JPS5879973A - Polymer of prostaglandin derivative, its preparation and remedy containing said polymer as active constituent - Google Patents

Abstract

NEW MATERIAL:An addition polymer of a PGB (prostaglandin) derivative, having 1,000-6,000 molecular weight, and expressed by the formula {R<1> is single bond, 1-5C straight or branched chain alkylene; R<2> is H or 1-10C straight or branched chain alkyl, etc. which may be substituted by OH; R<3> is H, 1-4C straight or branched chain alkyl; X is -(CH2)p[(p) is 0 or an integer 1-5], etc.; Y is =O, etc.; the double bond between the carbon atoms at the 13- and 14-positions is the trans configuration except when -R<1>-R<2> is n-pentyl and X is pentamethylene}and a salt thereof. EXAMPLE:An addition polymer of 17-phenyl-18,19,20-trinor-15alphabeta-PGB1 methyl ester. USE:Capable of preventing the oxidative phosphorylating ability of mitochondria, having the calcium ionophore activity, and useful for preventing and treating ischemic heart diseases. PROCESS:A compound of the formula is subjected to the Micheal reaction with a hydroxide, e.g. NaOH, of an alkali metal to give the aimed polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to prostaglandins (Pros taglan
Din.

Hereinafter, it may be abbreviated as PG. ) relating to polymers of derivatives. More specifically, the oxidative phosphorylation ability of midcontours
ation) and/or soil calcium ionophore (calciuyn 1onophore).
re) Polymers of PGB derivatives with high activity, their production methods, and pharmaceuticals containing them as active ingredients. Prostaglandins are derivatives of brostanic acid having the following structure.

Several types of prostaglandins are known, and the type depends on the structure and substituents of the alicyclic ring. For example, the alicyclic rings of prostaglandin E (PGE), A (PGA), and B (PCB) each have the following structures.

H Dotted lines in the above structural formulas or in other structural formulas herein follow generally accepted rules of nomenclature,
The group attached to it is on the back side of the ring plane, that is, α-configuration, the thick line 1 indicates that the group attached to it is on the front side of the ring plane, that is, β-configuration, and the wavy line ψ indicates that the group attached to it is α- or β-configuration. - Indicates that it is a placement.

These compounds are subclassified according to the position of the 2n) bond on the side chain attached at the 8- and 12-positions of the alicyclic ring. p
The c-1 compound has a trans double bond (trans-Δ13) between CI 3-014, and the PG-2 compound has a G 5-
For example, prostaglandin E1 (PGEI
) is represented by a first-order structural formula.

The structural formula of PCXE 2 as a compound of the PG-2 group corresponds to that in which there is a cis double bond between the carbon atoms at the 5th and 6th positions in the above structural formula.

Furthermore, when one or more methylene groups are removed from the aliphatic group at position 12 of the J]W cyclic ring of the prostaglandin, the compound becomes a true compound according to the general rules of compound nomenclature. Known as prostaglandins.

Prostaglandins generally have pharmacological properties. For example, they have an effect of stimulating smooth muscle contraction, a blood pressure lowering effect, a diuretic effect, a bronchodilation effect, a lipolysis inhibitory effect, a blood aggregation inhibitory effect, and a gastric acid secretion inhibitory effect. Therefore, they are effective in the treatment of hypertension, thrombosis, asthma, and gastrointestinal ulcers, as a curative agent (induction of labor and abortion in mammals, in the prevention of arteriosclerosis, and as a diuretic. It is a fat-bathing substance that exists in very small amounts in the trough tissue that secretes grandin.

By the way, mitochondria in normal cells oxidatively decompose sugars and lipids supplied by the blood using sugars also supplied by the blood, converting ATP (adenosine diphosphate) from ADP (adenosine diphosphate). It is produced and supplies the energy source necessary for cell activity, thereby maintaining the cell's potential energy. This function is called oxidative phosphorylation.

However, in aging (degenerated) intracellular mitochondria, this effect is weakened, and there are cases where it becomes impossible to supply sufficient energy. Furthermore, in aging intracellular mitochondria, Ca→ ions enter from the outside or are in a state where it is easy to enter, and as a result, the oxidative phosphorylation effect by Ca→→ ions is suppressed, and potential energy cannot be retained sufficiently. It will no longer be done.

Recent research in the PG domain has reported compounds useful for preventing the above-mentioned deterioration of oxidative phosphorylation ability. That is, a low polymer of PGB 1 having the following structural formula (molecular weight distribution: 1000 to 6000, hereinafter referred to as PGBx) prevents the deterioration of the oxidative phosphorylation ability of aging mitochondria. [Proceedings of the National Academy of Sciences of the United States]
ational Academy of 5sciences
s of the United 5tats of
America).

Volume 78, page 1598 (1979) and Biochemical and Biophysical Research Communications.
physical Re5aa,rch Commun
cations) + 89 volumes.

240-! (1979) and U.S. 1t-M Permit No. 4
153808]0 Also, in in vivo experiments, P
It has been reported that GBX has a surprising ameliorating effect on a monkey myocardial ischemia model and a rabbit cerebral ischemia model [: Physiol, Cbern, Phys.
ics.

12.81 (1980) and the same magazine, 12,545 (19
80)].

Also, very recently, it has been reported that a polymer using 15-PGBl methyl ester as a starting material has a similar effect (US Pat. No. 424,511).
(See No. 1).

Based on the above reports, the present inventors conducted extensive research to find a polymer that has the same effect as PGBx. As a result of screening various PCB derivatives, all PCB 9 conductor polymers were PGBx
P as a starting material rather than having similar useful effects.
The functional groups constituting the CB derivative include (1) a carboxyl group or its ester at the 1-position, (2) a cyclobentenone skeleton, (a bicar bond at the 3113-position and the 14-position, and an oxo group or an oxo group at the 4115-position). We found that only those polymers that have a hydroxyl group as an essential condition have PGBx-like activity.Furthermore, regarding modification at the 15th position and below, the conventional PG region is extremely difficult to modify. It has been found that polymers of 16-phenoxy derivatives, which have been considered to be useful modifications, do not have the PGBx-like r1 group 1.

Also, the known PGBx has a relatively low concentration of C30ft9/ml.
) has a strong effect of preventing deterioration of oxidative phosphorylation ability, but at higher concentrations 1. [If this happens, the effect will be weakened or not present at all.
The National Academy of Sciences is Op Junite, States of America, 7
Volume 6, 1598-? - see Ji (1979)],
Although it is expected that it will be difficult to set the dosage for practical application, it is expected that the dosage will be difficult to set when the polymer of the present invention is used, for example, in Example 1 described below.
．． It has been found that in the polymers synthesized in 7.9 and 16, no decrease in activity was observed even at high concentrations, and the maximal activity strength obtained at low concentrations was maintained.

Based on the above knowledge, the present inventors have developed the following formula: (1) hydrogen atom% ( ii) a straight chain or branched alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted by a hydroxy group; (m) a straight chain or branched alkyl group having 1 to 4 carbon atoms; a cycloalkyl group having 4 to 7 carbon atoms, which is substituted or unsubstituted; represents a phenyl group or naphthyl group that is not
~4 linear or branched alkyl group.

(In the formula, the double bond indicates a cis-configuration.), (iii)
-8-Convex H2-6H2-Convex H2-8H2- or (i-
)1 (wherein, /1/IAA represents (gamma- or β-configuration or a mixture thereof) or -O, and the double bond between the 16th and 14th positions has a trans-configuration.

However, the case where -R1-R2 represents n- represents an ethyl group and X represents a pentamethylene group is excluded. ] PC indicated by
The B derivative was subjected to a microaddition reaction ('MichaelAdd
Itj, on 1 (ea, ction), the molecular weight distribution obtained is 1000-6000.
So 4. The present invention was constructed based on the fact that the addition polymer has a strong anti-deterioration effect and/or calcium ionophore activity relative to mitochondrial oxidative phosphorylation ability.

In the starting material represented by the general formula (il), 11 is a straight or branched or branched alkylene group having 1 to 5 carbon atoms, such as methylene, conylene, lJmethylene, tetramethylene, pentamethylene, or These include isomers.

The white-chain or branched-chain alkyl group having 1 to 10 carbon atoms represented by R2 includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl groups, and isomers thereof.

The substituted or unsubstituted cycloalkyl group having 4 to 7 carbon atoms represented by R2 is cyclonotyl, cyclo is butyl, cyclohexyl, cycloheptyl group, or any position of these groups is substituted with methyl, ethyl, propyl or butyl group. The following groups are mentioned.

The substituted or unsubstituted phenyl group or naphthalene group represented by R2 is a phenyl group, a naphthalene group, or a methyl, ethyl, propyl, butyl group or an isomer thereof, fluorine, chlorine, bromine at any position of the phenyl group, naphthalene group, or ．． Examples include groups substituted with iodine and trifluoromethyl groups.

The linear or branched alkyl group having 1 to 4 carbon atoms represented by R3 includes methyl, ethyl, propyl, isopropyl, butyl, 5ec-butyl, and tert-butyl group.

Examples of -(OH2)p- represented by X include a single bond, methylene, ethylene, trimethylene, tetramethylene, and R-ntamethylene group.

Among the starting materials represented by the general formula ill, one preferred group includes hydrogen atoms, n-hexyl, n-hebutyl, n-octyl, n-nonyl, n-decyl, 1-
Methyl 4-ethyl, 1.1-dimethyl broken methyl, 2-methylhexyl, 1-human 90xyR-methyl, (1-human 90xmethyl)pentyl, 5-hydroxy butyl,
Cycloheptylmethyl, cyclohexylmethyl, handyl, 1-phenylethyl, 2-phenylethyl, 3-chlorobendi/lz, 3-17 fluoromethylbenzyl,
Naphthylmethyl % Compounds representing 1-naphthylethyl or 2-naphthyl or =0 are mentioned.

Another group of preferred starting materials includes R1-, R2 is 0
- represents a butyl group, R3 represents a hydrogen atom or a methyl group, X represents a single bond, a trimethylene group, J3H=C
Examples include compounds representing H-(CH2)3-, -0-(GHz)4-, or -〇.

It goes without saying that σ~), which influences the strength of the pharmacological action of the polymer of the present invention, is the structure of the starting material, but it has been found that it also largely depends on the degree of polymerization.

The molecular weight distribution of the polymer of the present invention is 1000 to 6000 (1
The degree of molecular weight ranges from 2 to 20), and useful pharmacological effects are observed even with molecular weights between 1 and 2.
(The degree of polymerization is 6 to 8).

Michael addition reactions are well known, for example, in alcohols or alcoholic water baths containing hydroxides, carbonates or bicarbonates of alkali metals such as lithium, sodium or potassium.

Above room temperature, preferably 50° to 80°C for 30 minutes to 60 minutes.
This is done by reacting for a period of time. The concentration of alkali is 0.1 to 4 normal, preferably 0.5 to 2 normal. The progress of the reaction (TiT synthesis K) was monitored by high performance liquid chromatography using a gel filtration column (hereinafter referred to as I (P
It is appropriate to carry out the reaction while monitoring L (abbreviated as 3). After the reaction is completed, post-treatment is carried out according to a conventional method, and gel ′f:′1]t″・1 column, for example, -t77
Sepbadex LH-20 [registered trademark, Pharmacia Fine Chemicals
By purifying and separating by chromatography using Cia Fine Chemicals (manufactured by Cia Fine Chemicals), it can be easily separated based on the difference in the degree of polymerization.

The structure of the obtained polymer is considered as follows275-
280nm, 119 case where Y=0 is 290~30
0nm) disappears, and 2 newly appears at 240-250nm.
- Absorption corresponding to the cyclobentenone skeleton is observed. Furthermore, the carbon-13 nuclear magnetic resonance spectrum (measured in deuterated chloroform) of the polymer.

205 ppm (carbonyl carbon at position 9) and 178
A wide signal is seen near ppm (the carbon of the carboxy group at the 1st position). Furthermore, 172 r+pm and 1
42 ppn], a wide range of signals based on the double bond carbons at positions 12 and 8 are seen, respectively, but the signals based on the double bond carbons at positions 16 and 14 have disappeared. From these data, it is understood that the structure of the polymer of the present invention has a considerable proportion of 2-cycloR-nthenone skeleton, but the double bonds at the 13th and 14th positions that were present in the raw material have disappeared. be done.

Therefore, the addition reaction is carried out at σ) active hydrogen in the raw material, for example at the 16th or 14th position when hydrogen at the 10th and 11th positions exhibits zero abstraction by an alkali. ) is presumed to occur. The active hydrogen generated by the anion is mainly hydrogen at the 10th and/or 11th positions, but there are also hydrogens at the 5th and 5th positions where X is 0, and when Y is =0, 16
There is a possibility that the hydrogen at the position is extracted and becomes an anion. Since the number of active hydrogens that generate anions is not necessarily one per starting material, for example, it is possible that two hydrogens at the 10th position both become anions and participate in the addition reaction, and the hydrogens at the 10th and 11th positions It is also speculated that one by one they become anions and undergo an addition reaction.

The location where the addition reaction occurs with the resulting anion is at position 13 or 14.
The reaction is mainly at the 12th position, but there is a possibility that the 12th position will also react.

It is presumed that the anion generated from the hydroxyl group at the 15th position is also involved in the Michael addition reaction. In other words, the anion produced by abstracting the hydrogen of the hydroxyl group of 15rg of the PCBl derivative used as the raw material is the 14' of the other raw material.
This corresponds to bond a in the figure below, which causes an addition reaction with the bond.

), the newly generated anion at position 16' or the original raw material 1
Addition reaction at the 4th place is C! It is thought that they ooze out (corresponding to the combination in the figure below) to form the figure below.

It is also possible that the ketone present in the raw material undergoes aldol condensation with the anion generated in the other raw material.

Although it is impossible to unambiguously determine the structure of the polymer of the present invention, it is thought that the reactions and bonds described above are intricately intertwined to constitute the polymer.

The PCB derivative represented by the general formula 1)1 in which Y represents 10 is produced by converting the hydroxyl group at the 15th position of the PCB derivative represented by the general formula 2) in which Y represents 10 to an oxo group. This oxidation reaction is well known, for example l
al Nankodo Publishing, edited by Tetsuji Kameya, “Organic Synthetic Chemistry 1 Synthesis Edition IJ17<Sm2O3 is-ji (1976) or John Wil
"Compendiurn of Organic Methods" published by ey & 5ons, Inc.
5ynthetic Methods) J Volume 1 (1971), Volume 2 (1974), Volume 6 (19
77), Section 48 or 168. Preferably, the manganese dioxide or di-derivatives are well known or can be prepared by known methods from the corresponding PGE or PGA derivatives. PC,E derivative or PGA derivative as PcTB
Methods of conversion into derivatives are well known, for example using a hydroxide, carbonate or bicarbonate of an alkali metal such as sodium or potassium □ in a suitable inert organic solvent such as methanol or ethanol. The reaction is carried out at room temperature for 30 minutes to 5 hours under heating.

Corresponding P from PCE derivative or PGA derivative
It is not necessary to carry out the reaction for synthesizing the CB derivative and the reaction for polymerizing the obtained PG and B derivatives separately, and if desired, the corresponding polymer of the PCB derivative can be obtained directly from the PGE derivative or PGA derivative.

The PGE derivative or PGA%4 conductor used as a starting material is known per se or synthesized by a known method. For example, (It) Compounds in which R2 represents a linear or branched alkyl group are
49.50-95250.5O-9S543.50-1
01340.50-116452 or 52-8515
The method described in any Specification 1 of No. 1.

+21 Compound '19 in which R2 represents a cycloalkyl group
I is JP 49109353.50-95250.50
-96543.50-123647.50-14833
9゜51-122040.51-125256.52-
27753 or 53-25544, the method described in 8g in the specification of either No. 27753 or No. 53-25544,
7-9465.50-95250 or 50-9654
The direction θ-1 (41
Compounds in which R2 represents a naphthyl group are disclosed in JP-A-49-920
53 or 50-10! M, the method described in any of the specifications of month
050 or 50-151845 Izuwagano Meimo I
ll =: The method described in J and (6)
Compounds kj-11'& 11 (or methods described in J54-44639) can be prepared by obvious application of the method.

The polymers of the invention in which R1 represents a hydrogen atom are converted into doves by known methods. Preferably, the salt is a non-toxic salt and is water bathable. Suitable bases include alkali metal bases such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts or non-toxic amine salts.

14. The polymer of the present invention and its non-toxic salts do not deteriorate the oxidative phosphorylation ability of intracellular mitochondria. Since it has It-blocking and/or calcium iono-7-oer activity, it is useful when it is desired to prevent deterioration of the oxidative phosphorylation ability of mammals including humans. The effect of the polymer of the present invention in preventing deterioration of oxidative phosphorylation and the calcium iono-7-oer activity were measured as follows.

(Al Mitochondrial preparation N7 method: Examine the liver of a rat that has been exsanguinated, and add 10 times its wet weight to Q, 3
M sucrose, 0.5 mM EDTA ffJi night (p
After adding H7, 35) and disrupting the homogenate I2,
Centrifuge for 10 minutes at 10,100 O to obtain a supernatant. The obtained supernatant was further centrifuged (xlooooF) for 15 minutes to obtain a precipitate, and the obtained precipitate was diluted with 7g of 7j weight (7) of 0.3M sucrose, 0.5mM EDTA.
Suspend in solution and centrifuge (X3000g) for 15 minutes to obtain a precipitate. This precipitate is 0.6M 5 times its wet weight.
A mitochondrial fraction was obtained by suspending the mitochondria in a 5 mM EDTA p solution. The obtained fractions were divided into 1~
2 Leave it standing.

Degradation method of 1b+6 tochondria 201M potassium phosphate M surgical solution (pH 7,35) 100f'l, 0.2M
α-ketogel sodium tarrate 14x (pH 7,3
5) Add 20 μl of methanol and 11.1 μl of mitochondria 11.1 μl (+ ?1liJ M 50 to 15 (] μl) of methanol to a mesoium consisting of 150/zg and 0, IM (magnesium fi acid water mrN11”10/l), Furthermore, water was added to make the total loss 2010/Zl, and this was designated as sample A. Instead of methanol in Kr=+h, methanol #'r% of the polymer of the present invention, 2 rlμl
Sample B is obtained by adding . Samples A and 4. u;+
B is degraded by heating 1 and 5 at 28C for 10 minutes, respectively.

Let oxidative phosphorylation ability measurement method: 33.3mM AMP (adenosine-phosphate),
Drunk liquor (pH 7.35) consisting of 33.3 mA ADP (adenosine diphosphate) and 667 mM potassium chloride.
) (pH 7,35) and 40 μi of 3.75% bovine serum albumin were shaken at 28 C for 20 minutes, 500 μl of 61% perchloric acid bath solution was added to stop the reaction, and the mixture was centrifuged for 5 minutes (3000 Rotate/min) to obtain the supernatant. The amount of 411J in the obtained supernatant was measured using Methods in Enzymology.
zymology), Vol, Vfl e 1
It was measured according to the method described on page 15, and the oxidative phosphorylation ability was defined as the loss of inorganic phosphorus.

Method of displaying fdl activity: Measure the oxidative phosphorylation ability of sample A and sample B, and determine the deterioration of the phosphorylation ability of sample A by 50%.
The concentration of the polymer of the present invention in sample B to be inhibited is adjusted to
C50).

Biochemistry Experiment Course from Rabbit Lower Limb White Muscle, Volume 15.

Using the sarcoplasmic reticulum prepared by the method described in 615, Biochemical and Biophysical Research Communications (Biochernica
l and Biophysical Research
hCommunications, L vol. 89, 240
It was measured according to the calcium ionophore activity measurement method described by J. (1979). That is, 100mM2-(
N-morpholino)ethanesulfonate (p) 17.0)
500/'l.

100mM magnesium 34ide aqueous solution 150111.
i M potassium chloride aqueous solution 100μd, 3.4η/me
Sarcoplasmic reticulum 2ooμl and imM Arsenazo (Ars
Add 140 μl of the solution to a 20 U cell and set it on the control side and sample side of a colorimeter (Hitachi W: Model 100-6 []). Next, when 10μl of a 10mM calcium chloride aqueous solution is added to the cell on the sample side, Qa++++n in the m solution reacts with arsenazoIll, and the absorbance at 675 nm increases compared to the control side, and conversely, the absorbance at 68 nm increases compared to the control side.
The absorbance at 5 nm decreases. Next, the cell Vc on the sample side
i Q mM 7denosine triphosphate (ATP) 100μ
When 1 is added, Ca++ ions are taken up by the sarcoplasmic reticulum, and Ca ion in the solution decreases to 675n.
The absorbance of m decreases and the absorbance of 6B5nmcr) increases.

After 1 minute and 60 seconds after adding ATP, the final concentration of 100μ9/ml was added to the cell on the sample side. When the polymer of the present invention is added to the bath solution, Ca++ ions are released into the bath solution, and the absorbance at 675 nm increases again and the absorbance at 685 run decreases. The sum of the increase (A675) on the sample side with respect to the absorbance at 6750 m on the control side and the decrease (A685) on the sample side with respect to the absorbance at 685 nm on the control side (Δ67
5+Δ685) was checked over time. Experiments were conducted using samples without the addition of the polymer, samples with the addition of the polymer of the present invention, and calcium ionophore-A23187 as a positive control instead of the polymer of the present invention [Calbiochem Beavering Corporation (Calbioch
ern "Behring Corp, ) ? )" was added to the sample, and the evaluation was performed when the pattern of change over time of Δ675 + Δ685 of the sample to which the polymer of the present invention was added is similar to the ξ turn when no polymer was added. The case where the pattern is similar to the pattern when r-JA23187 is added is evaluated as f ++ J, and the case where the pattern is intermediate between the pattern when there is no addition and the pattern when A23187 is added is evaluated as "+". did.

Polymer 11 of the present invention has oxidative phosphorylation activation effect and (
b) Calcium ionophore activity 1hi1: is listed in the table below.

1) to 5) are the activities in certain fractions obtained by separating the polymers obtained in each example by gel permeation column chromatography. Q] fraction HPLC [Column: TSK gel (, 250DH (
The retention time at the peak of [registered trademark, Toyo Soda Kogyo Toso), solvent: tetrahydrofuran, flow rate: 0.8 ml/min] is as follows.

1)---13,2 minutes 2)---13,6 minutes 3)---15,4 minutes 4)---13,1 minutes 5)---14,8 minutes and 15.4 minutes The polymer of the present invention and its non-toxic salt can prevent the deterioration of the oxidative phosphorylation ability of intracellular mitochondria and/or have calcium ionophore activity, so that The prevention of diseases caused by deterioration of the oxidative phosphorylation ability of blood cells, such as myocardial infarction, heart disease caused by ischemia such as heart failure, and brain damage caused by ischemia, as well as liver damage and kidney damage caused by ischemia. Effective for treatment. For these purposes, they are usually administered systemically, for example orally, enterally or parenterally.

Dosage depends on age, symptoms, desired therapeutic effect, administration method,
Although it varies depending on the treatment time, etc., the dosage per person per person is 1 to 1000 In9, preferably 10 to
200~, parenterally 0.1~100■, preferably 1
~50~. Examples of pharmaceutical compositions used for administration include tablets, pills, powders, granules, capsules, suppositories, injections, etc. These compositions can be prepared by known methods well known to those skilled in the art. can be manufactured.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. Note that l'-TLCJ in Reference Examples and Examples.

rIRJ%rNMRJ%rMS” and UVJノH
(2% Q represents "thin layer chromatography", "infrared absorption spectrum", "nuclear magnetic resonance spectrum", "ri amount analysis", and "ultraviolet absorption spectrum")2, separation by chromatography The proportion of the solvent described in the section indicates the volume ratio, the solvent in parentheses of [TLcJ indicates the developing solvent, and [IRJ, 1mMRJ and "U■]
Unless otherwise specified, measurements were made using the liquid film method and deuterated chloroform (CD) (J31i solution and ethanol m solution), respectively.

The molecular weight was measured by gel permeation chromatography (flow rate Q, 8 ml/min) using TSK Gel G2500H (registered trademark, manufactured by Toyo Soda Kogyo Co., Ltd.) as the column and tetrahydrofuran as the elution solvent. The molecular weight of the polymer was estimated from the calibration curve.

Reference Example 1 2.3,4,5.6-<2-oxa-6-oxo-6-syn[3α-(2- Tetrahydropyranyloxy)-octa-trans-1-enyl]-7-anti-
(2-tetrahydropyranyloxy)-cis-bisic
[15 Inl of a 10% potassium hydroxide water bath solution was added to 3,3,01 octa 7470 In9 and stirred at room temperature for 1 hour, then the reaction mixture was transferred to 50 d of ice water, neutralized with 1N hydrochloric acid, and slightly acidified with -I1111K. ethyl acetate 100m
Extracted with 1. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated until the solution had a concentration of about 20 rILe. A diethyl ether solution of diazomethane was added to the concentrated solution with OC until no more foaming was added, stirred at room temperature for 5 minutes, and then condensed.
Hydroxy-11α,15α-bis(2-tetrahydroranyloxy)-2,3,4,5,6-pentanorzorost-trans-13-enoic acid methyl ester 4
I got s 9 ttv.

NMR: δ = 5.20 to 5.80 (2H, r(1),
4.70 (21'I-m), 3.30-4.50
(7H, to), 6.68 (3H.

S), 1.10-2.80 (27H, m), 0.89
(3H, t).

MS: m/e=39'6,384,366.648,6
65.317.316.600.294.282.26
4゜250.247.232.229.210.85゜(1i) 155 μl of oxalylchloride dissolved in 1 me of methylene chloride under an argon atmosphere 1 ml of K methylene chloride! 213 μl of dimethyl sulfoxy dissolved in 1 me of methylene chloride Dropped at -7 Or', 15 at -78C
After stirring for a few minutes, 450% of the 9α monohydroxy compound (prepared above) dissolved in dichloromethane was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 60 minutes. Thereafter, 1 mg of triethylamine was slowly added, and after stirring at the same temperature for several minutes and further at room temperature for 5 minutes, the reaction mixture was diluted with 100 rug of ethyl acetate, washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. . The residue was eluted with ethyl acetate-cyclohexane (1:3).
9-oxo-I, purified by chromatography using a mixed bath solution of
Hχ, 15α-bis(2-tetrahydropyranyloxy)-2,3,4,5,6--! Phthanorzorost-trans-13-enoic acid methyl ester 408 tv? It's 4.

TLC (Vinegar r-stage ethyl: cyclohegisan-+): Rf
=0.53°NMR: δ-5,20~5.85 (2H, m), 4
．． 73 (2H, no), 3.20-4.40 (6H,
m), 3.68 (3H, s), 2.10-3.05
(6H, m), 1.10-2.10 (2DH, m
), 0.89 (3H, t).

MS: m/e=466 (M”), 4.35.395.
682°664.651.666.311.298.2
80.262.248,85゜(iii) Tetrahydrofury [1,5mlIl
c Dissolved 9-oxo compound (prepared above) 405
4.5 ml of 65 thiacetic acid was added to 1n9, stirred at 80C for 6 minutes, cooled to OC, and carbonated. The reaction product is ethyl acetate 1
00n+/, and the extract was sequentially diluted with water and saline (A
: Cleaned, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was eluted with ethyl acetate-cyclohexane (6:1).
Purification by silica gel column chromatography using a mixed bath liquid of
,5.6--! Tantanol-PGE, methyl ester 2
Obtained 10m9.

NMR: 5.40-5.85 (2H, m), 3
．． 90-4.50 (4H, m), 3.67 (3H, s)
, 2.80 (1H.

+idl, 2.3 () ~ 2.70 (4H, m),
2.32(1)], aa), 1.10-1.80 (8
H,m), 0.89 (3H,t).

MS: m/e=298 (M”), 280.267°2
62.248, 236, 227, 220.209°19
5.177.171.91° The following compound was obtained in the same manner as in Reference Example 1.

Ial17-phenyl-2,3,4,5,6,18,1
9,20-octanol-15 (Yβ-PGE, methyl ester starting material = 2-oxa-6-oxo-6-syn-
[3αβ-(2-tetrahydropyranyloxy)-5-
, y-x-nyl-intertrans-1-enyl]-7
-Anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3,6,0]octane (prepared as described below) 566.0 Yield: 259'l shell.

TLC (ethyl acetate: cyclohexane = 2:1): Rf
=010 and 0.14°NMR near, 00-7.50 (5H, m), 5.40~
5.90 (2H, m), 3.90-4.40 (2H, m
), 6.64 and 5.63 (3H, 2 (7) 8),
2.10-3.10 (IOH, m), 1.60-2.
10 (2H, m).

The starting material for Reference Example 1(a) is 2-oxa-3-oxo-
6-syn-formyl-anti-(2-tetrahuman 9
0 pyranyloxy)-cis-bisic[1[°6.3.0
] Produced from octane as follows.

Under an argon atmosphere, 5 ml of dry tetrahydrofuran (1K suspended in hydrogenated solution) (containing t (t 64%))
90 vaguely dry tetrahydrofuran l 5 rne l
c Dissolved dimethyl 2-oxo-4-phenylbutylbosphonate 768 ~ was slowly added using munitions, and stirred at the same temperature for 1 hour. The solution thus obtained was dissolved in 5 ml of dry tetrahydrofuran to dissolve [,ta2-;
,0] Okfin508#I! Added the mixture and stirred at the same temperature for 1 hour. The reaction fake was made acidic with glacial acetic acid, and the If-J-JP4 solution was concentrated under reduced pressure using silica gel. The obtained residue was purified by silica gel column chromatography using a mixed bath solution of ethyl acetate-cyclohexane (1:2) as an eluent to obtain 2-oxa-3-oxo-6- having the following physical properties. Shin-(3-
738〃v
I got it.

TLC (ethyl acetate: cyclohexane = 2:l): Rf
=0.40°NMR: δ”7.00-7.50 (5H, m), 6
．． 64C1H.

dd), 6.15 (IH, d), 4.80-5.10 (
IH, m ), 4.63 (IH, m ) 1.15.30
~4.40 (3H, m), 2.00~3.20 (
8H, m), 1.20-2.00 (8H, m).

MS: m/e=384(M”), 366.556,3
00°282.293,241.223.105.91
．． 85° Sodium borohydride 146 to 768 In9 (prepared above) dissolved in 10 parts of methanol
Add m9 at -20C, stir for 30 minutes at the same temperature, neutralize with glacial acetic acid to make it slightly acidic, and add 150f of ethyl acetate.
The extract was washed with water and saline sequentially.
After drying with magnesium sulfate, it was concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of methylene chloride in 1 VC of dihydrobilane (J
, 21nte and a catalytic amount of p-toluenesulfonic acid, stirred at room temperature for 60 minutes, and then added 150ml of ethyl acetate.
The extract was washed with saturated hydrogen carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography using a mixed solution of ethyl acetate and cyclohexane (1:2) as the eluent! 2-Ogizer 6-Oxo 6-Syn- [
', αβ-(2-tetrahydropyranyloxy)-5-
566 mL of 7enylbentertrans-1-enyl]-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3,3,0]octane was obtained.

TLC (ethyl acetate:cyclohexane-1:1)lf=
0.36°NMR: δ=7. OO~7.40 (5H, m),
5.30-5.70 (2H, m), 4.80-5.10
(IH, m), 4.155 (2H, m), 3.20
~4.40 (6i(,T11), 2.30~3.0
0(6Hpm)-1,20~2.30(16H,m).

MS: m/e=470 (M"), 686.668.6
02.284.2<56.193.185, i3Q, 1
17°91.85° Reference Example 2 9α-hydroxy-11α, 15αβ-bis(2-tetrahydropyranyloxy)-17-phenyl-18,1
9,20-trinorbroster trans-16-enoic acid melal ester (J under argon atmosphere, dry tetrahydrofuran 5 m
IJium (content: 64%)
90In9 dry tetrahydrofuran 5 rn13 J
((Bathed dimethyl 2-oxo-14-phenyldutylphosphonate) 7681 shell was added slowly at room temperature,
Stir for 1.5 hours at room temperature. In the thus obtained bath solution, 1α-acetoxy-2α-(6-medoxycarbonylhexyl) was dissolved in 51 Ll of dry tetrahydrofuran.
-3β-formyl-4α-(2-tetrahydropyranyloxy)cyclopentane 796 ml was slowly added at room temperature and stirred at room temperature for 40 minutes.

The reaction 7θ compound was neutralized with glacial acetic acid to make it slightly acidic, filtered once through silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of ethyl acetate and cyclohexane (1:3) as an eluent, and the following physical properties were determined. 9n-acetogycy 11α- with j
(2-tetrahydropyranyloxy)-15-oxo-
17-phenyl-18,19,20-) dinorprostol trans-16-enoic acid methyl ester 1.1Q was obtained.

TLO (ethyl acetate:inzene-1:4): Rf=0.
40°NMR: δ-705 to 750 (5H, m), 6.
72zn.

ddd), 6.20 (IH, dd), 5.15 (IH.

m), 4.55 (IH, m), 3.20-4.20 (
3H.

m ), 3.65 (3H, s ), 2.92 (4H, m
), 2.50-2.90 (2H, m), 2.28
(2H, t, ), 2.05 (3H, s ), 1.00
~2.00 (18H, m).

MS: m/e=528 (M"), 497.468.4
44.467.426.413.395.384,66
6°353% 340,335,208,133.10
5.91.85° (u) 15-oxo compound (prepared above) dissolved in 10 ml of methanol 1.11/1 with sodium borohydride 152In9 and a small amount of glacial acetic acid at -20°
After stirring for 60 minutes, the reaction mixture was neutralized with glacial acetic acid, made slightly acidic, and then added with 200 mL of ethyl acetate.
The extract was washed sequentially with water, saturated hydrogen carbonate, aqueous solution, and brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 9α-acetoxy-11α having the following physical properties. (2-tetrahydropyranyloxy)-1
5αβ-hydroxy-17-phenyl-18,19,2
0+) Linol broth)-) Approximately 1.1 g of lance-13-enoic acid methyl ester was wounded.

TLC (ethyl acetate:cyclohexane=i:2):Rf
=0.16 and 0.20°NMR: δ = 7.00 to 7.40 (5H, m), 5.3
0-5.90 (2H, m), 5.10 (IH, m), 4
40-4.80 (IH, m), 3.20-4.30 (
411+ m).

3.65 (3I-i,s), 2.70 (2](,t,
), 2.28 (2H, t), 2.10-2.80 (
2H, m), 2.05 (3H, s), 1.00~
2.10 (21H, m >.

MS: In/e = 452,446,42
8,421.415.410.397.684.368
．． 350.337°324%277.266.259,
105.91.85゜fiii) 15α dissolved in methylene chloride 10aA
About 1.1 m of the β-human ``roxy compound (prepared above), 0.22 m, l of dihydrobilane and 1 l of dihydrobilane 1j'
-1) -t/l/ -:+-, add sulfonic acid and stir at room temperature for 30 minutes, then dilute the reaction mixture with 30 ml of ethyl acetate and saturated hydrogen carbonate) IJJ solution and brine sequentially. After washing, drying over magnesium sulfate and concentration under reduced pressure, 9α-acetoxy-11α has the following physical properties.

15αβ-bis(2-tetrahydropyranyloxy)-
About 1.3 g of 17-phenyl-18,19,20-)linolprostol trans-13-enoic acid methyl ester was obtained.

TLC (ethyl acetate: cyclohexane-1:2): Rf
-〇, 38°NMR: δ=70(]-7,45(5H,m), 5.3
0-5.80 (2H, m), 5.10 (IH, m), 4
．． 50-4.90 (2H, m), 3.20-4.4
0 (6H, m), 5.66 (3H, s), 2.
05 (5H, s), 2.10-3.00 (6H, m)
, 1.00-2.10 (26H.

m).

MS: no/e=530.523,513,470,4
52°439%428.421.368.650,10
5゜91.85゜rfv) Methanol 10mA! 15-tetrahydro-90 pyranyloxy compound (prepared above) dissolved in
Add 828 m9 of potassium carbonate to about 1.69, stir for 40 minutes in SOC, then slowly add glacial acetic acid at 00 to 10 c to neutralize it and make it slightly acidic, then add 150 m9 of ethyl acetate.
Extracted with g. The extract was washed with saturated hydrogen carbonate solution (+7 um water) and brine, dried over fiRcII magnesium, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solution of ethyl acetate-cyclohexane (1:2) as an eluent to obtain the title compound with the following physical properties: 1.041! I got it.

TLC (ethyl acetate: cyclohexane = 02): Rf =
0.20゜NM:R:δ=7.00~7.50 (5H, rn)
, 5.20-5.80 (2H9m), 4.70 (2H
, m), 3.2.0-4.40 (7H, m), 3.6
<5 (3H, s), 2.10~3.00 (6H* m
), 1.10-2.10 (271-I,m).

MS:to/e=487.470.458452.43
9.421.398.386.3<S8.651.66
7.314° The following compound was prepared in the same manner as in Reference Example 2.

tal 9α-Hydroxy-11a, 15αβ-bis(2-jtratoclanyloxy)-16-7enyl 17.18゜1920-tetranorzolost-trans-13-enoic acid methyl ester 17 substances: 1α-acetoxy- 2α-(6-medoxycarboninohexyl)-3β-formyl-4(r-(2
-te)lahydrobilanyloxy)cyclotintan t
o y and dimethyl 2-oxo-ro-phenylbrobylphosphonate) 977 m9° Yield = 865 ~.

TLC (ethyl acetate: cyclohexane = 04): Rf=
0.27゜(bl 9α-hydroxy-11α, 15αβ-bis(
2-tetrahydropyranyloxy)-2,0-butylbrosto-trans-13-enoic acid methyl ester Starting material: 1α-acetoxy-2α-(6-medoxycarbonylhequinyl)-3β-formyl-4α-(2 -tetrahydropyranyloxy) cyclotonthane 1.199
and dimethyl 2-oxyundecylphosphonate)1.
251° Yield 1°: 1.71° TLC (ethyl acetate: cyclohexane-1:2): Rf
-〇, 60° Reference Example 6 1α-hydroxy-2α-(6-medoxycarponylhex-2-enyl)-6β-[3-(2-tetrahydro-ranyloxy)prohaltrans-1-enyl]-4 (r-C2-tetrahydropyranyloxy)cyclopentane In the same manner as (iii) and (iv) of Reference Example 2, i
Starting from II-acetoxy-2α-(6-medoxycarponylhex-2-enyl)-6β-(3-hydroxypropertrans-1-enyl)-4α-(2-tetrahydropyranyloxy)cyclopentane 1.029 The title compound 875m having the following physical properties as a raw material
I got g.

'! 'LC (ethyl acetate: cyclohexane = 1: 1
) :1(f=0.65°NMR:δ-5,65(2H,m),5.25(2i
(,m,), 4.70(2H,m), 3.05-4.
40 (9H, m), 3.157 (3H, s), 1.
90-2.70 (8H, m).

1.10-1.90 (16H, m).

MS: m/e=382,664.651.646.36
6゜ro15.298.292.280.267.262
．． 249%245,231.208%85゜Reference Example 4 17-phenyl-18,19,20-)linol-15α
β-PCTE 1 Methyl ester In the same manner as (ii) and (iii) of Reference Example 1, 9α
-Hydroxy-11α,15αβ-bis(2-y)rahitolopyranyloxy)-17-phenyl-18,19
, 20-) From 989m9 of linolbrosto trans-13-enoic acid methyl ester (prepared in Reference Example 2), the title compound 560~ having the following physical properties was obtained.

TLC (ethyl acetate: cyclohexane-2:1): Rf
=0.08 and 0.14°NMI' (: J-7,00-7,45 (5H, m)
, 5.30-6.00 (2H, m), 3.80-4.4
0 (2H, m), 6.65 and :v-64(3He
2 s ), 2.5 () - 3,00 (6H
, m), 2.10-2.50 (4H, rn),
1.00-2.10 (12H, m).

MS: +u/e=402 (M10,), 384.671
．． 366°353.340.335.613.297,
279.267.265.261.249.247.2
41.236.223.206.196.185.15
6.143.166.117.105.91゜Reference example 4
In the same manner as above, the following 11 compounds were obtained.

lal i 6-7: r-two fiv -17,18,
19,20-tetra,/#-15αβ-PGEI methyl ester starting material negative: 9α-hydroxy-11/l'
, 15αβ-bis(2-tetrahydropyranyloxy)-16-phenyl-17,18,19,20-tetranorpros)-) methylnisder lans-13-enoate [18 produced by yp in Reference Example 2(a) '('] Om, 7
°Yield: 337 #I, Io'I'LC (ethyl acetate: cyclohexane-7: filtrate):
1 (f=0.38 and 0,61°Ib12[]-]butyl-15αβ-PGE, methyl ester starting material = 9αhydroxy-11rr, 15αβ
-bis(2-tetrahuman L1 biranylogishi)-20-
7'Tylbrostotrans-13-enoic acid methyl ester [11,709° produced in Reference Example 2(b) Yield:
i, oog. ” TLG (ethyl acetate: cyclohexane = 2:1): Rf
=0.16 and 0.24°NMR: δ-5,40-5.80 (2H, m), 4
．． 10 (2H.

m), 3.67 (3'H, s), 2.72 (IH
, da), 2.50-3.10 (2H, wide
), 1.90-2.50 (5H, m ), 1.05-1
．． 90 (26H, r+r ), 0.85 (3H, t,
).

MS: m/e=424 (M+), 406.693.38
8.675.362.656.635.297,279
．． 265.247.207゜lcl 1617.18.19.20-<futa/ruPGE2') Methyl ester starting material: 1α-hydroxy-2α-(6-medoxycarbonylhex-2-enyl)-3β-[3 −(
2-tetrahydropyranyloxy)propertrans-
1-enyl]-4α-(2-tetrahyto90pyranyloxy)sifurontan (produced in Reference Example 6) 618
1R9゜Yield: 278~.

TLC (ethyl acetate:cyclohexane-5:l): Rf
=0.15°NMR: δ=5.75 (2H, m), 5.4[](
2H, m), 4.15 (2H, a), 3.90-4.3
0 (i ]'(, m ), 3.68 (3H, s), 2
．． 75 (IH, aa), 1.85-2.60 (11H,
m), 1.50-1.90 (2H.

m).

MS: m/e=296 (M”), 278.265.26
0°247.246.234.228.218.207
．． 168.94゜Reference Example 5 2.3,4,5.6-pentanol-PCBl methyl ester 2,3,4 dissolved in 5 ml of 50% aqueous ethanol
, 5.6-bentanol PGE, methyl ester (produced in Reference Example 1) 128 to 2Mσ) potassium hydroxide 15
Add 1.8 ml of 0% aqueous ethanol bath solution and incubate for 30 minutes at room temperature.
After stirring for a minute, the reaction mixture was poured into 2Qml of ice water.
The mixture was neutralized with 1N hydrochloric acid to make it slightly acidic, and then extracted with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was bathed in 3 rnl of diethyl ether, added with oc. until no more effervescence of diazomethane in diethyl ether was added, stirred for 5 minutes at room temperature and concentrated to give 130 m9 of the title compound with the following physical properties: .

TLC (chloroform:tetrahydrofuran:acetic acid=1
0:2:1):Rf=0.55°NMR:δ=
6.70 (IH, d), 6.25 (IH, aa),
4.00-4.50 (IH, m 3.3.65 (3H,
s), 3.30 (2H, s), 2.00-3.00 (
5H, m), 1.05-1.90 (8H, m),
0.85 (3H, t).

MS: m/e=280 (M”1.263,251,2
49°219.209, 191.181, 177.14
9°121° The following compound was obtained in the same manner as in Reference Example 5.

1a117-Fueni#-2,3,4,5,6,18,1
9,20-octanol-15αβ-PGB 1 methyl ester starting material = 17-phenyl-2,3,4,5,6
,18,19,20-octanol-15αβ-PGE1
Methyl ester [Reference example 11=l'c-produced] 25
7In9゜Yield: 156~.

TLC: (ethyl acetate:cyclohexane-1:1):R
f=016°NMR: 7.40 to δ-7,10 (5H, m), 6
80 (IH.

d), 6.34 (1H, d(i), 4.36 (IH
, m), 3.65 (3H, s), 3.33 (-'2H
, s), 2.30-3.10 (7H, m), 1.7
5-2.10 (2H, m).

MS: m/e=314(M”), 296,283.2<
S5.256.236.223.191.181.16
3°149.121.105.91°U■:λ=276nm.

lbl 17-7 E-Lou 18.1220- )
IJ/Rue 15(, Yβ-PCTBl methyl ester starting material: 17-phenyl-18,1'9,201 linol-15αβ-PGE 1 methyl ester (ε-Example 4
) 492-0 Yield: 333〃ν.

TLC (ethyl acetate:cyclohexane=02):Ht=
0.13°NMR: δ = 7.0b to 7.45 (5H', m), 6
．． '82 (I Hld) + 16.26 (I Htdd)
, 4.36 (iH,rn), 3.64 (3H,s)
, 2.50-3.10' (5H, m).

2.1 o~2. so (6H, xn)%1.80~
2.10 (2H'.

m), 1.10 to 1.80 (8H, zn).

MS: m/e = 384 (M+), 666.656.3
35.323.279.275.2<Sl, 251.2
49.247.246.219.217.199.10
5.91°UV: λ=, 279nm.

Icl 16-7-+: Niru 17.18, 19.
20-tetratrue 15αβ-PCB, methyl ester starting material: 16-fe-ru 17,18,19.
20-tetratrue 15αβ-PGE 1 methyl ester [Reference example 4 (l produced with al) 337IR9° Yield: 150rn9° TLC (ethyl acetate): Rf = 0.72° NMR
: δ-7,10~7.40 (5H, m), 6.82
(IH.

d), 6.28 (IH, dd), 4.40-4.70
(IH.

m), 3-65 (3H, s), 2.92 (2H, d),
2.50-2.70 (2H, rn), 2.39 (2
H,t,), 1.1()-1,95(8H,m).

MS: m/e=370CM"-'), 352,539.
621°279.247,219.91°UV:λ=279.5nm0 ial, 16,17.18,19.20-pentanol-PGB2 methyl ester starting material: 16.1'/, 18.19.20--
! > Tanol-PGE 2 methyl ester [Reference example 41c
1]278 m9゜Yield: 142 m9゜TLO (ethyl acetate: cyclohexane = 2:1) lf=
0.23°NMR: 6.96 (IH, d), 6.42 (I
H, dt), 5.38 (2H, m), 4.40 (2
H, m), 6.68 (3H, s), 3.05 (, 2H
, d), 2.95 (I H.

wide S), 1.95-2.80 (8H, m), 1
．． 50-1.95 (2H, m).

MS: +n, /e=, 278 (M”J, 260,247
．． 229.215.153, 105.91°UV:λ=277nrn.

Reference Example 6 Rhooxo-PGB1 6-Oquin-P soaked in 50% aqueous ethanol 11d
To GEI methyl ester (compound described in Example 3 of JP-A No. 54-44659) 285~ was added 3.75 N of a 2M potassium hydroxide 150-mass aqueous ethanol solution, stirred at room temperature for 1.5 hours, and then reacted. Pour the mixture into 69ml of ice water.
1, neutralized with 1N hydrochloric acid, made slightly acidic, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of ethyl acetate-cyclohexane (3:1) as an eluent to obtain the title compound 184~ having the following physical properties.

TLC (ethyl acetate: cyclohexane-5:1): Rf
-〇, 15°NMR: δ = 6.75 (IH, a)% 6.60 (2H,
Wide S), 6.30 (IH,, aa), 4.00-4
．． 60 (IH.

m), 3.45 (2H wide S), 2.10-3.10
(8H, m), 1.10-2.10 (12H, m), 0
．． 95 (3H, t).

MS: m/e=350. (M”), Ro62.286.2
79.251.263.222.215.204.18
7° The following compound was obtained in the same manner as in Reference Example 6.

ial PCB2 Starting material: PGE2201mj9゜ Yield: 150~.

'rLc (chloroform:tetrahydrofuran:glacial acetic acid=10:2:1): ln=0.55°NMR: δ=6.88 (IH+d), 6.63 (21(
, wide S), 6.28 (IH, da), s, o O~
5.60 (2H.

m), 4.00-4.50 (IH, m), 2.8
0-3.20 (2H, m), 2.50-2.80 (21
1, m), 1.90-2.50 (6H, m), 1.
00-1.90 (10H.

m), 0.89 (3H, t;).

MS: m/e=334 CM+), 616.305,2
87°266.245.266.217°UV: λ = 281 nm.

Reference example 7 2,3.4.5.6-pentanol-15-oxo-PG
B 1 Methyl ester 2,3.4.5.6- dissolved in methylene chloride 5#Il
−? Manganese dioxide 1.9611 was added to 126-126~ of tantanol-PGB1 methyl ester (produced in Reference Example 5) at room temperature in 4 portions every 30 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered once through silica gel,
It was further washed with ethyl acetate i Q Q rnl, and the obtained liquid f was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed acid solution of ethyl acetate-cyclohexane (1:4) as an eluent to obtain the title compound 96 as yellow crystals having the following physical properties.

Melting point = 44° ~ 47C0 TLC (ethyl acetate: cyclohexane = 1 = 1): Rf
=0.50°NMR: δ-7,60 (IH, d), 6.62 (IH,
a), 6.68 (3H, s), 3.43 (2H, S)
, 2.40~2.90 (6H, m), 1.40~
1.90 (2B, m), 1.10-1.50 (
4H, m), 0.91 (3H, t).

MS: m/e=278 ('M"l, 250.247,2
22.218.207.194.190.179.16
2.151°UV: λ-290nm 0 In the same manner as in Reference Example 7, the following compound was observed.

ta117-phenyl-2,3,4,5,'6.18.
19.2 [1-octano-15-oxo-PCB,
Methyl ester starting material: 17-phenyl-2,3
,4,5,6,18,19,20-octanoru 15α
β-PGB 1 methyl ester [produced in Reference Example 5(a)] 138~.

Yield: 116~ (pale yellow crystals).

Melting point = 60° ~ 62C0 TLC (ethyl acetate: cyclohexane = 1: 1)
:Rf=0.30°NMR:a"7.55 (IH, (1), 7.15~7
．． 40 (5H.

m), 6.58 (IH, d), 3.68 (3H, s
), 3.40 (2H, s), 3.00 (4H, s)
, 2.74 (2H, m), 2.52 (2I (, m).

MS: m/e-312 (M”), 284.281.25
2.208.176.148.105.91°Uv:λ
=291nnn'.

1b117-phenyl-18,19,20-)dinol-
15-okine-PGB1 methyl ester starting material = 17-phenyl-18,19,20-)dinol-15αβ-PGB1 methyl ester [Reference example 5 (b
) 330#19゜ Yield: 178~.

TLC (ethyl acetate:cyclohexane-1=2):F(
f-〇, 24゜NMIl(:δ-7,60(IH,a), 7.10~
7.40 (5H.

m), 6.53 (IH, d), 3.66 (3H, s
), 3.00(4H,s), 2.55+-2,75(
2H, m), 2.10-2.55 (6H, m), 1.
10-1.85 (8H, m MS: 382 (M+), 654.651.322.27
8゜249.246.217.199.105.91゜UV:λ-297nm 0 tel 16-phenyl-17,18,19,20
-Tetratrue 15-oxo-PCB, methyl ester starting material = 16-phenyl-17,18,19,2
0-tetratrue 15αβ-PCB, methyl ester [
[produced in Reference Example 5(C)]100~.

Yield: 381n9° TLC (ethyl acetate: cyclohexane = 1:1): Rf
=0.60゜hhMR2δ=7.18~8.20 (6H, m)
, 6.58 (IH.

d), 3.96 (2H, s), 3.66
(3H,s), 2.15+-2,90(3)
1, m), 1. [10-1.80 (8H.

m).

his:m/e=368(M+,), 351,347,
340.277.249.245.217.105.9
1°UV: λ=303mto.

+a+ 16.17.18,19.2 (1- is phthanol-15-oxo-PGB2 methyl ester starting material = 16.17.18,19.20-pentanol-PGB 2 methyl ester [manufactured in Reference Example 5(d) ] 126 ■.

Collection*Near 6m9°TLC (methylene chloride:ethyl acetate-3:1):) (f
-〇, 51°NME (: δ = 9.80 (IH, c+)% 7.65 (I
H, d), 6.54 (IH,' d (go), 5.4
'3 (2! (# ''), 3.68 (3H, s), 3
．． 19 (2H, d), 2. LO~2.90 (8H,
m), 1.50-2.00 (2F'+m).

MS: m/e=276 (M+), 247.245.21
5.188.176.145.165.105.91°Uv:λ-290nm 0 Reference Example 8 6.15-dioxo-Pf:rBt Mixed bath solution of methyl ester diethyl ether and ethyl acetate (1:1) 5
A diethyl ether solution of diazomethane was added to 6-okine-PGBI (produced in Reference Example 6) 184~ dissolved in 184 mL at DC until no more foaming occurred, stirred at room temperature for 5 minutes, and then concentrated under reduced pressure. The resulting residue was dissolved in 11Q ml of methylene chloride and the cal was dissolved in manganese dioxide.
29# was added in three portions at 20 minute intervals, stirred at room temperature for 30 minutes, and the mixture was washed with silica gel.
The obtained F[ was concentrated under reduced pressure.

The residue was eluted with ethyl acetate-cyclohexane (1:
The title compound 1 having the following physical properties was purified by silica gel column chromatography using the mixed bath solution of 2).
11~ was obtained as yellow crystals.

TLC (ethyl acetate: cyclohexane = 2:1): Rf
:=0.47°NMR: δ-7,50 (IH, d), 6.60 (IH,
d), 3.66 (3H, S), 3.50 (2H, s),
2.10-3.00 (IOH, m), 1.45-1.9
0 (6H.

m), 1.1O-=1.45(4H,m,), 0.90
(3H.

t).

MS: m/e=362(M+), 634,331,3
13°285.220.143.111°Uv:λ=291nm.

The following compound was obtained in the same manner as in Reference Example 8.

Ia115-oxo-PGB2 methyl ester starting material 2 PGB2 IT produced in Reference Example 6(a)] 150~
.

Yield 286rIui0 TLG (chloroform:tetrahydrofuran:acetic acid = 1Q:2:i): Rf = 0.75°NMR: δ-7,50 (IH, a), 6.55 (IH,
d), 5.00-5.65 (2H, m), 3.67
(3H, s), 6.00-3.30 (2H, cl), 1
．． 95-2. ．． 85 (10L(,m), 1.5
0-1.95 (4H, m'), 1.05-1.
5[J(4H,m), 0.91 (Il,t).

MS: m/e=346CM+), 615.258.24
7.215°Uv:λ=29+6nm 0 Example 1 17-phenyl-18,19,20-trinor-15<
iβ-PGB,) fk ester addition polymer 17-phenyl-18,19,20-) dinor-15α
119m9 of β-PCB, methyl ester [manufactured using 151 ml of reference material] was dissolved in 4.6 rnl of a 2NN hydroxyl solution containing 150 ml of water and stirred at 80C for 24 hours. The progress of the reaction was monitored by HPLC (bath medium: tetrahydrofuran, flow rate 20, 8 l/min) using a gel 1 permeation column (TSK Gel G2500H). After the reaction is completed, cool to room temperature and add 501 sobutanol 25
The pH was adjusted to 3 with 2NA chloric acid added with m1. After separating the isobutanol layer, it was washed with water. IN hydrogen carbonate)
The acidic substance was transferred to the aqueous layer using IJum water solution 25α. After separating the aqueous layer, the pH was again adjusted to 3 with 2N perchloric acid, extracted with inbutanol, and the extract was concentrated under reduced pressure to obtain the title polymer having the following physical properties.

HPLC peak retention time: 14.
0 minutes.

Now)) Now: 1000~5800°IR Niji=2950.1730.1600,1450.
1680.1250cIn-'.

U■2λ=240nm 0 Furthermore, the polymer obtained above was purified and separated by gel 1 percolumn chromatography (Sephadex LH-20) using methanol as the elution solvent to obtain an extract fraction. .

Thereafter, the following polymers were obtained in the same manner as in Example 1. In the column of polymerization method in the table, "11 method" means Example 1
"11al method" means that 15 equivalents of 1N hydrium hydroxide 750% hydrated ethanol m solution was used in place of the 2N hydrium hydroxide 150% hydrated ethanol solution used in Example 1. The same method as in Example 1 was used except that the "1 lb+ method" was used.
, “11cl method” and r 1 +a+ method” are those of Example 1.
In place of the 2N hydrium hydroxide 150% aqueous ethanol solution used in , 2M potassium carbonate 150% aqueous ethanol solution (60 equivalents) and 2N sodium hydroxide 150% solution were used.
60 equivalents of aqueous ethanol bath solution and 1 part of 2N lithium hydroxide
This shows that the same method as in Example 1 was used except that 50% of aqueous ethanol solution and 30% of water were used.

-7-' W*+ used in Examples 15, 16, 17J and 20 were all synthesized by known methods. The physical properties of these σ1 compounds are listed below.

1a116-hydroxymethyl-PGE, methyl ester (raw material of Example 15) TLC (chloroform:tetrahydrone:acetic acid = 1
0:2:1):Hr=0.10 and 014cNMR(
CDClR+acetone-d6 bath solution): δ=5.4-5
9 (2H, m), 3.64 (3H, s l, 3.5~
4.7 (7H, m), 2.17 (IH, dd), 0.
89 (38, t+.

+1)+2.3-dinol-)'GEl (Example 1
Origin of 6 4) Melting point near 2' ~ 74C6 NM) (: δ = AI9 (3H,)), 5.61 (2B,
m).

4.10 (2H, m).

IR (KBr method) Niji = 3400.3350.29'1
0゜2840.1720.170 [] cv -'
alc116-cyclohexyl-17.18.19,
2f]-tetratrue PGEI (Example 170) 1°LC (chloroform:tetrahydrofuran:mtriacid=10:2:1): Rf=o, 62°NMR: δ=5.45-5.70 (21 -1, m
), 5. [] [] ~ 5.30 (3H, m), 3.85
~4.3b (2H, Ill), 1.90~2.
90 (8H, rn), 0.80-1.90 (21B
, m).

1d116-(1-naphthyl 1-18.19.20-1
-Lino-PGE1 (raw material of Example 20) TLC (chloroform:tetrahydrofuran:am=
1o:2:1) :I(f=0.31°NMR:δ=Z1~8.2(7H,m), 5.15~5
．． 8(2)1゜m), 4.8”'-5,85(5H, m
), 3.3-4.3 (3H-m), 2.47-2
．． 82 [IH, d C1) c■R: υ=3350.3
000.2970.2930.2850.2660.1
740.171Ll, 1600°1510.1455.
1410.140(,1,1,380°1250.12
20.11/)0% 1080.1020°980.9
00,860, Li 30.810 (: In-1° (3 people)

Claims (1)

[Scope of Claims] 1. General formula [wherein R1 represents a single bond or a linear or branched alkylene group having 1 to 5 carbon atoms, R2 represents (11 hydrogen atoms, (l]) a hydroxy group (iii) a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted or unsubstituted; (iii) a straight-chain or branched alkyl group having 1 to 4 carbon atoms; or (1v) a phenyl group substituted or unsubstituted with a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a halogen atom, or a trifluoromethyl group. or represents a naphthyl group, R3 represents a hydrogen atom or a @ button having 1 to 4 carbon atoms or a branched chain alkyl group, and X represents
lit'-(cl(2+p-(where p&:t,
Set to 0 or an integer from 1 to 5. ), (1i) or a combination thereof. ) or - represents 〇, 16th place -
The double bond between positions 14 indicates a trans-configuration. However-
) Except when il-R2 represents an n-2 ethyl group and X represents a bantamethylene group. ] PCB derivative shown or corresponding 1) GE
Or an addition polymer having a molecular weight distribution of 1000 to 6000 obtained by subjecting a PGA derivative to a Michael addition reaction, or a nontoxic salt thereof. 2. General formula [wherein, R1 represents a single bond, a carbon number of 1 to 5 @, or a branched chain alkylene group, and R2 is (11 ice candy atoms, (]i) substituted with a hydroxy group or unsubstituted (iii) a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms substituted or unsubstituted by a straight-chain or branched-chain alkyl group having 1 to 4 prime numbers; cycloalkyl group, or (tv) represents a phenyl group or naphthyl group substituted or unsubstituted with a @hime or branched alkyl group having 1 to 4 carbon atoms, a norogen atom or a trifluoromethyl group, R3 represents a water ice atom or a linear or branched alkyl group having 1 to 4 carbon atoms; The bond indicates a cis-configuration), 1in
) (in the formula, the reading represents α- or β-configuration, or Δ- represents a mixture thereof) or -0, and the double bond between the 13th and 14th positions represents the trans-configuration X+. However, -R1, -1 (2 is an n-A antel group,
Except when X represents a cantamethylene group. A method for producing an addition polymer having a molecular weight distribution of 1,000 to 6,000, which comprises subjecting a PCB derivative represented by the following formula or a corresponding PGE or PGA derivative to a Michael addition reaction. 3. The process according to claim 2, wherein the Michael addition reaction is carried out in an alcohol or alcoholic water bath containing an alkali metal hydroxide, carbonate or bicarbonate. 4. The method according to claim 2, wherein the Michael batting force 11 reaction is carried out in an alcoholic water bath containing lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate. 5. The method according to claim 2, wherein the alkali concentration is 0.1 to 4 normal. 6. Starting material is 17-phenyl-18,19,20-)
The method according to Claim 2 Prophecy 1, which is IJ/Rue 15αβ-PC, B1 methyl ester. Z Process according to claim 2, in which the starting material is 6,15-dioxo-PGB 1 methyl ester 8, Process according to claim 2, in which the starting material is 15-oxo-PGB2 methyl ester Method. 9 Starting: 1 where the substance is 2.3.4.5.6--"phthanol-15-oxo-PGB1 methyl ester
The method according to claim 2. 10. Claim 2 in which the starting material is 9B2
The method described in section. 11. The starting material is 16.17.18.19.20-
The method according to claim 2, wherein the pentanol-15-okine-PGB 2 methyl ester is used. 12. Starting material is 16-phenyl-17,18゜1
The method according to claim 2, wherein the 9,20-tetratrue 15αβ-PGBL methyl ester. 16. The starting material is 17-phenyl-2,3,4,5
,6゜18,19.20-octanol-15-oxo-
3. The method of claim 2, wherein the PGB 1 methyl ester is PGB 1 methyl ester. 14, starting material is 17-phenyl-18,19,20-
3. The method of claim 2, wherein the trinor-15-oxo-PCTB1 methyl ester. 15. The starting material is 2.3.4.5.6-
3. The method of claim 2, wherein the GBI methyl ester is GBI methyl ester. 16. The method according to claim 2, wherein the starting material is 6-oxo-PC,B 1 . 17. Starting material is 20-phthyl-15αρ-PGE
2. The method according to claim 2, wherein the methyl ester is 1 methyl ester. 18, starting material is 16-phenyl-18,19,20-
3. The method according to claim 2, wherein the method is Torinol PGE 1. 19. The method of claim 2, wherein the starting material is 16-hydroxy-PCEI. 20, starting material is 16-hydroxymethyl-PGE1
The method according to claim 2, wherein the methyl ester is a methyl ester. 21. The method according to claim 2, wherein the starting material is 2,3-dinor-PGE1. 22, starting material is 16-cycloacyl 17, 18.1
9. The method according to claim 2, wherein 20-tetranoren E1. 2, the starting material is IS, 16-cystylutrans-Δ
24. The method according to claim 2, wherein the starting material is trans-Δ4-pGE. 25. The starting material is 16 -(1-naphthyl)-18, 19
, 20-) Renolu PGE.
The method described in section. 26, General formula [wherein R1 represents a single bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, R2 is a fil hydrogen atom, C11] substituted with a hydroxy group or not substituted A straight-chain or branched alkyl group having 1 to 10 carbon atoms, (1u) a cyclo having 4 to 7 carbon atoms substituted or unsubstituted by a straight-chain or branched alkyl group having 1 to 4 carbon atoms; R3 represents a straight or branched alkyl group having 1 to 4 carbon atoms, a phenyl group or a naphthyl group substituted or unsubstituted with a helogne atom or a trifluoromethyl group; Represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, (in the formula, the double bond indicates a cis-configuration), (iij) (in the formula, n mass is α- or β - configuration or a mixture thereof) or -0, and the double bond between the 13th and 14th positions indicates a trans-configuration. However, the case where -R1-R2 represents an n-pentyl group and X represents intamethylenez↓ is excluded. ]
Addition polymers with a molecular weight distribution of 1,000 to 6,000 obtained by subjecting GB i4 conductor or corresponding P(1,E or PGA derivatives to Michael addition reaction) or non-toxic salts thereof. A prophylactic or therapeutic agent for diseases caused by a decrease in oxidative phosphorylation ability.