JPS59175465A - Sulfone or sulfoxide compound of 5-thiaprostaglandin e1, and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, or 1-10C alkyl; R<2> is substituted or unsubstituted 1-1-C alkyl, or unsubstituted 5-6C cycloalkyl; n is 1 or 2). EXAMPLE:Sulfoxide of 5-thiaprostaglandin E1. USE:An inhibitor of blood platelet aggregation and vasodilator. PREPARATION:A compound shown by the formula II is reacted with an oxidizing agent, and, if necessary, hydrolyzed to give a compound shown by the formula I . For example, a peracid such as hydrogen peroxide, peracetic acid, perbenzoic acid, etc. is used as the oxidizing agent in the case of preparation of sulfoxide, and hydrogen peroxide, hydrogen peroxide and tungsten or vanadium catalyst, etc. are preferably used in the case of preparation of sulfone. The reaction is carried out at -78-50 deg.C, preferably at -20-30 deg.C usually for 30min-48hr.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel sulfone or sulfoxide compounds of the 5-thiaprostaglandin E family and processes for their production.

More specifically, the present invention provides anti-platelet aggregation effects.

5-thiaprostaclandin E, tjlA, a new compound that has pharmacological effects such as vasodilation and is useful as a pharmaceutical.
sulfone or sulfoxide compounds and methods for producing them.

Natural prostaglandins are autacoids with high biological and pharmacological activity, and therefore many studies have been conducted on their derivatives.Among the natural prostaglandins, prostaglandins Hunger has strong platelet aggregation inhibitory effects, vasodilatory effects, etc., and is being applied clinically.

As derivatives of prostaglandin Toko, many compounds are known in which the carbon atom in the prostaglandin Toko molecule is replaced with a sulfur atom. For example, 13s-11-deoxyprostaglandin E1 [TetrahedronLe
tters, 765. (1975): J.
Med, Chem, 20.1662 (1977)),
9 S-prostaglandin E+ (Tetrah
edron Letters + 4267 (1974
): I, 11 S-prostaglandin E.

CTetrahedron Letters, ]i
65. (197s)) are known.

Purpose of the Invention The present inventor has conducted extensive research to obtain new prostaglandins that overcome the pharmacological drawbacks of prostaclandin E. As a result, the pharmacological effects such as platelet aggregation and vasodilation Novel compound with action and useful as a pharmaceutical 5-
A sulfone or sulfoxide compound of thiaprostaglandin E and a method for producing the same have been discovered (7).

Structure and Effects of the Invention The 5-thiaprostaglandin E type sulfone or sulfoxide compound provided by the present invention is a 5-thiaprostaglandin E type sulfone or sulfoxide compound represented by the following formula [0]. .

In the above formula 0], R1 is a hydrogen atom or has 1 to 1 carbon atoms
0 alkyl group. Examples of such furkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group,
heptyl group.

Examples include octyl group, nonyl group, and decyl group, with hydrogen atom or methyl group being particularly preferred. R2 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted cycloalkyl group having 5 to 6 carbon atoms. Here, the substituents of the alkyl group and the dichlorofurkyl group include, for example, a haptic atom such as fluorine, chlorine, and bromine; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a methyl group, Monoalkyl groups such as dichloromethyl group and trifluoromethyl group; methoxy group, ethoxy group, propoxy group.

Examples include impropoxy group, methoxy group, and o) flukoxy group. Examples of the alkyl group having 1 to 10 carbon atoms substituted or unsubstituted with such a substituent include a methyl group, an ethyl group, and a propyl group.

Isopropyl group, glutyl group, t-butyl group, pentyl group, hexyl group, 2-methylhexyl group.

Examples include heptyl group, octyl group, nonyl group, and decyl group. Examples of the substituted or unsubstituted cycloalkyl group having 5 to 6 carbon atoms include a cyclopentyl group, a cyclohexyl group, and a cyclohexylmethyl group. Examples of such R2 include a pentyl group and a 2-methylhexyl group.

Cyclopentyl group, cyclobexyl group, and cyclohexylmethyl group are preferred.

In the above symbol, n represents an integer of 1 or 2. When n is 1, it represents a sulfoxide compound, and when n is 2, it represents a sulfone compound. The sulfone or sulfoxide compound of 5-thiaprostaglandin E of the above formula (1) is at the 8th position.

The carbon atoms at the 11th, 12th, and 15th positions are asymmetric carbon atoms, and the present invention includes all optical isomers based on these asymmetric carbon atoms or mixtures thereof.

The sulfone of the preferred 5-thiaprostaglandin E%lJ of the present invention is also L<.Specific examples of the sulfoxide compound are as follows.

ft+ Sulfoxide of 5-thiaprostaglandin E (2) Sulfone of 5-thiaprostaglandin E1 +3
), 20-methyl-5-thiaprostaglandin E, sulfoxide +4) 20-methyl-5-thiaprostaglandin E, sulfone (5117,20-dimethyl-5-thiaprostaglandin E, sulfoxide +6+17 .20-dimethyl-5-thiaprostaglandin E, sulfone (7116,17,18,19,20-pentanol-1
5-cyclohexyl-5-thiaprostaglandin E,
sulfoxide (8116,17,1g, 19.20-pentanol-1
5-cyclohexyl-5-thiaprostaglandin E,
sulfone (9116,17,18,19,20-pentatrue 1
5-cyclope/tyl-5-thiaprostaglandin E,
sulfoxide H16,17,18,19,20-pentanol-15-
The enantiomer of the sulfone aυ (1) to Ql of cyclopentyl-5-7 p-staglandin E, and the methyl ester of the compound of shrimp 03 (1+ to aυ) at position 15, and the 5-thiaprostagran of the present invention. The sulfone or sulfoxide compound of Zin E1 class is 5-thiaprostaglandin E, which is represented by the following symbol [wherein R1 and R2 are the same as defined above].

and an oxidizing agent, followed by hydrolysis if necessary.

Such oxidizing agents include, in the case of producing sulfoxide, peracids such as hydrogen peroxide, peracetic acid, perbenzoic acid, 9m-chloroperbenzoic acid; sodium metaperiodate, hydroperoxide, selenium dioxide, and PM acid, iodosylbenzene, hypochlorous acid, t-butylhydroperoxide, etc. are preferably used, and when producing sulfone, for example, hydrogen peroxide, hydrogen peroxide and tungsten or vanadium catalyst, peracetic acid, Perbenzoic acid 1m
-pp perbenzoic acid, ruthenium oxide, osmium oxide [■], etc. are preferably used.

As the reaction organic solvent, for example, water, acetic acid, methanol, methylene chloride, artform, 1,2-dichloroethane, benzene, ethyl acetate, etc., or a mixed solvent thereof are preferably used.

The reaction temperature is preferably in the range of -78°C to 50°C, and -20°C
A range of -30°C to 30°C is particularly preferred.

The reaction time varies depending on the reaction temperature of the raw material compound 1 and the type of oxidizing agent, but is usually 30 minutes to 48 hours.

For example, when attempting to produce a sulfoxide using an oxidizing agent capable of producing both a sulfoxide and a sulfone, the amount of oxidizing agent used may be insufficient to provide the sulfone, e.g. It is preferable to use an amount of about 1 to about 1.5 equivalents, and to monitor the reaction by TLC or the like.

After the reaction is completed, the target product is separated and purified by treating the reaction solution in a conventional manner. That is, for example, r-overconcentration,
It is separated and purified by a combination of methods such as p-mudography.

The product thus obtained has an ester group (R,
represents a furkyl group having 1 to 10 carbon atoms), it may be further subjected to a hydrolysis reaction if necessary. Such hydrolysis reaction is a known reaction, and can be carried out, for example, using an enzyme such as lipase in a solvent such as water, tetrahydrofuran, or ethyl ether.

5-thiaprostaglandin E represented by the above formula (0), which is a raw material in the production method of the present invention, is synthesized by the method shown in Chart 1 below.

Chart 1 As detailed above, the present invention provides a sulfone or sulfoxide compound of 5-thiaprostaglandin E, which has pharmacological effects such as antiplatelet aggregation effect and is useful as a pharmaceutical.

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Reference example 1 3 (S) -t-butyldimethylsilyloxy-1-
Iodine-1-octene 6.07? (16,5 mmo
l) in 30% anhydrous ether under argon atmosphere.
t-Butyllithium at 78°C16. sd(”M solution)
(33 mmol) and stirred for 1 hour.

Next, 1-pentynyl copper (112,1s t (16,s
mmol) and hexamethylphosphorustriamide5.
A solution of 4F (33 mmol) of 25- in anhydrous ether was added, and the mixture was further stirred at -78°C for 1 hour.

Added 20 g of an anhydrous ether solution of 3.18 f (15 mmol) of 4-t-butyldimethylsilyloxy-2-cyclobentenone, and heated to -78°C for 30 minutes.

Stirred at -50°C for 10 minutes. 7-oxo-5-thiaheptanoic acid methyl ester 2.92 (16.5 mmol)
A 10-solution of anhydrous ether was cooled to -50°C and added.
The mixture was stirred at -50°C to -40°C for 40 minutes. The reaction solution was poured into an acetic acid-sodium acetate buffer solution adjusted to pH 4, and extracted with hexane. Dry over anhydrous magnesium sulfate, concentrate, and separate and purify with silica gel chromatography to obtain 7-
5.22 of a mixture of hydroxy-pxy-5°-thiaprostaglandin E, 11°15-bis-t-butyldimethylsilyl ether and its enantiomer, 15-shrimp (yield 55%)
) was obtained.

TLCRf: o, 4s (solvent; hexane: ethyl acetate - 3:1) IR (cm'', neat): 3500.2950, 2880, 1740, 1460° 1440, 1360. 1250° NMR (δppm in CDCl4): 0 .9 (
s, 18H), 0.9-1.7 (m, lI
H).

1.7-3.1 (m, 1on), 3.7 (B,
3H) 13.7-4.4 (m, 3H) 15.65
(ml 2H).

Reference example 2 Body synthesis? -Hydroxy-5-thiap-p-staglandin E, methyl ester 11. Mixture of 15-bis-t-methyldimethylsilyl ether and its enantiomer 15-staglandin 1.
25? (1,98 mmol) was dissolved in 10 ml of anhydrous dichloromethane, and 4-dimethylaminopyridine 1
+659 (13.5 mmol) was added, and methanesulfonylcluride o, s d (6.7 mmol) was added at 0°C.
) was added, 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 by silica gel chromatography to obtain 5-thiabarb p-staglandin E, methyl ester 11.15-bis-L-butyldimethylsilyl ether and its enantiomer 15-staglandin. Ta. Of these, 7E150η (yield 12H) was obtained.

TLC 7℃ body, Rf: 0.65 (solvent; hexane: ethyl acetate-3=1) 72 bodies, Rf: 0.68 (solvent; hexane: ethyl acetate-3:1) 'r neat) ;2980,
2870. l 740.1640.1460゜136
0, 1255°NMR (δppm in CDC); 0.9 (1!+
181F(), 0.7~2.1 (m+13H)
.

2.1~2.8 (m, 6H)', 3.0~3.5
(m, 3H) 13.70 (11,3H), 3.
9-4.3 (m, 2H).

5.5 s (m, 2H), 6.8 (dt, I
H, J=7.5゜2.0) 72 pieces IR (crn-', neat); 2980.2
870.174o, -1450,1255NMR (δp
pm in CDC4) *0.9 (8,18H),
0.7-2.1 (m, 13H).

2.1-2.7 (m, 6H), 3.0-3.
6 (m, 3H).

3.7 (B, 3H), 3.7-4.35 (
yyl, 2H).

5.3-5.9 (m, IH), , 5.5
s (m, 2H) Reference Example 3 (7E) 5-1i-thiaprostaglandin E,
Methyl ester 11.15-bis-t-butyldimethylsilyl ether 91 ml (o, 1 s mmol), tributyltin hydride 1 ml (3, 7 mmol) and bis-t-butyl peroxide 2 om9 (o, 2 mmol)
l) and stirred at 100-110°C for 10 minutes.

Cooled and directly subjected to silica gel chromatography, 5
-Thiaprostaglandin E1 methyl ester 11.1
5-bis-t-butyldimethylsilyl ether 59T'
9C yield 65%) was obtained.

NMR (δppm in CDC4)'0.9 (It
, 1sH), 1.1+-1,6(m, 15
H).

1.7-2.8 (m, 9H), 3.7 (S
, 3H).

4-15 (m, 2H), s, 65 (m,
2H) Reference Example 4 Purified 5-thia-prostaglandin E.

Methyl ester 11. A mixture of 15-bis-t-butyldimethylsilyl ether and its 8,11゜12-isomer 36-9 was dissolved in 14-77 tonitrile [2. Hydrofluoric acid at room temperature. Add 0.7ml of (47ml aqueous solution) and stir for 30 minutes. After the reaction, neutralize with the returned sodium hydrogen oxide aqueous solution and perform the usual extraction operation. The solvent was distilled off under reduced pressure, and the crude product was purified by thin layer p-mudography (cyclohexane/ethyl acetate = 1/4).
-Thia-prostaglandin E, methyl ester 7v
7.511 g (yield 33%) of shrimp (yield 30.9 g) and 8.11.12-g (yield 33%) were obtained.

TLC (silica gel: cyclohexane/ethyl acetate-1
/4): s + Arp p staglandin El methyl ester Rf = 0.15, 8゜11.12 - Shrimp body R
f = o, 2on05-thiaprostaglandin E,
Methyl ester NMR (in CDCts, 1o MHz)
;Q, 9 (m, 3H), 1.2~1.6 (
m, 12H).

1.8-2.8 (m, 1OH), 3.67 (S
, 3H).

4.1~4.2 (r+b 2H)1 5.7 (m
+ 2H) IMass (70ev, m/l), 36
8(M-zs).

350.267.235 08.11.12-Shrimp body NMR (in CDC4,1o OMHz); 0.9
(Tnt 3H), 1.1-1.6 (m, 1
2 HLl, 8-2.9 (m, 10H), 3
．． 67 (S, 3H) 14.1~4.2 s (m
, 2H), 5.7 (m, 2HLMass
(70tvr m/l); 368 (M”-18),
350,267.235゜Example 1 17 g of 5-thiaprestograndin E1 methyl ester (o, o44 dishes o1) in 5 m! Dissolve sodium metaperiodate in 2 a y + g of methanol at room temperature.
Add 1 rnll aqueous solution of (o,i 3 mlTl0I) and stir as such for 2 hours. Add ethyl acetate and water.

After washing with saturated saline and drying, the solvent was distilled off, and the sulfoxide of 5-thiaprostaglandin E1 161R9 ( A yield of 92%) was obtained.

TLC (solution g: ethyl acetate 10 methanol) Rf =
=0.25 NMR (δppm in CDC4); 0.7-1.
0 (sH, m), 1.0 to 1.65 (8H, m
).

1.7-3.1 (14H1m), 3.6 s (3
H,,).

3.8-4.35 (2H1m)+, 5.6 (2H
, m) I R (on-', neat): 34
00.2950,2860', ] 740,143
5°1365, 1320. 1260. 1210.
1170゜Example 2 5-thiaprostaglandin E, methyl ester 12
txy (0,031 mmol) was dissolved in 0.5 ml of dichloromethane and metafluroperbenzoic acid 16119 was added.
(0,093 mmol) of 0.5 ml of 181
R) Add Tough Solution W'i at 0°C and stir for 1 hour.

The reaction was terminated with sodium hydrogen aqueous solution and extracted with ethyl acetate. After washing and drying, the solvent was distilled off and purified by column chromatography (7q reseal, solvent: ethyl acetate: n-hexane-2:l) to obtain the sulfonic form of 5-thiaprostaglandin E and methyl ester. 12zy(
A yield of 92%) was obtained.

TLC (solvent: ethyl acetate) Rf=0.2 NMR (δppm in CDC4); 0, '1~1
．． 0 (3H, m), 1.05~1.6 s (sH
, m11.65~2.8 (8H, m), 2.8~3
．． 4 (4H, m).

3.65 (3) (+s) + 3+8~4
, 3 (2H+m) + 5.65(2H,m)

Claims (1)

[Scope of Claims] L 5-thiaprostaglandin E represented by the following symbol. sulfone or sulfoxide compounds. 2. A sulfone or sulfoxide compound of 5-thiaprostaglandin E or the like according to claim 1, wherein R' in the above symbol is a hydrogen atom or a methyl group. 1. In the above substitute symbol, R1 is a pentyl group, 2-methylhexyl group, cyclopentyl group, cyclohexyl group, or cyclohexylmethyl group, 5-thiaprostaglandin E1 according to claim 1 or 2. Sulfone or sulfoxide compounds. 4. Formula (3) below In formula 1, RI and R2 are the same as defined above. ] and an oxidizing agent, and optionally hydrolyzed at °C. ] A method for producing a sulfone or sulfoxide compound of 5-thiaprostaglandin islands.