JPS58203964A - Prostaglandin-mimic compound, its preparation and remedy containing said compound - Google Patents

Abstract

NEW MATERIAL:The prostaglandin-mimic compound of formula I (R<1> is 1-5C alkylene; R<2> is 1-8C alkyl, 4-7C cycloalkyl which is unsubstituted or substituted with at least one 1-8C alkyl, etc.; the double bond between the 13 and 14 carbon atoms is trans; excluding the compound of formula II) and its cyclodextrin clathrate compound. EXAMPLE:2- Decarboxy-2-glycoloyl-6-oxo-15- ( 3-propylcyclopentyl ) -16,17,18,19,20- pentanol-pGE1. USE:Remedy for cell disorder. Useful for various diseases caused by the disorder of the cells of digestive organs, uropoietic organs, respiratory organs, circulatory organs, blood, etc. PROCESS:The compound of formula I can be prepared by hydrolyzing the compound of formula III (R<3> is tetrahydropyran-2-yl, etc.) under acidic condition.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a '4B prostaglandin-like compound, a method for producing the same, and a therapeutic agent using the compound.

Prostaglandin (hereinafter abbreviated as PG) is a derivative of brostanic acid having the following structure, and PC of extreme oils is known.

PG generally has pharmacological properties. For example, smooth muscle contraction action, blood pressure lowering action, diuretic action, platelet aggregation inhibiting action, gastric acid distribution and gastrointestinal ulcer inhibiting action, bronchodilator action, lipolysis inhibiting action, and egg implantation inhibiting action. It has an effect.

Therefore, prevention and treatment of hypertension, peripheral circulation disorders, asthma and gastrointestinal ulcers, treatment and prevention of thrombosis and myocardial infarction, induction of labor and abortion in pregnant mammals, improvement of fertilization in female mammals, estrus regulation, contraception and It is effective in normalizing menstruation and has a southern effect as a diuretic.

Recently, a woodcutter's PG has been reported to be effective in cell lines, and is known to be effective as a therapeutic agent for cell damage (for example, a therapeutic agent for liver and pancreatic disorders).
stroenterology volume 78.

777-781-'-ji (1980 pot), volume 81.

211-21'7? - Ji (1981) and Folia
Histachemica at Cytochemi
ca, '1.8, pages 611-318 (198
0 years) 8sho].

The present invention has the 4-embedding effect of 1-natural PG;
As a result of extensive research, we have conducted extensive research in order to find unique compounds that have one or more of these properties, are more erodible, more active, or have completely unknown oil properties. We discovered that a new compound in which the carboxyl group at the 1st position of brostanoic acid was replaced with glycoloyltsubaki 1 (-〇-0H20H group) and an oxo group was introduced at the 6th position carbon atom had a selectively strong cytoprotective effect. Completed the invention.

The present invention is based on the general formula (wherein R is a single bond or [-< represents a straight or branched alkylene group having 1 to 5 carbon atoms,
0 straight-chain or branched-chain alkyl group, or a cycloalkyl group having 4 to 7 carbon atoms that is unsubstituted or substituted with at least one straight-chain or branched alkyl group having 1 to 8 carbon atoms; or a phenyl or phenoxy group that is unsubstituted or substituted with at least one halogen atom, trifluoromethyl group, or furkyl group having 1 to 4 carbon atoms, and represents a double group between the carbon atoms at the 16th and 14th positions. The bond represents a transformer. However, compounds represented by the following formula are excluded. ), the novel prostaglandin-like compound shown by Sosai 1 et al.'s 7-clodextrin clathrate compound, the production method of Sosai 1 et al., and the compounds represented by general formulas (I) and (II) as one active ingredient. It relates to a cytotoxic therapeutic agent V containing as.

In the structural formula of this specification, the dotted line (---) represents the general 7
&C According to accepted nomenclature rules, the group attached to it is on the back side of the plane, i.e. in the α-configuration, and the thick line (\) indicates that the group attached to it is PI'l in the plane.
side, i.e., the β-configuration, and the wavy line () indicates that the group attached thereto is in the α- or β-configuration or a mixture thereof.

The present invention is directed to formula 11 (all compounds represented by Il, i.e., optically active "natural type" or its enantiomer or mixture thereof; This is related to the racemic body.

As is clear to those skilled in the art, the compound represented by the general formula (Il) has four asymmetric centers, and these four asymmetric centers are and the carbon atom at the 15th position.Historically, other asymmetric centers may occur due to R and the R group.As is well known, the presence of isomers in the asymmetric center However, the compounds represented by the general formula (Il) all have a configuration such that the @ buttons on the 8th and 12th carbon atoms of the alicyclic ring are triyx to each other. Therefore, the compounds represented by the general formula (Il) The side chains attached to the carbon atoms at the 8th and 12th positions of the compound have a trans-configuration, and isomers and mixtures thereof having hydroxyl groups at the 11th and 15th positions have the general formula (
Include the range of compounds shown in I). preferred -R
-R is, for example, n-a methyl, 1-methyl is methyl, 2-methylpentyl, 6-methylpentyl, 4-methylpentyl, 1,1-dimethylpentyl, 1.2-cymetyl, 1 ,4-dimethylpentyl, 1
-ethylpentyl, 2-etherpentyl, 1-7'ropylpentyl, 2-propylpentyl, n-hexyl, 1
-Methylhexyl, 1.1-cymeterhexyl, 1-ethylhexyl, 2-ethylhexyl, n-heptyl, 2
-Etherheptyl, n-nonyl, n-undecyl, cyclobutyl, 1-propyl 7 cloftel, 1-bunalcyclobutel 1-hentyl cyfurobunal, 2-propyl 7
Cloftel, 6-ethelcyclobutel, 6-propyl 7
clofter, cyclobennal, cyclopentylmethyl,
1-7 clobenthylethyl 2-cyclomethylethyl, 2-7 clobentelprovil, 2-ethylcyclopentyl, 2-propyl 7 clobentyl, 2-i cyclobentel
Crossmethyl, 1-methyl-3-propylcyclobenal, 2-methyl-3-propylcyclopentyl, 6-methylcyclopentyl, 6-ethylcyclobentyl, 3-
Methyl, 6-punalcyclosmethyl, propylfucro,
Cyclohexyl, 6-ethylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propyl/chlorohexyl, 2,6-dimethylcyclohexyl/
, cyclohexylmethyl, (1-methylcyclopentyl)methyl, 1-7 chlorohexyl ether, 2-7 chlorohexylethyl, 1-methyl-1-nochlorohexyl ethyl, 'r, -7 chloroheptylethyl, phenyl, benzyl , α-phenylethyl, β-phenylether, 1-phenylbennal, phenoxy7methyl, (3-chlorophenoxy7)methyl, (410lophenoxy)methyl, (3-
IJ fluoromethylphenoquine) contains methyl groups, etc.
However, more preferable -R-R is n-bennal, 1
-Methyl is methyl, i,i-dimethylpentyl, cyclobutyl, cyclo is methyl, 6-methylcyclopentyl,
6-ethylcyclobentyl, 6-propylfuco-methyl, 3-'thyl-7-lylopentyl, cyclohequinyl, 4-
7'ropylnochlorohexyl, benzyl, (6-chlorophenoxy)methyl group.

The undiscovered product is 2-decacyboquine represented by formula (n)
It is also a valuable drug that contains 2-glycoloyl-6-oxo-178,20-dimethyl-PGE and its cyclotextrin-containing compounds as active ingredients.

According to the present invention, the PG-like compound represented by the general formula (1) is a PG-like compound represented by the general formula
Tetrahydro I substituted with t, sl alkyl groups
keran-2-yl group, tetrahydrofuran-2-yl group, or 1-ethoxyethyl group, and other Wl: +i represents the same meaning as above);
,) compound obtained from Kotoriko by hydrolysis under acidic conditions. This hydrolysis reaction is generally well known, and includes, for example, an aqueous solution of an organic acid such as m acid, proonic acid, uric acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid υ) θ1
In a water bath solution of 1-silicate acid, preferably a water-miscible medium, for example a lower alkanol such as methanol or ethanol (preferably methanol) or 1,2-dimethoxyethane, dioxane or tetrahydrofuran. (2) p-toluenesulfonic acid in an anhydrous alkanol such as methanol or ethanol, or (2) p-toluenesulfonic acid or It is carried out at i&1 of 100-45C in the presence of an organic acid such as trifluoroacetic acid. Mild hydrolysis is preferred [2 (- a mixture of acid, water and tetrahydrofuran, - a mixture of water and methanol, a mixture of acetic acid, water and tetrahydrofuran or a mixture of luenesulfonic acid and hot water methanol). It is done using liquid.

The compound represented by the general formula (e) is a compound represented by the general formula (wherein, absolute 1% of the carbon atoms at the 1st and 6th positions, 1- represents a mixture of S, R, or R8, and - "all 6 carbon atoms. have the same meanings as above), or compounds represented by the general formula (in which the absolute configuration of the 1st-position sulfur atom is S and fc is H, respectively.
or R8 mixture, all symbols are 5llR+
: Expresses the same meaning as . ) by subjecting the compound to a mild oxidation reaction.

Preferably, the oxidation reaction under mild and neutral conditions is carried out, for example (1) in chloroform, methylene chloride, depressed carbon, 4111 halogenated mounds, water or toluene, 0°04, -p OC( Dimethyl sulfide-N in DImW
-Chlorosphucunimide lead body, thioaniso-A/-N-
This is carried out by reacting with a chlorosulfine chlorine complex, a dimethylsulfi 1-chlorine complex, IP, or a thioanisole-chlorine complex, followed by treatment with triethylamine [J, A+ner, Chc+n.

Soc,, 94.7586 (1972) #Sho],
or (2) in halogenated hydrocarbons such as chloroform, methylene chloride, carbon chloride, etc. from room temperature,
1 melon, preferably in DC with chromium trioxide-biricin moiety (
(For example, Collins reagent) or (3) acetone, dilute sulfuric acid, and Jones reagent 4 at temperatures from room temperature to DC.

The compound represented by the general formula (1) and the general formula (in the formula, the 1st, 5th, and 6th positions, 1+<child U),
*-1h: 1g each independently represents S, R-J, or f(S mixture), and all symbols have the same meaning as 1 and 1, respectively. It can be obtained by subjecting a compound to dehydrobromation reaction and then hydrolyzing it under acidic conditions.

The reagents used in the dehydrobromation reaction are well known: 1. y
”), for example, 1,5-diazavinchlo[5,4,
0] umpsen-5 (DBU), 1,5-diazabicyclo[4,5,0] nonene-5 (DBN) or 1,4-diazabi/chloro[2,2,01 octane (D
di-salt amines such as ABCO) or alkali metal alcoholades, e.g. lower sodium or potassium
Alcorado is taken. The reaction is carried out at a temperature of 40 to 110 C, preferably 40 to 8 DC, with or without a solvent when using an amine, preferably in toluene or without a solvent (when using an alcolade). Should the same lower alkanol be used as the solvent?

Hydrolysis under acidic conditions does not eliminate the R group (・YoVC
a) You have to do it because you are lazy. Hydrolysis under such pouring conditions is carried out in the presence of a water-miscible inert organic solvent, such as an ether such as dimethoxyethane, dioxane or tetrahydrofuran (preferably tetrahydrofuran), or in the presence of a A water bath of an organic acid, such as propionic acid, phosphoric acid or p-)luenesulfonic acid, or a water bath of an inorganic acid, such as cloth - carried out in acid or dilute sulfuric acid. Suitable solutions include vinegar, a mixture of water and tetrahydrofuran, a mixture of dilute hydrochloric acid and tetrahydrofuran, or dilute hydrochloric acid.

The compounds obtained by this hydrolysis are a compound represented by the -d formula and a compound represented by the general formula concave. Those skilled in the art will understand that the compound represented by the general formula αV) and the compound represented by the general formula M may exist in equilibrium.

A compound represented by the concave general formula (vt+) has the general formula r (wherein, the absolute configuration of the carbon atoms at the 5th and 6th positions each independently represents S or R or a mixture of R8, and all symbols are ) has the same meaning as (2,4-dioxa-6-meteruhekynyl)-?
! It can be obtained by a known method of carrying out an addition reaction with J-n-butylstampane. Preferred conditions for this reaction are, for example, 0-801
,' at a temperature of n-butyllithium and (2,4-diA
n-Butyllithium and (2
,4-dioxa-6-methyl-hexyl)-tri-n-
Obtained by distilling butylstannane [J,
Am, Chem, Soc, eloo, 1481 (
1978) #Sho].

The compound represented by the general formula (2) is a compound represented by the general formula (wherein, the absolute configuration of the carbon atoms at the 5th and 6th positions each independently represents S, R, or a mixture of R8, and R has 1 to 6 carbon atoms. 4 represents a straight-chain, branched-chain, or branched-chain alkyl group, preferably a methyl group, and other symbols have the same meanings as above. For this reaction, a 0° collar (80cv) in hexane, tetrahydrofuran or toluene is used, for example.
diisobutylaluminum hydride (D
iBAL) is preferably carried out using DIBAL at a temperature of -78C in toluene.

The starting material shown in the formula
No. 53-116365.

Cyclotext linkage of prostaglandins (1) compound represented by the general formula (Il) hp (k compound uses α-, β-, γ-cyclodextrin or a mixture thereof; and JP-A-4749057 specification 4#s can be obtained by using the self-mounted Qnonono method.

By converting it into a cyclodextrin clathrate compound, the stability of the prostaglandin-like compound represented by general formula (I) is increased, and its water-bathability is reduced, making it convenient for use as a drug.

In addition, the compound represented by formula (II) is described in conjunction with the method for producing the compound described in AiJ (11.
゜It is described in detail.

Compounds similar to whole brostagcindin and their cyclotextrin inclusion compounds represented by the general formulas (I) and (formula proviso) have a comparative effect on cell protection, although their axial negative effects on prostaglandins are comparatively small. Because it has a selectively strong effect and extremely low toxicity, it is an extremely effective cytotoxic therapeutic agent (it can be used as a therapeutic agent for all organ and tissue diseases caused by cell damage, i.e., a general formula f
Prostaglandin-like compounds and their cyclotextrin clathrate compounds represented by the formula 73 and formula (1) and formula (73) are used to treat (1) gastrointestinal diseases (such as hepatitis, fatty liver, and anal stiffness) caused by cytotoxic VC. 12+ urinary diseases (such as nephritis, diabetic nephropathy, cystitis, urethritis, etc.), F31 respiratory diseases (
(e.g., pneumonia, empyema, phlegmonitis, etc.), +41 circulatory system diseases (e.g., non-V pulse, cerebral aneurysm, cerebral isthmus, etc.), (5) blood diseases (e.g., anemia, etc.), and (6) other It is effective for various diseases and/or treatment of diseases (for example, diabetes and complications resulting therefrom).

For example, in laboratory experiments, (1) carbon tetrachloride causes a8
Liver damage in rats caused by
ff19 Application No. INj57-46580 Akig*, tc description for the same C(・ru.), 2-decarboxy-2-
Glycoyl-6-oxo-178,20-dimeblue PGE (hereinafter abbreviated as compound A) was 50μi
/KP When administered orally at a dose equal to the animal's body weight, the Y6 sex of glutamate oxaloacetate transmif-se (GOT) and glutamate pyruvate transaminase (GPT) in plasma was 11 that 580
% and 59.7%, and when administered subcutaneously at a dose of 20 μy/9 animal body weight, it inhibited plasma +7) GOT and GPT activities by 61.4% and 48.7%, respectively, and 2- Decalphox/-2-glycoloyl-6-okyne-15-(3-butyl/chloromethyl)-16,1s18.19.20-pentanol-PGE (hereinafter abbreviated as compound B) is 50/' GOT and GPT in plasma when administered orally at a dose of
2-decarboxy-2-glycoloyl-6-oxo-
15-1-propylcyclopentyl) -16,17,
18,19゜20-':np)ruPGE (hereinafter,
It is abbreviated as compound vlG. ) was orally administered at a dose of 50 μ9/dish to an animal body, which increased GOT and GP in plasma.
inhibited T activity by 46.7% and 45.1%, respectively;
(-) α-Naphthylisothio7γnate-induced liver damage in rats (Special request for detailed experimental methods!
It is described in specification 4k of No. 57-46580. ), Compound A was orally administered at a dose of 100 μ9/'-fl animal body weight-', and GOT and G in plasma were
'T's t8 sex and bilirubin fly respectively 490.
567 and 21.2%, and compound B was 1[
JllJ/#A) When administered orally at a dose of animal body weight, the activity of GOT and QPT in plasma and bilirubin wrinkles were inhibited by 56.1%, 61.6% and 60.6%, respectively, and Compound C inhibited 100μ , 9/i'P Animal body weight at °C
1° of iii WE and bottle amount 30.
3%, 41.7% and 15.2% inhibition, (iii
D (+l-galactosamine hydrochloride-induced liver damage in rats
-46580 No. 11t114. However, in this case), galactosamine hydrochloride is 3751w
6.12.18.24.3 From the administration of inhalation V.
The compound of the present invention was orally administered 7 times at 0, 36, and 42 hours, and blood was collected 48 hours after the first administration of galactosamine hydrochloride. ), compound B is 10
When administered orally at 0 μg/animal body i, the viscosity of GOT and GPT in plasma and bilirubin violet were 57.0%, respectively, and S4. It was suppressed by 0% and 66.0%.

On the other hand, the effects of Tokiichi on prostaglandin, particularly uterine muscle contraction, platelet aggregation inhibition, and hypotensive effects, were weak. For example, in a laboratory experiment, (1) Compounds A% B and C were administered intravenously to female rats on day 621 of pregnancy, at doses of 20.50 and 20 μg/Ky animal body weight, respectively. stimulates contractions of the uterine muscles,
(Ill compounds B and C when using human blood,
6.6x3-3 10~7.2 X10 and 1.8x10~1 respectively
．． The longitudinal beams of platelets emitted by adenosine diphosphate (ADP) at a concentration of 8 × 10 μg/WLt were
% inhibited and (lit) alloparbital-treated dogs intravenously, Compound A was 0.6 & 0.5 μ9
,/to? Dosage of 6 and 15 h per animal body weight, respectively
9, the effect was 14 and 2, respectively.
Lasting for 9 minutes, Compound B was added at 0.5 and 1.0 μg/2
At doses of 0.1 and 0.2 μ9/Ky of animal body weight, Compound C lowered blood pressure by 20 and 47 μH,9 respectively, and the effects lasted for 17 and 40 minutes, respectively. It showed blood pressure levels of 20 and 35 rImHg, and the effects lasted for 9 and 26 minutes, respectively.

Furthermore, the toxicity of the compounds of the present invention is very low;
Is it safe enough to use as a medicine?
Q was asked. For example, in the acute toxicity test vc2 using mice, LD5o@ in oral administration of compounds A, B, and C.
were 10-20, >10 and 5-10~/Kp animal weight, respectively, which were very low.

-5 The protein-taglandin-like compounds represented by formula (I) and formula (III) and their cyclodextrin clathrate compounds are usually administered systemically or locally in order to be used as therapeutic agents for cytotoxicity. , administered orally or parenterally.Dosage depends on age, body weight, symptoms, therapeutic effect, administration method,
It varies depending on processing time etc., but usually 1 hour per adult.
0.1 μy to 100 μμ, preferably 1 μg to 5
CJl'H range 4 is orally administered from 1 g to several times a day or per adult, 0.01 μI to 5 per infusion.
It is administered 111 times to 41 times per day, preferably in the range of 01 to 20 μl. Of course, as mentioned above, the dosage will vary depending on the conditions, so there are cases where a dosage lower than the above range is sufficient, and there are also cases where a range of dosage is absolutely necessary.

Solid compositions for administration to Japan according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances may be present in a small amount (and one inert diluent, such as lactose, mannitol, hydroxyl, hydrochloride,
Microwm cellulose, tenbun, polyvinylpyrrolidone,
Mixed with magnesium/aluminate metasilicate. Items in the group should be cooled using a cooling agent other than an inert diluent according to the usual method.
The wound may contain a lubricant, such as stearic acid, or a disintegrant, such as calcium/magnetic fiber gluconate. Tablets or pills may be coated with a film of gastrointestinal or fully soluble substances such as sucrose, ceratin, hydroxypropylcellulose, hydroquinopropylmenalcellulose fugrate, or two or more. It may be coated with layers. It may also be made into a gelatin-like gelatinous capsule.

Adult compositions for oral administration include pharmaceutically-enriched milk, bath liquid, suspension, elixirs, etc. Inert diluents commonly used, such as rice water and ethanol. In addition to the inert diluent, this composition also contains adjuvants such as wetting agents and suspending agents.
It may also contain sweetening agents, flavoring agents, aromatics, and preservatives.

Other compositions for oral administration include one or more active substances and sprays formulated according to known methods.

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

Examples of water-insoluble bath solutions and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as J-League oil, and -r-silcol polysorbates such as ethanol)80. Gum arabic, sodium alginate, etc.) Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These can be imaged, for example, by C filtration through a bacteria-retaining filter, sterilizing formulations or irradiation. Alternatively, a sterile homogeneous composition can be prepared and dissolved in a sterile or sterile injection solvent for stool administration before use.

Other compositions for parenteral administration include:

One or more oily substances may be sweetened and formulated in a manner known to the art. External use? & AIJ, liniments such as ointments, suppositories for intrarectal administration, and tsalaries for internal administration.

Preferred examples of compounds represented by the general formula (I) included in the present invention include, for example, N/carboino 2-glycoloyl-6-okino PGW1. 2-7ty rubogino-2-glycoloyl-6-oxo-
16-methyl-PGE.

2-Decalhoquino 2-Bulcoloyl-6-Oquino 1
6.16-dimethyl-PGE, 2-decarboxy-2
-Glycoyl-6-oxo-15-/Krotchilu 1
6.17.18.19.20-Pentanolu PGE
.

2-Nocalfoxy 2-glycoloyl-6-oxo-
15-chloro is butyl-16,1st 1B, 19゜2
u-pentanol-PI.

2-7 carpoquin-2-glycoloyl-6-oxo-1
6-(3-butylcyclo is butyl) -16゜1418
, 19.20-pentanol-PGE1.2-tecarboquine-2-glycoloyl-6-ox, no 1b-(6-ethelcyclopentyl) -16°17, 1 B, 19
．． 20- is tantanol-PGE, 2-decarboxy-2-
Glycoyl-6-iso-15-0-propylcyclobutyl)-16,17,18,19,20-pentanol-peh.

2-decacyboquine-2-glycoloyl-6-i'-'t
Meso-5-(3-butylcyclo is butyl) -16゜1
7, 18.19.20-Pentano-PGE1.2-Decarboxy-2-glycoloyl-6-oxo-15-7
Kurohekifuru 16.17.18.19゜20--! Tantanol-PGE, l2-decalhoki-2-glycoloyl-6-oxy:/-
15-(4-propylcyclohexyl)-16, 17,
18,19,20-pentanol-PGE, 2-decarboxy-2-glycoloyl-6-okino-16-phenyl-17,18,19,20-tetratrue PGE
and 2-decarboxy-2-glycoloyl-6-oxo-1
6-(6-chlorophenoxy) -17,18゜19,
20-tetratrue PGE1 and their cyclodextrin clathrates are considered.

Furthermore, the formula
E and its cyclodextrin clathrates are also mentioned as preferred compounds of the invention.

Hereinafter, the present invention will be explained in detail with reference to Examples and Examples.
The present invention is not limited to these examples. In addition, in the reference examples and examples, “TLCl, mouth (MRJ,
"IR" and ('-MassJ are respectively [thin layer chromatography], "nuclear magnetic resonance spectrum", and "infrared absorption-").
stands for ``cutor'' and ``quality cover analysis''. The solvent in parentheses described in the chromatographic separation section indicates the bathing solvent or developing solvent used. Unless otherwise specified, LH was measured by the enemy's gland method, and NMR was measured using a deuterated chloroform (GDGt) bath solution.

Reference example 1 9α-acetoki/-11α, 15S-dihydroquino 1
5-(3-globil 7 clobentyl)-16,17,1
8,19,2 (J-Pentanolz Roster-Z2-5+t
) Ran-2-13-dienoic acid methyl ester (1e
ss polar isomer and more polar isomer) 9α-acetoxy-11α-(tetrahydropyran-2
-yloxy)-158-hydroquino-15-1-propylcyclopentyl)-16°17, 18.19.20
-Pentaturu Prostar-/Bar 5, Trans-1t-,
> Enoic acid methyl ester (synthesized according to column 7 of JP-A-52-27753) 12. A mixture of 0.9, 200 methanol, and 300 ~ p-toluenesulfone salt of pyridine was heated at 50C. 8 hours passed. After the reaction is complete, the mixture is concentrated under reduced pressure and! ! Daigo ether 3Q[]at and 100Rt of saturated saline were added to the 1c pipe for extraction, and the organic layer was dried over anhydrous magnesium sulfate and compressed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:cyclohexane-5=1) to obtain the title compound having the following physical properties.

(If 1ess polar isomer yield: 3.2
2,9゜1"LG (ethyl acetate): Rf = 0.23゜NMR: δ
-5,64-5,23 (4H, m), 5.10 (1H,
m), 4.02-3.7/) (2H, m).

3.67 (3H-s)t 2.41:1 (2H, wide s).

2.30 (2H-t), 2.05 (3H,s).

2.55-1.03 (22H, m), 0.88 (3H.

m).

Ih (KBr &) Niji = 3500.2960.1735
CIll.

Mass: +m/e=450 (M), 432, 41
9,414672.654,339,321,261゜231.229゜(iil nl(1repolar isomer yield: 3
．． 7&0 TLC (ethyl Suzaka): Ftf=0.20ONM)
(: δ = 5.64-5.23 (4H, m), 5.10 (
1)(.

m), 4.02-3.76 (2H, m), 3.67+
(5H-8), 2-57 (2H-wide s)
.

2.30(2)1. t)t 2.60-1.03(22
H.

m), 2.05 (+H, s), 0.88 (3H, m).

Hl (KBrffi) Niji = 3500.2960.17
35cyx.

Mass: m/e=450(M”), 432,414,
372°354.339,321,261,231°2
9- In the same manner as in Reference Example 1, the following compounds were prepared in %w.

(a) 9α-acetochloride-11α, 15S-dihydroxy-15-(3-zotel7clobebutyl)-16,17
, 18, 19, 20-pentatuluprostar/2-5.
Trans-13-dienoic acid methyl ester (1es
s polar isomer and morepolar isomer) Starting material: 9α-acetoxy-11α-(tetrahydropyran-2-ylox7)-153-hydroxy-15-(6-notylcyclo is butyl) -16,17,18° 19.2
0-pentatubulostasis-5, trans-16-
Dienic acid methyl ester (synthesized according to the specification of JP-A-52-27753) 16.90 (1) 1ess polar isomer yield: 3.0
3,90 TLU (to/rio+V7:6'M%t-r-f-le=1
:2):Rf=0.7°NMt(:δ-5,64(IH,ad)t 5.49(
1i-1, aa).

5.37 (2H, m), 5.14 (1) i, m).

3.91 (2H, m), 3.68 (3H, s).

2.52 (18, m), 2.31 (2H, t).

2.07 (6 days, s), 0.89 (3H, m); IR (
Kljr〆,,-) Niji-3480, 1760, 171
7゜1248.972cx 0 Mass: m/e-464(M)y 44
6t 42B? 586t668゜(it +nore polar isomer yield: 27y
0 TLC (/lylohexane:ethyl acetate-1:2):Rf
=0.6°t4Mt(:δ-5,64(IH,aa),5.47(
1H, da).

534 (2Lm), 5.12 (IH, m).

3.89 (2H, m), 3.67 (3H, s).

2.51 (IH, m), 2.30 (2H, t,).

2.06 (3H, s), 0.88 (3H, m).

IR (KBr method) Niji=3450.1734.1247
．． 978cIn-'Mass: m, /e=464(M
), 446,428,387,386°668° Reference Example 2 9α-acetoxy-11α,15S-bis(tetrahydropyran-2-ylox:>)-1b-(3-propylcyclobenal)-16,1S 18.19゜20-Pentatulbrostasis-5, trans-16-dienoic acid methyl ester 9α-acetoxylic acid-11α, 15S-dihydroxy-1
5-(6-propyl butyl)-16,17,1
8,-19,20-Pentaturubrostasis-5,)
1ess p of lance-16-dienoic acid methyl ester
olar isomer [produced in Reference Example 1(1). )2
．． 0,9. A mixture of dihydropyran 1.01 and methylene 22 was stirred while cooling in a water bath. After adding p-toluenesulfonic acid as a catalyst to the reaction solution, the mixture was allowed to stand at room temperature. A few drops of pyridine was added to the reaction mixture, diluted with diethyl ether, washed sequentially with water and warm water, dried over 1° magnesium oxide anhydride, compressed under pressure, and measured for the following physical properties. 2.49 g of crude product of the title compound with
I got it.

TLG (ethyl acetate:noclohexane=1:2):R
f = O1 filter 4°NMR: δ-5,7-5,2 (4H, m), 5.1
(1E(,m), 4.7(2M,m), 4.1-
6.2 (6H, m), 3.67 (6) i, s), 2
．． 04 (3H, s), [1,9 (RoR2''m).

Engineering Rniji = 1767.1245, 1121,976cm
.

Mass: m, /e=587,517,462,423
, 414° In the same manner as in Reference Example 2, the following compound was obtained.

(a) 9α-acetoquino-11α, 1'5S-bis(tetrahydropyran-2-yl))-15-(ro-butyl/chlorobutyl) -16°17, 1d, 19,2
1J-Nintanol Brawl Star Zx-, 5, Tran 4-1
6-dienoic acid methyl ester starting material; 9α-acetoquine-11α, 15S-dihydroxy7-15-(3-butyl/clopentyl)-16,17,18,19,20- to phthanolprostasis-5, trans 1ess polar isomer of -13-u enoic acid methyl ester [#Example 1 (al(
11. 12.8B, 9° revenge: 3.5911
0 TLC (7 chlorohexane:ethyl acetate-2:1):Rf
-0,47°NMR: δ=5.7-5.3 (4H, m), 5.0
5 (IH, (II).

4.8-4.5 (2H, m), 4.2-3.7 (4H,
+n).

3.66 (3H, s), 3.47 (2H, m), 2.5
0 (IH, m), 2.39 (2H, t), 2.04 (3
H,s), 0.88 (3H,m).

IR Niji=1738,1245,1020,977ct
n.

Mass: m/e =548.530.517.4
99.446°686° Reference Example 6 9α-hydroxy-11α, 15S-bis(tetrahydropyran-2-yloxy) -15-<6-propylcyclobenal) -16,17,18,19°20-
Pentatuluprostasis-5,trans-13-dienoic acid methyl ester 9α-acetoxychloride-11α,15S-bis(tetrahydrobilan-2-ylox7)-15-(6-propylfuco is butyl)-16,17, 18°19,2 (1
-pentatuluprostasis-5,) lance-13-dienoic acid methyl ester (Reference flJ2″c produced)
After vigorously stirring a mixture of 2.47.9, anhydrous potassium carbonate 1.109 and methanol 251 at 50 tl' for 2.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ice.
It was poured into a mixture of N hydrochloric acid and extracted with ethyl acetate.

The extract was washed four times with water and saturated brine, dried over anhydrous magnesium sulfate, added with a diethyl ether solution of diazomethane, and stirred under reduced pressure to obtain the title compound 2.489 having the following physical properties.

TLG (ethylephchlorohexane acetate = 1:2):Rf
=0.20°NMI-1: δ-5,7-5,2(4H,m)r 4.
7(2H-m)t 4.2-3.3(7H,m), 3.
67(3H-s)y O,9(3H,m) Engineering Rniji=3500,1741,1021,976α
.

Mass: m/e=576(M), 545,52
7,492° 474.443° In the same manner as in Reference Example 6, the following compounds were prepared.

(a) 9α-Hydroquine-11α, 15S-bis(tetrahydropyran-2-yloxy)-15-(3-butyl 7-chloromethyl) -16°17, 18.19.20
-pentanolprosta-cis-5,trans-13-dienoic acid methyl ester Starting material: 9α-acetoxy 11α, 15S-bis(tetrahydropyran-2-yloxy)-15-(3-butyl 7 clobentyl) -16,17, 18,19,20-Pentatrubrostaph x-5,) Ran 2-13-dienoic acid methyl ester [Produced in Reference Example 2(a). 13.58,9゜Yield:
2.92,9°TLG (ethyl acetate:7chlorohexane=1:2):F
tf=0.60°NMI(:δ=5.6-5.3(4H,m), 4.7(
2H-m)t 4.2-4.0(2H,m), 3.75
(2H, m), 3.67 (3H, s), 3.48 (2H
, m), 2.32 (2H, t, ), 0.88 (3H, m
).

■R:shi=3500,1739,1022,976cr
a.

Mass: m/e=506,488,457,404,
386° (b) 9α-Hydrox-11α, 15S-bis(tetrahydropyran-2-yloxy)-15-cyclobenthyl 16.17.18.19.20-Pentatruprostar yx-5,) Lance-15- Dienoic acid methyl ester starting material: 9α-acetoxy7-11α, 15S-bis(
Tetrahydropyran-2-yloxy)-15-cyclo is anti-16, 17.18.19.20- is phthanolproster-
Cis-5, trans-16-dienoic acid methyl ester (synthesized according to Reference Example 14 of JP-A-51-122040) 2.01+.

Yield: 1.61.9°TLG (cyclohexane:ethyl acetate = 1:1)
:Rr=0.66°NMR: δ=5.6-5.25 (4H, m), 4.70
(2)1. m).

4.1 (2H, m), 3.83 (3H, m) 3.66 (
3H, a), 3.46 (2H, m).

IR:l/=3650-3200,2950,2860
,1740°1450.1440.1+70.1350
゜12400II.

Mass: m/e=485,450,432,419,
414゜401.381,360,548,330゜2
97.276° Reference Example 4 5-promo 6.9α-epoxy-11α, 15S-bis(tetrahydropyran-2-yloxy)-15-(
3-probylcyclobentyl) -16°17, 18.
19.20-Pentaturubrostotran 1-16-enoic acid methyl ester 9α-hydroxy-11α, 15S-bis(tetrahydropyran-2-yloxy)-15-(6-propylcyclo is methyl') -16,17 , 1B.

19.2o-pentanolprostasis-5,trans-13-dienoic acid methyl ester (produced in Reference Example 3) 2.48,9. 0.85N of N-bromosuccinimide was added to a mixed solution of 31i+j of methylene chloride and 5.951t of tetrahydrofuran at room temperature and stirred at a time for 1 hour. The reaction mixture was diluted with 100 ml of diethyl ether, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The remaining contents were subjected to silica gel column chromatography (cyclohexane: ethyl acetate =
4:1) to obtain the title compound 2 having the following physical properties:
．． 30.9 was obtained.

NM)(:δ=5.7-5.2(2H,m), 4.7(
2H, m) t 4.5 (IH, m), 3.67 (3H,
s)-0,9(3H.

m).

IR Niji=1741,1022,982CWL 0Ma
ss:m/e=555,553,541,539,52
3゜521.470,468,452,450゜426
．． 424° The following compound was obtained in the same manner as in Reference Example 4.

(a) 5-bromo-6,9α-epoxy-11α.

153-bis(tetrahydrobilan-2-yloxy)
-15-(5-butylcyclo is butyl)-16,17,
18,19,20-intanorprostoltrans-1
6-Enoic acid methyl ester starting material: 9α-hydroxy-11α, 15S-bis(tetrahydrobilan-2-yloxy)-15-(3-butylcyclo is butyl) -16,17,1B, 19.20-takuntanol prostar yx-5. (2) Nsu 1S-V enoic acid methyl ester [Produced in Reference Example 6(a). 12.90#.

Reserved: 3.14.9 NMR: δ = 5.7-5.25 (2H, m), 4.8-
4.5 (2H, m).

4.4-3.7 (7H, m), 3.69 (3H, s).

3.48 (2H, m), 0.89 (3H, m).

Engineering Rniji = 1738,1018,977cx.

Mass: m/e=568,566t 555,556
, 53b.

535.484,482,466.464,440゜(
b) 5-noromo6.9α-epoxy-11α.

153-bis(tetrahydrobilan-2-yloxy)
-15-cyclopentyl-16,17゜18.19.2
0-Pentatulprostol trans-13-enoic acid methyl ester starting material: 9α-hydroxy-11α, 15S-bis(
Tetrahydropyran-2-yloxy)-15-cyclo is butyl-16,17,18,19,20-pentatuluproster-
Cis-5, trans-16-dienoic acid methyl ester [Produced in Reference Example 6(b).

11.6oy0 Yield 1t: 1.9711°TLG (7 chlorohexane:ethyl acetate = 1:1)
:Rf=0.6゜NM)? : δ=5.68-5.3 (2H, m), 4.7
(2H, m), 4.55 (IH, m), 3.68 (3H
, s), 2.35(2)1. t).

■H Niji = 3600-3200, 2940, 2850,
1755°1440.1350,1320,1260°1240.1200.1130cm.

Mass: m/e =428y 426140
8t 384382+377.359,557,547
, 315° 311.304, 297° Reference Example 5 5-bromo6.9α-enboardoxy11α, 158-bis(tetrahyFropyran-2-yloxy)-15-(
3-Provircuclobutyl) -16°17, 18.
19.5-Bromo6.9α-Eboxy-11α,15S-bis(tetrahydropyran-2
-yloxy)-15-(3-propylcyclo is butyl)-16,17,1B, 19.20-Intanorprostol trans-16-enoic acid methyl ester (produced in Reference Example 4) 2.30. Cool f by -78CK,
To this was added dropwise 2.6 a4 of a 25% solution of diisobutylaluminum hydride dissolved in toluene, stirred at the same temperature for 60 minutes, then carefully added 0.71 g of methanol, raised to OC, and added 1.81 g of water. I stirred it vigorously. Add the reaction mixture liquid Klf water and magnesium hydroxide,
The collected body T4 fluid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane:ethyl acetate = 3:1) to obtain the title compound 2 having the following physical properties.
．． 1g was obtained.

NMR: δ=9.8(IH,t)t 5.7-5.2(
2H, m), 4.7 (2H, m), 4.5 (IH-m)
t O, 9 (3H.

m).

Work R Niji = 2725.1725,980cm.

Mass: m/e=440, 438, 422-420,
396°694° The following compound was obtained in the same manner as in Reference Example 5.

(a) 5-bromo-6,9α-epoxy-11α.

15S-bis(tetrahydropyran-2-yloxy)
-15-(3-,'Terncro is butyl)-16,17
, 18, 19, 20-Pentatuluprostotrans-
16-En-1-R Starting material: 5-,'Romo6,9α-Ebokiku-11α
, 15S-bis(tetrahuman 10pyran-2-yloxy)-15-(3-butylcyclo is butyl) -16,17,18゜19,2
0--<Tanorprostol 92-enoic acid methyl ester [Produced in Reference Example 4(a)]. 13.1611゜Yield:
2.71g.

NMR: δ-9,98 (IH,t,), 5.7-5.2
(2H, m).

4.68 (2H, m), 4.54 (IH, m).

4.47 (2H, m), 4.2-4.1 (IH, m).

4.1-3.7 (5H, m), 2.5 (2H, t).

0.89 (3H, m).

IR Niji=2730.1726,1022,980CW
i.

Mass: m/e 454.452.410.4 [
1B.

(b) 5-promo 6.9α-epoxy-11α.

153-bis(tetrahyH7obilan-2-yloxy)-15-cyclobentiru 16.17°1B, 19.
20--? Phthanorprostoltrans-16-ene-
1-R starting material: 5-promo 6.9α-epoxy-11α,
15S-bis(tetrahuman biran-2-yloxy)-15-7 clobenthyl 16.17.1 B, 19.20-pentatuluprostol trans-13-enoic acid methyl ester [Produced in Reference Example 4(b). 1
1.97g.

Yield: 1.46g.

TLG (cyclohexane: ethyl acetate = 2: 1)
:Rf=0.6°NMi(:δ-9,98(IH,t), 5.68-5.
3 (2141m) t4.7 (2H, m), 4.55 (I
H,m), 2.5(2)(,t).

IR Niji = 3650-3200, 2950, 2870,
1725°1450.1370.1350, 1320°1240.1200, 1130C1l.

Mass: m, / e = 48”) 94311
4299398t 396t380.354,352,
345,329.627゜617゜Example 6 1-Hydroquine-1-(2,4-dioxa-6-methylhexyl)-5-7'romo6.9α-evoquine-11
α, 15S-bis(tetrahydropyran-2-yloxy)-15-(3-propylcyclo is butyl)-16,
1st 18.19.20-tantanorprostoltrans-16-nintetrahydrofuran 40azK bathed (2,4-dioxa-6-methylhexyl)-triptylstanyl [
J, Am, Ghem, Soc, a 100 volumes.

1481 Peichi:) (1978). ]
3.0<l of a 1.6M solution of n-butyllithium in hexane was cooled to 4.91
was added dropwise over 7 minutes and stirred at the same temperature for 10 minutes. 5-promo 6.9α-epoxy-11α, 15S- dissolved in tetrahydrofuran 12 in bath solution C
Bis(tetrahyto90furan-2-yloxy)-15
-(3-propylcyclobutyl) -16,17,1
8,19,20-intanorprostoltrans-16
-en-1-r (produced in Reference Example 5) 1.63
1 was vortexed for 10 minutes with stirring, and after stirring for 30 minutes, the reaction mixture was poured into an aqueous ammonium chloride solution and extracted with diethyl ether. 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 (7 chlorohexane:ethyl acetate-1=1) to obtain the title compound 1.61.9 having the following physical properties.

NMR: δ = 4.8-4.2 (2H, m), 4.7 (3
H, m), 1.3 (3H, a), 1.2 (3H, t),
0.9 (3H.

m).

1 1R Niji=3480,1132,1020,980cI
L.

Mass: m/e=498,496,454,452°b In the same manner as Example 6, the following compound was obtained.

(a) 1-hydroxy-1-(2,4-dioxa-6-
Methylhexyl)-5-:l;'romo6,9α-y
lkiv-11α, 15S-bis(tetrahydropyran-
2-yloxy)-15-(3-butyl/clopentyl)-16,1s 18.19.20-Pentatuluprostotrans-16-ene starting material = 5-promo 6.9
α-Epoquin-11α, 15S-bis(tetrahydrofuran-2-yloxy)-15-(6-butylcyclopentyl)-16,17°18,19.2
0-Pentatulprostoltrans-16-ene-1-
R [Produced in Reference Example 5(a). 12,091° t: 1
．． 86.9°NMR: δ=5.7-5.2 (2Hsm), 4.8-4
．． 5 (3H, m).

4.2-4.1 (IH, m), 1.33 (3H, a).

1.22 (3H, t), 0.88 (3H, m).

IR:l/=3490.1135.1020.980c
m-1゜Mass: m/e=698.696.613
．． 611.596゜594.502,500,447,
445,444°442.468,466°(b) 1-hydroxy-1-(2,4-dioxa-6-
Methylhexyl)-5-pomo6.9α-epoxy7-
11α, 15S-bis(tetrahydrofuran-2-yloxy)-15-7 cloben-y-ru 16.17.
18,19.20-hen p, tyv prosto trans-16-ene starting material: 5-promo 6.9α-epoxy-11α
, 15s-bis(tetrahuman90furan-2-yloxy)-15-cyclo is methyl-16,17,18,19,20-pentatuluprostol-trans-13-en-1-al [Reference Example 5(b) Manufactured by. ]1.
43.9° convergence: 1.46!9° TLC (7 chlorohexane: ethyl acetate - 1:1): Rr
=0.25°NMR: δ=5.68-5.3(2H,m)t 4.7
(2H, m).

4.55 (IH, m), 4.15 (IH, m).

1, Ro5 (3H, d), 1.22 (RoH, t,).

Engineering Hniji = 3650-3200, 2940, 2870
,1440°1380.134[],1260,124
0,1200°113DCIIL.

Mass i m/e = 455,453,440
-43 By 411y409.373,542,34
0,314,312° Reference Example 7 1.9α-dihydroxy-1-(2,4-dioxa-3
-Methylhexyl)-11α,15S-bis(tetrahyto90bilan-2-yloxy)-15-(3-progylcyclointer)-16,17°18.19.20-
-! Phthanorprostol trans-13-en-6-one 1-human90x-1-(2,4-dioxa-6-methylhexyl)-5-7'romo6,9α-epoxy-1
1α,15S-bis(tetrahydrogyran-2-yloxy)-15-(3-propylcyclomethyl)-16
, 17,18,19,20--”phthanorprostoltrans-16-ene (Reference Example 6) 1.5
A mixture of 55.4 ml of 911.1.5-diazabicyclo(5,4,01 undecene and 2.8 ml of toluene) was treated at 50 C for 14 hours and then at 80 C for 5 hours, and then the reaction mixture was cooled with water. diluted with diethyl ether,
Mix well with cold 1N hydrochloric acid. The organic layer was washed successively with water, a saturated sodium bicarbonate aqueous solution, and a saturated saline solution, dried over anhydrous 4kv magnesium, and then linearly condensed under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane:ethyl acetate=1:1) to obtain 1.14 g of the title compound having the following physical properties.

'I'LC (Ethyl acetate: +)
1): Rf=0°05°NMR: δ=5.8-5.2 (2H, m), 4.8-4
．． 4 (3H, m).

0.9 (3H, m).

Engineering Rniji = 347 [], 170B, 1130, 1020
,977cx.

Mass: m/e=603,545,501,416,
407° The following compound was obtained in the same manner as in Reference Example 7.

(al 1,9α-dihydroxy-1-<2.4-:
)oxa-6-methylhexyl)-11α,15S-bis(tetrahydropyran-2-yloxyl)-15-(
3-butylcyclopentyl) -16°17, 1 B,
19.20-Pentatulprost-16-nin-6-one Starting material = 1-hydroxy-1-(2,4-dioxa-
6-methylhexyl)-5-promo6.9α-epoxy-11α,15S-bis(tetrahydropyran-2-yloxy)-15-(5-butylcyclopentyl)-16,17,18,19゜2〇-inter Norprostottrans-16-ene [Produced in Reference Example 6(a). ]1,84
g.

Yield: 1.02g.

TLC (cyclohexane:ethyl acetate-1:1)R
r=0.09°NMR: δ=5.5(IH-m)t 5.3(IH,m
), 4.7-4.4 (6, H, m), 4.1-3.2
(12H,m), 1.18(3H,t)t O,87(
5H, m).

Engineering Rniji = 3470, 1710, 1132, 1018,
976CIll.

(bl 1,9α-dihydroquine-1-(2,4-dioxa-6-methylhexyl)-11α, 15S-bis(tetrahydropyran-2-yloxy)-15-cyclobenthyl 16.17.18.19° 20-Intanolprostoltrans-13-en-6-one Starting material = 1-hydroxy7-1-(2,4-dioxa-
6-Methylhexyl)-5-normo6.9α-Eikik-11α, 15S-bis(tetrahydropyran-2-yloxy)-15-cyclopentele-16,1s18,19.20-Pentatruzorost-
Trans-16-ene [Produced in Reference Example 6(b). 11.45.90 Pupil convergence: 92
0 inches.

TLC (cyclohexane: ethyl acetate = 1:1): Rf
= 0.1°NMR: δ = 5.7-5.2 (2H, m), 4.7 (2
H, m), 4.55 (IH, m), 1.26 (3H, d
), 1.2 (3H, t).

IH Niji = 3650-3100, 2940, 2860,
1740°1710.1440,1370,1340°1240.1200,11303.

Mass: m/e=561,533,521,503,
475°459.433,419,407,374,3
56°648° Reference Example 8 l-(2,4-dioxa-6-methylhexyl)-11
(f, 1bS-bis(tetrahydropyran-2-yloxy)-15-(3-/ropylcyclopebutyl) -1
6,17,18,19,20-Pentatuluprostotrans-16-nin-1. <5.9-) Lyon-Collins reagent (methylene chloride 86 cod, pyridine 551,
Prepared from 3.36 g of chromium trioxide and 17.5 I of Celite. ), 1,9 dissolved in methylene chloride 16
α-dihydroquine-1-(2,4-dioxa-6-methylhexyl)-11α,15S-bis(tetrahydroquine 90
pyran-2-yloxy)-15-(3-propylcyclo is methyl) -16゜17.18,19.20-pentatuluprostoltrans-1'5-en-6-one (
(produced in Reference Example 7).

After adding 1.11 at room temperature and stirring for 20 minutes, adding 25.9 of sodium hydrogen sulfate-hydrate to the reaction mixture,
Stir for 10 minutes. The reaction solution was separated through a layer of anhydrous magnesium sulfate, and the solid was washed 6 times with methylene chloride.
The resulting organic layer was evaporated under reduced pressure. The residue was purified by gel column chromatography (/chlorohexane:ethyl acetate=
3:1) to obtain 0.40# of the title compound having the following physical properties.

'I'LO (cyclohexane:ethyl acetate = 1:1
) : Flf = 0.33° NMFI : δ = 5.8-5.3 (2H, m), 4.7
8 (IH, q).

4.7 (2H, m), 4.08 (2H, s), 3.57
(2)1. q), 1.33 (3H, d), 1.17 (3
H, t), 0.9 (3H, m).

IH Niji = 1742, 1717, 1115, 1080,
1037°1023.976(7).

Mass: m/e=617.515.458.430
．． 421°412.404,386°Consideration The following compound was obtained in the same manner as in Example 8.

(at 1-(2,4-dioxa-6-methylhexyl)-11α, 15S-bis(tetrahydropyran-2
-yloki7)-15-43-butyl7chloro is methyl)
-16,17,18,19,20-intanorprostol trans-13-ene-1,6,9-trione Idemitsu Monoga: 1,9α-dihyto90x-1-(2,4-
Dioxa-6-methylhexyl)-11α, 15S-bis(tetrahydrobilan-2-yloxy)-15-(3-butylcyclodentyl)-16,17°18,19.2
0-Pentatulprostoltrans-13-ene-6-
[Produced in Reference Example 7(a)] ] Q, 99.9° Yield: 0.
52g.

TLC (fuclohexane: ethyl acetate = 1:1): Rf
20, 66°NMR: δ=5.6(IH-m)t 5.4(IH,m
), 4.83 (3H, m), 4.78 (1H, q), 4
．． 8-4.6 (2H, m), 4.7-4.4 (4H, m
), 4.2-4.0 (IH, m), 4.09 (2H1d
), 1.34 (3H, a), 1.19<IH, t), 0
．． 88 (3H, t).

IR Niji = 1743.1715.976cm.

Mass: m/e=575,546-529,472,
444゜426.421,418,400゜(b) 1-(2,4-dioxa-6-methylhexfur)-11α,15S-bis(tetrahydropyran-
2-4 is Oki 7) -15-7 Kuro is Nchiru 16, 17
．． 18.19.20-Pentatuluprostotrans-
16-en-1,6,9-)ion starting material = 1,9α
-dihydrokycu1-(2,4-dioxa-6-methylhexyl)-11α,15S-bis(tetrahydropyran-2-yloxy)-15-fucurointhyl-16.17.18.19.20-pentatuluprostotrans - 16-en-6-one [produced in Reference Example 7(b)] 910 rW;/.

Yield: 448 ay.

'l'L+G (Schiff C1 hexay: acetate-c tyl=
1:2): Rf=0.5°NMH: δ-5,7-5,3(2H,m), 4.78-
4.65 (3H, m).

4.1(1)(,a), 1.35(3)(,d),
1.2 (3H, t).

I)? :1. I=3650-3100,2940,28
70,1740°1715.1450,1380,13
50,1260°1200,1130cm.

Mass: m/e=575* 519,490,473
,421°388.370,362,353,344°Example 1 1-hydroxymethyl-11α,15S-dihydroxy-15-(3-probylcyclobentyl)-16,17
, 18, 19, 20- is tantanorprostol trans-
16-ene-1,6,9-trione [i.e. 2-decarphokitou-2-glycoloyl-6-oxo-15-(3
-propylcyclopentyl)-16,17,18,19
,20-pentanol-PGE ]1-(2,4-dioxa-6-menalhexyl)-11α,15S-bis(tetrahydropyran-2-yloxy)-15-(3-propylcyclopentyl) -16,17,18,19 ，
20-Pentatuluprostotrans-16-nin-1
．． 6.9-) Rion (produced in Salmon Example 8) 0.3E
1.1, 65% acetic acid water bath solution and 0.1% tetrahydrofuran.
After stirring the red mixture at 50tZ' for 4 hours, the reaction mixture was diluted with ethyl acetate 1201, water, and tZ'. T! ,
The mixture was washed with a sodium bicarbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate = 82), and further pre-crystallized from a mixed solvent of 7 chlorohexane and ethyl acetate (2:1), yielding the following physical properties! IA title compound o, i1i
, v was obtained.

One point: 88-911? .

1'LC (ff5g1xteiv: formic acid = 80: 1
) :Rf=0.16°NM)i :δ-5,6(2
H, m), 4.23 (2H, s).

4.12 (IH, m), 3.87 (IH, m).

2.79 (IH, ati) t 2.65 (IH, m).

0.88 (3H, m).

IH (KBrL): C = 3470, 2860, 174
8゜1750.1707,1081.972+aa-'
.

Mass: m/e-422, 404, 386, 373,
355°328.309,296° In the same manner as in Example 1, the following compounds were obtained.

(a) 1-hydroxymethyl-11α, 15s-dihydroxy-15-(3-7'tylcyclopentyl) -1
6,17,18,19,20-ba7fi,/luprost-trans-16-nin-1,6.9-trione [i.e. 2-decacyboquine-2-glycoloyl-6-oxo-15-(3-butylncro Ventyl) -16,17
, 1B, 19.20-pentanol-PGE) Starting material: 1-(2,4-:)oxa-6-methylhexyl)-11α, 15S-bis(tetrasito90pyran-2-yluoquine)-15-(3 −
Butyl 7 chloro is methyl)-16,17,18,19,2
0-Pentatulprosttrans-16-nin-1°6.9-trione [Produced in Reference Example 8(a). 10.
51.9° Yield: 0.21g.

Melting point: 95-96C.

TLC (ethyl acetate: formic acid = 80: 1): Rf=
0.21°NMR: δ=5.60 (2H, m), 4.
24(2H,s)t 4.12(IH,m), 3.8
6 (IH, m), 2.79 (IH-da), o, ss (
3H-m).

IR (KBr method) Niji-3460, 1748, 1732
゜1710.1288,970cx-'.

Mass: m/e=418,400,382,369,
293゜257.229゜(b) 1-hydroxymethyl-11α, 15S-dihydroquine-15-cyclopentyl-16,17゜18,1
9.20- Pentaturprostoltrans-16-ene-1,6,9-trione [i.e. 2-decarboxy-2-glycoloyl-6-oxo-15-7 clopentyl] -16,17,18°19,20- Pentanol-PGE] Starting material: 1-(2,4-dioxa-6-methylhexyl)-11α, 15S-bis(tetrahydro-90 biran-2-yloxy)-15-cyclopentyl-16,1s18.19.20- −'Phthanolprostyltrans−
13-ene-1,6,9-)ion [Produced in Reference Example 8(b). ] 44,329g Rat collection: 120 reports.

Melting point: 81-831. '.

TLCi (ethyl acetate: formic acid = 80:1):
Rf=0.08°NMR: δ=5.57 (2H, m),
4.23 (2H, s), 4.1 (2H, q), 3.95
(IH, t), 3.2-2.2 (12H, m), 2.0
5-1.0 (14H, m).

IR (KBr method) Niji=3600-3100.2950
．． 2860°1760.1730,1710,1450
゜1400.1070C1! .

Mass: m/e=362,344,331,326,
315°293.257,229,201,148°Example 2 2-Decarboxy-2-glycoloyl-6-o*','
-15-C6-butylcyclobentyl)-16,1s1
8,19.20-pentanol-PGE 3kJ, magnesium stearate 100■, silicon dioxide 20■,
Talc 10wkg, cellulose gluconate karungu A (EG
G) Add 200■ and microcrystalline cellulose to make 101,
Until it becomes homogeneous (after mixing, tablet by the usual method, 1
100 tablets were obtained containing an occlusive substance (60 μFIO) in the tablets.

Example 6 2-decarboxy-2-glycoloyl-6-oxo-1
5-(3-,'chiru7riro is methyl)-16,17,1
8,19,20--Add lactose to E'Ntanol PG [3■ to make a total amount of 21g, mix until homogeneous, and then add No. 6 gelatin capsules &(1'A- break into 1 capsule) using the usual method. 1 capsule containing 60Hg of active substance
Obtained 00 pieces.

Example 4 2-Decalhoquinol 2- in chloroform 101
Glycoyl-6-oxo-15-(3-notyln clobentyl) -16,1718,19゜20-pentanol-PGh:30■ MCT (carbon #!I8-10
100 sty of fatty acid triglyceride) was added and mixed well. After removing chloroform by drying under reduced pressure, the mixture was filled using a soft capsule molding machine to obtain 1000 soft capsules each containing 60 Hg of active substance.

Example 5 2-pcarbokycu-2-glycoloyl-6-oxo-1
5-(3-7'tylcyclopentyl)-16.17.1
8,19.20--! Phthanol-PGE1 (K-7 chlorodextrin clathrate compound 6gIQ (500μg as active ingredient) was dissolved in 3QQaJ of distilled water for injection, the solution was sterilized and pumped out by a conventional method, and 6It 100 injections containing 5 μg of active substance in 1 ampoule were obtained.

Example 6 In the same manner as in Examples 2.6.4 and 5, tablets, capsules, and tablets containing 2-decarphoquico-2-glycoloyl-6-oxo-173,20-dimethyl-PGE as the active substance were prepared.
Soft capsules and injections (6 people)

Claims (1)

[Claims] 1. General formula (Narita, R&i) represents a single bond or a straight or branched chain alkylene group having 1 to 5 antiprimes, H2 is a straight chain or branched alkyl group having 1 to 8 carbon atoms; , or a 7-chloroalkyl group having 4 to 7 carbon atoms which is unsubstituted or substituted with at least one straight or branched alkyl group having 1 to 8 carbon atoms, or unsubstituted or less substituted (both 11(2
) represents a phenyl or phenoxy group in which a halogen atom or a trifluoromethane atom is replaced with an alkyl group having 1 to 4 carbon atoms, and the double bond between the carbon atoms at the 16th and 14th positions is Represents a transformer. However, compounds represented by the following formula are excluded. ) Prostaglandin analogue compounds and their cyclodextrin inclusion compounds. 2. The compound according to claim 1, wherein 2H is a straight or branched alkyl group having 1 to 8 carbon atoms. 3. Claim No. 3, wherein R is a 7-chloroalkyl group having 4 to 7 carbon atoms, which is unsubstituted or substituted with at least one linear or branched alkyl group having 1 to 8 carbon atoms. Compound according to item 1. 4. R is unsubstituted or less substituted (both 1 to 80 carbon atoms straight button or branched alkyl group 'C-71) and 7 is an ethyl group, according to claim 6 A compound of 5, R or unsubstituted or at least 1 (11!
The compound according to claim 1, which is a phenyl or phenoxy group substituted with a halogen atom or a trifluoromethyl group or an alkyl group having 1 to 4 carbon atoms.5. -hentyl, 1-methylbennal, 1,1-dimethylpentyl, 7-clopter, cyclo-methyl, 6-methylcyclopemethyl, 6-ethelcyclo-methyl, S-propyrunclopentyl, 3-7'-tylcyclopentyl, /clohequinyl, 4-propylcyclohexyl, benzyl or (3-chlorophenoxy)
The compound according to claim 1, which is a methyl group. 7. The compound is 2-decacyboquine-2-glycoloyl-6
-oxo-15-(3-propylcyclopentyl)-1
The compound according to claim 4 iC, which is 6,1su1B,19.2()-nitanol-PGE. 8. The compound is 2-decarboxy-2-glycoloyl-6
-Oxo-15-(3-'butyl 7 chloro is methyl) -
16,17,18,19,20--entanol-PGE
The compound according to claim 4, which is 9 The compound is 2-decarboxy-2-glycoloyl-6
-oxo-15-7 methyl-16゜1s 18.1
9. The compound according to claim 4, which is 20-pentanol-PGE. 10, general formula (wherein R3 is unsubstituted or substituted with at least one alkyl group, tetrahydropyran-2)
-yl group, tetrahydrofuran-2-yl group or 1
- represents an ethoxy ether group, and other symbols have the same meanings as in claim 1. ) Production of a compound represented by the general formula (in which all symbols have the same meanings as in claim 1) by hydrolyzing the compound represented by the formula under acidic conditions. Method. 11. Compounds represented by the general formula (in which all symbols have the same meanings as described in claim 1) or compounds reduced by the formula 1111
! ! Disability treatment agent. 122-decarpho/-2”-,/lifuroyl-6-oxo-15-(3-7'ropylcyclopentele)-16
, 17, 18, 19, 20- are Tantanoru PC, E1.
2-Decarboxy-2-glycoloyl-6-okine-1
5-(robutyluncro is methyl)-16, 17, 18
,19,2[1-pentanol-P(1,E 1,2-decalhoki2-glycoloyl-6-oxo-15-7
Methyl-16,17,18゜19,20--<butanol-PC:TM or 2-decarpho/-2-
The therapeutic agent for cytotoxicity according to claim 11, characterized in that the active ingredient is glycoyl-6-oxo-17S, 2[1-dimethyl-PC,F.