JPS59190963A - Novel prostaglandin d analog compound, its production and antitumor agent containing the same - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [A is formula II, III or IV (the broken line represents alpha-configuaconfiguration; symbol represents beta-configuration; the wavy line represents alpha-, beta-configuration or a mixture thereof; the bond between carbon atoms at the 12- and 13- positions and the bond between carbon atoms at the 14- and 15-positions informula II are respectively trans- or cis-configuration or a mixture thereof; the bond between carbon atoms at the 9- 10-positions in formula II is cis-configuration; the bond between carbon atoms at the 9- and 10-positions and the bond between carbon atoms at the 13- and 14-positions in formula IIIare respectively cis- or trans-configuration or mixture thereof; the bond between carbon atoms at the 13- and 14-positions in formula IV is trans-configuration); X is ethylene, etc.; R<1> is H or 1-4C alkyl; R<2> is 2-6C alkyl substituted by 1-3 OH groups; R<3> is single bond or 1-5C alkylene; R<4> is 1-8C alkyl, etc.] or a cyclodextrin clathrate compound thereof. USE:An antitumor agent having almost no pharmacological action unique to prostaglandin. PREPARATION:A compound expressed by formula V (R<5> is 1-ethoxyethyl, etc.) is hydrolyzed under acidic conditions to give a compound expressed by formula I (A is expressed by formula III) or a compound expressed by formula VI is hydrolyzed under acidic conditions to afford the compound expressed by the formula I (A is expressed by formula IV).

Description

[Detailed description of the invention]

The present invention relates to novel prostaglandin D-like compounds, methods for producing the same, and antitumor agents containing them. Prostaglandins are derivatives of brostanic acid with the following structure. Various types of prostaglandins are known, and the type depends on the structure and substituents of the alicyclic ring. For example, the ring rings of prostaglandin F (PGF), E (PGE), and D (PC,D ) each have the following structures. (PGF) (PCE) (F
GD) A dotted line in the above structural formula, or in any other structural formula herein, follows generally accepted nomenclature rules, and indicates that the group attached to it is on the back side of the ring plane, i.e. α
- configuration, the thick line indicates that the group attached to it is in front of the ring plane, ie, the β-configuration, and the wavy line indicates that the group attached to it has the α- or β-configuration, or a mixture thereof. These compounds are subclassified by the position of the double bond on the side chain at the 8th and 12th positions of the alicyclic ring. PC-
Compound 1 has a trans double bond (trans-Δ) between C and -0□4, and compound PG-2 has a cis double bond between C5 and 06 and a trans double bond (μ) between C13 and C14.
-Δ, trans-Δ). For example, prostaglandin D, (PCDl) and prostaglandin D2 (PGD2) are each represented by the following structural formulas. H and H When one or more methylene groups are further removed from the aliphatic group at position 12 of the ring of the prostaglandin, the compound is classified as a true prostaglandin according to the general rules of organic compound 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, inhibiting platelet aggregation, and inhibiting gastric acid secretion. Therefore, it is effective in treating hypertension, thrombosis, asthma, and gastrointestinal ulcers, inducing labor and abortion in pregnant mammals, preventing arteriosclerosis, and as a diuretic. They are fat-soluble substances that exist in very small amounts in each tissue that secretes prostaglandins into the living body of an animal. We believe that the present inventors have the pharmacological action of "natural" prostaglandins, or that they possess one or more of the properties of their sexual properties, have stronger activity, or that "natural" prostaglandins In order to discover a new compound with properties that have never been seen before, we conducted extensive research and found that the carboxyl groups at positions PC, D1, and PGD201 have the same meaning as a substituted amide group. )] is replaced by a new PGD class i! The hydroxyl group at the 9-position of these compounds is dehydrated, resulting in C0-C,. Compounds with a double bond introduced between them and the hydroxyl group at the 15th position of these compounds are also dehydrated, and the hydroxyl group at the 15th position of these compounds is dehydrated.
4”'15 A new compound with a double bond introduced between
The present invention has been completed by extracting an egg and demonstrating that it has a surprisingly strong anti-bacus effect, although it does not have or has very weak pharmacological properties that natural prostaglandins have. Several applications regarding PGD-like compounds have been filed so far. For example, compounds in which the carboxylic acid moiety at position 1 of PGD and PGD2 are converted include methanesulfonylamide (see JP-A-51-131859), alcohol (JP-A-52-89648). No. 52-89649 and No. 52-89650), amine compound (JP-A-52-83351)
See specification. ) Ketone rest (Unexamined Japanese Patent Publication No. 1983-14
See specification No. 1751. ), etc., but the hydroxyalkylamides of the present invention have a novel action, that is, an antitumor action, which has not been found at all in known PGD derivatives. The above-mentioned published specifications merely describe the pharmacological properties known to common prostaglandins, and there are no applications that focus on antitumor effects. Furthermore, several applications regarding PGD derivatives (9-deoxy-Δ-PCTD derivatives) in which the hydroxyl group at the 9-position is dehydrated have already been filed. For example, among the above-mentioned published specifications, all of the specifications other than JP-A-51-131859 describe 9-deoxy-Δ-PGD derivatives. However, the 9-deoxy-Δ derivatives included in the present invention are not disclosed at all. Furthermore, these compounds of the present invention have anti-inflammatory properties, which is completely different from known 9-deoxy-Δ derivatives. Furthermore, among the compounds included in the compounds of the present invention, 9
The hydroxyl groups at positions 1 and 15 are dehydrated to form C9-C1. Application related to PGD derivatives (9,15-dideoxy-13, 14-dihydro-Δ9, 12, 14-PGD derivatives) in which double bonds are introduced between C1□-C,3 and 014-C15 have never been found so far, and therefore these compounds are novel compounds. That is, the present invention is based on the general formula [wherein the symbol [A1] represents the formula or a mixture thereof, and represents 0□2-C in formula +11 and C
The double bonds between 14 and 015 are each 3 independent ones, and each represents a trans configuration, a 72 configuration, or a mixture thereof, and is C9-C□. The double bond between represents the yx configuration, and 09-C□ in formula (2). The double bonds between 013 and 013-C14 represent the Δμ and trans configurations, respectively, and the C and -C atoms in the formula (2). The double bond between represents a trans configuration. ), where X is an ethylene group or a group represented by - vinylene group, R represents a hydrogen atom or a straight chain or branched alkyl group having 1 to 4 carbon atoms, and R2 represents a straight chain or branched chain having 2 to 6 carbon atoms substituted with 1 to 3 hydroxyl groups; represents a chain alkyl group, R3 represents a single bond or a straight or branched alkylene group having 11 to 5 carbon atoms, and R represents a chain alkyl group having 1 to 8 carbon atoms;
A straight chain or branched chain alkyl group, a cycloalkyl group having 4 to 7 carbon atoms, unsubstituted or substituted with at least one straight chain or branched chain alkyl group having 1 to 8 carbon atoms, cloth or side groove P or represents a phenyl group or phenoxy group substituted with at least one halogen atom, trifluoromethyl group, or linear or branched alkyl group having 1 to 4 carbon atoms. However, when representing a RIJ-paper bond, R does not represent unsubstituted or substituted phenoxy 1. ] The present invention relates to prostaglandin D-like compounds shown in the following, or their cyclodextrin clathrate compounds, methods for producing these compounds, and antitumor agents containing these compounds as active ingredients. In the compound represented by the general formula f■+, yes (some asymmetric carbon atoms are present.For example, in the compound in which [A] represents a group represented by the formula , carbon atoms at positions 8, 9, 12 and 15) are asymmetric centers.Similarly, in the general formula (Il), [
Compounds in which A] is a group of the formula (nl or (ml) also have at least two (i.e., carbon atoms at positions 8 and 15) and one (i.e., carbon atom at position 8) asymmetric centers, respectively. Furthermore, when the alkyl group represented by R1 is a branched chain, other asymmetric carbon atoms may occur. However, the compound represented by the general formula (■+) of the present invention It also includes all isomers caused by carbon and mixtures thereof.In the general formula (Il), the alkyl group having 1 to 4 carbon atoms represented by Examples include isomers, and preferred R is a hydrogen atom, a methyl group, or an ethyl group.In the general formula CI+, the alkyl group having 2 to 6 carbon atoms substituted with 1 to 3 hydroxyl groups represented by R is 9
0xyethyl, dihydroxyethyl, trihython90xyethyl, human90xypropyl, dihython90xypropyl, trihydroxypropyl, hydroxybutyl, dihython90xybutyl, trihython90xybutyl, hydroxyinthyl, dihydroxy is methyl, trihython90xyRthyl, hydroxyhexyl, Dihydroxyhexyl, trihydroxyhexyl groups and isomers thereof are mentioned, and preferred R is 2-human 90xethyl group, 1.
1-bis(human 90oxymethyl)ethyl group (sunawachi,
2-methylpropane-t, 3-diol-2-yl group)
, 1-human 90oxymethylethyl group (ie, propanol-2-yl group). In the general formula (II), examples of the alkylene group having 1 to 5 carbon atoms represented by R include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and isomers thereof, and R is preferably a single bond, methylene or ethylene group. In the general formula (Il), the alkyl group having 1 to 8 carbon atoms represented by R includes methyl, ethyl, propyl, butyl,
Examples include methyl, hexyl, heptyl, octyl groups, and isomers thereof; butyl groups which are preferably unsubstituted or substituted with one or two methyl or ethyl groups are methyl or hexyl groups. It is. In the general formula (Il), the substituted or unsubstituted cycloalkyl group represented by R includes cyclobutyl, cyclo is methyl, cyclohexyl, cycloheptyl, and one or more methyl, ethyl, furoyl, butyl, and methyl. , cyclobutyl substituted with hexyl, heptyl or octyl group, cyclo includes methyl, cyclohexyl, cycloheptyl group, preferably unsubstituted or substituted with one methyl group, ethyl group, propyl group or butyl group In the general formula (Il), substituted or unsubstituted phenyl or phenoxy groups represented by R include phenyl, phenoxy and one or more fluorine atoms, Examples include phenyl or phenoxy groups substituted with chlorine atom, trifluoromethyl group, methyl group, ethyl group, propyl group or butyl group, preferably unsubstituted or with one chlorine atom, trifluoromethyl group , a phenyl group or a phenoxy group substituted with a methyl group or an ethyl group. In the general formula (yl, preferred R-R are butyl, intyl, is methyl, 1.1-:) mef yv -
E'en-F-ru, 1-ethyl is methyl, 2-ethylindyl, hexyl, 1-methylhexyl, 2-methylhexyl, 1-ethylhexyl, 2-ethylhexyl,
heptyl, 2-methylheptyl, 2-ethylheptyl,
Cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, cyclo is methyl, cyclosynthylmethyl, 2-cyclopanthylethyl, 3-ethylcyclotyl, 3 -Propylcyclo is methyl, 3-butylcyclo is methyl, cyclohexyl, cyclohexylmethyl, 2-
Cyclohexylethyl, 4-methylcyclohexyl, 4
-ethylcyclohexyl, 4-7'robylcyclohexyl, 4-, methylcyclohexyl, Chlorophenoxymethyl, 3
-trifluoro, methylphenoxymethyl, 4-11 fluoromethylphenoxymethyl, 4-methylphenoxymethyl, and 4-ethylphenoxymethyl. In the general formula (II), X is preferably a partner of sy, z-vinylene group, or ethylene group. Also, when the symbol [A] in the general formula (II) represents the formula (Tll or (2), The preferred configuration of the hydroxy group is the α-configuration. Compounds included in the present invention may be named as derivatives of PGD. For example, compounds included in the present invention and described in Example 1
A compound represented by the formula (all symbols have the same meanings as above) described in Example 8, a compound represented by the formula (all symbols have the same meanings as above) described in Example 8 The compound is
Named 9-deoxy-Δ-PGD2 ethanolamide, 9,15-dideoxy-13,14-t human rhoΔ9.12.14-PGD2N-ethylethanolamide 1 and PGD N,-ethyl-ethanolamide 9, respectively. be able to. Furthermore, the compound of the present invention is
Prostanamide represented by the following formula
can be systematically named as derivatives of e). In this case, the compounds represented by the above formulas (xh-1), (I (L-1) and (■c-1) are each h (5Z, 9
Z, 13E)-(15α)-N-(2-human 90xyethyl)-15-hydroxy-11-oxoprosta-
5,9,13-) IJ xy 7 Mi, )”, (5
Z, 9Z, 12EZ, 14EZ)-N-ethyl-(2-
(Hibyloxyethyl)-11-oxoprosta-5,9,
12,14-tetraenamide 9 and (5Z, 13
K) -N-xfcyl-N-(2-human90xyethyl)-9,15-uhuman90xy-11-oxopro7ter-5,13-dienamide. The compound of the present invention represented by the general formula (■1) is a compound of the present invention represented by the general formula (■α
), (yA) and (C'), that is, the compound represented by the general formula and (Jl-1 (in each formula, all symbols represent the same yellowish color as above)), These can be produced by the method described below.That is, according to the present invention, general formulas (xh) and (I
The compounds represented by C) each have the general formula (wherein R is 2-
It represents a tetrahydropyranyloxy group, a 2-tetrahydropyranyloxy group, or a 1-ethoxyethyl group, preferably a 2-tet\lahydrobyranyloxy group, and other symbols have the same meanings as above. ) and (wherein, all symbols have the same meanings as above, and the two R's represent the same groups) under acidic conditions. This hydrolysis reaction takes place in (1) an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, p-)luenesulfonic acid or an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid; at room temperature in the presence of a miscible organic solvent, e.g. a lower alkanol such as methanol or ethanol (preferably methanol), or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran (preferably 90 furan). (2) at a temperature of from 10 to 45° C. (preferably the reflux temperature of the solvent) in the presence of an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid in an anhydrous lower alkanol such as methanol or ethanol. It will be held in The hydrolysis is preferably carried out using a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, or p-). It is carried out using a mixture of luenesulfonic acid and anhydrous methanol. The compounds represented by the general formulas (Vl and (V'fi) are respectively represented by the general formula (in which all symbols have the same meanings as above) and the compounds represented by the general formula (in which all symbols have the same meanings as above). Synthesizes the acid halide or acid anhydride of the compound represented by the formula (in which R and R has the same meaning as above) in an inert organic solvent such as methylene chloride, tetrahydrofuran, N,N-u methyl formaldehyde at a temperature of 0°C to 40°C. It is preferably carried out at room temperature using chloroformic acid isobutyl ester or trimethylacetylene chloride in methylene chloride in the presence of a base such as triedylamine. Compounds also have the general formula (wherein,
All symbols have the same meaning as above. ) can be produced by reacting the compound shown in the general formula with the compound shown in the general formula diagram. This reaction is carried out in the same manner as the method for producing the compounds represented by general formulas (V) and (Vl) from the compounds represented by general formulas (■) and (■), respectively, described above. The compounds represented by the general formulas (■), (■) and (X) are
Although it can be produced by the method described in No. 73, it can also be produced by a series of reaction steps shown in Scheme A below. In the formula A, R represents an acyl group such as an acetyl group or a benzoyl group, R represents an alkylsulfonyl group or an arylsulfonyl group such as a mesyl group or a tosyl group, and other symbols have the same meanings as above. 1≦S1 All steps in the formula are carried out by known reactions, but to be clear, for example, step [a] involves selecting the hydroxyl group at the 11th position of the compound represented by the general formula (Xl). This is done by acylation. Such acylates are prepared in the presence of a tertiary amine such as pyridine, triethylamine in an inert organic solvent such as methylene chloride or in a hot solvent at temperatures below room temperature, preferably -
It is carried out using the corresponding acyl chloride or intoxicant, for example benzoyl chloride 9, at a temperature of 30 DEG to -40 DEG C. Step Ch] is a condensing agent, reportedly p-
) In the presence of luenesulfonic acid, sulfuric acid, and trifluoroacetic acid, using 2.3-u human 90-furan, 2,3-cyto 90 furan, ethyl vinyl ether, etc., from room temperature to -30°C
It is carried out at a temperature of It is preferably carried out at room temperature using 2,3-dihyto90pyran in the presence of the p-toluenesulfonate of pyridine or T)-)toluenesulfonic acid in methylene chloride. Step [c] comprises (11-lysine or in the presence of a tertiary amine such as triethylamine, in an inert organic solvent such as methylene chloride, or (fi) in lysine-30
This is carried out by reaction with an alkylsulfonyl chloride such as mesyl chloride 9 or an arylsulfonyl chloride 9 such as tosyl chloride 9 at a temperature of from °C to 50 °C. Step [d] uses a hydroxide of an alkali metal such as lithium, sodium or potassium in a hydrous lower alkanol such as aqueous methanol or aqueous ethanol,
Deacylation at a temperature of 0 to 60°C! It is done more. Step [el] is a reaction in which a hydroxyl group is converted into an oxo group or an OR group is simultaneously removed to form a double bond between C9 and Clo. Such oxidation reactions are well known, for example (α) “Organic Synthetic Chemistry ■Synthesis Line 1” published by Nankodo, edited by Tetsuji Kametani, 176-206-! ! -ji (August 1, 1976)
Or Ih'I John Wiley & 5ons
Published by Inc. 0 (USA) rcompendj, n
m of Orga, n]c 5ynthetiC+J
etbOdSJ Volume 1 (1971), Volume 2 (197
4), No. 3-3 (1977), section 48 or 168. Particularly preferred oxidation under mild neutral conditions is, for example, dimethylsulfi)''-N
-chlorosuccinimide 9 complex, thioanisole-N-
Chlorosuccinimide' complex, -, > methyl sulfibi chlorine complex, thioanisole-chlorine complex [above, J, A
m, Chem, Soc,, 94.7586 (197
2)], dicyclohexylcarbodiimide a ++
:) Methyl sulfoxide complex [J, Am, Chem
, Soc , , ! 37.5661 (1965)fg
pyridinium chlorochroma) (C5H5N
HCrO3CA [:Tetrahedron Le
tters, 2647 (1975)), sulfuric anhydride-pyridine complex [J-Am, Chem-3oc-8
9,5505 (1967)], chromium chloride/I/
CJ, Am-Chem-8oc, ship b5929 (19
75)], chromium trioxide-pyridine complex (e.g. Collins reagent), Jones reagent or chromic acid solution (prepared from chromium trioxide, manganese sulfate, sulfuric acid and water), oxalyl chloride 9 and dimethyl sulfoxide 9 [Swan (
Swern) For #-formed IF4-, Collins oxidation, Jones oxidation or Swan oxidation is preferred. Collins oxidation is carried out in halogenated hydrocarbons such as chloroform, methylene chloride, or carbon tetrachloride at temperatures from room temperature to 0°C. Jones oxidation is usually performed at temperatures below room temperature. Swann oxidation is carried out by reaction in a halogenated hydrocarbon such as chloroform or methylene chloride at -50 DEG to -60 DEG C., followed by treatment with triethylamine. [Step] is a reaction that separates from the OR group and forms a double bond at the same time, using an inert organic solvent such as methylene chloride, chloroform, carbon tetrachloride, diethyl ether, N, N-
Using an aqueous solution of an acid in dimethylformamide, tetrahydrofuran, or a mixed solvent of two or more thereof, such as an aqueous solution of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, or an aqueous solution of an organic acid such as acetic acid, propionic acid, or oxalic acid. It is produced by reacting at the reflux temperature of the solvent. Preferably, this is carried out using 1-dihydrochloric acid in tetrahydrofuran under reflux. The compound represented by the general formula (Xl) is known per se, and is described in the specification of % Application No. 1987-109806.
xxrn). In addition, the compound represented by the general formula (■α) is the compound represented by the general formula (I
b), (Try), (V) f or (vQ) is subjected to the reaction of step [f] in the above-mentioned scheme A, and the hydroxyl group or OR group is removed and a double bond is formed at the same time. The IJ clathrate compound has the general formula (Il), a prostaglandin D-like compound represented by Il.
Alternatively, using γ-cyclodextrin or a mixture thereof, Japanese Pat.
It can be obtained by using the method described in No. 39057. The stability of prostaglandin D-like compounds represented by the general formula (Il) is increased by converting them into cyclodextrin clathrates. Accessory metals do not exhibit all of the pharmacological effects specific to prostaglandins, such as lowering blood pressure, inhibiting platelet aggregation, stimulating uterine muscle contractions, and diarrheal effects, or these effects are very weak. It has been found that these compounds have an alarmingly strong anti-inflammatory effect and no decrease in toxicity (the fact that these compounds have a strong anti-inflammatory effect has been described above). Therefore, prostaglandin D-like compounds represented by the general formula (Il) and their cyclodextrin clathrates are useful for preventing tumors, such as leukemia and solid cancer. It can be used as a very effective and ideal antigenic tumor agent for efficacy, therapeutic effect and survival effect. For example, in laboratory experiments, human robotoma cells (KB
In an in vitro growth inhibition test using Cell. The experimental method and results are shown below. Proliferation inhibition test using human KB cells (Experimental method) KB cal was added to Eagle M original J culture solution containing 10% calf fat serum, and the number of cells in the culture solution was determined. 1×1
The ethanol solution of the compound of the present invention was adjusted to a concentration of 5 μg/ml or lower (3 points).
After growing 1111 cells so that the number of cells was 1,111, the cells were statically cultured at 37° C. for 4 days. As a control, a cell culture medium to which 0.1% ethanol was added was also cultured in the same manner. After culturing, the cells were stained with trypan blue to measure the number of viable cells, and the ■C5o value (50% growth inhibitory concentration) was determined from the inhibition rate relative to the control IZ. The results are shown in Table F. Proliferation inhibitory effect using human cancer cells (KB cel, 1) To use prostaglandin D-like compounds represented by the general formula fIl and their cyclodextrin inclusion compounds as antitumor agents, It is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, condition, therapeutic effect, 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. or 500 μg to 50 to 50 μg per adult
The drug is administered parenterally, preferably intravenously, once to several times a day. Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases it may be sufficient to use less bone than in the above-mentioned dosage range, and in other cases it may still be necessary to exceed the dosage 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, butotose, hydroxypropylcellulose,
Mixed with microcrystalline, 1% cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. 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. Tablets or pills may contain sucrose, seratin, human 90xypropyl cellulose, hypoxyprop2 as necessary.
It may be coated with a film of a gastric or enteric material such as methylcellulose phthalate, or it may be coated with two or more layers. 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, the compositions may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, 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 propyleg glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysolite 80, arabic, sodium alginate, and the like. 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 bicutiliary retention filter, by incorporation with 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 containing one or more active substances and formulated in a manner known per se, topical solutions such as creams, and for rectal administration. General formula (Ia) included in the present invention, including suppositories and pessaries for intravaginal administration, etc.
Among the compounds represented by
・12・+4-PCDI. 9.15-dideoxy-13,14-dihydro-Δ9,
12.14- P G D2. 9.15-dideoxy-13,14-dihyPlow16-
Methyl-Δ9,12・14-PGDI, 9.15
-~Dideoxy-13.14-dihydro-16-methyl-Δ9,12.14-p Gl) 2.9.15-dideoxy-13,14-dihyPlow16°16-dimethyl-Δ9・12,14 P G Dl ,9.15-dideoxy-13,14-dihydro16゜16-dimethyl-Δ9,12.14-p G D2.9.15-dideoxy-13,14-dihydro-17゜20-dimethyl-
Δ9·12.14- p GDi. (49) 9.15-dideoxy-13,14-, fuhydro 17
゜20-Dimethyl-Δ9・12・14- p G D
2. 9.15-,)deoxy-II3,14-,)hydro-15-(1-butylcyclobutyl)-16,17,
18,19゜20-pentanol Δ9,12.14-
pGr)1. 9.15-dideoxy-13,14-)hydro-15-
(1-butylcyclobutyl)-16,17,1B,19
゜20-pentanol Δ9・12↑14- p G D
2.9.15-dideoxy-43, ] 4-dihydro-15-cyclopentyl-16,17,18,19,2
0-pentanol Δ9・12.14- P G D 1
．． 9.15-,)deoxy-13,14-dihydro-1
5-cyclopentyl-16.17.18,19,2(+
-PentanoruΔ9・12・+4−PGD2.9.15
-,)deoxy-13,14-dihydro-15-(3-
Propylcyclohytyl)-16,17,18゜19.
20-pentanol Δ9112・14- P GD,
, 9,15-dideoxy-13,14-dihydro-15
(3-propylcyclopentyl)-16,17,18゜19.20-/tanol Δ9・12・14-p Q
D2, (50) 9.1.5--,'deoxy-13.14-dihyro-15-(3-butylcyclopentyl)-16,17,1
8,19,20--Pentanol Δ9,12・14-
PGDI. 9.15-dideoxy-13,14-,hydro-15
-(3-butylcyclopentyl-16,17,18,
19゜20-pentanol-Δ9・12・14-pGD2
．． 9.15-)deoxy-13,14-dihydro-15
(4-butylcyclobuty/l/)-16, 17, 1B
, 19. 20-pentanol Δ9! 12 drops 14. -pGD! 9.
15--, Jibu-Ki-Kishi 13.14-Jihi Plow 15
-(4-butylcyclobutyl) -16, 17, 18,
19. 20-pentanol Δ9・12.14- P G D2
．． 9.15-dideoxy-13,14-dihydro 16
-Phenyl-1,7,1B, 19.20-tetratrue Δ9,12.14-PG DI, 9.15-dideoxy-13,1,4-dihyro 1
6-phenyl 17.18,19.20-tetratuno r
Δ9. l2j4- P G D2. 9.15-dideoxy-13,14-7hydro-16-
Funinoxy 1.7.1119.20-Tetra True (
51) Δ9.12. +4- p G DI, 9,15-dideoxy-13,14-dihydro-16-
Funinoxy 17.18, 19.20-detranol Δ
9,12. lpm PGD2. 9.15-:,'deo-13.14-dihydro-1
6-(3-chlorophenoxy)-17,18,19,2
0-Tetra True Δ9.12.14- P G J, 9
, 15 ・dideoxy-13,14-dihydro-1
6-(3-chlorophenoxy)-17,18,19,2
0-tetranol Δ9・12・14. -PG D2.
9.15--deoxy-13,14-dihyro-16-
(3-trifluromethylphenoxy)-17,18,
19゜20-Tetra True Δ9 + + 2 + '
4-PGDt, 9.15-deoxy-13,14
-DihyPlow 16-(3-trifluoromethylphenoxy)-17,18,19゜20-TetratrueΔ9・1
2.”-PGD2, the corresponding ethanolamide, N-
Ethylethanolamide, N-methylethanolamide
, 2-methylzolonoξ-1,3-diol-2-amiP1 propanol-2-amiF, and the general formula (5
2) (Ib) Among the compounds shown, preferred are, for example, 9-deoxy-Δ9-PGD1. 9-deoxy-Δ9-PGD2. 9-deoxy-16-methyl-Δ9-PGD1.9-deoxy-16-methyl-9-PGD2.9-deoxy-
46,16-dimethyl-Δ9-PGD, 9-deoxy-16,16-dimethyl-Δ9-PGD2.9-deoxy-17,20-,dimethyl-Δ'-PGD1.9-deoxy-17,20-dimethyl-Δ9 -PGD2.9-
Deoxy-15-(1-butylcyclobutyl)-16°17.18,19.20-pe/tanol Δ9-PGD,
, 9-deoxy-15-(1-butylcyclobutyl)-
16゜17.18.19.20-pentanol Δ9-P
GD2.9-deoxy-15-cyclopentyl-16,
17,18゜19.20--Penku True Δ9-PGD
1,9-deoxy-15-cyclopentyl-16,17
,18゜19.20-pentanol Δ9-PGD2.9
-deoxy-15-(3-propylcyclointyl)-
16,17,18,19,20-pentanol Δ9-P
GD,, (58) 9-deoxy-15-(3-propylcyclopentyl)
-16,1,7,18,19,20-pentanol Δ9
-PGD2.9-deoxy-15-(3-butylcyclopentyl)-16,17,18,19,20-pentanol-Δ9-PGD1.9-deoxy-15-(3-butylcyclopentyl)-16°17.18 ,19°20-
Pentanol-Δ9- P G D2.9-deoxy-1
5-(4-butylcyclobutyl)-16°17.18,
19.20-Pentanol-Δ9”-P CDI, 9-deoxy-15-(4-butylcyclobutyl) 16゜1
7.18,19.20-pentanolΔ PGD2.
9-deoxy-16-phenyl-17,18,19,2
0-tetratrue Δ9-PGD, 9-deoxy-16-phenyl-17,18,19,2
0-Tetra True Δ9-PGD2. 9-deoxy-16-funinoxy 17, 18, 1
9.2'0-tetratrue Δ9-PGD2. 9-deoxy-16 to phenoxy-17, 18, 19,
20 Tetra True Δ9-PGD2. 9-deoxy-16-(3-chlorophenoxy)-17
. 18.19.20-tetratrue Δ9-PGD, (5
4) 9-deoxy-16-(3-chlorophenoxy)-17
゜18.19.20-Tetra True Δ9-PGD2.9
-deoxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetratrue Δ9-P
GD, 9-deoxy-16-(3-trifluoromethylphenoxy)-17,18,1920-tetratrue 3 examples-PGD2, corresponding ethanolamide, N-ethylethanolamide, N-methylethanolamide,
2-methylprono-1,3-diol-2-amyl
, pro, e-nol-2-amiP, and has the general formula (I
Among the compounds represented by c), preferred are:
For example, P G Dl, PGD2. 16-Methi, Ru PGD11. 16-methyl-PGD2. 16.16-Simethyl-PGD1. 16.16-Simethyl-PGD2. 17.20-dimethyl-PGDl, 17.20-cumethyl-PGD2, (55) 15-(1-butylcyclobutyl)-16,17,1
8. 19.20-pentanolup G D 1.15-(1
-butylcyclobutyl)-16,17,18゜19.2
0-pentanol-PGD2. 15-cyclopentyl-1,6,17,18,19,2
0- Beta True PGD1. 15-cyclopentyl-16,17,18,19,20
-Pentanolu PGD2. 15-(3-propylcyclopentyl)-16,17,
18°19.20-Pentanolu P G Dl. 15-(3-propylcyclopentyl)-1-6,17
, 18°19.20-pentanol-PGD2. 15-(3-butylcyclopentyl)-16,17,1
8゜19.20-pentanol-PGD, 15-(3-butylcyclopentyl)-16,17,1
8°19.20-pentanol-PGD2. 15-(4-butylcyclobutyl)-16,17,1,
8°19.20-pentanol-PGD1. 15-(4-butylcyclobutyl)-16,17,18
゜19.20-pentanol-PGD2, (56) 16-phenyl-17,1,8,19,20-tetratrue PGD, 16-phenyl-17,1,8,19,20-tetratrue PGD2. 16-Funinoxy17.18,19.20-Tetratrue PGD1. 16-Funinoxy17.18,19.20-Tetratrue PGD2. 16-(3-chlorophenoxy)-17, 18, 19,
20-Tetra True PGD1. 16-(3-chlorophenoxy)-17,18,19,
20-Tetra True PGD2. 16-(3-)lifluoromethylphenoxy)-17,
18°19.20-Tetra True PGD1. 16-(3-trifluoromethylphenoxy)-17,
18°19.20-tetratrue-PGD2, corresponding ethanolamine P, N-ethylethanolamide, N-methylethanolamide, 2-methylprono-1,3-diol-2-amide)4. Furopanol-2-amiP is mentioned. (57')-1 The present invention will be explained in detail below using reference examples and examples.
The present invention is not limited to these examples. In addition, rmpJ, "TLC", "■" in Reference Examples and Examples
R'', [NMRJ and l'-MasJ (1) No. F (5
7)-Possibility refers to "melting point", "thin layer chromatography", "
"infrared absorption spectrum", "nuclear magnetic resonance spectrum", and "mass spectrometry", and the proportion of solvent described in the section of separation by chromatography indicates the volume ratio,
"The solvent in parentheses in TLcj indicates the developing solvent, and [RJ
is measured by the liquid film method unless otherwise specified.
is deuterated chloroform (CDCI3) unless otherwise specified.
3) Measurement is performed using a solution. Reference example 1 (5Z, 13F)-(9α, llα, 15α)-11-
indiyloxy-9-methanesulfonyloxy-15
-(2-tetrahydropyranyloxy)prostar-5,
13-Dienoic acid methyl ester (5Z, 13E)-(9α, llα, 15α)-9 dissolved in 50 mA' of dry methylene chloride under argon atmosphere.
-Human90x-1s--:Nzoyloxy-15-(
2-tetrahydropyranyloxy)prostar-5,13
1.12 ml of triethylamine and 1.12 ml of triethylamine and mesylchloride)-'0 .5 Ll+/ was added at -20'C and stirred at the same temperature for 15 minutes. The reaction mixture was poured into 150ml of ice water, extracted with diethyl nephroside, the extract was washed successively with water and saturated brine, dried and concentrated under reduced pressure to obtain the title compound 3.239 having the following physical properties. was obtained as a crude product. TLC (rL-hexane:ethyl acetate=2:1)
:Rf=o, 51; NMR: δ-8,1~7.7 (2
H, rn), 7.6~7°] (3H, m), 5.7~
4.9 (6)1. m), 3.7(3H,,p),
3.0 (3H,,?). Reference Example 2 11-inzoyl compound (produced in Reference Example 1) dissolved in 133 ml of methanol 3.23. ! A suspension consisting of ilK, 12.69 μl of lithium hydroxide monohydrate, and 19 mu of water was added at 5°C, and the mixture was heated at the same temperature for 2 hours, and then at ambient temperature for 5 hours.
I stirred the time. Pour the reaction mixture into 300 g of ice water,
The pH was adjusted to 3 by adding 1N sodium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated edible water, and after drying, the residual pressure was reduced to f5.
Shrunk. The residue was purified by silica gel column chromatography (
A mixture of n-hexane and ethyl acetate, then ethyl acetate) was used to purify the title compound 2,01 having the following physical properties.
I got g. TLC (chloroform:THF:acetic acid=30:6:])
:Rf-0,44; NMR: δ=6.4-5.6 (2H,m), 5.
7-5.2 (4H, m), 5.15-4.9 (I
H,m), 4.8-4.6 (IH,m), 4
．． 3-3.1 (4H, rn), 3.0 (3H,,?
);■R Niji=3650~2400.2930.28
60.1720.1340.1170.970-. Jones reagent 4 was added to 1.24 g of the q-mesyl compound (produced in Reference Example 2) dissolved in 1211 L of acetone.
5 m/ml was added dropwise at -30°C and stirred at -20°C for 20 minutes. Dilute the reaction solution with diethyl ether, wash successively with water and saturated saline, and dry under reduced pressure of 1"!'!
i' (1~.) Separate the residue by gel column chromatography (mixture of ethyl acetate and hexane).
jlj l, the title compound F+1 having the following physical properties
0m47 was obtained. TLC (titylacetate: 1-hexane = 2:1): Rf, 27; NMR: δ = 764-7.52 (IH, 771), 6.
22~6.10 (18゜), 5.7~5.2 (4H
,m), 4.8~4.6 (IH.m), to~0.8 (3H,rn);
=1715.1590.1020 mer. Reference example 4 Same as reference example 1.2 and 3.

[, respectively.
Reference examples 2(h) and 2(C
), 2(C) and 2Cα), the following compounds having the following physical properties were obtained. (tzl (5Z, 9Z, 13E) - (15α,
17(Y)-17,20-dimethyl-11-oxo-1
5-(2-tetrahydro-90pyranyloxy)froster5. 9. 13-trienoic acid TLC (ethyl acetate: rL-hexane-2:1): Rf
-0,31; ■R Niji2940.1710.1590Crn-';
NMR: δ-7.63 to 7.52 (IH,m),
6.21-6.10 (I H. m), 5.7-5.2 (4H, m), 4.8-4.6
(IH.m), 1.0-0.8 (6H,yx). (hl (5Z, 9Z, 13E)-(15α)-16
,18-nitano-20-methyl-11-okita-15-
(2-tetrahyto90pyranyloxy)prostar-5,
9,13-trienoic acid TLC (ethyl acetate:n-hexane-2:1):Rf-
0,30' NMR: δ-7,64~7.53 (I H,m),
6.23-6.10 (1) Lm), 5.73-5.2
0 (4H, m), 4.8-4.6 (IH, m), 1
．． 0-0.8 (3H, m). FC+ (5Z, 9Z, 13E)-(15α)-16
-(3-chlorophenoxy)-11-oxo-15-(
2-tetrahydro-2ranyloxy)-17,18,19
,20-tetranorprosta-5,9,13-)lienoic acid TLC (ethyl acetate:TL-hexay-z:x):F
t, f = 0.27; Engineering R Niji = 1715, ]610.159 oCWL-”
NMR: δ-8,1~7.8(2I(,m),7.6~
6.7 (5H, m), 6.2-6.1 (IH,
m), 5.7-5.2 (4H, m). (di (9Z, 13E)-(15α)-11-4K:/-15-(2-tetrahuman 90 pyranyloxy)brostanoic acid TLC (ethyl acetate:?L-hexionone-2
:1:J. = 0.29' NJ-2940, 1735, 1715, 1590 儂-1゛t Summer MR: δ = 7.62 ~ 7.50 (I H,
m), 6.20-6.10 (IH. 711), 5.7-5.4 (2H, m), 4.8-
4.6 (I H. m), 1. Q~0.8 (3H,m). Reference Example 5 Dissolved in 15ml of methylene chloride under nitrogen atmosphere (5Z
, 13E)-(9ff, llα, 15ff)-9-hyP
Roxy 11- is anzoyloxy-15-(2-trahydryloxy-90-pyranyloxy)prostar-5°13-:)enoic acid (produced by the method described in Reference Example 2 of Japanese Patent Application No. 109806/1983). 2.3- to .77g :)
HiP Ro 2 Run 11I! 7 was added dropwise at room temperature, and then a catalytic amount of p-)toluenesulfonic acid was added and the mixture was stirred for 15 minutes. After that, 0.1 portion of triethylamine was added and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent,
The mixture was purified using a mixture of n-hexane and ethyl acetate) to obtain 3.95 g of the title compound having the following physical properties. TLC (n-hexane:ethyl acetate-2:1): Rf=
0.45; NMR: δ-8,1-7.9 (2H,m), 7.6
~7.3 (3H, m), 5.7~5.3 (4H,
m), 5.3-5.0 (IH,m), 4.7-4
．． 4 < 2 H, m), 3.7 (3 H, z),
0.8(3)(,t); ■Rniji=2940,1735.1720,1450,
1270°1110.1020 sieve. Reference Example 6 (5Z, 13E)-(dissolved in 4.8 ml of methanol)
9α, 11α, 15rv)-9,15-bis(2-trahydryloxypyranyloxy)-11-j-enzoyloxyprosta-5,J3-diene methyl ester (produced in Reference Example 5) 5(lotψ 2 hydroxyl oxidation power 1
) After adding 6 ml of rum aqueous solution and stirring at 50°C for 1.5 hours, it was cooled to 5°C, and 1N filler acid was added to adjust the pH to 2.
Adjusted to. Ice water], OOd was added to the reaction mixture and extracted with ethyl acetate, and the extract was washed with water and saturated brine in sequence, dried over magnesium acetate anhydride, and condensed under reduced pressure to obtain a title having the following physical properties. Compound 483■ was obtained as a crude product. The obtained product was subjected to the next reaction without being purified. TLC (inzene:ethyl acetate-2:1): R
f-0,07゜Reference Example 7 7) Dissolved in 10 ml of (5Z, 13E)-
(9α. 11α, 15α)-9,15-bis(2-trahydrobilanyloxy')-11-human 90xyprosta-5
, 13-dienoic acid (produced in Reference Example 6) 1. Q4
Cool to -30°C and add Jones reagent (trioxide).
3787%', concentrated sulfuric acid Q, 331 ml and water 1.41
Manufactured from m1. ) was added dropwise and stirred for 30 minutes at the same temperature, followed by 1 ml of isopropyl alcohol, followed by 1 ml of water.
00- was added. The reaction mixture was diluted with 50 d of diethyl ether.
Extraction was carried out three times (total of 150 ml), and the extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent, cyclohexane:ethyl acetate-2:1).
The title compound 652■ having the following physical properties was obtained. TLC (-benzene:ethyl acetate = 1:2)
: Rf-0,7:. NMR: δ = 10.1 (IH,, r), 5.7-5.2
(4H,m), 4.8-4,5 (2H,m),
10~O-7 (3H, m); 飄 ss: m/e-43
6,418° Reference Example 8 PGD2 (In the specification of Japanese Patent Publication No. 54-32773, Example 1 [B] Made in I-1 by Kanmatsu's method.) 11■
After refluxing a mixture of 1 liter of hydrochloric acid 0.28 TrLl and 0.28 m of tetrahydrofuran for 20 minutes, 501+L of diethyl ether was added, and the mixture was washed with saturated brine.
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane:ethyl acetate÷2=1) to obtain the title compound 3Tv having the following physical properties. TLC (chloroform:tetrahydrofuran:acetic acid=3
0:6:1): Rf=0.62″. NMR: δ-7,47 (IH, dcL), 6.96 (I
H, d), 6.46-6.15 (3H, m), 5.55
~5.28 (2H. m), 3.65 ~ 3.52 (IH, m), 0.90 (3
H,t)'. Engineering Rniji -3600~2400,2920.1725
．． 1700.1.625Cr++. Mass: y++/gm316゜Reference Bay'' - (5Z, 9Z, 13E) - (
15α)-15-(2-tetrahuman #0 pyranyloxy)-11-oxoprosta-5,9,13-)dienoic acid (produced in Reference Example 3) 200 m! 7 to methylene chloride 10m/! Triethylamine Q, l in solution dissolved in
ml and then 8 ml of chloroformic acid isobutyl ester.
After dropping 0 μl, it was stirred for 15 minutes. 40 μl of ethanolamine was added to this solution, stirred for 15 minutes, diluted with methylene chloride, washed with an aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: a mixture of ethyl acetate and 1-hexane) to obtain the title compound 175 having the following physical properties. Income *79
%. TLC (chloroform:tetrahydrofuran:acetic acid-1
0:2:1): Rf = 0.36; Engineering Rniji = 3320.1705.1650.1540
．． 1240, 1075.1020.980. 〒-1゛ NMR: δ-7,6rIH,・1d), 6.16(11
(, dd), 5.2-5.8 (4T-T, m),
4.6-4.8 (1,H,Tn), 3.0-4.2
(7H, m), 7. ,．． 73-3.0 (I H, r
n ), 2, FT -2,73(I T(, J, 0.7
-1.0 (3H, m, ). Reference Example 10 (5Z, 9Z, 13E)-( at room temperature under argon atmosphere
15α)-15-(2-tetrahydroranyloxy)-11-oxoprost-5+ 9+ 13-) lienoic acid (produced in Reference Example 3) 2501.4 was dissolved in methylene chloride Ion/ and triethylamine was added to the solution. ]2
511/! After adding 100 μl of chloroformic acid isobutyl ester dropwise, the mixture was stirred for 15 minutes. Add 2-amino-2-methylpropane-1,3 to this solution.
-Diol 95#'lo was incubated at the same temperature for 2 hours. Dilute the solution with methylene chloride and add hydrogen carbonate)
The mixture was washed with an aqueous solution of IJ and brine, dried over anhydrous sodium chloride and magnesium, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: a mixture of ethyl acetate and luhexane) to obtain 1.90 m9 of the title compound having the following physical properties. Yield 63%. TLC (Chloroform ditrahydrofuran: he=1
0:2:1):Rf-1IO134゛nTR Niji =3350.1705.1645.1540
．． 1450.1240.980cm, -'. NMR: δ = 7.57 (IH, dd), 6.1-6.2
(IH,m), 5.9-6.1 (IH,m), 5
．． 3-5.87 (4H, m), 4.6-=4.75
(IH,m), 3.4-4.2 (7H,m)
, 2.75-2.93 (IH, 771), 2.6-2.
72 (IH,m)1-22 (3H,s), 0
．． 8~1.0 (3H-”) '>Mass: m/g
= 505 (M), 487.474.456.42
1403.372.321゜Reference Example 11 1 Lienamide 7 L:=+' 7 At room temperature under atmosphere (5Z, 9Z,
13E)-(]5α)-15-(2-child trahito90pyranyloxy)-11-oxoprosta-5,9,13
- To a solution of 250 ml of trienoic acid (stuffed in Reference Example 3) dissolved in LO ml of methylene chloride, 7 ml of triethylamine was added.
125 μl was added thereto, and then 0.14 ml of chlorogye-1 maitus butyl ester was added, followed by stirring at the same temperature for 15 minutes. 88 μl of N-ethylethanolamine was added to this solution, and after stirring for 15 minutes, it was diluted with methylene chloride, washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: a mixture of ethyl acetate and luhexane) to obtain the title compound 249~ having the following physical properties. Yield 85%. TLC (chloroform:tetrahydrofuran:acetic acid-
10:2:1): Rf÷0.47' ■Rniji = 3420, 1705.1620.1440
．． 1015.975 ('s''''1゛NMR: δ=7.53-7.66 (I H,m),
6.09-6.22 (IH.m), 5.3-5.7 (4H,m), 4.6-4.
76 (12m), 3.96~4.15 (1,H,m
), 3.58-3.96 (4H, m), 3.28-3
．． 58 (5H, m), 2.75-2.92 (IH, m)
, 2.6-2.7 (I H,m), 1.19 (3H
, t), 0.8-1.0 (3H, m); Mass:
m7g-489 (M), 471.459.405.
388.387.305° Reference Example 2 The title compound having the following physical properties was obtained by the same operation as in Reference Example 9. Starting materials: (5Z, 9Z, 13E)-(15ff, 1
7α)-15-(2-tetrahyto902ranyloxy)
-11-oxo-17,20-dimethylprosta-5,
9,13-)rienoic acid (Reference Example 4 (produced by α1)
223■. Yield: 220 ■ TLC (Chloroform diatotracht 90 furan: acetic acid;
10:2:1): Rf=0.48' F■R Nizzy 3430.1705.1.622/! +17
-”. NMR: δ-7,56 (IH, m), 6.14 (IH
, m), 5.7-5.3 (4H, m), 4.68 (IH
, 771), 1.0-0.8 (6H. m); Mass: m7g-517 (M), 499° Reference Example 13 By the same operation as in Reference Example 9, the title compound having the following physical property values was obtained. 1 piece. Out R, substance: (5Z, 9Z, 13E)-(15α)-1
5-(2-tetrahuman90pyranyloxy)-20-methyl-11-oxo-16,18-ethanoprosta-5
,9,13-)dienoic acid (produced in Reference Example 4(b)) 202■ Yield: 191~ TLC (Chloroform: Tetrahydrofuran: Acetic acid;
10:2:1):R,f-0,50:. Engineering R Niji-3430, 1706, 1620; NMFt
: δ-7,57 (IH, m), 6.13 (IH, m),
5.7~s, 3 (4H, m), 4.67 (lH, m),
1.0-0.8 (3H, m):. Mass:yyl/g-529CM), 51]. Reference Example 14 By the same operation as Reference Example 9, the following physical property values were obtained. The title compound was obtained. LM-derived Th: (5Z, 9Z, 13K) - (15α)
-16-(3-chlorophenoxy)-11-oxo-1
5-(2-tetrahyto90pyranyloxy)-17,1
8,19,20-tetranorprosta-5,9,13-
) Dienic acid (produced in Reference Example 4(C)) 189■
~ Yield: 162■. TLC (chloroform:tetrahydrofuran:acetic acid =
1o:2:1):nf=o, 46; ■R Niji 3420.1705.1620, ], 60
0ryn-”F NMR: δ-7,62 (1i-T, d, d),
7.30-6.70 (4)1. m), 6.2
0(IH, dd), 5.78-5.3. (1(4H, m
), 4.68 (]H, mV. Mass: m/s = 559 (M ), 543.541
Reference Example 5 The title compound having the following physical properties was obtained by the same operation as in Reference Example 9. ItlQ product W: (9Z, 13K)-(15α)-15-
(2-trahydrobilanyloxy)-11-oxoprosta-9,13-dienoic acid (Reference Example 4 (manufactured by dl) 163 ■. Yield: 1604 TLC (chloroform:tetrahydrofuran:acetic acid≠)
0:2:1):Rf=0.48; Engineering Rniji -3420,1705,1602 NMR: δ-7,56 (IH, rlL), 6.13 (I
H, 7F, 5.7-5-3 (2H, m), 4.68
< IH, 771); Mass: m/g! 491 (M
), 4736 Reference Example 16 The title compound having the following physical properties was obtained by the same operation as in Reference Example 9. Starting material: (5z, 13E)-9,15-bis(2-tetrahydropyranyloxy)-11-oxoprosta-
5,13-dienoic acid (produced in Reference Example 7) 103
■. Yield: 90 ■ TLC (Chloroform: Tetrahydrofuran: Vinegar e
-10:2:r): Rf-0,43; ■R Niji = 3430.2930.1740.1645 minus -1°F NMR: δ-5,8~5.3 (4H,m), 4.8
~4.6 (2H, m), to ~0.8 (3H,
m) Example 1 (5Z, 9Z, 13E)-(11)-N-(2-hi)"
. PGD 2 amino) #183■ produced in Reference Example 9 was dissolved in 0.5 ml of tetrahydrofuran 90 furan, and 6
5 ml of 5% acetic acid was added and stirred at 80°C for 7 minutes. After cooling, the solution was diluted with ethyl acetate, diluted with hydrogen carbonate, washed with an aqueous solution of IJ and saturated saline,
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: a mixture of ethyl acetate and methanol) to obtain the title compound 108■ having the following physical properties. Yield 72%. TLC (chloroform; tetrahydrofuran: acetic acid; x
o:z:1):Rf-o, ]6; ■R Niji: 3320, ]700.1640.1240
．． 1050.975 (ML-"λ NMR: δ-7,590 (IH, dd), 6.18
(IH, dd), 5.3-5.8 (4H, m), 4
．． 0 to 4.2 (I H, m ), 3.70 (2 H, t
), 3.41 (2H, t), 2.8~z, 9s (xKm
), 2.6-2.75 (I H, ta ), o, sm
1.0 (3H, m+); Ma, ss: m/s5-377(), 359.288.
277.170゜Example 2 65% acetic acid (5m/ml) was added to a solution of PGD2A9TO''182'' produced in Reference Example 10 dissolved in 90% tetrahydrofuran and 0.5%, and the mixture was stirred at 80°C for 8 minutes. After cooling, the solution was diluted with ethyl acetate, washed with hydrogen carbonate, washed with 1 rum aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (eluent). Solvent: +q mixture of ethyl acetate and methanol) to obtain the title compound 74■ having the following physical properties. Yield: 49%. TLC (chloroform:tetrahydrofuran:acetic acid = 1
0:2:1): Rf haze 0.10'. Engineering Rniji -3350, 1700, 1640, 1540
, J450.1245.1040.97 sm” ”
'NMR: δ-7,59 (IH, dd, ), 6.16 (
IH, dd), 5.3-5.68 (4H, m), 4.0
~4.2 (IH,m), 352~3.76 (4
H,m), 2.8-2.92 (IH,m), 2
．． 61-2.7 (1 (I H, m), 1.22 (3H,
j), 0.8~IO (3H, m): Mass: m7g-421 (M), 4-03.39
0.372.354.321゜Example 3 PCr D2 ami)'230■ produced by male in Reference Example 11
65 in a solution of 0.5ml 1K of tetrahydrofuran.
% acetic acid was added, and the mixture was reacted at 80° C. for 8 minutes. After cooling, the solution was diluted with ethyl acetate, washed with an aqueous solution of hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: a mixture of ethyl acetate and methanol) to obtain the title compound No. 133 having the following physical properties. Convergence 70% 0 TLC (Chloroform: Tetrahuman 907 runs: Acetic acid =
10:2:1):Rf-0,33'. Engineering R Niji -3410, 1705, 1620, 1455
, 1240, 1050, 965 foil I NMR: δ-7,59 (IH, dd, ), 6.14 (I
H, tl), 5.28-5.80 (4H, tn'), 4
．． 0-4.2 (IH,m), 3.64-3-85
(2H, m), 3.27-3.56 (4H. m), 2.8-2.95 (I H, 771), 2.6
~2.73 (I H. m), 1.18 (3H,t), 0.8~1.0 (3H
,m)-. Mass: m/s5-405(), 387.334.3
16,050 Example 4 By the same operation as in Example 3, the title compound having the following physical properties was obtained. Starting material: Reference example] PGD2 amide produced in 2. 217 ■. Yield: 12omg. TLC (chloroform: trihydrofuran: acetic acid =
10:2:1'):Rf-0,34 Craftsman R-3410,1706,1622;NMR:
δ=7.60 (IH, d, d), 6.15 (IH, dd
), 5.80-5.26 (4H, m), 1.0-0
．． 8 (6H. 1):) Mass: m/s 5-433 (), 415° Example 5 The title compound having the following physical property values was obtained by the same operation as in Example 3. Starting material: PGD2 amide 184 produced in Reference Example 13
1R9° Yield: 110rRg. TLC (chloroform:tetrahydrofuran:acetic acid=
]0:2:]):Rf=0.35; Engineering Rniji=3410.1706.1620cx-”) NMR:δ=7.59 (IH, dd), 6.14 (1
Toki d, d), 5.82-5.28r4H, m), 1.0
~0.8 (3H, m):)Mass:mz”=44
5(M), 427° Example 6 The title compound having the following physical properties was obtained by the same operation as in Example 3. Starting material: PGD2 amide 151 produced in Reference Example 14
■ Yield: 286 ■ TLCT chloroformem: Tetrahydrofuran: 90 Furan: Acetic acid ÷
10:2:1): Rf 0,30″. IR Nijitomi 3410, 1705.1620.1600 (
7) -1' NMR: (5=7.62 (IH, dd), 7.30-6
．． 70 (4H, m), 6.20 (IH, dd), 5.
80-5.30 (4H, m)'? Ma, ss: m/$=475 (M ), 459.45
7゜Example 7 The same operation as in Example 3 ((by which the title compound having the following physical properties was obtained. Starting material: PCD 1 amide 15 produced in Reference Example 15)
51nq. Bone collection: 95■. TLC (chloroform:tetrahydrofuran:acetic acid =
]0:2:]): Rf=0.35;
H, dd), 5.70-5.3 (') (2H, m
) 'U Mas, g: m/ g-4 ('17 (M),
389° Example 8 A bay head compound having the following physical properties was obtained by the same operation as in Example 3. Starting material: PGD2 amide 82■ obtained in Biographical Example 16. IIv amount: 63 mq. ■R Nigi 3400.2925.1735.1620
cm''1-La NMR: δ=5.75-5.30 (4H, m'), 4.
52-4.42 (] IH?7+), 1.0-0.8
(3H,m). Example 9 (5Z, 9Z, 12EZ, 14EZ)-11-oxoprosta-5,9,12,14-traenoic acid (Reference Example 8
Manufactured by. ) 316 ~ in 15 ml of methylene chloride, 0.2 ml of triethylamine was added, and after stirring for 15 minutes, 0.2 ml of N-ethylethanolamine was added.
16ml was added and stirred for an additional 15 minutes. This solution was diluted with 150 ml of methylene chloride, washed with an aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under pressure. :Ethyl acetate:r
L-hephosa 7-1=2) to obtain 290 mg of the title compound 'VIA having the physical properties of lower=p. TLC (chloroform:tetrahydrofuran:acetic acid≠1
0:2:]):Rf=052; Engineering Rniji=3430.2930.1695,] 630
rs-1'F NMR: δ=7.55-7.44 (IH, m), 6.9
5 (IH, d), 6.5-6.2 (3H, m), 1
．． 0-0.8 (3H, m)゛) Mass: m7g-387 (M). Example 10 9-deoxy-Δ-PG dissolved in 5 ml of ethanol
D2 ethanolamide” (produced in Example 1) 1 g
Mix well with 5 g of microcrystalline cellulose and dry thoroughly.
After this, 100 μg of magnesium stearate, 20 μg of silicon dioxide, 10 μg of talc, and 200 mg of cellulose calcium gluconate (ECG) were added, and then microcrystalline cellulose was added to bring the total amount to 10 g, and the mixture was thoroughly mixed until homogeneous. 100 tablets containing 10 mg of active substance in each tablet were obtained by punching in the usual manner. Example 11 9-deoxy-Δ-PGD2 ethanolamide 1 (
Created in Example 1. ) of α-cyclodextrin and β
- Cyclodextrin inclusion compound [α-cyclodextrin 2.4. Dissolve 1 g of p- and β-cyclodextrin in 300 ydK of water, and add 10 ydK of PGD2 alcohol to this.
The mixture was prepared by adding 0.05 kg, stirring thoroughly, and concentrating under reduced pressure. ] in 1.50 ml of distilled water for injection, sterile-filtered by the usual method, dispensed into 5 ml ampoules, and dried in a sieve to obtain 11 n in 1 ampoule.
100 solid formulations for injection containing 9 active substances were obtained. Example 12 Tablets and solid preparations for injection containing the compounds produced in Examples 2 to 9 as active ingredients were obtained in the same manner as in Examples 11 and 12.

Claims (1)

[Claims] 1) General formula [wherein the symbol [A] represents the formula H (in each formula, the broken line represents the α-configuration, the symbol - represents the β-configuration, and the wavy line represents the α-configuration) , β-configuration, or a mixture thereof, and the double bonds between C1□-013 and C14'''15 in formula CnJ are each independent, and each represents a trans configuration, a cis configuration, or a mixture thereof. The double bond between C9 and C□ represents the cis configuration, and the double bond between C13 and C14 represents the 72 configuration and Σ
It represents the lZΔ configuration, and the double bond between C13 and C14 in formula W represents the 12-section configuration. ), X represents an ethylene group or a cis-vinylene group, R represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and R represents 1 to 3 represents a straight chain or branched chain alkyl group having 2 to 6 carbon atoms substituted with hydroxyl groups, R represents a single bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, and R represents a straight chain or branched chain alkylene group having 1 to 5 carbon atoms. 1 to 8 straight chain or branched alkyl group, unsubstituted or C4 to 7 cycloalkyl group substituted with at least one C1 to 8 straight chain or branched alkyl group, or unsubstituted Substituted or at least one halogen atom,) 1) 7 /
It represents a l/l/merol group, or a phenyl group or phenoxy group substituted with a straight or branched alkyl group having 4 to 4 carbon atoms. However, when R represents a star bond, R is an unsubstituted or substituted phenoxy group and is not represented. junction compound. 2) A prostaglandin-like compound according to claim 1 represented by the general formula (in the formula, all symbols represent the same taste as described in claim 1) or their cyclo Dextrin clathrates. 3) A prostaglandin D-like compound according to claim 1, represented by the general formula (in which all symbols have the same meanings as in claim 1), or sifurobukis thereof ) I
J-n clathrate compound. 4) Prostaglandin D-like compounds according to claim 1 represented by the general formula (in which all symbols represent the same yellow color as described in claim 1), or their Shiflov Kiss) ＋
J-n clathrate compound. 5) The compound according to any one of claims 1 to 4, wherein R is a hydrogen atom, a methyl group, or an ethyl group. 6) R or 2-human 90oxymethyl group, 1,1-bis(
Claims 1 to 5 which are human 90-oxymethyl)ethyl group or 1-human 90-oxymethylethyl group
A compound according to any of the following paragraphs. 7) R or 4++v, L-ro or 1 in Ip exchange
BooF-/L/, intyl or hexyl group substituted with one or two methyl or ethyl groups! to!
A compound according to any one of claims 1 to 6. 8) R is unsubstituted or cyclobutyl substituted with one methyl group, ethyl group or butyl group,
7. The compound according to any one of claims 1 to 6, wherein cyclo is a methyl or cyclohexyl group. 9) Any of claims 1 to 6, wherein R is unsubstituted or is a phenyl or phenoxy group substituted with one chlorine atom, trifluoromethyl group, methyl group, or ethyl group. Compounds described in the above section. 10) The compound is (5Z, 9Z, 12EZ, 14EZ
)-N-ethyl-N-(2-hiviroxyethyl)-11
The compound according to claim 1, which is -oxoprosta-5,9,12,14-tetraenamide. 11) The compound is (5Z, 9Z, 13E)-(15/
The compound according to claim 1, which is If)-N-(2-human 90xyethyl)-11-oxoprost-5,9,11-trienamide. 12) The compound is (5Z, 9Z, 13E)-(15/
I) -N-(1,3-cyto90xy-3-methylpropan-2-yl)-15-human90xy-11-oxoprost-5,9,13-)lienami P Compound according to item 1. 13) The compound is (5Z, 9Z, 13E)-(15α)-
The compound according to claim 1, which is N-ethyl-N-(2-hybroxyethyl)-15-human 90x-11-oxoprost-5,9,13-trienamide. 14) The compound is (9Z, 13E)-N-ethyl-N-(
2-human 90xethyl)-15-hydroxy-11-
The compound according to claim 1, which is oxoprosta-9,13-dienamide 9. 15) The compound is (5Z, 9Z, 13E)-(1
51′r, 17α)-N-ethyl-N-(2-human90
xyethyl)-15-hydroxy-? , 7.20-dimethylprostar 5.9.13-)lienamibi. 16) The compound is (5Z, 9Z, t3E)-(xsα
)-N~Ethyl-N-(2-human 90xethyl) -
15-human 90x-11-oxo-20-methyl-1
The compound according to claim 1, which is 6,18-ethanoprosta-5,9,13-to-11enamide. 17) The compound is (5Z, 9Z, 1.3E)-(
15/F)-N-ethyl-N-(2-hydroxyethyl)-16-(3-chlorophenoxy)-15-hydroxy-11-oxo-17,IR,19,20-tetranorprosta-5,9 , 13-) lienamide. 18) Change & thing (5Z, 1.3E) -N-xf
yv-N-(2-human90gyethyl)-9,15-dihydroxy-11-oxoprost-5,13-:)enamide. The compound according to claim aIr1. 19) General formula (wherein, the broken line represents α-configuration, the symbol - represents β-configuration, and the wavy line represents α-configuration, β-configuration, or a mixture thereof, between C9""010 and C13""14
The double bonds between represent the upper and Σlance configurations, respectively, or the ethylene group or yy. -Represents a vinylene group, R is a hydrogen atom or has 1 to 1 carbon atoms
4 represents a straight or branched alkyl group, R is 1 to 3
represents a straight or branched alkyl group having 2 to 6 carbon atoms substituted with hydroxyl groups, and R is a single bond or a straight chain or branched alkyl group having 1 to 5 carbon atoms.
represents a straight or branched alkylene group having 1 to 8 carbon atoms, R is an unsubstituted or at least one straight or branched alkyl group having 1 to 8 carbon atoms; cycloalkyl group having 4 to 7 carbon atoms substituted with, or phenyl substituted with unsubstituted or at least one halogen atom, trifluoromethyl group, or linear or branched alkyl group having 1 to 4 carbon atoms or phenoxy group, R is M-free or 2-tetrahydro-1? substituted with at least one alkyl group. Raniloo-11
- represents a group, a 2-tetrahydrofuranyloxy group, or a 1-ethoxyethyl group. However, when R represents a single bond, R is nothing! , 1% or substituted phenyl groups shall not be represented. ) A method for producing a prostaglandin D-like compound represented by the general formula (in the formula, all symbols have the same meanings as above), which comprises hydrolyzing the compound represented by the formula under acidic conditions. 20) A compound represented by the general formula (in which all symbols have the same meanings as described in claim 19. However, two Rs represent the same group) is hydrated under acidic conditions. A method for producing a prostaglandin D-like compound represented by the general formula (all symbols have the same meanings as above), which is characterized by decomposition. 21) General formula (in the formula, the double bonds between C1゜-013 and C14''''15 are each independent, and each represents the R2ケケケconfiguration, -7x configuration, or a mixture thereof, and other The symbols have the same meanings as described in claim 19.) A compound represented by the general formula (wherein, all symbols have the same meanings as described in claim 19) A method for producing a prostaglandin D-like compound represented by the general formula (in the formula, all symbols have the same meanings as above), which comprises reacting the compound in the presence of a base. 22) A general method characterized by reacting a compound represented by the general formula (in each formula, all symbols have the same meanings as described in claim 19 or 20) under acidic conditions. A method for producing a prostaglandin D-like compound represented by the formula (in which all symbols have the same meanings as above). 23) General formula [wherein the symbol [A] is the formula (in each formula, the broken line represents the α-configuration, the symbol 4 represents the β-configuration, and the wavy line represents the α-configuration, β-configuration, or a mixture thereof Expression, formula (C1□-C13 in 11 and C
The double bonds between 14" and 15 are each independent and each represents a trans configuration, a yxμ configuration, or a mixture thereof, and the double bond between C9 and C18 represents a yx configuration, and the double bond between C9 and C18 represents a yx configuration, and the double bond between C9 and C18 represents a yx configuration. ) in C9-C,. Between and C13-C14
The double bonds between C1, 3 and C14 in formula (2) represent the transformer and transformer configurations, respectively. ), X represents an ethylene group or a 4-vinylene group, R represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms, and R2 represents a group having 1 to 3 carbon atoms. represents a straight chain or branched chain alkyl group having 2 to 6 carbon atoms substituted with a hydroxyl group, R represents a single bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, and R represents a straight chain or branched chain alkylene group having 1 to 5 carbon atoms. ~8 straight or branched alkyl groups,
Unsubstituted or a C4-C7 cycloalkyl group substituted with at least one C1-C8 linear or branched alkyl group, or unsubstituted or with a small (both one) cycloalkyl group, Fluoromethyl group or carbon number 1-4
represents a phenyl group or phenoxy group directly substituted with a straight or branched alkyl group. However, when R represents a single bond, R does not represent an unsubstituted or substituted phenoxy group. ] Prostaglandin D
An anti-11III tumor agent containing a similar compound or a cyclodextrin clathrate thereof as an active ingredient.