CA1305149C - Dihydropyridine-5-phosphonic acid cyclic ester - Google Patents

Abstract

ABSTRACT
An optical isomer of a compound having the formula:

(I)

Description

~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:

GH3 ~
O ¦¦ ~ CO~CIIzC~ C~( ~ ) (I) .. ....
(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~

In the above formula (II), the two methyl groups at 4-and 6-positions of the dioxaphosphorinane ring assume cis configurations to each other.

OH or ~ 011 ? ~ , >
OH OH
CH3 CHs dl mixture C1i3 ~
~ C O ~ C a: C N 2 N~ ,~N C II(~) 2~C Q

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.

-R ~ OH

R~ 0~1 : R,R isomer ) ~ ( 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

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

.
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 .

HC(O) ~ ~
~ o~ ll ~cll ~~ (C) ~ oIPIC
C(O)CH~

R,R isomer or S,S isomer ~ ' ' , NH2 y COzCHzCHzN~ NCH( ~ ) . _ . . ... _ ................ ~

- NOz ~¦ ~ OzCNzCHzN NCII( ~ ) 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~

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 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 {~

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.

=

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 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 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.

NOz ~ > P-C=CH ~ +
- COCI~ 3 C~13C=C~ICO2CH2CH2N~NC~ (Ph) 2 :

o)$ o c,,zc H oc, (Ph) z ; - N

.
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~

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 (-)-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~

(+)-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.

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.

Claims (8)

1. An optical isomer of a compound having the formula:

(I) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume trans configurations to each other, which has a levo-rotatory angle of optical rotation attributable to the asymmetric carbon atom at 4-position of the dihydropyridine ring, and a pharmaceutically acceptable salt thereof.

2. The optical isomer according to Claim 1, which is a levo-rotatory optical isomer of a compound having the formula:

(I-R,R) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume (R,R) configurations.

3. The optical isomer according to Claim 1, which is a levo-rotatory optical isomer of a compound having the formula:

(I-S,S) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume (S,S) configurations.

4. A vasodilator composition comprising an effective amount of an optical isomer as defined in Claim 1 or its pharmaceutically acceptable salt, and a pharmaceutically acceptable diluent or carrier.

5. A process for producing a compound having the formula:

(I) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume trans configurations to each other, which comprises reacting a compound having the formula:

(II) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume trans configurations to each other, with a compound having the formula:

(III)

6. A method for purifying a levo-rotatory optical isomer of a compound having the formula:

(I-R,R) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume (R,R) configurations, which comprises dissolving the compound of the formula (I-R,R) in ethanol under heating, then cooling the solution, and collecting the precipitate thereby formed.

7. A method for purifying a levo-rotatory optical isomer of a compound having the formula:

(I-S,S) wherein the two methyl groups at 4- and 6-positions of the dioxaphosphorinane ring assume (S,S) configurations, which comprises dissolving the compound of the formula (I-S,S) in ethanol under heating, then cooling the ethanol solution, collecting the precipitate by filtration, evaporating the filtrate to dryness, dissolving the dried product in acetone under heating, and precipitating the optical isomer from the acetone solution.

8. The use of an optical isomer as defined in Claim 1 or its pharmaceutically acceptable salt for treating a disease of a circulatory organ of a mammal.