Note: Descriptions are shown in the official language in which they were submitted.
~3~
Our Ref.: NC-107
DIHYDROPYRI~INE-5-PHOSPHONIC ACID CYCLIC EST~R
The present invention relates to optically active
1,4-dihydropyridine-5-pho~phonic acid derivatives having
vasodilation activities and pharmaceutically accep-table
salts thereof.
A compound having the formula:
NO2
GH3 ~
O ¦¦ ~ CO~CIIzC~ C~( ~ ) (I)
CH3 H CH3
.. ....
(hereinafter referred to as Compound (I)) is disclosed in
U.S Patent 4,576,934 (hereinafter referred to as Reference
(a~).
Compound (I) has e~cellent characteristics such -that
it gradually reduces the blood pressure without
substantially affecting the heart rate, and yet such
action lasts for a long perlod of time. lLecture No. A-9,
delivered on October 13, 1985 at the 73rd Meeting of Kanto
~k
~3~
Divislon of Nippon Pharmacological ~ssocia-tion
(hereinafter referred to as Reference (b))]
Compound (I) has -three asymmetric carbon atoms, and it
should have optical and stereo isomers. However, the
above-mentioned References (a) and (b) disclose nothing on
such isomers.
As Compound (I) has three asymme-tric carbon atoms,
eight optical isomers are expected -to exist. The present
inventors have synthesized two isomers a~ong them by using
the meso isomer (the R,S isomer) and the dl mixture (a
mixture of the R,R isomer and the S,S isomer) o:E
2,4-pentanediol as -the starting material, and have tested
them for their pharmacological activities, whereby it has
been found that only the isomer of the formula (II)
prepared from the meso isomer has a strong negative
activity for cardiac muscle.
C~13
~ .
r O H
<, ~ ~ ~ >
~01{
CH3 meso isomer
,~ ' .
NOz
/
Cl13 H C113 (II)
:9~3~
--3--
In the above formula (II), the two methyl groups at 4-
and 6-positions of the dioxaphosphorinane ring assume cis
configurations to each other.
GH3 CH3
OH or ~ 011 ? ~ , >
OH OH
CH3 CHs
dl mixture
NO2
C1i3 ~
~ C O ~ C a: C N 2 N~ ,~N C II(~)
2~C Q
C113 / N
CH3 H CH3
lIII)
In the formula (III), the two methyl groups at 4- and
6-position of the dioxaphosphorinane ring assume trans
configurations to each other. ~ :
Then, with an aim to obtain a superior pharmaceutical
product, the present invento.rs have prepared all -the
:
optical isomers of the dl m1xture, then:subjected them to
: resolution, and tested them for their pharmacological
; : activities, whereby it has been found that, as wilL be
apparent from the pharmacolog1cal test results given
: hereinafter, levo-rotatory isomers of the formulas (V) and
~ ~ (VIII) exhibit remarkably superior effects as compared
;~ .
~3~ L4~
with dextro-rotatory isomers of the formulas (VI) and
(IX). The present invention has been accomplished on the
basis o~ this discovery.
CH3
-
R ~ OH
R~ 0~1
CH3
: R,R isomer
NO2
) ~ ( O 2 C~ ~ C1I zN\___/NCN( ~ )
CH3 C113 H Cfl3 (IV) (+)-R,R isomer
~ (-)-R,R isomer (V)
Optical resolution
(+)-R,R isomer (VI)
C~13
s r ]~
OH
CH3
S,S isomer
N0z
211C ~ ) 2
CH3 H CH3 (VII) (I)-S,5 isomer
~ S,S isomer ~VIII)
Optical resolution
~ ) ~S r S isomer (IX)
Namely, the present invention provides an optical
isomer o a compound having the formula:
N0z
CH3 ~
),1 ? C0~CN~CN~N NCN( ~ ) (I)
~: C~3 N 2HC Q
CH3 H CH3
.
wherein the two methyl groups at 4- and 6-positions of the
dioxaphosphorinane ring assume trans conigurations to
each other, which has a levo-rotatory angle of optical
~ rotation attributable to the asymmetric carbon atom at
: 4-position o~ the dihydropyridine ring, and a
~ ~ pharmaceuticaLly acceptable salt thereoE.
: 25
Now, the~synthesis of the compound of the present
invention will be described.
:~3~5~ 3
The process steps for the synthesis of the compound of
the present invention are as follows (in each of the
following steps, a R,R form product is obtained ~rom a R,R
form starting material, and a S,S form product is obtained
from a S,S form starting material.)
OH P(OMe) 3 ~ 0~
~ ` < /POCH 3
: ~ OH (A) ~ O
lO R,R isomer or S,S isomer R,R isomer or 5,S isomer
O C~13
ICllzCOCI~3 ~> O ¦¦ ¦
~ ( \PCHzC (O)
(B) ~ O'
R,R isomer or S,S isomer
.
NO2 NO2
HC(O) ~ ~
~ o~ ll ~cll
~~ (C) ~ oIPIC
C(O)CH~
R,R isomer or S,S isomer
~ ' '
,
-7-
NH2 y COzCHzCHzN~ NCH( ~ )
. _ . . ... _ ................ ~
- NOz
~¦ ~ OzCNzCHzN NCII( ~ )
0 CH3 H CH3
R,R isomer (IV) or S,S isomer (VII)
C)l _ _~ Hydrochlorlde of Compound (VI) or (VII)
Optical~ Hydrochloride of
: ~ resolution (in the case of- Compound
(F) R,R isomer) (V)((-)-R,R isomer)
Hydrochloride of
. Compound
: (VI)((~)-R,R isomer)
~ ~ ~25
: . ~ (in the case of- ~ Hydrochloride of
: S,S isomer) Compound
: (VIII)((-)-S,S isomer)
~ : 30 -~ Hydrochloride of
:~ : . Compound
(IX)((~)-S,S isomer)
Above Steps (A), (B) and (C) are conducted by
conventional methods in accordance wi-th Reference Examples
~ 3C?Sl''~
given hereinafter. The product obtained in Step (C) may
be used for the next Step (D) without purification or
isolation.
In Step (D), an inert solvent is employed. The inert
solvent may be an alcohol solvent such as methanol,
ethanol, propanol or isopropanol, an ether solvent such as
1,2-dime-thoxyethane or THF, an aromatic hydrocarbon
solvent such as benzene, toluene or xylene, a nitrile
solvent such as acetonitrile or benzonitrile, an amide
solvent such as DAM, DME or N-methylpyrrolidone, a
sulfoxide solvent such as DMSO or sulfolane, an ester
solvent such as ethyl acetate or butyrolactone, or
pyridine.
The reaction is conducted a-t a temperature within a
range of from room temperature to 200C, preferably from
60 to 140Ct for from L to 100 hours, preferably from 5 to
20 hours.
Compound tIV) or (VII) obtained in Step (B) is reacted
with hydrochloric acid to obtain a hydrochloride of
Compound (IV) or (VII) (Step ~E)).
Then, the respective hydrochlorides are dissolved in
ethanol under heating, and cooled, whereby a (-)-product
precipitates from the ethanol solution of the R,R isomer,
and a (~)-product precipitates from the ethanol solution
of the S,S isomer. The precipitates are collected from
the respective ethanol solutions, andt if necessary,
recrystallized from ethanol to obtain highly pure (-)-R,R
~3~S~
g
isomer and (~ S,S isomer, respectively (S-tep (F)).
After the coLlection of the precipitates from the
respective ethanol solutions, the respective e-thanol
filtrates are subjected to distillation under reduced
pressure to remove the solven-t to dryness, and the dried
residue is recrystallized from acetone to obtain a ~ R,R
isomer from the acetone solution of the R,R isQmer.
Whereas, from the ace-tone solution of the S,S isomer, a
(-)-S,S isomer is obtained. For further purifica-tion of
these products, the recrystallized produc-ts from acetone
are dissolved in ethanol, the solvent is evaporated under
reduced pressure to dryness, and the dried product is
recrystallized from acetone.
The pharmaceutically acceptable salt is meant or a
monoacid salt or diacid salt with a pharmacologically
inactive acid. For example, it may be a hydrochloride, a
sulfate, a nitrate, a lactate or a succinate.
Such a salt may be obtained by neutralizing the
hydrochlorlde obtained in the above described me-thod, and
then adding the corresponding acid.
~ As will be apparent from the results of the
antihypertensive tests given hereinafter, the compounds of
the present invention have vasodilator activities, and
thus useful for treating diseases of circulatory organs of
mammals, such as angina pectoris, disturbance of cerebral
circulation or hypertension.
Thus, the present invention provides a vasodilator
~3~
--10--
composition comprising an effective amount of the optical
isomer of the present invention or its pharmaceutically
acceptable salt, and a pharmaceutically acceptable diluen-t
or carrier. Such a composition may also be formulated
into a veterinary composition by combining the compound of
the present invention with a veterinarily acceptable
diluent or carrier.
Such compositions may be ~sed in the form suitable for
oral administrakion, e.g. tablets or capsules, in the form
suitable for transdermal administration, e.g. ointments or
plas-ters, in the form suitable for inhalation, e.g.
aerosols or solutions suitable for spraying, in the form
suitable for injec-tion administration, e.y. a sterilized
aqueous solution, or in the form of a suppository suitable
for use in anus, vagina or rectum.
The composition of the present invention usually
contains the compound of -the present invention in an
amount of from about 0.1 to about 99.5% by weight,
preferably from about 0.5 to about 95% by weight, based on
the total weight of the composition.
The compound of the present invention or the
composition of the present invention may be used in
combination with other pharmaceùtically or veterinarily
active compounds. Further, the composi-tion of the presen-t
invention may contain a plurality of the compounds of the
present invention.
The daily dose of the compound of the present
invention may be varied depending upon the type and the
condition of the desease to be cured and the type of the
patient (-the age, sex, sensitivity, etc.). In the case of
the intravenous adminis-tration, the daily dose is usually
from 0.0001 to 10 mg, preferably from 0.0005 to 1 mg, of
the active ingredient per 1 kg of -the body weight.
Likewise, in the case of the oral or transdermal
administration, the daily dose is usually from 0.001 to
100 mg o~ the active ingredien-t per 1 kg of the body
weight. Further, the daily dose in the case of the
administration in the form of a suppository to e.g. a
vagina or rectum, is usually from 0.001 to 200 mg,
preferably from 0.005 to 100 mg, of the active ingredient
per 1 kg of the body weight. The content of the active
ingredient in an aerosol, is usually from 0.1 to 10~ by
weight, preferably from 0.1 to 2% by weight. Such a daily
dose may be divided for administration twice or more times
per day.
The above-mentioned composition containing the
compound of the present invention may be prepared by a
conventional method, and a conventional excipient may be
incorporated therein.
Now, the present invention will be described in
further detail with reference to Test Examples, Reference
Examples, Working Examples and Formulation Examples.
Mowever, it should be understood that the present
invention is by no means restricted to such specific
-12-
Examples. In the following formulas, Ph means a phenyl
group.
TEST EXAMPI.E 1: Calcium antagonis-tic effects
10 mm in situ length of taenia caecum of guinea pig
was suspended at a tension of 1 g in a 20 ml organ ba-th
fllled wlth a physiological salt solution ~NaCL: 135 mM,
KCl: 5 mM etc.).
Thls solution was bubbled with a gas ml~ture of 95
2-5~ C2 and kept at 37C. Then, the preparatlon was
depolarlzed by a ~+ rich solutlon (NaCl: 40 mM, KCl: 100
mM). After 10-20 minutes equilibration period, 10 mM of
CaC12 was added to the bathing solution. The contraction
was produced, and then the test compound applied
cumulatively. The relaxation produced was e~pressed as
percentage of the maxlmum relaxation produced by 10 4 M
papaverlne, and the concentration of the compound
produclng 50% relaxatlon, i.e. ID50 (M), waS calculated-
p D50 (pID50=-log[ID50] are summarlzed in
Table 1.
TEST EXAMPLE 2: Antihypertensive effects (Venous
injection)
The antlhypertensive effects of compounds of the
;~ present lnvention were tested by using spon-taneously
hypertenslve rats ~SHR) anesthetlzed with urethane-~-
chloralose. This test was conducted with a group of 3 to
5 SHR by measuring the blood pressure at the common carotid
artery of each rat. Each test compound was dissolved ln
3~ tween 80-physiological salt solution, and injected into
the Eemoral veln. From the relation be-t~een the dose
and the maximum pressure drop, ED30 (mg/kg) i.e. a dose
required for 30% pressure drop, was obtained. The results
5 are shown in Table 1.
TEST EXAMPLE 3: Antihypertensive effects
(Oral administration)
A compound of the present invention was dissolved in a
solvent of PEG:H2O = 3:1 and orally administered to a
group o~ 4 SHR at a dose of 15 mg/kg. The blood pressure
was measured by a tail-cuff method (by using KN-210-1,
manufactured by Natsume Seisakusho)~
The results were represented by the pressure drop (~)
relative to the blood pressure prior to the
administra-tion, and are given in Table 1.
Table 1: Pharmacological effects of various isomers
_
Type of pID50 ED30 mmHg(~)
isomer (mg/kg) 2 hrs. 4 hrs. 6 hrs.
(V) (-)-R,R 8.02 0.023 22 23 30
(VI) (~)-R,R7.12 ~0.557 2 -1 _
(VIII) (-)-S,S7.94 0.048 22 27 1
(IX) (~-S,S <6 1.659 0 4 _
TE~ST EXAMPLE 4: Toxicity test
The test compound was suspended in a 0.5~ ~C aqueous
solution to obtain a 1 w/w~ suspension, which was orally
{~
-14-
administered to three ddY male mice of 4 weeks old. The
mice were observed for 7 days. No mice died even at a
dose o~ 600 mg/kg of the compound o~ Example 1 i.e. the
(-)-R,R isomer.
REFERENCE EXAMPLE 1
=
ro~l O
~ + P(OMe) 3 ~ OCH
10 g of (+)-(2S,4S)pentane-2,4-diol and 13.6 g of
trimethylphosphite were mixed, and heated at 100C on an
oil bath. After completion of distilling methanol off,
the residue is distilled under reduced pressure to obtain
colorless transparent 2-methoxy-~4S,6S)-4,6-dimethyl-
1,3,2-dioxaphosphorinane. bp: 70-72C/15 mmHg.
Yield: 7.5 g
NMR(CDC13): ~(ppm);4.8-4.0(2H,m)j 3.5(3H,d,J=12Hz),
2.2-1.5(2H,m), 1.45(3H,d,J=7Hz),
1.25(3H,d,J=7Hz)
A similar operation was conducted by using
; (-)-(2R,4R)pentane-2,4-dioL as the starting material,
whereby 2-methoxy-(4R,6R~-4,6-dimethyl-1,3,2-
; dioxaphosph~rinane was obtained.
'
ffl
-15-
REF~RENCE EXAMPLE 2
-
~ > P - OCH 3 ~ ICHzCOCH 3
~
_ O
<7 ) ICH2COCH3
6.2 g of iodoacetone was dissolved in 60 ml of
benzene, and the solution was heated on an oil bath at
8QC. A benzene solu-tion (20 ml) of 5.5 g o~
2-methoxy-(4S,6S)-4,6-dimethyl-1,3,2-dloxaphosphorinane
obtained in Reference Example 1, was dropwise added over a
period of 10 minutes. After the completion of the
dropwise addition, the mixtu~e was kept at 80C ~or 1
hour, and then ~he solvent was distilled off under reduced
pressure. The residue was subjected to silica gel column
chromatography (developer soLvent: ethyl acetate/methanol
= 9/1 (v/v), Rf value: 0.4) to obtain 4.2 g o~ desired
20 2-acetonyl-(4S,6S)-4,6-dimethyl-1,3,2-dioxaphosphorinane-
2 oxlde as a colorless transparent liquid.
NMR(CDC13) ~(ppm);5.0-4.5~2H,m), 3.1(2~,d,J=23Hz),
3.3(3H,s), 1.95(2H), 1.5(3H,dd,J=6.3Hz,
J=O.SHz), 1.4(3H,dd,J=6.3Hz,J=1.5Hz)
A similar operation was conducted by using
2-methoxy-(4R,6R)-4,6-dimethyl-1,3,2-dioxaphosphorinane as
: :
~3~S~
~16-
the starting material to obtain
2-acetonyl-( 4R, 6R) -4,6-dimethyl-1,3,2-dioxaphosphorinane-
2-oxide.
Rl~FERENCE EXAMPLE 3
> IICNZCOCII3 +
- GHO
NOz
> P-C=CH
--~ COCH 3
'
3 . 3 8 g of 2-acetonyl-(4R,6R)-4,6-dimeth~l-1,3,2-
dioxaphosphorinane-2-oxide and 2.4 g of
m-nitrobenzaldehyde were dissolved in 15 ml of benzene,
and 0.5 ml of piperidine was added thereto. The mixture
was refluxed for 5 hours. The reaction solution was
subjected to silica gel chromatography (d2veLcper
solu-tion: ethyl acetate/methanol = 9/1 ~v/v), Rf value:
0.4) to obtain 1.78 g~of desired
; 2-tl-acetyl-2-(3-nitrophenyl)ethenyl)-(4R,6R)-4,6-
dimethyl-1,3,2-dioxaphosphorinane-2-oxide as a yellow
viscous liquid.
NMR(CDC13): ~(ppm);8.5-7.3(5H,m), 5.2-4.4(2H,m),
2.3(3H,s), 2.0(2H,m), 1.55(3H,d,J=6Hz),
3~.~5
-17
1.4~(3H,d,J=6Hz)
A similar operation was conducted by using
2-acetonyl-(4S,6S)-4,6-dimethyl-1,3,2-dioxaphosphorinarle-
2-oxide as the s-tarting material to obtain
2-(1-acetyl-2-(3-nitrophenyl)ethenyl)--(4S,6S)-
4,6-dimethyl-1,3,2-dioxaphosphorinane-2-oxide.
EXAMPLE 1
NOz
~ > P-C=CH ~ +
- COCI~ 3
C~13C=C~ICO2CH2CH2N~NC~ (Ph) 2
N H 2
:
NO2
o)$ o c,,zc H oc, (Ph) z
; - N
CH 3 H CH 3
.
1.7 g of 2-(1-acetyl-2-(3-nitrophenyl)ethenyl)-
(4R,6R)-4,6-dimethyl-1,3,2-dioxaphosphorinane-2-
~:~ oxide and 1.9 g of 3-aminocrotonic acid
.
4-diphenylmethyl-1-piperadinoethyl ester were dissolved in
I0 ml of toluene, and the solution was re1uxed for 10
:: : hours. After cooling, the reaction solution was subjected
to silica gel chromatography (developer: ethyl
~.3~
-18-
acetate/methanol = 9/1 (v/v), Rf value: 0.4) to obtain 2.3
g oE desired 5-[(4R,6R)-4,6-dime-thyl-1,3,2-
dioxaphosphorinan-2 yl]-1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-3-pyridinecarboxylic acid
4-diphenylmethyl-1-piperadinoe-thyl ester P-oxide, as a
yellow liquid.
NMR(CDC13): ~(ppm);8.1-7.1(14H,m), 6.2~1H,broads),
4.9-4.1(6H,m)l 2.7-2.2(16H,m), 1.75(2H,m),
1.5-1.0(6H,m)
A similar operation was conducted oy using
2-(1-acetyl-2-(3-nitrophenyl)ethenyl)-(4S,6S)-4,6-
dimethyl-1,3,2-dioxaphosphorinane-2-oxide as -the starting
material to obtain 5-[(4S,6S)-4,6-dimekhyl-1,3,2-
dioxaphosphorinan-2-yl]-1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-3-pyridinecarboxylic acld
4-diphenylmethyl-1-piperadinoethyl ester P-oxide.
Synthesis of a hydrochloride
5.76 g of 5-[(4R,6R)-4,6-dimethyl-1,3,2-
dioxaphosphorinan-2-yll-1,4-dihydro-2,6-dimethyl-4-
; 20 (3-nitrophenyl)-3-pyridinecarboxylic acid
4-diphenylmethyl-1-piperadirloethyl ester P-oxide was
dissolved in 28.8 g of ethanol, and 1.89 g of 35~
hydrochloric acid was added. Then, the solvent was
distilled oEf under reduced pressure to obtain a yellow
viscous hydrochloride. The angle of rotation o~ this
product was [a]25: +8.9C (c=1.03, MeOH).
~5~
-19- .
Optical resolution
The hydrochloride thus ob-tained was recrystallized
twice with 43 g of ethanol to obtain (-)-5-[(4R,6R)-4,6-
dimethyl-1,3,2-dioxaphosphorinan-2-yl]-1,4 dihydro-Z,6-
dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid
4-diphenylmethyl-l-piperadinoethyl ester P-oxide
dihydrochloride.
Pale yellow crystal, mp: 172-177
[~]25: -16.8C (c=0.51, MeOH)
The mother liquors used for the recrystallization were
put together, and the solvent was distilled off under
reduced pressure, the residue was recrystallized with
acetone in an amount of 20 times the weight of the
residue. The pale yellow crystal thus obtained was again
dissolved in ethanol, and -the solvent was distilled off
under reduced pressure. The residue was recrystallized
with acetone in an amount of 20 times the weight of the
residue to obtain (-~)-5-[(4R,6R)-4,6-dimethyl-1,3,2-
dioxaphosphorinan-2-yl)]-1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-3-pyridinecarboxylic acid
4~diphenylmethyl-l-piperadinoethyl ester P-oxide
dihydrochloride~
Pale yellow crystal, mp: 159-164C
[~D5: ~34.8C (c=0.51, MeOH)
~ree amine NMR(CDC13):
NMR values (~) (ppm) corresponding to various hydrogen
atoms were recorded.
~ 5
-20-
(-)-R,R isomer
C113 (1 . 39, J=0.4511z)
~4.2,m)H ~ 0
/ H(4.$,m) /
~ 0 /
CH3~1.32,dd,J=0.45Hz,J=0.0811z)
(+)-R,R isomer
CH~(1.51,d,J=0.45~z)
(4.5,m)H ~ 0---7
(4-7,m)
~J--o
CH3(1.02,dd,J=0.45Hz,J=0.08Hz)
~ ~ '
A similar operation was conducted by using :
5-[(4S,6S)-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl]-
.
: 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-
~: pyridinecarboxylic acid 4-diphenylmethyl-1-piperadinoethyl
P-oxide as the starting material, whereby a (~)-S,S isomer
:~ 20 precipitated from -the ethanol solution, and a (-)-S,S
somer precipitated from the acetone solution. The
(+)-S,S isomer was recrystallized from ethanol for
puriflcation. Likewise,~the (-)-S,S isomer was dissolved
in ethanol, and after distilling off the solvent and an
: 25 addition of acetone, recrystallized from acetone for
puri~ication.
~3QS~
-21-
(+)-S,S isomer
Pale yellow crystal, mp: 172~177C
[~25 +16.9C (c-0.52, MeOH)
~L~
Pale yellow crystal, mp: 159-164C
[a]25: _34.8C (c=0.51, MeOH)
The NMR spectrum of free amine in the case of the
(~)-S,S isomer exactly corresponded to the spectrum of the
(-)-R,R isomer. Likewise, the NMR spectrum o free amine
in the case of the (-)-S,S isomer exactly corresponded to
the spectrum o the (~)-R,R isomer.
FORMULATION EXAMPLE 1: Tablets
Composition (1,000 table-ts)
Hydrochloride of the (-)-R,R isomer5.0 (9)
of Example 1
Lactose 190.0
Corn starch 75.0
Crystal cellulose powder 25.0
Methyl cellulose 3.0
Magnesium stearate 2.0
300.0
The above ingredients in the respective amounts were
introduced in-to a twin shell mixer and uniformly mixed.
This powder mixture was tableted by a direct compression
method to obtain tablets haviny a weight of 300 mg per
tablet.
-22-
FORMULATION EXAMPLE 2: Capsules
Composition (1,000 tablets)
H~drochloride of the (-)-R,R isomer 5.0 (g)
of Example 1
Corn starch 145.0
Crystal cellulose powder . 145.0
Magnesium stearate 5.0
300.0
10The above ingredients in the respective amounts were
introduced into a twin shell mixer and uniformly mixed.
Thi~ powder mixture was packed in hard gela-tin capsules in .
an amount of 300 mg per capsule.
FORMULATION EXAMPLE 3: Syrups
Composition (2% syrupsj
Hydrochloride of the (-)-R,R isomer 2.0 (g)
of Example 1
: ~ Sugar 30 0
: Glycerin 5 0
Flavoring agent 0.1
96~ ethanol 10.0
Methyl p-hydroxybenzoate 0.03
Distilled water : Add to bring the total
: amount to 100.0 g
25The sugar and the hydrochloride of the compound of
Example were dissolved in 60 g of warm water, and after
cooling the solution, a solution of the flavoring agent in
~3~5~
glycerin and ethanol was added. Then, water was added to
thls mixture to bring the to-tal amount to 100.0 g..
FORMULATION EXAMPLE 4: powder
Composition
Hydrochloride of the (-)-R,R isomer 1.0 (g)
of ~xample 1
Lactose 88.0
Crystal cellulose powder 10.0
Methyl cellulose 1.0
1 0 ~
ioo. o
The above ingredients Ln the respective amounts were
introduced into a twin shell mixer and uniformly mixed to
obtain a powder.
