JPH0967285A - Isocarbacyclins - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject perorally adminstrable compound having proliferation inhibiting action on blood smooth muscle cells, high in activity and useful for preventing and treating restenosis after percutaneous coronary angioplasty. SOLUTION: A compound of formula I [X is a halogen, cyano, an amide, aminomethyl, an α-hydroxyalkyl, a (substituted)amine, OH, an alkoxy, a (halogen-substituted)alkyl, an ester, carboxyl or carbamoyl; (m) is 0 or 1; (n) is 0-4] and/or its enantiomer, e.g. (1S, 5S, 6S, 7R)-3-(p-cyanobenzyl)-6-[(1E, 3S)-3- hydroxy-5-phenylpentenyl]-7-hydroxybicyclo[3.3.0]-2-octane. The compound is obtained by reacting a 2,6,7-tri-substituted-3-methylene-bicyclo[3.3.0]octane intermediate with an organozinc compound containing an equivalent of carboxyphenyl group, a mono-substituted phenyllithium or a mono-substituted phenylmagensium halide in the presence of a cuprous salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to isocarbacyclines having a 3,6,7-trisubstituted bicyclo [3.3.0] -2-octene structure, and post-PTCA containing them as an active ingredient. The present invention relates to a preventive or therapeutic agent for restenosis.

[0002]

2. Description of the Related Art Prostaglandins have various physiological actions such as strong platelet aggregation inhibitory action, vasodilatory hypotensive action, gastric acid secretion inhibitory action, smooth muscle contraction action, cell protection action and diuretic action. , A compound useful for treating or preventing myocardial infarction, angina, arteriosclerosis, hypertension, duodenal ulcer, induction of labor, abortion and the like.

Natural prostacyclin is a local hormone produced mainly in the vascular endothelium in the living body, and has a strong physiological activity such as an inhibitory effect on platelet aggregation.
Attempts have been made to directly use this product as a drug by utilizing its vasodilatory action and the like (P.J. Lewis,
J. O. Grady, Clinical Phar
macology of Prostalandi
n). However, since natural prostacyclin has an enol ether bond which is easily hydrolyzed in the molecule,
It is easily deactivated under neutral or acidic conditions. Therefore, it cannot be said to be a preferable compound as a drug because of its chemical instability. Therefore, synthetic studies of synthetic prostacyclin derivatives that show the same activity as natural prostacyclin and are chemically stable have been earnestly conducted (Synt).
hsis, 1984, 449). Above all, the oxygen atom at the 6- and 9-positions of prostacyclin was replaced with a methine group (-CH =).
9 (O) -methano-Δ ^{6 (9,} which is a prostacyclin that sufficiently satisfies the chemical stability.
α ⁾ -Prostaglandins I ₁ (isocarbacyclins) are synthesized, exhibiting potent biological activity such as platelet aggregation inhibitory action and vasodilatory hypotensive action comparable to natural prostacyclin, and are considered to be useful as pharmaceuticals. (JP-A-59-210044, JP-A-61-1975)
No. 18).

However, these isocarbacyclines have been studied as chemically stable synthetic prostacyclin derivatives, and their target biological activities are basically the same as those of prostacyclin, and the prostacyclin derivatives have the same biological activity. The carboxylic acid at the 1-position, which is considered to be essential for the expression of basic biological activity, is always present as an ester form which is free or hydrolyzed in vivo to give a carboxylic acid (Medicinal Re
search Reviews. Vol. 5, pp.
1-53 (1985), Acta Physiolog.
ica Hungarica, Vol. 64, pp. Two
25-230 (1984) etc.).

Therefore, while having the same 3,6,7-trisubstituted bicyclo [3.3.0] -2-octene skeleton as isocarbacyclines, it has a carboxylic acid free or ester at the 1-position. It has been assumed that compounds that do not have so far not been synthesized and have no prostacyclin-like biological activity.

On the other hand, percutaneous coronary angioplasty (PTCA)
Is a surgical method that has rapidly progressed in recent years because it has a low degree of invasiveness to patients and an excellent initial therapeutic effect as a therapeutic method for ischemic heart disease. It is said that more than 30,000 cases are performed annually in Japan and 300,000 cases in the United States. However, the biggest drawback of coronary restenosis appearing within a few months after surgery in 30-40% of patients after PTCA remains unsolved.

As a mechanism of occurrence of restenosis after PTCA, R. "Vascular injury-reaction hypothesis" by Ross, that is, vascular endothelial cell injury caused by some cause induces adhesion and aggregation of platelets locally at the injury site, and secondary release of PDGF, cytokines, etc. It has been widely accepted that the application of the hypothesis that arteriosclerosis is established by the proliferation of vascular smooth muscle cells and intercellular substances in the rat. Therefore, P using antiplatelet agents, anticoagulants, etc.
Although clinical trials to prevent restenosis after TCA have been attempted, currently, although the GPIIb / IIIa antibody that suppresses platelet adhesion has been approved in the United States, it is used only in limited patients because of side effects that tend to bleed. Is the situation.
Thus, a drug having a clinically sufficient effect has not been found yet. Furthermore, compounds that suppress one or both of "migration of vascular smooth muscle cells from the intima to the media and proliferation in the media", which are deeply involved in the mechanism of restenosis, also prevent restenosis. Has been strongly expected as a drug for, for example, some of the angiotensin-converting enzyme inhibitors have been clinically tested as "compounds that may suppress the proliferation of vascular smooth muscle cells", but their usefulness has been recognized. No clinically effective drug has been found yet.

By the way, 3,6,7-trisubstituted bicyclo [3.3.0] -2- having a phenylene group at the 3-position side chain
Octenes are known to have a vascular smooth muscle cell proliferation or migration inhibitory action (Japanese Patent Application No. 6-18725).
0). However, it was found that these compounds should be improved, such as instability due to metabolic decomposition of the 6-position side chain and rather low inhibitory activity.

[0009]

The problem to be solved by the present invention is to proliferate orally administrable highly active vascular smooth muscle cells, which is strongly expected as a drug for preventing restenosis after PTCA. To find a drug with an inhibitory effect.

[0010]

The present inventors have found that the PTCA
As a result of diligent research on a compound having a vascular smooth muscle cell growth inhibitory action which is desired as a preventive or therapeutic agent for subsequent diseases such as restenosis, isocarbacyclines having a specific structure have been known so far. The inventors have found that the compound has higher activity than that of the compound and is difficult to metabolize, and thus reached the present invention.

That is, the present invention provides the following formula [I]:

[0012]

Embedded image

[In the formula, X is a halogen atom located in ortho, meta or para, a cyano group, an amide group, an aminomethyl group, a linear or branched α-hydroxyalkyl group, or an optionally substituted amino. Represents a group, a hydroxyl group, an alkoxy group, an alkyl group, an aryl group, a halogen-substituted alkyl group, an ester group, a carboxyl group or a carbamoyl group, m is 0 or 1, and n is an integer of 0 to 4. ] And / or an enantiomer thereof isocarbacyclines.

The present invention further provides a prophylactic or therapeutic agent for restenosis after PTCA, which comprises as an active ingredient a compound represented by the above formula [1] and / or its enantiomer isocarbacyclins.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION In the above formula [I], X is a halogen atom located at ortho, meta or para, a cyano group, an amido group, an aminomethyl group, a linear or branched α-hydroxyalkyl group, It represents an optionally substituted amino group, hydroxyl group, alkoxy group, alkyl group, aryl group, halogen-substituted alkyl group, ester group, carboxyl group, or carbamoyl group. Hereinafter, these substituents will be described more specifically.

The halogen atom may be any of fluorine, chlorine, bromine and iodine, of which fluorine is preferred.

The amino group constituting the amide group is C _{1 to} C ₆
It may be mono- or di-substituted by the alkyl group of.
Also, an amide composed of a C _{4 to} C ₈ cyclic amine may be used,
Particularly, piperidinoamide is preferable.

The alkyl group portion of the linear or branched α-hydroxyalkyl group is preferably a C _{1 to} C ₆ alkyl group, and is preferably a dimethylhydroxymethyl group.

The amino group may be mono- or di-substituted by a C ₁ -C ₆ alkyl group, with a dimethylamino group being particularly preferred.

The alkoxy group is preferably a linear or branched C _{1 to} C ₆ alkyl group or a phenyl group.

The alkyl group is preferably a linear or branched C _{1 to} C ₉ alkyl group.

The halogen of the alkyl group substituted with halogen may be any of fluorine, chlorine, bromine and iodine, of which fluorine is preferred. The alkyl group moiety is preferably a linear or branched C _{1 to} C ₆ alkyl group, of which the trifluoromethyl group is preferred.

The ester group is preferably a linear or branched C _{1 to} C ₆ alkyl group or a phenyl group ester, and among them, a methyl ester is preferable.

In the above formula [I], n represents an integer of 0 to 4. Among them, n is preferably an integer of 1 to 3, and most preferably 2.

The preferred specific examples of the isocarbacyclines of the present invention are as follows. (01) (1S, 5S, 6S, 7R) -3- (p-Cyanobenzyl) -6-[(1E, 3S) -3-hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3. 0] -2-octene (02) (1S, 5S, 6S, 7R) -3- (p-methoxycarbonylbenzyl) -6-[(1E, 3S)-
3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (03) (1S, 5S, 6S, 7R) -3- (p-carbamoylbenzyl) -6- [ (1E, 3S) -3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (04) (1S, 5S, 6S, 7R) -3- (p-hydroxy Methylbenzyl) -6-[(1E, 3S) -3
-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (05) (1S, 5S, 6S, 7R) -3- (p-dimethylhydroxymethylbenzyl) -6- [(1E, 3
S) -3-Hydroxy-5-phenylpentenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene (06) (1S, 5S, 6S, 7R) -3- (o-piperidinocarbonylbenzyl) -6-[(1E, 3S)
-3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (07) (1S, 5S, 6S, 7R) -3- (m-piperidinocarbonylbenzyl) -6-[(1E, 3S)
-3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (08) (1S, 5S, 6S, 7R) -3- (p-piperidinocarbonylbenzyl) -6-[(1E, 3S)
-3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (09) (1S, 5S, 6S, 7R) -3- (p-aminomethylbenzyl) -6 -[(1E, 3S) -3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (10) (1S, 5S, 6S, 7R) -3- (p -Methoxybenzyl) -6-[(1E, 3S) -3-hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (11) (1S, 5S, 6S, 7R ) -3- (p-Dimethylaminobenzyl) -6-[(1E, 3S) -3-
Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (12) (1S, 5S, 6S, 7R) -3- (p-hydroxybenzyl) -6-[(1E 3S) -3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (13) (1S, 5S, 6S, 7R) -3- (p-phenylbenzyl) -6-[(1E, 3S) -3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (14) (1S, 5S, 6S, 7R) -3- (O-Trifluoromethylbenzyl) -6-[(1E, 3S)-
3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (15) (1S, 5S, 6S, 7R) -3- (m-trifluoromethylbenzyl) -6 -[(1E, 3S)-
3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (16) (1S, 5S, 6S, 7R) -3- (p-trifluoromethylbenzyl) -6 -[(1E, 3S)-
3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (17) (1S, 5S, 6S, 7R) -3- (o-fluorobenzyl) -6- [ (1E, 3S) -3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (18) (1S, 5S, 6S, 7R) -3- (m-fluoro Benzyl) -6-[(1E, 3S) -3-hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (19) (1S, 5S, 6S, 7R)- 3- (p-Fluorobenzyl) -6-[(1E, 3S) -3-hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (20) (1S, 5S , 6S, R) -3- [2-
(P-Cyanophenyl) ethyl] -6-[(1E, 3
S) -3-Hydroxy-5-phenylpentenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene (21) (1S, 5S, 6S, 7R) -3- [2-
(P-Aminomethylphenyl) ethyl] -6-[(1
E, 3S) -3-Hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (22) (1S, 5S, 6S, 7R) -3- (p-trifluoro Methylbenzyl) -6-[(1E, 3S)-
3-Hydroxy-4-phenylbutenyl] -7-hydroxybicyclo [3.3.0] -2-octene (23) (1S, 5S, 6S, 7R) -3- (p-trifluoromethylbenzyl)- 6-[(1E, 3S)-
3-Hydroxy-6-phenylhexenyl] -7-hydroxybicyclo [3.3.0] -2-octene (01) ′ to (23) ′ (01) to (23) have 6-position side chain configuration. Examples thereof include isomers (1E, 3R), but are not limited thereto.

The isocarbacyclines of the present invention are typically 2,6,7-trisubstituted-3-methylenebicyclo [3] derived from commercially available NS-11 (manufactured by Nissan Chemical Industries, Ltd.). .3.0] octane intermediate (24), in the presence of cuprous salts, an organozinc compound containing a carboxyphenyl group equivalent, or ortho, meta or para monosubstituted phenyllithium, Alternatively, it can be produced by a method of reacting phenylmagnesium halide substituted with ortho, meta or para.

The isocarbacyclines of the present invention can be administered orally or parenterally, for example, rectally, subcutaneously, intramuscularly, intravenously, transdermally, etc., for the above-mentioned purpose. It may be administered orally or intravenously.

For oral administration, a solid preparation or a liquid preparation can be prepared. Examples of solid preparations include tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is mixed with a pharmaceutically acceptable carrier such as sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose and the like. Formulation operation is performed according to a conventional method, but additives for formulation other than the above carrier,
For example, a lubricant such as calcium stearate or magnesium stearate may be contained.

For example, in the above solid preparation, an enteric substance such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer, or methacrylic acid or methyl methacrylate copolymer can be added. It is also possible to spray an aqueous solution or an aqueous solution of the above-mentioned organic solvent to form an enteric coating film to obtain an enteric coated preparation. Solid preparations such as powders and granules can be wrapped in enteric-coated capsules.

Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, syrups or elixirs. These preparations can also use a commonly used pharmaceutically acceptable carrier, for example, an oily base such as coconut oil, fractionated coconut oil, soybean oil or corn oil containing water or liquid paraffin as a carrier. .

The pharmaceutically acceptable carrier includes, if necessary, auxiliary agents, fragrances, stabilizers or preservatives which are usually used. Liquid formulations may also be administered in capsules made of an absorbable material such as gelatin. Solid formulations for rectal administration include suppositories which contain the active ingredient and are manufactured by conventional methods.

The preparation for parenteral administration is administered as a sterile aqueous or non-aqueous liquid, suspension or emulsion. Non-aqueous solutions or suspensions are pharmaceutically acceptable carriers, for example propylene glycol, polyethylene glycol, vegetable oils such as olive oil or soybean oil, injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizing agents. These solutions, suspensions, and emulsions can be sterilized by, for example, filtering through a bacteria-retaining filter, heating, blending a sterilizing agent, or irradiating with ultraviolet rays. Alternatively, a sterile solid preparation may be produced and dissolved in sterile water or a sterile solvent for injection immediately before use. Further, water was added to a homogenous solution of vegetable oil such as soybean oil, phospholipid such as lecithin, and isocarbacyclines of the present invention, and homogenization was performed using a homogenizer such as a pressure jet homogenizer or an ultrasonic homogenizer. A fat emulsion or the like can also be used as an injection.

The dosage form for transdermal administration is, for example, an ointment,
Examples include creams. These are manufactured by a usual method.

When the agent of the present invention is used for prevention of restenosis after PTCA, it depends on the degree of symptoms, age, sex, body weight, administration route, etc. of the patient, but as the amount of isocarbacyclins in it. , Usually 1 μg / day for adults
About 1 mg can be administered. Such a dose may be administered once to several times a day, for example, in 2 to 6 divided doses.

[0035]

【Example】

 [Example 1]

[0036]

Embedded image

From the commercially available compound NS-11 to intermediate (25)
In a 500 mL eggplant flask equipped with a synthetic magnetic stirrer of 0.492 g (12.95 mmo) of lithium aluminum hydride.
l) was added and the atmosphere was changed to nitrogen. Add tetrahydrofuran (THF) (100 mL) to suspend,
Cooled to 80 ° C. NS-11 purchased from Nissan Chemical
9.226 g (24.24 mmol) of THF (50 m
The L) solution was added dropwise over 10 minutes, and the mixture was stirred for 2 hours as it was. The cooling bath was removed, ether (200 mL) was added, and saturated aqueous sodium sulfate solution was added in excess to cause white precipitation. The organic layer was decanted, dried over anhydrous magnesium sulfate, and filtered and concentrated to obtain a crude alcohol as a yellow liquid. The alcohol was placed in a 500 mL eggplant flask, dissolved in methylene chloride (150 mL), and pyridine (25 mL) and methyl chloroformate (1 mL) on an ice bath.
6 mL) methylene chloride solution (20 mL) was added in order,
Stir for 1 hour. Remove the ice bath and add methanol (10m
L), water (100 mL), saturated aqueous sodium chloride solution (100 mL), hexane (100 mL), and ether (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100mL). Combine the organic layers,
The extract was washed with saturated saline, saturated potassium hydrogen sulfate aqueous solution, and saturated saline (100 mL each). The extract was dried over anhydrous magnesium sulfate, filtered and concentrated, and then subjected to silica gel column chromatography (hexane-ethyl acetate / 10: 1) to obtain 10.46 g (23.7) of a colorless liquid ester carbonate (25).
5 mmol, 98.0%) was obtained.

[Embodiment 2]

[0039]

Embedded image

Synthesis of Intermediate (24b) In a 200 mL eggplant-shaped flask equipped with a magnetic stirrer, 10.46 g (23.8 mmol) of compound (25) was charged, and T
It was dissolved in HF (50 mL). Tetra-n-butylammonium fluoride (1.0 mol / L THF
Solution) (45 mL) was added and stirred for 2 hours. The reaction solution was directly concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate / 1: 1) to obtain 5.18 g (15.9 mmol, 6) of desilylated product (27) as a colorless liquid.
6.9%) was obtained.

5.18 g (15.9 mmol) of the compound (27) was placed in a 300 mL eggplant flask equipped with a magnetic stir bar, and dimethyl sulfoxide (DMSO) (80 mL) was added.
, Triethylamine (30 mL) and 11.9 g (75.0 mmol) of sulfur trioxide pyridine complex were sequentially added, and the mixture was stirred at room temperature for 1 hour. After that, water (200 mL) was added while the reaction solution was placed in an ice bath, and the mixture was stirred well and extracted with ether (100 mL × 2). The organic layer is water (50m
L) and saturated brine (50 mL), which were then washed, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off and concentrated, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate / 3: 1 → 2: 1), and 3.87 g (11.9 mmol, 11.9 mmol, aldehyde (28) of yellow oil was obtained.
75.2%).

In a 500 mL eggplant flask equipped with a magnetic stir bar, sodium hydride (1.01 g, 25.3 mmo) was added.
1) was put into the reaction vessel to create a nitrogen atmosphere. THF
(50 mL) was added to the suspension to prepare the compound (2
6b) (6.16 g, 24.0 mmol) in THF (2
0 mL) solution was added dropwise. The mixture was stirred for 15 minutes as it was, and then the compound (28) (3.87 g, 11.9 mmol).
THF (30 mL) solution of was added dropwise. After stirring for 2 hours, saturated aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). Saturated saline (50m
It was washed with L) and dried over anhydrous magnesium sulfate.
The desiccant was filtered off, concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate / 5: 1 → 3: 1) to obtain 4.23 g (9.3%) of yellow oily enone (29b).
0 mmol, 77.9%) was obtained.

In a 300 mL eggplant-shaped flask equipped with a magnetic stir bar, 4.23 g (9.30 mmo) of compound (29b) was added.
1) was added and dissolved in methanol (100 mL). Cerium (III) chloride heptahydrate 4.23 g (11.4 m
(mol) was added and dissolved, and the mixture was stirred on an ice bath, and 0.60 g (15.8 mmol) of sodium borohydride was added little by little. Stir for 15 minutes on an ice bath, and wash with water (5
0 mL) and saturated aqueous ammonium chloride solution (100 mL)
Was added and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated to give crude alcohol. This was placed in a 300 mL eggplant flask equipped with a magnetic stir bar, and N, N-dimethylformamide (D
It was dissolved in MF) (100 mL). Imidazole 1.6
0 g (23.5 mmol), N, N-dimethylaminopyridine 0.044 g (0.36 mmol), tert-
Butyldimethylchlorosilane 1.93 g (12.8 mm
ol) was added in that order and the mixture was stirred at room temperature overnight. Water (50m
L) was added, the mixture was extracted with hexane (150 mL × 2), the organic layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the oily crude product obtained by concentration was subjected to silica gel column chromatography (hexane-ethyl acetate / 10: 1) to give 15
-4.08 g (7.15 mmo) of siloxy compound (30b)
1, 76.9%) was obtained.

Compound (30b) (4.08 g, 7.15 mmol) was placed in a 100 mL eggplant flask equipped with a magnetic stir bar.
Was added and dissolved in methanol (30 mL). 1.0N
When a sodium hydroxide aqueous solution (8 mL) was added, the reaction solution became cloudy. After stirring at room temperature for 6 hours, 1.0
Aqueous N sodium hydroxide solution (2 mL) was added, and the mixture was stirred for 45 minutes, then saturated brine (50 mL) and 0.1 N hydrochloric acid (20 mL) were added, and the mixture was well stirred, and ethyl acetate (100
mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. 200 mL of oily crude product obtained by filtering off the drying agent and concentrating
Transfer to eggplant flask, o-phenanthroline 9.6mg
Was charged into the flask to create a nitrogen atmosphere. THF (50
mL) was added and dissolved, cooled to -80 ° C, and n-butyllithium (1.66M hexane solution) was added dropwise. It took 5.8 mL until the reaction solution was colored red. 11.3 g of diethyl chlorothiophosphate (59.8 mmo)
A solution of 1) in THF (30 mL) was added dropwise, the cooling bath was removed, and the mixture was stirred overnight. Water (50 mL) and saturated aqueous ammonium chloride solution (100 mL) were added to add ethyl acetate (100 m).
L), the organic layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the crude oily product obtained by concentration was purified by silica gel column chromatography (hexane-ethyl acetate / 10:
It was subjected to 1) to obtain a yellow oil (31b).

The compound (31b) obtained above was placed in a 200 mL eggplant flask equipped with a magnetic stir bar, toluene (100 mL) was added, and the mixture was heated under reflux overnight. The mixture was allowed to cool and concentrated to give a brown oily substance. This product was subjected to silica gel column chromatography (hexane-ethyl acetate / 2: 1 →
1: 1 → ethyl acetate only) to give compound (24b)
1.15 g (1.73 mmol) and its de-THP form 0.
46 g was obtained.

The dehydrogenated THP was dissolved in methylene chloride (20 mL), and p-toluenesulfonic acid monohydrate (0.07
g) 3,4-dihydro-2H-pyran under catalyst (0.5 m
It was converted to (24b) by reacting with L). Similarly, by silica gel column chromatography purification (24b)
0.33 g (0.50 mmol) was obtained.

By the same method, the compound (25a) was converted to the compound (24a) from the compound (25a) and the compound (2a).
Compound (24c) was synthesized from 5) and compound (26c).

[Embodiment 3]

[0049]

Embedded image

Synthesis of Compounds (02) and (02) ' 0.39 g (6.01 mmol) of zinc powder was placed in a 50 mL eggplant flask equipped with a magnetic stirrer and ignited under vacuum to dry the system and zinc dust. It was The inside of the flask is made into a nitrogen atmosphere, THF (1 mL) is put in and suspended,
1,2-Dibromoethane (40 mL) was added and the mixture was heated to 65 ° C. and stirred for 1 minute. After cooling to room temperature and adding chlorotrimethylsilane (80 mL), foaming occurred. Stir for 20 minutes at room temperature and methyl p-iodobenzoate (obtainable easily from p-iodobenzoic acid and methanol) 1.3.
A solution of 4 g (5.13 mmol) of DMF (10 mL) was added. The resulting suspension was stirred overnight on a 40 ° C. warm water bath. I got a dark brown suspension.

Copper (I) chloride was added to a 100 mL eggplant flask.
0.502 g (5.07 mmol), lithium chloride 0.1.
426g (10.1mmol) was put and the inside of a container was made into a nitrogen atmosphere. THF (10 mL) was added thereto to dissolve the salt, and the brown suspension obtained above was added.
0.334 g (0.50 mmol) of the compound (24b) was added to the brown suspension obtained by stirring at room temperature for 30 minutes.
THF solution (10 mL) was added and the mixture was stirred overnight on a warm water bath at 55 ° C. A saturated ammonium chloride aqueous solution (50 mL) was added to the obtained suspension, and ethyl acetate (10 mL) was added.
0 + 50 mL). The organic layer was saturated brine (10
It was washed with 0 mL × 2) and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the crude oily product obtained by concentration was filtered through silica gel to obtain a colorless oily crude product. The oily crude product was transferred to a 100 mL eggplant flask equipped with a magnetic stir bar and dissolved in methanol (30 mL).
0.1N hydrochloric acid (2.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2), and the organic layer was saturated brine (50 mL).
It was washed with mL × 2). After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the oily crude product obtained by concentration was purified by silica gel column chromatography (hexane-ethyl acetate / 2: 1 → 1: 1 → 1: 2). The low polarity fraction of colorless needles (02) '70 .0 mg (0.16
92.0 mg (0.23 mmol, 45.1) of a highly polar fraction (02) of colorless needle crystals as in the case of
%) Was obtained.

Example 4 Synthesis of Compounds (01) and (01) 'In the same manner as in the synthesis of compounds (02) and (02)', p-
It was synthesized from iodocyanobenzene and compound (24b).

Example 5 Synthesis of Compound (03) 40 mg (0.09 mmol) of Compound (02) was placed in a glass tube (10 mL) for a pressure bottle, charged with a magnetic stir bar, and added with THF (2 mL) to dissolve it. did. After adding concentrated ammonia water (5 mL) to this, put it in a pressure bottle, quickly close the lid, and put it on a water bath at 100 ° C for 4
Stirred for hours. A 1N sodium hydroxide aqueous solution (5 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20 mL × 2), the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the crude product obtained was
Purified using PLC, compound (03) (18 mg, 3
2.0%) was obtained.

Example 6 Synthesis of Compound (04) In a 25 mL eggplant-shaped flask equipped with a magnetic stir bar, 20 mg (0.05 mmol) of Compound (02) was placed, nitrogen atmosphere was added, and THF (5 mL) was added to dissolve. did. Lithium aluminum hydride (5 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour and then heated and stirred for several minutes. A saturated aqueous solution of sodium sulfate was carefully added dropwise to the obtained reaction mixture to generate a white precipitate. The supernatant was collected by decantation, the precipitate was washed with ethyl acetate, and this washing and the above supernatant were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate / 1: 1 → 1: 2 → ethyl acetate only) to give compound (04) (19.4 mg,
97.0%) was obtained.

Example 7 Synthesis of Compound (05 ) 22.2 mg (0.051 mmol) of Compound (02) was placed in a 50 mL two-necked flask equipped with a magnetic stirrer,
Dissolve in THF (10 mL), cool to 0 ° C. and methylmagnesium bromide (3.0 mol / L ether solution)
(1.0 mL) was added, the cooling bath was removed, and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution (15 m
L) was added, the mixture was extracted with ethyl acetate (100 mL), and the organic layer washed with saturated brine (30 mL) was dried over anhydrous magnesium sulfate. After filtration and concentration, silica gel column chromatography (hexane-ethyl acetate / 2: 1 →
1: 1 → 1: 2), the compound (05) (15.2 m)
g, 70.0%) was obtained.

Example 8 Synthesis of Compound (08) In a 50 mL two-necked flask equipped with a magnetic stirrer, 86 mg (1.0 mmol) of piperidine was placed, and toluene (10
mL). Trimethylaluminum (1.0 mol / L hexane solution) (1.0 mL) was added to this solution, and the mixture was stirred at room temperature for 15 minutes, and then compound (02) 2 was added.
2.2 mg (0.051 mmol) of toluene (10 m
What was melt | dissolved in L) was added, and it stirred at 60 degreeC for 18 hours. The reaction solution was returned to room temperature, 1N hydrochloric acid (10 mL) was added, and the mixture was stirred, and further, a 1N sodium hydroxide aqueous solution (10
(mL) was added and extracted with ethyl acetate (100 mL), and the organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate / 1: 1 → 1: 2 → ethyl acetate only) to obtain compound (08) (20.0 mg, 80.0%).

Example 9 Synthesis of Compound (06) O-obtained by the same synthetic method as for Compound (02)
A compound (0
It was synthesized by the same synthesis method as in 8).

Example 10 Synthesis of Compound (07) m-obtained by the same synthetic method as for Compound (02)
A compound (0
It was synthesized by the same synthesis method as in 8).

Example 11 Synthesis of Compound (09) Compound (0) was placed in a 25 mL eggplant flask equipped with a magnetic stir bar.
1) 12.8 mg (0.032 mmol) was added to make a nitrogen atmosphere, and dissolved in THF (5 mL). Lithium aluminum hydride (5 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour and then heated and stirred for 1 hour. A 1N aqueous sodium hydroxide solution (0.3 mL) was added dropwise to the obtained reaction mixture, and then a saturated aqueous sodium sulfate solution was carefully added dropwise to form a white precipitate. The supernatant was collected by decantation, the precipitate was washed with ethyl acetate, and this washing and the above supernatant were combined and dried over anhydrous sodium sulfate. After concentration by filtration, it was subjected to HPLC to give the compound (09)
(10.5 mg, 97.0%) was obtained.

[Embodiment 12]

[0061]

[Chemical 6]

Synthesis of Compounds (11) and (11) 'In a 100 mL eggplant flask equipped with a magnetic stir bar, N, N-.
Dimethyl-4-iodoaniline (easily obtained from 4-iodoaniline and methyl iodide) 0.301 g (1.
(22 mmol), and dried under vacuum, and then the system was made a nitrogen atmosphere. THF (10 mL) was added thereto to form a solution, which was cooled to −80 ° C. and n-butyllithium (1.6
4M hexane solution) 1.35 mL (2.21 mmol)
Was added and the mixture was stirred at −80 ° C. for 1 hour.

In a 100 mL eggplant flask equipped with a magnetic stirring bar, 0.197 g (1.99 mmol) of copper (I) chloride was added.
And 0.202 g (4.76 mmol) of lithium chloride
, And heated under vacuum to dry. After making the system a nitrogen atmosphere, THF (10 mL) was added, and the mixture was stirred at room temperature for 20 minutes to be dissolved.

The solution of 4- (N, N-dimethylamino) phenyllithium prepared above was added dropwise to the solution at room temperature to give 1
0.164 g of compound (24b) after stirring for 0 minutes
A solution of (0.25 mmol) in THF (10 mL) was gradually added, and the obtained reaction solution was stirred overnight on an oil bath at 40 ° C.

Aqueous saturated ammonium chloride solution (50 mL)
Was added, and the mixture was extracted with ethyl acetate (80 mL), and the organic layer washed with saturated brine (50 mL × 2) was dried over anhydrous magnesium sulfate. The desiccant was removed, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (hexane-ethyl acetate / 10: 1) to give a slightly colored oily substance. This crude product was placed in a 100 mL eggplant flask equipped with a magnetic stir bar, and methanol (30
mL). 1.0N hydrochloric acid (0.5 mL) was added dropwise with vigorous stirring, and the mixture was stirred at room temperature for 3 hours. Saturated sodium hydrogen carbonate solution (50 mL) was added here, and ethyl acetate (100 mL
(mL) and the organic layer washed with saturated saline (50 mL) was dried over anhydrous magnesium sulfate. The colorless oily substance obtained by removing the desiccant and concentrating under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate /
2: 1 → 1: 1 → 1: 2), and the compound (11) ′ (10.3 mg, 10.0%) of the low polarity fraction and the compound (11) (21.7 mg, 21.7 mg, of the high polarity fraction). 21.0%) as a colorless oil.

[Embodiment 13]

[0067]

[Chemical 7]

Synthesis of Compounds (19) and (19) 'In a 100 mL eggplant flask equipped with a magnetic stir bar, copper (I) chloride (1.06 g, 10.7 mmol) and lithium chloride (1.11 g, 26.3 mmol). ) Was added and heated under vacuum to dry. After making the system a nitrogen atmosphere, TH
F (10 mL) was added and the mixture was stirred at room temperature for 20 minutes to dissolve it. Here, magnesium (0.258g, 10.6
mmol) and 4-bromofluorobenzene (1.827)
g, 10.4 mmol) separately prepared 4-fluorophenyl magnesium bromide (ether solution),
After stirring at room temperature for 10 minutes, compound (24b) (0.2
A solution of 86 g (0.43 mmol) in THF (10 mL) was gradually added, and the obtained reaction solution was stirred overnight at room temperature.

Saturated ammonium chloride aqueous solution (50 mL)
Was added, extracted with ethyl acetate (150 mL), and the organic layer washed with saturated brine (50 mL) was dried over anhydrous magnesium sulfate. The desiccant was removed, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (hexane-ethyl acetate / 20: 1 → 10: 1) to obtain a solid substance that slightly fluoresces. The crude product was placed in a 500 mL eggplant flask equipped with a magnetic stir bar and dissolved in methanol (40 mL). 1. With vigorous stirring
0N hydrochloric acid (4.0 mL) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate (100 mL) was added to this, extracted with ethyl acetate (200 mL), and saturated brine (50 m).
The organic layer washed with L) was dried over anhydrous magnesium sulfate. The desiccant was removed, and the colorless oily substance obtained by concentration under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate / 2: 1 → 1: 1 → ethyl acetate only) to give a low-polarity product of the colorless oily substance. Minute (19) '(21.3m
g, 0.054 mmol, 12.6%) and a highly polar fraction of colorless oil (19) (54.1 mg, 0.138 mmo)
1, 32.1%) was obtained.

[Example 14] Synthesis of compounds (10) and (10) 'In the same manner as in the synthesis of compounds (19) and (19)',
It was synthesized from p-bromoanisole and compound (24b).

Example 15 Synthesis of Compounds (12) and (12) ′ Compounds (19) and (19) ′ were synthesized in the same manner as described above.
It was synthesized from p- (tert-butyldimethylsilyloxy) bromobenzene and compound (24b).

Example 16 Synthesis of Compounds (13) and (13) ′ Compounds (19) and (19) ′ were synthesized in the same manner as described above.
Synthesized from p-bromobiphenyl and compound (24b).

[Example 17] Synthesis of compounds (14) and (14) 'In the same manner as in the synthesis of compounds (19) and (19)',
It was synthesized from o-bromobenzotrifluoride and compound (24b).

Example 18 Synthesis of Compounds (15) and (15) ′ Compounds (19) and (19) ′ were synthesized in the same manner as described above.
It was synthesized from m-bromobenzotrifluoride and compound (24b).

[Example 19] Synthesis of compounds (16) and (16) 'In the same manner as in the synthesis of compounds (19) and (19)',
It was synthesized from p-bromobenzotrifluoride and compound (24b).

Example 20 Synthesis of Compounds (17) and (17) ′ Compounds (19) and (19) ′ were synthesized in the same manner as described above.
It was synthesized from o-bromofluorobenzene and compound (24b).

[Example 21] Synthesis of compounds (18) and (18) 'In the same manner as in the synthesis of compounds (19) and (19)',
It was synthesized from m-bromofluorobenzene and compound (24b).

Example 22 Synthesis of Compounds (22) and (22) ′ Compounds (19) and (19) ′ were synthesized in the same manner as described above.
It was synthesized from p-bromobenzotrifluoride and compound (24a).

[Example 23] Synthesis of compounds (23) and (23) 'In the same manner as in the synthesis of compounds (19) and (19)',
It was synthesized from p-bromobenzotrifluoride and compound (24c).

[Embodiment 24]

[0081]

Embedded image

Synthesis of compound (20) 3.63 g (8.23 mmol) of compound (25) and tris (dibenzylideneacetone) dipalladium (0.27)
g, 0.29 mmol) in a 500 mL flask and dissolved in THF (200 mL) under a nitrogen stream.
-Bis (diphenylphosphino) ethane (0.29 g,
0.73 mmol) and 4-cyanobenzylphenyl sulfone (2.74 g, 10.64 mmol) were sequentially added, and the mixture was heated under reflux for 8 hours. The heating was stopped and the cooled reaction solution was concentrated under reduced pressure and then subjected to silica gel column chromatography (hexane-ethyl acetate / 10: 1 → 4: 1),
Colorless powder of bicyclic benzyl sulfone (32) 4.41 g
(7.08 mmol, 86.1%) was obtained. Compound (3
2) was placed in a 200 mL eggplant flask, and methanol (1
Dissolved in 100 mL of magnesium (0.85 g, 3
5.0 mmol) was added and the mixture was stirred overnight. A saturated ammonium chloride aqueous solution (50 mL) was added thereto, extracted with ethyl acetate (500 mL), and the organic layer washed with saturated saline (100 mL) was dried over anhydrous magnesium sulfate.
After filtration and concentration, the obtained yellow oily substance was placed in a 200 mL eggplant-shaped flask and dissolved in THF (100 mL) to prepare tetra-
n-Butyl ammonium fluoride (1.0 mol / L
(THF solution) (20 mL) was added and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained oily product was subjected to silica gel column chromatography (hexane-ethyl acetate /
1.14 g (3.09 mmol, 4) of colorless oily alcohol (33) which was subjected to 2: 1 → 1: 1 → ethyl acetate only).
3.7%).

0.95 g (2.57 mm) of compound (33)
ol) into a 100 mL eggplant flask and add DMSO (2
Dissolved in 0 mL) and triethylamine (2.86 g, 2
8.2 mmol), sulfur trioxide pyridine complex (1.97)
g, 12.4 mmol) was added and the mixture was stirred for 3 hours. The solution was poured into ice cold water (50 mL) and washed with ether (150 m
Lx2), extracted with water (100 mL) and saturated saline (1
00 mL). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then silica gel column chromatography (hexane-ethyl acetate / 5: 1 →
2: 1), and the yellow liquid aldehyde (34) 0.6
3 g (1.73 mmol, 67.2%) was obtained.

In a 100 mL eggplant flask equipped with a magnetic stir bar, 0.041 g (1.040 mmo) of sodium hydride was added.
l) was added and a nitrogen atmosphere was created. THF (20 mL) was added to make a suspension, and compound (26b) (0.2
A solution of 90 g (1.132 mmol) in THF (10 mL) was added dropwise. After stirring for 45 minutes, compound (34)
(0.275 g, 0.753 mmol) of THF (10
(mL) solution was added dropwise and stirred for 1.25 hours. Add saturated ammonium chloride aqueous solution (50 mL) and stir well,
Extracted with ether (50 mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration, silica gel column chromatography (hexane-ethyl acetate / 8: 1) was performed and 0.21 g (0.42 mmo) of colorless oily 15-keto compound (35b) was obtained.
1, 36.8%).

In a 100 mL eggplant flask equipped with a magnetic stir bar, 0.11 g (0.23 mmol) of compound (35b) was added.
Was added and dissolved in methanol (20 mL). Cerium (III) chloride heptahydrate 0.44 g (1.19 mmo)
1) was added and dissolved, and the mixture was cooled to -40 ° C. 0.05 g (1.39 mmol) of sodium borohydride
Was added and stirred for 30 minutes. Ethyl acetate (10
(0 mL) was added, the mixture was returned to room temperature, washed with water (50 mL × 2) and saturated saline (50 mL × 2) in that order, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration, colorless oily 15-hydroxy compound 0.12 g (0.23 mm
ol, 100%). This 15-hydroxy form is
The mixture was placed in a 300 mL eggplant flask equipped with a magnetic stir bar, dissolved in methanol (30 mL), p-toluenesulfonic acid monohydrate (0.05 g) was added, and the mixture was stirred for 30 minutes.
Thereafter, ethyl acetate (100 mL), potassium carbonate and magnesium sulfate were added and the mixture was stirred overnight. The filtered filtrate was concentrated, and the obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate / 1: 1 → 1: 2) to give 0.03 g (0) of the compound (20) ′ in the low polar fraction. ．
06 mmol, 25.8%) and 0.04 g (0.10 mmol, 44.3%) of the compound (20) of the high polarity fraction.
I got

[Example 25] Synthesis of compound (21) Lithium aluminum hydride (4 mg) was placed in a 100 mL flask having a magnetic stirrer, and the inside of the flask was made a nitrogen atmosphere. THF (10 mL) was added to suspend the reaction, and 0.03 g (0.07 mmo) of the compound (20) was added to the suspension.
A solution of 1) in THF (10 mL) was added dropwise. Lithium aluminum hydride was further added in 8 mg and 11 mg portions in two portions, and the mixture was stirred for 5 hours. A saturated sodium sulfate aqueous solution and a 5N sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated and purified by high performance liquid chromatography (HPLC). Hold time 21.5
Of the peak observed in 10 minutes was freeze-dried, and 0.01 g (0.03 mmol, 42.
9%) was obtained.

[Embodiment 26]

[0088]

Embedded image

Synthesis of Phosphonic Acid Ester (26b) 5.07 g (33.7 mmol) of 3-phenylpropionic acid was placed in a 300 mL eggplant flask equipped with a magnetic stir bar. Methanol (40 mL) and 1,2-dichloroethane (100 mL) were added and stirred. Concentrated sulfuric acid (1.0 mL) was added thereto, and the mixture was heated under reflux overnight. After cooling down
Water (100 mL) was added and the organic layer was separated. This organic layer was mixed with saturated aqueous sodium hydrogen carbonate (100 mL x 2) and saturated saline (10 mL).
(0 mL), and the extract was dried over anhydrous magnesium sulfate. After filtration and concentration, a colorless oily crude ester was obtained.

In a 300 mL eggplant flask equipped with a magnetic stir bar, 8.70 g (70.1 m) of dimethyl methylphosphonate was added.
(mol) and put in a nitrogen atmosphere. THF (120m
L) was added to form a solution and cooled to -78 ° C. 40 mL of n-butyllithium (1.66 M, hexane solution) (6
6.4 mmol) was added dropwise, and after the addition was completed, 2 at the same temperature
Stirred for hours. Then the crude ester THF (5
0 mL) solution was added dropwise. After the dropping, the mixture was stirred at the same temperature for 3 hours, the cooling bath was removed, and the temperature was gradually raised. After the reaction solution was brought to room temperature, saturated ammonium chloride aqueous solution (100 mL) and water (50 mL) were added and well stirred, and ethyl acetate (100 mL) was added.
mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The colorless oily substance obtained by filtration and concentration was subjected to silica gel column chromatography (hexane-ethyl acetate / 1: 2), and 2
Dimethyl-oxo-4-phenylbutylphosphonate (2
6b) 7.31 g (28.5 mmol, 80.6%) were obtained.

In a similar manner, compound (26a) was prepared from phenylacetic acid and compound (2a) was prepared from 4-phenylbutyric acid.
6c) were respectively synthesized.

¹ H NMR spectra of compounds (01) to (23)
Vector data

[0093]

[Table 1]

[0094]

[Table 2]

Example 27 DNA synthesis of PGI ₂ derivative on human vascular smooth muscle cells
Measurement of growth inhibitory activity A 96-well plate (manufactured by Corning) was inoculated with 5 × 10 ³ cells / well of normal human aorta-derived vascular smooth muscle cells (manufactured by Kurabo) and cultured for 3 days.
The medium was changed from a growth medium (SGM; Kurabo Industries) to a basal medium (SBM; Kurabo Industries) and cultured for 24 hours. To this, a growth medium (SGM) containing an ethanol solution containing the test compound was added. After 16 hours, ³ H-thymidine (manufactured by Amersham) was added at 0.5 mCi / well, and 8
After hours, frozen at -20 ° C. Then, after returning to room temperature and melting, cell harvester (manufactured by Lab Science)
Was used to adsorb cells having ³ H-thymidine incorporated into the nucleus on a glass filter. Then, the amount of ³ H-thymidine incorporated in the glass filter was measured using a liquid scintillation counter (manufactured by Hewlett Packard).

Table 3 shows the measurement results (IC ₅₀ value) of the DNA synthesis inhibitory activity of the isocarbacyclins of the present invention on human vascular smooth muscle cells. In the above compound number (0
2), (08), (11), (16), and (19)
It can be seen that the compound represented by has a high growth inhibitory activity on human vascular smooth muscle cells. The activity of the known isocarbacyclines is on the order of 10 ^-6 at most (Japanese Patent Application No. 6-187250), and the activity is 10 ^-7 to 10 ^-8. You can see that it is expensive.

[0097]

[Table 3]

Example 28 A tablet having the following composition was produced. Active ingredient 200 μg Lactose 180 mg Potato starch 50 mg Polyvinylpyrrolidone 10 mg Magnesium stearate 5 mg The active ingredient, lactose and potato starch are mixed and evenly moistened with a 20% ethanol solution of polyvinylpyrrolidone and passed through a 20 mm mesh sieve, 45
It was dried at ° C and passed through a 15 mm mesh again. The granules thus obtained are mixed with magnesium stearate,
Compressed into tablets.

As the active ingredient, compound (16):
(1S, 5S, 6S, 7R) -3- (p-trifluoromethylbenzyl) -6-[(1E, 3S) -3-hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] ] -2-Octene was used.

[Example 29] Hard gelatin capsules each having one capsule having the following composition were produced. Active ingredient 100 μg Microcrystalline cellulose 195 mg Amorphous silicic acid 5 mg Active ingredient, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into a hard gelatin capsule.

As the active ingredient, compound (16):
(1S, 5S, 6S, 7R) -3- (p-Trifluoromethylbenzyl) -6-[(1E, 3S) -3-hydroxy-5-phenylpentenyl] -7-hydroxybicyclo [3.3.0] ] -2-Octene was used.

[0102]

INDUSTRIAL APPLICABILITY The isocarbacyclins of the present invention are mainly used for vascular smooth muscle cells after various angioplasty (for example, percutaneous coronary angioplasty), arterial bypass surgery, organ (organ) transplantation and the like. As a suppressor of thickening of blood vessels (for example, causing restenosis after percutaneous coronary angioplasty) caused by proliferation of blood vessels, or as a preventive or therapeutic agent for blood vessel thickening or blockage, and prevention or treatment of arteriosclerosis It is useful as an agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/445 A61K 31/445 C07C 69/76 C07C 69/76 Z 215/70 215/70 235 / 42 9547-4H 235/42 255/53 9357-4H 255/53 C07D 295/18 C07D 295/18 Z // A61K 31/557 ABN A61K 31/557 ABN C07M 7:00 (72) Inventor Kazuto Watanabe Tokyo 4-3-2 Asahigaoka, Hino City, Teijin Limited, Tokyo Research Center (72) Inventor, Koji Tomimori 2-1-1, Uchisaiwaicho, Chiyoda-ku, Tokyo Within Teijin Limited

Claims (12)

[Claims] 1. The following formula [1]: [In the formula, X is a halogen atom located in ortho, meta or para, a cyano group, an amide group, an aminomethyl group, a linear or branched α-hydroxyalkyl group, an optionally substituted amino group, a hydroxyl group. Represents an alkoxy group, an alkyl group, an aryl group, a halogen-substituted alkyl group, an ester group, a carboxyl group, or a carbamoyl group, m
Is 0 or 1 and n is an integer from 0 to 4. ] The compound represented by these, and / or isocarba cyclins which are its enantiomers. 2. The isocarbacyclines according to claim 1, wherein n = 1 in the formula [I]. 3. The isocarbacyclines according to claim 1, wherein n = 2 in the formula [I]. 4. The isocarbacyclines according to claim 1, wherein n = 3 in the formula [I]. 5. The isocarbacyclines according to claim 1, wherein m = 0 in the formula [I]. 6. The isocarbacyclines according to claim 1, wherein m = 1 in the formula [I]. 7. The isocarbacyclines according to claim 1, wherein in the formula [I], X is a methoxycarbonyl group. 8. The isocarbacyclines according to claim 1, wherein in the formula [I], X is a trifluoromethyl group. 9. The isocarbacyclines according to claim 1, wherein in the formula [I], X is a piperidinocarbonyl group. 10. The isocarbacyclines according to claim 1, wherein in the formula [I], X is a fluoro group. 11. The isocarbacyclines according to any one of claims 1 to 6, wherein in the formula [I], X is a dimethylamino group. 12. A PTCA containing the isocarbacycline according to any one of claims 1 to 6 as an active ingredient.
A preventive or therapeutic agent for subsequent restenosis.