JP3181677B2 - Bicyclic enol lactones and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel bi-cyclic enol lactones and its production how. This novel bicyclic enol lactone is a prostaglandin (hereinafter PG)
That) is an enol acylate analogs of E _1.

[0002]

BACKGROUND OF THE INVENTION PGE ₁ , PGE ₂ , and derivatives thereof are known to induce biochemical and physiological effects in various mammalian systems. PGE ₁ contracts smooth muscle in the vas deferens of the male reproductive system in mammals and uterine smooth muscle in the female reproductive system. It also stimulates gastrointestinal smooth muscle contraction, suppresses gastric secretion, and affects the tracheal smooth muscle of the respiratory tract. In addition, PGE ₁ inhibits platelet aggregation and in the cardiovascular system, by its action on vascular smooth muscle, becomes a vasodilator.

[0003] was, but I, PGE ₁ and its analogs, wide clinical application is expected, Ru is expected to be a large role in drug occupied in the future these PG compounds (Sim, AK,
Arzneim-Forsch / Drug Res., 1206-1209 (1986)). Ma
In addition , PG analogs are typical of local hormones,
Proposed that these related drugs require a drug release system that takes into account their autacoid properties and chemical properties, as they are locally produced and act locally when needed. Have been.

[0004]

However, natural PGE
₁ has poor storage stability and is easily decomposed under acidic or basic conditions. One example of solving this problem is the analog of PGE ₁ enol acylate, for example, methyl 9-acetoxy-11α , 15S.
- dihydroxy prostaglandin -8, 13E--dien-1-oate, methyl 9, 11α, 15S- triacetoxy prostaglandin -8, 13E--dien-1-oate like (see JP-B-60-33827) has been known . Further, as an example in which the storage stability is dramatically improved, an analog composition described in JP-A-3-204853 can be mentioned.

[0005] Only PGE ₁ derivatives having improved thereby and bicyclic structure the weaker qualitative and has been examples are not reported.

[0006]

The present inventors have SUMMARY OF THE INVENTION As a result of intense research and development, by introducing a bi-cyclic enol lactone structure as prodrugs of PGE _1, while maintaining a strong platelet aggregation inhibiting action in, I began to have seen that in vivo stability is higher.

The present invention relates to the following novel bicyclic enol lactones and a method for producing the same. It is expressed by the following formula [1]
Bi-cyclic enol lactones that.

[0008]

Embedded image

Wherein n is 0 or 1, R ¹ and R ² are the same or different and are each a hydrogen atom, an acyl group or a protecting group for a hydroxyl group other than an acyl group, R ^{3 is a} hydrogen atom, a methyl group, or a vinyl group, R ^4: the following substituents
A hydrocarbon group having 10 or less carbon atoms, which may have (Y) . Substituent (Y): halogen atom, hydroxy group, carbon
An acyloxy group of the number 7 or less, substituted with a halogen atom
Alkoxy, cyano, carboxyl, charcoal
An alkoxycarbonyl group having a prime number of 1 to 6 and a substituent (Q)
An alicyclic hydrocarbon group which may have a substituent (Q)
Optionally substituted cycloalkyloxy group, substituent (Q)
A phenyl group which may have a substituent or a substituent (Q)
A phenoxy group which may be present; Provided that the substituent
(Q) is a halogen atom, a hydroxy group, having 7 or less carbon atoms
May be substituted with an acyloxy group or a halogen atom
Alkoxy group, cyano group, carboxyl group, having 1 to 1 carbon atoms
6 substituted with an alkoxycarbonyl group or a halogen atom
An alkyl group which may be substituted.

In the formula [1], R ¹ and R ² represent a hydrogen atom or a hydroxyl-protecting group. As the protecting group for the hydroxyl group, a commonly used protecting group (for example, TWGreene, Protective Gr
Oupsin Organic Synthesis, 1981, protecting groups described in John Wiley & Sons) are preferable, and examples thereof include a triorganosilyl group, an acyl group, and an ether-based protecting group. Also, R
¹ and R ² may be an acyl group other than an acyl group which is a commonly used protecting group. Here, an acyl group which is a commonly used protecting group will be described.

Specific protective groups include, for example ,
Groups. Trimethylsilyl, t- butyl dimethyl silyl group, diphenylmethyl silyl group, which triorganosilyl group such dimethylisopropylsilyl group. Acyl groups such as acetyl, propionyl and benzoyl groups ; Methyl group, benzyl group, methoxybenzyl group, trityl group . Ether protecting groups such as dimethoxytrityl, methoxymethyl, methoxyethoxymethyl, trimethylethoxymethyl, ethoxyethyl, tetrahydropyranyl, and tetrahydrofuranyl groups;

[0012] R ³ is a hydrogen atom, methylation group, or it is a vinyl group, if a methyl radical, n in the formula [1]
Is preferably O.

[0013] R4 is substituted (Y) is a hydrocarbon group having 10 or less which may carbons, hydrocarbon group part excluding the substituents (Y), i.e. skeletal portion, the 1 carbon atoms
It is preferably an aliphatic hydrocarbon group of 8 or an alicyclic hydrocarbon group having 3 to 10 ring members. The aliphatic hydrocarbon group may be linear or branched, and may have an unsaturated bond. In the case of an aliphatic hydrocarbon group having a substituent (Y) , the substituent (Y) is, for example, a halogen atom, a hydroxy group, an acyloxy group having 7 or less carbon atoms, or an alkoxy group optionally substituted with a halogen atom. , A cyano group, a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms, an alicyclic hydrocarbon group optionally having a substituent (Q) , and a cycloalkyl optionally having a substituent (Q) oxy group, a substituent (Q) a phenyl group which may have a have a good phenoxy group which may have a substituent (Q).

[0014] having a substituent (Q), alicyclic hydrocarbon group, a cycloalkyl group, in the case of a phenyl group or a phenoxy group, the substituent (Q) is substituted with further halogen atoms in addition to the May be an optionally substituted alkyl group. It is to be noted that the halogen atom, fluorine atom
Child, chlorine atom, bromine atom, and an iodine atom say.

Preferred R ⁴ is the following groups: Also linear carbon atoms which may be have 3-8 substituted by a halogen atom
It is properly branched alkyl group, alkenyl group or alkynyl group. A cycloalkyl group having 4 to 7 ring members which may be substituted with an alkyl group ; An alkoxy group, a phenyl group, an alkyl group having 1 to 5 carbon atoms Moshiku is substituted with a phenoxy group. The halogen atom is preferably a fluorine atom. The alkyl group as a substituent of the cycloalkyl group is preferably an alkyl group having 4 or less carbon atoms, that is, a lower alkyl group. This alkoxy group is also preferably an alkoxy group having 4 or less carbon atoms, that is, a lower alkoxy group.

[0016] The most preferred R ⁴ is a linear Moshiku branched chain alkyl group having 4 to 7 carbon atoms, a cycloalkyl group having ring members 5-6 or carbon atoms substituted with phenoxy group 1, 4 alkyl group.

Examples of R ⁴ include the following specific examples, but R ⁴ is not limited thereto.

Propyl, butyl, pentyl, hexyl, heptyl, octyl, 1-methylbutyl, 2-methylbutyl, 2-methylhexyl,
Methylpentyl group, 1,1-dimethylpentyl group, 6-
Methyl-5-heptenyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group, 1,1-difluoropentyl group, 1-fluoropentyl group .

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3 -Butylcyclopentyl group, 3-pentylcyclopentyl group,
4-propylcyclohexyl group .

Benzyl group, 2-phenylethyl group, phenoxymethyl group, 2-phenoxyethyl group, 1-phenoxy-1-methylethyl group, 2-methoxyethyl group,
An ethoxyethyl group.

Of these, preferred R ⁴ is butyl, pentyl, hexyl, (R)-or (S)
-2-methylhexyl group, 1-methylpentyl group, 1-
Methylbutyl group, 1,1-dimethylpentyl group, 6-methyl-5-heptenyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group, 1,1-difluoropentyl group, 1-fluoropentyl Group, 2-phenoxyethyl group, 1-phenoxy-1-methylethyl group, 2
-A methoxyethyl group.

The bicyclic enol lactone of the present invention comprises P
It can be considered as a prodrug of the GE ₁ derivative . The compounds of the present <br/> invention is enzymatically hydrolyzed in situ (e.g. esterases, with lipase), produces PGE ₁ derivative. Similarly, also non-enzymatic hydrolysis of 9-enol lactone (enol acylate) gives PGE ₁ derivatives.

The bi-cyclic enol lactones of the present invention, both one or the water <br/> acid groups may be esterified ester modified product. That is, both one or the R ^1, R ² may be an acyl group. The acyl group may be other than the above-mentioned commonly used acyl group as a protecting group for a hydroxyl group. These acyl groups, for example, alkanoic acids, cycloalkane acid, alkenoic, cycloalkene acid, arylalkanoic acids, aromatic carboxylic acids, or an acyl group obtained by removing hydroxyl group from the carboxyl group, such as heterocyclic carboxylic acid is there. Further, it may be an acyl group obtained by removing a hydroxyl group from one carboxyl group of a polyvalent carboxylic acid.

The above-mentioned modified ester can be synthesized by reacting an unprotected hydroxy compound with a carboxylating agent, preferably a carboxylic anhydride. For example,
As the carboxylating agent, an anhydride of a monovalent carboxylic acid or a mixed acid anhydride can be used.

The purpose of producing these prodrugs is to
The purpose is to obtain a long-term effect. In PG drug treatment, PGE ₁ and PGE ₂ PGE group, such as is usually very active at doses of small amounts (<10mg / kg), and the action time is very short. In addition, the PGs of the PGE group are susceptible to removal of the 11-hydroxyl group (even under slightly acidic or basic conditions),
Generate a PG of the GB group. This conversion can be significantly reduced by bicyclic enol lactonization. That enol lactone, a neutral Moshiku are stable to hydrolysis under acidic conditions, PGA group and PG
This is because conversion to group B can be prevented.

The compound of the present invention has, for example, the following formula [2]
Can be produced by reacting a 2-cyclopenten-1-one represented by the following formula with a vinyl metal compound.

[0027]

Embedded image

Wherein R ^{1 is a} hydrogen atom, an acyl group, or a hydroxyl-protecting group other than an acyl group, and X is an active ester.
Group formed from a phenyl group, a triorganosilyl group, or an imide compound substituted with a halogen atom.
Groups or mixed acid anhydride group that will be formed from the preferred that.

[0029] As the phenyl group substituted by a halogen atom, a pentafluorophenyl group, etc. can be used pentachlorophenyl group, the triorganosilyl group, triorganosilyl group used as a protecting group of the above-described hydroxyl group Can be used. Imide compound
The group formed from, can be used a group formed from the imide compound used in forming the usual activated ester, for example, Sukushin'imi de, phthalate Lee <br/> Mi de, 5-norbornene - 2,3 Jikarubokishiimi de
It can be used a group formed from Do etc..

[0030] As groups that will be formed from a mixed acid anhydride,
For example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a decanoyl group, a lauroyl group, a linear Moshiku branched chain acyl groups such as palmitoyl group or a benzoyl group, penta Examples include a fluorobenzoyl group and a cycloalkylcarbonyl group having 3 to 8 ring members which may have a substituent.

The vinyl metal compound to be reacted with 2-cyclopenten-1-ones includes, for example, an organolithiocuprate ligand prepared from a compound represented by the following formula [3].

[0032]

Embedded image

In the formula [3], Z represents an iodine atom , a trimethyltin group , a triethyltin group , a tripropyltin
And an organotin group such as a tributyltin group and a triphenyltin group. n, R ¹ , R ³ and R ⁴ have the same meanings as in the formula [1].

The organo lithium Ok Prato literature methods (Organic Reactions, vol. 38, chapter 2.) can be prepared, as a ligand, having 6 to 12 carbon atoms preparative <br/> Li scan (dialkyl Amino) phosphine, having 3 to 12 carbon atoms
And a dialkyl sulfide having 2 to 12 carbon atoms is preferred. In particular, tri scan (dimethylamino) phosphine, tri (n- butyl) phosphine, diisopropyl sulfide, dimethyl sulfide is preferred.

The organolithiocuprate is usually prepared from the compound of the formula [3], alkenyllithium prepared from alkyllithium, and an inorganic copper reagent, but a reagent prepared from alkenyllithium and a Lewis acid catalyst can also be used. Examples of the Lewis acid catalyst, dimethyl zinc, diethyl zinc, dipropyl zinc, dibutyl zinc, dialkyl zinc or diaryl zinc and diphenyl zinc is used, it boron fluoride ether complex, also be used as titanium tetrachloride .

[0036] 2 -Cyclopenten-1-ones and vinyl
The reaction with the metal compound is a 1,4-conjugate addition reaction, and the reaction intermediate, lithium enolate, reacts with the active ester moiety (corresponding to the first position in the PGE ₁ number) in the molecule to form an intramolecular molecule. Forms an enol acylate. The reaction is carried out, for example, in an inert solvent such as ether, tetrahydrofuran, hexane, pentane or toluene under an inert atmosphere, for example, under nitrogen or argon.
It is carried out by stirring for 0.5 to 24 hours in a temperature range of from 50C to + 50C.

The compound of the formula [1] in which R ¹ and R ² are hydroxyl-protecting groups may be deprotected if necessary. Deprotection can be performed under ordinary conditions. For example, when the protecting group is a triorganosilyl group, tetrabutylammonium fluoride or hydrofluoric acid is used, and when the protecting group is a tetrahydropyranyl group, p- Toluenesulfonic acid, pyridinium-p-toluenesulfonic acid, hydrofluoric acid, and the like can be used. As the reaction solvent, a mixed solvent such as acetonitrile-water, tetrahydrofuran-water, and ether-water, or an inert solvent such as tetrahydrofuran can be used, and a temperature in a range from -70 ° C to a solvent reflux temperature is used.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0039]

EXAMPLES Example 1] (11R, 12R) - 1 2- hydroxy -1 1- [(1E, 3S) -3- hydroxy
-1-octenyl] -2-oxabicyclo [8.3.0] torideca-1
(10) - en-3-one Synthesis of

[0040]

Embedded image

(1E, 3S) -1-iodo-3- (t-butyldimethylsiloxy) -1-octene (950 mg, 2.4 mmol) in ether (10
ml) solution was cooled to -78 ° C and t-butyllithium (f =
A hexane solution of 1.41 ( 3.19 ml, 4.5 mmol) was added dropwise. After stirring for 2 hours at the same temperature, tributylphosphine - dropwise copper (I) iodide complex (822 mg, 2.21 mmol) and tributylphosphine (0.54 ml, 2.19 mmol) and ether (8 ml) solution of 50 -78 ° C. Stirred for minutes . Next (4R) -4 -t-
Butyldimethylsiloxy-2- (6-carboxyhexyl) -2-
Cyclopenten-1-one (681mg, 2.0mmol), N- hydroxysuccinimide emissions imide (230mg, 2.0mmol), dicyclohexylcarbodiimide (454mg, 2.2mmol), and ethers of the active ester prepared from dimethylformamide (8 ml) solution It was dropped.

At -78 ° C for 20 minutes, -30 to -2
Stirred at 0 ° C. for 30 minutes. The temperature was raised to 0 ° C., the reaction solution was poured into a saturated aqueous solution of ammonium sulfate (70 ml), the organic layer was separated, and the aqueous layer was extracted with ether (70 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was cooled to 0 ° C. and subjected to silica gel chromatography (hexane: ethyl acetate = 100: 1 to 63:
Purification was performed in 1) to obtain an adduct.

The prepared adduct (396 mg, 0.7 mmol) was dissolved in acetonitrile (15 ml), 46% hydrofluoric acid (3.9 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a mixture of a 20% aqueous potassium carbonate solution (50 ml) and methylene chloride (15 ml). After drying over magnesium sulfate,
After filtration, the solvent was distilled off under reduced pressure. Silica gel chromatography of the residue at 0 ° C. (hexane: ethyl acetate = 2: 1 to 1: 2)
And the title compound (60 mg) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.88 (3H, t, J = 4.5 Hz), 1.
2-1.6 (14H, m), 1.7-2.1 (4H, m), 2.3-2.7 (3H, m), 2.9-3.0 (2
H, m), 4.0-4.2 (2H, m), 5.4-5.6 (2H, m).

[0045] [Example 2] (11R, 12R) - 1 2- hydroxy -1 1- [(1E, 3S, 5S) -3- hydroxy-5-methyl-1-nonenyl] -2-oxabicyclo [8.3 .
0] trideca-1 (10) - en-3-one Synthesis of

[0046]

Embedded image

As in Example 1, (1E, 3S) -1-iodo-3-
Instead of (t-butyldimethylsiloxy) -1-octene,
(1E, 3S, 5S) -1-Iodo-3- (t-butyldimethylsiloxy)-
The title compound (50 mg) was obtained using 5-methyl-1-nonene. ¹ H-NMR (CDCl ₃ ): δ 0.8-0.9 (6H, m), 1.1-1.7 (15H, m),
1.8-2.1 (4H, m), 2.3-2.6 (3H, m), 2.9-3.1 (2H, m), 4.5-5.0
(2H, m), 5.4-5.6 (2H, m).

[0048] [Example 3] (11R, 12R) - 1 2- hydroxy -1 1- [(1E, 3S) -3- hydroxy
-3-cyclopentyl-1-propenyl] -2-oxabicyclo
[8.3.0] trideca-1 (10) - en-3-one Synthesis of

[0049]

Embedded image

As in Example 1, (1E, 3S) -1-iodo-3-
Instead of (t-butyldimethylsiloxy) -1-octene,
( 1E , 3S ^* ) -1-iodo- 3- (t-butyldimethylsiloxy) -3-
The title compound (50 mg) was obtained by separating the optical isomers by column chromatography using cyclopentyl-1-propene.

¹ H-NMR (CDCl ₃ ): δ 1.1-2.15 (21H, m), 2.3-
2.6 (3H, m), 2.9-3.1 (2H, m), 3.8-3.9 (1H, m), 4.1-4.2 (1H,
m) , 5.4-5.65 (2H, m).

[0052] [Example 4] (11R, 12R) - 1 2- hydroxy -1 1- [(1E, 3S) -3- hydroxy
4-phenoxy-4-methyl-1-pentenyl] -2-oxabicyclo [8.3.0] trideca-1 (10) - en-3-one Synthesis of

[0053]

Embedded image

(1E) -1-Iodo-3- (t-butyldimethylsiloxy) -4-methyl-4-phenoxy-1-pentene (519 mg,
A solution of 1.2 mmol) in ether (5 ml) was cooled to −78 ° C. and tert-butyllithium (f = 1.41 in pentane solution 1.60) was added.
ml, 2.25 mmol) was added dropwise. After stirring at the same temperature for 2 hours, tributylphosphine-copper (I) iodide complex (417 m
g, 1.11 mmol) and tributylphosphine (0.274 ml,
A solution of 1.10 mmol) in ether (4 ml) was added dropwise. -7
After stirring 50 minutes at 8 ° C., (4R) -4-t-butyldimethylsiloxy-2- (6-penta-chlorophenoxy carboxymethyl sulfonyl hexyl <br/>) -2-cyclopenten-1-one (587 mg, 1.0 mmol) in ether (16 ml) was added dropwise.

At -78.degree. C. for 20 minutes, -30 to -2
Stirred at 0 ° C. for 30 minutes. After the temperature was raised to 0 ° C. and stirred for 18 hours, the reaction solution was poured into a saturated aqueous solution of ammonium sulfate (40 ml), the organic layer was separated, and the aqueous layer was washed with ether (40 ml).
Extracted. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was cooled to 0 ° C. and purified by silica gel chromatography (hexane: ethyl acetate = 100: 1-80: 1) to obtain an adduct.

The adduct prepared (21.3 mg, 0.034 mmol)
Was dissolved in acetonitrile (2 ml), 46% hydrofluoric acid (0.18 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 4 hours. The reaction solution was poured into a mixture of a 20% aqueous potassium carbonate solution (20 ml) and methylene chloride (10 ml). After drying over magnesium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography at 0 ° C. (hexane: ethyl acetate = 1: 1).
1) and purified Shimegi掲compound 11mg with (11R, 12R) - 1 2- hydroxy -1 1- [(1E, 3R) -3- hydroxy-4-phenoxy-4-methyl-1-pentenyl] -2 Oxabicyclo [8.3.0] Trideca
-1 (10) - was obtained en-3-one (2.3 mg).

¹ H-NMR (CDCl ₃ ): δ 1.00 (6H, s), 1.2-1.4 (2
H, m), 1.50-2.15 (8H, m), 2.15-2.60 (3H, m), 2.90-3.05 (3H,
m), 4.10-4.2 (2H, m), 5.60-5.75 (2H, m), 6.95-7.00 (2H, m),
7.15-7.20 (1H, m), 7.25-7.35 (2H, m).

[Biological activity test 1] Blood was collected using sodium citrate (3.8%) (blood:
1000 liters of peripheral blood treated with sodium citrate = 9: 1)
centrifugation at pm for 10 minutes to collect platelet rich plasma, and the remaining to 3000 r.
After centrifugation at pm for 15 minutes, platelet poor plasma was collected. 5 μl of a ₁ mg / ml ethanol solution (in terms of PGE ₁ ) of the sample prepared in Example 2 was added to 495 μl of platelet poor plasma.
In addition, the mixture was shaken at 37 ° C. After 10 minutes cool this with ice,
Platelet rich plasma 2 diluted appropriately with physiological saline and pre-incubated at 37 ° C. for 1 minute
In addition to the 15 [mu] l, it was induced platelet aggregation at 40μM of ADP solution 25μl after 1 minute further.

The aggregation rate when 10 μl of physiological saline was put in place of the sample was taken as 100%, and the aggregation inhibition rate (%) was calculated and plotted on a semi-log graph paper. ED ₅₀ ) was read. For comparison,
The same process have natural PGE ₁ Nitsu, the same test was carried out. Table 1 shows the results. From this result, Example 2
The compounds understood to have the natural PGE ₁ equivalent or more platelet aggregation inhibiting activity.

[0060]

[Table 1]

[0061] [bioactive Test 2] 4 hours at 37 ° C. Human peripheral blood was allowed to stand for 1 hour at low temperature further, and centrifuged for 15 minutes at 3000rpm at 4 ° C., and serum was collected. 20 μl of a 1 mg / ml ethanol solution of the compound of Example 2 was added to 1980 μl of the serum, and the mixture was shaken at 37 ° C. 0 min, 15 min, 30 min, 60 min, sampled after 150 minutes was measured conversion amount to 17,20- dimethyl -PGE ₁ of each sample by high performance liquid chromatography. The result is shown in FIG. FIG. 1 is a graph showing the conversion rate of the compound of Example 2 into 17,20-dimethyl-PGE ₁ in human serum.
I is the conversion of the compound of Example 2, curve II is 17,20-
It represents the generation rate of dimethyl -PGE _1. The chart compound real <br/>施例2 gradually 17,20- dimethyl -PGE
It is shown that it has changed to ₁ .

Further, the same treatment was carried out for 17,20-dimethyl-PGE _{1 and the} resulting mixture was subjected to high performance liquid chromatography.
The remaining amount was measured by ( HPLC ) . The result is shown in FIG. Figure 2 is a graph showing a residual ratio of 17,20- dimethyl -PGE ₁ in the human serum, 1
It has been shown that 7,20-dimethyl-PGE ₁ gradually disappears.

[0063] In addition, each sample in physiological saline 1
After dilution to 1:00, the platelet aggregation inhibition rate was calculated in the same manner as in the bioactivity test 1. The results are shown in FIGS. 3 and 4. FIG. 3 is a graph showing the platelet aggregation inhibition rate of the compound of Example 2, and shows that the compound of Example 2 maintains its activity for a long time. Figure 4 is a graph showing the platelet aggregation inhibition rate 17,20- dimethyl -PGE _1, 17,20- dimethyl -PGE ₁ has been shown to be lost in a relatively short period of time in their activity.

These results show that the compound of Example 2 is gradually converted to its active form in human serum. In addition, although the active substance is not stable in human serum, it can be seen that the platelet aggregation inhibitory activity is sustained by enollactonization as in the compound of Example 2.

[0065]

The compounds of the present invention exhibits, in vivo stability compared to PGE ₁ is high, it is possible to gradually change the corresponding PGE ₁ compounds in vivo, for a long time maintains its physiological activity be able to. It was although I, the compounds of the present invention are useful as PGE ₁ prodrug.

[Brief description of the drawings]

FIG. 1 is a graph showing the conversion rate of a compound of the present invention in serum.

FIG. 2 is a graph showing the conversion rate of a comparative compound in serum.

FIG. 3 is a graph showing the platelet aggregation inhibition rate of the compound of the present invention.

FIG. 4 is a graph showing the platelet aggregation inhibition rate of a comparative compound.

──────────────────────────────────────────────────続 き Continuation of the front page Examiner Ikuharu Oya (56) References JP-A-51-149246 (JP, A) JP-A-52-118486 (JP, A) JP-A-52-3089 (JP, A) JP-B-60-33827 (JP, B2) US Patent 4032543 (US, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 313/00 A61K 31/00-31/80 CA (STN ) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. Bicyclic enol lactones represented by the following formula [1]. Embedded image Wherein n is 0 or 1, R ¹ and R ² are the same or different and are each a hydrogen atom, an acyl group, or a protecting group for a hydroxyl group other than an acyl group, and R ^{3 is a} hydrogen atom, a methyl group, or a vinyl group. , R ^4: the following substituent group (Y) 10 carbon atoms which may have a
The following hydrocarbon groups: Substituent (Y): halogen atom, hydroxy group, carbon number 7
Even if it is substituted with the following acyloxy group or halogen atom
Good alkoxy, cyano, carboxyl, carbon number
Having 1 to 6 alkoxycarbonyl groups and a substituent (Q)
Optionally having an alicyclic hydrocarbon group and a substituent (Q)
Having an optionally substituted cycloalkyloxy group and a substituent (Q)
Having an optionally substituted phenyl group or a substituent (Q)
A phenoxy group which may be substituted. Provided that the substituent (Q) is a halogen atom,
Group, acyloxy group having 7 or less carbon atoms, substituted with halogen atom
Optionally substituted alkoxy, cyano, carboxy
Group, an alkoxycarbonyl group having 1 to 6 carbon atoms, or
An alkyl group which may be substituted with a halogen atom
You. Wherein R ⁴ is the substituent (Y) 1 to 8 carbon atoms which may have an aliphatic hydrocarbon group or has the location <br/> substituent (Y) The bicyclic enol lactone according to claim 1, which is an alicyclic hydrocarbon group having 3 to 10 ring members which may be present. Wherein R ⁴ is a linear or branched alkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom, carbon atoms which may be substituted with a halogen atom 3-8
Linear or branched alkenyl group, a linear or branched alkynyl group having 3 to 8 carbon atoms which may be substituted by a halogen atom, and 3 ring members which may be substituted by an alkyl group A cycloalkyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 5 carbon atoms substituted with an alkoxy group, an alkyl group having 1 to 5 carbon atoms substituted with a phenyl group, or 1 to 5 carbon atoms substituted with a phenoxy group. The bicyclic enol lactone according to claim 1, which is an alkyl group. 4. R ⁴ is a linear alkyl group having 4 to 7 carbon atoms, a branched alkyl group having 4 to 7 carbon atoms, and a ring member having 5 to 6 carbon atoms.
The bicyclic enol lactone according to claim 1, which is a cycloalkyl group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms substituted with a phenoxy group. 5. A PGE ₁ prodrug consisting of bi-cyclic enol lactones according to claim 1, 2, 3 or 4. 6. The process for producing a bicyclic enol lactone according to claim 1, wherein a 2-cyclopenten-1-one represented by the following formula [2] is reacted with a vinyl metal compound described below. Method. Embedded image R ^{1 is a} hydrogen atom, an acyl group, or a protecting group for a hydroxyl group other than an acyl group, and X is a group that forms an active ester. Vinyl metal compound: a reaction product obtained by reacting a compound represented by the following formula [3] with alkyl lithium to form alkenyl lithium, and then reacting the alkenyl lithium with an inorganic copper reagent or a Lewis acid catalyst. . Embedded image Wherein n is 0 or 1, R ^{2 is a} hydrogen atom, an acyl group, or a protecting group for a hydroxyl group other than an acyl group, R ^{3 is a} hydrogen atom, a methyl group, or a vinyl group; and R ^{4 is a} substituent (Y) shown below. May have 10 carbon atoms
The following hydrocarbon groups: Substituent (Y): halogen atom, hydroxy group, carbon number 7
Even if it is substituted with the following acyloxy group or halogen atom
Good alkoxy, cyano, carboxyl, carbon number
Having 1 to 6 alkoxycarbonyl groups and a substituent (Q)
Optionally having an alicyclic hydrocarbon group and a substituent (Q)
Having an optionally substituted cycloalkyloxy group and a substituent (Q)
Having an optionally substituted phenyl group or a substituent (Q)
A phenoxy group which may be substituted. Provided that the substituent (Q) is a halogen atom,
Group, acyloxy group having 7 or less carbon atoms, substituted with halogen atom
Optionally substituted alkoxy, cyano, carboxy
Group, an alkoxycarbonyl group having 1 to 6 carbon atoms, or
An alkyl group which may be substituted with a halogen atom
You. Z: an iodine atom or an organotin group. 7. The method according to claim 6, wherein X is a phenyl group substituted with a halogen atom, a triorganosilyl group, a group formed from an imide compound, or a group formed from a mixed acid anhydride. .