JPH039906B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel prostaglandin D analogs. Prostaglandins are derivatives of prostaglandins 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, prostaglandin F (PGF),
The alicyclic rings of E (PGE) and D (PGD) each have the following structures. [Formula] [Formula] and [Formula] Dotted lines in the above structural formulas or other structural formulas herein indicate that the attached group is in the ring plane, in accordance with generally accepted nomenclature rules. The thick line 〓 indicates that the group attached to it is on the front side of the ring plane, that is, the β-configuration, and the wavy line indicates that the group attached to it is α- or β-configuration.
- configuration, or a mixture thereof. These compounds are subclassified according to the position of the double bond on the side chain at the 8th and 12th positions of the alicyclic ring. PG-1 compounds have a trans double bond (trans-Δ ¹³ ) between C ₁₃ and C ₁₄ , and PG-2 compounds have
It has a cis double bond between _C5 and _C6 and a trans double bond (cis- ^Δ5 , trans- ^Δ13 ) between _C13 and _C14 . For example, prostaglandin D ₁ (PGD ₁ )
and prostaglandin D ₂ (PGD ₂ ) are each represented by the following structural formula. as well as Furthermore, when one or more methylene groups are removed from the aliphatic group at position 12 of the cycloaliphatic ring of a prostaglandin, the compound becomes a nor-prostaglandin according to the general rules of organic compound nomenclature. The number of methylene groups removed is indicated by adding di- or tri- before the prefix "nor". Prostaglandins generally have pharmacological properties. For example, they have the effect of stimulating smooth muscle contraction, lowering blood pressure, diuresis, bronchodilation,
It has lipolysis inhibiting action, platelet aggregation inhibiting action, and gastric acid secretion inhibiting action. 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 "natural" prostaglandins have pharmacological effects, or have stronger activity in one or more of their properties, or that "natural" prostaglandins have As a result of extensive research to discover new compounds with properties that have never been seen before,
A novel PGD in which the carboxyl group at position 1 of PGD ₁ and PGD ₂ is replaced by a substituted amide group [i.e., [formula] group (in the formula, R ¹ and R ² have the same meanings as below)] Similar compounds, compounds in which the hydroxyl group at position 9 of those compounds is dehydrated and a double bond is introduced between C ₉ and C ₁₀ , and furthermore, the hydroxyl group at position 15 of those compounds is also dehydrated, and the hydroxyl group at position 15 of those compounds is dehydrated, and the hydroxyl group _at position ₁₅ is dehydrated, ,
Contrary to the fact that new compounds with double bonds introduced between _C12 - _C13 and _C14 - _C15 do not have the pharmacological properties of "natural" prostaglandins, or have very weak pharmacological properties. discovered that the antitumor effect was surprisingly strong and completed the present invention. Several applications regarding PGD-like compounds have been filed so far. For example, as a compound in which the carboxylic acid moiety at position 1 of PGD ₁ and PGD ₂ is converted, methanesulfonyl amide compound (JP-A-51-1999-1)
See specification No. 131859. ), alcohol (JP-A-52-89648, JP-A-52-89649 and JP-A-52-
See specification No. 89650. ), amine body (JP-A-Sho
See specification No. 52-83351. ) ketone bodies (see the specification of JP-A-54-141751), etc.
There is no disclosure of the hydroxyalkylamide compound of the present invention, and more importantly, these compounds of the present invention have a novel action that has not been found at all in known PGD derivatives, that is, an antitumor action. At the point. 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 in which the hydroxyl group at the 9-position is dehydrated (9-deoxy-Δ ⁹ -PGD derivatives) have already been filed. For example, in the above-mentioned published specifications other than JP-A-51-131859, these 9-deoxy-Δ ⁹ -
There is a description of PGD derivatives. However, no 9-deoxy- ^{Δ 9} -derivatives as included in the present invention are disclosed. Furthermore, the fact that these compounds of the present invention have antitumor activity is that
This is completely different from deoxy- ^Δ9 derivatives. Furthermore, among the compounds included in the compounds of the present invention, the hydroxyl groups at the 9- and 15-positions are dehydrated, resulting in C ₉ -C ₁₀
PGD derivatives ( _{9,15 - dideoxy -} 13,14
-dihydro- _Δ9,12,14 -PGD derivatives) have not been found to date, and therefore these compounds are new compounds. That is, the present invention provides the general formula [In the formula, symbol [A] is the formula [formula] [formula] or (In each formula, the dashed 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.
The double bonds between C ₁₂ and C ₁₃ and between C _{14 and} C ₁₅ are each independent, and each represents a trans configuration, a cis configuration, or a mixture thereof _;
The double bonds between C ₉ and _{C 10} and C ₁₃ and C ₁₄ in formula () represent cis configuration and trans configuration, respectively.
The double bond between _C13 - _C14 represents a trans configuration. )
represents ^a group represented ^by Represents a straight chain or branched chain alkyl group having 2 to 6 carbon atoms substituted with a hydroxyl group, R ³ represents a single bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, and R ⁴ represents a straight chain or branched chain alkylene group having 1 to 5 carbon atoms. 1
-8 linear or branched alkyl group, unsubstituted or C4-7 cycloalkyl group substituted with at least one C1-8 straight-chain or branched alkyl group, or unsubstituted or at least 1
represents a phenyl group or phenoxy group substituted with halogen atoms, trifluoromethyl groups, or linear or branched alkyl groups having 1 to 4 carbon atoms. However, when R ³ represents a single bond, R ⁴ does not represent an unsubstituted or substituted phenoxy group. ] The present invention relates to a prostaglandin D-like compound shown in the following, or a cyclodextrin clathrate thereof. The compound represented by the general formula () has several asymmetric carbon atoms. For example, a compound in which [A] represents a group of formula () has at least 4 carbon atoms (i.e., 8-, 9-,
carbon atoms at positions 1 and 15) are asymmetric centers. Similarly, in the general formula (), compounds in which [A] represents a group represented by the formula () or () have at least two (i.e., carbon atoms at the 8th and 15th positions) and one (i.e., carbon atoms at the 8th and 15th positions), respectively. , carbon atom at position 8). Furthermore, when the alkyl group represented by R ¹ is a branched chain, other asymmetric centers may occur.
However, the compound represented by the general formula () of the present invention also contains all isomers caused by asymmetric carbon atoms and mixtures thereof. In the general formula (), the number of carbon atoms represented by R ¹ is 1
-4 alkyl groups include methyl, ethyl, propyl, butyl groups and isomers thereof, and preferred R ¹ is a hydrogen atom, a methyl group or an ethyl group. In the general formula (), the alkyl group having 2 to 6 carbon atoms and substituted with 1 to 3 hydroxyl groups represented by R ² includes hydroxyethyl, dihydroxyethyl, trihydroxyethyl, hydroxypropyl, dihydroxypropyl, trihydroxypropyl. , hydroxybutyl, dihydroxybutyl,
trihydroxybutyl, hydroxypentyl, dihydroxypentyl, trihydroxypentyl,
Hydroxyhexyl, dihydroxyhexyl, trihydroxyhexyl groups and their isomers are mentioned, and preferred ^R2 is 2-hydroxyethyl group, 1,1-bis(hydroxymethyl)ethyl group (i.e., 2-methylpropane-1, 3-diol-2-yl group) and 1-hydroxymethylethyl group (i.e., propanol-2-yl group). In the general formula (), the number of carbon atoms represented by R ³ is 1
Examples of the alkylene group of ~5 include methylene, ethylene, trimethylene, tetramethylene, pentamethylene groups, and isomers thereof, and R ³ is preferably a single bond, a methylene group, or an ethylene group. In the general formula (), the number of carbon atoms represented by R ⁴ is 1
-8 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl groups and isomers thereof, preferably unsubstituted or one or two methyl or A butyl group substituted with an ethyl group, a pentyl group or a hexyl group. In the general formula (), the substituted or unsubstituted cycloalkyl group represented by R ⁴ includes cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, and one or more methyl, ethyl, propyl, butyl, pentyl, hexyl, Examples include cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups substituted with heptyl or octyl groups, preferably unsubstituted or substituted with one methyl, ethyl, propyl, or butyl group. , cyclopentyl group or cyclohexyl group. In the general formula (), the substituted or unsubstituted phenyl group or phenoxy group represented by R ⁴ includes phenyl, phenoxy, and one or more fluorine atoms, chlorine atoms, trifluoromethyl group, methyl group, and ethyl group. , a phenyl group or a phenoxy group substituted with a propyl group or a butyl group, preferably a phenyl group that is unsubstituted or substituted with one chlorine atom, trifluoromethyl group, methyl group or ethyl group; It is a phenoxy group. In the general formula (), preferred examples of R ³ -R ⁴ include butyl, pentyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 1,
1-dimethylpentyl, 1-ethylpentyl, 2
-ethylpentyl, hexyl, 1-methylhexyl, 2-methylhexyl, 1-ethylhexyl,
2-ethylhexyl, heptyl, 2-methylheptyl, 2-ethylheptyl, cyclobutyl, 1-
Propylcyclobutyl, 1-butylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, cyclopentylmethyl, 2-cyclopentylethyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-
Butylcyclopentyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 4
-Methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, benzyl, 2-phenylethyl, 4-methylbenzyl, 4-ethylbenzyl,
Phenoxymethyl, 2-phenoxyethyl, 3-
Chlorophenoxymethyl, 4-chlorophenoxymethyl, 3-trifluoromethylphenoxymethyl, 4-trifluoromethylphenoxymethyl,
Examples include 4-methylphenoxymethyl and 4-ethylphenoxymethyl. In the general formula (), X is preferably a cis-vinylene group or an ethylene group. Also, the symbol [A] in the general formula () is the formula ()
or (), the preferred configuration of the hydroxyl group at the 15th position is the α-configuration. Compounds included in the invention can be named as derivatives of PGD. For example, the formula included in the invention and described in Example 1 (All symbols have the same meanings as above.) A compound represented by the formula described in Example 8 (All symbols have the same meanings as above.) A compound represented by the formula described in Example 9 The compounds represented by are each 9-deoxy-
They can be named Δ9 ^- _{PGD2ethanolamide} , 9,15-dideoxy-13,14-dihydro- ^Δ9,12,14 _- PGD2N-ethylethanolamide and _PGD2N -ethyl-ethanolamide. Furthermore, the compound of the present invention has the following formula: Prostanamide indicated by
can be systematically named as derivatives of
In this case, the compounds represented by the above formulas (b-1), (a-1) and (c-1) are (5Z,
9Z, 13E)-(15α)-N-(2-hydroxyethyl)
-15-hydroxy-11-oxoprosta-5,
9,13-trienamide, (5Z, 9Z, 12EZ,
14EZ)-N-ethyl-(2-hydroxyethyl)-
11-oxoprosta-5,9,12,14-tetraenamide and (5Z,13E)-N-ethyl-N-
It can be named (2-hydroxyethyl)-9,15-dihydroxy-11-oxoprosta-5,13-dienamide. The compound of the present invention represented by the general formula () is a compound represented by the general formula (a), (b) and (c), that is, the compound represented by the general formula and (In each formula, all symbols represent the same meanings as above.) These compounds can be produced by the method described below. That is, according to the present invention, the compounds represented by the general formulas (b) and (c) each have the general formula (In the formula, R ⁵ represents a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, unsubstituted or substituted with at least one alkyl group, or a 1-tetrahydrofuranyl group.
It represents an ethoxyethyl group, preferably a 2-tetrahydropyranyl group, and the other symbols have the same meanings as above. ) and (In the formula, all symbols represent the same meanings as above, and two R ⁵ represent the same group.) It is obtained by hydrolyzing the compound represented by the following under acidic conditions. This hydrolysis reaction is carried out using (1) an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid or hydrochloric acid;
In an aqueous solution of an inorganic acid such as sulfuric acid, phosphoric acid, preferably a water-miscible organic solvent, such as a lower alkanol such as methanol or ethanol (preferably methanol), or 1,2-dimethoxyethane, dioxane or tetrahydrofuran. (2) in an anhydrous lower alkanol such as methanol or ethanol, such as p-toluenesulfonic acid or trifluoroacetic acid, in the presence of an ether (preferably tetrahydrofuran) at a temperature from room temperature to 80°C (preferably at the reflux temperature of the solvent); It is carried out at temperatures of 10-45°C in the presence of organic acids. 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-toluenesulfonic acid and anhydrous methanol. It is done using liquid. Compounds represented by the general formulas () and () are each represented by the general formula (In the formula, all symbols have the same meanings as above.) Compounds represented by and general formula (In the formula, all symbols represent the same meanings as above and two R ⁵ represent the same group.) Synthesize the acid halide or acid anhydride of the compound represented by the formula, and combine the obtained compound with the general formula (In the formula, R ¹ and R ² have the same meanings as above.) A compound represented by the formula is prepared in an inert organic solvent such as methylene chloride, tetrahydrofuran, or N,N-dimethylformaldehyde at a temperature of 0°C to 40°C. Obtained by reaction. Preferably, it is carried out using chloroformic acid, isobutyl ester or trimethylacetyl chloride in methylene chloride in the presence of a base such as triethylamine at room temperature. The compound represented by the general formula (a) also has the general formula (In the formula, all symbols have the same meanings as above.) It can be obtained by reacting a compound represented by the following formula with a compound represented by the general formula (). This reaction is carried out in the same manner as the method for producing the compounds represented by the general formulas () and () from the compounds represented by the general formulas () and (), respectively. Compounds represented by general formulas (), () and () are disclosed in Japanese Patent Publication No. 52-42856 and Japanese Patent Publication No. 54-32773.
Although it can be produced by the method described in the specification, it can also be produced by a series of reaction steps shown in the following Scheme A. In formula A, R ⁶ represents an acyl group such as an acetyl group or a benzoyl group, R ⁷ represents an alkylsulfonyl group or an arylsulfonyl group such as a mesyl group or a tosyl group, and the other symbols have the same meanings as above. Each step in the diagram is performed by a known reaction, but to briefly explain, for example, step [a]
is carried out by selectively acylating the hydroxyl group attached to the 11th position of the compound represented by the general formula (XI). Such acylation is carried out in the presence of a tertiary amine such as pyridine, triethylamine in an inert organic solvent, such as methylene chloride or neat, at a temperature below room temperature, preferably at a temperature of -30 to -40°C. This is carried out using acyl chlorides or acid anhydrides such as benzoyl chloride. Step [b] is a process in which 2,3-dihydropyran, 2,3-dihydropyran, 2,3- It is carried out using dihydrofuran, ethyl vinyl ether, etc. at temperatures ranging from room temperature to -30°C. It is preferably carried out using 2,3-dihydropyran in methylene chloride in the presence of p-toluenesulfonate of pyridine or p-toluenesulfonic acid at room temperature. Step [c] involves the addition of mesyl chloride (i) in the presence of a tertiary amine such as pyridine or triethylamine in an inert organic solvent such as methylene chloride, or (ii) in pyridine at a temperature of -30°C to 50°C. This is carried out by reacting with an alkylsulfonyl chloride such as or an arylsulfonyl chloride such as tosyl chloride. Step [d] is lithium,
This is carried out by deacylation using an alkali metal hydroxide such as sodium or potassium at a temperature of 0 to 60°C. Step [e] converts a hydroxyl group to an oxo group, or
Alternatively, it is a reaction in which the OR ⁷ group is simultaneously eliminated and a double bond is formed between C ₉ and C ₁₀ . Such oxidation reactions are well known, for example: (a) "Organic Synthesis Chemistry Synthesis Edition 1" published by Nankodo, edited by Tetsuji Kametani, pages 176-206 (August 1, 1976)
or (b) “Compendium of Organic Synthetic” published by John Wiley & Sons, Inc. (USA).
Methods” Volume 1 (1971), Volume 2 (1974)
), Volume 3 (1977), Section 48 or 168
is described in detail. 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.Am.Chem.Soc., 94 ,
7586 (1972)], dicyclohexylcarbodiimide-dimethyl sulfoxide complex [J.Am.
Chem.Soc., 87 , 5661 (1965)], pyridinium chlorochromate (C ₅ H ₅ NHCrO ₃ Cl)
[See Tetrahedron Letters, 2647 (1975)],
Sulfuric anhydride-pyridine complex [J.Am.Chem.Soc.,
89, 5505 (1967)], chromyl chloride [J.Am.
Chem.Soc., 97 , 5929 (1975)], chromium trioxide-pyridine complex (e.g. Collins reagent),
This is carried out using John's reagent or chromic acid solution (manufactured from chromium trioxide, manganese sulfate, sulfuric acid and water), oxalic acid chloride and dimethyl sulfoxide (Swern oxidation), etc. Collins oxidation, John's oxidation or Swern oxidation are preferred. It is oxidation. Collins oxidation is carried out in a halogenated hydrocarbon such as chloroform, methylene chloride, or carbon tetrachloride at temperatures from room temperature to 0°C. Jones oxidation is usually carried out at temperatures below room temperature. Swan oxidation is carried out in halogenated hydrocarbons such as chloroform and methylene chloride from -50℃ to -
This is carried out by reacting at 60°C and then treating with triethylamine. Step [f] is a reaction in which the ^OR5 group is eliminated and a double bond is formed at the same time, using an inert organic solvent such as methylene chloride, chloroform, carbon tetrachloride, diethyl ether, N,N-dimethylformamide, tetrahydrofuran, or the like. using an aqueous solution of an acid, for example an aqueous solution of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or an organic acid such as acetic acid, propionic acid, oxalic acid, in a mixed solvent of two or more of the above, at the reflux temperature of the solvent. Manufactured by reaction. Preferably, this is carried out by refluxing 1N hydrochloric acid in tetrahydrofuran. The compound represented by the general formula (XI) is known per se, and is disclosed in Japanese Patent Application No. 109806/1983 as a compound represented by the general formula (). In addition, the compound represented by the general formula (a) can be obtained by subjecting the compound represented by the general formula (b), (c), () or () to the reaction of step [f] in the above-mentioned scheme A to obtain a hydroxyl group. Alternatively, it can also be produced by eliminating the OR ⁵ group and simultaneously forming a double bond. Prostaglandin D represented by general formula ()
The similar compound cyclodextrin clathrate is
It can be obtained by the method described in Japanese Patent No. 790979 and Japanese Patent Application Laid-Open No. 47-39057 using α-, β- or γ-cyclodextrin or a mixture thereof. The stability of the prostaglandin D-like compound represented by the general formula () is increased by converting it into a cyclodextrin clathrate compound. Prostaglandin D represented by general formula ()
Similar compounds and their cyclodextrin clathrate compounds have pharmacological effects specific to prostaglandins, such as hypotensive action, platelet aggregation inhibitory action,
It has been found that the antitumor effect is surprisingly strong and the toxicity is extremely low, even though the effect of stimulating uterine muscle contractions and the effect of diarrhea are either absent or very weak. (There is no mention in the above-mentioned prior art specifications that these compounds have a strong antitumor effect.) Therefore, prostaglandin D-like compounds represented by the general formula () and their cyclodextrin clathrate compounds are highly effective for preventing, treating, and prolonging the survival of tumors, such as leukemia and solid cancer. It can be used as an ideal antitumor agent. For example, in a laboratory experiment, the compound of the present invention showed an excellent inhibitory effect in an in vitro growth inhibition test using human floor of mouth cancer cells (KB cells). The experimental method and results are shown below. Growth inhibition test using human floor of mouth cancer cells (KB cells) <Experimental method> KB cells were added to Eagle containing 10% calf bile serum.
Add to the MEM culture solution and increase the number of cells in the culture solution by 1x.
The ethanol solution of the compound of the present invention was adjusted to a final concentration of 5 ^μg /ml and lower (3 μg/ml).
After adding the cells so that the number of cells reached 100.degree. C.), the cells were cultured stationary at 37.degree. 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 IC ₅₀ value (50% growth inhibitory concentration) was determined from the inhibition rate relative to the control. The results are shown in the table below. [Table] Prostaglandin D represented by general formula ()
Similar compounds and their cyclodextrin clathrates are usually administered systemically or locally, orally or parenterally, as antitumor agents. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, processing time, etc., but it is usually 5 mg to 500 mg per adult, once a day.
given once to several times or per adult,
The dose is administered parenterally, preferably intravenously, once to several times a day in the range of 500 μg to 50 mg. Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases it may be sufficient to use a smaller amount than the above dosage range, and in other cases it may be necessary to exceed the above dosage range. Solid compositions for oral administration include tablets,
Includes powders, granules, etc. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, dextrose, hydroxypropyl cellulose, microcrystalline cellulose, starch,
Polyvinylpyrrolidone is mixed with magnesium aluminate metasilicate. The compositions may contain additives other than inert diluents in conventional manner, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate. Tablets or pills may be coated with a film of gastric or enteric substances such as white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose 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, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic 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 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,
Examples include polysorbate 80, gum arabic, and sodium alginate. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of sterilizing agents, 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:
External solutions containing one or more active substances and formulated in a manner known per se, liniments such as lozenges, suppositories for intrarectal administration and pettu saris for intracavitary administration, etc. are included. . Among the compounds represented by the general formula (a) included in the present invention, preferred are, for example, 9,15-dideoxy-13,14-dihydro-
Δ ^9,12,14 -PGD ₁ 9,15-dideoxy-13,14-dihydro-
Δ ^9,12,14 -PGD ₂ , 9,15-dideoxy-13,14-dihydro-16-
Methyl Δ ^9,12,14 -PGD ₁ , 9,15-dideoxy-13,14-dihydro-16-
Methyl- ^Δ9,12,14 - _PGD2 , 9,15-dideoxy-13,14-dihydro-16,
16-dimethyl- ^Δ9,12,14 - _PGD1 , 9,15-dideoxy-13,14-dihydro-16,
16-dimethyl- ^Δ9,12,14 - _PGD2 , 9,15-dideoxy-13,14-dihydro-17,
20-dimethyl- ^Δ9,12,14 - _PGD1 , 9,15-dideoxy-13,14-dihydro-17,
20-dimethyl-Δ ^9,12,14 -PGD2, 9,15-dideoxy-13,14-dihydro-15-
(1-butylcyclobutyl)-16, 17, 18, 19, 20
-Pentanol-Δ ^9,12,14 -PGD ₁ , 9,15-dideoxy-13,14-dihydro-15-
(1-Butylcyclobutyl)-16, 17, 18, 19, 20
-Pentanol-Δ ^9,12,14 -PGD ₂ , 9,15-dideoxy-13,14-dihydro-15-
Cyclopentyl-16,17,18,19,20pentanol- ^Δ9,12,14 - _PGD1 , 9,15-dideoxy-13,14-dihydro-15-
Cyclopentyl-16,17,18,19,20-pentanol- ^Δ9,12,14 - _PGD2 , 9,15-dideoxy-13,14-dihydro-15-
(3-propylcyclopentyl)-16, 17, 18,
19,20-pentanol- ^Δ9,12,14 - _PGD1 , 9,15-dideoxy-13,14-dihydro-15
(3-propylcyclopentyl)-16, 17, 18,
19,20-Pentanol- ^Δ9,12,14 - _PGD2 , 9,15-dideoxy-13,14-dihydro-15-
(3-butylcyclopentyl)-16, 17, 18, 19,
20-pentanol- ^Δ9,12,14 - _PGD1 , 9,15-dideoxy-13,14-dihydro-15-
(3-butylcyclopentyl)-16, 17, 18, 19,
20-Pentanol- ^Δ9,12,14 - _PGD2 , 9,15-dideoxy-13,14-dihydro-15-
(4-Butylcyclobutyl)-16, 17, 18, 19, 20
-Pentanol-Δ ^9,12,14 -PGD ₁ , 9,15-dideoxy-13,14-dihydro-15-
(4-Butylcyclobutyl)-16, 17, 18, 19, 20
-Pentanol-Δ ^9,12,14 -PGD ₂ , 9,15-dideoxy-13,14-dihydro-16-
Phenyl-17,18,19,20-tetranol-
Δ ^9,12,14 -PGD ₁ , 9,15-dideoxy-13,14-dihydro-16-
Phenyl-17,18,19,20-tetranol-
Δ ^9,12,14 -PGD ₂ , 9,15-dideoxy-13,14-dihydro-16-
Phenoxy-17,18,19,20-tetranol-
Δ ^9,12,14 -PGD ₁ , 9,15-dideoxy-13,14-dihydro-16-
Phenoxy-17,18,19,20-tetranol-
Δ ^9,12,14 -PGD ₂ , 9,15-dideoxy-13,14-dihydro-16-
(3-chlorophenoxy)-17,18,19,20-tetranor- ^Δ9,12,14- _PGD1 , 9,15-dideoxy-13,14-dihydro-16-
(3-chlorophenoxy)-17,18,19,20 ^- tetranorΔ9,12,14- _PGD2 , 9,15-dideoxy-13,14-dihydro-16-
(3-trifluoromethylphenoxy)-17, 18,
19,20-tetranor- ^Δ9,12,14 - _PGD1 , 9,15-deoxy-13,14-dihydro-16-
(3-trifluoromethylphenoxy)-17, 18,
19,20-tetranol-Δ ^9,12,14 -PGD ₂ , corresponding ethanolamide, N-ethylethanolamide, N-methylethanolamide, 2-
Methylpropane-1,3-diol-2-amide and propanol-2-amide are mentioned, and among the compounds represented by the general formula (b), preferable ones include, for example, 9-deoxy-Δ ⁹ -PGD ₁ , 9-deoxy- ^Δ9 - _PGD2 , 9-deoxy-16-methyl- ^Δ9 - _PGD1 , 9-deoxy-16-methyl-Δ9- _PGD2 , ⁹ -deoxy-16,16-dimethyl-Δ ⁹ −
PGD ₁ , 9-deoxy-16,16-dimethyl-Δ ⁹ −
PGD ₂ , 9-deoxy-17,20-dimethyl-Δ ⁹ −
PGD ₁ , 9-deoxy-17,20-dimethyl-Δ ⁹ −
PGD ₂ , 9-deoxy-15-(1-butylcyclobutyl)
−16,17,18,19,20−Pentanol−Δ ⁹ −
PGD ₁ , 9-deoxy-15-(1-butylcyclobutyl)
−16,17,18,19,20−Pentanol−Δ ⁹ −
PGD ₂ , 9-deoxy-15-cyclopentyl-16,17,
18,19,20-pentanol- ^Δ9 - _PGD1 , 9-deoxy-15-cyclopentyl-16,17,
18,19,20-pentanol- ^Δ9 - _PGD2 , 9-deoxy-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanol- ^Δ9-
_PGD1 , 9-deoxy-15-(3-propylcyclopentyl)-16,17,18,19,20-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-
PGD ₂ , 9-deoxy-15-(4-butylcyclobutyl)
−16,17,18,19,20−Pentanol−Δ ⁹ −
PGD ₁ , 9-deoxy-15-(4-butylcyclobutyl)
−16,17,18,19,20−Pentanol−Δ ⁹ −
_PGD2 , 9-deoxy-16-phenyl-17,18,19,20
-Tetranor- ^Δ9 - _PGD1 , 9-deoxy-16-phenyl-17,18,19,20
-tetranol- ^Δ9 - _PGD2 , 9-deoxy-16-phenoxy-17,18,19,
20-tetranol- ^Δ9 - _PGD1 , 9-deoxy-16-phenoxy-17,18,19,
20-tetranor- ^Δ9 - _PGD2 , 9-deoxy-16-(3-chlorophexy)-
17,18,19,20-tetranol- ^Δ9- _PGD1 , 9-deoxy-16-(3-chlorophenoxy)-
17,18,19,20-tetranol- ^Δ9 - _PGD2 , 9-deoxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranol- ^Δ9
-PGD ₁ , 9-deoxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranol-Δ ⁹
-PGD ₂ , corresponding ethanolamide, N-ethylethanolamide, N-methylethanolamide, 2-
Methylpropane-1,3-diol-2-amide and propanol-2-amide are mentioned, and among the compounds represented by the general formula (c), preferable ones include, for example, PGD ₁ , PGD ₂ , 16-methyl- _PGD1 , 16-methyl- _PGD2 , 16,16-dimethyl- _PGD1 , 16,16-dimethyl- _PGD2 , 17,20-dimethyl- _PGD1 , 17,20-dimethyl- _PGD2 , 15-(1 -butylcyclobutyl) -16, 17, 18,
19,20-pentanol-PGD ₁ , 15-(1-butylcyclobutyl)-16,17,18,
19,20-pentanol- _PGD2 , 15-cyclopentyl-16,17,18,19,20-petanol- _PGD1 , 15-cyclopentyl-16,
17,18,19,20-pentanol-PGD ₂ , 15-(3-propylcyclopentyl)-16,17,
18,19,20-pentanol-PGD ₁ , 15-(3-propylcyclopentyl)-16,17,
18,19,20-pentanol-PGD ₂ , 15-(3-butylcyclopentyl)-16,17,
18,19,20-pentanol-PGD ₁ , 15-(3-butylcyclopentyl)-16,17,
18,19,20-pentanol-PGD ₂ , 15-(4-butylcyclobutyl)-16,17,18,
19,20-pentanol-PGD ₁ , 15-(4-butylcyclobutyl)-16,17,18,
19,20-pentanol-PGD ₂ , 16-phenyl-17,18,19,20-tetranol-
PGD ₁ , 16-phenyl-17,18,19,20-tetranol-
_PGD2 , 16-phenoxy-17,18,19,20-tetranol- _PGD1 , 16-phenoxy-17,18,19,20-tetranol- _PGD2 , 16-(3-chlorophenoxy)-17,18 ,19,20
-tetranol-PGD ₁ , 16-(3-chlorophenoxy)-17, 18, 19, 20
-Tetranol-PGD ₂ , 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranol-PGD ₁ , 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranol-PGD ₂ , corresponding ethanolamide, N-ethylethanolamide, N-methylethanolamide, 2-
Examples include methylpropane-1,3-diol-2-amide and propanol-2-amide. 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, "mp", "TLC", "IR", "NMR" and "Mass" in reference examples and examples.
The symbols represent "melting point,""thin layer chromatography,""infrared absorption spectrum,""nuclear magnetic resonance spectrum," and "mass spectrometry," respectively, and are listed in the section for separation by chromatography. The proportion of solvent indicates the volume ratio, the solvent in the box of "TLC" indicates the developing solvent, "IR" is measured by liquid film method unless otherwise specified, and "NMR" indicates that there is no special statement. If not available, measurements are made using deuterated chloroform (CDCl ₃ ) solution. Reference example 1 (5Z, 13E)-(9α, 11α, 15α)-11-benzoyloxy-9-methanesulfonyloxy-15-
(2-Tetrahydropyranyloxy)prosta-5,13-dienoic acid methyl ester (5Z,13E)-(9α,11α,15α)-9-hydroxy-11-benzoyl dissolved in 50 ml of dry methylene chloride under argon atmosphere. Oxy-15-(2-tetrahydropyranyloxy)prosta-5,13-dienoic acid methyl ester (manufactured by the method described in Reference Example 2 of JP-A-59-1463) 2.8 g
1.12 ml of triethylamine and 0.58 ml of mesyl chloride were added to the mixture at -20°C, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into 150 ml of ice water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried and concentrated under reduced pressure to obtain 3.23 g of the title compound having the following physical properties as a crude product. obtained as. TLC (n-hexane: ethyl acetate = 2:1): Rf
= 0.51; NMR: δ = 8.1 to 7.7 (2H, m), 7.6 to 7.1 (3H,
m), 5.7-4.9 (6H, m), 3.7 (3H, s), 3.0
(3H, s). Reference example 2 (5Z, 13E)-(9α, 11α, 15α)-11-hydroxy-9-methanesulfonyloxy-15-(2-
Tetrahydropyranyloxy)prostar-5,
13-Dienoic acid To 3.23 g of 11-benzoyl compound (produced in Reference Example 1) dissolved in 133 ml of methanol, a suspension consisting of 12.6 g of lithium hydroxide monohydrate and 19 ml of water was added at 5°C. The mixture was stirred at the same temperature for 2 hours and then at room temperature for 5 hours. The reaction mixture was poured into 300 ml of ice water, the pH was adjusted to 3 by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane and ethyl acetate mixture, then ethyl acetate) to obtain 2.01 g of the title compound having the following physical properties. TLC (chloroform:tetrahydrofuran:acetic acid = 30:6:1): Rf = 0.44; NMR: δ = 6.4-5.6 (2H, m), 5.7-5.2 (4H,
m), 5.15-4.9 (1H, m), 4.8-4.6 (1H, m),
4.3 ~ 3.1 (4H, m), 3.0 (3H, s); IR: ν = 3650 ~ 2400, 2930, 2860, 1720, 1340,
1170, 970cm ^-1 . Reference example 3 (5Z, 9Z, 13E)-(15α)-11-oxo-15-
(2-Tetrahydropyranyloxy)prosta-5,9,13-trienoic acid To 1.24 g of the 9-mesyl compound (produced in Reference Example 2) dissolved in 12 ml of acetone, add 4.5 ml of Johns reagent at -30°C. It was added dropwise and stirred at -20°C for 20 minutes. Dilute the reaction mixture with diethyl ether,
The mixture was washed successively with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mixture of ethyl acetate and n-hexane) to obtain 610 mg of the title compound having the following physical properties. TLC (ethyl acetate: n-hexane = 2:1): Rf
= 0.27; NMR: δ = 7.64-7.52 (1H, m), 6.22-6.10
(1H, m), 5.7~5.2 (4H, m), 4.8~4.6 (1H,
m), 1.0 to 0.8 (3H, m); IR: ν=1715, 1590, 1020 cm ^-1 . Reference Example 4 Similarly to Reference Examples 1, 2, and 3, Reference Examples 2(b), 2(c), and 2(c) in JP-A-59-1463, respectively,
The following compounds having the following physical properties were obtained from the compounds described in 2(e) and 2(a). (a) (5Z,9Z,13E)-(15α,17α)-17,20-dimethyl-11-oxo-15-(2-tetrahydropyranyloxy)prosta-5,9,13-trienoic acid TLC (acetic acid Ethyl:n-hexane=2:1):Rf
= 0.31; IR: ν = 2940, 1710, 1590 cm ^-1 ; NMR: δ = 7.63 to 7.52 (1H, m), 6.21 to 6.10
(1H, m), 5.7~5.2 (4H, m), 4.8~4.6 (1H,
m), 1.0-0.8 (6H, m). (b) (5Z,9Z,13E)-(15α)-16,18-ethano-20-methyl-11-oxo-15-(2-tetrahydropyranyloxy)prosta-5,9,13
-Trienoic acid TLC (ethyl acetate: n-hexane = 2:1): Rf
= 0.30; IR: ν = 1713, 1590 cm ^-1 ; NMR: δ = 7.64 to 7.53 (1H, m), 6.23 to 6.10
(1H, m), 5.73-5.20 (4H, m), 4.8-4.6
(1H, m), 1.0-0.8 (3H, m). (c) (5Z,9Z,13E)-(15α)-16-(3-chlorophenoxy)-11-oxo-15-(2-tetrahydropyranyloxy)-17,18,19,20-tetranol Prostar-5.9,13-trienoic acid TLC (ethyl acetate: n-hexane = 2:1): Rf
= 0.27; IR: ν = 1715, 1610, 1590 cm ^-1 ; NMR: δ = 8.1 to 7.8 (2H, m), 7.6 to 6.7 (5H,
m), 6.2-6.1 (1H, m), 5.7-5.2 (4H, m). (d) (9Z,13E)-(15α)-11-oxo-15-(2
-tetrahydropyranyloxy)prostar-
9,13-dienoic acid TLC (ethyl acetate: n-hexane = 2:1): Rf
= 0.29; IR: ν = 2940, 1735, 1715, 1590 cm ^-1 ; NMR: δ = 7.62 to 7.50 (1H, m), 6.20 to 6.10
(1H, m), 5.7-5.4 (2H, m), 4.8-4.6 (1H,
m), 1.0-0.8 (3H, m). Reference example 5 (5Z, 13E)-(9α, 11α, 15α)-9,15-bis(2-tetrahydropyranyloxy)-11-benzoyloxyprosta-5,13-dienoic acid methyl ester Chlorinated under nitrogen atmosphere (5Z,13E)-(9α,11α,15α)-9-hydroxy-11-benzoyloxy-15-(2-tetrahydropyranyloxy)prosta-5,13-dienoic acid (JP-A-Sho) dissolved in 15 ml of methylene. 1 ml of 2,3-dihydropyran was added dropwise to 3.77 g at room temperature, followed by adding a catalytic amount of p-toluenesulfonic acid and stirring for 15 minutes. rear,
0.1 ml of triethylamine was added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: 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 (1H, m),
4.7~4.4 (2H, m), 3.7 (3H, s), 0.8 (3H,
t); IR: ν=2940, 1735, 1720, 1450, 1270, 1110,
1020cm ^-1 . Reference example 6 (5Z, 13E)-(9α, 11α, 15α)-9,15-bis(2-tetrahydropyranyloxy)-11-hydroxyprosta-5,13-dienoic acid Dissolved in 4.8 ml of methanol (5Z , 13E) − (9α,
11α,15α)-9,15-bis(2-tetrahydropyranyloxy)-11-benzoyloxyprosta-5,13-dienoic acid methyl ester (produced in Reference Example 5) (500 mg) and 2N aqueous potassium hydroxide solution
Add 1.6ml and stir at 50℃ for 1.5 hours, then heat to 5℃
The mixture was cooled to pH 2, and 1N hydrochloric acid was added to adjust the pH to 2. 100 ml of ice water was added to the reaction mixture and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 483 mg of the title compound having the following physical properties. Obtained as product. The obtained product was subjected to the next reaction without being purified. TLC (benzene: ethyl acetate = 2:1): Rf =
0.07. Reference example 7 (5Z, 13E)-(11α, 15α)-9,15-bis(2
-tetrahydropyranyloxy)-11-oxoprosta-5,13-dienoic acid (5Z,13E)-(9α,
11α,15α)-9,15-bis(2-tetrahydropyranyloxy)-11-hydroxyprosta-5,
1.04 g of 13-dienoic acid (produced in Reference Example 6) was cooled to -30°C, and Johns reagent (chromium trioxide)
378 mg, 0.331 ml of concentrated sulfuric acid and 1.41 ml of water. ) was added dropwise and stirred at the same temperature for 30 minutes.
1 ml of isopropyl alcohol was added followed by 100 ml of water. The reaction mixture was extracted three times with 50 ml of diethyl ether (total 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 purified by silica gel column chromatography (elution solvent: cyclohexane:ethyl acetate = 2:1) to obtain 652 mg of the title compound having the following physical properties. TLC (benzene: ethyl acetate = 1:2): Rf =
0.7; NMR: δ = 10.1 (1H, s), 5.7-5.2 (4H, m),
4.8-4.5 (2H, m), 1.0-0.7 (3H, m); Mass: m/e = 436, 418. Reference example 8 (5Z, 9Z, 12EZ, 14EZ)-11-oxoprosta-5,9,12,14-tetraenoic acid PGD ₂ (Example 1 in the specification of Japanese Patent Publication No. 54-32773)
[B] Manufactured by the method described. ) 11 mg, 0.28 ml of 1N hydrochloric acid, and 0.28 ml of tetrahydrofuran were refluxed for 20 minutes, and then 50 ml of diethyl ether was added.
was added, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane:ethyl acetate = 2:1) to obtain 3 mg of the title compound having the following physical properties. TLC (chloroform:tetrahydrofuran:acetic acid = 30:6:1): Rf = 0.62; NMR: δ = 7.47 (1H, dd), 6.96 (1H, d), 6.46
~6.15 (3H, m), 5.55 ~ 5.28 (2H, m), 3.65 ~
3.52 (1H, m), 0.90 (3H, t); IR: ν = 3600 ~ 2400, 2920, 1725, 1700, 1625
cm ^-1 . Mass: m/e=316. Reference example 9 (5Z, 9Z, 13E)-(15α)-N-(2-hydroxyethyl)-15-(2-tetrahydropyranyloxy)-11-oxoprosta-5,9,13-trienamide Argon atmosphere Below, at room temperature (5Z, 9Z, 13E) −
(15α)-15-(2-tetrahydropyranyloxy)
200 mg of -11-oxoprosta-5,9,13-trienoic acid (produced in Reference Example 3) was dissolved in methylene chloride 10
ml of solution, add 0.1 ml of triethylamine, then add 80 μl of chloroformic acid isobutyl ester.
was added dropwise, and then stirred for 15 minutes. After adding 40μ of ethanolamine to this solution and 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 n-hexane) to obtain 175 mg of the title compound having the following physical properties. Yield 79%. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.36; IR: ν = 3320, 1705, 1650, 1540, 1240, 1075,
1020, 980cm ^-1 ; NMR: δ = 7.6 (1H, dd), 6.16 (1H, dd), 5.2−
5.8 (4H, m), 4.6-4.8 (1H, m), 3.0-4.2
(7H, m), 2.73-3.0 (1H, m), 2.6-2.73
(1H, m), 0.7−1.0 (3H, m). Reference example 10 (5Z, 9Z, 13E)-(15α)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-
15-(2-tetrahydropyranyloxy)-11-
Oxoprosta-5,9,13-trienamide (5Z,9Z,13E)- at room temperature under argon atmosphere
(15α)-15-(2-tetrahydropyranyloxy)
250 mg of -11-oxoprosta-5,9,13-trienoic acid (produced in Reference Example 3) was dissolved in methylene chloride 10
Add 125μ of triethylamine to the solution dissolved in ml, and then add chloroformic acid isobutyl ester
After dropping 100μ, it was stirred for 15 minutes.
Add 2-amino-2-methylpropane-
95 mg of 1,3-diol was added and stirred at the same temperature for 2 hours. The solution was diluted with methylene chloride, washed with an aqueous sodium bicarbonate solution and 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 n-hexane) to obtain the title compound having the following physical properties.
Obtained 190mg. Yield 63%. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.34; IR: ν = 3350, 1705, 1645, 1540, 1450, 1240,
980cm ^-1 ; NMR: δ = 7.57 (1H, dd), 6.1−6.2 (1H, m),
5.9~6.1 (1H, m), 5.3~5.87 (4H, m), 4.6~
4.75 (1H, m), 3.4~4.2 (7H, m), 2.75~2.93
(1H, m), 2.6-2.72 (1H, m), 1.22 (3H,
s), 0.8 to 1.0 (3H, m); Mass: m/e = 505 (M ⁺ ), 487, 474, 456, 421,
403, 372, 321. Reference example 11 (5Z, 9Z, 13E)-(15α)-N-ethyl-N-
(2-hydroxyethyl)-15-(2-tetrahydropyranyloxy)-11-oxoprosta-
5,9,13-trienamide (5Z,9Z,13E)- at room temperature under argon atmosphere
(15α)-15-(2-tetrahydropyranyloxy)
250 mg of -11-oxoprosta-5,9,13-trienoic acid (produced in Reference Example 3) was added to 100 mg of methylene chloride.
Add 125μ of triethylamine to the solution dissolved in
ml and stirred at the same temperature for 15 minutes. Add 88μ of N-ethylethanolamine to this solution,
After stirring for 15 minutes, the mixture 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 n-hexane) to obtain 249 mg of the title compound having the following physical properties. Yield 85%. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.47; IR: ν = 3420, 1705, 1620, 1440, 1015, 975cm
^-1 ; NMR: δ=7.53~7.66 (1H, m), 6.09~6.22
(1H, m), 5.3-5.7 (4H, m), 4.6-4.76 (1H,
m), 3.96-4.15 (1H, m), 3.58-3.96 (4H,
m), 3.28-3.58 (5H, m), 2.75-2.92 (1H,
m), 2.6-2.7 (1H, m), 1.19 (3H, t), 0.8-
1.0 (3H, m); Mass: m/e = 489 (M ⁺ ), 471, 459, 405, 388,
387, 305. Reference example 12 (5Z, 9Z, 13E)-(15α, 17α)-N-ethyl-
N-(2-hydroxyethyl)-15-(2-tetrahydropyranyloxy)-11-oxo-17,
20-Dimethylprosta-5,9,13-trienamide The title compound having the following physical properties was obtained by the same operation as in Reference Example 9. Starting material: (5Z, 9Z, 13E)-(15α, 17α)-15-
(2-tetrahydropyranyloxy)-11-oxo-17,20-dimethylprosta-5,9,13-
Trienoic acid (produced in Reference Example 4(a)) 223 mg. Yield: 220 mg TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.48; IR: ν = 3430, 1705, 1622 ^{cm -1} ; NMR: δ = 7.56 (1H, m), 6.14 (1H, m), 5.7
-5.3 (4H, m), 4.68 (1H, m), 1.0~0.8 (6H,
m); Mass: m/e=517 (M ⁺ ), 499. Reference example 13 (5Z, 9Z, 13E)-(15α)-N-ethyl-N-
(2-Hydroxyethyl)-15-(2-tetrahydropyranyloxy)-11-oxo-20-methyl-16,18-ethanoprosta-5,9,13-trienamide By the same operation as in Reference Example 9, The title compound having the following physical properties was obtained. Starting material: (5Z, 9Z, 13E)-(15α)-15-(2-
Tetrahydropyranyloxy)-20-methyl-
11-oxo-16,18-ethanoprosta-5,
9,13-trienoic acid (produced in Reference Example 4(b))
202mg Yield: 191mg TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.50; IR: ν = 3430, 1706, 1620; NMR: δ = 7.57 (1H, m), 6.13 (1H, m) ), 5.7
~5.3 (4H, m), 4.67 (1H, m), 1.0 ~ 0.8 (3H,
m); Mass: m/e=529 (M ⁺ ), 511. Reference example 14 (5Z, 9Z, 13E)-(15α)-N-ethyl-N-
(2-hydroxyethyl)-16-(3-chlorophenoxy)-11-oxo-15-(2-tetrahydropyranyloxy)-17,18,19,20-tetranorprosta-5,9,13- Trienamide By the same operation as in Reference Example 9, the title compound having the following physical properties was obtained. Starting material: (5Z, 9Z, 13E)-(15α)-16-(3-
chlorophenoxy)-11-oxo-15-(2-tetrahydropyranyloxy)-17, 18, 19, 20
-tetranorprosta-5,9,13-trienoic acid (produced in Reference Example 4(c)) 189 mg. Yield: 162 mg TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.46; IR: ν = 3420, 1705, 1620, 1600 cm ^-1 ; NMR: δ = 7.62 (1H, dd), 7.30 ~ 6.70 (4H,
m), 6.20 (1H, dd), 5.78-5.30 (4H, m),
4.68 (1H, m); Mass: m/e = 559 (M ⁺ ), 543, 541; Reference example 15 (9Z, 13E)-(15α)-N-ethyl-N-(2-
hydroxyethyl)-15-(2-tetrahydropyranyloxy)-11-oxoprost-9,13
-Dienamide The title compound having the following physical properties was obtained by the same operation as in Reference Example 9. Starting material: (9Z,13E)-(15α)-15-(2-tetrahydropyranyloxy)-11-oxoprosta-9,13-dienoic acid (produced in Reference Example 4(d))
163mg. Yield: 160mg. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.48; IR: ν = 3420, 1705, 1602 cm ^-1 ; NMR: δ = 7.56 (1H, m), 6.13 (1H, m), 5.7
~5.3 (2H, m), 4.68 (1H, m); Mass: m/e = 491 (M ⁺ ), 473. Reference example 16 (5Z, 13E)-N-ethyl-N-(2-hydroxyethyl)-9,15-bis(2-tetrahydropyranyloxy)-11-oxoprosta-5,
13-Dienamide 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).
103mg. Yield: 90mg. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.43; IR: ν = 3430, 2930, 1740, 1645 cm ^-1 ; NMR: δ = 5.8 to 5.3 (4H, m), 4.8 to 4.6 ( 2H,
m), 1.0-0.8 (3H, m). Example 1 (5Z,9Z,13E)-(15α)-N-(2-hydroxyethyl)-15-hydroxy-11-oxoprost-5,9,13-trienamide (i.e. 9-deoxy- ^Δ9 -PGD ₂ ethanolamide) 183 mg of PGD ₂ amide produced in Reference Example 9 was dissolved in 0.5 ml of tetrahydrofuran, and 65%
5 ml of acetic acid was added and stirred at 80°C for 7 minutes. After cooling, the solution was diluted with ethyl acetate.
It was washed with an aqueous sodium hydrogen carbonate 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 methanol) to obtain the title compound having the following physical properties.
Obtained 108mg. Yield 72%. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.16; IR: ν = 3320, 1700, 1640, 1240, 1050, 975cm
^-1 ; NMR: δ=7.60 (1H, dd), 6.18 (1H, dd), 5.3
~5.8 (4H, m), 4.0 ~ 4.2 (1H, m), 3.70 (2H,
t), 3.41 (2H, t), 2.8-2.95 (1H, m), 2.6
~2.75 (1H, m), 0.8 ~ 1.0 (3H, m); Mass: m/e = 377 (M ⁺ ), 359, 288, 277, 170. Example 2 (5Z,9Z,13E)-(15α)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-
15-hydroxy-11-oxoprosta-5,
9,13-trienamide (i.e., 9-deoxy- ^{Δ 9} -PGD ₂ 2-methyl-1,3-propanediol 2-amide) A solution of 182 mg of PGD ₂ amide produced in Reference Example 10 dissolved in 0.5 ml of tetrahydrofuran. 5 ml of 65% acetic acid was added to the mixture, and the mixture was stirred at 80°C for 8 minutes. After cooling, the solution was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: a mixture of ethyl acetate and methanol).
74mg of the title compound having the following physical properties
I got it. Yield 49%. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.10; IR: ν = 3350, 1700, 1640, 1540, 1450, 1245,
1040, 975cm ^-1 ; NMR: δ = 7.60 (1H, dd), 6.16 (1H, dd), 5.3
~5.68 (4H, m), 4.0~4.2 (1H, m), 3.52~
3.76 (4H, m), 2.8~2.92 (1H, m), 2.61~
2.70 (1H, m), 1.22 (3H, s), 0.8~1.0 (3H,
m); Mass: m/e=421 (M ⁺ ), 403, 390, 372, 354,
321. Example 3 (5Z, 9Z, 13E)-(15α)-N-ethyl-N-
(2-hydroxyethyl)-15-hydroxy-11
-Oxoprosta-5,9,13-trienamide (i.e. 9-deoxy-Δ ⁹ -PGD ₂ N-ethylethanolamide) 65% in a solution of 230 mg of PGD ₂ amide prepared in Reference Example 11 dissolved in 0.5 ml of tetrahydrofuran. 5 ml of acetic acid was added and reacted at 80°C for 8 minutes. After cooling, the solution was diluted with ethyl acetate, 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 methanol) to obtain 133 mg of the title compound having the following physical properties. Yield 70%. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.33; IR: ν = 3410, 1705, 1620, 1455, 1240, 1050,
965cm ^-1 ; NMR: δ = 7.59 (1H, dd), 6.14 (1H, dd), 5.28
~5.80 (4H, m), 4.0 ~ 4.2 (1H, m), 3.64 ~
3.85 (2H, m), 3.27~3.56 (4H, m), 2.8~
2.95 (1H, m), 2.6-2.73 (1H, m), 1.18 (3H,
t), 0.8-1.0 (3H, m); Mass: m/e = 405 (M ⁺ ), 387, 334, 316, 305. Example 4 (5Z, 9Z, 13E)-(15α, 17α)-N-ethyl-
N-(2-hydroxyethyl)-17,20-dimethyl-15-hydroxyprosta-5,9,13-trienamide (i.e. 9-deoxy- ^Δ9
-17,20-dimethyl-PGD ₂ N-ethylethanolamide) By the same operation as in Example 3, the title compound having the following physical properties was obtained. Starting material: PGD ₂ amide 217 produced in Reference Example 12
mg. Yield: 120mg. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.34; IR: ν = 3410, 1706, 1622; NMR: δ = 7.60 (1H, dd), 6.15 (1H, dd), 5.80
~5.26 (4H, m), 1.0 ~ 0.8 (6H, m); Mass: m/e = 433 (M ⁺ ), 415. Example 5 (5Z, 9Z, 13E)-(15α)-N-ethyl-N-
(2-hydroxyethyl)-15-hydroxy-11
-oxo-20-methyl-16,18-ethanoprosta-5,9,13-trienamide (i.e.
9-deoxy-Δ ⁹ -16,18-ethano-20-methyl-PGD ₂ N-ethylethanolamide) The title compound having the following physical properties was obtained by the same operation as in Example 3. Starting material: PGD ₂ amide 184 produced in Reference Example 13
mg. Yield: 110mg. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.35; IR: ν = 3410, 1706, 1620 cm ^-1 ; NMR: δ = 7.59 (1H, dd), 6.14 (1H, dd), 5.82
−5.28 (4H, m), 1.0 to 0.8 (3H, m); Mass: m/e = 445 (M ⁺ ), 427. Example 6 (5Z, 9Z, 13E)-(15α)-N-ethyl-N-
(2-hydroxyethyl)-16-(3-chlorophenoxy)-15-hydroxy-11-oxo-17,
18,19,20-tetranorprosta-5,9,13
-trienamide (i.e. 9-deoxy-
Δ ⁹ -16-(3-chlorophenoxy)-17, 18,
19,20-tetranol-PGD ₂ N-ethylethanolamide) By the same operation as in Example 3, the title compound having the following physical properties was obtained. Starting material: PGD ₂ amide 151 produced in Reference Example 14
mg Yield: 86 mg TLC (chlorophorem:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.30; IR: ν = 3410, 1705, 1620, 1600 cm ^-1 ; NMR: δ = 7.62 (1H, dd), 7.30 ~6.70 (4H,
m), 6.20 (1H, dd), 5.80-5.30 (4H, m); Mass: m/e = 475 (M ⁺ ), 459, 457. Example 7 (9Z,13E)-(15α)-N-ethyl-N-(2-
Hydroxyethyl)-15-hydroxy-11-oxoprosta-9,13-dienamide (i.e., 9-deoxy-Δ ⁹ -PGD ₁ N-ethylethanolamide) By the same operation as in Example 3, the following physical properties were obtained. The title compound was obtained. Starting material: PGD ₁ amide 155 produced in Reference Example 15
mg. Yield: 95 mg TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.35; IR: ν = 3410, 1706, 1602 ^{cm -1} ; NMR: δ = 7.58 (1H, dd), 6.13 (1H, dd), 5.70
~5.30 (2H, m); Mass: m/e = 407 (M ⁺ ), 389. Example 8 (5Z,13E)-N-Ethyl-N-(2-hydroxyethyl)-9,15-dihydroxy-11-oxoprosta-5,13-dienamide (i.e., PGD ₂ N-ethylethanolamide) Performed By the same operation as in Example 3, the title compound having the following physical properties was obtained. Starting material: 82 mg of PGD ₂ amide obtained in Reference Example 16. Yield: 63mg. IR: ν=3400, 2925, 1735, 1620 cm ^-1 ; NMR: δ=5.75−5.30 (4H, m), 4.52–4.42
(1H, m), 1.0-0.8 (3H, m). Example 9 (5Z, 9Z, 12EZ, 14EZ)-N-ethyl-N-
(2-Hydroxyethyl)-11-oxoprosta-5,9,12,14-tetraenamide (i.e. 9,15-dideoxy-13,14-dihydro-
^Δ9,12,14 - _PGD2N -ethanolamide) (5Z,9Z,12EZ,14EZ)-11-oxoprosta-5,9,12,14-tetraenoic acid (produced in Reference Example 8) 316 mg Add 0.2 ml of triethylamine to a solution dissolved in 15 ml of methylene chloride, then add 0.16 ml of chloroformic acid isobutyl ester, stir, and then add 0.16 ml of N-ethylethanolamine.
was added and stirred for an additional 15 minutes. This solution was diluted by adding 150 ml of 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: ethyl acetate:n-hexane=1:2) to obtain 290 mg of the title compound having the following physical properties. TLC (chloroform:tetrahydrofuran:acetic acid = 10:2:1): Rf = 0.52; IR: ν = 3430, 2930, 1695, 1630 cm ^-1 ; NMR: δ = 7.55-7.44 (1H, m), 6.95 (1H,
d), 6.5-6.2 (3H, m), 1.0-0.8 (3H, m); Mass: m/e = 387 (M ⁺ ). Reference example 17 9-deoxy-Δ ⁹ dissolved in 5 ml of ethanol
- 1 g of PGD ₂ ethanolamide (produced in Example 1) was mixed well with 5 g of microcrystalline cellulose,
After sufficient drying, magnesium stearate
Add 100mg of silicon dioxide, 20mg of silicon dioxide, 10mg of talc, 200mg of cellulose calcium gluconate (ECG), and further add microcrystalline cellulose to make the total amount 10g.
After mixing thoroughly until homogeneous, the mixture was compressed in a conventional manner to obtain 100 tablets containing 10 mg of active substance in each tablet. Reference Example 18 _Inclusion compound of α- ^cyclodextrin and β-cyclodextrin [α-
Dissolve 2.4 g of cyclodextrin and 1 g of β-cyclodextrin in 300 ml of water, and add PGD ₂ to this.
The mixture was prepared by adding 100 mg of ethanolamide, stirring thoroughly, and then concentrating under reduced pressure. ] Distilled water for injection 150
ml, sterilized by standard methods, dispensed into 5 ml ampoules in 1.5 ml portions, and freeze-dried.
100 solid preparations for injection containing 1 mg of active substance in 1 ampoule were obtained. Reference Example 19 In the same manner as Reference Examples 17 and 18, tablets and solid preparations for injection containing the compounds produced in Examples 2 to 9 as active ingredients were obtained.

Claims (1)

[Claims] 1. General formula [In the formula, symbol [A] is the formula [formula] [formula] or (In each formula, the dashed 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.
The double bonds between C ₁₂ and C ₁₃ and between C _{14 and} C ₁₅ are each independent, and each represents a trans configuration, a cis configuration, or a mixture thereof _;
The double bond between C ₉ - C ₁₀ and C ₁₃ - C ₁₄ in formula () represents a cis configuration and a trans configuration, respectively.
The double bond between _C13 - _C14 represents a trans configuration. )
represents ^a group represented ^by Represents a straight chain or branched chain alkyl group having 2 to 6 carbon atoms substituted with a hydroxyl group, R ³ represents a single bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, and R ⁴ represents a straight chain or branched chain alkylene group having 1 to 5 carbon atoms. 1
-8 linear or branched alkyl group, unsubstituted or C4-7 cycloalkyl group substituted with at least one C1-8 straight-chain or branched alkyl group, or unsubstituted or at least 1
represents a phenyl group or phenoxy group substituted with halogen atoms, trifluoromethyl groups, or linear or branched alkyl groups having 1 to 4 carbon atoms. However, when R ³ represents a single bond, R ⁴ does not represent an unsubstituted or substituted phenoxy group. ] A prostaglandin D analog compound or a cyclodextrin clathrate compound thereof. 2 General formula (In the formula, all symbols have the same meanings as described in claim 1.) A prostaglandin analog compound according to claim 1, or a cyclodextrin clathrate thereof. 3 General formula (In the formula, all symbols have the same meanings as described in claim 1.) A prostaglandin D analogue compound according to claim 1, or a cyclodextrin clathrate compound thereof . 4 General formula (In the formula, all symbols have the same meanings as described in claim 1.) A prostaglandin D analogue compound according to claim 1, or a cyclodextrin clathrate compound thereof . 5. The compound according to any one of claims 1 to 4, wherein R ¹ is a hydrogen atom, a methyl group, or an ethyl group. 6 Claim 1 in which R ² is a 2-hydroxymethyl group, a 1,1-bis(hydroxymethyl)ethyl group, or a 1-hydroxymethylethyl group
A compound according to any one of Items 1 to 5. 7. Any one of claims 1 to 6, wherein R ⁴ is unsubstituted or a butyl, pentyl, or hexyl group substituted with one or two methyl or ethyl groups. Compounds described in. 8. Any one of claims 1 to 6, wherein R ⁴ is unsubstituted or a cyclobutyl, cyclopentyl, or cyclohexyl group substituted with one methyl group, ethyl group, or butyl group. Compounds described in. 9. Any of claims 1 to 6, wherein R ⁴ is unsubstituted or 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-
The compound according to claim 1, which is ethyl-N-(2-hydroxyethyl)-11-oxoprost-5,9,12,14-tetraenamide. 11 The compound is (5Z, 9Z, 13E)-(15α)-N-
(2-hydroxyethyl)-11-oxoprosta-
The compound according to claim 1, which is a 5,9,11-trienamide. 12 The compound is (5Z, 9Z, 13E)-(15α)-N-
(1,3-dihydroxy-3-methylpropane-
2-yl)-15-hydroxy-11-oxoprost-5,9,13-trienamide. 13 The compound is (5Z, 9Z, 13E)-(15α)-N-
The compound according to claim 1, which is ethyl-N-(2-hydroxyethyl)-15-hydroxy-11-oxoprost-5,9,13-trienamide. 14 The compound is (9Z,13E)-N-ethyl-N-
(2-hydroxyethyl)-15-hydroxy-11-
The compound according to claim 1, which is oxoprosta-9,13-dienamide. 15 The compound is (5Z, 9Z, 13E)-(15α, 17α)-
N-ethyl-N-(2-hydroxyethyl)-15-
Hydroxy-17,20-dimethylprosta-5,
The compound according to claim 1, which is a 9,13-trienamide. 16 The compound is (5Z,9Z,13E)-(15α)-N-
The compound according to claim 1, which is ethyl-N-(2-hydroxyethyl)-15-hydroxy-11-oxo-20-methyl-16,18-ethanoprosta-5,9,13-trienamide. . 17 The compound is (5Z, 9Z, 13E)-(15α)-N-
Ethyl-N-(2-hydroxyethyl)-16-(3
-chlorophenoxy)-15-hydroxy-11-oxo-17,18,19,20-tetranorprosta-
The compound according to claim 1, which is a 5,9,13-trienamide. 18 The compound is (5Z,13E)-N-ethyl-N-
The compound according to claim 1, which is (2-hydroxyethyl)-9,15-dihydroxy-11-oxoprost-5,13-dienamide.