JPS59164770A - Novel prostaglandin d analog compound, its preparation and antitumor agent containing it - Google Patents

Abstract

NEW MATERIAL:A prostaglandin (PG for short) D analog compound shown by the formula I {[A] is group shown by the formula II, III (double bond between C9-C10 is Z, etc.; X is ethylene, or cis-vinylene; C13-C14-C15 is group shown by the formula IV (double bond in C13-C14 is E), etc.; R is -CO-CR<3>=CR<4>R<5>(R<3>, R<4>, and R<5> are H, or 1-4C alkyl), etc.; R<1> is single bond, or 1-5C alkylene; R<2> is 1-8C alkyl, etc.}, or its cyclodextrin inclusion compound. EXAMPLE:1-O-(3,3-Dimethylacryloyl)-PGD2 alcohol. USE:A strong antitumor agent, having extremely low toxicity. PREPARATION:For example, a compound shown by the formula V (R<b> is H, etc.) is reacted using an aqueous solution of an acid such as HCl, etc. in an inert organic solvent such as methylene chloride, etc. at the reflux temperature of the solvent, to prepared the compound shown by the formula I (with the proviso that R=R<b>).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel prostaglandin D-like compounds, methods for their production, and anti-[11Ell agents containing them.

Prostaglandins are derivatives of prostaglandins with the following structure.

Different types of prostaglandins are known; the type depends on the structure and substituents of the alicyclic field. For example, prostaglandin F (PGF), E(P(1,
The alicyclic rings of E) and D (PGD) each have the following structures.

(PGF) (PGE) (PGD) In accordance with generally accepted nomenclature rules, in the above structural formula or in any other structural formula herein, the dotted line indicates that the group attached thereto is in the ring plane. The wavy line indicates that the group attached to it is in the front side of the boundary plane, that is, the α-configuration, and the wavy line indicates that the group attached to it is in the α- or β-configuration, or a mixture thereof. .

These compounds are separated by the double bond position W# on the side chain at the 8th and 12th positions of the alicyclic ring. PG-1 compounds have a trans double bond (trans-Δ) between C13 and C14, and PC-2 compounds have a C5-
It has an El double bond between 06 and a trans double bond ('-Δ5, trans-Δ13) between 013 and CI4.

For example, prostaglandin D1 (PGDl) and prostaglandin D2 (PGD2) are each represented by the following structural formulas.

When one or more methylene groups are further removed from the aliphatic group at position 12 of the cycloaliphatic base of a prostaglandin, the compound is classified as a true prostaglandin according to the general rules of organic nomenclature. The number of methylene groups removed is indicated by the prefix ``nor'' followed by a ``gee'' or ``tree.''

Prostaglandins generally have pharmacological properties. For example, they have the effect of stimulating smooth muscle contraction, lowering blood pressure, diuresis, bronchodilation, inhibiting lipolysis, and
(Has an inhibitory effect on p-platelet aggregation and gastric acid secretion.

Therefore, it is effective in the treatment of hypertensive syndrome, thrombosis, asthma and gastrointestinal ulcers, induction of labor and abortion of pregnant breasts and ribs, prevention of arteriosclerosis, and as a diuretic. They are fat-soluble substances present in very small amounts in each silk thorn that secretes prostaglandins into the living body of an animal.

The inventors believe that the pharmacological effects of "natural" prostaglandins, or that have a different or better nature, stronger activity, or "
As a result of extensive research to discover a new compound with properties that are not found in natural prostaglandin, we found that (the carboxyl group at position 1 of 11PGDl and PGD2 is an acryloyloxymethyl group or carno-Z PGD substituted with a moyloxymethyl group [each has the same meaning as in the following]
Similar compounds, PGD similar compounds in which the hydroxyl group at the 9-position of these compounds is dehydrated and a double bond is introduced between C9-Clo, and one of their similar compounds
PGD-like compounds in which the hydroxyl group at position 5 is dehydrated and a double bond is introduced between C1□-013 and C14"C15, and (21PGD, and the carboxyl group at position 1 of PGD2 is human The hydroxyl groups substituted with a methyl group [-CH20H group or -aH2-o-cop8 group (in the formula, R8 has the same meaning as below)] and at the 9- and 15-positions are dehydrated to form C9-Clo between C12-CI3 and C
14""15 PGD-class compounds with a double bond introduced between them do not have the pharmacological properties of "natural" prostaglandins, or have very weak pharmacological properties, but have anti-1111! The present invention was completed by discovering that the tumor effect is stronger as the skin gets weaker.

Conventionally, PGD-like compounds and 9-deoxy-Δ −
Several applications regarding PGD-like compounds have been filed. For example, compounds in which the carboxylic acid moiety at position 1 of these compounds has been converted include methanesulfonylamide (
See JP-A-51-131859. ), alcohols and their acyl derivatives (Japanese Patent Application Laid-open No. 1983-18
No. 9648, No. 52-89649 and No. 52-896
See specification No. 50. ), amine body (#!j Kaisho 5
See specification No. 4-83351. ), ketone derivatives (see JP-A-54-141751), etc., but the acryloyloxy and carbamoyloxy forms shown in ftl above are conversions that have never been seen before. This is a novel derivative that was not expected from the prior art.

On the other hand, hydroxymethyl compounds or their acyl derivatives are known as PGD-like compounds and 9-deoxy 9 -Δ -PGD order compounds as described above, but C9-C□ as shown in (2) above.
.

Compounds of PGD class I and I in which double bonds are introduced between C12 and C13 and between C14 and C15 are completely new and are derivatives that were not expected from the prior art.

More importantly, these compounds of the present invention exhibit novel effects that have not been found in known PGD derivatives.
In other words, it has an antitumor effect. The above-mentioned published specifications merely describe the pharmacological properties known to common prostaglandins, and there are no applications focusing on the anti-lIN tumor action.

Therefore, the present invention relates to completely new PGD analogue compounds, methods for producing them, and antitumor agents containing these compounds as active ingredients.

[In the formula, [A] represents a group represented by the formula (TI) (TID (TV), and X is an ethylene group (-0H20H2-)
or -, yx=vinylene group (il (A) is of the formula (
(IT) or (III), it represents a group represented by the formula; (ii) When (A) represents a group represented by the formula (TV'), it represents a group represented by the formula; and R is (il) When (A') represents a group represented by the formula (IT) or (m), the formulas R, R, JP? and R are each independent, and hydrogen represents a group represented by an atom or a linear or branched alkyl group having 1 to 4 carbon atoms. (In the formula, R represents a straight or branched alkyl group having 1 to 4 carbon atoms, and the other symbols have the same meanings as above.

), R1 represents a single bond or a straight or branched alkylene group having 1 to 5 carbon atoms, and R
is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, or a 4-carbon straight-chain or branched alkyl group having 1 to 8 carbon atoms, which is unsubstituted or substituted with at least one straight-chain or branched alkyl group having 1 to 8 carbon atoms;
~7 cycloalkyl groups, or phenyl or phenoxy groups that are unsubstituted or substituted with at least one halogen atom, trifluoromethyl group, or linear or branched alkyl group having 1 to 4 carbon atoms. In the expression, formula (in the kaol and decoy, the double bond between C9 and C1° represents 2, in the formula (■, the double bond between C□3 and C, 4 represents E, and in the formula (■, C1□ -01
The seven double bonds between 3 and C14-015 are each independent and represent E, Z or a mixture thereof (ie, EZ). However, when R represents a single bond, R
shall not represent a substituted or unsubstituted phenoxy group. ] The present invention relates to PGD-like compounds shown in the following, their cyclodextrin clathrate compounds, methods for producing them, and antitumor agents containing these compounds as active ingredients.

Several asymmetric carbon atoms exist in the compound represented by the general formula (Il. For example, in the general formula (II), [A') represents a group represented by the formula (III), and C□3-C14-C
In a compound in which l3 represents a group represented by the formula (■), there are four asymmetric carbon atoms (i.e., carbon atoms at the 8th, 9th, 12th, and 15th positions), and [A] is In a compound in which C13-014-015 represents a group represented by the formula (■), the carbon atoms at the 8th, 12th and 15th positions are asymmetric carbon atoms, and (A) is In a compound representing a group represented by the formula (Vl), the carbon atom at position 8 is an asymmetric carbon. Furthermore, K R', F(2, R3, R' , R5,R
6° When the alkyl moieties of the various substituents represented by R7 and R8 are branched, other asymmetric carbon atoms may occur. However, the compound represented by the general formula ([1) of the present invention also contains each isomer caused by an asymmetric carbon and a mixture thereof.

In the general formula (11), examples of the alkylene group having 1 to 5 carbon atoms represented by R include methylene, ethylene, trimethylene, tetramethylene, intamethylene groups, and renal derivatives thereof, and R1 is preferably a single bond or methylene or It is an ethylene group.

In the general formula (tl), the alkyl group having 1 to 8 carbon atoms represented by R is methyl, ethyl, propyl, butyl,
Examples include methyl, hexyl, heptyl, octyl groups, and isomers thereof, and preferably butyl, intyl, and hexyl groups that are unsubstituted or substituted with one or two methyl or ethyl groups.

In the general formula (Il, R represents a substitution or no ft,
Examples of substituted cycloalkyl groups include l-butyl, cyclosyntyl, cyclohexyl, cycloheptyl groups and one or more methyl, ethyl, propyl, butyl, R-methyl, hexyl, heptyl or octyl groups or their atomized forms. Substituted cyclobutyl, cyclotetanthyl, cyclohexyl, cycloheptyl groups are mentioned, preferably cyclobutyl, cyclocinthyl or cyclohexyl groups which are unsubstituted or substituted with one methyl, ethyl, pro2yl or butyl group. It is.

In the general formula Trl, the substituted or unsubstituted phenyl or phenoxy group represented by R includes phenyl, phenoxy group and one or more fluorine atom, chlorine atom, trifluoromethyl group, methyl, ethyl, propyl or butyl group. Substituted phenyl or phenoxy groups are mentioned, preferably phenyl or phenoxy groups which are unsubstituted or substituted with one chlorine atom, trifluoromethyl group, methyl group or ethyl group.

In the general formula (Tl, preferred R-El is butyl, intyl, 1-methyl is methyl, 2-methylzunthyl, 6-methyl is methyl, 1,1-dimethylpentyl, 1-ethyl is methyl, 2-ethyl is methyl , hexyl, 1-methylhexyl, 2-methylhexyl, 1-ethylhexyl, 2-ethylhexyl, heptyl, 2-methylheptyl, 2-ethylheptyl, cyclobutyl, 1
-propylcyclobutyl, 1-7'tylcyclobutyl,
3-ethylcyclobutyl, 3-propylcyclobutyl,
Cyclo is methyl, cyclo is methylmethyl, 2-cyclohexyl ethyl, 6-ethylcyclohythyl, 3-7'lopyl, 3-butylcyclo is methyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 4- Methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, zundil, 2-phenylethyl, 4-
Methyl benzyl, 4-ethylbenzyl, phenoxymethyl, 2-phenoxyethyl, 3-chlorophenoxymethyl, 4-chlorophenoxymethyl, 3-trifluoromethylphenoxymethyl, 4-trifluoromethylphenoxymethyl, 4-ethylphenoxymethyl , 4-ethylphenoxymethyl.

In the general formula (Il, R, R, F?, R, R and R8
The alkyl group having 1 to 4 carbon atoms represented by is methyl,
Examples include ethyl, propyl, butyl groups and isomers thereof, and preferred R3, R4 and R5 are each independently a hydrogen atom or a methyl or ethyl group, and preferred R and R are both a hydrogen atom or a methyl or ethyl group. and preferred R8 is a methyl or ethyl group.

In the general formula (Tl, preferred R is a hydrogen atom,
Acryloyl, 2-methylacryloyl, 2-ethylacryloyl, 3-methylacryloyl, 3-ethylacryloyl, 3.3-dimethylacryloyl, 3.3-u
Ethyl acryloyl, 2. s-'>methyl acryloyl, 2.3-') ethyl acryloyl, 2.3.3-')
Examples include dimethylacryloyl, 2.3.3-triethylacryloyl, carbamoyl, dimethylcarmemoyl, diethylcarbamoyl, acetyl, proionyl, and the like.

Furthermore, in the general formula (IIIC, preferable X is dipositive (-
It is a vinylene group, and in the general formula (II), C13
When -C14-015 represents a group represented by the formula C■, the preferred configuration of the hydroxyl group attached to the 15th-position carbon atom is the α-configuration.

As mentioned above, compounds included in the present invention can be named as derivatives of PGD. For example, the compounds represented by the formulas, which are representative compounds of the compounds of the present invention, are each 1-G)-(3,3-dimethylacryloyl)-
They are named PGD2 alcohol and 1-0-carbamoyl-9-deoxy-Δ-PGD2 alcohol. Additionally, all compounds included in the present invention can be systematically named as derivatives of orostane, represented by the formula rostane. In this case, the compounds represented by a and b above, and the compound of the present invention represented by the formula, are each (5Z, 13E)-(98, 15
8)-1-0-(3,3-dimethylacryloyl)-1
1-oxoprosta-5,13-diene-1,9,15
-) Riolu, (5Z, 13E)-(15S)-1-0
-carnomimoyl-11-oxoprosta-5,9,1
3-) diene-1,15-diol and (5Z, 14E
Z)-11-oxoprost-5,9,12,14-tetraen-1-ol.

According to the present invention, the compound of the present invention represented by the general formula (Il) can be produced by the following method.

First, a group represented by the general formula (Il represents the general formula meaning for the compound of the present invention), and other symbols have the same meanings as above. ] A 1-0-acryloyl-PGrl alcohol visiting conductor or a 1-0-acryloyl-PGrl alcohol derivative, and a 1-0-acryloyl-PGrl alcohol derivative represented by the general formula (in which all symbols have the same meanings as above). 0-acryloyl-9-deoxy-Δ-P
GD alcohol derivative or 1-0-carbamoyl9
-deoxy-Δ -PGD flucol derivative, further represents a group represented by the general formula (wherein R is a hydrogen atom or in the formula 0, all symbols have the same meanings as above), and other symbols are It has the same meaning as above. ).

A PGD-like compound represented by the general formula (Tl?) is a compound having the general formula
-yl group or tetrahydrofuran-2-yl group or 1-ethoxyethyl group, preferably tetrahydrofuran-2-yl group, preferably tetrahydrofuran-2-yl group, preferably tetrahydrofuran-2-yl group,
Table 109 represents a ran-2-yl group, R represents an R group or a group represented by formula 0 (in which all symbols have the same meanings as above), and other symbols have the same meanings as above. ] The compound represented by is dissolved in an inert organic solvent such as methylene chloride, chloroform, carbon tetrachloride, diethyl ether, N
, N-dimethylformamide, tetrahydrofuran, or a mixed solvent of two or more thereof, an aqueous solution of an acid, such as an organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or an organic acid such as acetic acid, propionic acid, or oxalic acid. It is produced by reacting an aqueous solution of K at the reflux temperature of the solvent. Preferably, it is produced by refluxing 1N hydrochloric acid in tetrahydrofuran.

The compound represented by the general formula (■) includes a PGD-like compound represented by the general formula (■α), and the general formula [wherein R is a hydrogen atom or the formula -○OR (R8 in f has the same meaning as above] represents a group represented by ), and other symbols have the same meanings as above. ] Includes PGD-like compounds represented by the general formula (I
The compounds represented by α) and (■α) are represented by the general formula [wherein, R11 is an R9 group or the formula -COR8 (wherein, R
8 represents the same meaning as above. ), and other symbols have the same meanings as above. It is produced by hydrolyzing the OR9 groups at the 9- and 15-positions of the compound represented by the above formula, and the 11 OR group when the oR11 group represents an OR9· group, into a hydroxyl group under acidic conditions. This hydrolysis is carried out in (1) an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, T)-)luenesulfonic acid or an aqueous solution of an inorganic acid such as chloride, sulfuric acid, phosphoric acid, preferably with water; from room temperature in the presence of a miscible organic solvent, for example a lower alkanol such as methanol or ethanol (preferably methanol), or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran (preferably tetrahydrofuran). at a temperature of 75°C (preferably a temperature below 45°C),
or (2) carried out in an anhydrous lower alkanol such as methanol or ethanol in the presence of an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid at a temperature of 10 to 45°C. The hydrolysis is preferably carried out using a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, or a mixture of p-)luenesulfonic acid and anhydride. It is carried out using a mixture of methanol.

The compound represented by the general formula (■) includes a PGD analogous compound represented by the general formula (Ih), and the general formula (where all symbols have the same meanings as above). ] PGD indicated by
Although similar compounds are included, general formulas (Ib) and (■α)
The compounds represented by the formula (in the formula, all symbols have the same meanings as above) are the OR group and the OR group at the 15th position of the compound represented by the general formula
K is produced by hydrolyzing the 0R11 group to a hydroxyl group under acidic conditions. This hydrolysis is carried out by the method described above for producing the compounds represented by the general formulas (■α) and (■α).

tLP represented by general formulas (Iα), (Ih) and (■c)
The series of reactions described above for producing GD analogs is shown in Scheme A below. In the formula, all symbols have the same meanings as above.

Further according to the invention, R represents the same meaning as in the formula. ) A compound represented by the general formula (Il,
In other words, a compound represented by the general formula (in which all symbols have the same meanings as above) is a compound represented by the general formula (in which all symbols have the same meanings as above). (In the formula, HtZ7 represents a chlorine atom, a bromine atom, or an iodine atom, and the other symbols have the same meanings as above.

) It can also be produced by reacting with an acid halide 9 shown in the following formula to selectively acylate the hydroxyl group at the 1-position. The acylation reaction is carried out in the presence of a tertiary amine such as pyridine or triethylamine in an inert organic solvent such as methylene chloride or without a solvent at a temperature below room temperature, preferably between 0°C and -
It is carried out at a temperature of 20°C.

Similarly, the general formula (1) in which R represents a group represented by the formula -〇OR (wherein R represents the same meaning as above and -f')
Among the compounds represented by the general formula (in which all symbols have the same meanings as above), and the compounds represented by the general formulas (■) and (Vllll),
The compounds represented by the general formula and (in the formula, all symbols have the same meanings as above) are the compounds represented by the general formula (in the formula, all symbols have the same meanings as above), respectively. It can also be produced by reacting with an acid halide represented by the general formula % (in which all symbols have the same meanings as above) and selectively acylating the hydroxyl group at the 1-position.

The general formula (xTC)c, which is the starting material for the r-silation reaction,
'tab > and (xTC), that is, the compounds represented by (Xl) are all compounds included in the general formula (C), (■α) or (■α).

Compounds represented by general formulas (TX) and (2) can be produced by a series of reaction steps shown in the following schemes B and OK, respectively. In the diagram, R is a trimethylsilyl group,
triethylsilyl group, tributylsilyl group, ter
t-butyldimethylsilyl group, tri-butyldimethylsilyl group,
It represents a trisubstituted silyl group such as a triphenylsilyl group, preferably a tert-butyldimethylsilyl group, and T is an alkylsulfonyl group or a substituted or unsubstituted group.
It represents a sulfonyl group, preferably a mesyl group or a tosyl group, and other symbols have the same meanings as above.

All steps in Schemes B and C are carried out by known reactions, but to briefly explain, for example, step [a] is a reaction to protect a hydroxyl group, and an inert organic solvent such as methylene chloride, chloroform, diethyl ether, etc. The reaction is carried out using 2,3-dihydrobyran, 2,6-cyhydrofuran, ethyl vinyl ether, etc. in the presence of a condensing agent such as p-)luenesulfonic acid, sulfuric acid, trifluoroacetic acid, etc. at a temperature from room temperature to -60°C. It will be done. It is preferably carried out at room temperature using 2,5-dihydropyran in the presence of the T)-)luenesulfonic acid salt of pyridine in methylene chloride or p-toluenesulfonic acid.

Steps [b] and [C] are acylation reactions, which are carried out by the methods described above for producing compounds represented by the general formulas (C''l and (Id), respectively).

Step [d] is a carbamoylation reaction using an inert organic solvent such as methylene chloride, tetrahydrofuran,
diethyl ether, N,N-dimethylformamide 9 (
in the presence of a base such as triethylamine or pyridine, preferably in diethyl ether),
, ) or (X■) and phenyl chloroformate at 0°C, then liquid ammonia,
Or it can be done by making it correspond.

The step (=) is a reaction that converts the 0R12 group into a hydroxyl group.This reaction is described by John Wiley & 5o
ns, Inc. (USA), “Protect
iveGroups in Organic 5ynt
hesis”, pages 39-50 (1981) (hereinafter referred to as
It is abbreviated as Document A. ), but is preferably carried out using tetrabutylammonium fluoride (n-Bu4N+F-) in tetrahydrofuran at room temperature.

Step] is a reaction in which a double bond is formed between C9 and 018 by converting the hydroxyl group into an oxo group or simultaneously eliminating the OT group. This type of oxidation reaction is well known,
For example, (C1 Nankodo Publishing, edited by Tetsuji Kametani [Organic Synthetic Chemistry ■Synthesis Edition 1], pages 176-206 (August 1, 1976), or (AI John Wiley & 5ons,
Inc. (USA) Publisher: Compendium o
f Organic 5ynthetic Method
dsJ Volume 1 (1971), Volume 2 (1974),
6 (1977), Section 48 or 168. Particularly preferred oxidation under mild and neutral conditions is, for example, dimethylsulfide-N-chlorosuccinimide complex, thioanisole-N-chlorosuccinimide complex, dimethylsulfide-chlorine complex, thioanisole-chlorine complex [the above, J, Amer, Ohem
-8oc, see Matashima 7586 (1972)], dicyclohexylcarbodiimide dimethyl sulfoxide complex [: J, Amer.

Chem-8oc, 87t 5661 (1965)], viridinium chlorochromate (C5H5NHC
rO3C4) (Tetrahedron Lett, e
rs, 2647 (1975,)], sulfuric anhydride-pyridine complexes [J, Amer, Chem.

Soc...? 9.5505 (1967)], Chromium chloride A/ (J, Amer, Chem, Sac, ,
97.5929 (1975)], chromium trioxide
Pyridine complexes (e.g. Collins reagent), Jones reagent or chromic acid solution (prepared from chromium trioxide, manganese sulfate, sulfuric acid and water), oxalyl chloride and dimethyl sulfoxy P (Swern oxidation), etc. Preferred are Collins oxidation, Jones oxidation or Swan oxidation. Collins oxidation with chloroform,
The reaction is carried out in a halogenated carbon atom such as methylene chloride or carbon tetrachloride at a temperature from room temperature to 0°C. Jones oxidation is usually performed at temperatures below room temperature. Swan conversion is carried out at -50°C in halogenated hydrocarbons such as chloroform and methylene chloride.
It is carried out by reacting at ~-60°C followed by treatment with triethylamine. .

The starting materials in Schemes B and C, compounds represented by general formulas (XIV) and (X■), can be produced by a series of reaction steps shown in the following scheme. All symbols in the diagram have the same meanings as above.

Each step in the diagram is performed by a known reaction, but to briefly explain, for example, step [1] is a reaction that selectively converts the hydroxyl group at position 11 into two oFll groups,
The reaction is described in detail in Document A, but preferably from dimethylaminopyridine, dimethylformamide,
By reacting a chlorosilane compound represented by the formula G/l-R (wherein R has the same meaning as above) at a temperature of room temperature to 50°C in the presence of a base such as pyridine, imidazole, or trimethylamine. It is done. In this case, the reaction must be carried out carefully so that the hydroxyl group at the 9-position is not simultaneously converted into an OR group.

The step [i] is a reaction of converting the hydroxyl group at the 9-position into an OR9 group, and can be carried out in the same manner as the above-mentioned step [a].

Step [t] is a reaction for converting the hydroxyl group at the 9-position into an OT group, and includes the following steps: 0) In the presence of a tertiary amine such as pyridine or triethylamine, in an inert organic solvent such as methylene chloride,
Alternatively, it is carried out by reaction with an alkylsulfonyl chloride such as mesyl chloride 9 or an allylsulfonyl chloride such as tosyl chloride in pyridine at a temperature of -60°C to 50°C.

Step [)] is a reaction to reduce -C00CH3 group to -CH20H group, and any reducing agent can be used as long as it is used for this purpose, but preferably in an inert organic solvent such as hexane, tetrahydrofuran, or toluene. ,0
It is carried out using diisobutylaluminum ramno-idryp (DIBAL) at temperatures between .degree. C. and -30.degree.

The compound represented by the general formula (XX) is a known compound per se, and is disclosed as a compound represented by the general formula (XXIIT) in Japanese Patent Application No. 109806/1983.

A cyclodextrin clathrate compound of a prostaglandin D-like compound represented by general formula (II) is disclosed in Japanese Patent No. 790979 and Japanese Patent Application Laid-open No. 111347 using α-1β- or γ-cyclodextrin or a mixture thereof.
It is obtained by using the method described in the specification of No.-39057. By converting it into a cyclodextrin clathrate, the neutrality of the prostaglandin D-like compound represented by the general formula (Il) is increased.

Compounds similar to prostaglandin D represented by the general formula Although the anti-lung cancer effect is surprisingly strong and has extremely low toxicity, it is effective against lung cancer, such as leukemia and solid cancer. It can be used as a very effective and ideal anti-tumor agent for preventive, therapeutic and life-prolonging effects against type cancer.

For example, in laboratory experiments, human locus carcinoma cells (KB
In an in vitro growth inhibition test using cell), the compound of the present invention showed an excellent inhibitory effect.

The experimental method and results are shown below.

Clause η Proliferation inhibition test using human locus carcinoma cells (KBcell) <Experimental method> KB cells were added to Eagle MEM culture solution containing 1.0% calf fat serum, and the number of cells in the culture solution was reduced to 1. ×10
After adding the ethanol solution of the compound of the present invention to a final concentration of 5 μg β or lower (3 points), the solution was incubated at 67° C. for 4 days. As a control, 0.0 μg of ethanol was added. A cell culture medium to which 1% was added was cultured in the same manner.After culturing, the number of living cells was counted by staining with trypan blue staining method, and the ID5° value (5
0 coefficient growth inhibitory concentration) was determined. The results are shown in the table below.

Prostaglandin D-like compounds represented by the general formula (II) and their cyclodextrin inclusion compounds K used as antitumor agents are usually administered systemically or locally.
Administered orally or parenterally.

The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, processing time, etc., but it is usually administered once to several times a day in the range of 5 to 500 cm per adult. 500μg to 50■ per adult per dose
The drug is administered parenterally, preferably intravenously, once to several times a day. Of course, as mentioned above, the dosage varies depending on various factors, so in some cases it may be sufficient to use a smaller amount than the above-mentioned dosage range, and in other cases it may be necessary to exceed the above range.

Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. mixed with magnesium acid. The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate, in accordance with conventional methods. The tablet or tip may be coated with a film of a gastric or enteric substance such as white gelatin, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, or may be coated with two or more layers, if necessary. Additionally, the capsule may be made of an absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , including ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics and preservatives.

'Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline.

Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of disinfectants, or by irradiation.

They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Other compositions for parenteral administration include topical solutions, liniments such as lozenges, and suppositories for rectal administration, which contain one or more active substances and are formulated in a manner known per se. and four-touch saris for intravaginal administration.

Among the compounds represented by the general formula (1) included in the present invention, preferable examples include kohl, kohl, 1-0-carbamoyl-PGD2 alcohol, 1-0-
Carnomimoyl-16-methyl-PGD2 alcohol, 1-0-carbamoyl-16,16-dimethyl-PGD
2 alcohol, '1-0-carbamoyl'7+ 20-:) methyl-PGD2 alcohol, alcohol, hexyl)-16,17,1B, 19. ．． 20-pentanol-P1.7υ2 alcohol, alcohol, 1-0-(dimethylcarbamoyl)-PGD2 alcohol, 20-pentanol-PGIJ2 alcohol, alcohol, alcohol, monoru, monoru, cole, cole, cole, trifluoromethylphenoxy) -17,18,19゜20-tetratrue9-deoxy-Δ9-P(7D2 alcohol, (5Z, 14EZ)-11-oxo-16-pheny(5
Z, 14EZ)-1-0-7 cetyl-11-or, (5Z, 14EZ)-1-0-7 cetyl-11-, -
Tetraen-1-ol, 1-ol, 1-ol, ol, 14-tetraen-1-ol, -ol, ol, 1-oxo 15-cyclobenzyl 16.1/, 18゜#shin1in, 14-tetraen- Examples thereof include 1-ol, 1-ol, and corresponding compounds in which X represents an ethylene group.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, "TLC", "NMRJ", "
"Engineering R" and "jMassJ" respectively represent "thin layer chromatography,""nuclear magnetic resonance, spectrum,""infrared absorption spectrum," and "mass spectrometry," and BM in the structural formula below
S, THP and MS represent a tert-butyldimethylsilyl group, a tetrahydropyran-2-yl group and a mesyl group (methanesulfonyl group), respectively. The solvent in parentheses listed in the chromatographic separation section indicates the elution solvent or developing solvent used. Unless otherwise specified, IR was measured using a liquid film method, and NMR was measured using a deuterated chloroform (CDC13) solution.

Reference Example 1 (5Z, 13E)-(
9α, 11α, 158)-9,11-dihydroxy-1
5-(trahydropyran-2-yloxy)prosta-5,13-dienoic acid methyl ester C%Mfi 1983
, -109806 Specification Reference Example 1) 5g
, dimethylaminopyridine 134Tnq and tert
- Add 8.33 g of 7' methyldimethylchlorosilane,
Stir at 35°C for 1 hour. After adding 500ml of diethyl ether to the reaction mixture, the mixture was washed successively with water-cooled 1N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of 11-hexane and ethyl acetate, then ethyl acetate alone) to obtain 66 g of the title compound (containing some impurities) having the following physical properties.

TLC (n-hexane:ethyl acetate = 2:1)
: Rf-0,74, :NMR: δ=5.5-5.1
(4H, rn), 4.7-4.5 (I H, m
), 4.3-6.2 (5H, m), 3.6 (3H9,
9), 09 (9H, -?), 1.0~0.8 (3H,
t); Engineering R Niji = 3500.2960.1765.12
50.1015.975cIn, -": Mass: m/e=509,407° Compounds shown in Table 1 were obtained in the same manner as in Reference Example 1. The compounds used as starting materials were each disclosed in a patent application. Showa 57-1098
Reference Example 1 (α), 1 (h), I CC of Specification No. 06
1 and 1 ($lK listed 0 Reference example 2 9-hydroxy form dissolved in 56Tnl of methylene chloride (
Manufactured in Reference Example 1. ) 6.69 at room temperature 2.6-:
) 3.16 m5 of human 90 pyran and 68.5 mQ of Tl-) luenesulfonic acid monohydrate were added and stirred at the same temperature for 1 hour. T) by adding triethylamine to the reaction mixture.
After adjusting to H9, diethyl ether 30011/Y was added, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane, then a mixture of n-hexane and ethyl acetate) to obtain 6.3 g of the title compound having the following physical properties.

TLC (n-hexane:ethyl acetate=5:1):
Rf=0.40; NMR: δ=5.6-5.0 (4H
, m), 4.7~4.4 (2H, m), 4.3~
3.1 (7H, rn), 3.6 (3H,,t), 0
．． 9 (12H,! and m): Engineering R Niji = 2920.2850.1740.1450
．． 1250.1120.1020.985cm.

Mazz: m/g=593.565.548.509
．． 49 Compounds shown in Table 2 were obtained in the same manner as in Reference Example 2.

Reference Example 6 0M5 9-Hydroxy compound dissolved in 60 mJK of methylene chloride (produced in Reference Example 1) To 7.13 and f, 6.6- triethylamine was added at -60°C, and 6.1 units of mesyl chloride was added dropwise. The mixture was stirred at the same temperature for 40 minutes and then at 0°C for 20 minutes. 50° of water and 150° of methylene chloride were added to the reaction mixture, and the methylene chloride layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane) to obtain the title compound 6.91 having the following physical properties.

TLC (ethyl acetate:n-hexane=1:3):R
f=0.42; NMR (CCJ4 solution): δ-5,6~
5.2 (4H, etc.), 4.9 (IH, m), 4.6 (
I H, door), 3.6 (3H, -9), 2.9 (3H,
1? ), 0.9 (9H2#), 0.1 (6H,z)
; Engineering R: υ=2940.1740.1358.1173
．． 912cm-”.

Reference Example 4 To 6.3 g of the methyl ester compound (produced in Reference Example 2) dissolved in 5 Qm/' of tetrahydrofuran, 1.
76M (mol) solution 12m/! Add dropwise at 0°C, stir at the same temperature for 30 minutes, add 5.2 d of methanol, stir at the same temperature for 10 minutes, add 2 d"k of water, raise the temperature to 65°C with vigorous stirring, and stir at the same temperature for 60 minutes. The reaction mixture was filtered through a layer of magnesium sulfate, and the liquid was concentrated under reduced pressure to obtain the title compound 5 having the following physical properties.
．． 649'l crude product was obtained.

TLC (n-hexane: ethyl acetate = 5:1): R' =
[1,13; NMR: δ-5,6~5.1 (4H, m
), 4.8-4.4 (2H, m), 4.4-3.
2 (9H, m), 0.9 (12H, r and m); I
R Niji = 35nO12960, 2850, 1160,
1255,1160,1020,985 letters.

Compounds shown in Table 6 were obtained in the same manner as in Reference Example 4.

Can Reference Example 5 1.72 g K of the alcohol (produced in Reference Example 4) dissolved in methylene chloride 13'111, 0.49 ml of 2,3-dihydropyran, and 5.1 az& of hiltoluenesulfonic acid monohydrate were added. , and stirred for 5 minutes at 27°C. Triethylamine was added to the reaction mixture to adjust the pH to 8, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in 13 dK of dry tetrahydrofuran under an argon atmosphere, 1.4 g of tetrabutylammonium 70lide was added, and the mixture was stirred at 25°C for 2 hours and then at 35°C for 30 minutes. 200 grams of diethyl ether was added to the reaction mixture, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (
Purification with a mixture of n-hexane and ethyl acetate, then ethyl acetate alone) yielded the title compound 1. having the following physical properties.
4 II was obtained.

TLG (n-hexane: vinegar flJx chill-3: 11
:Rf-0,11:NMR:δ-5,6~51(4H,
Tiger), 4.7-4.4 (3H, folding), 4.4-3.1'
r 11H, m); Engineering R Niji-3500, 2930,
2860, 1430, 1350, 1200, 1160,
1020,980CIl *Ma, y#: m/g=4
90,406.388゜Compounds shown in Table 4 were obtained in the same manner as in Reference Example 5. Reference Example 6 0H,0THP Alcohol compound dissolved in methylene chloride (produced in Example 4) 1 After adding .92 g of Nigiri gin 0.73+iJ7 and cooling to OoC, 0.5 ml' of 6,6-dimethylacryloyl chloride was added dropwise and stirred at the same temperature for 20 minutes. Pour the reaction mixture into 200 ml of ice water,
Extracted with diethyl ether 300 rni.

The extract was washed successively with cold 1N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate to 11%, and concentrated under reduced pressure. The resulting residue was dissolved in 14.5 mJ of dry tetrahydrofuran under an argon atmosphere and diluted with tetrabutylammonium fluoride (2.26 F!). 'ft and stirred at 27°C for 1 hour and then at 35°C for 2.5 hours. The reaction mixture was poured into 15Qm of ice water and extracted with 300M ethyl acetate. The extract was washed successively with cold water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride, then a mixture of ethyl acetate and n-hexane) to obtain the title compound having the following physical properties at 1.4°C g'Y.

TLC (ethyl acetate:n-hex:y=1:5>:Rf
-0,24; NMFI 2δ=5.8~5.65 (I
H, m), 5.7-5.1 (4H, m),
4.8-4.5 (2H, m), 4.3-3.2 (
7H, m), 4.15 (3H, t), 2.18 (3H
,,? ), 1.9 (3H, ?): Mass: m/e=4B8,470.686° Reference Example 7 Alcohol compound dissolved in 20 d of dry diethyl ether under an argon atmosphere (produced in Reference Example 4) 1. 937
．． Add 0.75 ml of pyridine to 9 at room temperature, and then heat to 0°C.
After adding 0.7 g of phenylchloroformate (()o-cocz) dropwise, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into 100 d of ice water, extracted with 200 ml of diethyl ether, and the extract was washed successively with water, a saturated aqueous copper sulfate solution, water, and saturated brine.
After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain a phenyl carbonate compound. Next, under an argon atmosphere, -78℃
To 501 nl of liquid ammonia cooled to . The reaction mixture was diluted with 303 ml of cold diethyl ether and 3% hydroxide).
), washed successively with cold water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in 15 mA &c of dry tetrahydrofuran (tetrabutylammonium fluoride)'2.25 under an argon atmosphere.
j9 was added and stirred at 27°C for 1 hour, then stirred at 35°C for 30 minutes. The reaction mixture was poured into 150 ml of ice water and extracted with 300 ml of ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (
The mixture was purified with a mixture of n-hexane and ethyl acetate to obtain 1.09 g of the title compound having the following physical properties.

TLC (ethyl acetate:n-hexane-1:i): Rf-
0,25; Engineering R Niji = 3650-6100.2930.
2850.1720.1335.1120.1075.
1020.980α.

Compounds shown in Table 5 were obtained in the same manner as in Reference Example 7.

Note that in Reference Example 7 (α1), dimethylamine was used instead of liquid ammonia used in Reference Example 7.

Reference Example 8 Under an argon atmosphere, 2.36 ml of chromium trioxide was added to 3.81 ml of pyridine dissolved in 59 ml of dry methylene chloride at room temperature.
! Add i+ while stirring vigorously, then celite 1
Add 2 g'a' and further dissolve 10 dK of methylene chloride to add 11-human 90 hosi form (produced in Reference Example 5) 1.4
．． It was added all at once to F= at 5°C and stirred at the same temperature for 10 minutes. The reaction mixture was filtered through Celite, and the solution F was washed successively with a saturated aqueous copper sulfate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound 1.33 having the following physical properties. ! 7 was obtained as a crude product.

TLC (ethyl acetate: n-hexyl=1:3): Rf
= 0.29; Engineering R Niji = 2930.2860.174
0.1200.1130.1075.980cIrL.

Compounds shown in Table 6 were obtained in the same manner as in Reference Example 8.

Reference Example 9 Under an argon atmosphere, chloride Q dissolved in dry methylene chloride 11aK, dimethyl sulfoxide 0.8 dissolved in dry methylene chloride 1.1++11K in 5 mA.
It was dropped at -50 to -60°C over 1 m/' and stirred for 10 minutes at the same consistency. In this solution, the 11-hydroxy compound [produced in Reference Example 5(-)] was dissolved in dry methylene chloride 3d.

32.24g was dropped at -50 to -60℃, and 2
Stir for 0 minutes. Furthermore, 3.19 ml of triethylamine was added dropwise to this solution at -50 to -60°C, and the mixture was stirred at the same temperature for 5 minutes and then at room temperature for 30 minutes. The reaction mixture was poured into 100 g of ice water, extracted with diethyl ether 2501111, the extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound 2 having the following physical properties. .25.9 was obtained by combining the crude product. TLC (ethyl acetate:n-hexyl-1:1):R
f-0,70: NMR: δ = 7.45 (IH, dd),
6.05 (IH, d4), 5.8-5.0 (4H, m
), 4.8~4.45 (2H, vn), 4.3~
3.0 (7H, book); Engineering R Niji = 2940.2860.1710.1590
．． 1450.1350.1120.1080.1030
．． 980cIIL.

Reference Example 10 11-hydroxy form dissolved in acetone 13m/IIC [
Produced in Reference Example 7(b). ) 8.9 rtrl of Jones reagent was added dropwise to 2.61# at -15 to -25°C, and stirred at the same temperature for 50 minutes. Pour the reaction mixture into ice water 150-
The mixture was poured into a container and extracted with 300% of ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane) to obtain the title compound 785 chaff having the following physical properties.

TLC (ethyl acetate di-n-hex 7=3:1):
Rf = D, 62: NMR: δ = 7.59 (IH
, dd ), 6.15 (IH, dd ), 5.7-5.
2 (AH, m), 5.2-4.6 (3H, m
), 4.05 (2H; t), 4.1-3.2 (3H,
m): Engineering R Niji = 37500-3100.2960
．． 2860.1705.1600.1A00.1630
．． 1070.970crrL.

Reference Example 11 H Tetrahythm 90 Furan 1, 9. dissolved in 3.1 mA.
15-Tris-THP body (produced in Reference Example 8) 92
Add 15.6ml of 0mQK65% acetic acid aqueous solution and 80℃
I stirred it for 8 minutes. Add 350T of ethyl acetate to the reaction mixture.
After cooling, the mixture was washed successively with water and saturated brine (1ω), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane, then ethyl acetate only), and further recrystallized from a mixture of diethyl ether and n-hexane to obtain the title compound 1157nI having the following physical properties. ? I got it.

Melting point: 45°C: TLC (chloroform: tetrahydrofuran: acetic acid =
10:2:1): Rf=0.29; NMR: δ=5. <53 (IH, dd), 5.42 (I
H, d, d), 565-5.35 (2H, ya), 4.
55-4. ．． d (I H.

rrL), 4.09 (IH, ctt), 5.66
(2H,t), 2.85(1H,dd), 2.43(
2H, d, ): IR (KBr method) Niji = 3370.29
20.2850.1720.1410.1310.11
50.1055.970crrL-1:Masz:m/
e=558cM), 620.602.267.2A9
．． 231° The following compound was obtained in the same manner as in Reference Example 11.

(101) Starting material: 1,15-bisTHP compound produced in Reference Example 9: TLC (Chloroform: Tetrahydrofuran: Acetic acid =
10:2:1): Rf=D, 45; NMR: δ=7.58 (IH, dtt), 6.15 (I
H, dd), 5.67 (IH, dd), 5.55 (IH
, dg), 5.7-5.3 (2H, m), 4.09
(IH, d, t), 6.61C2H, t"), 2.9
~2.75 (IH, m), 2.66 (IH, gg
); IR:l/ ~3650~3100.2930.28
60,1705.1590.1460.1650.11
65.1050.970cm.

M(Z,?JP: m7g-320(M), 30
2.249.231.43°tetrahydrof90 francs4.
9,15-bisTHP compound dissolved in 5 ml [Reference example]
8 (manufactured for $1) 65% acetic acid aqueous solution 1 to 890
5mA! was added and stirred at 80°C for 20 minutes. The reaction mixture was poured into 200 ml of ice water and diluted with diethyl ether 3
Extracted with 00 ml.

While cooling the extract, wash it sequentially with water and saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate and n-
The title compound 2801η having the following physical properties was obtained.

TLC (ethyl acetate:n-hexaney=1:1):R
f=0.24; NMR: δ-5,7 to 5.65 (I
H, rn), 5.65-5.35 (4H.

m), 4.52~A, A 3 ('I H, m), 4
16-4.0 (3H, 77ri, 2,84 (IH,, fd
), 2.15 (3H.

S), 1.88 (3H,,?'l; IR (KBr method) Niji = 5650 ~ 3030.2920
．． 2850.1715.1645.1440.1225
．． 1145.1075.970cm.

Mags: m/g=420 (M), 402.6
84.649.361° Compounds shown in Table 7 were obtained in the same manner as in Example 1.

(103) rlrvi) 1,9.15-) Lith THP body (produced in Reference Example 8).

), 17 m7 of trihydrofuran, and 6.5 rnl of 1N hydrochloric acid were refluxed for 1 hour, then 250 g of cold diethyl ether was added, and while cooling, the mixture was washed successively with water and saturated brine, and with anhydrous magnesium sulfate. After drying, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane),
A standard compound 116I119 having physical property values according to the method was obtained.

TLC (Chloroform: Tetrahydrofuranic acid = 1
0:2:1)”, FIf=0.67; NM
R; δ=7. A8 (IH, dd'%, 6.95 (IH,
d), 6.35 (IH, dd), 6.45-6.15
(2H, m), 5.6-5.25 (2H, m),
3.63 (2H, t), 3.7-3.5 (IH, 771
) ; Engineering R Niji = 3500.2960.2850.1690
．． 1625, (105) 1580.1450.1205.1070.1020.
975 closed-1; Ma, se: m/e=502 (M), 2'51,1
90° In the same manner as in Example 2, the compounds shown in Table 8 were obtained.

(106) Example 3 0 6001 nQ of alcohol (produced in Example 2) dissolved in 10 m7 of dry methylene chloride in an arunone atmosphere
I/C pyridine 0.4817 was added at room temperature, and after cooling to -50°C, 3.21 mJ of acetyl chloride was added dropwise to -6
Stir at 0℃ for 10 minutes, then heat to -30℃ for 10 minutes.
The mixture was heated to -60°C and stirred for 10 minutes. Pour the reaction mixture into 100ml of ice water and add 250ml of diethyl ether.
pt, and the mixture was washed successively with water, a saturated aqueous copper sulfate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane) to obtain the title compound 373■ having the following physical properties.

TLC (ethyl acetate: n-hexyl-1:2): R, f
=o, 57: NMR: J = 7.46 (IH, dd), 6
．． 95C1H, d), 6.35 (109) (IH, dd), 6.45~S, 12 (2H, m)
, 5.58-5.24 (2H, m), 4.04 (2H,
t), 6.66-3.50 (IH, m), 2.0A (
3H, #): Engineering Rniji = 2930.2860.173
5.1690.1630.1575.1450.136
5.1240.1040.975cm-”: Mσ, ?y: m/g-344 (M), 302,27
3. Compounds shown in Table 9 were obtained in the same manner as in Example 3.

(110) Example 4 Methylene tetrachloride 15++t7! alcohol dissolved in [
Produced in Example 2(C). ] Add 2.5 ml of pyridine to 660η under ice-cooling, and then add 0.89 ml of 3-dimethylacryloyl chloride! was added dropwise and stirred at the same temperature for 60 minutes. Ice and 5CJOml of diethyl ether were added to the reaction mixture, which was washed successively with 0.24N hydrochloric acid and saturated brine, dried over anhydrous I'I#magnesium, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane) to obtain the title compound 750■ having the following physical properties.

TLC (ethyl acetate: n-hexyl=1:5): Rf-
0,44: NMR: δ=745 (IH, td,), 6.
9 A (i H, d”), 6.45-6.13 (3
H, m), 5.65 (IH, m), 5.55 (112) to 5.26 (2H, m), 4.05 (2H, t), 6
．． 57 (IH, m), 2.16 (3H,, r), 2.0
8 (3H,,9), 1,00-0.72 (6H.

m): Engineering R Niji = 2930.1712.1692.1633
Me.

Mo, 9S: m/e=412 (M”>.

Compounds shown in Table 10 were obtained in the same manner as in Example 4.

(113) Example 5 (5Z, 14EZ)-11- dissolved in ethanol 5g
Oxoprosta-5,9,12,14-tetraene-1
- All 1jl is mixed well with 5g of microcrystalline cellulose, and after thoroughly drying, magnesium stearate 1001n
Q, silicon dioxide 20mQ, talc 10m9, cellulose calcium gluconate (EC(,) 200mQ'l added,
Furthermore, by adding microcrystalline cellulose, the overall view becomes 1[[+,
After mixing well until homogeneous, tablet by conventional method.
100 tablets containing 10 RQ of active substance in each tablet were obtained.

Example 6 Inclusion compound of α-cyclodextrin and β-cyclodextrin [α-
2.4 g of cyclodextrin and 1 g of β-cyclodextrin were dissolved in 30 M of water, and Kole K (5Z, Li
1EZ)-11--Jl-tub I: Il+-5°9, 1
2t 14-te) Raen-1-, +! --/I/10
After adding omQ'y and stirring thoroughly, the mixture was concentrated under reduced pressure. ] (115) in distilled water for injection with 15-'OdK, filtered aseptically by a conventional method, dispensed into 5mA' ampoules in 1.51rL portions, and freeze-dried to obtain 11RQ of the active substance in each ampoule. 100 solid preparations for injection containing the following ingredients were obtained.

(116)

Claims (1)

[Claims] 1. General formula [wherein [A] is formula (II) (m) (IV)
represents a group represented by, or represents an ethylene group or a cis-vinylene group, and C13-C□4-Cl3 is (it
(A) represents a group represented by the formula (m or a group represented by (m)), (iii) When (A) represents a group represented by the formula (IV), the group represented by the formula where R is (jl) When (A) represents a group represented by formula (IT) or (Iff), (wherein, R3, R4, R5, R6 and R7 are each independent, , hydrogen atom or carbon number 1-4
represents a straight or branched alkyl group. ) represents a group represented by (i) When [A] represents a group represented by formula (mV), represents a linear or branched alkyl group of numbers 1 to 4;
The other symbols have the same meanings as above. ), R1 represents a (branch) bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, R represents a straight chain or branched alkyl group having 1 to 8 carbon atoms, a substituted a cycloalkyl group having 4 to 7 carbon atoms which is unsubstituted or substituted with at least one straight or branched alkyl group having 1 to 8 carbon atoms, or which is unsubstituted or has at least one halogen atom; Represents a phenyl group or phenoxy group substituted with a trifluoromethyl group or a linear or branched alkyl group having 1 to 4 carbon atoms, and in formula (IID and formula (1v)), the double bond between C9''''10 The bond is 2
In formula (V), the double bond between C13-014 represents E, and in formula (vr), the double bonds between C1□-G13 and C14-Cl3 are each independent, and E , Z or a mixture thereof. However, when R represents a single bond, R does not represent a substituted or unsubstituted phenoxy group. ] A low prostaglandin DQ compound or a cyclodextrin inclusion complex thereof. 2. The range of the general formula has the same meaning as described in item 1. ), and other symbols have the same meanings as in claim 1. ] The compound according to claim 1. All symbols have the same meaning as in claim 1. ) The compound according to claim 2, which represents a group represented by: 4. The compound according to claim 6, wherein the compound is 1-0-(3,3-dimethylacryloyl)-PGD2 alcohol. has the same meaning as described in claim 1. ) The compound according to claim 2, which represents a group represented by: 6. The compound according to claim 5, wherein the compound is 1-0-carnomimoyl-PGD2 alcohol. Z compound is 1-0-(dimethylcarbamoyl)-PG
The compound according to claim 5, which is a D2 alcohol. 8. Claims represented by the general formula (wherein R represents the same meaning as described in claim 2, and other symbols represent the same meanings as described in claim 1) A compound according to item 1. All symbols have the same meaning as in claim 1. ) The compound according to claim 8, which represents a group represented by: 10. The compound according to claim 9, wherein the compound is 1-0-(6-dimethylacryloyl)-9-7'oxy-Δ-PGD2 alcohol. The numbers have the same meanings as in claim 1. )
The compound according to claim 8, which represents a group represented by: 12, the compound is 1-0-carbamoyl-9-deoxy-
Claim 11 which is Δ-PGD2 alcohol
Compounds described in Section. 16. General formula ゛b [In the formula, R is a hydrogen atom or the formula. (In the formula, all symbols have the same meanings as described in claim 1.) and other symbols have the same meanings as described in claim 1. ] The compound according to claim 1. □ 14. The compound according to claim 13, wherein Rh represents a hydrogen atom. 15. The compound according to claim 14, wherein the compound is (5Z, 14EZ)-11-oxoprost-5,9,12,14-tetraen-1-ol. 16. The compound according to claim 14, wherein the compound is (14EZ)-1,1-oxoprost-9,12,14-trien-1-ol. 1Z compound is (5Z, 14EZ)-(17S)-11
-oxo-17,20-dimethylprosta-5,9,1
15. The compound according to claim 14, which is 2.14-tetraen-1-ol. 1 day, the compound is (5Z, 14EZ)-11-oxo-1
5-(3-brolcyclo is methyl)-16°17.1
B, 19.20--? Phthanol Prostar-5,9゜12
．． 15. The compound according to claim 14, which is 14-tetraen-1-ol. 19 The compound is (5Z, 14EZ)-11-oxo-1
6-(3-chlorophenoxy)-17,18°19.2
15. The compound according to claim 14, which is 0-tetranorprosta-5,9,12,14-tetraen-1-ol. (In the formula, all symbols have the same meanings as defined in claim 1.) The compound according to claim 13, which represents a group represented by the following formula. 21, the compound is (5Z, 14EZ)-1-0-(
21. The compound according to claim 20, which is 3,3-dimethylacryloyl)-11-oxoprost-5,9,12,14-tetraen-1-ol. 22, the compound is (5Z, 14EZ)-(17S)-
1-0-(3,!1-dimethylacryloyl)-11-
Oxo-17,20-dimethylprosta-5,9,12
21. The compound according to claim 20, which is 14-te)dien-1-ol. □23,
The compound is (5Z, 14Ez)-1-0-(3,3
-dimethylacryloyl)-11-oxo-15-(6
-propylcyclo is methyl) -16,17゜18,19
．． 21. The compound according to claim 20, which is 20-syntanolprosta-5,9,12°14-tetraen-1-ol. 24, the compound is (5Z, 14EZ) -1-0-
(3,3-dimethylacryloyl)-11-oxo-1
6-(6-chlorophenoxy) -17,18,19,
21. The compound according to claim 20, which is 20-tetranorprosta-5,9,12,14-tetraen-1-ol. The symbols have the same meanings as in claim 1. ) The compound according to claim 13, which represents a group represented by: 26, the compound is (5Z, 14EZ) -1-0-force y
vvamoiroux 11-oxoprostard-5,9,12,1
Claim 2 which is 4-tetraen-1-ol
Compound according to item 5. 27. The compound according to claim 16, wherein R represents a group represented by the formula -00R8 (wherein R8 has the same meaning as defined in claim 1). 28, Compound power (5Z, 14EZ) -1-0-
7 cetyl-11-oxoprosta-5,9,12,14
-Tetraen-1-ol Claim 27
Compounds described in Section. 29 The compound is (5Z, 14EZ)-(178)-1-
28. The compound according to claim 27, which is 0-acetyl-11-oxo-17,20-dimethylprosta-5,9,12,14-tetraen-1-ol. 60, the compound is (5Z, 14EZ)-1-0-7cetyl-11-oxo-15-(3-propylcyclo is methyl)-1(S, 17.18.19.20--?phthanolprosta-5 , 9,12,14-tetraen-1-ol.Filter 1. The compound is (5Z, 14EZ)-1-0-7cetyl-11-oxo-16- (3-chlorophenoxy) −
17,18,19,20-tetranorprosta-5,9
, 12,14-tetraen-1-ol. and (wherein R is unsubstituted or substituted with at least one alkyl group) tetrahydrobilane-2
-yl group, tetrahydrofuran-2-yl group, or 1-ethoxyethyl group, R has the same meaning as described in claim 2, and other symbols have the same meaning as described in claim 1. Represents obscurity. ), each of which is characterized by hydrolyzing the OR groups at the 9- and 15-positions of compound I to a hydroxyl group under acidic conditions (in the formulas, all symbols have the same meanings as above). A method for producing a compound represented by 36, general formula [in the formula, R represents the same meaning as described in claim 13, R represents the same meaning as described in claim 32, R or R group (in the formula, R represents the same meaning as described in claim 32), represents the same meaning as described in claim 62) or a group represented by the formula (in the formula, all symbols have the same meaning as described in claim 1), and other symbols are It has the same meaning as stated in claim 1. ] A method for producing a compound represented by the general formula (in which all symbols have the same meanings as above), which comprises refluxing the compound represented by the above in an aqueous acid solution. 34 general formula (in which all symbols have the same meanings as described in claim 1). (represents an atom, and other symbols have the same meanings as in paragraph 1 of the patent claim.) characterized by reacting with an acid halide represented by
A method for producing a compound represented by the general formula () (in the formula, all symbols represent the same sounds as above). 35, a compound represented by the general formula (in the formula, all symbols have the same meanings as in claim 1) ＞, represents the same meaning as described in Section 64 of Tetrasaccharide, and is characterized by being made to react with an acid halide represented by R [*Represents the same meaning as described in Section 1, Box 1 of A method for producing a compound represented by the formula (in which all symbols have the same meanings as described above). 66. General formula [wherein all symbols have the same meanings as described in claim 1] .) An antitumor agent containing a prostaglandin D-like compound or a cyclodextrin clathrate thereof as an active ingredient.