JPH0655715B2 - 9-deoxo-6,9-dimethylene prostaglandin E1s - Google Patents

Description

TECHNICAL FIELD The present invention relates to a methyleneated prostaglandin E ₁ and a method for producing the same. More specifically, the present invention provides 6-methylene prostaglandin E ₁ and 9-deoxy-9-methylene-6-oxoprosta which are expected to be pharmaceuticals such as cardiovascular drugs, anti-ulcer drugs, and cytopathic drugs. Method for producing glandine E ₁ and 9-deoxy-6.9-dimethylene prostaglandin E ₁ by reacting 6-oxoprostaglandin E ₁ with a methyleneating reagent and 9-deoxy which is a novel compound -6.9- relates dimethylene prostaglandin E ₁ compound.

<Prior Art> Natural prostaglandins (hereinafter sometimes abbreviated as PG) are known as local hormones (autocoids) having biologically and pharmacologically high activities. Therefore, studies to develop new types of pharmaceuticals by skillfully utilizing these physiological characteristics of PG have been conducted not only for natural PGs but also for various derivatives.

Among the natural PGs, PGE and PGF are compounds that have been known for a long time, and PGE ₂ and PGE ₂ α have already been commercialized as a labor-promoting agent by utilizing their uterine smooth muscle contracting action. PGE ₁ is used as a therapeutic agent for peripheral circulation by utilizing physiological actions such as platelet aggregation inhibitory action and blood pressure lowering action.

A method via a 2-substituted-2-cyclopentenone which is an important intermediate (CJSin et al., Journal of the American Chemical Society (J. Am. Chem. Soc. ), 97, 865 (1975)] and the like.

Aside from the method of obtaining PGs by biosynthesis, the method of obtaining by chemical synthesis has many steps to obtain a starting material, while even if the starting material can be easily obtained, a prosta The production of glandins still involves many steps and therefore has drawbacks such as very low overall yield.

In recent years, in order to overcome these difficulties, a three-component coupling process method has been devised as a direct synthesis method of a PG skeleton, which uses a coupling addition reaction to a 2-cyclopentenone system and a trapping process of enolate.・ G.Stork et al.
Journal of the American Chemical Society (J.Am.Chem.Soc), 97,6260 (1975), K.G., Punch (KGUntch), etc. Chem.) 44, 3755].
(Noyori et al., Tetrahedron Lees
tters), 23,4057, (1982) and Tetrahedron Letters, 23,5563 (1982)].

On the other hand, 6-oxoprostaglandin E ₁ which is the starting material in the present invention is known to have a potent platelet aggregation inhibitory action equivalent to prostacyclin and a hypotensive action based on smooth muscle relaxation action. [Seeb
CP Quilley et al., European Journal of Pharmacology, Volume 57, 273-276
Page, 1979; PYKWong (PYKW
ong) et al., European Journal of Pharmacology, 60, 245-248, 1979; CNBerry et al., Pharmacology,
26, 324-330 1983; RJ Griffiths et al., Brititsushiyu Journal of Pharmacology, 79, 149-
155, 1983]. It is known that some of the analogs of the above compounds have not only a platelet aggregation inhibitory action and an antihypertensive action but also an excellent antiulcer action (JP-A-53-8).
4942, JP 54-44639, JP 55-141465
(See Japanese Laid-Open Patent Publication No. 58-74660). Various PGE ₁ derivatives are also actively synthesized both inside and outside. One of the PGE ₁ derivatives, 9-deoxy-9-methylene-6-oxo-prostaglandin E ₁ compound (see JP 58-10560) have been proposed, the preparation of such a PGE ₁ derivative is 6- Although it is a method of obtaining it from oxoprostaglandin E ₁ , it is a reaction via 9-hydroxysulfoximine as an intermediate and requires two steps.

The present inventors <object of the present invention> The novel prostaglandin E ₁ derivatives and 6-oxo-prostaglandin E ₁ derivative exploration and intensive studies with a result to find that simple production process around the compound of 9- deoxy-9-methylene-6-oxo-prostaglandin E ₁ compound, 9-deoxy -6.9- dimethylene prostaglandin E ₁ compound and 6-methylene prostaglandin succeeded in synthesizing E ₁ include, reached the present invention It was done.

<Structure of the Invention> In the present invention, the following formula [II-a] 9-deoxo-6,9-dimethylene prostaglandin E ₁ which is a compound represented by the formula (3), its stereoisomer or a mixture thereof in any ratio. For reference, the following formula [I] 6-oxoprostaglandin E ₁ which is a compound represented by the formula, its stereoisomer or a mixture thereof at an arbitrary ratio, is reacted with a methyleneating agent, and if necessary, subjected to a deprotection reaction. Next formula [II] There is provided a process for producing a methyleneated prostaglandin E ₁ which is a compound represented by the formula, its stereoisomer or a mixture thereof in any ratio.

The 6-oxoprostaglandins E ₁ represented by the above formula [I], which is a starting material, are known compounds and are produced by a method separately proposed by the present inventors (JP-A-60-11461). (See reaction formula below).

In the above formula [I], R ¹ represents a C _{1 to} C ₁₀ alkyl group. Examples of the C _{1 to} C ₁₀ alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, Examples thereof include linear or branched ones such as octyl group, nonyl group and decyl group. Preferred is a methyl group.

In the above formula [I], R ² and R ³ are the same or different and each represent a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a tetrahydropyranyl group. It represents a group that forms an acetal bond.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include:
Trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t- butyl-dimethyl-tri (C ₁ ~C ₄₎ alkylsilyl group such as a silyl group, t- butyl diphenyl diphenyl like enyl silyl group (C ₁ -C ₄ ) An alkylsilyl group, a (C ₁ -C ₄ ) alkylphenyl group such as a dimethylphenyl group, a tribenzylsilyl group and the like can be mentioned as preferable ones. Bird (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 a methoxymethyl group, a 1-ethoxyethyl group, a 2-methoxy-2-propyl group, and a 2-ethoxy- group.
2-propyl group, (2-methoxyethoxy) methyl group,
Examples thereof include a benzyloxymethyl group, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, and 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. Therefore, the hydroxyl-protecting group having such properties can be used in place of the silyl group or the group forming an acetal bond.

In the above formula [1], R ⁴ represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula [I], R ⁵ is a linear or branched C ₃
C ₈ alkyl group; a phenyl group; a phenoxy group; C ₃ -C ₁₀
A cycloalkyl group; or a linear or branched C ₁ -C ₅ alkyl group substituted with a C ₁ -C ₆ alkoxy group, a phenyl group, a phenoxy group or a C ₃ -C ₁₀ cycloalkyl group. In addition, as another reference example, a linear or branched C ₃ -C ₈ alkyl group containing an oxygen atom;
Substituted phenyl group; Substituted phenoxy group; Substituted C _3-
C ₁₀ cycloalkyl group; or a substituted phenyl group, a substituted phenoxy group, or a linear or branched C ₁ -C ₅ alkyl group substituted with a substituted C ₃ -C ₁₀ cycloalkyl group Is mentioned.

The linear or branched C ₃ -C ₈ alkyl group which may contain oxygen includes 2-methoxyethyl group, 2-ethoxyethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, 2 -Hexyl group, 2-methyl-2-
Examples thereof include a hexyl group, a 2-methylbutyl group, a 2-ethylpentyl group, a 2-methylhexyl group and a 2,2-dimethylhexyl group. Butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-
A 2-hexyl group, a 2-methylbutyl group, and a 2-methylpentyl group are preferable.

Substituted phenyl group, substituted phenoxy group, or C ₃ -C
_As the substituent of the substituted cycloalkyl group of ₁₀ , for example,
Examples thereof include a halogen atom, a protected hydroxyl group (eg, a silyloxy group, a C _{1 to} C ₆ alkoxy group, etc.), a C _{1 to} C ₄ alkyl group and the like. Examples of the C _{3 to} C ₁₀ cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group and the like. 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, examples of the C ₁ -C ₆ alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, a t-butoxy group and a hexyloxy group. Can be mentioned. An optionally substituted phenyl group,
Examples of the substituent of 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 may be the same as those exemplified above. Straight or branched chain C ₁
The -C ₅ alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, t- butyl group, a pentyl group. Such R ⁵ is 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.

Further, in the compound represented by the above formula [I], the configuration of the substituent bonded to the cyclopentanone ring has the same configuration as that of natural prostaglandin E _1. Although it is an isomer, in the present invention, the stereoisomer or a mixture thereof in any ratio is included.

Further, since the carbon to which R ⁴ , R ⁵ and OR ³ are bonded is usually an asymmetric carbon, there are two kinds of stereoisomers, but in the present invention, any stereoisomer is included.
Any proportion of stereoisomeric mixtures may be used.

The methyleneating agent has the following formula [III] Is selected from compounds represented by.

Nozaki et al. (Tetrahedron Letters
2417 (1978), 26, 5581 (1985)) and Ronhard (L.Lom
bardo) et al (Tetrahedron Letters 23 , 4293 (198
It is described in the literature of 2)) and is adjusted by the method described in the literature.

In the present invention, methylene bromide-zinc-titanium tetrachloride (CH ₂ Br ₂ -Zn-TiCl ₄ ) or methylene iodide-
Zinc-titanium tetrachloride (CH ₂ I ₂ -Zn-TiCl ₄ ) or the latter with Ti
A reagent to which (NEt ₂ ) ₄ is added is preferably used.

The amount of the methylene-forming reagent to be used varies depending on whether 1 or 2 methylene is introduced into the 6-oxoprostaglandin E ₁ which is a starting material. Perform equimolar reactions stoichiometrically.

However, the amount used depends on the active state of the reagent,
It is preferable to add a reagent while tracking the reaction by TLC or the like. Usually, 0.5 to 20 equivalents, preferably 1.0 to 5 equivalents are preferable with respect to 1 mol of 6-oxoprostaglandin E ₁ species.

The reaction temperature is -78 ° C to 100 ° C, particularly preferably -30.
A temperature range of about 40 ° C to 40 ° C is adopted. The reaction time is
Although it depends on the reaction temperature, it is usually about 1 hour at 0 ° C.

The reaction is carried out in the presence of an organic medium. As such an organic medium, an inert organic medium which does not react with the reaction reagent is used, and examples of the medium include saturated hydrocarbons such as pentane, hexane, heptane, and cyclohexane; benzene, toluene, xylene, and the like. Aromatic hydrocarbons; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol and dimethyl ether; halogen solvents such as dichloromethane, chloroform and carbon tetrachloride are used. Dichloromethane is preferably used. After the reaction, it is separated and purified by the usual means (post-treatment, extraction, washing, chromatography).

The reaction product is subjected to deprotection of hydroxyl group and deprotection of carboxylic acid, if necessary.

Deprotection of a hydroxyl group is a reaction known per se, and when the protective group is a group that forms an acetal bond together with the oxygen atom of the hydroxyl group, acetic acid, a pyridinium salt of p-toluenesulfonic acid, a cation exchange resin or the like is used. This is done by processing. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, it is carried out, for example, by treatment with acetic acid, tetrabutylammonium fluoride, cesium fluoride or the like.

Deprotection of carboxylic acid is a reaction known per se, and is carried out by allowing oxygen such as lipase to act.

In the compound represented by the formula [II], R ¹¹ , R ²¹ , R ³¹ , R ⁴ ,
The definitions of R ⁵ and n are the same as those described above, and preferred examples thereof are the same as the groups exemplified for R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n in the above formula [I]. To be

In addition, among the compounds represented by the formula [II], the following formula [II
-a] The compounds represented by are novel compounds, and preferred specific examples thereof include the compounds shown below.

(1) 9-deoxo-6,9-dimethylene PGE ₁ (2) 17,20-dimethyl-9-deoxo-6,9-dimethylene PGE ₁ (3) 16,17,18,19,20-pentanor-15 -Cyclopentyl-9-deoxo-6,9-dimethylene PGE ₁ (4) 16,17,18,19,20-pentanor-15-cyclohexyl-9-deoxo-6,9-dimethylene PGE ₁ (5) 16,16 - dimethyl-9-deoxo-6,9-dimethylene PGE ₁ (6) 9,15- Jideokiso -6,9-dimethylene-16-hydroxy-PGE ₁ (7) 9,15- Jideokiso 6,9 dimethylene -16 -Hydroxy-16-methyl PGE ₁ (8) (1) to (7) methyl ester form.

(9) A compound in which the hydroxyl groups of (1) to (8) are protected by a trimethylsilyl group, a t-butyldimethylsilyl group and a tetrahydropyranyl group.

(10) An enantiomer of (1) to (9).

However, the present invention is not limited to these.

The compound represented by the formula [II] thus obtained is 6-
It can be regarded as an analogue of oxoprostaglandin E ₁ and is expected not only to selectively exert physiological activities peculiar to E-type prostaglandins such as circulatory system action, antiulcer action and cytoprotection action. , Which can be expected to have long-lasting action, is a compound group useful as a pharmaceutical.

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

Example 1 6-oxo PGE, methyl ester disilyl compound 6.0 g
(9.8 mmol) in 200 ml of methylene chloride solution, 0 ℃
Adjusted separately (L. Lambard et al. Tetrahedron Lett., 23 , (19
82)) The CH ₂ Br ₂ —Zn—TiCl ₄ was added to the reaction system until the amount of raw materials was reduced while the reaction was monitored by TLC. During this time, the mixture was stirred for about 2 hours. The reaction was neutralized with non-sodium water, filtered through celite (3), and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off, followed by silica gel column chromatography (hexane: ethyl acetate = 2).
0: 1 → 5: 1), 2.66 g (44.5%) of monomethylene compound (mixture of 9 methylene compound and 6 methylene compound) and 6,
Thus, 1.16 g (19.5%) of 9-dimethylene compound was obtained.

Spectral data <monomethyl methylene _{body> NMR (δppm, CDCl 3)} : 0.8 (S, 18H), 0.8~1.0 (m, 3H), 1.0~
2.0 (m, 12H), 2.0〜2.8 (m, 10H), 3.7 (S, 3H), 4.0 (m, 2H), 4.6
5 (m, 2H), 5.4 (m, 2H).

IR (cm ^-1 , neat): 2950,2870,1745,1720,1650,1460,1360,
1250.

<6,9-dimethylene form> NMR (δ ppm, CDCl ₃ ): 0.8 (S, 18H), 0.8 to 1.0 (m, 3H), 1.0 to
2.0 (m, 12H), 2.0 ~ 2.6 (m, 10H), 3.60 (S, 3H), 3.9 (m, 2H), 4.
7 (m, 4H), 5.35 (m, 2H).

IR (cm ^-1 ,, neat): 2950,2870,1740,1640,1460,1360,125
0.

Reference example 1 1.16 g (1.9 m) of mixture of 9-methylene and 6-methylene
mol) in 50 ml ether and cooled to 0 ° C.
10 drops of MeONa (28% in MeOH) was added thereto and stirred for 15 minutes. Aqueous ammonium chloride solution was added to terminate the reaction, extraction with ether was performed, and the mixture was subjected to column chromatography (hexane: AcOEt = 15: 1, silica gel).
9 Methylene compound 860 mg (74% Rf = 0.5, hexane: AcOEt
= 4: 1) and 6 methylene A type 210 mg (23% Rf =
0.4, hexane: AcOEt = 4: 1) was obtained.

NMR (δ ppm, CDCl ₃ ): <9 methylene body> 0.8 (S, 18H), 0.8 to 1.0 (m.3H), 1.0 to 1.9 (m, 12H), 1.9 to 2.7
(m, 10H), 3.6 (S, 3H), 3.6〜4.2 (m, 2H), 4.55 (m, 1H), 4.75
(m, 1H), 5.35 (m, 2H).

<6 methylene body> 0.8 (S, 9H), 0.8 ~ 1.0 (m, 3H), 1.0 ~ 2.6 (m, 20H), 3.6 (S.3
H), 4.0 (m, 1H), 4.65 (m, 1H), 5.3 (m, 2H), 6.1 (dd, 1H, J = 6H
z, 2Hz), 7.3 (dd, 1H, J = 6Hz, 3Hz).

Reference example 2 9 methylene 6oxo PGE, methyl ester disilyl compound 105 mg 10.33 mmol) was dissolved in 4 ml of acetonitrile,
Add 0.2 ml of pyridine and cool to 0 ° C. HF / PY (0.4 ml) was added, the temperature was returned to room temperature in 10 minutes, and the mixture was stirred for 2 and a half hours. The reaction was terminated with an aqueous NaHCO ₃ solution, and extraction was performed with ethyl acetate. Washed with KHSO ₄ aqueous solution, saturated saline solution,
It was dried over anhydrous magnesium sulfate. After distilling off the solvent, column chromatography (silica gel, hexane: AcOEt
= 1: 1.5), and 53 mg (81%) of 9 methylene 6oxoPGE and methyl ester were obtained.

_{NMR (ppm, CDCl 3):} 0.7~1.0 (m, 3H), 1.0~1.8 (m, 12H), 1.8
~ 2.9 (m, 10H), 3.4 ~ 4.0 (m, 2H), 3.55 (S, 3H), 4.5 (m, 1H),
4.7 (m, 1H), 5.3 (m, 2H).

IR (cm ^-1 ,, neat): 3400,2950,2870,1735,1710,1655,1460,
1440,1410,1370,1200,1175,1080.

Example 2 Disilyl form of 6,9 dimethylene PGE ₁ methyl ester 289m
g (0.48 mmol) was dissolved in 10 ml of acetonitrile, 0.5 ml of pyridine was added, 1 ml of HF / PY was added at 0 ° C., 10 minutes later, the mixture was returned to room temperature and stirred for 3 hours. It was neutralized with NaHCO ₃ and extracted with AcOEt. The extract was washed with an aqueous KHSO ₄ solution and an aqueous NaCl solution, dried, concentrated, and subjected to column chromatography (silica gel hexane: AcOEt = 1: 1) to obtain 142 mg (79%) of 6,9-dimethylene PGE ₁ methyl ester.

NMR (δ ppm, CDCl ₃ ): 0.7 to 1.0 (m, 3H), 1.0 to 1.7 (m, 12H),
1.7 to 2.7 (m, 10H), 3.4 to 4.1 (m, 2H), 3.5 (S, 3H), 4.5 to 4.8
(m, 4H), 5.2 ~ 5.4 (m, 2H), IR (cm ^-1 , neat): 3400,2950,2870,1740,1640,1445,1200,
1170,1070,1010.

Claims (4)

[Claims] 1. The following formula [II-a]: 9-deoxo-6,9-dimethylene prostaglandin E ₁ which is a compound represented by the formula, its stereoisomer or a mixture thereof at any ratio. 2. The 9-deoxo-6,9-dimethylene prostaglandin E ^{1 according to} claim 1, wherein R ¹¹ is a hydrogen atom or a methyl group. 3. R ²¹ and R ³¹ are the same or different and each is a hydrogen atom, tri (C ₁ -C ₄ ) alkylsilyl group, diphenyl (C ₁ -C ₄ ) alkylsilyl group, phenyldi (C ₁
-C ₄₎ alkylsilyl group, 2-tetrahydropyranyl group of the claims in the range of the first term or the second term according 9-
Deoxo-6,9-dimethylene prostaglandin E ₁
Kind. Wherein ^{R 5} is a butyl group, a pentyl group, a hexyl group, a heptyl group, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl group, 2-methylpentyl group, a cyclopentyl group, a cyclohexyl group 9-deoxo-6,9-dimethylene prostaglandin E _{1 according to} any one of claims 1 to 3, which is a phenyl group, a phenyl group, a phenoxy group, a cyclopentylmethyl group, or a cyclohexylmethyl group. Kind.