (1H,
brs), 3.26 (2H, t, J=7 Hz), 3.63 (2H, t, J=6 Hz), 3.69 (2H, t, J=7
Hz), 3.76 (2H, t, J=6 Hz), 7.0-7.4 (2H, m), 7.45 (2H, s), 7.77 (1H,
dd, J=2, 7 Hz)
Reference Example 2
[0434] The following compound was obtained in the same manner as in
Reference Example 1. [0435]
3-(2-(1-benzothiophene-2-yl)ethoxy)-1-propanol
[0436] NMR (CDCl.sub.3).delta.ppm: 1.68 (1H, brs), 1.86 (2H, qn,
J=6 Hz), 3.17 (2H, t, J=6 Hz), 3.67 (2H, t, J=6 Hz), 3.76 (4H, t,
J=6 Hz), 7.07 (1H, s), 7.2-7.4 (2H, m), 7.67 (1H, d, J=8 Hz), 7.77
(1H, d, J=8 Hz) [0437]
3-(2-(1-benzothiophene-3-yl)ethoxy)-1-propanol
[0438] IR (neat)cm.sup.-1: 3395, 2942, 2867, 1427, 1113, 762,
732
[0439] NMR (CDCl.sub.3).delta.ppm: 1.83 (2H, qn, J=6 Hz), 2.27 (1H,
t, J=6 Hz), 3.13 (2H, t, J=7 Hz), 3.65 (2H, t, J=6 Hz), 3.74 (2H,
t, J=6 Hz), 3.78 (2H, t, J=7 Hz), 7.18 (1H, s), 7.34 (1H, dt, J=1,
7 Hz), 7.39 (1H, dt, J=1, 7 Hz), 7.76 (1H, dd, J=1, 7 Hz), 7.86
(1H, dd, J=1, 7 Hz) [0440]
3-(2-(1-benzothiophene-5-yl)ethoxy)-1-propanol
[0441] IR (neat)cm.sup.-1: 3398, 2939, 2866, 1438, 1110, 704
[0442] NMR (CDCl.sub.3).delta.ppm: 1.82 (2H, qn, J=6 Hz), 2.29 (1H,
t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.64 (2H, t, J=6 Hz), 3.71 (2H,
t, J=7 Hz), 3.73 (2H, q, J=6 Hz), 7.22 (1H, dd, J=1, 8 Hz), 7.28
(1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.66 (1H, d, J=1 Hz), 7.80
(1H, d, J=8 Hz) [0443]
3-(2-(1-benzothiophene-6-yl)ethoxy)-1-propanol
[0444] IR (neat)cm.sup.-1: 3389, 2942, 2865, 1397, 1111, 819,
693
[0445] NMR (CDCl.sub.3).delta.ppm: 1.82 (2H, qn, J=6 Hz), 2.24 (1H,
t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.64 (2H, t, J=6 Hz), 3.71 (2H,
t, J=7 Hz), 3.74 (2H, q, J=6 Hz), 7.21 (1H, d, J=8 Hz), 7.28 (1H,
d, J=5 Hz), 7.38 (1H, d, J=5 Hz), 7.70 (1H, s), 7.75 (1H, d, J=8
Hz) [0446] 3-(2-(1-benzothiophene-7-yl)ethoxy)-1-propanol
Reference Example 3
Production of 4-(2-(3-chloropropoxy)ethyl)-1-benzothiophene
[0447] 1.40 g of 3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol was
dissolved in 7.0 ml of methylene chloride. Thereafter, 1.10 ml of
thionyl chloride and 0.05 ml of N,N-dimethylformamide were added to
the obtained solution, and the obtained mixture was then heated to
reflux for 5 hours. Subsequently, the solvent was distilled away
under a reduced pressure. The residue was purified by column
chromatography (eluent; hexane:ethyl acetate=20:1), so as to obtain
1.43 g of a yellow oil product,
4-(2-(3-chloropropoxy)ethyl)-1-benzothiophene.
[0448] IR (neat)cm.sup.-1: 2867, 1413, 1113, 760
[0449] NMR (CDCl.sub.3).delta.ppm: 1.99 (2H, qn, J=6 Hz), 3.23 (2H,
t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.59 (2H, t, J=6 Hz), 3.75 (2H,
t, J=7 Hz), 7.18 (1H, dd, J=2, 7 Hz), 7.29 (1H, t, J=7 Hz), 7.1-7.3
(2H, m), 7.45 (2H, s), 7.76 (1H, dd, J=2, 8 Hz)
Reference Example 4
[0450] The following compound was obtained in the same manner as in
Reference Example 3. [0451]
2-(2-(3-chloropropoxy)ethyl)-1-benzothiophene
[0452] NMR (CDCl.sub.3).delta.ppm: 2.04 (2H, qn, J=6 Hz), 3.16 (2H,
t, J=7 Hz), 3.62 (2H, t, J=6 Hz), 3.66 (2H, t, J=6 Hz), 3.75 (2H,
t, J=7 Hz), 7.06 (1H, s), 7.25 (1H, dt, J=1, 7 Hz), 7.30 (1H, dt,
J=1, 7 Hz), 7.67 (1H, dd, J=1, 7 Hz), 7.77 (1H, dd, J=1, 7 Hz)
[0453] 3-(2-(3-chloropropoxy)ethyl)-1-benzothiophene
[0454] IR (neat)cm.sup.-1: 2865, 1427, 1115, 762, 732
[0455] NMR (CDCl.sub.3).delta.ppm: 2.02 (2H, qn, J=6 Hz), 3.13 (2H,
t, J=7 Hz), 3.61 (2H, t, J=6 Hz), 3.62 (2H, t, J=6 Hz), 3.79 (2H,
t, J=7 Hz), 7.19 (1H, s), 7.34 (1H, dt, J=1, 7 Hz), 7.39 (1H, dt,
J=1, 7 Hz), 7.77 (1H, dd, J=1, 7 Hz), 7.86 (1H, dd, J=1, 7 Hz)
[0456] 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene
[0457] IR (neat)cm.sup.-1: 2864, 1438, 1113, 755, 701
[0458] NMR (CDCl.sub.3).delta.ppm: 2.01 (2H, qn, J=6 Hz), 3.00 (2H,
t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.61 (2H, t, J=6 Hz), 3.70 (2H,
t, J=7 Hz), 7.22 (1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.42
(1H, d, J=5 Hz), 7.68 (1H, d, J=1 Hz), 7.79 (1H, d, J=8 Hz) [0459]
6-(2-(3-chloropropoxy)ethyl)-1-benzothiophene
[0460] IR (neat)cm.sup.-1: 2864, 1113, 820, 761, 695, 652
[0461] NMR (CDCl.sub.3).delta.ppm: 2.00 (2H, qn, J=6 Hz), 3.00 (2H,
t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.61 (2H, t, J=6 Hz), 3.70 (2H,
t, J=7 Hz), 7.21 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.37 (1H,
d, J=5 Hz), 7.72 (1H, s), 7.73 (1H, d, J=8 Hz) [0462]
7-(2-(3-chloropropoxy)ethyl)-1-benzothiophene
[0463] IR (neat)cm.sup.1: 2866, 1460, 1395, 1115, 795, 701
[0464] NMR (CDCl.sub.3).delta.ppm: 2.00 (2H, qn, J=6 Hz), 3.17 (2H,
t, J=7 Hz), 3.60 (4H, t, J=6 Hz), 3.82 (2H, t, J=7 Hz), 7.20 (1H,
d, J=8 Hz), 7.33 (1H, t, J=8 Hz), 7.35 (1H, d, J=5 Hz), 7.42 (1H,
d, J=5 Hz), 7.70 (1H, d, J=8 Hz)
Reference Example 5
Production of
3-(2-(1-benzothiophene-5-yl)ethoxy)propyl=methanesulfonate
[0465] 2.03 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)-1-propanol was
dissolved in 16.8 ml of methylene chloride. Thereafter, 2.43 ml of
methanesulfonyl chloride, 4.37 ml of triethylamine, and 0.10 g of
4-(dimethylamino)pyridine were added to the obtained solution,
while cooling on ice. The obtained mixture was stirred at the same
temperature for 30 minutes and then at a room temperature for 12
hours. Thereafter, methyl chloride and water were added to the
reaction mixture, and an organic layer was separated. The organic
layer was successively washed with water and a saturated saline
solution, and then dried over anhydrous magnesium sulfate. The
solvent was then distilled away under a reduced pressure. The
residue was purified by column chromatography (eluent; hexane ethyl
acetate=5:1), so as to obtain 1.40 g of
3-(2-(1-benzothiophene-5-yl)ethoxy)propyl=methanesulfonate.
[0466] IR (neat)cm.sup.-1: 2937, 2866, 1352, 1174, 1114, 943, 705,
529
[0467] NMR (CDCl.sub.3).delta.ppm: 1.97 (2H, qn, J=6 Hz), 2.81 (3H,
s), 2.98 (2H, t, J=7 Hz), 3.54 (2H, t, J=6 Hz), 3.70 (2H, t, J=6
Hz), 4.26 (2H, t, J=7 Hz), 7.20 (1H, dd, J=1, 8 Hz), 7.28 (1H, d,
J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.65 (1H, d, J=1 Hz), 7.79 (1H, d,
J=8 Hz)
Reference Example 6
Production of 2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic acid
and 2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)acetic acid
(1) Production of 2,4-dimethoxyphenethyl=acetate
[0468] 15.0 g of 2-(2,4-dimethoxyphenyl)-1-ethanol was dissolved in
150 ml of methylene chloride. Thereafter, 9.32 ml of acetic
anhydride, 13.8 ml of triethylamine, and 0.10 g of
4-(dimethylamino)pyridine were added to the obtained solution,
while cooling on ice. The obtained mixture was stirred at the same
temperature for 30 minutes and then at a room temperature for 12
hours. Thereafter, water was added to the reaction mixture. The pH
of the mixture was adjusted to pH 1.5 by addition of 6 mol/l
hydrochloric acid, and an organic layer was separated. The organic
layer was successively washed with water and a saturated saline
solution, and then dried over anhydrous magnesium sulfate. The
solvent was then distilled away under a reduced pressure. The
residue was purified by column chromatography (eluent; hexane ethyl
acetate=5:1), so as to obtain 17.2 g of an achromatic oil product,
2,4-dimethoxyphenethyl=acetate.
[0469] IR (neat)cm.sup.-1: 2958, 1736, 1509, 1243, 1035, 834
[0470] NMR (CDCl.sub.3).delta.ppm: 2.03 (3H, s), 2.87 (2H, t, J=7
Hz), 3.80 (6H, s), 4.22 (2H, t, J=7 Hz), 6.41 (1H, d, J=9 Hz), 6.46
(1H, s), 7.05 (1H, d, J=9 Hz)
[0471] Also, 2,5-dimethoxyphenethyl=acetate was obtained in the
same above manner.
[0472] IR (neat)cm.sup.-1: 2952, 1736, 1502, 1226, 1048, 802,
710
[0473] NMR (CDCl.sub.3).delta.ppm: 2.01 (3H, s), 2.90 (2H, t, J=7
Hz), 3.74 (3H, s), 3.76 (3H, s), 4.25 (2H, t, J=7 Hz), 6.74 (3H,
s)
(2) Production of 5-acetyl-2,4-dimethoxyphenethyl=acetate
[0474] 17.0 g of 2,4-dimethoxyphenethyl=acetate was dissolved in
170 ml of methylene chloride. Thereafter, 5.93 ml of acetyl
chloride and 12.1 g of aluminum chloride were added to the obtained
solution, while cooling on ice. The obtained mixture was stirred at
the same temperature for 1 hour. Thereafter, the reaction mixture
was poured into ice water, and an organic layer was separated. The
organic layer was successively washed with water and a saturated
saline solution, and then dried over anhydrous magnesium sulfate.
The solvent was then distilled away under a reduced pressure.
Diisopropyl ether was added to the residue, and precipitated
crystals were then collected by filtration. The obtained crystals
were washed with diisopropyl ether and then dried, so as to obtain
13.9 g of a yellow crystal,
5-acetyl-2,4-dimethoxyphenethyl=acetate.
[0475] NMR (CDCl.sub.3).delta.ppm: 2.01 (3H, s), 2.57 (3H, s), 2.88
(2H, t, J=7 Hz), 3.90 (3H, s), 3.93 (3H, s), 4.21 (2H, t, J=7 Hz),
6.42 (1H, s), 7.68 (1H, s)
[0476] Also, 4-acetyl-2,5-dimethoxyphenethyl=acetate was obtained
in the same above manner.
(3) Production of 5-acetyl-4-hydroxy-2-methoxyphenethyl=acetate
[0477] 13.9 g of 5-acetyl-2,4-dimethoxyphenethyl=acetate was
dissolved in 70 ml of acetonitrile. Thereafter, 13.9 g of aluminum
chloride and 7.82 g of sodium iodide were added to the obtained
solution, while cooling on ice. The obtained mixture was stirred at
50.degree. C. for 3 hours. Thereafter, the reaction mixture was
poured into ice water, ethyl acetate was then added to the obtained
mixture, and an organic layer was then separated. The organic layer
was successively washed with water and a saturated saline solution,
and then dried over anhydrous magnesium sulfate. The solvent was
then distilled away under a reduced pressure, so as to obtain 13.3
g of a yellow oil product,
5-acetyl-4-hydroxy-2-methoxyphenethyl=acetate.
[0478] Also, 4-acetyl-5-hydroxy-2-methoxyphenethyl=acetate was
obtained in the same above manner.
(4) Production of
1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone
[0479] 13.3 g of the above
5-acetyl-4-hydroxy-2-methoxyphenethyl=acetate was dissolved in 30
ml of ethanol. Thereafter, 21 ml of a 5 mol/l aqueous sodium
hydroxide solution was added to the obtained solution, and the
obtained mixture was stirred at a room temperature for 17 hours.
Thereafter, water and ethyl acetate were added to the reaction
mixture, and the pH of the obtained mixture was adjusted to pH 1 by
addition of 6 mol/l hydrochloric acid. Thereafter, an organic layer
was separated. The organic layer was successively washed with water
and a saturated saline solution, and then dried over anhydrous
magnesium sulfate. The solvent was then distilled away under a
reduced pressure. Diisopropyl ether was added to the residue, and
precipitated crystals were then collected by filtration. The
obtained crystals were washed with diisopropyl ether and then
dried, so as to obtain 8.30 g of a yellow crystal,
1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone.
[0480] Also,
1-(2-hydroxy-4-(2-hydroxyethyl)-5-methoxyphenyl)-1-ethanone was
obtained in the same above manner.
[0481] NMR (CDCl.sub.3).delta.ppm: 1.6-1.8 (1H, m), 2.61 (3H, s),
2.90 (2H, t, J=7 Hz), 3.8-4.1 (2H, m), 3.84 (3H, s), 6.84 (1H, s),
7.06 (1H, s), 11.98 (1H, s)
(5) Production of
2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone
[0482] 10.0 g of
1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone was
dissolved in 100 ml of methylene chloride. Thereafter, 2.94 ml of
bromine was added dropwise to the obtained solution. The obtained
mixture was stirred at a room temperature for 1 hour. Thereafter,
the reaction mixture was poured into ice water, and an organic
layer was separated. The organic layer was successively washed with
water and a saturated saline solution, and then dried over
anhydrous magnesium sulfate. The solvent was then distilled away
under a reduced pressure, so as to obtain 16.4 g of a yellow oil
product,
2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethan-
one.
[0483] Also,
2-bromo-1-(2-hydroxy-4-(2-hydroxyethyl)-5-methoxyphenyl)-1-ethanone
was obtained in the same above manner.
[0484] IR (neat)cm.sup.-1: 3376, 2941, 1644, 1496, 1243, 1034, 757,
690
[0485] NMR (CDCl.sub.3).delta.ppm: 1.5-1.8 (1H, m), 2.91 (2H, t,
J=7 Hz), 3.8-4.1 (2H, m), 3.85 (3H, s), 4.40 (2H, s), 6.89 (1H, s),
7.07 (1H, s), 11.51 (1H, s)
(6) 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol
[0486] 16.4 g of the above
2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone
was dissolved in 70 ml of methanol. Thereafter, 17.3 g of sodium
acetate was added to the obtained solution, and the obtained
mixture was then heated to reflux for 5 minutes. After cooling,
water and ethyl acetate were added to the reaction mixture, and an
organic layer was separated. The organic layer was successively
washed with water and a saturated saline solution, and then dried
over anhydrous magnesium sulfate. The solvent was then distilled
away under a reduced pressure. The residue was dissolved in 150 ml
of methanol. Thereafter, 6.30 g of sodium borohydride was dividedly
added to the obtained solution, and the obtained mixture was
stirred at a room temperature for 1 hour. Subsequently, 6 mol/l
hydrochloric acid was added to the reaction solution, so that the
pH thereof was adjusted to pH 1. The obtained solution was further
stirred at a room temperature for 1 hour. This reaction mixture was
concentrated under a reduced pressure. Thereafter, water and ethyl
acetate were added thereto, and an organic layer was separated. The
organic layer was successively washed with water and a saturated
saline solution, and then dried over anhydrous magnesium sulfate.
The solvent was then distilled away under a reduced pressure. The
residue was purified by column chromatography (eluent:hexane:ethyl
acetate=4:1), so as to obtain 1.48 g of a light yellow crystal,
2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol.
[0487] NMR (CDCl.sub.3).delta.ppm: 1.79 (1H, brs), 2.97 (2H, t, J=7
Hz), 3.84 (2H, t, J=7 Hz), 3.86 (3H, s), 6.66 (1H, d, J=3 Hz), 7.03
(1H, s), 7.35 (1H, s), 7.51 (1H, d, J=3 Hz)
[0488] Also, 2-(5-methoxy-1-benzofuran-6-yl)-1-ethanol was obtained
in the same above manner.
[0489] NMR (CDCl.sub.3).delta.ppm: 2.04 (1H, brs), 2.98 (2H, t, J=6
Hz), 3.86 (2H, t, J=6 Hz), 3.86 (3H, s), 6.68 (1H, d, J=2 Hz), 7.02
(1H, s), 7.31 (1H, s), 7.55 (1H, d, J=2 Hz)
(7) Production of 2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic
acid
[0490] 1.75 g of 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol was
dissolved in a mixed solution consisting of 7.0 ml of tert-butanol
and 1.75 ml of N,N-dimethylformamide. Thereafter, 2.2 g of
1-chloroacetylpiperidine and 1.54 g of potassium tert-butoxide were
added to the obtained solution, while cooling on ice. The obtained
mixture was stirred at the same temperature for 30 minutes and then
at a room temperature for 2 hours. Thereafter, water and ethyl
acetate were added to the reaction mixture. The pH of the obtained
mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric
acid, and an organic layer was separated. The organic layer was
successively washed with water and a saturated saline solution, and
then dried over anhydrous magnesium sulfate. The solvent was then
distilled away under a reduced pressure. The residue was dissolved
in 10.5 ml of a 90% aqueous ethanol solution. Thereafter, 0.91 g of
sodium hydroxide was added thereto, and the obtained mixture was
then heated to reflux for 3 hours. After cooling, water and ethyl
acetate were added to the reaction mixture. The pH of the obtained
mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric
acid, and an organic layer was separated. The organic layer was
successively washed with water and a saturated saline solution, and
then dried over anhydrous magnesium sulfate. The solvent was then
distilled away under a reduced pressure. Thereafter, diisopropyl
ether was added to the residue, and precipitated crystals were then
collected by filtration. The obtained crystals were washed with
diisopropyl ether and then dried, so as to obtain 1.42 g of a
yellow crystal, 2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic
acid.
[0491] IR (neat)cm.sup.-1: 2939, 1734, 1426, 1252, 1200, 1148,
1094, 1022, 771
[0492] NMR (DMSO-d.sub.6).delta.ppm: 2.88 (2H, t, J=7 Hz), 3.64
(2H, t, J=7 Hz), 3.82 (3H, s), 4.01 (2H, s), 6.81 (1H, d, J=2 Hz),
7.22 (1H, s), 7.44 (1H, s), 7.82 (1H, d, J=2 Hz)
[0493] Also, 2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)acetic acid
was obtained in the same above manner.
[0494] NMR (DMSO-d.sub.6).delta.ppm: 2.90 (2H, t, J=7 Hz), 3.66
(2H, t, J=7 Hz), 3.82 (3H, s), 4.02 (2H, s), 6.86 (1H, d, J=2 Hz),
7.15 (1H, s), 7.46 (1H, s), 7.88 (1H, d, J=2 Hz)
Reference Example 7
Production of 3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid
[0495] (1) 29 mg of potassium hydroxide, 83 mg of tetra-n-butyl
ammonium bromide, and 5.67 ml of tert-butyl acrylate were added to
4.60 g of 2-(1-benzothiophene-5-yl)-1-ethanol, and the obtained
mixture was then stirred at 45.degree. C. to 50.degree. C. for 2
hours. After cooling, water and toluene were added to the reaction
mixture. The pH of the mixture was adjusted to pH 1 by addition of
6 mol/l hydrochloric acid, and an organic layer was separated. The
organic layer was washed with water and then dried over anhydrous
magnesium sulfate. The solvent was then distilled away under a
reduced pressure. The residue was purified by column chromatography
(eluent; hexane:ethyl acetate=5:1), so as to obtain 7.70 g of an
achromatic oil product,
3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid tert-butyl.
[0496] IR (neat)cm.sup.-1: 2978, 2867, 1729, 1368, 1159, 1112,
702
[0497] NMR (CDCl.sub.3).delta.ppm: 1.43 (9H, s), 2.49 (2H, t, J=6
Hz), 2.99 (2H, t, J=7 Hz), 3.70 (2H, t, J=6 Hz), 3.70 (2H, t, J=7
Hz), 7.21 (1H, dd, J=2, 8 Hz), 7.27 (1H, dd, J=1, 5 Hz), 7.41 (1H,
d, J=5 Hz), 7.6-7.7 (1H, m), 7.78 (1H, d, J=8 Hz)
[0498] (2) 7.60 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)propionic
acid tert-butyl was dissolved in 22.8 ml of toluene. Thereafter, 94
mg of p-toluenesulfonic acid monohydrate was added thereto, and the
obtained mixture was heated to reflux for 6 hours. After cooling,
water and ethyl acetate were added to the reaction mixture, and an
organic layer was separated. The organic layer was dried over
anhydrous magnesium sulfate. The solvent was then distilled away
under a reduced pressure. The residue was crystallized from a
toluene-cyclohexane mixed solution (1:4; 23 ml), so as to obtain
5.30 g of a light red crystal,
3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid.
[0499] IR (KBr)cm.sup.-1: 2860, 1719, 1273, 1128, 706
[0500] NMR (CDCl.sub.3).delta.ppm: 2.63 (2H, t, J=6 Hz), 3.00 (2H,
t, J=7 Hz), 3.73 (2H, t, J=7 Hz), 3.74 (2H, t, J=6 Hz), 7.20 (1H,
dd, J=1, 8 Hz), 7.28 (1H, dd, J=1, 5 Hz), 7.41 (1H, d, J=5 Hz),
7.6-7.7 (1H, m), 7.79 (1H, d, J=8 Hz)
Formulation Example 1
[0501] Component (i): A mixture consisting of 50 mg of
1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol maleate
(hereinafter referred to as compound A), 20 mg of lactose, 25 mg of
corn starch, and 40 mg of Avicel PH101 (manufactured by Asahi Kasei
Corp.)
[0502] Component (ii): 10 mg of Kollidon CL (manufactured by BASF),
10 mg of Avicel PH302 (manufactured by Asahi Kasei Corp.), 18 mg of
light anhydrous silicic acid, and 2 mg of magnesium stearate
[0503] Component (i) was kneaded with a 5% polyvinylpyrrolidone K30
aqueous solution and then dried at 60.degree. C. Thereafter,
component (ii) was mixed with the above mixture. The obtained
mixture was formulated into a round tablet with a weight of 175 mg
and a diameter of 8 mm, thereby obtaining a tablet containing 50 mg
of compound A.
Formulation Example 2
[0504] Component (i): A mixture consisting of 50 mg of compound A,
20 mg of lactose, and 53 mg of corn starch
[0505] Component (ii): 7 mg of Kollidon CL (manufactured by BASF),
18 mg of Avicel PH302 (manufactured by Asahi Kasei Corp.), and 2 mg
of magnesium stearate
[0506] Component (i) was kneaded with a 5% polyvinylpyrrolidone K30
aqueous solution and then dried at 60.degree. C. Thereafter,
component (ii) was mixed with the above mixture. 150 mg of the
obtained mixture was filled in a size-3 gelatin capsule, so as to
obtain a capsule agent.
Formulation Example 3
[0507] 1 g of compound A was weighed. 80 ml of a parenteral
solution (Japanese Pharmacopoeia) was added to the obtained
compound for dissolution. A 0.1 mol/l aqueous sodium dihydrogen
phosphate solution and a 0.1 mol/l aqueous sodium phosphate
solution were added to the above solution, so that the pH of the
mixture was adjusted to pH 7.5. Thereafter, an appropriate amount
of sodium chloride was added as an isotonizing agent to the
obtained solution. A parenteral solution was further added thereto,
so as to obtain exactly 100 ml of a solution. This solution was
filtrated through a membrane filter (pore size: 0.2 .mu.m) under
aseptic environment, so as to obtain a solution used as eyedrop.
The obtained solution was filled in a polyethylene eyedrop bottle
(volume: 5 ml) under aseptic environment, and the bottle was then
hermetically closed, so as to obtain an eyedrop agent containing 1
w/v % compound A.
Formulation 4
[0508] 1 g of compound A was weighed. 80 ml of a parenteral
solution (Japanese Pharmacopoeia) was added to the obtained
compound for dissolution. A 0.1 mol/l aqueous potassium dihydrogen
phosphate solution and a 0.1 mol/l aqueous sodium dihydrogen
phosphate solution were added to the above solution, so that the pH
of the mixture was adjusted to pH 7.5. Thereafter, an appropriate
amount of sodium chloride was added as an isotonizing agent to the
obtained solution. A parenteral solution was further added thereto,
so as to obtain exactly 100 ml of a solution. This solution was
filtrated through a membrane filter (pore size: 0.2 .mu.m) under
aseptic environment, so as to obtain a solution used as eyedrop.
The obtained solution was filled in a polyethylene eyedrop bottle
(volume: 5 ml) under aseptic environment, and the bottle was then
hermetically closed, so as to obtain an eyedrop agent containing 1
w/v % compound A.
INDUSTRIAL APPLICABILITY
[0509] The alkyl ether derivative represented by the general
formula [1] or a salt thereof shows the effect of protecting
retinal nerve cells, and thus it is useful as a preventive and/or
remedy for retinal nerve diseases such as glaucoma, diabetic
retinopathy, retinal artery obstruction, retinal venous
obstruction, macular degeneration, and retinopathy of
prematurity.
* * * * *