JPH01104040A - Prostaglandin ds and sedative and hypnotic agent containing said prostaglandin ds - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [(X) is formula II, etc.; R1 is H, salt, protecting group or 1-4C alkyl; R2 is H or methyl; R3 is OH, methyl, etc.; R4 and R5 are H, methyl, halogen, etc.; R6 is 1-9C alkyl (substituted by a 1-9C alkyl, etc.), etc.]. EXAMPLE:13,14-Dihydro-15-keto-16R,S-methyl-prostaglandin D. USE:A sedative and hypnotic agent or central nervous system agent capable of exhibiting sleep inducing and sedative action by peripheral administration, such as oral administration, subcutaneous or intravenous injection. PREPARATION:Corey lactone expressed by formula 1 as a raw material is subjected to the Collins oxidation to provide an aldehyde expressed by formula 2, which is then reacted with dimethyl (2-oxoalkyl)phosphonate to afford an alpha,beta-unsaturated ketone expressed by formula 3. The resultant ketone is subsequently reduced to provide a saturated ketone expressed by formula 4, which is then subjected to ketanolization, etc., to afford the aimed compound expressed by formula 1.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel prostaglandins D and sedative/hypnotic agents containing the same.

Prior Art and Problems Prostaglandin is a general term for brostanic acids, and 5
ESFSA due to the way the keto group or hydroxyl group is introduced in the member ring part.
Classified into SB, C, DSH, etc.

Prostaglandins have a stimulating effect on the uterine muscle, as well as vasodilation and
It has various physiological and pharmacological effects such as inhibiting platelet aggregation and causing inflammation.

Prostaglandin Dfffi (hereinafter referred to as PGDs) has a group represented by H as a 5-membered ring structure, and can be roughly divided into 5-6
PGD, in which the carbon bond at position is a double bond.

pc where H and the carbon bond at position 17-18 are double bonds
pGD, for example, is known to have analgesic, sedative, sleep-inducing, and body temperature regulating effects. However, the effects of PGD2 vary significantly depending on its administration method. For example, experiments using rats have shown that peripheral administration such as subcutaneous injection, intravenous injection, or oral administration does not induce physiological sleep, but direct administration into the ventricles of rats induces sleep. Therefore, PGD2 presents difficulties in its method of administration. Furthermore, PGD simultaneously exhibits platelet aggregation inhibiting action, tracheal constriction action, intestinal constriction action, vasodilatory action, etc., and also has side effects such as strong diarrhea. Therefore,
The use of PGD2 as a sedative/hypnotic agent is problematic.

On the other hand, the existence of free prostaglandin D analogs in which carbons at the 13th and 14th positions are saturated and carbonyl at the 15th position is present in human or animal metabolites has been confirmed. These 13.14-dihydro-15-keto prostaglandins D are etc., and the corresponding PGD, PG
D, and PGD3 are known to be substances that are naturally produced in vivo through metabolic reactions mediated by enzymes.

These 13,14-dihydro-15-keto PGDs show almost no of the various physiological activities that PGDs have, and have been reported as physiologically and pharmacologically inactive metabolites (acta physiology). Scandinavica (Act
ta Physiologica 5caandi
navica) Volume 66, No. 509-. 1966).

However, the inventor found that the above metabolite 13.14
In examining the pharmacological activity of -dihydro-15-keto PGD2, direct intracisternal administration of 13.14-dihydro-15-keto PGD2 produced a sedative effect, and intracerebroventricular administration showed a sleep-inducing effect. I found that I was accepted. Furthermore, 13.14-dihydro-15-keto P
When evaluating the pharmacological activity of derivatives of GDs, the 16th and 1st
Compounds having substituents at the 7th, 19th and/or 20th positions, compounds having a methyl group or hydroxymethyl group at the 9th carbon position, compounds having an alkoxy group at the end of the ω chain, and carbons at the 5th and 6th positions. By forming a compound with a triple bond, 13.14-dihydro-15-
Keto PGD analogs are administered not only intracerebroventricularly, but also subcutaneously,
PG can also be administered by peripheral administration such as intravenous injection or oral administration.
It has been found that it exhibits sedative and sleep-inducing effects, which are one of the pharmacological activities of class D. Also, 13.
14-dihydro-15-keto PGD analogs do not exhibit, or exhibit only minimal pharmacological and physiological effects, such as platelet aggregation inhibiting effect, tracheal constriction effect, intestinal constriction effect, and vasodilatory effect, which PGDs simultaneously have. It was found that the degree of

Problem 1. Means for Solving the Problems The present invention provides - Formula: 1, - Formula (A) (B) (C) II (D) R6: hydrogen, physiologically acceptable salt, physiologically acceptable protecting group or C, -C, alkyl group, R3: hydrogen or methyl group, R,3: hydroxyl group, methyl group or human convex oxymethyl group, R4 and R6: hydrogen, methyl group, hydroxyl group or halogen. However, R4 and R5 may be the same or different.

R8; C3~ which may have a branch or double bond
01~ with C8 alkyl group or ether WmM
It represents a C9 alkyl group, and the carbons at the 2nd and 3rd positions may have a double bond.

(However, R3, R,, R4 and R6 are hydrogen,
R3 is a hydroxyl group, R6 is n-butyl, 2-3
Prostaglandin D class and general formula, except when the carbon at position is a single bond and (X) is ASC or D, and the general formula, (A) (B) (D) R1; hydrogen, physiology a physiologically acceptable salt, a physiologically acceptable protecting group or a C1-C4 alkyl group, R7; hydrogen or methyl group, R3; hydroxyl group, methyl group or hydrodimethyl group, R4 and R6; hydrogen, methyl group , hydroxyl or halogen. However, R4 and R5 may be the same or different.

Re: C3~ which may have a branch or double bond
C8- with C9 alkyl group or ether substituent
It represents a C3 alkyl group, and the carbons at the 2nd and 3rd positions may have a double bond. ] Provided is a sedative/hypnotic agent containing 13,14-dihydro-15-keto PGDs represented by:

-(X)- in formula [1] indicates the above four types of structures.

The compound PGD, in which -(X)- is a series of prostaglandins, and the compound PGD, in which -(X)- is a series of prostaglandins. Therefore, in the case of 6-keto PG Dr type prostaglandins, the convex part is 5.6-dehydro PGD, type prostaglandins.

In the present invention, R1 represents hydrogen, an ester residue, a salt residue, or a protecting group. In the present invention, R1 is preferably an ester residue, more preferably a saturated or unsaturated alkyl group that may have a branch, particularly an alkyl group that may have a branch and has 1 to 4 carbon atoms. , such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, tertiary-butyl groups, etc.

a) PGDs may form a salt with a suitable alkali,
When using this as a medicine, a physiologically acceptable alkali is used. Examples of alkalis include alkali metals, alkaline earth metals, ammonia, lower amines, alkanolamines, nitrogen-containing heterocyclic compounds, and examples include sodium, potassium, calcium, magnesium, methylamine, dimethylamine, cyclopentylamine, benzylamine, and piperidine. , monoethanolamine, jetanolamine, monomethylethanolamine, tromethamine, lysine, tetraalkylammonium salts, and the like. Examples of the protecting group include alkyl silicones such as trimethyl silicon and triethyl silicon, tetrahydroxypyran, and the like.

R2 is hydrogen or a methyl group, and the carbons at the 2nd and 3rd positions may have a double bond.

R3 is a hydroxyl group, a methyl group, or a hydroxymethyl group, which may have an α2β configuration or a mixture thereof with respect to the carbon at the 9-position.

R4 and R5 are each independently hydrogen, methyl group, hydroxyl group or halogen. R4 and R6 may be the same or different.

R6 is a saturated or unsaturated C3 which may have a branch.
~C9 alkyl group, especially 0 as an alkyl group
4 to C0 is preferred. Further, as the C4-C0 alkyl group, a straight-chain alkyl group or an alkyl group having one branched methyl group is particularly preferable.

Further, R6 is a saturated or unsaturated C1-C9 alkyl group having an ether substituent, and the alkyl group is preferably a C3-C8 alkyl group, particularly preferably a straight-chain alkyl group. Ether substituents include methoxy group,
Examples include ethoxy groups, and those having a substituent at the terminal of the alkyl chain are particularly preferred.

Typical compounds of the invention include, for example, 13.14-
Dihydro-15-keto PGD, alkyl ester; 13.14-dihydro-15-keto-16,16-dimethyl-PGD, and its alkyl ester; 13.14-dihydro-I5-keto-19-methyl~P
GD, and alkyl esters thereof; 13.14-dihydro-15-keto-16R,S-fluoro-PGD, and alkyl esters thereof; 13.14-dihydro-15
-keto-20-methoxy-PGD, and its alkyl ester; 13.14-dihydro-15-keto-18-
Methoxy-19,20-bis-true PGD and its alkyl ester; 13.14-dihydro-15-keto-19-ethoxy-
20-True PGD and its alkyl ester; 13.14-dihydro-15-keto-20-methoxyethyl-PGD2 and its alkyl ester; 13.14-dihydro-15-keto-20-methoxy-
Δm-PGD and its alkyl ester; 13.14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD and its alkyl ester; 13.14-dihydro-15-keto-16R,S- Methyl-20-methoxy-PGD and its alkyl ester; 13.14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGD and its alkyl ester; 13.14-dihydro-15-keto-19 -methyl-2
0-Methoxy-PGD, and its alkyl ester; 13.14-dihydro-15-ketol 16R,S-fluoro20-methoxy-PGD, and its alkyl ester; 13.14-dihydro-15-keto to 5,6- Dehythro PGD and its alkyl ester; 13.14-
13. Dihydro-15-keto-5,6-dehydro-20-methoxy-PGD and alkyl esters thereof; 13. 14-dihydro-15-keto-5,6-dehydro-9β-hydroxy-PGD and alkyl esters thereof; 13. 14-dihydro-15-keto-5,6-dehydro-9β-hydroxy-20-methoxy-PGD, and alkyl esters thereof; and the like.

For the synthesis of prostaglandin D of the present invention, for example, as shown in the attached synthesis charts 1 to 8, commercially available Corey lactone (1) is used as a starting material, and this is subjected to Collins oxidation to obtain aldehyde (2), which is then added to dimethyl ( α, β-unsaturated ketone (3
). The desired compound can be obtained by reducing this α,β-unsaturated ketone (3) by chemical reduction or catalytic reduction, and further performing ketamelation, introduction of an α-chain, Jones oxidation, etc.

The prostaglandin D class of the present invention may be used as a drug for animals and humans, and is usually used systemically or locally by oral, intravenous injection, or subcutaneous injection. Dosage depends on animal, human, age, body weight, symptoms, therapeutic effect,
It varies depending on the administration method, processing time, etc.

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,
It is mixed with glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc. The composition is prepared according to conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrin calcium gluconate, α-1β- or γ-cyclodextrin, dimethyl- Etherified cyclodextrin such as α-, dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin, branched cyclodextrin such as glucosyl-, maltosyl-cyclodextrin, formylated cyclodextrin, sulfur-containing cyclodextrin , misoprodol, and phospholipids. When the above-mentioned cyclodextrins are used, stability is increased because they form inclusion compounds with the cyclodextrins. Furthermore, stability is increased by using phospholipids and forming them into liposomes. Tablets or pills may be coated with a film of gastric or enteric substances such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc., or may be coated with two or more layers, if necessary. Additionally, capsules may be made of absorbable materials 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. , ethanol, and vegetable oils such as coconut. In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, fragrance agents, and preservatives. Moreover, this liquid composition can also be used by encapsulating it in a soft capsule as it is.

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, emulsions, and surfactants.

Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These can be sterilized, for example, by filtration through bacteria-retaining filters, 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.

Example 1 (see Synthesis Chart 1) 13. Synthesis of 14-dihydro-15-keto PGD2 ethyl ester (11), R=Et: t-t) 1s-2-oxa-3-oxo-6R-(3- Synthesis of oxo-1-trans-octenyl)7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane (3): Using Collins reagent prepared in dichloromethane (87ff), dichloromethane ( Dissolved in 20M (-
)-Coley lactone (1) (2,000 g) was oxidized to obtain aldehyde (2). Sodium hydride (50%
, 0.2649) was suspended in dry THF (45 m
After adding the THF solution of 5y), the mixture was stirred at room temperature for 90 minutes. A solution of aldehyde (2) in THF (4Qx) was added dropwise to this, and the mixture was left at room temperature overnight.

The crude product obtained by conventional treatment was subjected to chromatography (
Ethyl acetate-hexane = 1:3)L. Yield: 1°618g (64%).

1-2) Is-2-oxa-3-oxo-6R-(3,
3-ethylenedioxy-1-octyl)-7R-(4-
phenylbenzoyl)oxycis-bisicCff(3
,3,O) Synthesis of octane (5): Enone (3) (1,
618? ) was catalytically reduced using palladium-carbon, and the resulting saturated ketone (4) was converted into a ketal (5) using ethylene glycol and p-4 luenesulfonic acid in benzene. Yield O12010y (70%).

1-3) Is-2-oxa-3-oxo-6R-(3,
Synthesis of 3-ethylenedioxy-octyl)-7R-hydroxy-bicyclo(3,3,O)octane (6): Ketal (500,20109) in anhydrous methanol,
Potassium carbonate (0,1169) was added and stirred at room temperature. After the reaction was completed, acetic acid was added. The crude product obtained by conventional treatment was subjected to chromatography (ethyl acetate to beef sanitation).
1+l)L, alcohol (6) was obtained. Yield o, 09
o9<73%).

1-4) Synthesis of 13.14-dihydro-15,15-ethylenedioxy-PGF, α(8): Alcohol (
6) (0,0900 toluene (10 m), diisobutylaluminum hydride (D I BAL-Hll,
5-M) to obtain lactol (7).

(4-carboxybutyrintriphenylphosphonium bromide (0,54069)
A DMSO solution of lactol (7) was added to the ylide obtained from 13.14-dihydro-15,15-ethylenedioxy-PGF.

α(8) was obtained. Yield receipt 06449 (53%).

1-5) 13.14-dihydro-15,15-ethylenedioxy-PGF2α ethyl ester (9), R=
Synthesis of Et: Carboxylic acid (8XO, 0644y) was converted into acetonitrile (
Diazobicycloundecene (DB) at 60'C in LM)
Ethyl esterification was performed using U80.024+ and ethyl iodide. Yield 0.05949 (86%).

1'-6) 13.14-dihydro-15-keto P
Synthesis of GF, α-ethyl ester (10), R=Et: Ethyl ester (9) was mixed with acetic acid:water:THF (3:1:1)
It was dissolved in a mixed solvent (6 inches) and left at room temperature. The crude product obtained by conventional treatment was chromatographed (ethyl acetate = 1 + 1), 13.14-dihydro-15
-Keto PGF, α-ethyl ester (10) was obtained. Yield 0.0457g (86%).

1-7) 13.14-dihydro-15-keto-PG
Synthesis of D, ethyl ester (11), R=Et: Ethyl ester (1000,04579) was dissolved in acetone (10 m
C) Jones oxidation in. The crude product obtained after conventional treatment was chromatographed (ethyl acetate to beef san-1:
3) I did. yield 0.02609<57%).

In Figure 1, 13.14-dihydro-15-keto PGD
, jl-thyl ester (11), n, m for R=Et.

r, is shown.

Example 2 (see Synthesis Chart 1) 13.14-dihydro-15-keto-PGD2 (11)
, R=H synthesis: Carboxylic acid (8) is deketalized by a conventional method to obtain 13,
14-dihydro-15-keto-PGF, α(10), was obtained. Jones oxidation of this yielded 13.14-dihydro-15-keto-PGD, (11), R=H.

Example 3 (see Synthesis Chart 1) Synthesis of 13.14-dihydro-15-keto PGD, methyl ester (11), R=Me: 13.14-dihydro-15-keto-PGDz (1■), R= H(0,10
6y) was converted into methyl ester with diazomethane. Chromatography (ethyl acetate-hexane = 1:3) L, 1
3.14-dihydro-15-keto PGD, methyl ester (11), R=Me was obtained. Collection ff10.0610
9 (50%).

In addition, the carboxylic acid (8) was prepared using DBU and methyl iodide in acetonitrile to form the methyl ester (9), R=
After Me, 13.14-dihydro-15-keto-P
GD2 methyl ester (11), R=Me.

In Figure 2, 13.14-dihydro-15-keto PGD
, methyl ester (11), R=Me n, m.

r, is shown.

Example 4 (see Synthesis Chart 1) 13. Synthesis of 14-dihydro-15-keto PGDtn-butyl ester (11), R=n-Bu = (=)-Carboxylic acid (8) obtained from Corey lactone (1) ) in acetonitrile with n-butyl bromide and DBU.
n-butyl ester (9), except that R=n-Bu,
In the same manner as in Example 1, 13.14-dihydro-15-
Keto-PGD2 n-butyl ester (11),
R=n-Bu was obtained.

In Figure 3, 13.14-dihydro-15-keto PGDt
n-butyl ester (11), R=n-BU n, m
, r, is shown.

Example 5 (see Synthesis Chart 2) 13.14-dihydro-15-keto-20-methoxy-
Synthesis of PGD, methyl ester (20), R = M e: Same as Example 1 using (-)-Coley lactone (1) and dimethyl (7-medoxy 2-oxoheptyl) phosphonate obtained by a conventional method. 13. ．． 1
4-dihydro-15-keto-20-methoxy-PG
D*methyl ester (20) was synthesized. In addition, methyl esterification of carboxylic acid (17) is possible with both diazomethane, methyl iodide, and DBU.

In Figure 4, 13.14-dihydro-15-keto-20-
Methoxy-PGD, methyl ester (20), R=Me
n, m, r, are shown.

Example 6 (see Synthesis Chart 3) 13.14-dihydro-15-keto-20-methoxy-
Synthesis of PGD, (31): 6-1) Is-2-oxa-3-oxo-6R-(3R
,S-hydroxy-8-methoxy-1-octyl)7R
Synthesis of -(p-phenylbenzoyl)oxybicyclo(3,3,0)octane (21): l5-2-oxa-3-oxo-6R-(8-methoxy-3-oxooctyl)7R- p-phenylbenzoyloxy-cis-bicyclo(3,3,O)octane (13) (1,58
49: methanol-THF (3:2) mixed solvent (50
After reduction with NaB H4 in x(2), alcohol (21) was synthesized by chromatography (ethyl acetate-to-oxane=2:1) L. Yield 0, 70709 6-2) IS-2-oxa-3-oxo-6R-(3R
,S-hydroxy-8-methoxy-1-octyl)7R
-Synthesis of hydrobovine cis-bicyclo(3,3°0)octane (22): l5-2-oxa-3-oxo-6R-(3R.

S-Hydroxy(8-methoxy1-octyl)7R-
p-phenylbenzoyloxy-cis-bicyclo(3,
3,0) octane (2180,7070 g) was dissolved in a mixed solvent of methanol (30) and THF (20+), potassium carbonate (0,20349) was added, and the mixture was stirred for 4 hours. 22) was obtained. Yield 0
．． 39259 6-3) IS-2-oxa-3-oxo-6R-(3R
,5-t-butyldimethylsilyloxy-8-methoxy-1-octyl)7R-t-butyldimethylsilyloxy-cis-bicyclo(3,3,O)octane (23) Synthesis of Nidiol (22XO, 39259) t-Butyldimethylsilyl chloride (0,59289
) and dimethylaminopyridine (0,640 g) to obtain silyl ether (23). Yield 0.3642
9 s-4) Synthesis of 13.14-dihydro-11-15R,S-di(t-butyldimethylsilyloxy)-20-methoxy-PGFtα methyl ester (26) The silyl ether (2300,36429) was dissolved in toluene:/ (In 20R, DIBAr, -H (1,5-M, 1°4m) was reduced, and lactol (24) was obtained by treatment in a conventional manner.

Separately, (4-carboxybutyl)triphenylphosphonium bromide (1,223y) and potassium butoxide (
The lactol was added to the ylide in THF (180 mC). After the reaction was completed, carboxylic acid (25) was obtained by treatment in a conventional manner.

This was treated with diazomethane to produce methyl ester (26).
I got it. Yield ff10゜6-5) Tetrapyranyl etherification of compound (26): The above methyl ester (26) (0,1769) was added to p-toluenesulfone H (U
Tetrapyranyl ether (27) was prepared by using IJi medium) and dihydropyran. Yield ff10.222g
.

6-6) 13. l 4-dihydro-15R,S-
Synthesis of hydroxy-20-methoxy-9-(2-tetrapyranyl)oxy-PGF2α (29): Methyl ester (27) (0,22209) was dissolved in THF (10+) and tetrabutylammonium fluoride (1 μ, 1. 9
1 m of water was added and allowed to stand at room temperature.

Diol (28) was obtained by treatment in a conventional manner. Yield 0,
8169 This diol (28) (0,8169) was dissolved in methanol (
10o2) dissolved in 20% sodium hydroxide (5 cheeks)
was added and kept at room temperature for 2 hours. Carboxylic acid (29) was obtained by treatment in a conventional manner.

6-7) l 3.14-dihydro-15-keto-2
Synthesis of 0-methoxy-PGD, (31): carboxylic acid (
29) was subjected to Jones oxidation (2.6M, 0.15a+) at -37°C in acetone (101+).

1 obtained by conventional treatment 3. ．． 14-dihydro-
15-keto-20-methoxy-9-(2-tetrapyranyl)oxy-pGD, (30) was obtained. This compound (3
0) was dissolved in acetic acid-water-THF (4:2:1) mixed solvent (7 volumes) and kept at 40-43°C for 3 hours. After conventional treatment, chromatography (ethyl acetate-beef san=4:
1) L, 13.14-dihydro-15-keto-20-methoxy-PGD, (31) was obtained. Yield 0.0599 Figure 5 shows 13.14-dihydro-15-keto-20-
The n, m, and r of Metgyushi PGD, (31) are shown.

Example 7 (see Synthesis Chart 2) 13.14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD, methyl ester (32)
Synthesis: 13.14 in the same manner as in Example 5 using H(-)-Coley lactone (1) and dimethyl (7-medoxy 2-oxoheptyl) phosphonate obtained by a conventional method.
-dihydro-15-keto-3R.

S-methyl-20-methoxy-PGDt methyl ester (32) was synthesized.

In Figure 6, 13.14-dihydro-15-keto-3R,
S-Methyl-20-methoxy-PGD, methyl ester (32), n0m, r, t.

Example 8 (see Synthesis Chart 2) 13. Synthesis of 14-dihydro-15-keto-20-methoxyethyl-PGD, methyl ester (33): H(-)-Coley lactone (1) and 13.14-
Dihydro-15-keto-20-methoxyethyl-PGD
, methyl ester (33) was synthesized.

In Figure 7, 13.14-dihydro-15-keto-20-
Methoxyethyl-PGD, n of methyl ester (33)
, m, r, are shown.

Example 9 (see synthesis charts 2 and 4) 13.14-
Dihydro-15-keto-20-methoxy-Δ'-PGD
, Synthesis of methyl ester (38): 9-1) 13.14-dihydro-15',15-ethylenedioxy-20-methoxy-9,11-di(L-
Synthesis of (butyldimethylsilyloxy)-PGF, α-methyl ester (34): 13.14-dihydro-15,15-ethylenedioxy-20-methoxy-PGF, α-methyl ester (18)
(0,54729>) in DMF (10 liters) using butyldimethylsilyl chloride (0,94289) and imidazole (0,85199), 13°14-dihydro-15,15-ethylenedioxy- 20-methoxy-9,11-di(t-butyldimethylsilyloxy)-
PGF, α-methyl ester (34) was obtained. Yield: 8015 g 9-2) 13.14-dihydro-15,15-ethylenedioxy-20-methoxy-9,11-di(t-butyldimethylsilyloxy)-Δ'-PGF.

Synthesis of α-methyl ester (36): Cyclohexylisopropylamine (0,07 m2) and n-butyllithium (1
6-M, 0.265 mQ), lithium cyclohexylisopropylamide was prepared. To this was added methyl ester (34) (0,14129) in THF (4 m
A solution of was added dropwise and stirred for 2 hours. TH of diphenyl diselenide (0,132 g) and HMPA (0,074 inches)
F (add 2 m of solution and incubate at -70 °C for 1 hour, -40 ~
Stirred at -30'C for 1.5 hours. Through conventional processing,
11,247 g of selenide (35) was obtained. Zelenid (3
500, 12479) in ethyl acetate (6 yen) and methanol (4 yen), and hydrogen peroxide solution (30% 80.5 J).
112) and stirred at room temperature for 1 hour. The crude product obtained by conventional treatment was chromatographed (ethyl acetate-to-beef chloride = 1:6), and Δ! -PGF, α-methyl ester (36) was obtained. Yield: 091g 9-3) Synthesis of 13.14-dihydro-15-keto-20-methoxy-Δ''-PGF, α-methyl ester (37): Δ'-PGF, α-methyl ester (36) (0,545
89) was dissolved in acetic acid:water:THF (10:3.3:l) mixed solvent (20ffC) and kept at 55°C for 3.5 hours.

By treatment in a conventional manner, 13.14-dihydro-15-keto-20-methoxy-Δ'-PGF, α-methyl ester (
37) was obtained. Yield: 0.2935g.

9-4) l 3.14-dihydro-15-keto-2
0-Methoxy-Δ”-PGD, methyl ester (38)
Synthesis of: 13.14-dihydro-15-keto-20-methoxy-
Δ”-PGF, α methyl ester (37XO, 3277
g) was Jones oxidized (2,67-M, 0.25-M) at -40'C in acetone (20 mQ).

The crude product obtained after the conventional treatment was subjected to chromatography (ethyl acetate: hexane = 6:4), 13.14-dihydro-15-keto-20-methoxy-Δ2-PG D t
Methyl ester (38) was obtained. Yield 0.204g Figure 8 shows 13.14-dihydro-15-keto-20-
Methoxy-Δ! -PGD,, 'indicates n, m, r of thyl ester (38).

Example 10 13,14-dihydro-15-keto-18-methoxy-
19,20-bis-true PGD, methyl ester (39
) Synthesis of 13.14-dihydro-15-keto-18 in the same manner as in Example 5 using H (=)-Coley lactone (1) and dimethyl (5-methoxy-2-oxopentyl) phosphonate. -methoxy-19,20-bistrue PGD,
Methyl ester (39) was synthesized.

In Figure 9, 13.14-dihydro-15-keto-18-
The n, m, and r of methoxy-19,20-bis-true PGD, methyl ester (39) are shown.

Example 11 (see Synthesis Chart 2) 13.14-dihydro-15-keto-20-methoxy'/
Synthesis of PGD2 ethyl ester (20), R = Et: 13,14-dihydro-15,15-ethylenediexy-20-methoxy-PGF, α (17) in acetonitrile with ethyl iodide and DBU. The same procedure as in Example 5 was carried out except that ethyl ester (18) was used, and l
3.14-dihydro-15-keto-20-methoxy-
PGD, ethyl ester (20) was synthesized.

In Figure 10, 13.14-dihydro-15-keto-20
-methoxy-PGD, ethyl ester (20), R=E
Indicates n, m, r of t.

Example 12 (see Synthesis Chart 2) 13,14-dihydro-15-keto-20-methoxy-
PGD, n-butyl ester (20), R""n-BL
Synthesis of 13.14-dihydro-15,15-ethylenedioxy-20-methoxy-PGF2α (17) using n-butyl iodide and DBU in acetonitrile to form n-butyl ester (18), R 13.14-dihydro-15-keto-
20-methoxy-PGD2n-butyl ester (20)
, R=n-Bu was synthesized.

In Figure 11, 13.14-dihydro-15-keto-20
-Methoxy-PGDtn-butyl ester (20), R=n-Bu, where n, m, and r are shown.

Example 13 13,14-dihydro-15-keto-1f3 R,S-
Methyl-20-methoxy-PGD, methyl ester (4
Synthesis of 13. 14-dihydro-15-keto-15R,S-methyl-20-methoxy-PGD, methyl ester (40
) was synthesized.

In Figure 12, 13.14-dihydro-15-keto-15
R,S-methyl-20-methoxy-PGD, n, m, r of methyl ester (40) are shown.

Example 14 (see Synthesis Chart 2) 13.14-dihydro-15-keto-19-ethoxy-
Synthesis of 20-true PGD2 methyl ester (41); Proceed in the same manner as in Example 5 using (-)-Coley lactone (1) and dimethyl (6-nitoxy 2-oxohexyl) phosphonate obtained by a conventional method. 13.1
4-dihydro-15-keto-19-ethoxy-20-true PGD2 methyl ester (41) was synthesized.

In Figure 13, 13.14-dihydro-15-keto-19
-ethoxy-20-true PGD2 methyl ester (4
1) indicates n, m, r.

Example 15 (see Synthesis Chart 2) 13,14-dihydro-15-keto-19-ethoxy-
20-True P GD , n-butyl ester (42
) Synthesis of 13.1 in the same manner as in Example 5 using (=)-Coley lactone (1) and dimethyl (6-nitoxy 2-oxohexyl) phosphonate obtained by a conventional method.
4-dihydro-15-keto-19-ethoxy-20-true PG'D, n-butyl ester (42) was synthesized.

In Figure 14, 13. l 4-dihydro-15-keto-
n, m, r of 19-ethoxy-20-true PGD 2n-butyl ester (42) are shown.

Example 16 (See Synthesis Chart 5) (±03.l Synthesis of 4-dihydro-15-keto-5,6-zohydro PGD, methyl ester (50): 16-1) (±) 13.14-dihydro Synthesis of -5,5-dehydro-11,15R,S-bis(t-butyldimethylsilyl)oxy-PGE, methyl ester (44): (±)1-iodo-3-(2-tetrahydropyranyl)
Oxy-1-octene (1,852 g) was dissolved in ether (2
Vinyl lithium was prepared using t-butyllithium (pentane solution 1.92M, s, sa) at -78°C in 5 scraps C).Meanwhile, cupric iodide (0°9522y) was Suspended in THF (25 iρ), added tri-n-butylphosphine (3.24 m) to make it homogeneous, and then stirred at -78°
It was set as C. The vinyl lithium solution prepared previously was added to this, and the mixture was stirred at -78°C for 15 minutes. To this (±)4-
A solution of L-butyldimethylsilyloxy-2-cyclobentenone (4301,012 g) in THF (25 kg) was added dropwise. After dropping HMPA (4,62 iC), add triphenyltin chloride (2°029 g) to THF (10 cm
) solution was added. After stirring for 30 minutes at -78°C, -35
The temperature was raised to °C. To this, HMPA (4
, 62ff12) Add the solution dropwise and heat at -40°C to -30°
After stirring at C for 35 hours, the mixture was further allowed to stand at -20°C for 11.5 hours. The crude product obtained after the conventional treatment was subjected to chromatography (ethyl acetate:hexane=1:5) L, (±)1
3.14-dihydro-5,6-dihydro-11,15R
,S-bis-(t-butyldimethylsilyl)OgyushiP
GE2 methyl ester (44) (1,510″g) was obtained.

16-2) (±)13.14-dihydro-5,6-
Dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF, α-methyl ester (45
) Synthesis of: (±)13.14-dihydro-5,6-dihydro-11
,15R,S-bis-'(t-butyldimethylsilyl)
Oxy-PG Et methyl ester (4481,5
109) was reduced with sodium borohydride (NaBH-) in ethanol at -12°C to give (±)13.14=
Dihydro-5,6-dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF, α-methyl ester (45) was obtained. Yield: 0.942 g In addition, 0.23859 pieces of 9β monolithic (46) were produced as by-products.

18-3) (±)13.14-dihydro-5,6-
Dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrapyranyl)oxy~PGF! Synthesis of α-methyl ester (47): (±)
13,14-dihydro-5,6-dihydro-11,15
R,S-bis-(t-butyldimethylsilyl))oxy-PGF, α-methyl ester (45) (0°98429
) in dichloromethane (20 m) using dihydropyran and di-toluenesulfonic acid (±) 13.14
-dihydro-5,'6-zohydro 11.15R,S-
Bis-(t-butyldimethylsilyl)oxy~9-(2
-tetrapyranyl)oxy-PGF, α-methyl ester (47) was obtained. Yield 0.7516-4) (±)1
3.14-dihydro-5,6-dihydro-11,15R
,S-dihydroxy-9-(tetrapyranyl)oxy-
Synthesis of PGF, α-methyl ester (48): (±)13.14-dihydro-5,6-dihydro-11
,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrapyranyl)oxy-PGF2α
Methyl ester (4700,44849) was dissolved in THF (5
Tetrabutylammonium fluoride (1-M,
Diol (48) was obtained using 1.3n. Yield 0.
2174g 16-5) 13.14-dihydro-15-keto-5
,6-dihydro-9-(2-tetrapyranyl)oxy-
Synthesis of PGD, methyl ester (49) Nidiol (4
800,21749) in acetone (10 m, Jones oxidation (2,67-M, 0.05 mQ>L, 13.
14-dihydro-15-keto-5゜6-dihydro-9-
(2-tetrapyranyl)okine-PGD, methyl ester (49) was synthesized. Yield 0.1039 16-6) l 3.14-dihydro-15-keto-
Synthesis of 5,6-dihydro-PGD2 methyl ester (50): 13.14-dihydro-15-keto-5,6-dihydro-9-(2-tetrapyranyl)oxy-PGD2 methyl ester (49) (0,103 g ), acetic acid:THF:
It was dissolved in water (3:l:1) mixed solvent (50 yen) and kept overnight at 100 yen. After conventional treatment, chromatography (±)
-13,14-dihydro-15-keto-5,6-zohydro PGD, methyl ester (50) was obtained. Yield 0.
04989 Figure 16 shows (±)-13,14-dihydro-15-keto-5,6-zohydro POD, methyl ester (50
), n, m, r, are shown.

Example 17 (see composite charts 5 and 6) 13, 14
-dihydro-15-keto-5,6-zohydro PGD,
Synthesis of n-butyl ester (52): 17-1) 13.14-dihydro-5,6-dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrapyranyl) Oxy-P
Synthesis of GF, α(51): 1 obtained in the same manner as in Example 16 using 4R-t-butyldimethylsilyloxy-2-cyclobentenone (43). l 4-dihydro-5,6-dihydro-1
1,15R,S-bis-(t-butyldimethylsilyl)
Oxy-9-(2-tetrapyranyl)oxy-pGF2
Carboxylic acid (51) was obtained by mixing α-methyl ester (4700,7580 g) with a 20% aqueous sodium hydroxide solution in methanol. Yield 0.62029 17-2) 13.14-dihydro-5,6-dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrapyranyl)oxy-P
Synthesis of GF2αn-butyl ester (52): carboxylic acid (5100,1660y) in acetonitrile, DB
Using U and n-butyl iodide (0,09169), n-butyl ester (52) was obtained. Yield 0.164
8g Thereafter, in the same manner as in Example 16, 13.14-dihydro-15-keto-5,6-dihydro-PGD2 butyl ester (52) was synthesized.

In Figure 15, 13.14-dihydro-15-keto-5,
6-zohydroPGD, methyl ester (52) n,
m, r, are shown.

Example 18 (see composite charts 5 and 7) 18-t)
13. Synthesis of 14-dihydro-15-keto-5,6-dihydro-9β-PGD, methyl ester (59): Using 4R-t-butyldimethylsilyloxy-2-cyclobentenone (1), Example 1 obtained in the same way as 16
3.14-dihydro-5,6-dihydro-11,15R
, S-bis-t-butyldimethylsilyloxy-PGE
1 obtained by reducing 1(44) with N a B H4
3.14-dihydro-5,6-dihydro-11,15R
, S-bis-t-butyldimethylsilyl-PGF, β-methyl ester (4600°24909) was converted into tetrapyranyl ether (53) using dihydropyran in a conventional manner.
And so. Yield 0°777g 18-2) 13.14-dihydro-15-keto-5
,6-dihydro-11,15R,S-dihydro-9-(
Synthesis of 2-tetrapyranyl)oxy-pGFtβ methyl ester (54): The above tetrapyranyl ether (5380, 27779)
13. with tetrabutylammonium fluoride (1-M, 6.1 uQ) in THF (2 M solution) at room temperature.
14-dihydro-15-keto-5,6-dihydro-11
,15R,S-dihydro-9-(2-tetrapyranyl)
Oxy-PGF, β-methyl ester (54) was obtained. Yield: 0.1734g.

18-3) 13.14-dihydro-15-keto-5
, 6-dihydro-9β-(2-tetrapyranyl)oxy-PGD, synthesis of methyl ester (58) The above diol (54) (0,0816 g) was dissolved in acetone (15 m12
), Jones oxidation (2,67-M, 0
．． 17 Shoulder, 13.14-dihydro-15-keto-5
,6-dihydro-9β-(2-tetrapyranyl)oxy-PGD, methyl ester (58) was obtained. Yield 0.0
5059 18-4) 13.14-dihydro-15-keto-5
, 6-dihydro-9β-PG'D, methyl ester (5
Synthesis of 9): 13,14-dihydro-15-keto-5,6-dihydro-9β-(2-tetrapyranyl)oxy-PGD, methyl ester (58X0.05059), acetic acid:THF
:Water (3:1:1) mixed solvent (6 liters) and left at room temperature for 20 hours. The crude product obtained after treatment in a conventional manner was subjected to chromatography (hexane-ethyl acetate-3=1-1:
1) L, 13.14-dihydro-15-keto-5,6-
Dihydro-9β-PGD, methyl ester (59) was obtained. Collection ff10.031 Figure 17 shows 13,14-dihydro-15-keto-5,6-dihydro-9β-PGD,
n, m, r of methyl ester (59) are shown.

Example 19 (see Synthesis Chart 7) 13. Synthesis of 14-dihydro-15-keto-5,6-dihydro-9β-PGD, (57): 19-1) 13
．． 14-dihydro-5,6-dihydro-15R,S-hydroxy-(2-tetrapyranyl)oxy-PGF, β
Synthesis of (55): 13,14-dihydro-5,6-dihydro-15R,S-hydroxy-(2-tetrapyranyl)oxy-PGF, β-methyl ester (54) (0,0
8939) in methanol (4 MIC) was added with a 20% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2.5 hours.

After conventional treatment, carboxylic acid (55) was obtained. Yield 0°78
7g 19-2) 1°3.14-dihydro-15-keto-
Synthesis of 5,6-dihydro-9β-(2-tetrapyranyl)oxy-PGD2 (56): The above diol (55) (0,07879) was dissolved in acetone C
Jones oxidation (2,67-
M, 0.17xi2). Obtained after conventional treatment. The crude product was chromatographed L, 13.14-dihydro-
15-keto-5,6-dihydro-9β-(2-tetrapyranyl)oxy-PGD, (56) was obtained.

Yield 0.03449 19-3) 13. l Synthesis of 4-dihydro-15-keto-5,6-dihydro-9β-PGD, (57) The above carboxylic acid (56) (0,03449>), acetic acid:
Dissolved in THF:water (3:l:1) mixed solvent (5 liters),
Stirred at room temperature for 21.5 hours. The crude product obtained after conventional treatment was chromatographed to give 13,14-dihydro-15-keto-5,6-dihydro-9β-PGD, (5
7) was obtained. Yield 0.0152g Figure 18 shows 13.14
-dihydro-15-keto-5,6-dihydro-9β-P
GD, (57) n, m.

Indicates r2.

Example 20 Synthesis of 13,14-dihydro-15-keto-16,l 6-dimethyl-PGD, methyl ester (60): (-)-Coley lactone (1) and dimethyl (3,3- 13 in the same manner as in Example 1 using dimethyl-2-oxoheptyl)phosphonate.
．． 14-dihydro-15-keto-16,16-dimethyl-PGD, methyl ester (6O) was synthesized.

Figure 19 shows 13.14-dihydro-15-keto-16,
16-dimethyl-PGD, n of methyl ester (60)
, m, r, are shown.

Example 21 (See Synthesis Chart 1) Synthesis of (±)13.14-dihydro-15-keto PGD, methyl ester (11), R=Me = (±)-Coley lactone was used, and the same procedure as in Example 1 was carried out. te(±)13
．． 14-dihydro-15-keto PGD, methyl ester (II), R=Me was synthesized.

Figure 20 shows (±) 13.14-dihydro-15-keto-
PGD2 methyl ester (11), R=Me n, m
, r, is shown.

Example 22 13,14-dihydro-15-keto-19-methyl-P
Synthesis of GD, methyl ester (61): 13.14-dihydro- 15-keto-19-methyl-PGD, methyl ester (61) was synthesized.

In Figure 21, 13.14-dihydro-15-keto-19
-Methyl-PGD, n, m of methyl ester (61)
, r, is shown.

Example 23 13,14-dihydro-I5-keto-16,16-dimethyl-20-methoxy-PGD, methyl ester (62
) Synthesis of H υ (=)-Coley lactone (1) and dimethyl (3,
3-dimethyl-7-medoxy 2-oxoheptyl) phosphonate in the same manner as in Example 1 Yohi 22,
13.14-dihydro-15-keto-16,l 6-dimethyl-20-methoxypgd, methyl ester (6
2) was synthesized.

Figure 22 shows 13.14-dihydro-15-keto-16,
16-dimethyl-20-methoxy-pcD, n, m, r of methyl ester (62) are shown.

Example 24 (see Synthesis Chart 8) Synthesis of 13,14-dihydro-15-keto-15R,S-fluoro-PGD, methyl ester (74) = 24-1
) l5-2-oxa-3-oxo-6R-(4R,
S-fluoro-3R,S-hydroxy-1-octyl)-
Synthesis of 7R-p-phenylbenzoyloxy-7subicyclo(3,3,0)octane (64): (-)-Coley lactone (1) and dimethyl (3R
, S-fluoro-2-oxoheptyl) phosphonate, l5-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,S-
Oxo-1-octyl)-7R-(p-phenylbenzoyl)-cis-bicyclo(3,3,0)octane (6382,779) was dissolved in methane (90% alcohol) at 0°C.
was reduced with N a B H4 to obtain alcohol (64). Yield 2.91924-2) l5-2-oxa-
Synthesis of 3-oxo-6R~(4R,S-fluoro-3R,S-hydroxy-1=octyl)-7R-hydroboxybicyclo(3,3,O)-octane (65): The above alcohol (64 ) (2,919) in methanol (1
Diol (65) was prepared using potassium carbonate (0,829) in 20i12). Yield 1.61924-3)
3R-2-oxa-3-oki-no6R-(4R,
Synthesis of S-fluoro-3R,5-t-butyldimethylsilyloxy-1-octyl)-7R-(t-butyldimethylsilyl)oxy-cis-bicyclo(3°3.0)-octane (66): Above Diol (65X1.611iJ) in DMF (3+
Using t-butyldimethylchlorosilane and imidazole in ++Q), bis-silyl ether (66) was obtained. Synthesis of 16 R,S-fluoro-13,14-dihydro-11,15R,S-bis(t-butyldimethylsilyloxy)-P G F 2α (68): bis-silyl Ether (66) (2: 479) was reduced with D I BAL-H in a conventional manner to obtain lactol (67).
I got it. (4-Carboxybutyl)triphenylphosphonium bromide (6,339), sodium hydride (6
0%, 1. ．． Lactol (67) was added to the ylide obtained using DMSO (209) and DMSO (160 m
+i2) solution was added and stirred at room temperature for 15 hours. After treatment in a conventional manner, 11,15R,S-bis-t-butyldimethylsilyloxy-PGF, α(68) was reduced to 0.8879.9
．． 15-bis-1-butyldimethylsilyloxy-PG
0.996 g of F, α(69) was obtained.

24-5) 16 R,S-fluoro-13,14-dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF, α-methyl ester (70)
Synthesis of 11.15R,S-bis-t-butyldimethylsilyloxy-PGF, α(68) (0,887 g) in acetonitrile (25 mm), DBU (0,46 ff12) and iodomethane (0, 47ml12) was added and kept at 40°C for 3.5 hours. Methyl ester (
70) was obtained. Yield: 0.738g.

24-6) Synthesis of tetrapyranyl ether (71) The above methyl ester (70) was converted into tetrapyranyl ether (71) using dihydropyran and p-toluenesulfonic acid.

24-7) Synthesis of 16 R,S-fluoro-13,14-dihydro-15R,S-hydroxy-9-(2-tetrapyranyl)oxy-PGF, α-methyl ester (72): The above tetrapyranyl ether (71) was dissolved in THF (20N) and tetrabutylammonium fluoride (1,0
-M, 18xρ) THF solution was added and stirred at room temperature for 2 hours. The crude product obtained by conventional treatment was subjected to chromatography (hexane-ethyl acetate = 2 = 1 to 1:1).
, 16 R,S-fluoro-13,14-dihydro-15
R,S-hydroxy-9-(2-tetrapyranyl)oxy-PGF, α-methyl ester (72) was obtained. Collection i1
0.487924-8) 13.14-dihydro-1
Synthesis of 5-keto-16R,S-fluoro-9-(2-tetrapyranyl)oxy-PGD, methyl ester (73)
51M (1), 20 'Cte'; q-77: Oxidation (2,67-M, 1.1.9) After treatment in a conventional manner, the obtained crude product was chromatographed (hexane- Ethyl acetate = 5:1) L, 13.14-dihydro-15-keto-16R, S-fluoro-9-(2-tetrapyranyl)
Oxy-PGD, methyl ester (73) was obtained.

Yield 0.3739 24-9) 13.14-dihydro-15-keto-1
Synthesis of 6R,S-fluoro-PGD, methyl ester (74): The above tetrapyranyl ether (7300,373g) was dissolved in acetic acid:THF:water (3:1:1) mixed solvent (25d) and heated to 45°C. It lasted for 7 hours. The crude product obtained after treatment in a conventional manner was chromatographed (hexane-ethyl acetate =
4:l)L, 13. l 4-dihydro-15-keto-
16R,S-fluoro-PGD, methyl ester (74)
was synthesized. Collection jlo, 221gδ: 0.91 (
3H, t, J=6Hz), t.

1 to 2.93 (23H, m), 2.64 (3H, S
), 4.3-4.5 (1,5H, m), 4.98 (
0゜5H, dd, J=6Hz), 5.50 (2H, m
) Test Example 1 Sleep-inducing effect of 13.14-dihydro-15-keto-prostaglandin D administered into the third ventricle.

PGD (manufactured by Funakoshi) and 13.14-dihydro-15-keto-PGD obtained in this example were used as test specimens.

The animals used were male SD rats (body weight 350-4009).

Electroencephalograms were recorded on a polygraph using electrodes implanted into the rats' heads. The myoelectric electrode was inserted into the posterior cervical muscle and fixed.

For administration into the third ventricle, a stainless steel cannula with a diameter of 0.35 mm was inserted and fixed from the surface of the cerebral cortex until the tip of the cannula reached the third ventricle.

Observation of brain waves was conducted after a recovery period of more than one week after the surgery. × The experiment was conducted in a cage with a height of 45 cm, with the rat able to move freely.

A 1 ff19/ffc ethanol solution of the specimen was prepared, and the required amount was taken into a test tube, dried with nitrogen gas, and sterilized physiological saline was added and dissolved by vigorous stirring.

Into the third ventricle at a rate of 20μQ/hour, from 8:00 p.m.
Injected for 0 hours. As a control group, physiological saline was administered on the day before the administration of the test specimen.

EEG and myoelectric signals were recorded for 24 hours, and the amount of sleep of the rats was measured by electromyography and electroencephalogram recorded on a polygraph. The amount of slow wave sleep was determined using high amplitude slow waves as an index.

The results of administering 13.14-dihydro-15-keto-PGD are shown in FIG.

In FIG. 23, (a) shows the curve when 13.14-dihydro-15-keto-PGD was administered, and (b) shows the curve when physiological saline was administered.

Intracerebroventricular administration of 13.14-dihydro-15-keto-PGD increased the amount of sleep (Figure 23).

The above evaluation results are summarized in Table-1.

Test Example 2 Sleep-inducing effect of peripheral administration (oral administration, intravenous administration, subcutaneous injection) of 13.14-dihydro-15-keto PGDs: 13.14-dihydro-15 obtained in this example as a specimen - Using keto PGDs, P as a comparative specimen
GD2 (manufactured by Funakoshi) was used.

The animals used were 5 week old male 5lc-ddY mice. Intracortical fan waves were recorded by bipolar induction from electroencephalogram recording electrodes. The myoelectric electrode was inserted into the posterior cervical muscle and fixed.

Observation of EEG after a recovery period of one week or more,
Triangular stand installed at 0cm (IOXIOXLoam)
The experimental animal was placed on top of the test, and the level of arousal was increased.

For oral administration, the specimen was dissolved in physiological saline containing 0.5% carboxymethyl cellulose, and the concentration was adjusted so that a predetermined amount of the specimen was contained in 10 ml/kg. For intravenous administration, the sample was dissolved in physiological saline and administered through the tail vein. One group used 3 to 5 animals.

The test substance was administered 20 minutes after placing the mouse on the table, and electroencephalograms and electromyography were recorded using a polygraph for 80 minutes thereafter.

Based on the recordings, the brain wave levels were divided into the following four stages, which are schematically shown in Figures 24 to 27 as sleep progress charts over time.

(i) Awakening period (AW); brain waves are low amplitude and frequency 7-8H
There are many z ones. In addition, a clear electromyogram appears. (ii) Slow wave shallow sleep stage (SWLS); high amplitude slow waves of the brain waves (4 Hz or less) are observed, but the duration is 3
It is 0 seconds or less. (iii) Slow wave deep sleep phase (SWDS)
; EEG becomes high amplitude and slow, lasting for 30 seconds or more. (iv.
) Paradoxical sleep period (PS); the electroencephalogram is a low amplitude wave, but the electromyographic signal has completely disappeared. In addition, Fig. 24 to 2
The arrow in Figure 7 indicates administration at that time.

Figure 24 shows the sleep progress chart when physiological saline was administered intravenously, and Figure 25 shows the sleep progress chart when 5 mg/kg of 13.14-dihydro-15-keto PGD, methyl ester was intravenously administered. It was shown to. Even when physiological saline is administered intravenously, no 5WDS is observed, but 13.14-dihydro-15-keto-PGD2 ethyl ester has 5 m9
/kg intravenously administered to induce sleep in which 5WDS appears. Similarly, 13.14-dihydro-15-keto-
PGD2 ethyl ester, 13; 14-dihydro-1
5-keto-P G D 2n-butyl ester is 5rt
Intravenous administration of r'il/9 induced sleep in which 5WDS appeared.

Figure 26 shows the sleep progress chart when physiological saline containing 0.5% carboxymethyl cellulose was orally administered.13.1
4-dihydro-15-keto-20-methoxy-PGD,
Figure 27 shows the sleep progress chart when 51M9/kg of methyl ester was orally administered.
Although no appearance of DS was observed, 13.14-dihydro-
15-Keto-20-methoxy-PGD, methyl ester, induced sleep manifesting in 5WDS at an oral dose of 5 m9/kg.

Similarly, 13.14-dihydro-15-keto-3R,S
-Methyl-20-methquine-PGD2 methyl ester and 13,14-dihydro-15-keto-18-methoxy-18,19-dinol PGD, -Me ester also
Administration of mg/kg Po clearly showed the sleep-inducing effect of 5WDS.

Other test specimens showed the sleep-inducing effect of 5WDS when administered with 10xg/kg of P and O.

Table 1 shows the evaluation results of the presence or absence of sleep-inducing effects from the above measurements.
summarized in. In the table, + indicates that there was an effect, and - indicates that there was no effect.

Test Example 3 Sedative effect of intracisternal administration of 13.14-dihydro-15-keto prostaglandin D.

Compound 13゜14- obtained in the above example as a specimen
Dihydro-15-keto-PGD, 13,14-dihydro-15-keto-PGD2 methyl ester, 13. l
4-dihydro-15-keto-PGD2 ethyl ester, 13.14-dihydro-15-keto-PGD2n
-Butyl ester and PGD2 (manufactured by Funakoshi) and physiological saline were used for comparison.

An Img/xff ethanol solution of the specimen was prepared, and the required amount was taken into a test tube, dried with nitrogen gas, sterilized physiological saline was added, and ultrasonic waves were applied to form micelles. 10μA was used for intracisternal administration, and 10μQ of physiological saline was used for the control group.
was administered.

Animals were 4 male ddY mice (body weight 32-349) per group.
~6 animals were used.

Automex ■ (manufactured by Columbus Industries: Automex flCo) was used to measure mouse activity.
The behavior was expressed as the behavior fi (counts) using ``lombt+s Instruments''. A decrease in the amount of activity indicates a sedative effect.

The above sample was intracisternally administered to mice at a rate of 200 μy/9 times, and the amount of activity (count) over time after administration was measured. 13.14-dihydro-15-keto-PGD,
, 13.14-dihydro-15-keto-PGD2 ethyl ester, 13.14-dihydro-15-keto-PGD
2-ethyl ester, 13.14-dihydro-15-keto-P GD , n-butyl ester has a sedative effect when administered intracisternally at a dose of 9 to 0.2R9/, and PGD exhibits a sedative effect when administered intracisternally at a dose of 9 to 0.02 m9/. did. The evaluation results of its sedative effect are summarized in Table-1.

Test Example 4 Sedative effect of peripheral administration (oral administration, intravenous administration, subcutaneous injection) of 13.14-dihydro-15-keto PGDs: The same specimens and comparative specimens as in Test Example 2 were used.

The animals were 5-week-old male 5lc-dd)' mice in groups of 6.
~14 animals were used. MK-ANtMEX (manufactured by Muromachi Kikai Co., Ltd.: MK-ANtMEX) was used to measure the amount of mouse activity.
ACTIVITY METERModel D S
E) was used to count and measure the amount of activity. A decrease in the amount of activity indicates a sedative effect.

The test samples were administered to mice, and the presence or absence of sedative effects was evaluated. The results are summarized in Table I.

PGD showed sedative effects when administered intravenously at 1 m9/9, but 13.14-dihydro-15-keto-'P
GD showed no sedative effect at 5 mg/kg. 13.14-dihydro-15-keto-PGD.

methyl, ethyl, n-butyl esters of 5 m9/k
Intravenous administration of 1.5 g showed a sedative effect.

13.14-dihydro-15-keto-20-methquin-
PGD, methyl ester, exhibited sedative effects both when administered orally at 5 q/9 and when administered intravenously at 1 m9/9. 13.14-dihydro-15-keto-3R,S
-Methyl-20-methoxy-PGD, -Me ester showed a sedative effect when administered orally at 5 mg/&9. Other test specimens showed sedative effects when administered intravenously at 10 mg/kg.

Furthermore, it was confirmed that I3,14-dihydro-15-keto PGD derivatives according to the present invention not shown in Table 1 have similar sedative and sleep-inducing effects.

Table-1 Specimen; 1:13.14-dihydro-15-keto-PGD.

2:13,14-dihydro-15-keto-PGD.

methyl ester 3:13.14-dihydro-15-keto-PGD.

ethyl ester 4:13,14-dihydro-15-keto-PGD.

n-Butyl ester 5: 13,14-dihydro-15-keto-20-methoxy-PGD, methyl ester 6: 13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD, methyl ester 7:13.14~dihydro-15-keto-18-methoxy-19,20-bistrue-PGD, methyl ester 8:13,14~dihydro-15-keto-20-methoxy-PGD, ethyl ester 9:'13, 1.4-dihydro 15-keto-20-methoxy-PGD, n-butyl ester 10:13.14
-dihydro-15-keto-20-methoxy-PGD.

11:13.14~dihydro-15-keto-20-methoxy-Δ'-PGD, methyl ester 12:13,14
-dihydro-15-keto-16R1S-methyl-20-
Methoxy-PGD, methyl ester 13: 13,14-dihydro-15-keto-20-methoxyethyl-PGD, methyl ester 1.4: 13
．． 14-dihydro-15-keto-19-ethoxy-20
-True PGD2 Butyl Ester 15:13.14-dihydro-15-keto-19-ethoxy-20-True PGDtn-Butyl Ester 16:13.14-dihydro-15-keto-16,16
-Simethyl-20-methoxy-PGD, methyl ester 17:13,14-dihydro-15-keto-19-methyl-PGD, methyl ester 11! l: 13,14-dihydro-15-keto-16R
1S-fluoro-PGD, methyl ester 19: 13,14-dihydro-15-keto-5,6-dihydro-9R-PGD, methyl ester 20: PGD
, (manufactured by Funakoshi) 21: Physiological saline *1 Intracerebroventricular administration *
2. Intracisternal administration *3. Oral administration *4. Intravenous injection *5. Subcutaneous injection
It also has significant sleep-inducing and sedative effects when administered peripherally, such as by subcutaneous injection or intravenous injection.

In addition, the present invention 13.14-dihydro-15-keto PG
Class D is the blood TFI and aggregation inhibition that PGDs have at the same time.
Physiological and pharmacological effects such as tracheal constriction, intestinal constriction, and vasodilatory effects do not occur at all or are significantly reduced.

Therefore, the present invention 13.14-dihydro-15-keto P
When GDs are administered peripherally, such as by oral administration, subcutaneous injection, or intravenous injection, it is possible to obtain centrally acting drugs that exhibit sleep-inducing and sedative effects, which are extremely excellent in practical terms. Therefore, the present invention 13.14-dihydro-15-
Keto PGDs are useful as sleeping pills and tranquilizers.

[Brief explanation of the drawing]

Figure 1 shows 13.14-dihydro-15-keto PGD,
Ethyl ester, Figure 2 is 13.14-dihydro-15-keto-PGD!
, (thyl ester, Figure 3 shows 13.14-dihydro-15-keto-PG
D*n-butyl ester, Figure 4 is 13.14-dihydro-15-keto-20-methoxy-PGD, methyl ester, Figure 5 is 13.14-dihydro-15-keto-20-methoxy-PGD, , Figure 6 shows 13.14-dihydro-15-keto-3R,S
-Methyl-20-methoxy-PGD, methyl ester, Figure 7 shows 13.14-dihydro-15-keto-20-
Methoxyethyl-PGD, methyl ester. Figure 8 shows 13. l 4-dihydro-15-keto-2
0-Methoxy-△”-PGD, methyl ester, Figure 9 shows 13.14-dihydro-15-keto-18-methoxy-19,20-bisnor~PGD. Methyl ester, Figure 10 shows 13.14-dihydro -15-keto-20-
Methoxy-PGD, ethyl ester, Figure 11 shows 13.
14-dihydro-15-keto-20-methoxy=PG
D tn-butyl ester, Figure 12 is 13.14-
Dihydro-15-keto-15R, S-methyl-20-methoxy PGD, methyl ester, Figure 13 shows 13.14-dihydro-15-keto-19-
Ethoxy-20-true PGD2 butyl ester, Figure 14 shows 13.14-dihydro-15-keto-19-
Ethoxy-20-true PGD2 butyl ester, Figure 15 shows 13.14-dihydro-15-keto-5,6
-Zohydro PGD, methyl ester, Figure 16 is (1
)-13,14-dihydro-15-keto-5,6-zohydro PGD, methyl ester, Figure 17 shows 13.14
-dihydro-15-keto-5,6-dihydro-9R-P
GD, methyl ester, Figure 18 is 13.14-dihydro-15-keto 5.6
-Zohydro 9R-PGD, Figure 19 is 13.14-
Dihydro-15-keto-16,16-dimethyl-PGD
, methyl ester, Figure 20 shows (1) 13.14-dihydro-15-keto PGD, methyl ester, Figure 21 shows 13.14-dihydro-15-keto-19-
Methyl-PGD, methyl ester, Figure 22 is 13.1
4-dihydro-15-keto-16,16-cymethyl-2
0-Methoxy-PGD, -methyl ester, Figure 23 shows 13.14-dihydro-15-keto-PGD
Figures 24 to 27 are sleep progress charts. Patent applicant Agent: Ueno Pharmaceutical Applied Research Institute Co., Ltd.
Patent attorneys Aohaku Ao and 2 others Figure 7

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, (X); ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
A), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (B), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (C), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (D) R_1; Hydrogen, physiological a physiologically acceptable protecting group or an alkyl group of C_1 to C_4, R_2; hydrogen or methyl group, R_3; hydroxyl group, methyl group or hydroxymethyl group, R_4 and R_5; hydrogen, methyl group, hydroxyl group Or halogen. However, R_4 and R_5 may be the same or different. R_6; C_ which may have a branch or double bond
It represents a 1 to C_9 alkyl group or a C_1 to C_9 alkyl group having an ether substituent, and the carbons at the 2-3 positions may have a double bond. (However, R_1, R_2, R_4 and R_5 are hydrogen, R_3 is a hydroxyl group, R_6 is n-butyl, the carbons at the 2nd and 3rd positions are single bonds, and (X) is A,
C or D)] Prostaglandin D represented by: 2, the first in which R_4 and/or R_5 are halogen;
Prostaglandin D class described in section. 3. Prostaglandin D according to item 1, wherein R_4 and/or R_5 are fluorine atoms. 4, the first in which R_4 and/or R_5 are methyl groups
Prostaglandin D class described in section. 5. Prostaglandin D according to item 1, wherein the terminal carboxyl group of the α chain is an alkyl ester. 6. Prostaglandin D according to item 1, wherein the terminal of the ω chain is an alkoxy group. Prostaglandin D according to item 1, which is a 7,9β-hydroxy form. 8,13,14-dihydro-15-keto-16R,S-
2. Prostaglandin D according to item 1, which is methyl-prostaglandin D or an alkyl ester thereof. 9,13,14-dihydro-15-keto-16,16-
2. Prostaglandin D according to item 1, which is dimethyl-prostaglandin D or an alkyl ester thereof. 10,13,14-dihydro-15-keto-16R,S
-Prostaglandin D according to item 1, which is fluoro-prostaglandin D or an alkyl ester thereof. 11. Prostaglandin D according to item 1, which is 11,13,14-dihydro-15-keto-20-methoxy-prostaglandin D or an alkyl ester thereof. 12. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, (X); ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
A), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (B), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (C), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (D) R_1; Hydrogen, physiological a physiologically acceptable protecting group or an alkyl group of C_1 to C_4, R_2; hydrogen or methyl group, R_3; hydroxyl group, methyl group or hydroxymethyl group, R_4 and R_5; hydrogen, methyl group, hydroxyl group Or halogen. However, R_4 and R_5 may be the same or different. R_6; C_ which may have a branch or double bond
It represents a 1-C_9 alkyl group or a C_1-C_9 alkyl group having an ether substituent, and the carbons at the 2-3 positions may have a double bond. ] A sedative/hypnotic agent characterized by containing prostaglandin D represented by the following as an active ingredient.