JPH0210153B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 5-thia-Δ ⁷ -prostaglandin A and a method for producing the same. Natural prostaglandins are autacoids with high biological and pharmacological activity.
They have strong platelet aggregation inhibitory and vasodilatory effects, and some, such as prostaglandin E ₁ , have already been applied clinically. On the other hand, many studies have been conducted on various derivatives to overcome the pharmacological disadvantages of natural prostaglandins, namely their ability to have various physiological activities at the same time, their short duration of physiological activity, and their inability to be taken orally. . Furthermore, prostaglandin types A and D are known to be cytotoxic to cancer cells. Since prostaglandins have a wide range of physiological activities, they have the potential to be developed into various pharmaceutical products by chemically modifying their skeletons. The present inventor focused on these characteristics of prostaglandins, and as a result of intensive research to obtain new prostaglandin derivatives, discovered a novel 5-thia-△ ⁷ -prostaglandin A class and a method for producing the same. It has been reached. The 5-thia-△ ⁷ -prostaglandin A provided by the present invention has the following formula [] [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, R ² represents a linear or branched alkyl group having 1 to 10 carbon atoms or a 5- to 6-membered cycloalkyl group, display

[Formula] indicates that 7Z isomer, 7E isomer, or 7Z isomer and 7E isomer coexist in any proportion. ] 5-Thia-△ ⁷ -prostaglandin A represented by or when R ¹ represents a hydrogen atom, it is a non-toxic salt of the acid. In the above formula [], R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. Examples of such alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group,
Examples include pentyl group, hexyl group, heptyl group, octyl group, nonyl group, and decyl group, with hydrogen atom, methyl group, and ethyl group being particularly preferred. R ² represents a linear or branched alkyl group having 1 to 10 carbon atoms or a 5- to 6-membered cycloalkyl group. Examples of linear or branched alkyl groups having 1 to 10 carbon atoms include methyl group, ethyl group, propyl group,
Isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group,
Examples include nonyl group and decyl group. Examples of the 5- to 6-membered cycloalkyl group include a cyclopentyl group and a cyclohexyl group. Among these, R ² is preferably a pentyl group, 2-methylhexyl group, cyclopentyl group, or cyclohexyl group. Display of the above formula []

[Formula] indicates that 7Z isomer, 7E isomer, or 7Z isomer and 7E isomer coexist in any proportion. The carbon atoms at the 12th and 15th positions of the 5-thia-△ ⁷ -prostaglandin A of the present invention are asymmetric carbon atoms, and the absolute configuration of such asymmetric carbon atoms may be either the R-configuration or the S-configuration. or a mixture of both in any proportion. Therefore, in the present invention, 5-thia-
△ ⁷ - Prostaglandins can also be obtained,
These compounds are also expected to have different biological activities than those having the same configuration as natural prostaglandins. Among the 5-thia-△ ⁷ -prostaglandins of the present invention, when R ¹ in the above formula [] is a hydrogen atom, it is possible to combine it with a base by utilizing the fact that it has a carboxylic acid moiety in the molecule. It can also be used as a toxic salt. As the salt in this case, any base may be used as long as it is a pharmacologically acceptable non-toxic salt. Examples of the base include sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Inorganic bases such as ammonia, ethanolamine, diethanolamine and the like are preferably used. Specific examples of the 5-thia-Δ ⁷ -prostaglandin A of the present invention are as follows. (1) 5-thia-△ ⁷ -prostaglandin A ₁ (2) 17,20-dimethyl-5-thia-△ ⁷ -prostaglandin A ₁ (3) 16,17,18,19,20-pentanol 15-Cyclohexyl-5-thia-△ ⁷ - Prostaglandin A ₁ (4) 16,17,18,19,20-Pentanol-15-cyclopentyl-5-thia-△ ⁷ - Prostaglandin A ₁ (5) 20-Methyl-5-thia-△ ⁷ -Prostaglandin A ₁ (6) Enantiomer of the compounds (1) to (5) and epimer at the 15-position (7) of the compounds (1) to (6) Sodium salt, potassium salt, calcium salt, ammonium salt, ethanolammonium salt or diethanolammonium salt (8) Methyl ester of the compound of (1) to (6) 5-thia-△ ⁷ -prostaglandin A obtained by the present invention These are novel prostaglandins, and in particular, they have a new skeleton in which they have a double bond at the 7th and 8th positions and a sulfur atom at the 5th position. On the other hand, prostaglandins are known to have various physiological activities, and research on the synthesis of various derivatives is currently being conducted. 5- in the present invention
Chia-△ ⁷ -Prostaglandin A also has the potential to develop new medicinal effects in the sense that it has a new skeleton, and is expected to have anticancer, blood pressure lowering, antiulcer, and antiviral effects, for example. The compound represented by the above formula [] of the 5-thia-△ ⁷ -prostaglandin A of the present invention is the following formula [] [In the formula, R ¹ , R ² , display

[Formula] is the same as the above definition. R ³ and R ⁴ are the same or different and represent a hydrogen atom or a tri(C ₁ -C ₆ ) hydrocarbon silyl group. ] It is produced by treating 5-thia-Δ ⁷ -prostaglandins represented by the following with an acidic compound, and then subjecting it to deprotection and/or hydrolysis and/or salt-forming reaction, if necessary. In the above formula [], R ¹ , R ² and the expressions are the same as defined above, and R ³ and R ⁴ are the same or different and represent a hydrogen atom or a tri(C ₁ -C ₆ ) hydrocarbon silyl group. Examples of the tri(C ₁ -C ₆ ) hydrocarbon silyl group include tri(C ₁ -C ₄ )alkylsilyl groups such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl; diphenyl groups such as t-butyldiphenylsilyl group; ( _C1 - _C4 )alkylsilyl groups are mentioned. Among the compounds of the above formula [], groups R ³ and R ⁴
When is a hydrogen atom, the compound has the following formula [] [In the formula, R ¹ and R ² are the same as defined above, and R ³ ,
R ⁴ represents a tri(C ₁ -C ₆ ) hydrocarbon silyl group. ] 7-Hydroxyprostaglandins represented by the following are reacted with a reactive derivative of an organic sulfonic acid in the presence of a basic compound, and then subjected to a deprotection reaction. As the acidic compound used when treating the compound of the above formula [], mineral acids such as hydrofluoric acid, hydrochloric acid, and sulfuric acid, and organic acids such as acetic acid, oxalic acid, and p-toluenesulfonic acid are preferably used. .
The amount of acidic compound used depends on the raw material compound []
The amount ranges from 1 to 200 times, preferably from 1 to 10 times, by mole. The solvent used at this time is preferably an alcohol such as methanol, ethanol, or isopropyl alcohol; water, dioxane, tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), or a mixed solvent thereof; particularly preferred are: water, methanol,
THF, acetonitrile, and their mixed solvents. The amount of solvent to be used is sufficient as long as it allows the reaction to proceed quickly, and is usually 1 to 1000 times the volume of the starting compound [ ], preferably 5
~400 times the volume is used. The reaction temperature varies depending on the raw material compounds, reagents, and solvents used, but is 0°C.
The temperature range is 120°C to 120°C, preferably 10°C to 80°C. The reaction time varies depending on the conditions, but is preferably about 30 minutes to 48 hours, more preferably 1
Hours to 24 hours. The progress of the reaction is monitored by methods such as thin layer chromatography. The above reaction can also be carried out as follows. That is, after the reaction of the 7-hydroxyprostaglandins of the general formula [] with a reactive derivative of an organic sulfonic acid, a deprotection reaction is performed using an acidic compound such as hydrofluoric acid or acetic acid. , the above reaction can be carried out following the deprotection reaction in the same reaction system. In this way, a PGA-type compound of the above formula [] is obtained, and such a compound can be further subjected to a deprotection reaction, a hydrolysis reaction, and a salt-forming reaction, if necessary. Deprotection of the tri(C ₁ -C ₆ ) hydrocarbon silyl group can be carried out as follows. For example, in the presence of tetrabutylammonium fluoride or cesium fluoride (more preferably in the presence of a basic compound such as triethylamine), halogenated hydrocarbons such as dichloromethane and chloroform;
Ethers such as tetrahydrofuran; benzene,
The reaction is carried out in a reaction solvent such as a hydrocarbon such as toluene (preferably a reaction solvent other than water) at about the same temperature and for about the same time. Alternatively, the tri(C ₁ -C ₆ ) hydrocarbon silyl group can also be removed by subjecting it to a normal deprotection reaction using an acidic compound such as hydrofluoric acid or acetic acid. Hydrolysis of the ester group is carried out by treatment with lipase, esterase, etc. in water or a solvent containing water. The salt-forming reaction can be carried out by a neutralization reaction between 5-thia-Δ ⁷ -prostaglandin A having a free carboxyl group and the above-mentioned inorganic base or organic base. 5-thia-△ represented by the above formula [] of the present invention
⁷ -Prostaglandins are produced by reacting 7-hydroxyprostaglandins represented by the above formula [] with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to form the corresponding 7-organosulfonyloxy Prostaglandins are produced by treating the prostaglandins with a basic compound and, if necessary, subjecting them to deprotection and/or hydrolysis and/or salt production reactions. The 7-hydroxyprostaglandins represented by the above formula [] are produced by the method for producing 7-hydroxyprostaglandins E described in JP-A-57-7464, as exemplified in Chart 1 below. Synthesized by a method similar to The target compound is separated and purified by treating the reaction solution in a conventional manner. That is, they are separated and purified by a combination of extraction, washing, drying, concentration, chromatography, and the like. According to the present invention, 5-thia-△ ⁷ -prostaglandin A can be obtained by the method detailed above, and such compounds are expected to have pharmacological effects such as anticancer, hypotensive, and antiulcer effects. It is something that will be done. The present invention will be explained in more detail with reference to Examples below. Reference Example 1 Synthesis of 15-epi form of 5-thia-△ ⁷ -prostaglandin E ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 7-hydroxy obtained in Reference Example 1 -5-Thiaprostaglandin E ₁ methyl ester 11,15-
1.25 g of a mixture of bis-t-butyldimethylsilyl ether and its enantiomer 15-epi form
(1.98 mmol) in 10 ml of anhydrous dichloromethane, 1.65 g of 4-dimethylaminopyridine.
(13.5 mmol) was added thereto, and 0.5 ml (6.7 mmol) of methanesulfonyl chloride was added at 0°C, and the mixture was stirred at 0°C for 5 hours, and further stirred at room temperature for 1 hour. Water was added and extracted with dichloromethane. It was dried over anhydrous magnesium sulfate, concentrated, and then separated and purified using silica gel chromatography to obtain 5-thia-△ ⁷ -prostaglandin E ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer. A mixture of 15-epi forms was obtained. Of these, 7E
The 7Z form is 590 mg (yield 49%), and the 7Z form is 150 mg (yield 12
%). TLC, 7E form , Rf: 0.65 (solvent; hexane: ethyl acetate = 3:1) 7Z form , Rf: 0.68 (solvent; hexane: ethyl acetate = 3:1) 7E form IR (cm ^-1 , neat): 2980 , 2870, 1740, 1640, 1460, 1360,
1255 NMR (δ ppm in CDCl ₃ ): 0.9 (s.18H), 0.7~2.1 (m.13H), 2.1~2.8
(m.6H), 3.0~3.5 (m.3H), 3.70 (s.3H),
3.9~4.3 (m.2H), 5.55 (m.2H), 6.8 (dt,
1H, J=7.5, 2.0) 7Z body IR (cm ^-1 , neat): 2980, 2870, 1740, 1450, 1255 NMR (δ ppm in CDCl ₃ ): 0.9 (s.18H), 0.7-2.1 (m. 13H), 2.1~2.7
(m.6H), 3.0~3.6 (m.3H), 3.7 (s.3H),
3.7~4.35 (m.2H), 5.3~5.9 (m.1H), 5.55
(m.2H) Reference example 2 16,17,18,19,20-pentanol-15-cyclohexyl-5-thia-△ ⁷ -prostaglandin E ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether Synthesis of 16,17,18,19,20-pentanol-15-cyclohexyl-7-hydroxy-5-thiaprostaglandin E ₁ methyl ester 11,15-bis-t-
Butyldimethylsilyl ether 560mg
(0.87 mmol) in 5 ml of anhydrous dichloromethane, 4-dimethylaminopyridine 530 (4.35 mmol)
and methanesulfonyl chloride at 0℃.
170μ (2.2 mmol) was added, and the mixture was stirred for 2 hours and further stirred at room temperature for 3 hours. Add water;
Extracted with dichloromethane. Dry over anhydrous magnesium sulfate, concentrate, and separate and purify using silica gel chromatography to obtain 16,17,18,19,20-pentanol-15-cyclohexyl-5-thia-△ ⁷ -prostaglandin E ₁ methyl ester 11 , 15-bis-t-butyldimethylsilyl ether 315mg
(Yield 58%, mixture of 7E and 7Z isomers, 7E:7Z=
4:1) IR (cm ^-1 ), neat): 2970, 2860, 1740, 1640, 1455, 1355, 1260 NMR (δ ppm in CDCl ₃ ): 0.9 (s.18H), 0.9 ~ 2.2 (m.13H) ), 2.2~2.7
(m.6H), 3.0~3.65 (m.3H), 3.65 (s.3H),
3.7~4.4 (m.2H), 5.2~5.9 (m.0.2H, 7Z body),
5.5 (m.2H), 6.9 (t, 0.8H, J = 8, 7E form) Reference example 3 (7E)-7,8-dehydro-5-thiaprostaglandin E ₁ methyl ester and its enantiomer 15 -Synthesis of epiform (7E)-7,8-dehydro-5-thiaprostaglandin E ₁ methyl ester 11,15-bis-
213 mg (0.35 mmol) of t-butyldimethylsilyl ether and its enantiomer 15-epi form were dissolved in 10 ml of acetonitrile, and a 40% aqueous hydrogen fluoride solution was added.
Add 0.5ml and stir at room temperature for 30 minutes. After 40 minutes, add sodium bicarbonate aqueous solution to terminate the reaction.
Extract with ethyl acetate. After drying, the solvent was distilled off, and the product was separated and purified using thin layer chromatography.
(7E)-7,8-dehydro-5-thiaprostaglandin E ₁ methyl ester and its enantiomer 15
-100 mg (yield 75%) of a mixture of epi isomers was obtained. TLC, Rf: 0.45 (solvent; hexane: ethyl acetate = 1:4) IR (cm ^-1 , neat): 3400, 2770, 2750, 2670, 1720, 1640,
1440, 1240 NMR (δ ppm in CDCl ₃ ): 0.9 (m.3H), 0.7-2.0 (m.8H), 1.9 (dd.2H,
J=7), 2.2~3.0(m.8H), 3.25(d.2H, J=
8), 3.5 (m.1H), 3.7 (s.3H), 4.2 (m.2H),
5.65 (m.2H), 6.8 (dd.J=8.0, 1.5) Other compounds can be deprotected in the same manner. Example 1 (7E)-7,8-dehydro-5-thiaprostaglandin A ₁ methyl ester and its 12-
Synthesis of epiform (7E)-7,8-dehydro-5-thiaprostaglandin E ₁ methyl ester 11,15-bis-
Dissolve 121 mg (0.2 mmol) of t-butyldimethylsilyl ether and its enantiomer 15-epi form in 10 ml of acetonitrile, and add 40% aqueous hydrogen fluoride solution.
Add 0.5 ml, warm to 40°C, and stir for 4 hours. After the reaction, the temperature is returned to room temperature, an aqueous sodium bicarbonate solution is added to terminate the reaction, and extraction is performed with ethyl acetate. After drying, the solvent was distilled off and purified by thin layer chromatography (solvent: hexane: ethyl acetate = 1:3) to obtain (7E)-7,8-dehydro-5-thiaprostaglandin A ₁ methyl Ester (Rf=
0.5) 23 mg (yield 32%) and its 12-epi form (Rf
=0.57) 24 mg (yield 33%) was obtained. (7E)-7,8-dehydro-5-thiaprostaglandin A ₁ methyl ester IR (cm ^-1 , neat): 3450, 2950, 2870, 1735, 1700, 1645,
1580, 1435 NMR (δ ppm in CDCl ₃ ): 0.8-2.2 (m.14H), 2.2-2.8 (m.4H), 3.3
(d.2H, J=8.0), 3.7 (s.3H), 4.0~4.35
(m.2H), 5.5 (dd.1H, J=15.0, 6.0), 5.9
(dd.1H, J=15.0, 6.0), 6.4(dd.1H, J=
6.0, 2.0), 6.7 (t.1H, J=8.0), 7.5 (dd.1H,
J=6.0, 3.0) Mass (20eV, m/e): 366 (M ⁺ ), 348, 215, 134, 120, 101 (100%) 12-epi form IR (cm ^-1 , neat): 3450, 2950 , 2870, 1735, 1700, 1645,
1580, 1435 NMR (δ ppm in CDCl ₃ ): 0.8-2.2 (m.14H), 2.2-2.8 (m.4H), 3.35
(d.2H, J=8.0), 3.7 (s.3H), 3.9~4.4
(m.2H), 5.4 (dd.1H, J=16.0, 6.0), 5.85
(dd.1H, J=46.0, 6.0), 6.4(dd.1H, J=
6.0, 2.0), 6.7 (t.1H, J=8.0), 7.4 (dd.1H,
J=6.0, 3.0) Mass has the same pattern as (7E)-7,8-dehydro-5-thiaprostaglandin A ₁ methyl ester. Example 2 16,17,18,19,20-pentanol-15-cyclohexyl-7(E)-7,8-dehydro-5-
Synthesis of thiaprostaglandin A ₁ methyl ester 16,17,18,19,20-pentanol-15-cyclohexyl-7(E)-7,8-dehydro-5-thiaprostaglandin E ₁ methyl ester 102mg
(0.26 mmol) was dissolved in 2 ml of tetrahydrofuran, 0.5 N hydrochloric acid aqueous solution was added, and the mixture was heated to 40°C.
Stir for an hour. The reaction was terminated by adding an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried, the solvent was distilled off, and purified by thin layer chromatography to obtain 16,17,18,19,20-pentanol- 55 mg (yield 56%) of 15-cyclohexyl-7(E)-7,8-dehydro-5-thiaprostaglandin A ₁ methyl ester was obtained. TLC: Rf = 0.5 (solvent; hexane: ethyl acetate = 1:3) IR (cm ^-1 , neat): 2960, 2860, 1740, 1700,
1645, 1575 NMR (δ ppm in CDCl ₃ ): 0.8-2.2 (m.14H), 2.2-2.7 (m.4H), 3.3
(d.2H, J=8.0), 3.65 (s.3H), 3.9~4.3
(m.2H), 5.5 (dd.1H, J=15.0, 6.0), 5.9
(dd.1H, J=15.0, 6.0), 6.4(dd.1H, J=
6.0, 2.0), 6.7 (t.1H, J=8.0), 7.5 (dd.1H,
J=6.0, 3.0)

Claims (1)

[Claims] 1. The following formula [] [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, R ² represents a linear or branched alkyl group having 1 to 10 carbon atoms or a 5- to 6-membered cycloalkyl group, The expression [formula] indicates that the 7Z form, the 7E form, or the 7Z form and the 7E form coexist in any proportion. ] 5-thia-△ ⁷ -prostaglandin A or a non-toxic salt of the acid when R ¹ is a hydrogen atom. 2 Claim 1 in which R ¹ is a hydrogen atom, a methyl group or an ethyl group in the above formula []
5-thia-△ ⁷ -prostaglandin A described in section
or non-toxic salts of the acids when R ¹ represents a hydrogen atom. 3 In the above formula [], R ² is a pentyl group,
5-thia-△ ⁷ -prostaglandin A according to claim 1 or 2, which is a 2-methylhexyl group, cyclopentyl group or cyclohexyl group, or when R ¹ represents a hydrogen atom, the acid Non-toxic salts. 4 The following formula [] [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, R ² represents a linear or branched alkyl group having 1 to 10 carbon atoms or a 5- to 6-membered cycloalkyl group, R ³ and R ⁴ are the same or different and represent a hydrogen atom or a tri(C ₁ - _{C 6} ) hydrocarbon silyl group, and the expression [Formula] is a 7Z form, a 7E form, or a 7Z form and a 7E form coexisting in any proportion. to show that ] The following formula is characterized in that 5-thia-△ ⁷ -prostaglandins represented by are treated with an acidic compound, and then subjected to deprotection and/or hydrolysis and/or salt-forming reaction as necessary. [] [In the formula, R ¹ , R ² and the expression [formula] are the same as the above definition. ] A method for producing a non-toxic salt of 5-thia-△ ⁷ -prostaglandin A represented by the following formula or an acid thereof when R ¹ represents a hydrogen atom. 5. The method for producing a non-toxic salt of 5-thia-△ ⁷ -prostaglandin A or an acid when R ¹ represents a hydrogen atom according to claim 4, wherein the acidic compound is an inorganic acid. 6 Claim 4 in which R ¹ is a hydrogen atom, a methyl group or an ethyl group in the above formula []
A process for producing a non-toxic salt of 5-thia- ^Δ7 -prostaglandin A or the acid according to item 5 or 5, when R ¹ represents a hydrogen atom. 7 In the above formula [], R ² is a pentyl group,
Claims 4 to 2-methylhexyl group, cyclopentyl group, or cyclohexyl group
6. A method for producing a non-toxic salt of 5-thia- ^Δ7 -prostaglandin A or the acid according to any one of item 6, when R ¹ represents a hydrogen atom.