JPH0660155B2 - Isocarbacyclines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to novel isocarbacyclines. More specifically, 9 (O) -methano-Δ in which oxygen atoms at positions 6 and 9 of prostaglandin I ₁ are substituted with a methylene group (-HC =)
^{The present invention} relates to a compound which is a synthetic intermediate of ^{6 (9α) -prostaglandin} I ₁ ^{(isocarbacycline)} and which is itself a novel isocarbacycline derivative.

<Prior art> Prostacyclin is a local hormone produced mainly in the inner wall of blood vessels of arteries in the living body, and is an important factor that regulates cell functions of the living body by its strong physiological activities such as platelet aggregation inhibitory activity and vasodilatory activity. Attempts have been made to use this product directly as a medicine [(PJ Lewis & J.O.Grady) Clinical Pharmacodies of Prostacyclin “ (Clinical Pharm
acology of Prostacyclin "Raven Pre
ss), New York (NY), 1981].

However, since natural prostacyclin has an enol ether bond which is very easily hydrolyzed in the molecule, it is easily inactivated under neutral or acidic conditions, and it cannot be said to be a preferable compound as a drug because of its chemical instability. Therefore, a chemically stable synthetic prostacyclin derivative having physiological activity similar to that of natural prostacyclin has been intensively studied both inside and outside.

Among them, derivatives of prostacyclin in which the 6th and 9th oxygen atoms are substituted with a methylene group, that is, 9 (O) -methanoprostacyclin (carbacycline) is known as a prostacyclin that sufficiently satisfies chemical stability. DOR [Mortons (DRMortons) "Prostacyclin (Prostacyclin)" Jar Earne Vane and S. Bergstrom (JRVane and
S. Bergstrom), Editions, Raven Press, New York (Eds, Raven Press, NY), 1979, pp31-41
(See) Expected as a pharmaceutical product. But this 6,9 (O)
-Methanoprostacyclin has a weaker biological activity than that of natural prostacyclin, and its action selectivity cannot be said to be specific, so that it cannot be said to be a preferable compound.

In recent years, isocarbacycline, one of the double bond isomers of carbacyclin, namely 9 (O) -methano-Δ
^{6 (9α)} - prostaglandin I ₁ class is found to exhibit the strongest inhibiting platelet aggregation action among the homologues, it has fallen as application as a medicament is expected [Ikegami et al, Tetrahedron Letters (Tetrahedron Let
t.), 24 , 3493 (1983), JP-A-59-13744.
Five〕.

Conventionally, the following method is known for the production of 9 (O) -methano-Δ ^{6 (9α) -prostaglandin} I ₁ ( ^{isocarbacycline)} .

(1) Ikegami et al., Tetrahedron L
etters), 24, 3493 (1983 ) and Chemistry Letters (Chemistry Letters)), 1984, 1069: (2) Ikegami et al., Tetrahedron L
etters), 24,3493 (1983): (3) Ikegami et al., Journal of the Chemical Society, Chemical Communications (J. Chem.S.
oc., Chemical Communications), 1984 , 1602; (4) Shibasaki et al., Tetrahedron L
etters)) 25,5087 (1984): (5) Shibasaki et al., Tetrahedron L
etters), 25, 1067 (1984): (6) Kojima et al., Chemical and Far-Massile-Teutical Bretain (Chem.Pharm.Bull.), 32, 2866 (1984): (7) Kojima et al., JP-A-60-28943: 7 methods.

Of these seven methods, method (1) and method (5) use PGE ₂ as a starting material, lead to a key intermediate through several steps, and obtain the desired isocarbacycline through several steps. It is hard to say that it is an industrial manufacturing method.

Further, both the method (2) and the method (3) require a multi-step process from an expensive corey lactone to obtain a corresponding starting material and a key intermediate, and the total yield is not high, which is not necessarily industrial. There is a drawback that it is not an advantageous method.
The method (6) and the method (7) are not preferable as a production method intended to be a medicinal product because the final product can be obtained only in the dl form.

Finally, in method (4), not only the starting material whose optical activity is easily obtained from (R) -4-hydroxy-2-cyclopentenone by the method of the present inventors (Japanese Patent Laid-Open No. 57-
155116), the induction of the key intermediate from the starting material is also a method that can be industrially produced without any problems. However, in the process from the key intermediate to the final isocarbacyclines, there are many difficulties such as the use of organomercury compounds, loss of regiospecificity, and incorporation of indivisible by-products. In addition, there is a big drawback that the total yield is low and it cannot be a practical or industrial manufacturing method.

<Problems to be Solved by the Invention> The present inventors have paid attention to the above-mentioned various points, and 9 (O) -methano-Δ
As a result of intensive research to find a method for producing ^{6 (9α) -prostaglandin} I ₁ ^{(isocarbacyclines)} , the use of isocarbacyclines having an arylsulfonyl group as an intermediate can achieve the object. The inventors have found that and reached the present invention.

<Means for Solving Problems> That is, in the present invention, the following formula [I] In the formula, A is a carboxyl group or a carboxylate group (-C
Represents OOR ¹ ). R ¹ represents a C ₁ -C ₄ alkyl group. R ² and R ³ are the same or different and represent a hydrogen atom or a tri (C ₁ -C ₇ ) hydrocarbon silyl group,
⁴ represents a hydrogen atom or a methyl group, R ⁵ represents a linear or branched C _{3 to} C ₉ alkyl group, an alkenyl group or an alkynyl group; or a C _{3 to} C ₁₀ cycloalkyl group, and n represents 0 or 1 And Ar represents a phenyl group.

There is provided a novel isocarbacycline which is a compound represented by the formula, its stereoisomerism or a mixture thereof in any ratio.

In the above formula [I], A represents a carboxy group or a carboxylate group (COOR ¹ ). As another reference example for A, 4-methyl-2,6,7-trioxabicyclo [2.2.2] oct-1-yl group or 2,2-bis (hydroxymethyl) prop-1-yloxy group is used. A carbonyl group can be mentioned. R ¹ represents a C _{1 to} C ₄ alkyl group, and other reference examples include an alkenyl group.
The C ₁ -C ₄ alkyl group of R ¹ is a methyl group, an ethyl group,
Examples thereof include a propyl group and a butyl group, and examples of the alkenyl group include a 2-propene group and a 3-butene group, but a methyl group and a 2-propene group are preferable.

In the above formula [I], R ² and R ³ are the same or different and represent a hydrogen atom or a tri (C ₁ -C ₇ ) hydrocarbon silyl group, but as another reference example, a group forming an acetal bond with an oxygen atom of a hydroxyl group. Can be given.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, A diphenyl (C ₁ -C ₄ ) alkylsilyl group such as t-butyldiphenylsilyl group, a di (C ₁ -C ₄ ) alkylphenyl group such as dimethylphenyl group, or a tribenzylsilyl group is preferable. It can be mentioned as a thing. Tri (C ₁ -C ₄ ) alkylsilyl, diphenyl (C ₁ -C ₄ ) alkylsilyl and phenyldi (C ₁ -C ₄ ) alkylsilyl groups are preferable, and t-butyldimethylsilyl group and trimethylsilyl group are particularly preferable. .

Examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy- group.
2-propyl group, (2-methoxyethoxy) methyl group,
Examples thereof include a benzyloxymethyl group, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, or a 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-4-yl group. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, 6,6-dimethyl-3-oxa-2-
The oxobicyclo [3.1.0] hex-4-yl group is particularly preferred. Of these, a 2-tetrahydropyranyl group is particularly preferable.

It is to be understood that these silyl groups and the groups forming an acetal bond are protecting groups for hydroxyl groups. These protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to give free hydroxyl groups useful as drugs.

In the above formula [I], R ⁴ represents a hydrogen atom or a methyl group, and another reference example is a vinyl group.

In the above formula [I], R ⁵ represents a linear or branched C ₃ -C ₈ alkyl group, alkenyl group, alkynyl group or C ₃ -C ₁₀ cycloalkyl group which may contain an oxygen atom. As other reference examples of R ⁵ , alkyl group, alkenyl group, alkynyl group containing oxygen atom; substituted or unsubstituted phenyl group; substituted or unsubstituted phenoxy group; substituted C ₃ ~ A C ₁₀ cycloalkyl group; or a C _{1 to} C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group or an optionally substituted C _{3 to} C ₁₀ cycloalkyl group Represents a linear or branched C _{1 to} C ₅ alkyl group.

As the straight chain or branched chain C _{3 to} C ₈ alkyl group, alkenyl group or alkynyl group which may contain oxygen,
2-methoxyethyl, 2-ethoxyethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group,
Examples thereof include a 2-hexyl group, a 2-methyl-2-hexyl group, a 2-methylbutyl group, a 2-methylpentyl group, a 2-methylhexyl group, and a 2,2-dimethylhexyl group. Butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2
-Methylbutyl group, 2-methylpentyl group, 4-hexyn-1-yl group, 4-hexyn-2-yl group, 3-pentyn-1-yl group, 4-heptin-2-yl group, 5-heptene- A 2,6-dimethyl-1-yl group is preferred.

Substituted phenyl group, substituted phenoxy group, or C _{3 to} C ₁₀
Examples of the substituent of the substituted cycloalkyl group of include a halogen atom, a protected hydroxyl group (eg, a silyloxy group,
Such as C ₁ -C ₆ alkoxy group), such as C ₁ -C ₄ alkyl group. Examples of the cycloalkyl group C ₃ -C _10, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, cyclohexenyl group, heptyl group cyclopropyl, cyclooctyl group, etc. cyclodecyl. A cyclopentyl group and a cyclohexyl group are preferred.

C ₁ -C ₆ alkoxy group, optionally substituted phenyl group, optionally substituted phenoxy group, or optionally substituted C ₃ -C ₁₀ straight-chain or branched group In the branched chain C ₁ -C ₅ alkyl group,
The C ₁ -C ₅ alkoxy group such as methoxy group, ethoxy group, propyloxy group, isopropyloxy group, a butoxy group, t-butoxy group, and hexyloxy group. Examples of the substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted C _{3 to} C ₁₀ cycloalkyl group and the C _{3 to} C ₁₀ cycloalkyl group are the above-mentioned examples. Can be the same as. As the linear or branched C _{1 to} C ₅ alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, etc. Can be mentioned. Examples of R ⁵ include butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2
-Methylbutyl, 2-methylpentyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, cyclopentylmethyl, cyclohexylmethyl groups and the like can be mentioned as preferable ones. In addition, the substituent may be bonded to any position thereof.

In the above formula [I], n represents 0 or 1. Ar represents a phenyl group, but another reference example is a substituted phenyl group. Examples of the substituent include those mentioned above. Preferable examples include a phenyl group and a p-tolyl group.

In the compound represented by the above formula [I], the bicyclo [3.3.0] octane ring itself and its bicyclo [3.3.0]
The carbon bonded to the substituent bonded to the octane ring; the carbon substituted with the hydroxyl group on the ω chain and the like have stereoisomers due to the asymmetric environment. And a stereoisomeric mixture in any proportion thereof may be used. Further, the compound represented by the formula represents all of these stereoisomers and a mixture of these isomers at an arbitrary ratio, and the compound having the stereostructure represented by the formula is most preferred.

Preferred specific examples of the novel isocarbacyclines represented by the above formula [I] provided in the present invention will be shown together with reference examples.

(1) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E, 3S) -3-
Hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene (2) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-carbomethoxybutyl-6-[(E, 3S) -3-hydroxy-1-nonenyl] -7-hydroxybicyclo [3.3.0] -2-octene (3) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-carbomethoxybutyl-6-[(E, 3S) -3-hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene (4) (1S, 5S, 6S, 7R) -2-Phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E, 3S) -3-
Hydroxy-4,4-dimethyl-1-octenyl] -7-
Hydroxybicyclo [3.3.0] -2-octene (5) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E, 3S) -3-
Hydroxy-5-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene (6) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E, 3S) -3-
6-[(E, 3S, 5S) ...] Form of hydroxy-5-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.0] -2-octene (7) (6) (8) (6 )) 6-[(E, 3S, 5R) ...] body (9) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl-6-[(E, 3S) -3-hydroxy-3-cyclopentyl-1-propenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene (10) (1S, 5S, 6S, 7R) -2-phenylsulfonylbutyl-3- (4-carbomethoxybutyl) -6-[(E, 3S)
-3-Hydroxy-3-cyclohexyl-1-propenyl] -7-hydroxybicyclo [3.3.0] -2-octene (11) (1S, 5S, 6S, 7R) -2-phenylsulfonylbutyl-3- ( 4-carbomethoxybutyl) -6-[(E, 3S)
-3-Hydroxy-3-cyclohexyl-1-butenyl] -7-hydroxybicyclo [3.3.0] -2-octene (12) (1S, 5S, 6S, 7R) -2-phenylsulfonylbutyl-3- ( 4-carbomethoxybutyl) -6-[(E, 3S)
-3-Hydroxy-5-phenoxy-1-pentenyl]
-7-Hydroxybicyclo [3.3.0] -2-octene (13) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E, 3S) -3-
Hydroxy-5-ethoxy-1-pentenyl] -7-hydroxybicyclo [3.3.0] -2-octene (14) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-carbomethoxy-4-hydroxy-4-methyl-
1-octenyl] -7-hydroxybicyclo [3.3.0]
-2-octene (15) (1S, 5S, 6S, 7R) -2-phenylsulfonylbutyl-3- (4-carbomethoxybutyl) -6-[(E, 4R)
-4-Hydroxy-4-methyl-1-octenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene (16) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E) -4-hydroxy-4-vinyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene (17) (1S, 5S, 6S , 7R) -2-Phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E) -3-hydroxy-1-hepten-7-yn-1-yl] -7-
Hydroxybicyclo [3.3.0] -2-octene (18) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
(4-Carbomethoxybutyl) -6-[(E) -3-hydroxy-1-octen-6-yn-1-yl] -7-
Hydroxybicyclo [3.3.0] -2-octene (19) (1) to (18) 2-p-tolylsulfonyl compound.

(20) A compound in which the methyl ester of (1) to (19) is a carboxylic acid.

(21) A compound in which the methyl ester of (1) to (18) is an allyl ester.

(22) (1) to (19) 3- [4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] oct-1-yl) butyl compound (23) (1) to Enantiomer of the compound of (22).

(24) Stereoisomers derived from the asymmetric carbons at the 1-, 5-, 6-, and 7-positions of the compounds of (1) to (22) and the asymmetric carbon in which the hydroxyl group on the 6-position substituent is substituted.

Examples thereof include, but are not limited to, compounds in which the hydroxyl groups of these compounds are protected by the protecting groups exemplified above.

The novel isocarbacyclines represented by the above formula [I] are represented by the following formula [IV] 3,6,7-trisubstituted bicyclo (3.
3.0] -2-octenes were reacted with arylthiochloride in the presence of a base to give the following formula [II-2] A compound represented by the following formula, its stereoisomer or a mixture of bicyclo [3.3.0] octanes in an arbitrary ratio thereof is obtained, and by subjecting this to an oxidation reaction, the following formula [II-1] A compound represented by the following formula, its stereoisomer or a mixture of bicyclo [3.3.0] octanes at any ratio thereof, which is treated with a base to give the following formula [III] [In the formula, X and A'are the same as defined above. ] It is obtained by reacting with a halide represented by and further subjecting to a deprotection reaction and a hydrolysis reaction, if necessary.

The starting material for this reaction, 3,6,7 represented by the above formula [IV]
In the trisubstituted bicyclo [3.3.0] -2-octenes R
²¹ and R ³¹ are the same or different and represent a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group forming an acetal bond with the oxygen atom of the hydroxyl group. Such tri (C ₁ ~C ₇₎
As the group that forms an acetal bond with the oxygen atom of the hydrocarbon silyl group or the hydroxyl group, the same groups as those exemplified as R ² or R ³ in the above formula [I] can be preferably mentioned.

In the above formula [IV], R ⁴ represents a hydrogen atom, a methyl group, or a vinyl group, and R ⁵ is a linear or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom; substituted or unsubstituted A phenyl group; a substituted or unsubstituted phenoxy group;
A substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group; or a C ₁ -C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃ ~ C ₁₀ represents a linear or branched C _{1 to} C ₅ alkyl group substituted with a cycloalkyl group,
Preferred examples are the same as those exemplified for R ⁵ in the above formula [I].

In the formula [IV], n represents 0 or 1.

3,6,7-Trisubstituted-bicyclo [3.3.0] -2-octenes represented by the formula [IV] are described in, for example, Shibasaki et al., Tetrahedron Letters, 25,50.
It is manufactured in the same manner as the method described in 87 (1984), but the manufacturing process is briefly introduced as shown in the following process chart. That is, Manufacturing process.

By reacting the alcohol represented by the above formula [IV] with aryl thiochloride in the presence of a base, the above formula [II-
2] to form a sulfoxide form.
Arylthiochloride is phenylthiochloride,
P-tolyl thiochloride is preferably used. The amount used is 0.5 to 10 mole times, preferably 1 to 3 mole times, relative to 1 mole of the starting alcohol represented by the above formula [IV]. This reaction is carried out in the presence of a base, but various nitrogen-containing organic bases can be used as the base, preferably triethylamine, diisopropylethylamine,
Pyridine, dimethylaminopyridine, collidine, DB
U, DBN, etc. are used. The reaction temperature is −50 ° C. to 200 ° C., preferably −30 ° C. to 30 ° C. The reaction time varies depending on the reaction temperature, but at 0 ° C., 1 hour is sufficient. The reaction is carried out in an organic solvent, and the solvent used is, for example, an ether solvent such as ethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; a halogen solvent such as chloroform, carbon tetrachloride or dichloromethane; an aromatic solvent such as benzene or toluene. ; Other D
MF, DMSO, etc. are used. Ethyl ether and tetrahydrofuran are preferably used.

Thus, the sulfoxide derivative represented by the above formula [II-2] is obtained. Then, the sulfone compound represented by the above formula [II-1] can be obtained by subjecting it to an oxidation reaction. Examples of the oxidizing agent include permanganate, chromic acid, ruthenium tetroxide, hydrogen peroxide, organic peracid and the like. It is preferable to use an organic peracid, particularly preferably m-chloroperbenzoic acid. The amount of the oxidizing agent used is 1 mol of the sulfoxide compound represented by the above formula [II-2].
It is 0.2 to 20 times by mole, preferably 1 to 3 times by mole. The reaction temperature is -78 ° C to 100 ° C, preferably -30 ° C to 3
It is in the range of 0 ° C., and the reaction time is about 1 hour at 0 ° C., although it varies depending on the reaction temperature. The reaction is carried out in an organic solvent, and any solvent used for a usual oxidation reaction may be used,
For example, ether solvents such as ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; halogen solvents such as chloroform, carbon tetrachloride and dichloromethane;
Aromatic solvents such as benzene and toluene are used. Dichloromethane and chloroform are preferably used. Thus, the sulfone compound represented by the above formula [II-1] can be obtained.

The above formulas [II-2] and [II-1] thus obtained are represented by the following formula [II] And a stereoisomer thereof or a mixture of bicyclo [3.3.0] octanes in an arbitrary ratio thereof, which are novel compounds per se. R ²¹ ,
Specific examples of R ³¹ , R ⁴ , R ⁵ , and Ar are the same as those exemplified in the above formula [I] or the above formula [IV].

Then, the sulfone compound represented by the above formula [II-1] is treated with a base and then reacted with a halogen compound represented by the above formula [III], and if necessary, a deprotection reaction and a hydrolysis reaction are carried out to obtain the above compound. The novel isocarbacyclines represented by the formula [I] are obtained.

In the halide represented by the above formula [III], X represents a halogen atom, and examples thereof include chlorine, bromine and iodine. A ′ represents a 4-methyl-2,6,7-trioxabicyclo [2,2,2] oct-1-yl group or a carboxylate group (—COOR ¹ ), and specific examples of R ¹ are the above. It is the same as that illustrated for A in the formula [I].

The halide is used in an amount of 0.5 to 30 mol times, preferably 1 to 10 mol times, relative to 1 mol of the sulfone compound represented by the above formula [II-1]. The base used in this reaction is
Organolithium compounds are used, for example, n-butyl lithium, sec-butyl lithium, t-butyl lithium, phenyl lithium, methyl lithium, naphthyl lithium,
Trityl lithium or the like is used. Preferably n-butyllithium is used. The amount used is 0.5-30 mol times, preferably 1-10 mol times, relative to 1 mol of the sulfone compound represented by the above formula [II-1]. The reaction temperature is -100 ° C to 100 ° C, preferably -78 ° C to 20 ° C.
The reaction time is 5 minutes to 50 hours, preferably 10 minutes to 2 hours. The reaction is carried out in an organic solvent, and the solvent used is an ether solvent such as ether, tetrahydrofuran or dioxane; or a hydrocarbon solvent such as n-hexane or benzene. Ether and tetrahydrofuran are preferably used.

The reaction solution thus obtained may be post-treated in accordance with a commonly used method. For example, an organic mixture obtained by adding a sparingly soluble organic solvent to water such as hexane, pentane, petroleum ether, ethyl ether, and ethyl acetate is washed with saline, etc., if necessary, and anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous After drying with a desiccant such as calcium chloride, the organic medium is removed under reduced pressure to obtain a crude product.
The crude product is optionally subjected to column chromatography,
It can be purified by a purification means such as thin layer chromatography or liquid chromatography. Such a post-treatment is similarly performed in the case of the above formulas [II-2] and [II-1].

Then, the obtained product is subjected to a deprotection reaction and a hydrolysis reaction, if necessary, to finally obtain a novel isocarbacycline represented by the above formula [I].

When the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, the protecting group for the hydroxyl group is removed, for example, by using acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin as a catalyst, and removing, for example, water. , Tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like are preferably used as a reaction solvent. The reaction is usually performed in the temperature range of -78 ° C to + 30 ° C for 10
Minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, the above-mentioned is performed in the presence of, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride water, pyridine-hydrogen fluoride. It is carried out in such a reaction solvent at similar temperatures and for similar times.

In the case of a compound of the formula [III] in which A is a 4-methyl-2,6,7-trioxabicyclo [2.2.2] oct-1-yl group, deprotection of the above protected hydroxyl group is performed. Under the conditions (for example, reaction under a catalyst such as acetic acid, a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin), A is converted to a 2,2-bis (hydroxymethyl) prop-1-yloxycarbonyl group. To be converted.

This 2,2-bis (hydroxymethyl) prop-1-yloxycarbonyl group is hydrolyzed under the usual ester group hydrolysis conditions, that is, lithium hydroxide, sodium hydroxide, potassium hydroxide in water or a solvent containing water. -40 ° C ~ 1
In the temperature range of 00 ° C, preferably 0 ° C to 50 ° C for 10 minutes to
By reacting for 24 hours, A is converted into a compound having a carboxy group.

Similarly, when A is an ester group represented by —COOR ¹ , it is converted into a carboxylic acid form by a hydrolysis reaction as in the above conditions.

The compound represented by the above formula [II], which is a raw material for synthesizing the novel isocarbacycline represented by the above formula [I], is a novel compound itself, and its specific example is a compound from which a hydroxyl-protecting group is removed. For example, the following may be mentioned.

(25) (1S, 5S, 6S, 7R) -2-Phenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] octane (26) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3 −
Methylene-6-[(E, 3S) -3-hydroxy-1-nonenyl] -7-hydroxybicyclo [3.3.0] octane (27) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3 −
Methylene-6-[(E, 3S) -3-hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.
0] octane (28) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-4,4-dimethyl-1-octenyl] -7-hydroxybicyclo [3.3.0] octane (29) (1S, 5S, 6S, 7R) -2 -Phenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-5-methyl-1-octenyl] -7-hydroxybicyclo [3.3.
0] octane (30) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-5-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.
0] Octane (31) (30) 6-[(E, 3S, 5S) ……] body (32) (30) 6-[(E, 3S, 5R) ……] body (33) (1S , 5S, 6S, 7R) -2-Phenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-3-cyclopentyl-1-propenyl] -7-hydroxybicyclo [3.3.0] octane (34) (1S, 5S, 6S, 7R) -2-Fu Enenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-3-cyclohexyl-1-propenyl] -7-hydroxybicyclo [3.3.0] octane (35) (1S, 5S, 6S, 7R) -2-Ph Enenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-3-cyclohexyl-1-butenyl] -7-hydroxybicyclo [3.3.0] octane (36) (1S, 5S, 6S, 7R) -2-Phenyl Enenylsulfonyl-3-
Methyleneme-6-[(E, 3S) -3-hydroxy-5-phenoxy-1-pentenyl] -7-hydroxybicyclo [3.3.0] octane (37) (1S, 5S, 6S, 7R) -2-Ph Enenylsulfonyl-3-
Methylene-6-[(E, 3S) -3-hydroxy-5-ethoxy-1-pentenyl] -7-hydroxybicyclo [3.
3.0] Octane (38) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
Methylene-6-[(E, 4S) -4-hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.
0] octane (39) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
Methylene-6-[(E, 4R) -4-hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.
0] octane (40) (1S, 5S, 6S, 7R) -2-phenylsulfonyl-3-
Methylene-6-[(E) -4-hydroxy-4-vinyl-1-octenyl] -7-hydroxybicyclo [3.3.
0] 2-p-tolylsulfonyl compound of octane (41) (25) to (40) (42) (25) to (40) 2-p-tolylsulfinyl compound (43) (25) to (40) 2-phenylsulfinyl derivative of) The compound in which the hydroxyl group of the compounds exemplified above is protected by the protecting group exemplified above corresponds to the compound represented by the above formula [II].

Thus, the compound represented by the above formula [I] having an isocarbacycline skeleton is produced.

<Effects of the Invention> The novel isocarbacycline obtained in the present invention may itself have isocarbacyclin-like activity, for example, platelet aggregation inhibitory action, vasodilatory action, antihypertensive action, anti-SRS-A action, cytoprotective action and the like. Be expected. It is also a useful compound as an intermediate for synthesizing isocarbacycline, which is promising as a drug.

<Examples> Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 (1S, 5S, 6S, 7R) -3-Hydroxymethyl-6-[(E, 3
S) -3-t-Butyldimethylsilyloxy-1-octenyl] -7-t-butyldimethylsilyloxybicyclo [3.3.0] -2-octene 400 μg (0.79 mmol) in ether solution (5 ml) with triethylamine 330 μl
(2.4 mmol) was added and cooled to 0 ° C. Thiofenyl chloride (1 mmol / ml) (950 μl, 0.95 mmol) was added dropwise thereto, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to terminate the reaction, and ether extraction was performed. It was dried over anhydrous magnesium sulfate and the solvent was distilled off. Subjected to column chromatography (hexane: ethyl acetate = 10: 1), (1S, 5S,
6S, 7R) -2-Phenylsulfonylbutyl-3-methylene-6-[(E, 3S) -3-t-butyldimethylsilyloxy-1-octenyl] -7-t-butyldimethylsilyloxybicyclo [3.3 .0] Octane 392 mg (81
%) Was obtained.

TLC (hexane: ethyl acetate = 4: 1, Rf = 0.35,0.
4) NMR (δ ppm, CDCl ₃ ): 0.85 (s, 18H), 0.7-2.6 (m, 18H), 3.1-4.2 (m, 3H), 4.65-5.5 (m, 4H), 7.4 (m, 5H) IR (cm ^-1 , neat): 2950,2850,1460,1440,1360, 1250,1110,1045 Example 2 A methylene chloride solution (2 ml) containing 130 mg (0.21 mmol) of the sulfoxide compound was cooled to 0 ° C., and m-chloroperbenzoic acid 5
4 mg (0.32 mmol) was added and stirred for 40 minutes. Heavy sodium was added to terminate the reaction, and the mixture was extracted with hexane. After drying the organic layer, the solvent was distilled off and the residue was subjected to column chromatography (silica gel hexane: ethyl acetate = 10: 1) to obtain 107 mg (80%) of a sulfone compound.

NMR (δppm, CDCl ₃ ): 0.9 (s, 18H), 0.7-3.3 (m, 18H), 3.5-4.2 (m, 3H), 4.7 (br.s, 1H), 5.1 (br.s, 1H) , 5.45 (m, 2H), 7.3 to 8.1 (m, 5H) IR (cm ^-1 , neat): 2950, 2860, 1650, 1510, 1460, 1440, 1385, 1360, 1310, 1255 Example 3 105 mg (0.17 mmol) of the sulfone compound was made into a 500 μl THF solution and cooled to −78 ° C. under a nitrogen atmosphere. 1.17 ml (0.183 mmol) of n-butyllithium (0.156M, hexane) was added, and 10 minutes later, 1 ml of HMPA (hexamethylphosphoric triamide) was added and stirred for 30 minutes. Then 4-
42 mg (0.18 mmol) of methyl iodobutyrate in THF (1 ml)
The solution was added and stirred for 1 hour. Aqueous ammonium chloride solution was added, and the mixture was extracted with ether. After drying the organic layer, column chromatography (hexane: ethyl acetate = 25: 1),
Then, the product was purified by TLC (benzene: ethyl acetate = 20: 1) and recovered 36 mg (34%), α product 42 mg (35%).
%), And 12 mg (10%) of the γ product was obtained.

γ product NMR (δppm, CDCl ₃ ): 0.9 (s, 18H), 0.8-2.8 (m, 26H), 3.6 (s, 3H), 3.6-4.2 (m, 2H), 5.4 (m, 2H), 7.5 to 8.0 (m, 5H) Example 4 A solution of 20 mg (0.027 mmol) of disilyl compound in 1 ml of acetonitrile was cooled to 0 ° C., 100 μl of pyridine and 200 μl of hydrofluoric acid-pyridine were added, and the mixture was stirred for 1 hour. The reaction was terminated with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure, and silica gel column chromatography (hexane:
Ethyl acetate = 1: 42 2% methanol) to obtain 9 mg (65%) of a diol.

NMR (δ ppm, CDCl ₃ ): 0.7 to 1.0 (m, 3H), 1.0 to 3.0 (m, 23H), 3.5 to 4.2 (m, 2H), 3.65 (s, 3H), 5.35 to 5.6 (m, 2H) , 7.3 to 7.9 (m, 5H) Example 5 320 mg of alcohol (0.6 mmo)
315 mg (82%) of the sulfoxide compound was obtained from l).

_{NMR (δppm, CDCl 3):} 0.85 (s, 18H), 0.7~2.5 (m, 22H), 3.1~4.2 (m, 3H), 4.6~5.5 (m, 4H), 7.4 (m, 5H) Example 6 In the same manner as in Example 2, 276 μg (87%) of a sulfone compound was obtained from 310 μg of the sulfoxide compound.

NMR (δppm, CDCl ₃ ): 0.9 (s, 18H), 0.7-3.4 (m, 22H), 3.5-4.2 (m, 3H), 4.7 (br.s, 1H), 5.1 (br.s, 1H) , 5.45 (m, 2H), 7.3 to 8.1 (m, 5H) Example 7 In the same manner as in Example 3, 20 μg (16%) of the target γ product and 65 μg (51%) of the α product were obtained from 10 mg (0.17 mmol) of the sulfone compound.

γ Resultant NMR (δppm, CDCl ₃ ): 0.9 (s, 18H), 0.8-2.8 (m, 30H), 3.6 (s, 3H), 3.6-4.2 (m, 2H), 5.4 (m, 2H), 7.5 to 8.1 (m, 5H) Example 8 From 251 μg (0.52 mmol) of alcohol, 210 μg (68%) of sulfoxide was obtained in the same manner as in Example 1.

NMR (δ ppm, CDCl ₃ ): 0.9 (s, 9H), 1.1 (s, 3H), 0.7 to 1.7 (m, 11H), 1.7 to 3.0 (m, 7H), 3.1 to 4.2 (m, 3H), 4.65 ~ 5.5 (m, 4H), 7.4 (m, 5H) Example 9 In the same manner as in Example 2, 200 μg of sulfoxide compound (0.34
158 μg (77%) of a sulfone compound was obtained from (mmol).

NMR (δ ppm, CDCl ₃ ): 0.9 (s, 9H), 1.1 (s, 3H), 0.7 to 3.3 (m, 18H), 3.5 to 4.2 (m, 3H), 4.7 (br.s, 1H), 5.1 (br.s, 1H), 5.45 (m, 2H), 7.3 to 8.1 (m, 5H), Example 10 In the same manner as in Example 3, 140 μg of sulfone (0.23 mmo
From l), 27 μg (17%) of the desired product γ product and 76 μg (17%) of the α product were obtained.

γ Resultant NMR (δppm, CDCl ₃ ): 0.9 (s, 9H), 0.8-2.8 (m, 26H), 1.1 (s, 3H), 3.5-4.3 (m, 2H), 5.5 (m, 2H), 7.5 to 8.0 (m, 5H) Example 11 As in Example 1, 290 μg of alcohol (0.57 mm
ol) to give 25 / mg (71%) of the sulfoxide compound.

NMR (δppm, CDCl ₃ ): 0.9 (s, 18H), 0.1-2.5 (m, 16H), 3.1-4.1 (m, 3H), 4.6-5.5 (m, 4H), 7.4 (m, 5H) Example 12 In the same manner as in Example 2, 240 μg of sulfoxide (0.39
(21 mmol) (86%) was obtained from the sulfone compound.

NMR (δppm, CDCl ₃ ): 0.9 (s, 18H), 1.0-3.3 (m, 16H), 3.5-4.2 (m, 3H), 4.7 (br.s, 1H), 5.1 (br.s, 1H) , 5.45 (m, 2H), 7.3 to 8.1 (m, 5H) Example 13 In the same manner as in the Example, 30 μg (17%) of the target γ product and 79 μg (45%) of the α product were obtained from 150 mg (0.24 mmol) of the sulfone compound.

γ Resultant NMR (δppm, CDCl ₃ ): 0.9 (s, 9H), 1.0-2.9 (m, 24H), 3.65 (s, 3H), 3.6-4.2 (m, 2H), 5.4 (m, 2H), 7.5 ~ 8.0 (m, 5H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display area A61K 31/557 ACL

Claims (6)

[Claims] 1. The following formula [I]: Isocarbacyclines which are compounds represented by, their stereoisomers, or a mixture thereof at any ratio. 2. The isocarbacyclines according to claim 1, wherein A is a carboxy group or a methoxycarbonyl group. 3. The isocarbacyclines according to claim 1 or 2, wherein R ² and R ³ are the same or different and each is a hydrogen atom, a trimethylsilyl group or a dimethyl-t-butylsilyl group. 4. A method according to claim 1, wherein R ⁴ is a hydrogen atom.
Item 6. The isocarbacycline according to any one of items 3 to 3. ^{5. A} butyl group, a pentyl group, a hexyl group, a heptyl group, a 2-hexyl group, a 2-methyl-2-hexyl group, a 2-methylbutyl group, a 2-methylpentyl group, a cyclopentyl group and a cyclohexyl group. The isocarbacyclines according to any one of claims 1 to 4, which is 6. Claims 1 to 5 in which n = 0.
Item 2. The isocarbacyclines according to any one of items.