JPS5869861A - 4-thiaprostaglandin e1 derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R<1>, R<2> are H, alkyl, aralkyl, substituted aralkyl; R<3>, R<4> are H, protecting group; R<5> is H, methyl; R<6> is 1- 10C alkyl, cycloalkyl). EXAMPLE:16,17,18,19,20-Pentanol-15-cyclohexyl-4-thiaprostaglandin E1 amide. USE:Preventive or remedy for thrombosis, vasodilator or antiulcerative, because it has activities of inhibiting blood platelet coagulation, vasodilation, ulcer resistance. It is distinguished by its durative activity by oral administration. PREPARATION:The reaction of a carboxylic acid of formula II (R<31>, R<41> are protecting group) with an amine of formula III is carried out in the presence of a condensation agent such as dicyclohexylcarbodiimide or chloroformic ester- triethylamine, when needed, deprotection is effected, to give the objective compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 4-thiaprostaglandin E, a derivative, and a method for producing the same.

Natural prostaglandins are said to be local hormones with high biological and pharmacological activity, and therefore many studies have been conducted on their derivatives. Natural prostaglandin E1 has strong platelet aggregation inhibitory and vasodilatory effects, and clinical applications are being attempted.

The present inventor has overcome the pharmacological disadvantages of prostaglandin E, and developed a new prostaglandin E, which can be administered orally and is long-lasting. As a result of intensive research to obtain a conductor, we discovered a unique 4-thiaprostaglandin E, its derivatives, and a method for producing the same, leading to the present invention.

The 4-thiaprostaglandin E, n4 form provided by the present invention is a 4-thiaprostaglandin E1 derivative represented by the following formula [1].

In formula (I), R1 and Ha are each a hydrogen atom, an alkyl group, a ti1-substituted or unsubstituted 7ralkyl group,
Substituted or unsubstituted Cyl: +furkyl group.

Or represents a substituted or unsubstituted phenyl group. Examples of such alkyl groups include methyl, ethyl, propyl, and isopropyl groups.

Examples include furkyl groups having 1 to 10 carbon atoms such as butyl group and decyl group, and examples of substituted or unsubstituted 7-ralkyl groups include the phenyl group optionally having a substituent such as methyl group, chlorine atom, or methoxy group. Examples of the substituted or unsubstituted dichlorofurkyl group include a benzyl group and a phenethyl group, which may be substituted. Examples of the substituted or unsubstituted dichlorofurkyl group include a cyclopentyl group and a cyclohexyl group, which may be substituted with a methyl group, a chlorine atom, etc. Or, examples of unsubstituted phenyl groups include methyl group, chlorine atom, and fluorine atom!
Methoxy group! Represents a phenyl group which may be substituted with one or more hydroxyl groups. Furthermore, Ht and Rt may be trapped together to form a 5- to 6-ring. Examples of such groups include a morpholino group, a pyrrolisif group, a piperidino group, a piperazide group, and a group including a nitrogen atom. Seven groups can be mentioned.

Ra and R4 are the same or different and represent a hydrogen atom or a cyclic group. As such a protecting group, any leaving group may be used as long as it is a group that can stably exist without being eliminated during the reactions and post-treatment steps carried out in the present invention. A specific example of such a protective eel group is t.
-Butyldimethylsilyl group, trimethylsilyl group, methoxymethyl group, 1-ethoxyethyl group, 2
-Ethoxy-2-propyl group, 2-methoxy-2-propyl group, methoxyethoxymethyl group, methylthiomethyl group, benzyloxymethyl group, tetrahydropyranyl group, tetrahydrofuranyl group, etc. 7-cetals are used. Particularly preferred examples include t-butyldimethylsilyl group and tetrahydropyranyl group. Further, Rs represents a hydrogen atom or a methyl group.

Re represents a furkyl group or Schiff-furkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group! Hentyl group, hexyl group.

Examples include 2-methylhexyl group, Schiff-pentyl group, cyclohexyl group, and particularly preferred ones include:
Examples include pentyl group, hexyl group, 2-methylhexyl group, and cyclohexyl group.

Further, at least the 8th and 11th positions in the 4-thiaprostaglandin E1 derivative of the present invention.

The carbon atoms at the 12th and 15th positions (according to Prustabrangin nomenclature) are asymmetric carbon atoms, and the absolute configuration of such asymmetric carbon atoms may be either the R configuration or the S configuration (or any combination of both). Although it may be a mixture of proportions, due to the chemical characteristics of the production method of the present invention, there are two types of relative configurations at positions 8, 11, and 12 as shown in the following formulas (T-a)' and (1-b'). It is a possible isomer, i.e.

Specific examples of the preferred 4-chi7 prostagrange/E,m conductor of the present invention are as follows.

0C44-thiaprostaglandin E, (hereinafter referred to as 48P
It is abbreviated as GE. ) 7 mid.

+11+ 45PGE, N-methyl 7mid.

(Shun 4SPGE, N, N-dimethyl.

(1314SPGE, N+Ni+Rusik ts hexyl 7mide.

041 45PGE+ N-7enyl7! T
(1514SPGE, N-benzylamide.

66) 48PGE, morpholinamide.

(1η 48PGE, pyrrolidineamide, '(field 45PGE, piperidineamide.

(1→ (1 决～-15-position epimer of a compound or its enantiomer.

(e) 20-methyl 45PGE, amide.

(N-methyl 7mido of zl 2o methyl 45PGE+, N.

N-dimethyl7mide, N,N-methylcyclohexylamide, N-phenylamide, N-benzyl7mide, morpholine7mide, pyrrolidinemide, or piperidine7mide.

#4 ■* 15-position epimer of compound 1211 or its enantiomer.

(30) 17,2G-dimethyl 48PGE, amide.

-1 to 17.18.19.20-pentanol-15-cyclohexyl 48PGE, 7mido.

-15-methyl 45PGE, 7mid.

46G1 17.20-dimethyl 48PGE, , 1
6.17.1 &19゜20-pentanol-15-cyclohexyl 45PGE+ or 15-methyl 45P
GE, N-methylamide F, N,N-dimethyl 7mide, N-butyl 7mide, N,N-methylcyclohexyl 7mide, N-phenylamide, N,N-diethylamide, N-benzylamide, morpholine 7mide , pyrrolidine amide, or piperidine 7amide.

(701(3011+1.15 of the compound of (501,-)
−-position epimers or their enantiomers.

- One or two of the two hydroxyl groups of the above compound are t
-butyldimethylsilyl group 7' t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group,
Protecting groups of 1-ethoxyethyl group, 2-ethoxy-2-propyl group, 2-methoxy-2-propyl group, methoxyethoxymethyl group, methylthiomethyl group, benzyloxymethyl group, or tetrahydropyranyl group 1
Examples include, but are not limited to, compounds protected by type or 2al type protecting groups.

Therefore, the 4-thiaprostaglandin E, II of the present invention
The conductor is a carboxylic acid represented by the following formula OR'R"NH・
・・・・・・・・・・・・QID [In the formula, Ht', R
t is the same as defined above. It is produced by reacting the amines represented by ] in the presence of a condensation aid, followed by deprotection if necessary.

The carboxylic acids represented by Nitaku, which is one of the raw materials in the production method of the present invention, can be easily provided according to the following steps by a method separately proposed by the present inventor.

The reaction is carried out by bringing the carboxylic acids represented by 2) into contact with the amines represented by the formula Qll). This reaction itself is a well-known 7-amidation reaction, and the reaction conditions are, for example, 14-■
It is introduced in detail on pages 1002 to 1017,
Any of them is preferably used.

The amount of amines used during the reaction varies slightly depending on the reaction conditions employed, but is usually 0.8 to 3 amines per carboxylic acid.
0 equivalent, preferably 1 to 5 equivalents. The reaction temperature varies slightly depending on the condensation aid used, but it ranges from 100℃ to 100℃.
The temperature is preferably -78°C to 50°C, more preferably -40°C to 30°C. The reaction time also depends on the condensation aid used and the reaction temperature, and is usually
It is appropriate to conduct the reaction while monitoring it using analytical means such as madography, but it usually takes 10 minutes to 48 hours.
Preferably it is from 30 minutes to 10 hours. In order to make the reaction proceed smoothly, it is preferable to use a condensation aid, and such condensation aids are also explained in detail in the above-mentioned reference books, and any of them can be suitably used. Since the carboxylic acid fist represented by and the reaction product are relatively unstable under strongly acidic or strongly basic conditions, consideration must be given to this point. Specific examples of such condensation aids include dicyclohexyl sulfodiimide, lyaa formate and triethylamine, triphenylphosphine and dipyridyl disulfide,
There are oxalyl chloride, thionyl chloride, etc., and the 7-amidation reaction proceeds under the conditions in which they are usually used.

The reaction may be carried out in a solvent. The optimum reaction solvent used varies depending on the condensation aid used, but it is usually ethyl ether.

It is selected from tetrahydrofuran, jetoxyethane, dimethoxythane, chloroform, methylene chloride, carbon tetrachloride, benzene, toluene, 7-cetonitrile, and the like.

The reaction product can be isolated through conventional post-treatments, extraction operations, separation operations using common separation means, and the like.

Further, the 4-thi y:jt-staglandin El derivative of the present invention can be produced by a method other than the above-mentioned production method. An example is shown below.

The reaction conditions for this reaction were the same as those used when adding thiol esters or thiol carboxylic acids, which were proposed separately by the present inventor, such as azopi'sisobutyl rhonitrile, t-butyl hydroperoxide, etc. In the presence of a radical generator, the compound of formula [IV] and 2M
This is achieved by reacting K with a compound of

The 4-thiaprostagrasin E derivative obtained in this manner is further subjected to a hydroxyl group-removal reaction, if necessary.The method for removing the binding group varies depending on the binding group. In the case of a 7-cetal-type binder group, acetic acid, p-toluenesulfonic acid + p-toluenesulfonic acid pyridine salt, cation exchange resin, etc. are used, and the reaction is carried out in the presence of water or an alcohol such as methanol. In the case of a silyl ether type carrier group, the reaction is carried out under the conditions commonly used below.
Compounds containing fluorine ions such as hydrofluoric acid are used, and reaction solvents include water, tetrahydrofuran, ethyl ether, dioxane, methanol, ethanol, 7cetone, and acetonitrile.

Although the reaction temperature and reaction time vary somewhat depending on the catalyst used, it is sufficient to conduct the reaction at a temperature in the range of 78°C to 120°C for 10 minutes to 3 days. Isolation of the product is carried out by conventional methods.

4-thiaprostaglandin E represented by the formula α], a derivative thereof, its epimer, and its enantiomer, or a mixture thereof in any proportion, produced by the above steps, has an inhibitory effect on platelet aggregation and a vasodilatory effect. action,
It has an antiulcer mechanistic action, and is useful as a drug that is influenced by these physiological actions, such as a thrombosis treatment or prevention drug, an antihypertensive agent, and an antiulcer agent. The present invention is an amide tetraconductor of 4-naapus taglandin islets, and its characteristics are that it can be administered orally and is expected to have sustained activity.

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

Example 1 16,1? , 9.20-pentanol-15-cyclohexyl-4-thiaprostaglandin E, (hereinafter P
(abbreviated as GE)11. A mixture of Is-bis-1-butyldimethylsilyl ether and its 15-epi enantiomer (12
0q, 0.203 mmoj) of methylene chloride (2
111 (Cool the HIM to -70℃, Trier+Lua J
7 (2L5q, 31sj, 0.223fikj), then isobutyl chloroformate (24'% Fs2
s pi, o, 21 mmol) was added. After 5 minutes, the cooling vessel was removed, aqueous ammonia (lIRl) was added, and the mixture was stirred for 10 minutes. Methylene chloride (s od) was added, the organic layer was washed with aqueous ammonium chloride solution, and the organic layer was separated. After drying the organic layer over magnesium sulfate,
Concentration under reduced pressure yielded 118 ml of oily product. 3D this
The product was dissolved in a mixture of 100% acetic acid, 20% tetrahydrofuran, and 21% water, and worked up by a conventional method under stirring at room temperature for 1 day.

The obtained crude product was subjected to column chromatography (5 g of silica gel, developing solvent: ethyl acetate: methanol = 1
9:1) Separate with K, 16°17, 18.19.2
0-pentanol-15-cyclohexyl-a-+7PG
E-r-amide (21q, 55 μmoA! +27%)
and its 15-epi enantiomer (ls, sq, 4tamoj,
20%). 16.17.1 &, 19.20-
Pentanol-15-cyclohexyl-4-thia PGE
, amide; Nuclear magnetic resonance absorption spectrum (cocis r g (p
pm) ): 1.0-3.0 (27H), 3.55-
4.5(2H)t543-翫To(2H), 6.0(2
H).

Mass spectrum (20.19 votes/e) = 365 (M-H
, O), 347 (365-H, O).

Infrared absorption spectrum (CB (J, solution): 335G, 1
730, 1665, 1590 letters.

15-epi mirror; nuclear magnetic resonance absorption spectrum (CDC11@ (ppm
) ) '1, 0- & 0 (27H) t 16
S-4,33(2H) *s,a 8-5.7s (
2H), s, o (2H).

Mass spectrum (20 m, m/e): 365 (M-H
,0)9347(365-14,0).

Infrared absorption spectrum (CHC 1m solution): 3400.1
730,1665,1595 knee 1° Example 2 4-thia PGE, s 1. t s-bis-t-butyldimethylsilylnyfk (15&7, 0.25mm
o/) 3d in methylene chloride, dicyclohexylcarbodiimide (62 capes, αs mmol
) and dimethylamine (50% aqueous solution, 50 μl) were added and stirred at room temperature for 18 hours. Methylene chloride and water were added to the reaction solution and the crude product was obtained by normal work-up, which was
Dissolved in acetonitrile 51% containing hydrofluoric acid,
Stirred at room temperature for 30 minutes. Hydrogen carbonate)! Neutralize by adding 1 um aqueous solution, extract with ethyl acetate, dry and concentrate,
Through column separation, 4-thia PGE, :) methyl 7mide (52q, 0.14 mmol, 56%) was obtained.

Nuclear magnetic resonance absorption spectrum (cocz, , &(ppm
)): 0.9 (3B), t, o-ao (24H
).

195.10 (61), 3.65-4.25 (23 ()
.

5.45-5.78 (2H).

-f soot vector (zoav, m/e): 381 (M-
H,O), 363(381-HtO).

Example 3 1F(S)l 20-dimethyl-4-thia PGE,
11゜15,-Bis-t-dityldimethylsilyl ether (t26a?, 0.2 mmol) was dissolved in 1 tL77 of chloride of 31, and l-methyl-2-fluoropyridinium methylsulfate) ( 56° groan.

0,2 s mmol) s cyclohexylmethylamine (2 sq, o 25 mvnol> +
t vx-+t y min (3o q,
o, s mmol) in methylene chloride were added sequentially, and the mixture was stirred at room temperature for 18 hours. Water was added and extracted with methylene chloride to obtain a crude product, which was stirred at room temperature for 30 minutes in acetonitrile (5114%C%) containing 5% fluoric acid. After the same post-treatment, it was separated by column chromatography (hexane:ethyl acetate = l:s) and
, 20-dimethyl-4-thia PGE+ (64q
+ (11,3 mmol 1165%) was obtained.

Nuclear magnetic resonance absorption spectrum (CDCl5, &(ppm
)): 0.90 (3H), 0.95 (3H), 1.0-
λo (35H).

165-4.20 (2H), L40-5.75 (2H)
.

Mass spectrum (2oev, m/s): 477 (M-H
, 0), 45G (477-14, O).

□ノ

Claims (1)

[Claims] 1. 4-thiaprostaglandin E represented by the following formula (1). derivative. 4-thiaprostaglandin E, a derivative according to claim 1, wherein IR" and R' are a hydrogen atom, a t-butyldimethylsilyl group, or a tetrahydropyranyl group. 9LR is a pentyl group, a hexyl group , 2-methylhexyl group or cyclohexyl group, and R8 is a hydrogen atom, the 4-thiaprostagra/zine E, M conductor according to claim 1 or claim 2. The 4-thiaprostaglandin E1 conductor according to claim 1 or 2, wherein R@ is a methyl group.・・・・・・・・・(Foundation) [In the formula, R1,
RJ is the same as defined above. The following formula U is characterized by reacting amines represented by ] in the presence of a condensation aid and deprotecting as necessary] [wherein R' + R, R'' I W , R''
, R'it supra definition 116, a patent claim in which the condensation auxiliary agent is dicyclohexylcarbodiimide, polyproformic acid ester-triethylamine, triphenylphosphine-dipyrsyl diulfide, oxacyl chloride, or thionyl chloride. A method for producing a 4-chip-staglandin E derivative according to item 5.