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Patent 1259074 Summary

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(12) Patent: (11) CA 1259074
(21) Application Number: 562864
(54) English Title: CARBOSTYRIL DERIVATIVE AND PROCESS FOR PREPARING SAME
(54) French Title: DERIVE DE CARBOSTYRIL ET PROCEDE DE PREPARATION
Status: Expired
Bibliographic Data
(52) Canadian Patent Classification (CPC):
  • 260/289
  • 260/289.5
(51) International Patent Classification (IPC):
  • C07D 215/26 (2006.01)
  • C07D 207/48 (2006.01)
  • C07D 215/60 (2006.01)
(72) Inventors :
  • TSUNASHIMA, AKIRA (Japan)
  • IWAKUMA, TAKEO (Japan)
  • IKEZAWA, KATSUO (Japan)
  • TAKAITI, OSASI (Japan)
(73) Owners :
  • TANABE SEIYAKU CO., LTD. (Japan)
(71) Applicants :
(74) Agent: KIRBY EADES GALE BAKER
(74) Associate agent:
(45) Issued: 1989-09-05
(22) Filed Date: 1984-12-21
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
8334494 United Kingdom 1983-12-24

Abstracts

English Abstract



Abstract:
The present invention is directed to compounds of the
formula:

Image (I)

wherein YO is a protected hydroxy group and a process for
preparing the same. These compounds are intermediates useful
in the preparation of carbostyril derivatives which show
potent bronchodilating activity and are useful as
bronchodilators.


Claims

Note: Claims are shown in the official language in which they were submitted.



Claims:
1. A compound of the formula (I)

(I)
Image

wherein YO is a protected hydroxy group.
2. A compound as claimed in claim 1 wherein YO is
a substituted or unsubstituted phenyl-lower alkyloxy group.
3. A compound as claimed in claim 1 wherein YO is
a benzyloxy group.
4. A process for preparing a compound of the formula:

Image (I)

wherein YO is a protected hydroxy group, which comprises the
step(s) of:
reducing a compound of the formula:

Image (II)






Image (III)


wherein YO- is a hydroxy group or a protected hydroxy group.
5. A process as claimed in claim 4 wherein YO is a
substituted or unsubstituted phenyl-lower alkyloxy group.
6. A process as claimed in claim 4 wherein YO is a
benzyloxy group.

51

Description

Note: Descriptions are shown in the official language in which they were submitted.


?r~
-




Carbostyril derivative and process for preparing same
The present application has been divided out of
Canadian Patent Application Serial No. 470,917, filed
December 21, 1984.
This invention relates to novel intermediates useful
in the preparation of carbostyril derivatives and a process
for preparing same.
According to the invention there is provided a
. componnd of the formula:

c
(I)


Y H
wherein YO is a protected hydroxy group.

The compounds II) are useful as intermediates in the
preparation of carbostyril derivatives of the formula:

CH



H ~ 3
(I)

H




~ .


or a pharmaceutically acceptable acid addition salt thereof.
The carbostyril derivatives and pharmaceutically
acceptable acid addition salts thereof show potent ~2-adreno-
ceptor stimulating action and are useful as bronchodilators.
The compound (I) of the present invention can exist in
the form of four optical isomers (i.e., the (R)(R)-, (R)(S)-,
(S)(R)- and (S)(S)-isomers) due to the two asymmetric carbon
atoms involved in the side chain.
OH CH3
-CH - CH2 - NH - CH - CH2 ~ OCH3



wherein the asterisk denotes an asymmetric carbon atom.
The present invention includes within its scope all four
optical isomers and mixtures thereof.
Throughout the specification, the terms "(R)(R)-isomer",
"(R)(S)-isomer", "(S)(R)-isomer" and (S)(S)-isomer" mean the
configuration of the asymmetric carbon atoms at the position
of -CH(OH)- and that of -C~(CH3)-, respectively. Therefore,
for example, "(S)~R)-isomer" means that the asymmetric
carbon atom at the position of -CH(OH)- has (S)-configuration
and the asymmetric carbon atom at the position of -CH(CH3)-
has (R)-configuration. Further, throughout the specification,
~ the term "~-isomer" means a stereoisomer which is a mixture
of (R)(R)- and (S)(S)-isomers, and the term "~-isomer" means
a stereoisomer which is a mixture of (R)(S)- and ~S)(R)-isomers.
Besides, the com~ounds of the present invention have the
following two tautomeric structures which are mut-lally
convertible from one to another. Both of these isomers are
also included within the scope of the present invention.


3L2~




~ H ~ ~ 3
~0
Y H ~

N ~ OCH3

~ H


According to the present invention, the compound (I)
is prepared by reducing a compound of the formula:



H ~ 3
(II)

YO H
CH
~N/~--OCH3
~o (III)
Y H
wherein YO- is a protected hydroxy~ to give a
compound of the formula:

1~i3C!7~



~ N ~ ~ OCH3 (I)
~ .'
Y H
wherein YO- is the same as defined above.


In the above-mentioned reactions, a wide variety of
protecting groups which have been usually employed to protect
hydroxy group can be used as the protecting group (Y).
Examples of such protecting group include lower alkanoyl
such as formyl, acetyl and pivaloyl; sustituted or unsubsti-
tuted phenyl-lower alkyl such as benzyl, p-methoxybenzyl and
3,4-dimethoxybenzyl; substituted or unsubstituted ben2yloxy-
carbonyl such as benzyloxycarbonyl and p-methoxybenzyloxy-
carbonyl; or substituted or unsubstituted phenylsulfonyl
such a~ benzenesulfonyl and p-toluenesulfonyl.
The reduction of the compound (II) or (III) can be
accomplished by reacting it with a reducing agent in a
solvent. Suitable examples of the reducing agent include
sodium borohydride, lithium aluminium hydride, lithium
borohydride, sodium monoacetoxyborohydride, diborane or
sodium cyanoborohydride. Methanol, ethanol, isopropanol,
dimethylformamide, dimethylsulfoxide, tetrahydrofuran,


125~r~7r~,
-- 5 --
ether, dimethoxyethane, diglyme, dioxane, toluene or a mixture
thereof is suitable as the solvent. It is preferred to carry
out the reaction at a temperature of -20 to 30C.
To obtain the carbostyril derivatives of the formula:




HO ~ H
~ 'I

H



5 the hydroxy protecting group Y is removed from the compound
of formula I.
The removal of the protecting group can be conducted
by conventional methods for example, hydrolysis, organic base
treatment or reduction. For example, when the protecting
group is formyl, acetyl or benzenesulfonyl, said group may be
removed by hydrolysis of the compound (I) with an acid or an
alkali. Suitable examples of such acid include, for example,
formic acid, trifluoroacetic acid, benzenesulfonic acid,
p toluenesulfonic acid, hydrochloric acid or hydrobromic acid.
Suitable examples of such alkali include, for example, sodium
carbonate, potassium carbonate, sodium hydroxide or potassium
hydroxide. This reaction may be conducted with or without a
solvent. Examples of the solvent include water, methanol,
ethanol or dioxane. It is preferred to carry out the reaction
20 at a temperature of -30 to 70C, especially 20 to 50C. When

the protecting group is benzyl, p-methoxybenzyl, 3,4-dimethoxy-
benzyl, benzyloxycarbonyl or p-methoxybenzyloxycarbonyl, the



removal of said protecting group may be conducted by catalytic
hydrogenation o~ the compound (I) in hydrogen gas in the
presence of a catalyst. This catalytic hydrogenation is
preferably carried out at a temperature of 0 to 100C,
5 especially 20 to 40C, under atmospheric or increased pressure.
Preferred examples of the catalyst include palladium-BaCO3,
palladium-charcoal and palladium-black. Methanol, ethanol,
tetrahydrofuran, water or a mixture thereof is suitable as the
reaction solvent. Further, when the protecting group is acetyl
10 or pivaloyl, said group may be removed by the treatment of the
compound (I) with an organic base. The treatment of the
compound (I) can be carried out by conventional methods, for
example, by treating it with an organic base such as methylamine,
dimethylamine, ethylamine or diethylamine. This reaction may
15 be conducted with or without a solvent. Examples of the solvent
include water, methanol, ethanol, dioxane or a mixture thereof.
It is preferred to carry out the reaction at a temperature of 0
to 100C, especially 20 to 70C.
When a racemic modification of the compound (II) or
20 (III) (YO- = a protected hydroxy) is used as the starting
compound in the above-mentioned reaction, the compound (I) in
which YO- is a protected hydroxy, i.e., a compound of the
formula:




~ - N ~ ~-OCH (I)
~0
Y'O H

37f~
-- 7 --
wherein Y'O- is a protected hydroxy, is obtained in the form
of a mixture of two stereoisomers (i.e., ~- and~ -isomers) and
may be, if required, separated into each of the stereoisomers
prior to removal of the protecting group (Y') th~refrom. For
example, each one of the a- and ~-isomers of the compound (I')
may be obtained by acylating the compound (I') to give a
compound of the formula:


COR CH3
H3
~ (V)

Y'O H
wherein RCO- is an acyl group and Y'O- is the same as defined
above, subjecting said eompound (V) to chromatography to
separate it into each of ~- and ~-isomers thereof, and then
removing the acyl group therefrom. The aeylating agent
whieh is used for aeylation of the eompound (I') ineludes,
for example, aeetyl chloride, aeetyl bromide, chloroaeetyl
chloride, p-nitrobenzoyl chloride, and the like. The
aeylation is preferably carried out in the presence of an
acid aceeptor (e.g., sodium hydroxide, potassium hydroxide,
sodium earbonate, potassium earbonate, sodium bicarbonate,
potassium biearbonate) in a solvent (e.g., ethyl acetate,
methylene ehloride, chloroform, benzene, water or a mixture
thereof) at a temperature of 0 to 30C. Subsequent ehromato-
graphic separation of ~- and B-isomers of the compound (V)
can be effeeted on a column of siliea gel, using methanol,


~L2~




chloroform, methylene chloride, ethyl acetate, benzene,
n-hexane or a mixture thereof as an eluant. Then, the
removal of the acyl group from the thus-separated each
stereoisomer (~- or ~-isomer) of the compound (V1 can be
5 accomplished by conventional hydrolysis thereof, ~or example,
by treating said isomer with a base (e.g., potassium hydroxide,
sodium hydroxide, potassium carbonate, sodium carbonate) or
an acid le.g., hydrochloric acid, sulfuric acid, nitric
acid) in a solvent te.g., ~ater, aqueous methanol, aqueous
lO ethanol) at a temperature of 20 to lOQC.
~ he ~- or ~-isomer of the compound (I') obtained
above (i.e., a mixture of (R)(R)- and (S)(S)-isomers thereof
or a mixture of (R)(S)- and (S)(R)-isomers thereof) may be,
if required, further separated into each of the optical
15 isomers of the compound tI'). For example, each one of
(R)(R)- and (S)(S)-isomers of the compound (I') may ~e
obtained by acylating the ~-isomer of the compound (I')
with an optically active acylating agent to give a compound
of the formula:



COR' CH
HO ~ I ~ 3
~ ~V')

y' H

20 wherein R'CO- is an optically active acyl group and Y'O is


~L25~ ~7~
. g _

the same as defined above, subjecting the compound ~V') to
chromatography to separate it into each of (R)(R~- and
(S)(S)-isomers of the compound (V'), and then removing the
acyl group therefrom. The optically active acylating agent
which is used for acylation of the compound (I~) includes,
for example, an optically active 1-(2-naphthylsulfonyl)-
pyrrolidine-2-carbonyl chloride. The acylation of the
compound (I') is carried out in the presence of an acid
acceptor ~e.g., sodium hydroxide, potassium hydroxide,
sodium carbonate, potassium carb3nate, sodium bîcabonate,
potassium bicarbonate) in a solvent (e.g., ethyl acetate,
methylene chloride, chloroform, benzene, water or a mixture
thereof) at a temperature of 0 to 30C. Subsequent chromato-
graphic separation of the (R)(R)- and (S~(S)-isomers of the
compound tV') and the removal of the acyl group therefrom
may be carried out in the same manner as mentioned hereinbefore.
Each one of (R)(S)- and (S)(R)-isomer of the compound (I')
may be obtained from the B-isomer of the compound (I~) in
the same manner as above.
On the other hand, the compound (I') which is
prepared from an optical isomer of the compound (II) or
(III) (YO- = a protected hydroxy) is a mixture of two optical
isomers thereof which are a pair of diastereoisomers. For
example, a mixture of (R)(R)- and (S)(R)-isomers of the
compound (I~) is obtained when the (R)-isomer of the compound
(II) or (III) (YO- = a protected hydroxy) is used as the starting

~L25~7.~


-- 10 --

compound, while a mixture of (R)(S)- and (S)(S)-isomers of
~he compound (I') is obtained when the (S)-isomer of the
compound (II) or (III) (YO- = a protected hydroxy) is used
as the star~ing compound. However, said mixture may be, if
required, separated into each of the two optical isomers of
the compound (I') prior to removal o~ the protecting group
(Y') therefrom. For example, each one of the (R)(R)- and
(S)(R)-isomers of the compound (I') may be obtained by
subjecting the compound (I') to fractional recrystallization;
or by acylating the compound (I') to give the compound (V),
subjecting the compound (V) to chromatography to separate it
into each of (R)(R)- and (S)(R)-isomers of the compound (V),
and then removing the acyl group therefrom. The fractional
recrystalli~ation is carried out by recrystallizing the
compound (I') from a solvent (e.g., methanol, ethanol,
isopropanol, water or a mixture thereof). The acylation of
the compound (I') the chromatographic separation and the
removal of the acyl group may be carried out in the same
manner as described hereinbefore. Each one of the (R)(S)-

and (S)(S)-isomers of the compound ~I') may be obtained in
the same manner as above.
Moreover, since the B-isomer (or ~-isomer) of the
compound (V) separated above can be readily converted into
the ~-isomer lor B-isomer) of the compound (I') the compound
(I') may be, if required, recovered exclusively in the form
of either the ~- or B-isomer thereof. For example, the


3L 25~3/`~7L~
- 11



conversion of the B-isomer of the compound (V) into the ~-isomer
of the compound lI') is carried out by treating said B-isomer
with thionyl chloride in a solvent (e.g., methylene chloride,
chloroform, benzene, toluene, tetrahydrofuran, dioxane or
dimethoxyethane) to give an ~-isomer of a compound of the
formula:



CH3
RCOOy~N/~ocH3


~ (VI)


Y'O H


wherein RCO- and Y'O- are the same as defined above, and
then removing the acyl group therefrom. The conversion of
the ~-isomer of the compound (V) into the ~-isomer of the
compound (1') may be carried out in the same manner as
above.
Furthermore, the optical isomer of the compound (V)
separated above can be readily convertecl into an optical
isomer of the compound (I') in which the asymmetric carbon
atom at the position of -CH(OH)- has the opposite configuration
from that of the former optical isomer. For example, the

conversion of the (S)(R)-isomer of the compound (V) into the
(R)(R)-isomer of the compound (I~) is carried out by treating
the compound (V) with thionyl chloride in a solvent (e.g.,
methylene chloride, chloroform, benzene, toluene, tetrahydro-




', '

5~
- 12 -



furan, dioxane or dimethoxyethane) to give the (R)(R)-isomer
of the compound (VI), and then removing the acyl group
therefrom. The conversion oP the (R)(R)-, (R)(S)- or
(S~(S)-isomer of the compound lV) into the (S)(R)-, (S)(S)-

or (R)(S)-isomer of the compound (I') . may be respectively
carried out in the same manner as above.
The starting compound (II) and (III) of the present
invention is a novel compound and can be prepared, for
example, by the steps of halogenating or oxidizing a compound
of the formula:



COCH3
~ (VII)
Y'


wherein Y'O- is the same as defined above, to give a compound
of the formula:



COCH2X COCH(OH)2
(VIII) or ~ ~ (IX)

~ N ~ O ~ N ~ O
Y'O H Y'o H



wherein X is halogen atom and Y'O- is the same as defined
above, reacting the compound (VIII) or (IX) with a compound
lS of the formula:




. .


.~ .

- 13 - 1 25 ~r~
IH3




H2N-CHCH24~oCH3 (X)

to give a compound of the formula:



CH3
N ~ oc~3
~ (II')


Y' H
or
CH
N ~ H3
~ (III')


Y'O H
wherein Y'O- is the same as defined above.



The compound of the formula (VII) to be used in the
above-mentioned process may be prepared, for example, by
oxidizing O-protected 5-ace~yl-8-hydroxyquinoline with 80 %

m-chloroperbenzoic acid in a solvent (e.g., chloroform,
methylene chloride, tetrahydrofuran, acetonitrile), and then
heating the resultant O-protected 5-acetyl-8-hydroxyquinoline
N-oxide in a solvent (e.g., acetic anhydride). Alternatively,
the compound (VII) may be prepared by introducing a protecting
group (Y') into 5-acetyl-8-hydroxycarbostyril (c~., Japanese


~ 14 --

patent publication (unexamined) No. 141879/1976) in a conven-
tional manner.
Halogenation of the compound IVII) is preferably
carried out in a so~vent (e.g., chloroform, methylene chloride,
tetrahydrofuran, methanol or a mixture thereoE) at 20 to
60C under stirring. Suitable examples of the halogenating
agent include N-bromosuccinimide, N-chlorosuccinimide,
bromine or chlorine.
On the other hand, oxidation of the compound (VII) is
preferably carried out at 20 to 100C in the presence of an
oxidizing agent (e.g., selenium dioxide) in a solvent (e.g.,
dioxane, tetrahydrofuran or an aqueous mixture thereof).
The reaction of the compound (VIII) or (IX) with the
compound (X) may be accomplished at 10 to 30C in a solvent
(e.g., d~methylsulfoxide, dimethylformamide, chloroform,
methanol, ethanol or a mixture thereof) under stirring.
Further, the removal of the protectinq group (Y') from the
compound (II') or (III') may be carried out in the same
manner as mentioned hereinbefore.
The compound or an acid addition salt thereof prepared
from the intermediate of formula (I) shows potent broncho-
dilating activity and long-lasting therapeutic effect thereof,
can produce selective stimulation of ~2-adrenoceptor and hence
is useful for treatment or prophylaxis of various chronic
obstructive pulmonary diseases such as bronchial asthma or
chronic bronchitis. For example, when estimated
by the use of isolated tracheal chains of




.

~;253~4
- 15 -


guinea pigs, the bronchodilating activity of 8-hydroxy-5
1-hydroxy-2-~N-(~lR)-2-(p-methoxyphenyl~-1-methylethyl)-
amino3ethyl3carbostyril of the present invention is about lO
and 100 times as strong as those of procaterol (chemical
name; 8-hydroxy-5-~1-hydroxy-2-(isopropylamino~butyl~carbostyril
hydrochloride hemihydrate, J. Med. Chem., 20(8), 1103(1977~)
and Isoproterenol (chemical name: 4-~1-hydroxy-2-~(1-methyl-
ethyl)amino~ethyl}-1,2-benzenediol hydrochloride), respectively.
Moreover, since the compound is characteri~ed by the
high potency ratio of the ~2-adrenoceptor stimulating action
to the ~1-adrenoceptor stimu~ating action such as positive
chronotropic action (e.g., increase in heart rate), said
compound of the invention has particulary high safety for
use as a bronchodilator. In addition, the toxicity of the
15 compound is considerably low.
The carbostyril derivative can be used for pharmaceuti-
cal use in the form of either the free base or an acid
addition salt thereof. Pharmaceutically acceptable acid
addition salts of the carbostyril derivative include, for
example, salts thereof with an inorganic acid such as hydrochlo-
ric acid, hydrobromic acid, phosphoric acid, nitric acid or
sulfuric acid, and an organic acid such as acetic acid,
propionic acid, glycolic acid, lactic acid, malic acid, fumaric
acid, malonic acid, succinic acid, aspartic acid, ascorbic
acid, glutamic acid, nicotinic acid or methanesulfonic acid.
Such pharmaceutically acceptable salts may be prepared, for


~2ssa7~
- 16 -
for example, by treating the free base of the compound with a
stoichiometrically equimolar amount of an acid.

The compound and a salt thereof can be administered
either orally or parenterally. The pharmaceutical preparation
of the compound may be either solid preparations such as
tablets, pills, powders~ capsules or granules, or liquid
preparations such as solutions, suspensions or ~mulsions.
Such preparations may be prepared in a conventional manner,
for example, by admixing a compound or a pharmaceutically
acceptable salt thereof ~ith a conventional carrier or
diluent such as calcium carbonate, calcium phosphate, corn
starch, potato starch, lactose, talc, and magnesium stearate.
The daily dose of the compound or a salt thereof may
vary depending on the administration route, the age, weight
or conditions of patients and the severity of diseases to be
treated. In general, however, a preferred dose of said
compound or a salt thereof may be 0.01 to 30~g, especially
0.01 to 3 ~g, per kilogram of body weight per day.
Practical and presently-preferred embodiments of the
present in~ention and the invention described in Canadian Patent
Application Serial No. 470,917 filed December 21, 1984 from
which the present application has been divided are illustratively
shown in the following Examples.


Experiment 1
(Bronchodilating activity)
Isolated tracheal muscle preparations of Male Hartley
guinea pigs (body weight: 430 - 645 g) were used to estimate




., ;. .: .

~L 2/5~3'3~L~

-- 17 --

the bronchodilating activity of a test compound according to
Magnus' method. The preparation was suspended in an organ
bath fillPd with 20 ml of Tyrode's solution (37C), and said
solution was continuously bubbled with air. Histamine 2HCl
5 was added to the bath (final concentration; 1 x 10 g/ml) and
the test compound was added thereto about 15 minutes after
the addition of histamine 2HCl. Tension changes in the
tracheal smooth muscle were recorded isometrically with a
force-displacement transducer. Molar concentration of the
test compound which produced 50 % relaxation of the histamine-
induced tracheal contraction were estimated from the
concentration-response curve, and the potency ratio of the
test compound to Isoproterenol was calculated therefrom.
The result are shown in Table 1.



Table 1


Test compounds Potency ratio

Comp. No. 1 166
Comp. No. 2 78
Comp. No. 3 52
Procaterol 17
Isoproterenol

Note; Comp. No. 1: 8-Hydroxy-5-~(lR)~l-hydroxy-2-~N-((lR)-2-(p-
methoxyphenyI)-l-methylethyl)amino]ethyl~-
carbostyril hydrochloride




:



. . .

- ~S~7~


Comp. No. 2: 8-Hydroxy-5-~l-hydrOxy-2-~N-(2-(p-methoxy-
phenyl)-l-methylethyl)amino~ethyl} carbostyril
hydrochloride (d~-isomer obtained in Example 3
mentioned hereinafter)
Comp. No. 3: 8-Hdroxy-5-{l-hydroxy-2--~N-t2-(p-methoxy-
phenyl)-l-methylethyl)amino~ethyl}carbostyril
hydrochloride (a mixture of ~- and ~-isomers)
Chemical name of procaterol : 8-Hydroxy-S-tl-hydroxy-2-
(isopropylamino)butyl~carbostyril
hydrochloride hemihydrate
Chemical name of Isoproterenol : 4-~l-hydroxy-2-~(l-
methylethyl)amino~ethyl}-l,2-benzenediol
hydrochloride.

Experiment 2
tMethod )
Inhibitory effect on antigen-induced bronchoconstriction
Male Hartley guinea pigs (body weight: 2$0 - 520 g)
were passively sensitized by intravenous injection of rabbit
antiserum against ovalbumin (0.2 ml/lO0 g of body weight,
PCA titer: x 10001. 24 hours later, the animals were
anesthetized with ~-chloralose (120 mg/kg. i.v.) and immobilized
with gallamine triethiodide (5 mg/kg, i.v.) under artificial
respiration. Lung volume changes were measured as overflow
of air from the lung by the Konzett-Rossler method (cf.
Arch. Exp. Pathol. Pharmakol., l95, 71 (1940)). The test
compound was administered intravenously to the animals one
minute before said animals were challenged with ovalbumin
lS (30 ~g/kg, i.v). The ED50 ~i.e., the dose of the test
compound which is necessary to produce 50 % reduction of
antigen-induced bronchoconstriction) was estimated from the
dose-response curve.




' ~,
,

lZ5~^~7~
-- 19 --

Acute toxic_ity
A test compound was dissolved in S % glucose solution,
and the test compound solution t0.2 ml/10 g of body weight)
was administered intra~enously to Male ddY strain mice (body
weight: 25 - 28 g). The LD50 of the test compound was
estimated by the Up and Down method.
(Results)
The results are shown in the following Table 2.



Table 2

.. ._ _ :
Inhibitory effect Acute Therapeutic
Test compounds* on antigen-induced toxicity index
bronchoconstriction ~LD 0)
(ED50) (,ug/kg) (mg/kg) (LD50/ED50)
. . _ ~
Comp. No. 1 0.09 84.6 9.4 x lo
Comp. No. 2 0.18 91.3 5.1 x 10
Procaterol 0.64 - 70.3 1.1 x 105



Note; * : same as shown in the footnote of Table 1.




Example 1
(1) 293 mg of 5-acetyl-8-benzyloxycarbostyril are

dissolved in 15 ml of chloroform, and 200 mg of N-bromo-
succinimide are added thereto. The mixture is refluxed for
2 hours under stirring. 300 mg of N-bromosuccinimide are

12S3.~,17
- 2û -



added to the mixture and 4 hours after the commencement of
the reaction, 100 mg of N-bromosuccinimide are further added
thereto. Six hours after the reaction is started, the
mixture is cooled and is allowed to stand at 20C for 2
5 days. Precipitated crystals are collected by filtration.
Then, the crystals are washed with methanol and ether and
then dried. 110 mg of 5-bromoacetyl-8-benzyloxycarbostyril
are thereby obtained as colorless crystals. On the other
hand, the filtrate is concentrated to dryness, and the
10 residue is treated in the same manner as above, whereby 60
mg o~ 5-bromoacetyl-8-benzyloxycarbostyril are further
recovered from the filtrate. Total yield: 170 mg (45.8 ~)
M.p. 203 - 205C (decomp.)
(recrystallized from methanol-chloroform)

Mass (m/e): 373, 371 (M )
IRI> nu~ol (cm~l) 1675


NMR (d6-DMSO) ~: 4.85(s 2H), 5.39(s, 2H), 6.65(d,
J-10 Hz, lH), 7.2 - 7.7(m, 6H),
7.86(d, J=9Hz, lE3),

8.51(d, J=10 Hz, lH)
(2) 750 mg of S-bromoacetyl-8-benzyloxycarbostyril
are dissolved in S ml of dimethylsulfoxide, and 660 mg of
N-(2-(p-methoxyphenyl)-1-methylethyl)amine are added thereto.
The mixture is stirred at room temperature for l.S hours,

25 whereby a mixture containing 8-benzyloxy-5-fl-oxo-2- CN (2-
(p-methoxyphenyl)-1-methylethyl)aminol ethyl~carbostyril is


~LZS~7~

- 21 -



obtained. 10 ml of methanol and 380 mg of sodium borohydride
are added to the mixture, and the mixture is further stirred
at room temperature for one hour. The reaction mixture is
extracted with chloroform, and the extract i5 washed with
water, dried and then evaporated under reduced pressure to
remove chloroform. The residue is purified by silica gel
chromatography ~solvent; chloroform : methanol = 9 : 1), and
then treated with an ethanol-hydrogen ~hloride solution.
The crude product thus o~tained is recrystallized from a
mixture of isopropanol and ether. 210 mg of 8-benzyloxy-
5-~1-hydroxy-2-~N-(2-(p-methoxyphenyl)-1-methylethyl)amino~-
ethyl}carbostyril monohydrochloride are obtained as colorless
crystals. (a mixture of ~- and ~-isomers) Yield: 21.2
M.p. 193 - 212C

Mass (m/e): 440 (M _ H2O)
IR ~ chloroform ( -1) 1660

(3) 495 mg of 8-~enzyloxy-5-{1-hydroxy-2-~N-(2-(p-
methoxyphenyl)-1-methylethyl)amino~ethyl}carbostyrll monohydro-
chloride are dissolved in a mixture of 26 ml of tetrahydro-furan
2Q and 4 ml of water, and 2S0 mg of 10 % palladium-charcoal are
added thereto. The mixture is stirred at room temperature
for 1.5 hours under a hydrogen atmosphere. After the
reaction, the mixture is filtered to remove catalyst, and a
10 ~ methanolic hydrogen chloride solution is added to the
filtrate. The mixture is concentrated under reduced pressure~

and the residue is recrystallized from a mixture of isopropanol




.

1 Z 5 ~ ~7L~



and ether. 350 mg of 8-hydroxy-5~ hydroxy-2-CN-(2-tp-
methoxyphenyl-1-methylethyl)amino3ethyl}carbostyril dihydro-
chloride are obtained as colorless crystals. ~a mixture of
~- and ~-isomers) Yield: 79.3 %
M.p. 143 - 154C (decomp.)
IR ~ max l (cm 1): 1640
Example ?
tl) 8.35 g of selenium dioxide are dissolved in 10
ml of water, and 250 ml of dioxane and 14.65 g of S-acetyl-8-
benzyloxycarbostyril are added thereto. ~he mixture is
refluxed for 24 hours under stirring. After the reaction,
300 ml of dioxane is added to the mixture, and the mixture
is filtered to remove inorganic materials. Inorganic
materials are washed with 200 ml of methanol and 200 ml of
15 dioxane. The filtrate and washings are combined and concent-
rated to a~out 200 ml under reduced pressure. 600 ml oP
water and 20 ml of 10 % hydrochloric acid are added to the
solution, and the solution is allowed to stand at 20C for 3
hours. Precipitated crystals are collected by filtration,
20 washed with isopropanol-ether and n-hexane and then dried.
14.97 g of 8-benzyloxy-5-(dihydroxyacetyl)carbostyril 1/3
hydrate are obtained. Yield: 88.5 ~ The product is
recrystallized from a mixture of dioxane and water to give
pale yellow needles.
M.p. 132 - 147C
IR ~ maU~ol (cm 1): 1655, 1682




:; .;.. ,.. ;, .. .. :
' .

~2~f~7~
23



(2) 993 mg of 8-benzyloxy-5-(dihydroxyacetyl)-
carbostyril 1/3 hydrate are dissolved in 10 ml of dimethyl-
sulfoxide, and 500 mg of N-(2-(p-methoxyphenyl)-1-methylethyl)-
amine are added thereto. The mixture is stirred at room
temperature for 2 hours, whereby a reaction mixture containing
8-benzyloxy-5-~1-oxo-2-~N-(2-(p-methoxyphenyl)-1-methylethyl)-
imino~ethyl~carbostyril is obtained. The reaction mixture
is ice-cooled, and 10 ml o~ methanol and 460 mg of sodium
borohydride are added thereto. The mixture is stirred at
room temperature for 2 hours. m e reaction mixture is
extracted with chloroform, and the extract is washed with
water and 10 ~ hydrochloric acid, dried and then evaporated
under reduced pressure. The residue is recrystallized from
a mixture of isopropanol and etherO 1010 mg of 8-benzyloxy-
5-{1-hydroxy-2{N-(2-(p-methoxyphenyl)-1-methylethyl)amino3-
ethyl~carbostyril monohydrochloride are obtained as colorless
crystals (a mixture of~ - and ~-isomers). Yield: 68 %
M.p. 193 - 212C
Mass(m/e): 440 (M -H20)
IR ~ chlorOform ( -l) 1660
(3) 8-Benzyloxy-S-~1-hydroxy-2-~N-(2-(p-methoxy-
phenyl)-1-methylethyl~amino~ethyl3carbostyril monohydrochloride
is treated in the same manner as described in Example 1-(3),
whereby 8-hydroxy-5-~1-hydroxy-2- [N- ( 2- (p-methoxyphenyl)-1-
25 methylethyl)amino]ethyl~carbostyril dihydrochloride is
obtained. (a mixture of a- and ~-isomers)


1 2~ Lit


- 24 -



Example 3
(l) 2.65 g o~ 8-benzyloxy-5-(dihydroxyacetyl)-
carbostyril 1/3 hydrate, 1.65 g of N-(2-(p-methoxyphenyl)-1-
methylethyl)amine, 30 ml of dimethylsufoKide, 760 mg of
5 sodium borohydride and 20 ml of methanol are treated in the
same manner as described in Example 2-(2l. Then, the
reaction mixture is extracted with ethyl acetate. The
extract is ice-cooled under stirring, and 300 ml o~ an
aqueous 3 % sodium hydroxide solution are added thereto. A
lO solution of 2.51 g of acetyl chloride in 10 ml of ethyl
acetate is added dxopwise to the mixture at S - 10C. The
mixture is stirred at room temperature overnight. The
ethyl acetate layer is washed with a saturated sodium bicarbonate
solution and a saturated sodium chloride solution successively,
15 dried and then evaporated under reduced pressure to remove
ethyl acetate. The residue is chromatographed on the
column of silica gel (solvent, chloroform : methanol = 30 :
1), whereby the ~- and B-isomers o~ 8-benzyloxy-5-~1-hydroxy-
2-~N-(2-(p-methoxyphenyl)-1-methylethyl)-N-acetylamino~ethyl}-
20 carbostyril are obtained, respectively.



U-isomer (i.e., a mixture of 8-benzylcxy-5-~(lR)-1-hydroxy-
2-[N-((lR)-2-(p-methoxyphenyl)-1-methylethyl)-N-
acetylamino3ethyl~carbostyril and 8-benzyloxy-S-

~(lS)-l-hydroxy-2-~N-(lS)-2-(p-methoxyphenyl)-1-
methylethyl)-N-acetylaminolethylscarbostyril)




... .

~2~ 7~

- 25 -

Yield: 640 mg (16 %), colorless needles
M.p. 177 - 180C (recrystallized from ethyl acetate)
Mass (m/e): 482 (M -H2O)
~ nu~ol (cm~l) 1640, 3260~ 3342
NMR (CDCl3) ~ : 1.28 ~d, J= 6.5 Hz, 3H), 1.82 (s,
3H), 2066 td, J= 6.5 Hz, 2H),
3.77(s, 3H), 5.19 (s, 2H),
6.6 - 7.4 (m, 7H), 7.4 (s, SH),
8.35 (d, J= 10.5 H~, lH)

lO ~-isomer (i.e., a mixture of 8-benzyloxy-5-~(lR)-l~hydroxy-
2-~N-((lS)-2-(p-methoxyphenyl)-1-methylethyl)-N-
acetylamino~ethyl~carbostyril and 8-benzyloxy-
5-~(lS)-1-hydroxy-2-~N-((lR)-2 (p-methoxyphenyl)-1-
methylethyl)-N-acetylamino3ethyl}carbostyril)

Yield: 1.805 g (45.1 %), colorless prisms
M.p. 162 - 163C (recrystallized from ethyl acetate)
Mass (m/e): 482 (M _H2O)
~ nu~ol (cm~l) 1665, 3160~ 3490
NMR (CDCl3) u~: 1.18 (d, J= 6.5 Hz, 3H), 1.91 (s,
3H), 2.5 - 2.8 (m, 2H), 3.76(s, 3H),
5.17 (s, 2H), 6.5 - 7.35 (m, 7H),
7.39 (s, 5H), 8.42 (d, J=10.5 Hz, lH)
(2 - a) 500 mg of 8-benzyloxy-5-~1-hydroxy-2-~N-
(2-p-methoxyphenyl-1-methylethyl)-N-acetyl aminoi ethyl} carbostyril

5~ ~,7~
- 26 -



(d-isomer) are added to a mixture of 15 ml of methanol and 6
g of an aqueous 5 ~ sodium hydroxide solution. The mixture
is refluxed ~or 5 hours under stirring. After the reaction,
the mixture is evapora~ed under reduced pressure to remove
methanol. The residue is acidified with 10 ~ hydrochloric
acid and extracted with chloroform. The ex~ract is washed
with water, dried and then evaporated under reduced pressure
to remove chloroform. The residue is xecrystallized from a
mixture of isopropanol and ether. 47Q mg of 8-benzyloxy-S-

{1-hydroxy-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)amino~ ethyl}-
carbostyril monohydrochloride ~-isomer) are obtained as
colorless needles. Yield: 95 %
M.p. 200 - 203C
Mass (m/e): 440 (M -~2)
IR ~ ~ol (cm ): 1652, 2350 - 2750, 3280, 3405
(2 - b) 750 mg of 8-benzyloxy-S-~1-hydroxy-2-LN-
(2-(p-methoxyphenyl)-1-methylethyl)-N-acetylamino~ethyl~-
carbostyril (~-isomer) are treated in the same manner as
described in paragraph (2-a). 680 mg of 8~benzyloxy-5-{1-

hydroxy-2-~N-(2-(p-methoxyphenyl)-1-methylethyl)amino3ethyl~-
carbostyril monohydrochloride (B-isomer) are obtained as
colorless needles. Yield: 91.6 ~
M.p. 217 - 219C (recrystallized from isopropanol-ether)
Mass (m/e): 440 (M -H2O)
IR ~ max (cm~1): 3290, 3400

1 ;25~r~7~
- 27 -



(3 - a) 247 mg of 8-benzyloxy-5-{l-hydroxy-2-[N-(2
(p-methoxyphenyl)-l-methylethyl3amino~ethyl3carbostyril
monohydrochloride (~-isomer) are dissolved in a mixture of 5
ml of tetrahydrofura~ and 1.5 ml of water, and 100 mg of 10
~ palladium-charcoal are added thereto. The mixture is
stirred at room temperature under a hydrogen atmosphere for
1 hourO After the reactionf the mixture is filtered to
remove catalyst, and 2 ml of a 10 % methanolic hydrogen
chloride solution is added to the filtrate. The mixture is
condensed under reduced pressure, and the residue is recrysta-

llized from a mixture of isopropanol and ether. 183 mg of
8-hydroxy-S~ hydroxy-2- ~N-(2- (p-methoxyphenyl)-1-methylethyl)-
amino~ethyl}carbostyril dihydrochloride-l/3 hydrate (~-isomer)

are obtained as colorless crystals. Yield: 82
M.p. 154 - 155C (decomp.)
IR ~ nu]ol (C -11 1638 3140 3330
NMR (D2O) ~ : 1.36 (d, J= 7 Hz, 3H), 2.92 (d, J= 8
Hz, 2H), 3.32 (d, J- 6 Hz, 2H),
3.77 (s, 3HI, 5.45 (5, J= 6 HZ, lH),
6.62 (d, J= 10 Hz, lH), 6.80 (d, J= 8

Hz, 2H), 6.95 (d, J= 8HZ, lH),

7.10 (d, J= 8 Hz~ 2H), 7. 20 (d,
J= 8 Hz, lH),
8.08 (d, J= 10 Hz, lH)




-; :

'

~l 2531rl7
- 28



Monohydrochloride:
colorless prisms
M.p. 213 - 216C ~decomp.) (recrystallized
from methanol-water)
(3 - b) 247 mg of 8-benzyloxy-5-~1-hydroxy-2-LN-

(2-(p-methoxyphenyl)-1-methylethyl)amino~ethyl}carbostyril
monohydrochloride (B-isomer) are treated in the same manner
as described in paragraph (3 - a). 175 mg o~ 8-hydroxy-5-
fl-hydroxy-2-~N-(2-(p-methoxyphenyl)-1-methylethyl)amino~ethyl3-
carbostyril dihydrochloride (B-isomer) are obtained as
colorless crystals. Yield: 79.5 ~
M.p. 161 - 163C (decomp.) (recrystallized from

isopropanol-ether)
~ nu~ol (cm~l) 1640, 3160, 3375

NMR(D2O) : 1.38 (d, J= 6Hz, 3H), 2.8 - 3.8 ~m,
5H), 3.7.7 (s, 3H), 5.40 (q, J 8 Hz,
S Hz, lH), 6.62 (d, J= 9 Hz, lH),
6.81 (d, J= 8 Hz, 2H), 6.96 (d, J= 8
Hz, lH), 7.11 (d, J= 8 Hz, 2H),
7.19 (d, J = 8 Hz, lH), 8.07 (d,
J= 9 Hz, lH )
Example 4
(1) 4.60 g of 8-benzyloxy-5-~1-hydroxy-2-~N-(2-(p-
methoxyphenyl)-1-methylethyl)amino~ethyl~carbostyril (~-isomer~
are dissolved in 300 ml of chloroform, and 300 ml of an

25 aqueous S ~ potassium carbonate solution are added thereto.

~Z~i3

-- 29 --

3.6 g of (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl
chloride are added dropwise to the mixture with stirring
under ice-cooling, ana the mixture is stirred at room
temperature for 2 hours. The chloroform layer is collected,
dried and then concentrated under reduced pressure to remove
solvent. The residue is chromatographed on the column of
silica gel (solvent, chlorofrm : methanol - 49 : 1), whereby
the following two compounds are obtained, respectively.
8-benzyloxy-5-l(lR)-1-hydroxy-2-~N-((lR)-2-(p-methoxy-

phenyl)-1-methylethyl)-N-((2S)-1-(2-naphthylsulfonyl)pyrrolidine-

2-carbonyl)amino]ethyl}carbostyril
Yield: 2~1 g (28.2 %), colorless caramel
IR ~ nu~ol (cm ) 3390, 1650, 1605

Mass (m/e): 727 (M ~ H2O)
8-benæyloxy-5-~(lS)-1-hydroxy-2-tN-((lS)-2-(p-methoxy-
phenyl)-1-methylethyl)-N-((2S)-1-(2-naphthylsulfonyl)pyrrolidine-
2-carbonyl)amino~ethyl}carbostyril
Yield: 2.2 of (29.5 %), colorless caramel
IR ~ max l (cm 1): 3390, 1650, 1605
Mass (m/e): 727 (M ~ H2O)
(2-a) 2.61 g of 8-benzyloxy-5-~lR)-1-hydroxy-2-tN-((lR)--
2-(p-methoxyphenyl)-1-methylethyl)-N-((2S) 1-f2-naphthylsulfonyl)-
pyrrolidine-2-carbonyl)amino~ethyl}carbostyril are dissol~ed
in 100 ml of methanol, and 35 ml of lN potassium hydoxide-methanol
and 10 ml of water are added thereto. The mixture is
refluxed for 3 hours with stirring. The mixture is concentrated


3 -- ~ 9!f~7~

under reduced pressure to remove solvent. The residue is
extracted with chloroform, and the extract is washed with 5
~ hydrochloric acid, dried and then concentrated under reduced
pressure to remove solvent. The residue is recrystallized
5 ~rom a mixture of isopropanol and water. 1.1 g of 8-benzyloxy-
S-{(1~)-1-hydroxy-2- ~N- ( ~ lR ) -2-(p-methoxyphenyl)-1-methylethyl)-
amino3ethyl}carbostyril hydrochloride are obtained as colorless
; prisms. Yield: 63.6 ~
M.p. 203 - 205C (decomp.)
lO Free base:
M.p. 130.5 - 132.5C
r~ D -45.31 (c = 1.05, methanol)
IR ~ mU~ol (cm 1): 3340, 3160, 1640
Mass (mte): 440 (M ~ H2O)
NMR (CDC13) C~ : 1.08 (d, J = 6.7 Hz, 3H), 2.5 - 3.0
(m, SH), 3.76 (s, 3H,), 4.~ - S.10 (m,
lH), 5.14 (s, 2H), 6.5 - 7.3 (m, 7H),
7.39 (s, SH), 8.0S (d, J = 9.6 Hz, lH)
(2-b) 2.61 g of 8-benzyloxy-S-~(lS)-1-hydroxy-2-~N-
20 ((lS)-2-(p-methoyphenyl)-1-methylethyl)-N-((2S)-1-(2-naphthyl-
sulfonyl)-pyrrolidine-2-carbonyl)amino]ethyl}carbostyril are
dissolved in 100 ml of methanol, and 35 ml of lN potassium
hydroxide-methanol and 10 ml of water are added thereto.
The mixture is refluxed for 3 hours with stirring. The
25 mixture is concentrated under reduced pressure to remove
solvent. The residue is extracted with chloroform, and the


1 ~,59,r~7~¦

- 31 -



extract is dried and concentrated under reduced pressure to
remove solvent. The residue is recrystallized twice from
ethyl acetate. 1.1 g of 8-benzyloxy-5-~(lS)-1-hydroxy-2-
~N-((lS)-2-(p-methoxyphenyl)-1-methylethyl)amino~ethyl~-

carbostyril are obtained as colorless needles. Yield: 68.8 %
M.p. 130.5 - 132C

~d~D ~ 40 9 (c = 1.0, chloroform)
~ nu~ol (cm~l) 3340, 3160, 1640

Mass (m/e): 458 (M ), 440 (M - H2O)
NMR (CDCl3) ~ : 1.08 (d, J = 6.7 Hz, 3H), 2.5 -
3.0 (m, 5H~, 3.76 (s, 3H), 4.8 -
5.10 (m, lH), 5.14 (s, 2H) 6.5 -
7.3 (m, 7~), 7.39 (s, 5H),
8.05 (d, J = 9.6 Hz, lH)
(3-a) A mixture of 3.5 g of 8-benzyloxy-5-{(lR)-1-
hydroxy-2-[N-((lR)-2-(p-methoxyphenyl)-1-methylethyl)amino]-
ethyl}carbostyril hydrochloride, 240 mg of 10 % palladium-
charcoal, 100 ml of tetrahydrofuran and 10 ml of water is
shaken at room temperature at an atmospheric pressure under
20 a hydrogen atmosphere for 2 hours. Insoluble materials are
collected by filtration and washed with an aqueous 10 %
ethanol solution. The filtrate and washings are combined,
and the combined solution is concentrated under reduced
pressure to remove solvent. The residue is crystallized
25 with a mixture of ethanol, water and isopropyl ether, and

crystalline precipitates are collected by filtration. 2.38


32 - ~3 37~

g of 8-hydroxy-5-~(lR)-1-hydroxy-2-[N-((lR)-2-(p-methoxyphenyl)-
1-methylethyl)amino]ethyl~carbostyril hydrochloride are
obtained as colorless crystals. Yield: 83 %
M.p. 170.0 - 171.5C (decomp.)
~D -64.40 (c = 1.00, methanol)
IR ~ maU~ 1 (cm 1)~ 3300 (broad), 1640, 1610, 1600
NNR ~D2O) ~ : 1.3S (d, J a 7Hz, 3H), 2.92 (d,
J = 8Hz, 2H), 3.32 (d, J = 6H2, 2N),
3.77 (s, 3H), 5.45 ~t, J = 6Hz, lH),

6.62 (d, J = lOHz, lH), 6.80 ~d, J =
8Hz, 2H), 6.95 (d, J = 8Hz, 1~), 7.10
(d, J = 8~z, 2H), 7.20 (d, 8Hz, 1~),
8.08 (d, J = lO~z, 1~)
(3-b) A mixture of 916 mg of 8~benzyloxy-5-f(lS)-1-
hydroxy-2-[N~ s)-2-(p-methoxyphenyl)-l-methylethyl)amino]
ethyl3carbostyri.1, 100 mg of 10 ~ palladium-charcoal, 2 ml
of lN hydrochloric acid and 20 ml of tetrahydrofuran is
shaken at room temperature at an atmospheric pressure under
a hydrogen atmosphere for 2 hours. Insoluble materials are
collected by filtration and washed with an aqueous 10 ~
ethanol solution. The filtrate and washings are combined,
and the combined solution is concentrated under reduced
pressure to remove solvent. The residue is crystallized
with a mixture of methanol and ether, and crystalline
25 precipitates are collected by filtration. 623 mg o~ 8-
hydroxy-5-~(lS)~1-hydroxy-2-~N-((lSj-2-(p-methoxyphenyl)-1




, . . ..

~L25~ 7

- 33 -



methylethyl)amino)ethyl~carbostyril hydrochloride are obtained
as colorless crystals. Yield: 77 %
M.p~ 166 - 167C (decomp.)

~ D + 65.5 tc = 1.0, methanol)
I~ ~ u~ l (cm l): 3390, 3320, 1640, 1610, 1600
The Mass and NMR data of this product are identical
with those of the product obtained in the above-mentioned
paragraph (3-a).
Example 5
(1) 330 mg of 8-benzyloxy-5-(dihyroxyacetyl1carbostyril
1/3 hydrate, 165 mg of (R)-N-(2-(p-methoxyphenyl)-1-methyl-
ethyl)amine, 7 ml of dimethylsulfoxide, 7 ml of methanol and
38 mg of sodium borohydride are treated in the same manner
as descri~ed in Example 2-(2) except that the reduction
15 reaction is conducted at 0 to 10C. Then, the reaction
mixture is extracted with ethyl acetate. The extract is
washed with water, dried and then concentrated under reduced
p~essure to remove solvent. 10 ml of ethyl acetate and 10
ml of an aqueous 10 % potassium carbonate solution are added
20 to the residue, and 0.5 ml of acetyl chloride are added to
the mixture with stirring under ice-cooling. The mixture
is stirred at the same temperature for 30 minutes. The
ethyl acetate layer is collected and washed with water and a
saturated sodium chloride solution, successively. The
25 ethyl acetate solution is dried and concentrated under
reduced pressure to remove solvent. The residue is chromato-




. ~
,
.

7~
- 34 -



graphed on the column of silica gel (solvent, methanol :
chloroform = 1 : 19), whereby the following two compounds
are obtained, respectively.
8-benzyloxy-5-{(lR)-1-hydroxy-2-[N-((lR)-2-(p-methoxy-
5 phenyl)-1-methylethyl)-N-acetylamino3ethyl}carbostyril
Yield: 50 mg (10 ~), colorless caramel
Mass ~/e): 482 (M -H2O)
8-benzyloxy-5-~(lS)-1-hydroxy-2-~N ((lR)-2-(p-methoxy-
phenyl)-1-methylethyl)-N-acetylaminolethyl}carbostyril
Yield: 410 mg (82 %), colorless carmel
Mass (m/e): 482 (M -~2)
(2) 8-benzyloxy-5-~(lR)-1-hydroxy-2-~N-((lR)-2-(p-
methoxyphenyl)-1-methylethyl~-N-acetylamino3ethyl}carbostyril
is treated in the same manner as described in Example 3 -

(2-a) and (3-a), whereby 8-hydroxy-5-~(lR)-1-hydroxy-2-~N-
((lR)-2-(p-methoxyphenyl)-1-mthylethyl)amino~ethyl~carbostyril
hydrochloride is obtained.
Example 6
8-benzyloxy-5-~(lR)-1-hydroxy-2-~N-((lR)-2-(p-methoxy-
20 phenyl)-1-methylethyl)-N-(p-nitrobenzoyl)amino~ethyl3carbostyril
is obtained in the same manner as described in Example 5 -
(1). A mixture of 3.7 g of 8-benzyloxy-5-i(lR)-l-hydroxy-2-
~N-((lR)-2-(p-methoxyphenyl)-1-methylethyl)-N-(p-nitrobenzoyl)-
amino~ ethyl~carbostyril, 100 ml of 96 ~ potassium hydroxide-

25 ethanol and 10 ml of water is refluxed for one hour understirring. The mixture is concentrated under reduced pressure


/

~2~
- 35 -



to remove solvent. The residue is extracted with chloroform,
and the extract is washed with water, 10 ~ hydrochloric acid
and a saturated sodium chloride solution, successively.
The chloroform solution is dried and concentrated under
reduced pressure to remove solvent. The residue is recrystal-
lized from an aqueous 10 % isopropanol solution. 1.85 g of
8-benzyloxy-5-~(lR)-1-hydroxy-2-~N-((lR)-2-(p-methoxyphenyl)-
1-methylethyl)amino~ethyl~carbostyril hydrochloride are
obtained as colorless prisms. Yield: 65 ~
The physico-chemical properties of this product are
identical with those of the product obtained in Example
4-(2-a).
(3) 8-bezyloxy-S- t ( lR~-1-hydroxy-2-~N-((lR)-2-(p-
methoxyphenyl)-1-methylethyl)amino3ethyl~carbostyriI hydrochloride
15 is treated in the same manner as described in Example 4 -

(3-a), whereby 8-hydroxy-5-~(lR)-1-hydroxy-2-~N-~(lR)-2-(p-
methoxyphenyl)-1-methylethyl)amino3ethyl~carbostyril hydrochloride
is obtained.
Example 7
(1) 10 g of 8-benzyloxy-S-(dihydroxyacetyl)carbostyril
1/3 hydrate, S g of (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine,
100 ml of dimethylsulfoxide, 100 ml of methanol and lulS g
of sodium borohydride are treated in the same manner as
described in Example 2 - (2). Then, the reaction mixture
25 is extracted with ethyl acetate. The extract is concentrated
under reduced pressure to remove solvent. 250 ml of ethyl


~ 5'~7~
- 36 -



acetate and a slution of 8.36 g of potassium carbonate in 70
ml of water are added to the residue, and 3.76 g of chloroacetyl
chloride are added aropwise thereto at 5 to 7C under stirring.
The ethyl acetate layer is collected and washed with water
and a saturated sodium chloride solution, successively.
The ethyl acetate solution is dried and concentrated under
reduced pressure to remove solvent. The residue is dissolved
in 80 ml of hot methanol, and the solution is allowed to
stand at room temperature. Crystalline precipitates are
collected by filtration. 10.2 g of 8-benzyloxy-5-~lS)-1-
hyroxy-2-~N-((lR)-2-(p-methoxyphenyl)-1-methylethyl~-N-chloro-
acetylamino~ethyl}carbostyril hemihydrate are obtained as
colorless needles. Yield: 61.9 %
M.p. 109 - 114C
Mass ~m/e): 516 (M -H2O)
~D -106.83 (c = 1.02, chloroform)
(2) 7.12 g of 8~benzyloxy-5-~(lS)-l-hydroxy-2-~N-
((lR)-2-(p-methoxyphenyl)-1-methylethyl)-N-chloroacetylamino~-
ethyl}carbostyril hemihydrate are dissolved in a mixture of
70 ml of chloroform and 70 ml of methanol, and the solution
is concentrated under reduced pressure to remove solvent.
The residue is dissolved in 70 ml of methylene chloride, and
2.38 g of thionyl chloride are added thereto at 5 to 7C.
The mixture is stirred at the same temperature for one hour.
Then, the mixture is concentrated under reduced pressure to
remove solvent. The residue is dissolved in 70 ml of


~25~7~
- 37 -



dioxane, and 15 ml of water are added thereto at room temperature.
The mixture is stirred at the same temperature for one hour.
A solution of 9.3 g o 96 ~ potassium hydroxide in a mixture
of 50 ml of water and 50 ml of methanol is added to the
5 mixture, and the mixture is stirred for 20 minutes. The
mixture is concentrated under reduced pressure to remove
solvent. The residue is extracted with ethyl acetate, and
the extract is washed with water and a saturated sodium
chloride solution, successively. The ethyl acetate solution
lO is dried and concentrated under reduced pressure to remove
solvent. The residue is recrystallized from a mixture of
ethyl acetate and benzene. 4.13 g of 8-benzyloxy-5-{~lR)-1-
hydroxy-2-~N-(tlR)-2-(p-methoxyphenyl)-1-methylethyl)amino~-
ethyl}carbostyril are obtained as colorless needles.
15 Yield: 67.7 %
The physico-chemical properties of this product are
identical with those of the product obtained in Example 4
- ~2-a).
(3) 8-benzyloxy-5-~(lR)-1-hydroxy-2-~N-((lR)-2-(p-
20 methoxyphenyl)-1-methylethyl)amino3ethyl}carbostyril is
treated in the same manner as described in Example 4 -
(3-a), whereby 8-hydroxy-S-~(lR)-1-hydroxy-2-~N-((lR)-2-(p-
methoxyphenyl)-1-methylethyl)amino]ethyl~carbostyril is
obtained.




:

125~
-- 38 --



Example 8
(1) 2 g of 8-benzyloxy-5-{1-hydroxy-2- [N-(2-(p-
methoxyphenyl)-l-methylethyl)-N-acetylamino~ ethyl}carbostyril
(B-isomer) are dissolved in 25 ml of methylene chloride, and
5 960 mg of thionyl chloride are added thereto at 5 to 10C.
The mixture is stirred at 10 to 15C for one hour. l~en,
the mixtllre is concentrated under reduced pressure to remove
excess thionyl chloride and methylene chloride. The residue
is dissolved in 80 ml of water, and the solution is allowed
10 to stand at room temperature for 4 hours. The solution is
concentrated under reduced pressure to remove water. The
residue is crystallized with a mixture of water and tetrahydro-
furan~ and the resultant crystals are recrystallized from a
mixture of methanol, chloro~orm and ether. 1.6 g of 8-

15 benzyloxy-5~ acet~xy-2- ~N-(2-(p-methoxyphenyl)-1-methylethyl)-

amino~ ethyl} carbostyril (C(-isomer) hydrochioride-methanol
are obtained as colorless prisms. Yielcl: 70.3 96
M.p. 175 - 178C (decomp.)
~lass (m/e): 501 (M + 1) , 500 (M ), 499 (M - 1)
440 (M, -cH3cooH)
IR )~ mU~l (Cm ): 3350, 2400 - 2150, 1740, 1673
Free base:
NMR(CDCl3)~: 1.08 (d, J = 6.5Hz, 3H), 1.94 (s,
3H), 2.4 - 3.3 (m, 5H), 3.74 Is, 3H),
5.14 (s, 2H), 6.14 (q, J = 5.8Hz, lH),
6.6 - 7.1 ~m, 7H), 7.26(s, 5H~, 8.06

(d, J = 10Hz, lH),

~25~

- 39 -



l21 0.5 g of 8-benzyloxy-5-{1-acetoxy-2-~N-(2-tp-
methoxyphenyl~-l-methylethyl)amino~ethyl~carbostyril (~-isomer)
hydrochloride.methanol is dissolved in a mixture of lO ml of
methanol and 2 ml of water, and 180 mg of triethylamine are
5 added thereto. The mixture is refluxed for 5 hours under
stirring. The mixture is concentrated under reduced pressure
to remove solvent. The residue is extracted with chloro~orm,
and t~e extract is washed with 5 ~ hydrochloric acid. The
chloroform solution is dried and concen~rated under reduced
10 pressure to remove solvent. The residue is recrystallized
from a mixture of isopropanol and ether. 365 mg o~ 8-benzyloxy-
5-~1-hydroxy-2-~N-(2-(p-methoxyphenyl)-1--methylethyl)amino~ethyl} -
carbostyril (~-isomer) hydrochloride are obtained. Yield:
86.1 %
The physico-chemical properties of this product are
identical with those of the product obtained in Example 3 -
(2-a).
(3) 8-benzyloxy-5-{1-hydroxy-2-[N-(2-(p-methoxy-
phenyl)-L-methylethyl)amino~ethyl}carbostyril(~-isomer~
20 hydochloride is treated in the same manner as described in
Example 3 - (3-a), whereby 8-hydroxy-5-~L-hydroxy-2-~N-(2-(p-
methoxyphenyl)-1-methylethyl)amino~ethyl}carbotyril (~-isomer)
hydrochloride is obtained.
_xample 9
(1) 100 mg of 8-benzyloxy-5-{1-hydroxy-2-~N-2-(p-
methoxyphenyl)-l-methylethyl)-N-acetylamino)ethyl~carbostyril

125~7~

- 40 -



(B-isomer) are dissolved in 2 ml of methylene chloride, and
35.7 mg of thionyl chloride are added thereto under ice-cooling.
The mixture is stirred for 15 minutes. After the reaction,
the mixture is concentrated under reduced pres sure. 4 ml
5 of dioxane are added to the residue. The mixture is ice-cool~d
and 75 mg of potassium acetate are added thereto. The
mixture is stirred at room temperature for 15 minutes. 40
mg of sodium hydroxide are added to the mixture, and the
mixture is stirred at room temperature for O.S hour. After
10 the reaction, the mixture is extracted with ethyl acetate.
5 ml of an aqueous 5 ~ sodium hydroxide solution are added
to the organic layer. The mixture is stirred under cooling
and treated with 45 mg of acetyl chloride. After the
reaction, the organic layer is collected, washed with water,
15 dried and then evaporated under reduced pressure to remove
ethyl acetate. The residue is recrystallized from ethyl
acetate. 80 mg o~ 8-benzyloxy-5-{1-hydroxy-2-tN-(2-(p-methoxy-
phenyl) 1-methylethyl)-N-acetylamino~ethyl~carbostyril (~-isomer)
are obtained as colorless needleds. Yield: 80
M.p. 177 ~ 180C
IR-spectrum and Rf-value of the product are identical
with those of the product obtained in Example 3 - (1).
(2) 8-Benzyloxy-5-~1-hydroxy-2-~N-(2-(p-methoxyphenyl)~
1-methylethyl)-N-acetylamino3ethyl~carbostyril (~-isomer) is
25 converted to the corresponding B-isomer in the sa~e manner
as described above.


~Z5~17l~



Example 10
(l) 10.84 g o~ 8-benzyloxy-S-(dihydroxyacetyl)-
carbostyril 1/3 hydrate and 5.66 g o~ N-(2-(p-methoxyphenyl)-
l-methylethy)amine are dissolved in lO0 ml of dimethylsulfoxide,
5 and the solution is stirred at room ~emperature for one
hour. The mixture is extracted with chloroform, and the
extract is washed with water and a saturated sodium chloride
solution, successLvely. m e chloro~orm solution is dried
and concentrated under reduced pressure to remove solvent.
10 The residue is crystallized with a mixture o~ ethyl acetate
and n-hexane, and crystalline precipitates are collected by
filtration. 13 g of 8-benzyloxy-5-~1-oxo-2-~N-(2-(p-methoxy-
phenyl~-l-methylethyl)imino~ethyl}carbostyril are obtained
as yellow solid. Yield: 87.6
M.p. 151 - 152C
Mass (m/e): 454 ~M )
IR ~ maUxol ~cm ): 1660, 1650
NMR~CDC133 ~: 1.32 (d, J = 7Hz, 3H), 2.8 - 2.9 ~m,
2H), 3.77 ~s, 3H0, 5.24 ~s, 3H), 6.70
and 8.58 ~lH each, d, J = lOHz), 6.79
and 7.04 ~2H each, d, J a 9Hz), 6.91
and 7.36 (lH each, d, J = 9Hz), 7.40
~s, SH), 7.78 ~s, lH)
(2) 8-benzyloxy-5-{1-oxo-2-~N-~2-(p-methoxyphenyl)-
25 1-methylethylJimino3ethyl}carbostyril is treated in the same
manner as described in Example 2 - (2) and (3), whereby




, .,

~253~?7~ .
- 42 -



8-hydro~r5-~l-hydroxy-2-[N-(2-(p-methoxypheny~ -methylethyl)
amino ethyl carbostyril is obtained. (a mixture of ~- and
~-isomers)
Example 11
(lj One g of 8-benzyloxy-5-(dihydroxyaCetYl)carbostyri
1/3 hydrate and 520 mg of (R)-~-(2-(p-methoxyphenyl)-1-methyl-
ethyl)amine are dissolved in 10 ml of dimethylsuloxide, and
the solution is stirred at room temperature ~or one hourO
After the reaction is completed, the mixture is treated in
10 the same manner as described in Example 10 - (1). 1.06 g
of 8-benzyloxy-5-{1-oxo-2-~N-((lR)-2-(p-methoxyphenyl)-1-methyl-
ethyl)imino~ethyl~carbostyril are obtained as pale yellow
scalesO Yield: 75 ~
M.p. 114 - 116C
~d]20 _97,50 (c = 1.06, methanol)
IR~maUx 1 (cm 1): 1670, 1625
The Mass and NMR data of this product are identical
with those of the product obtained in Example 10 -(1).
(2) 8-benzyloxy-S-{1-oxo-2-~N-((lR)-2-(p-methoxy-
20 phenyl)-1-methylethyl)imino~ethyl~carbostyril is treated in
the same manner as described in ~xample 2 - (2) and Example
5, whereby 8-hydroxy-S-{(lR)-1-hydroxy-2-[N-(~lR)-2-(p-methoxy-
phenyl)-1-methylethyl)amino3ethyl}carbostyril hydrochloride
is obtained.


~L 2r~;~?,rs~
- 43 -



Example 12
(1~ A solution o~ 1.65 g of (R)-N-(2-(p-methoxyphenyl)
methylethyl)amine in 5 ml of dimethylsulfoxide is added to a
solution of 3.3 g of 8-benzyloxy-5-(dihydroxyacetyl)carbostyril
1/3 hydrat~ in 45 ml of dimethylsulfoxide, and the mixture
is stirred at room temperature for 30 minutesO 60 ml of
methanol are added to the mixture under ice-cooling, and
0.39 g of sodium borohydride is added thereto at 5 to 10C.
The mixture is stirred at the same temperature for 15
minutes. The mixture is concentrated under reduced pressure
to remove solvent. The residue is extracted with ethyl
acetate, and the extract is washed with water and a saturated
sodium chloride solution, successi~ely. The ethyl acetate
solution is dried and concentrated under reduced pressure to
remove solvent. The residue is converted to its hydrochloride,
and the hydrochloride is crystallized with a mixture o~
isopropanol and and ethyl acetate. The resultant crystals
are recrystallized 3 times from ethanol. 2.28 g of 8-benzyloxy-
5-~(lS)-1-hydroxy-2- CN- ~ ( lR)-2-(p-mehoxyphenyl)-1-methylethyl~-

amino~ethyl~carbostyril hydrochloride 1/3 ethanol hemihydrateare obtained as colorless needles. Yield: 46 %
M.p. 164.5 - 167C
C~DO + 9 60 (c - 1.0, methanol)
Mass (m/e): 440 (M -H2O))

IR ~ nujol Icm~1): 3405, 3350, 3200, 2740 - 2450,
1650, 1605
.




'' "'' ~` :-

5~ 3

- 44 -



MMR(d6-DMSO) :1.15 (d, J = 8Hz, 3H), 2.4 - 2.8 (m,
2H, 2. 82 - 3.9 (m, 4H), 3.72 (s, 3H), 4~36
(broad s, lH~, 5.33 (s, 2H), 6.58 (d, J
= lOHz, 1~), 6.86 (d, J = 9Hz, 2H),
7.14 td, J = 9Hz, 2~), 8.36 ~d, J =
lOHz, 1~), 6.8 - 7.7 (m, 7H)
(2, 8-benzyloxy-5-{(lS)-1-hydroxy-2-~N-~(lR)-2-(p~
methoxyphenyl)-l-methylethyl)amino]ethyl~carbos~yril hydrochloride
is treated in the same manner as described in Example 4 -
(3-a), whereby 8-hydroxy-5-~(lS~-1-hydroxy-2-~N-((lR)-2-(p-methoxy-
phenyl)-1-methylethyl~amino~ethyl¦carbostyril is obtained.
Example 13
(1) A solution of 7.8 g of bromine in 30 ml of
methylene chloride is added dropwise to a refluxing solution
15 of 13 g of 5-acetyl-8-benzyloxycarbostyril and 7.56 g of boron
trifluoride etherate in 170 ml of methylene chloride,and the
mixture is refluxed for 30 minutes under heating. The mixture
is concentrated under reduced pressure to remove solvent.
The residue is made alkaline with an aqueous 10 % potassium
20 carbonate solu~ion,.and the resultant precipitates are collected
by filtration. The crystals are recrystallized from a mixture
of chloroform and methanol. 12.51 g of 5-bromoacetyl-8-
benzyloxycarbostyril are obtained as pale yellow needles.
~ield: 75.7 ~


~LZ~ 3 ~7L~

- 45 -

The physico-chemical properties of this product are
identical with those of the product obtained in Example 1 -
(1) .
(2) A mixture of 3.72 g of 5-bromoacetyl-8-benzyl-
S oxycarbostyril, 3~3 g of N-(2-(p-methoxyphenyl)-1-methylethyl)-
amine, 2.6 g of sodium bicarbonate, 10 ml of methylPne
chloride and 2 ml of dimethylformamide is refluxed for 30
minutes under stirring. The mixture is concentrated under
reduced pressure to remove solvent. The residue is extracted
with chloroform, and the extract is washed with 10 ~ hydrochloric
acid, dried and then concentrat~d under reduced pressure to
remove solvent. The residue is rcrystallized form a mixture
of ethanol and isopropanol. 3.53 g o~ 8-benzyloxy-5~ oxo-
2-~N-(2-(p-methoxypheyl)-1-methylethyl)amino3ethyl~carbostyril
15 hydrochloride are obtained as colorless needles. Yield:
71.6 %
M~p. 201.5 - 208C (decomp.)
Mass ~m~e): 456 (M ), 335, 121
IR ~ axl (cm ): 3380, 1690, 1660
(3) 8-benzyloxy-S-~1-oxo-2-~N-(2-(p-methoxyphenyl)-1-
methylethyl)amino3ethyl~carbostyril hydrochloride is treated
in the same manner as described in Example 1 - (2) and ~3),
whereby 8-hydroxy-5-{l-hydroxy-2-~N-(2-(p-methoxyphenyl)-l-
methylethy~amino~ethyl~carbostyril dihydrochloride is obtained.
(a mixture of ~- and B-isomers)

lL2~9! ~74~

- ~6 -

(Preparation of Starting Compounds)

Preparation 1
(lJ 27 g of 5-acetyl-8-hydroxyquinoline hydrochloride
are dissolved in 540 ml of anhydrous dimethylformamide and
50 g of powdered potassium carbonate are added thereto.
18.4 g of ~enzyl chloride are added to the mixture at 50C
under an argon atmosphere, and the mixture is stirred at the
same temperature fox 4.5 houxs and then further stirred at
room temperature for 1.5 hours. After the reaction, water
is added to the mixture, and the aqueous mixtùre is extracted
with ethyl acetate. The extract is washed with water, a
saturated sodium chloride solution, dried and then evaporated
under reduced pressure to remove ethyl acetate. The residue
is recrystallized from ethanol. 19.1 g of 5-acetyl-8-benzyl-
oxyquinoline are obtained as brownish prisms. 6.35 g ofsaid product are further recovered from the mother liquor.
Total yield: 25.S g (76.1 %) M.p. 131 - 133C
t2) 5 g of 5-acetyl-8-benzyloxyquinoline are
dissolved in 50 ml of chloroform. The solution is ice-cooled
and 3.12 g of 80 % m-chloroperbenzoic acid are added thereto
under stirring. The mixture is stirred at room temperature
for 24 hours and at 50C for 7.5 hours. The mixture is
then stirred at room temperature for 64 hours. 2 g of 80 %
m-chloroperbenzoic acid are further added to the mixture
during the reaction. After the reaction, chloroform is

31 2~r~7,~
- ~7 -



added to the mixture. The mixture is washed with water, a
4 ~ sodium bicarbonate solution and a saturated sodium chloride
solution, dried and then evaporated under reduced pressure
to remove chloroform. 5-Acetyl-8-benzyloxyquinoline-N-oxide
is obtained as yellow solid.
M.p. 136.5 - 137.5C (recrystallized from acetone)
The yellow product obtained above is dissolved in 60
ml of acetic anhydride, and the solution is stirred at 100C
for 8.5 hours. After the reaction, the mixture is evaporated
under reduced pressure and the residue is recrystallized
from methanol. l.9S g of 5-acetyl-8-benzyloxycarbostyril
are obtained as pale brownish prisms. 1.06 g of said
product is further re¢overed from the mother liquor. Total
yield: 3.01 g (56.8 %) M.p. 174 - 176C
PreParation 2
15.23 g of S-acetyl-8-hydroxycarbostyril and 15.7 g
of benzyl chloride are added tO a mixture of 200 ml of
acetone and 90 ml of water, and 10.35 g of potassium carbonate
are added thereto. The mixture is refluxed for 12 hours
under stirring. Then, the mixture is evaporated under
reduced pressure to remove acetone, and the residue is
extracted with chloroform. The extract is washed with
water, dried and evaporated under reduced pressure to remove
chloroform. The residue is recrystallized from a mixture
of ethyl acetate and n-hexane. 10.14 g of 5-acetyl 8-benzyl-
oxycarbostyril are obtained as prisms. 1.58 g of said

~ZS9~374
- 48 -

product are further recovered from the mother liquor.
Total yield: 11.72 g (53.3 ~)
Preparation 3
(1) 19.3 g of ~-methyltX-nitro-p-methoxystyrene
are dissolved in a mixture of 180 ml of methanol and 60 ml
of tetrahydrofuran, and 11.4 g of sodium borohydride are
added thereto under ice-cooling. The mixture is stirred at
room temperature overnight. 3 g of 10 ~ palladium-charcoal
and 30 ml of methanol, are added to the mixture, and the
mix~ure is shaken at rcom temperature at an atmospheric
pressure under a hydrogen atmosphere for 9 hours. Insoluble
materials are filtered off, and the filtrate is concentrated
under reduced pressure to remove solvent. The residue is
extracted with chloroform, and the extract is dried and concentrated
under reduced pressure to remove solvent. 15.5 g of N-(2-(p-
methoxyphenyl)-1-methylethyl)amine are obtained as colorless
oil. Yield: 94.4 % B.p. 110 - 115C/5 mm~g
(2) 81.7 g of N-(2-(p-methoxyphenyl)-1-methylethyl)-
amine and 150 g of (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-
carboxylic acid are dissolved in 1000 ml of methanol and thesolution is concentrated under reduced pressure to remove
methanol. The residue is recystallized twice ~rom a mixture
of ethyl acetate and isopropanol (1 : 1), ow e from isopropanol,
twice from a mixture of isopropanol and ethanol (1 : 1) and
then from a mixture of isopropanol and ethanol (1 : 2).
57.56 g of a salt of (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)-


~L,25~1

- 49 -



amine with [s)-1-(2-naphthylsulfonyl)Pyrrolidine-2-carboxyilic
acid are obtained as colorless needles. M.p. 163.5 - 167C
The above-obfained salt ~57.56 g) is converted to its
free base by using an aqueous potassium carbonate, and the
free ~ase is distilled under reduced pressure. 14.22 g o~
tR)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine are obtained
as colorless oil. Yield: 35 % B.p. 90-95C/2 mmHg
Hydrochloride:
M.p. 252 - 254C (decomp.)
[~ D -23.2 (c = 2.0, water)




:..,....,..,. .:-

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Administrative Status

Title Date
Forecasted Issue Date 1989-09-05
(22) Filed 1984-12-21
(45) Issued 1989-09-05
Expired 2006-09-05

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1988-03-29
Owners on Record

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Current Owners on Record
TANABE SEIYAKU CO., LTD.
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 1993-09-08 1 12
Claims 1993-09-08 2 29
Abstract 1993-09-08 1 11
Cover Page 1993-09-08 1 20
Description 1993-09-08 49 1,626