JP3534433B2 - platelet aggregation inhibitor - Google Patents

Description

[Detailed description of the invention]

[0001]

BACKGROUND OF THE INVENTION _1. Field of the Invention The present invention relates to a platelet aggregation inhibitor containing a prostaglandin (hereinafter abbreviated as PG) E1 analogue as an active ingredient.

[0002]

2. Description of the Related Art Platelet aggregation inhibitors are used for the treatment and prevention of thrombotic diseases such as transient ischemic attack, prevention of recurrence of cerebral infarction, unstable angina pectoris, peripheral arterial occlusion and essential thrombocythemia. used for Among various platelet aggregation inhibitors, PGE ₁ and its analogues, which are structurally similar to the platelet aggregation inhibitor of the present invention, are used for treatment of peripheral arterial occlusion since they also have vasodilating action.

[0003]

However, these have the drawback that they are rapidly metabolized in vivo and therefore their effects do not last. In addition, when administered orally, it induces diarrhea as a side effect, so that high doses could not be administered and sufficient effects could not be obtained. The present invention is a conventional P
It is an object of the present invention to provide a novel platelet aggregation inhibitor that has superior efficacy, long-lasting efficacy, and reduced side effects as compared to GE ₁ -type platelet aggregation inhibitors.

[0004]

SUMMARY OF THE INVENTION The present invention provides the formula

[0005]

(wherein A represents an ethylene group, vinylene group or ethynylene group, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms) or a salt thereof as an active ingredient. It is a platelet aggregation inhibitor. In the present invention, the alkyl group having 1 to 6 carbon atoms is
A linear or branched chain, such as a methyl group,
ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group,
Examples include an isopentyl group. The salt of the compound of formula (I) is a compound of formula (I) in which R is a hydrogen atom,
They are salts with metals such as sodium, potassium and aluminum, and salts with organic amines such as trialkylamines.

The compound of formula (I) is, for example, PCT/JP92/00 filed on April 21, 1992 by the applicant of the present application.
It can be easily produced by the method described in JP-A-513.

[0008]

[0009]

(In the reaction formula, A has the same meaning as above, and R
¹ and R ² are the same or different and represent a hydroxyl-protecting group, and R ³ is R excluding a hydrogen atom. Here, the hydroxyl-protecting group is one commonly used in the field of prostaglandins, such as t-butyldimethylsilyl, triethylsilyl, phenyldimethylsilyl, tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl groups, ethoxyethyl groups, benzyl groups, and the like. ) That is, first, the method of Sato et al. [Journal of
Organic Chemistry (J.Org.Che
m. ), Vol. 53, p. 5590 (1988)]
0.8 to 2.0 equivalents of the organoaluminum compound of formula (III) is added to the compound of formula (II) known by
Compounds of formula (IV) stereospecifically by reaction at 10-30°C, preferably 0-10°C in an inert solvent (e.g. benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) is obtained. Here, the organoaluminum compound of formula (III) can be prepared, for example, by the method of Sato et al. [Tetrahedron Lett.
7083 (1989)].

[0011]

(In the formula, R ² has the same meaning as defined above.) 0.8 of an alkyllithium (eg, n-butyllithium, t-butyllithium, etc.) is added to the acetylene compound represented by the above formula.
-1.5 equivalents at -20 to 30°C, preferably -10 to 0
C., more preferably at ₁₀ to 30.degree. Diethyl aluminum halide represented (e.g. diethyl aluminum chloride, dimethyl aluminum chloride, etc.)
Prepare by adding 1.5 equivalents. It is preferable to use an inert organic solvent (eg, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) in this reaction.

Next, the compound of formula (IV) is combined with 0.5 to 4 equivalents of the organocopper compound represented by formula (V) and 0.5 to 4 equivalents of chlorotrimethylsilane with an inert solvent (e.g., tetrahydrofuran, diethyl). ether, methylene chloride, toluene, n-hexane, etc.) at -78 to 40°C to give the compound of formula (VI). Here, the organocopper compound of formula (V) is represented by formula I-( _CH2 ) ₃ -A- ^COOR3 (VIII) ⁽ wherein R3 and A have the same meanings as above). From the iodine compound, a known method [P. Knoche
et al., Journal of Organic Chemistry, 53:2390 (1988)]. That is, the iodine compound of formula (VIII) is combined with 0.8 to 5 equivalents of zinc activated with, for example, 1,2-dibromomethane, chlorotrimethylsilane, iodine, etc., and an inert solvent such as tetrahydrofuran, diethyl ether, n -hexane, n-pentane, dioxane, etc.) to be represented by the formula ^IZn- ( _CH2 ) ₃ -A- ^COOR3 (wherein R3 and A are as defined above). lead to organozinc compounds. At this time, heating may be performed as necessary. The heating temperature depends on the boiling point of the solvent,
It is usually 30 to 150°C, preferably 40 to 80°C.
By reacting the resulting organozinc compound at -50 to 10°C in the inert solvent containing copper cyanide (1 to 2.5 equivalents) and lithium chloride (2 to 5 equivalents),
An organocopper compound of formula (V) can be obtained.

Then, the compound of formula (VI) is treated with an inorganic acid (eg, aqueous solution of hydrochloric acid) or an organic acid or its amine salt (eg, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, etc.) and an organic solvent. (e.g. acetone, methanol, ethanol, isopropanol,
diethyl ether or a mixed solvent thereof),
Hydrolysis at 0-40° C. stereoselectively gives compounds of formula (VII). Finally, the hydroxyl-protecting group of the compound of formula (VII) is deprotected using methods conventional in the field of prostaglandins to give the compound of formula (I) wherein R is a group other than a hydrogen atom [ compound of formula (Ia)].

The compound of the present invention [compound of formula (Ib)] wherein R is a hydrogen atom in formula (I) can be obtained by hydrolyzing the ester moiety of the compound of formula (Ia). Hydrolysis is carried out by reacting the compound of formula (Ia) in a buffer such as phosphate buffer or Tris-HCl buffer, optionally using an organic solvent (mixed with water such as acetone, methanol or ethanol). by reacting with the enzyme. Enzymes to be used include enzymes produced by microorganisms (e.g., enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), and enzymes prepared from animal organs (e.g., enzymes prepared from porcine liver and porcine pancreas).
A specific example of commercially available enzymes is lipase
VII (manufactured by Sigma, derived from microorganisms of the genus Candida), Lipase AY (manufactured by Amano Pharmaceutical Co., derived from microorganisms of the genus Candida), Lipase MF (manufactured by Amano Pharmaceutical Co., derived from microorganisms of the genus Pseudomonas), PLE-A (Amano Pharmaceutical Co., prepared from porcine liver), Esterase (Sigma, prepared from porcine liver), Lipase II (Sigma, prepared from porcine pancreas), Lipoprotein Lipase (Tokyo Kasei Kogyo Co., Ltd., prepared from porcine pancreas) and so on. The amount of the enzyme to be used may be appropriately selected according to the potency of the enzyme and the amount of the substrate [compound of formula (Ia)], but is usually 0.1 to 20 parts by weight of the substrate. The reaction temperature is 25 to 50°C, preferably 30 to
35°C.

The platelet aggregation inhibitors of the present invention can be administered orally or parenterally (eg, intravenously, intrarectally, intravaginally). As dosage forms for oral administration, for example, solid preparations such as tablets, granules and capsules, and liquid preparations such as solutions, fat emulsions and liposome suspensions can be used. When used as this oral preparation, α,
It can also be formulated by forming an inclusion compound with β- or γ-cyclodextrin, methylated cyclodextrin, or the like. As preparations for intravenous administration, aqueous or non-aqueous solutions, emulsifiers, suspensions, solid preparations dissolved in a solvent for injection immediately before use, and the like can be used. In addition, dosage forms such as suppositories can be used as preparations for rectal administration, and pessaries and the like can be used as preparations for intravaginal administration.
The dosage is 0.1-100 μg, which is administered 1-3 times daily.
Administer in divided doses.

[0017]

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a platelet aggregation inhibitor having excellent efficacy and sustained efficacy. Moreover, the platelet aggregation inhibitor of the present invention is a conventional PG
It hardly induces diarrhea, which is the most serious problem with systemic platelet aggregation inhibitors, at doses that exhibit definite pharmacological effects.

The effects of the present invention will be specifically described below by way of test examples. Test Example 1 [Guinea pig platelet aggregation inhibition test] Male Hartley guinea pigs (weighing 300
~500 g) were used in groups of 5 or 6 animals. After dissolving the test drug in ethanol, it was suspended in a 0.5% carboxymethyl cellulose solution. The final concentration of ethanol was 1% or less. Oral administration of 50 μg/kg of test substance (5 cc/kg as solution), 2 or 8
After 1 hour, the animals were anesthetized by intraperitoneal administration of 20 mg/kg of pentobarbital, the abdomen was opened, and 9 volumes of blood per 1 volume of 3.2% sodium citrate were collected from the abdominal aorta using a plastic syringe. 12 blood
After centrifugation at 0×g for 10 minutes, the supernatant was used as PRP. The remaining blood was further centrifuged at 1100 xg for 10 minutes to obtain platelet poor plasma (PPP). PP the platelet count of PRP
P was adjusted to 4-6 x ¹⁰⁵ platelets/ ^mm3 . Measurement of platelet aggregation is the method of Born (Nature, 1st
94, p. 927, 1962). That is, 275 μl of P
After incubating RP for 3 minutes at 37° C. under stirring at 1000 rpm, platelet aggregation was induced by adding 25 μl each of ADP (final concentration 3 μM) or collagen (final concentration 3 μg/ml). The maximum change in light transmittance was defined as the maximum aggregation rate. Using the 0.5% carboxymethyl cellulose solution administration group as a control group, the aggregation inhibition rate of the test substance administration group with respect to the maximum aggregation rate was calculated by the following formula.

[0019]

[Number 1]

The results are shown in Table 1. As a comparative compound, a compound (limaprost) obtained by changing the triple bond portion at the 13 and 14 positions of Compound 1 produced in Production Example 1 to a double bond
[Tsuboi et al., Arch. Intern. Pharmacodyn. Ther., No. 247
Vol., p. 89 (1980)]. Moreover, in this test, the condition of feces was observed until 2 hours after administration. Significant diarrhea was observed in the limaprost-administered group,
In the group administered with the compound of the present invention, only mild loose stools were observed.

[0021]

[Table 1]

Test Example 2 [Rabbit Platelet Aggregation Inhibition Test] New Zealand white rabbits weighing 2.5 to 4.0 kg were divided into groups of 4 and subjected to the test. Under ether anesthesia, 9 volumes of blood per 1 volume of 3.2% sodium citrate solution were collected from the common carotid artery of this rabbit. The collected blood was centrifuged at 1100 rpm for 15 minutes, and the upper layer was platelet-rich plasma (PRP). Measurement of platelet aggregation was carried out by Born's method (Nature, Vol. 194, Vol. 9).
27, 1962). PRP
Various concentrations of test drug 1 dissolved in ethanol in 275 μl
After 3 minutes with stirring at 37° C. and 1000 rpm, 25 μl of an aggregating agent [adenosine diphosphate (ADP) final concentration 5 μM] was added, and the maximum aggregation rate (platelet aggregation The maximum change in light transmittance within 5 minutes after induction) was measured. The anti-aggregation activity was calculated by calculating the anti-aggregation rate against aggregation when ethanol was used instead of the test drug solution, and the IC ₅₀ value was obtained from the dose-response curve. The results are shown in Table 2. The compound numbers in the table are the compound numbers shown in Production Examples below. The _IC50 values are shown as mean values.

[0023]

[Table 2]

Test Example 3 [Human Platelet Aggregation Inhibition Test] Blood was collected from a human and immediately mixed with 1/10 volume of 3.8% sodium citrate aqueous solution. After centrifugation at 180×g for 15 minutes at room temperature, PRP was obtained from the upper layer. Measurement of platelet aggregation is the method of Born (Nature, 194
Vol., p.927, 1962).
Using an aggregometer, 100 μl of PRP and 5 μl of test drug solutions of various concentrations dissolved in ethanol were added, and after incubation for 1 minute at 37° C. under stirring at 1000 rpm, platelet aggregation was induced by adding 5 μl of ADP. Aggregation rate was determined. Aggregation-inhibiting activity was calculated by calculating the inhibition rate against aggregation when ethanol was used instead of the test drug solution, obtaining IC ₅₀ from the dose-response curve, and simultaneously measuring the IC ₅₀ of PGE ₁ . It was evaluated as relative activity. Table 3 shows the results. The compound number is the compound number shown in the manufacturing examples described later.

[0025]

[Table 3]

[0026]

EXAMPLES The present invention will now be described in more detail with reference to Production Examples and Examples. Production Example 1 (2E,17S)-17,20-dimethyl-2,3,1
3,14-tetradehydro-PGE1 methyl ester
(Compound 1) (1) (3S,5S)-3-(t-butyldimethylsiloxy)-5-methylnon-1-yne (3.85 g) was dissolved in 28.8 ml of benzene and dissolved in n-butyl at 0°C. Lithium (1.95 M, hexane solution, 6.4 ml) was added,
The mixture was stirred at the same temperature for 30 minutes. Diethylaluminum chloride (0.97 M, hexane solution, 1
4.8 ml) was added, and after the temperature was raised to room temperature, the mixture was stirred for 30 minutes. To this solution at room temperature was added (4R)-2-(N,N-diethylamino)methyl-4-(t-butyldimethylsiloxy)cyclopent-2-en-1-one (0.25 M,
Benzene solution, 38.4 ml) was added and stirred for 15 minutes. The reaction solution was hexane (100 ml)-saturated ammonium chloride aqueous solution (100 ml)-hydrochloric acid aqueous solution (3M, 30
ml) with stirring, the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (50 ml). The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: hexane:ether = 10:1) to give (3R,4R)-2-methylene-3-[ (3′S,5′S)-3′-(t-butyldimethylsiloxy)-5′-methylnon-1′-ynyl]
3.72 g of 4-(t-butyldimethylsiloxy)cyclopentan-1-one are obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm: 0.09, 0.10 and 0.12 (3s, 1
2H), 0.89 (s, 18H), 0.80-0.99
(m, 6H), 1.00-1.72 (m, 9H), 2.
32 (dd, J=7.4Hz, 18.0Hz, 1H),
2.71 (dd, J = 6.6 Hz, 18.0 Hz, 1
H), 3.47-3.56 (m, 1H), 4.15-
4.33(m, 1H), 4.44(dt, J = 1.6H
z, 7.0Hz, 1H), 5.54 (d, J = 2.6H
z, 1H), 6.13 (d, J=3.0Hz, 1H) IR (neat): 2930, 2850, 1740, 1
640, 1460, 1360, 1250, 1120, 1
080,835,770 cm ^-1

(2) (4E)-5-carbomethoxypent-4-enylzinc(II) iodide (0.64M solution in tetrahydrofuran, 2.81m) at -70°C
l) copper (I) cyanide/lithium dichloride (392 m
2.25 ml of the tetrahydrofuran solution of g) was added and stirred at the same temperature for 15 minutes. To this solution, 3 ml of a solution of the compound (434 mg) obtained in the above (1) and 0.21 ml of chlorotrimethylsilane in diethyl ether was added at -70°C, and the temperature was raised to room temperature over about 2 hours while stirring. 15 ml of a saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried and concentrated, and the resulting residue was dissolved in 3.5 ml of ether-isopropyl alcohol (1:4) and treated with p-toluenesulfonic acid pyridine salt (8.8 mg, 0.5 mg). 035mm
ol) was added, and the mixture was stirred at room temperature for 12 hours. 20 ml of hexane and 1 saturated aqueous sodium bicarbonate solution were added to the reaction mixture.
After extraction with 0 ml, the organic layer was dried and concentrated, and the residue obtained was subjected to silica gel column chromatography (developing solvent: hexane:ether = 4:1) (2E, 17
S)-17,20-dimethyl-2,3,13,14-tetradehydro _- PGE1 methyl ester 11,15
-bis(t-butyldimethylsilyl ether) 532m
obtained g.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm: 0.10 (s, 6H), 0.11 (s, 3
H), 0.13 (s, 3H), 0.83-0.98
(m, 6H), 0.89 (s, 9H), 0.90 (s,
9H), 1.06-1.82 (m, 15H), 2.11
~2.29 (m, 3H), 2.17 (dd, J = 7.0
Hz, 18.0 Hz, 1H), 2.59-2.77
(m, 2H), 3.73 (s, 3H), 4.23-4.
35 (m, 1H), 4.43 (dt, J=1.5Hz,
7.0Hz, 1H), 5.82 (dt, J = 1.5H
z, 15.7 Hz, 1 H), 6.96 (dt, J=6.
9Hz, 15.7Hz, 1H) IR (neat): 2954, 2930, 2858, 2
234, 1748, 1728, 1660, 1463, 1
436, 1362, 1326, 1259, 1198, 1
124, 1092, 1006, 838, 779, 670
cm ^-1

(3) The compound (532m
g, 0.857 mmol) to acetonitrile (29 m
l) and dissolved in 50% aqueous hydrofluoric acid solution (6.
9 ml) was added. After stirring for 90 minutes at 0° C., the reaction was poured into ethyl acetate (40 ml) and saturated aqueous sodium bicarbonate (230 ml). Extract with ethyl acetate, wash with saturated aqueous sodium bicarbonate solution and saturated brine,
The residue obtained after drying and concentration was subjected to silica gel column chromatography (developing solvent; ethyl acetate: methanol =
40:1) to give 305 mg of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz)
δ ppm: 0.83-0.97 (m, 6H), 1.0
8-1.90 (m, 15H), 2.12-2.30
(m, 4H), 2.62 (dd, J=9.0Hz, 1
0.5Hz, 1H), 2.75 (dd, J = 7.3H
z, 18.5Hz, 1H), 2.92 (br.s, 2
H), 3.72 (s, 3H), 4.27-4.36
(m, 1H), 4.47 (dt, J = 1.0 Hz, 6.
7 Hz, 1 H), 5.68 (d, J = 15.7 Hz, 1
H), 6.96 (dt, J=7.4Hz, 15.7H
z, 1H) IR (neat): 3380, 2910, 2230, 1
720, 1700, 1650, 1435, 1270, 1
040 cm ^-1

Production Example 2 (2E,17R)-17,20-dimethyl-2,3,1
3,14-tetradehydro-PGE1 methyl ester
(Compound 2) (1) In Production Example 1 (1), (3S,5S)-3-
(t-butyldimethylsiloxy)-5-methylnona-1
- with (3S,5R)-3-(t-butyldimethylsiloxy)-5-methylnon-1-yne in place of yne,
(3R, 4R)- in substantially the same manner as in Production Example 1 (1)
2-methylene-3-[(3′S,5′R)-3′-(t
-butyldimethylsiloxy)-5'-methylnona-1'
-ynyl]-4-(t-butyldimethylsiloxy)cyclopentan-1-one was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.03-0.15 (m, 12H), 0.8
0-0.93 (m, 24H), 1.06-1.80
(m, 9H), 2.33 (dd, J=7.4Hz, 1
7.9Hz, 1H), 2.71 (dd, J = 6.4H
z, 17.9Hz, 1H), 3.41-3.56 (m,
1H), 4.20-4.32 (m, 1H), 4.44
(t, J = 6.6Hz, 1H), 5.55 (br.s,
1H), 6.14 (br.s, 1H) IR (neat): 2920, 2850, 2210, 1
730, 1630, 1450, 1360, 1240, 1
100, 1080, 820, 760 cm ^-1

(2) Using the compound obtained in (1) above, the title compound was obtained in the same manner as in Production Example 1 (2) and (3). ¹ H-NMR (CDCl ₃ , 300 MHz) δppm:
0.70-0.98 (m, 6H), 1.05-1.90
(m, 15H), 2.02-2.36 (m, 4H),
2.55 (br.s, 2H), 2.43-2.84
(m, 1H), 2.77 (dd, J=7.3Hz, 1
8.6Hz, 1H), 3.74(s, 3H), 4.28
~4.56 (m, 2H), 5.84 (d, J = 15.7
Hz, 1H), 6.99 (dt, J=7.5Hz, 1
5.7Hz, 1H) IR (neat): 3390, 2930, 2860, 2
220, 1730, 1660, 1460, 1440, 1
280,1040 cm ^-1

Production Example 3 (17R)-17,20-dimethyl-2,2,3,3,
13,14-hexadehydro -PGE1 methyl ester
(Compound 3) In Production Example 1(2), (4E)-5-carbomethoxypent-4-enylzinc(II) iodide is replaced with 5
- using carbomethoxypent-4-ynylzinc (II) iodide, using the compound obtained in Production Example 2 (1) in place of the compound obtained in Production Example 1 (1), essentially producing Example 1
The title compound was obtained in analogy to (2) and (3). ¹ H-NMR (CDCl ₃ , 300 MHz) δppm:
0.90 (t, J = 6.4Hz, 3H), 0.93
(d, J = 6.6 Hz, 3H), 1.12-1.86
(m, 15H), 2.08 (d, J=5.9Hz, 1
H), 2.18-2.29 (m, 1H), 2.24 (d
d, J = 8.9Hz, 18.6Hz, 1H), 2.32
~2.41 (m, 2H), 2.51 (d, J = 3.4H
z, 1H), 2.66 (ddd, J = 1.8Hz, 8.
1Hz, 11.2Hz, 1H), 2.77 (ddd, J
= 1.3Hz, 7.2Hz, 18.6Hz, 1H),
3.77 (s, 3H), 4.28-4.39 (m, 1
H), 4.43-4.52 (m, 1H) IR (neat): 3412, 2930, 2861, 2
237, 1747, 1715, 1436, 1384, 1
260, 1153, 1078, 821, 754 cm ^-1

Production Example 4 (17R)-17,20-dimethyl-13,14-dide
Hydro-PGE 1 methyl ester (compound 4) In Preparation 1(2), (4E)-5-carbomethoxypent-4-enylzinc(II) iodide was substituted with 5
- with carbomethoxypentylzinc(II) iodide,
Production Example 2 (1) instead of the compound obtained in Production Example 1 (1)
The title compound was obtained in substantially the same manner as in Production Example 1 (2) and (3) using the compound obtained in . ¹ H-NMR (CDCl ₃ , 300 MHz) δppm:
0.80-0.98 (m, 6H), 1.08-1.86
(m, 19H), 2.16-2.35 (m, 2H),
2.31 (t, J=7.4Hz, 2H), 2.55~
2.81 (m, 1H), 2.74 (dd, J = 7.0H
z, 18.2Hz, 1H), 3.67(s, 3H),
4.26-4.53 (m, 2H) IR (neat): 3390, 2930, 2860, 2
240, 1740, 1460, 1260, 1170, 1
070,730 cm ^-1

Production Example 5 (2E,17S)-17,20-dimethyl-2,3,1
500 mg of 3,14-tetradehydro-PGE1 (compound 5) lipase VII was dissolved in 22.5 ml of phosphate buffer (10 mM, pH 7.0), and 2.5 ml of 5
(2E, 17S) dissolved in 0% (v/v) acetone-water
50 mg (0.127 mmol) of -17,20-dimethyl-2,3,13,14-tetradehydro _- PGE1 methyl ester (compound obtained in Preparation 1) was added,
°C for 5 hours. The reaction mixture was diluted with 30 ml of ethyl acetate.
The organic layer was washed with 30 ml of saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:methanol=40:1) to obtain 41 mg of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz)
δ ppm: 0.86-0.94 (m, 3H), 0.9
1 (d, J=6.3Hz, 3H), 1.10-1.88
(m, 15H), 2.18-2.35 (m, 3H),
2.24 (dd, J = 8.8Hz, 18.6Hz, 1
H), 2.64 (ddd, J = 1.7Hz, 8.1H
z, 11.2Hz, 1H), 2.76 (ddd, J =
1.2Hz, 7.3Hz, 18.6Hz, 1H), 4.
28-4.38 (m, 1H), 4.47 (dt, J =
1.7Hz, 7.1Hz, 1H), 5.84 (dt, J
= 1.5Hz, 15.6Hz, 1H), 7.06(d
t, J=7.1Hz, 15.6Hz, 1H) IR (neat): 3391, 2930, 2859, 2
239, 1741, 1698, 1654, 1461, 1
381, 1285, 1164, 1076, 984, 75
7 cm ^-1

Preparation Examples 6 to 8 The compounds prepared in Preparation Examples 6 to 8 below were prepared in Preparation Examples 2 to 4.
Among the compounds obtained in Preparation Example 5, using the corresponding raw materials
It is produced by hydrolysis in the same manner as Production Example 6 (2E,17R)-17,20-dimethyl-2,3,1
3,14-tetradehydro-PGE1 (compound 6) 1H ^- NMR ( _CDCl3 , 300 MHz) ?ppm:
0.86-0.95 (m, 3H), 0.93 (d, J =
6.6 Hz, 3H), 1.09-1.86 (m, 15
H), 2.18-2.31 (m, 3H), 2.24 (d
d, J=9.1Hz, 18.5Hz, 1H), 2.64
(ddd, J = 1.7Hz, 8.3Hz, 11.4H
z, 1H), 2.76 (ddd, J = 1.3Hz, 7.
3Hz, 18.5Hz, 1H), 4.27-4.37
(m, 1H), 4.43-4.51 (m, 1H), 5.
84 (dt, J=1.4Hz, 15.6Hz, 1H),
7.60 (dt, J = 7.0Hz, 15.6Hz, 1
H) IR (neat): 3368, 2930, 2860, 2
238, 1745, 1697, 1653, 1462, 1
383, 1285, 1158, 1071, 984, 75
8,668 cm ^-1

Production Example 7 (17R)-17,20-dimethyl-2,2,3,3,
13,14-hexadehydro -PGE1 (compound 7) 1H ^- NMR ( _CDCl3 , 300 MHz) ?ppm:
0.82-0.96 (m, 3H), 0.93 (d, J =
6.6 Hz, 3H), 1.10-1.88 (m, 15
H), 2.22-2.32 (m, 1H), 2.26 (d
d, J=9.0Hz, 18.6Hz, 1H), 2.37
~2.44(m, 2H), 2.68(ddd, J=1.
7Hz, 8.2Hz, 11.3Hz, 1H), 2.78
(ddd, J = 1.2Hz, 7.4Hz, 18.6H
z, 1H), 4.29-4.39 (m, 1H), 4.4
5-4.52 (m, 1H) IR (neat): 3391, 2930, 2861, 2
237, 1740, 1697, 1462, 1384, 1
259,1154,1071,757 cm ^-1

Production Example 8 (17R)-17,20-dimethyl-13,14-dide
Hydro-PGE1 (compound 8) 1H ^- NMR ( _CDCl3 , 300 MHz) ?ppm:
0.85-0.97 (m, 3H), 0.93 (d, J =
6.6 Hz, 3H), 1.10-1.84 (m, 19
H), 2.17-2.30 (m, 1H), 2.24 (d
d, J=9.2Hz, 18.5Hz, 1H), 2.35
(t, J = 7.3 Hz, 2H), 2.65 (ddd, J
= 1.7Hz, 8.3Hz, 11.4Hz, 1H),
2.76 (ddd, J = 1.2 Hz, 7.3 Hz, 1
8.5 Hz, 1 H), 4.27 to 4.37 (m, 1
H), 4.43-4.52 (m, 1H) IR (neat): 3369, 2930, 2859, 2
237, 1740, 1713, 1462, 1384, 1
235,1159,1071 cm ^-1

Example 1 (tablet) 5 mg of compound 5 and 500 mg of α-cyclodextrin
was dissolved in 80 ml of distilled water and lyophilized. This freeze-dried product, 80 g of crystalline cellulose, 48.5 g of lactose and 10 g of carboxymethylcellulose calcium are mixed, and 10 g of hydroxypropylcellulose is mixed with 1 part of purified water.
00 ml as a binder and granulated using a fluid bed granulator. After adding and mixing 1 g of magnesium stearate to this granulated product, tablets with a weight of 150 mg per tablet were produced to obtain tablets containing 5 μg of compound 5 per tablet.

Example 2 (capsule) 5 mg of compound 5 and 500 mg of γ-cyclodextrin
was dissolved in 80 ml of distilled water and lyophilized. This freeze-dried product, 50 g of crystalline cellulose, 77.5 g of potato starch, and 10 g of low-substituted hydroxypropyl cellulose were mixed, and 1 part of hydroxypropyl cellulose was mixed.
Granulation was carried out using a fluidized bed granulator using a liquid obtained by dissolving 0 g in 100 ml of purified water as a binder. Hardened oil 1 to this granule
After adding and mixing g and 1 g of magnesium stearate, 150 mg was filled into No. 3 capsules to obtain capsules containing 5 μg of compound 5 per capsule.

Example 3 (fine granules) 5 mg of compound 5 and 500 mg of β-cyclodextrin
was dissolved in 80 ml of distilled water and lyophilized. After mixing 659.5 g of this freeze-dried product, corn starch and 300 g of mannitol, 40 g of hydroxypropylmethylcellulose dissolved in 600 ml of purified water was used as a binder and granulated using a fluidized bed granulator. Fine granules containing 55 μg were obtained.

──────────────────────────────────────────────────── ──Continued from the front page (72) Inventor Kazuya Kameo 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Toru Tanami 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Ken Muto 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Naoya Ono 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Jun Goto Taisho Pharmaceutical Co., Ltd. 3-24-1 Takada, Toshima-ku, Tokyo (56) References JP-A-5-345758 (JP, A) JP-A-5-310689 (JP, A ) International Publication 92/18472 (WO, A1) (58) Researched field (Int.Cl. ⁷ , DB name) A61K 31/557 C07C 405/00 504

Claims (1)

(57) [Claims] [Claim 1] Formula (Wherein, A represents an ethylene group, a vinylene group or an ethynylene group, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.) Aggregation inhibitor.