JPS61100593A - Griseolic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R1, R2 are H, hydroxyl-protecting group; R3, R4 are H, COOH-protecting group; R5 is H, alkoxy; R6 is H, halogen; or R5 and R6 form a double bond or R2 and R5 may form a single bond; A is formula II (R7 is amino, hydroxyl; R8 is H, azide); where the case in which R8 is H and R5 and R6 form a double bond is excluded] and its salt. EXAMPLE:5'beta-Chloro-4'alpha-hydroxy-4',7'-anhydrogriseolic acid. USE:Remedy for cerebrovascular diseases, brain metabolism activator: it is an action to inhibit phosphodiesterase with low toxicity. PREPARATION:For example, griseolic acid of formula III, as a starting material, is allowed to react with a halogen such as chlorine in an aqueous alkali such as sodium hydroxide at a pH of higher than 12 at 0 deg.C to room temperature to give a compound of formula I (where R1, R3, R4 and R8 are H; R6 is halogen; R7 is amino; R2 and R5 form a single bond).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to griseol acid derivatives, more specifically those represented by the general formula [wherein R and R2 are the same or different and represent a hydrogen atom or a hydroxyl group protecting group, and R3 and R4 are the same or differently represents a hydrogen atom or a protecting group for a carboxyl group, R5 represents a hydrogen atom, a halogen atom, an acyloxy group, or an alkoxy group, R6 represents a hydrogen atom or a halogen atom, or R5 and R6 are combined. A double bond may be formed or R2 and R5 may be taken together to form a single bond, and A is represented by the formula (wherein R7 is an optionally substituted amino group or an optionally substituted hydroxyl group). and R8 represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted mercapto group, a cyclic amino group, an azide group, or a halogen atom).

However, this excludes the case where R8 represents a hydrogen atom and R5 and R6 together form a double bond. ] and a pharmaceutically acceptable non-toxic salt thereof.

The present inventors have developed a cAMP-degrading enzyme [phosphogesterase (
As a result of research on inhibitors, it was found that these compounds have excellent PDK inhibitory effects. P.D.
] 1i)), it is widely distributed in animal tissues (organs), acts as a second messenger for various hormonal actions, and plays an important physiological and biochemical role. Furthermore, it is known to be involved in cell division, proliferation, differentiation, cardiac contraction, hematopoiesis, effects on the central nervous system, immune response, and release of insulin and histamine. c A
M P has a wide variety of physiological effects as described above, and the enzyme that decomposes cAMP (cAMPPD)
Since inhibitors of E) increase the level of cAMP in cells, they can be used as cardiovascular agents, anti-asthma agents, smooth muscle relaxants, neuropsychiatric agents, anti-inflammatory agents, cancer treatment agents, anti-diabetic agents, etc. It is expected that

Therefore, as a result of intensive research on the pharmacological effects of the griseol acid derivatives (1) of the present invention, it was found that these compounds have excellent effects on improving brain metabolism, enhance the anticancer effect when used in combination with anticancer drugs, and enhance insulin C. The present invention was completed based on the discovery that the effect is enhanced and the toxicity is extremely low.

In the general formula (1), the "hydroxyl group protecting group" in the definition of R and R2 preferably includes an aliphatic acyl group such as formyl, acetyl, propionyl, n-butyryl, imbutyryl, and pivaloyl; benzoyl, p -) Luoyl, p-anisoyl, p-chlorobensoyl, p-
Aromatic acyl groups such as nitrobenzoyl; tetrahydropyranyl groups such as tetrahydrobilan-2-yl, 4-methoxytetrahydrobilan-4-yl; trilower alkylsilyls such as dimethylisopropylsilyl, tart-butyldimethylsilyl The "carboxyl group protecting group" which is a group and which does not meet the definitions of R and R4 is preferably a lower alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl; , p-nitrobenzyl,
Aralkyl groups such as benzhydryl; or aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- Lower alkoxycarbonyloxyethyl groups such as propoxycarbonyloxyethyl, 1-impropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-imbutoxycarbonyloxyethyl, phthalidyl groups, (2-oxo-5-methyfluori It is a protecting group for carboxyl groups that are easily hydrolyzed in vivo, such as 3-dioxolen-4-yl) methyl group, and is a "halogen atom" in the definition of R5, R6 and R8.
represents fluorine, chlorine, bromine, and iodine, and the "acyloxy group" in the definition of R5 preferably represents an aliphatic group such as formyloxy, acetoxy, propionyloxy, butyryloxy, imbutyryloxy, and pivaloyloxy. Lower acyloxy group; benzoyloxy, p-
It is an aromatic acyloxy group such as toluoyloxy, p-anisoyloxy, p-chlorobenzoyloxy, p-nitrobenzoyloxy, and "alkoxy group" is preferably methoxy, ethoxy,
It is a lower alkoxy group such as propoxy, impropoxy, butoxy, imbutoxy, tert-butoxy, and the "optionally substituted hydroxyl group" in the definition of R2 and R8 is preferably a hydroxyl group; ethoxy, ethoxy,
Lower alkoxy groups such as propoxy, impropoxy, butoxy, isobutoxy, 5ea-butoxy, tart-butoxy, pentoxy, hexyloxy; aralkyloxy groups such as benzyloxy, phenethyloxy, 3-phenylpropyloxy; phenoxy, p- Aryloxy groups such as methylphenoxy, p-methoxyphenoxy, p-chlorophenoxy; aliphatic lower acyloxy groups such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy; benzoyloxy, p-toluoyloxy, An aromatic acyloxy group such as p-anisoyloxy, p-chlorobenzoyloxy, p-nitrobenzoyloxy, and "optionally protected amino group" preferably refers to an amino group; methylamino , dimethylamino, diethylamine, propylamine, dipropylamino, isopropylamino, butylamino, inbutylamino, 5ec-butylamino, tsrt-butylamino, pentylamino, hexylamino, mono- or di-lower alkylamino groups: 2 -Hydroxy-substituted lower alkylamino groups such as hydroxyethylamino, 3-hydroxypropylamino; amino-substituted lower alkylamino groups such as 2-aminoethylamino, 3-aminopropylamino; benzylamino, p-methylbenzylamino, ruamino groups in arals such as p-methoxybenzylamino, p-chlorobenzylamino, phenethylamino, α- or β-naphthylmethylamino; anilino, p-)lucino,
p-anisidine, p-chloroanilino, α or β-
Arylamino groups such as naphthylamino; hydroxyamino groups; lower alkoxyamino groups such as methylamino, ethoxyamino, and propoxyamino; hydrazino groups; aliphatic lower acylamino groups such as acetamide, propionylamide, butyrylamide, and imbutyrylamide group; aromatic acylamido group such as benzamide, p-toluoylamide, p-anisoylamide, p-chlorobenzamide, p-nitrobenzamide, R81
7) "Optionally substituted mercapto group" in the definition preferably refers to a mercapto group; methylthio, ethylthio, propylthio, isopropylthio, butylthio, inbutylthio, g8C-pteυthio, tart-butylthio, pentylthio, hexylthio. Lower alkylthio groups such as: aralkylthio groups such as pendylthio, phenethylthio, 3-phenylfurobylthio; aliphatic lower acylthio groups such as acetylthio, propionylthio, butyrylthio, imbutyrylthio; benzoylthio,
These are aromatic acylthio groups such as p-toluoylthio, p-anisoylthio, and p-chlorobenzoylthio, and the "cyclic amino group" preferably refers to groups such as 1-pyrrolidinyl, piperidino, morpholino, and 4-methyl-1-piperazinyl. It is an aliphatic cyclic amino group.

In the general formula (1), substituents R5 and R6 are ---
Compounds that together form a double bond are represented by the general formula (wherein R1jR2, R3, R4 and R7 have the same meanings as defined above, and R1 excludes the hydrogen atom in the definition of R8 above. A compound in which the substituents R2 and R5 together form a single bond can be represented by the general formula (wherein R,, R3, R4, R6, R, and R8 has the same meaning as above.)

The griseol acid derivative having the general formula (1) has an asymmetric carbon atom in its structural formula and has stereoisomers, and the compounds of the present invention include these isomers and mixtures thereof. It is. For example substituents R5 and R6
When is not a hydrogen atom, its coordination may be R8 and either R or S.

Further, the compound (1) of the present invention can be made into a pharmacologically acceptable non-toxic salt, and such salts are preferably those of an alkali metal or alkaline earth metal such as sodium salt, potassium or calcium salt. I can give you some salt.

Next, specific examples of the compound (1) of the present invention are listed below, but the present invention is not limited to these compounds. Note that the nomenclature is based on griseolic acid CAI.

(1) 4β-acetoxy-5-hydro-o2.07-
Diacetylglyseolic acid dimethyl ester (2) 4β
-Bromo-5-hydro-02,07-diacetylglyseol acid dimethyl ester (3) 4β,5-dihydro-o2,o7-dia'thi'
Glyseol acid dimethyl ester (4) 4β,5-dihydroglyseol acid (5) 8-desamino-6-hydroxy-4β-acetoxy-5-hydro-02,o7-diacetylglyseol acid dimethyl ester (6) 6 -disamino-6-hydroxy-4α-acetoya-/-5-ht. -02,. 7-Diacetylglyseol acid dimethyl ester (7) 6-disamino-6-hydroxy-4β-chloro-5-hydro-〇2.07-Diacetylglyseol acid dimethyl ester (8) 6-fsamino-6-hydroxy 51
-dihydroglyseolic acid am) 6-fsamino-6-hydroxy-4β-methoxy-5di-chloro-O,o-diacetylglyseolic acid dimethyl ester-6-disamino-6-hydroxy-4β-methoxy 5(-bromo"o2,o7-diacetylglyzeol acid dimethyl ester!36-fsamino-6-hydrocy4α-hydroxy-5pebro:fny4,7-anhydroglyseol acid (L44α-hydroxy- 5(-chloro-4,7-anhydroglyseol acid (154α-hydroxy-5(L-bromo4j7-anhydroglyseol acid member 4α-hydroxy-5q-iodo-4,7-anhydroglyseol) ol acid (1?) 8-bromo 4α-hydroxy-5q-chloro-4,7-anhydroglyzeol acid as 8-bromo 4α-hydroxy-5(-bromo 4,7-anhydroglyseol acid moiety 8-bromo-4α-hydroxy-5(X-iodo-
4,7-Anhydroglyseolic acid (2) 8-bromo 4α-hydroxy-51X-bromo 4,7-anhydroglyseolic acid dibenzhydryl ester r21J8-mercapto-4α-hydroxy-5CL-
Bromo 4.7-Anhydroglyzeolic acid dibenzhydryl ester (S) 8-Mercaptoglyzeolic acid dibenzhydryl ester (C) 8-Mercaptoglyzeolic acid (Foundation) 8-Methoxy-4α-hydroxy- 5(-pro%-4.7-7
dibenzhydryl ester of dihydroglyseolic acid (c) 8-methoxyglyseolic acid dibenzhydryl ester C18-methoxyglyseolic acid@8-bromoglyzeolic acid@8-7'romo6-desamino-6- Hydroxyglyzeolic acid g48-Bromoglyzeolic acid dibenzhydryl ester (to) 8-Azidoglyzeolic acid dibenzhydryl ester Gυ 8-Aminoglyzeolic acid dibenzhydryl ester @ 8-aminoglyzeolic acid W 5CL-puO-%-4 (X-4 droxy-4,7
-Anhydroglyseolic acid dibenzhydryl ester (2) 4α-hydroxy-5CL-iodo-4,7-
Anhydroglyseolic acid dimethyl ester @ 5α-
Iodo-4α-hydroxy-4,7-IP anhydroglyseolic acid dibenzhydryl ester C116-disamino-6-hydroquine-5α-bromo 4α-hydroxy-4j? -Anhydroglyseolic acid dibenzhydryl ester (b) 6-zosamino-8-hydroxy-5α-bromo-4α- and droxy-4
,7-anhydroglyseol acid dimethyl ester@N', N', 02-) Lihe:/zo(#-5'
(!-BuOmo4α-HydroNakashi4,7-Anhi)”
O/IJ zeolic acid dimethyl ester @N',N',02-) lipenzoyl-5α-iodo-4α-hydro-4,7-anhydroglyzeolic acid dimethyl ester-4β-chloro-5-hydro-o2, o7-Diacetylglyseolic acid dimethyl ester Cetylglyseolic acid dimethyl ester (42) 6-disamino-6
-Hydroxy-4β-iodo-5-hydro-02,07
-Diacetylglyseolic acid dimethyl ester (43) 6-disamino-6-hydroxy-5α-
Chloro-4α-hydroxy-4,7-anhydroglyseolic acid (44) 6-disamino-6-hydroxy-5α-
Iodo-4α-hydroxy-4,7-anhydroglyseolic acid (45) 8-chloro-5α-bromo 4α-hydroxy-4,7-anhydroglyseolic acid (46)
II-chloro-5α-iodo-4α-hydroxy-4,
7-Anhydroglyseolic acid (47) 8-Methylthioglyseolic acid (4B) 8-Benzylthioglyseolic acid (49) 8-Phenylthioglyseolic acid (50) 8-Hydroxyglyseolic acid (51)
8-benzyloxyglyseolic acid (52) 8
-Phenoxyaminoglyseolic acid (53) 8-Methylaminoglyseolic acid (54) 8-benzylaminoglyseolic acid (55) 8-phenylaminoglyseolic acid (56) 8-chloro-6-disamino- 6-
Hydroxyglyzeol dimethyl ester 92 (59) 8-Bromoglyseol phthalidyl niscarbonyloxy)ethyl ester ester (62) 8-bromo 6-disamino-6-hydroxybrizeol i datalidyl ester (65) 8
-Bromo-6-disamino-6-hydroxymethyl ester (65) 1m-methoxyglyseol valoyl Φ dimethyl ester (66) 8-aminoglyseol 17 valoyloxymethyl ester anhuman glyceol i baloyloxy Methyl ester anhydroglyseol d ~ thalidyl ester anhydroglyseol acid (1-ethoxycarbonyloxy) ethyl ester (70) 5α-iodo-4α-hydroxy-4,7
-φ Anhydroglyseolic acid phthalidyl ester (71)
Blunt-iodo-4α-hydroxy-4,T-L anhydroglyzeolic acid pivaloyloxymethyl esterbonyloxy)ethyl estermethyl-1,3-dioxolen-4-yl)methyl estermethy/I/- 1,3-dioxolene-4-yl) methyl ester-1,3-dioxolene-4-yl/L/) methyl varnish 5
-Methyl-1,3-dioxolen-4-yl) methyl ester The novel griseolic acid derivative having the general nitrate according to the present invention can be produced, for example, by the reaction steps shown below. The griseol acid represented by the formula (A), which is a starting material, is a known compound. gri
saoaurantiacus)8ANK63479
(Feikoken Bacillus No. 5223) (25)
(24) alan
CA) Q3 a3
(141(LEj
α9aIJ -〇! + (to) In the above formula, R, > and R4゜ are the above-mentioned R3 and R4
represents a carboxyl group protecting group in the definition of R4
1 and "12" represent the hydroxyl group protecting group in the definition of R1 and R2 described above, R150 represents the alkoxy group in the definition of R5 described above, and MuCO represents the protecting group of the hydroxyl group in the definition of R5 described above.
represents an acyloxy group in the definition of
8 represents an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted mercapto group, or a cyclic amino group, and 2 and 2 are chlorine,
Indicates halogen atoms such as bromine and iodine.

The reaction reagents and reaction conditions in each of the above steps are described below.

This is a step in which carboxylic acid is added to the double bond of 0-glyseolic acid.

- Reaction solvent: There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting material and the carboxylic acid to be added to some extent, but a carboxylic acid to be added such as acetic acid is preferably used.

O reaction reagent: together with carboxylic acids such as acetic acid and propionic acid, strong acids such as anhydrous hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or trifluoromethanesulfonic acid, or platinum oxide to accelerate the reaction. Catalysts may also be added.

O reaction temperature: Although not limited to %, it is preferably 0°C to 1°C.
Temperatures up to 00°C are preferred.

O reaction time: Although it varies depending on the reaction temperature and reaction reagent, it is usually from 1 hour to 3 days.

This is a step of adding hydrohalic acid to the O double bond.

O Reaction solvent: There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting material to some extent, but an organic acid such as acetic acid is preferably used.

O reaction reagent A hydrohalic acid such as hydrochloric acid, hydrobromic acid, or hydroiodic acid to be added to the double bond is used.

O reaction temperature: Usually carried out at 0°C to room temperature, but 80 to 1
It may be heated to about 00°C.

O reaction time: Varies depending on reaction solvent, reaction reagent, etc.
Usually it is 1 to 72 hours.

This is a step of adding a halogen atom to a hair alkoxy group at the O double bond.

O Reaction solvent: There is no particular limitation as long as it does not inhibit the reaction, but usually an alcohol such as methanol or ethanol to be added is used.

O Reactant 2: Usually the halogenating agent to be added, such as fluorine, chlorine, bromine, iodine, NO8, NB8
Alternatively, Nl19 or the like is used.

O reaction temperature: Although not particularly limited, the reaction is usually carried out at around 0°C to room temperature.

O reaction time: varies depending on the reaction temperature and reaction reagent, but
Usually it takes 1 minute to 30 minutes.

This is a step of reducing the halogen at position 04 using a reducing agent.

O Reaction Reagent 2 There is no particular limitation as long as it is a reducing agent that is commonly used for reducing halogen, but reduction with tri-n-butyltin α4 tote or zinc dust is preferable.

O Reaction solvent: There are no particular limitations as long as it does not inhibit the reaction, but the preferred solvent varies depending on the reagent used. When tri-n-butyltin hydride is used, aromatic hydrocarbons such as benzene, toluene, and xylene are preferred. When using zinc powder, lower aliphatic carboxylic acids such as acetic acid containing water or alcohols such as methanol and ethanol are preferable.

O Reaction temperature When using nitri-n-butyltin hydride, a temperature near the boiling point of the solvent is suitable, and in the case of reduction with zinc dust, a temperature from room temperature to about 100°C is suitable.

O reaction time is 2 to 10 hours when using nitri-n-butyltin hydride, and 2 to 20 hours when using zinc powder.

1) Removal of alkyl ester (methyl ester):
Dissolve in an alkaline aqueous solution such as sodium hydroxide or potassium hydroxide with a concentration of 11 to 1 N at room temperature according to a conventional method.
This is carried out by reacting for ~15 hours.

Peng) Removal of benzhydryl ester: This is carried out according to a conventional method, usually by using fluoroacetic acid in the presence of a solvent such as anisole and reacting at 0° C. to room temperature for 10 minutes to several hours.

6) 4', TI-anhydro compound synthesis step (10th degree 1st
Step 1) 5 from a griseolic acid derivative having a double bond in the O-sugar moiety
This is a process for synthesizing a compound having a halogen at the ' position and an anhydro bond between the 4' and 77 positions.

O reaction reagent: Hydroxide with pH 12 or higher) IJum,
It is carried out using halogens such as fluorine, chlorine, bromine, and iodine in an alkaline aqueous solution such as potassium hydroxide.

・Reaction solvent 2 Water is usually used, but when using a reagent that is insoluble in water such as iodine, it is preferable to use a mixture of an alcohol such as methanol and water.

O Reaction temperature: Usually carried out at 0°C to room temperature.

O reaction time: Although it varies depending on the reaction reagent or reaction temperature, it is usually 30 minutes to 6 hours.

T) Halogenation step at position 8 (12th step) This is a step of introducing a halogen into position 8 of the O adenine nucleus.

O reaction reagent: There is no particular limitation as long as it is a reagent that can introduce a halogen into the 8-position of the adenine derivative, but preferably, for example, bromine water is used in a pH 4 buffer such as a heptalytic acid buffer. It is better.

O Reaction solvent 2 Usually, an aqueous solution tube whose pH is adjusted to 4 is used.

・Reaction temperature 2 OI is usually carried out at 0°C to around room temperature. O reaction time is usually 1 to 10 hours.

a) Esterification step of carboxylic acid moiety (Step 13) This is a step of reacting carboxylic acid and diphenyldiazomethane to obtain dibenzhydryl ester according to a conventional method.

0 Reaction solvent: There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but a mixed solvent of water and acetone is preferably used.

・Reaction temperature: 20°C to 1G (L) There is no particular restriction, but the reaction is usually carried out at room temperature.

O Reaction time: Although it varies depending on the reaction temperature, it usually takes 15 to 24 hours when the reaction is carried out at room temperature.

1) Methyl esterification using diazomethane A methyl esterification reaction using a carboxylic acid and diazomethane, trimethylsilyldiazomethane or 1-methyl-3-p-)lyl triazene is carried out according to a conventional method.

- Reaction solvent: There is no particular restriction as long as it does not inhibit the reaction and dissolves the starting material to some extent, but usually a mixture of acetone and water or a mixture of DMF and water is used.

O reaction temperature: There is no particular restriction, but the reaction is usually carried out between 0° C. and room temperature.

O reaction time: varies depending on the reaction temperature, but is 1 to several hours when reacting at 0°C to room temperature @ s) Substitution reaction step of halogeno group at 8-position (Step 14-20) Halogeno group at 18-position, Preferably, the bromo group is reacted with various nucleophiles such as sodium methoxide, sodium bisulfide, sodium azide, methylamine, dimethylamine, benzylamine, piperidine, morpholine.
This is a step of obtaining a griseolic acid derivative substituted at the position. When the nucleophilic reagent is an amine, the reaction is performed with an excess amount of the amine without using a deoxidizing agent, but when the nucleophile is other than an amine, a deoxidizing agent such as triethylamine, which itself does not act as a nucleophilic agent, is used. It is preferable to do so.

O Reaction solvent: Although not particularly limited as long as it does not inhibit the reaction, it is usually preferable to use alcohols such as methanol and ethanol, or dimethylformamide or dimethyl sulfoxide.

O Reaction temperature: No particular limitation (usually carried out at room temperature or the boiling point of the solvent used).

O reaction time: Varies depending on the nucleophile used, but usually 20 hours at room temperature and about 6 hours at boiling point.

4'α-hydroxy-47 with halogen bonded at position 31
, 7/- by treating the anhydroglyseolic acid derivative under acidic conditions or with zinc dust.
This is the process of regenerating the double bond between the 1st positions.

1) When the halogen at the 5' position is chlorine or bromine: Start by heating the material with zinc powder in a mixed solvent such as water-methanol or diluted ethanol, or by heating it in a solution of a hydrous organic acid such as hydrous acetic acid. It is reacted with zinc powder at room temperature to 80°C.

I) When the halogen at the 5' position is iodine, the double bond can be regenerated with good yield by the method described in 1) above, but in addition to this, the presence of inorganic salts such as potassium iodide and acidic sodium sulfite can also be used. Double bonds can be easily regenerated by adjusting the PHt of the aqueous solution of the starting material to -0 to 3 in the absence of water and maintaining the temperature at 0°C to 60°C.

11) Step of converting azide to amine group (21st step) This is a step of converting the 8-position azide group to an amino group, using a catalyst such as palladium-carbon and an alcohol such as methanol or ethanol. or,
This is accomplished by leaving hydrogen sulfide in an organic base such as pyridine at room temperature for 10 to 30 hours.

12) Deamination and conversion step at the 6-position (18th step) - This is a step of converting the amino group at the 6-position into a hydroxyl group, and is usually carried out in a mixed solution of an organic carboxylic acid such as acetic acid containing water. This is achieved by bringing the temperature to room temperature from ℃.

To explain in detail the pharmacological action of the griseolic acid derivative of the present invention, this family of compounds (!) exhibits a strong PDE inhibitory action, has an action to promote brain function recovery against brain dysfunction caused by oxygen deprivation, and has an effect on cerebral ischemia. It improves intracerebral glucose metabolism and high-energy phosphate metabolism in rats subjected to cerebral ischemia; it has an effect of restoring the flexibility of red blood cells decreased by actis; it increases cerebral blood flow in rabbits; Promoting recovery of brain function (righting reflex),
It exhibits pharmacological effects such as enhancing the anticancer effect and enhancing the action of insulin when used in combination with anticancer drugs.

A more specific explanation will be given below by showing test examples regarding its pharmacological action.

Test Example 1 Phosphogesterase (I'DPI) inhibitory activity CAMP
PDE uses a crude enzyme solution derived from rat brain, and the inhibitory activity measurement method is described in Anne Rhys Pichard and Wai Nie Chun, Journal of Biological Chemistry, Vol. 251, pp. 5728-5T37 (1976). It was carried out according to the method described. That is, 14C-labeled CAMP (final concentration 114 μM) was used as the t-substrate, and this series compound (dissolved in DM802-5μJ), 20 μM of snake venom and 40 μJ of crude enzyme solution were added to Q, 2M) Lis-HCl buffer (pH 8,0 ) and mix in a total volume of 100
μ! Incubate at 30°C for 20 minutes. After the reaction was completed, the reaction solution was treated with resin Amberlite IRP-58, and CAMPPDE was determined from the amount of radioactivity of the remaining adenosine.
@ Harmful activity was calculated as a 100% rate. Furthermore, CGMPPDE
The same procedure was carried out using 140-labeled cGMP as the substrate instead of CAMP.

C-human MP PDP, CGMP of this family of compounds
The inhibitory activity against PDFt is shown in Table 1 as a 50% inhibition value (I5°).

As shown in Table 1, this family of compounds is c-AMPPDE.
, c-GMP PDE was found to have extremely strong and specific inhibitory activity. The I50 value of theophylline, a known inhibitor of this enzyme, is CAM
360 μM for PPDE, CGMP PDB
This substance has a PD concentration of 196 μM.
It can be seen that it has very strong inhibitory activity as an Fi inhibitor.

Table 1 CAMP PDFt, CGMP PDB
I50 value compound for C-human MP PDFf CGMP PDP
12a 35 3219
3.9 3.220
2.5 1.716
30.4 49.821
25, 0 1
F1 Test Example 2 Method One group of 5 male Wistar rats was used. Pe
drugs or vehi simultaneously with ntobarbital anesthesia
-cle (OMO solution) was administered orally, the neck was immediately incised, Q, 5 mj of blood was collected from the jugular vein, and the rotational viscometer (
Blood viscosity was measured using Tokyo Keiki).

Thirty minutes after drug administration, the bilateral carotid arteries were ligated, and one hour later (90 minutes after drug administration), the same amount of blood was collected from the jugular vein, and the blood viscosity was measured in the same manner.

The rotational viscometer has four levels of shear speed (37, 5, 75).

150 and 375 s = ), the average blood viscosity and standard error at each shear speed were calculated, and a -test was performed between the values before ligation and 60 minutes after ligation in each group, and a significant ( The number of shearing speeds at which an increase in blood viscosity (y < o, os) was not observed was expressed as a number (g). That is, when no significant viscosity difference was observed before and after ligation at all shear speeds +1-)+-
become. At this time, the vehicle
It was confirmed that the amount was 10 sho in the administration group.

As shown in Table 2, Example 26a compound (10119/
- or above), a significant blood viscosity improving effect was observed.

Test Example 3 Concussion Experiment Method OMO or OMO suspension of drug was administered intraperitoneally 30
After 50 minutes, a 16F weight was dropped from a height 503 above the mouse's head, and the time until recovery of righting reflex and spontaneous movement was measured.

Amount of crystallization Rightward reflex Spontaneous movement OMO-2071,4±29.28 185.9±51
．． 0826a 10 17 2 (L!i±2..
92 TZ, B±15.71**: P<8.0
5 Therefore, the compound (1) of the present invention can be used as a therapeutic agent for cerebral circulatory system diseases,
For example, it is useful as a therapeutic agent for stroke aftereffects, a therapeutic agent for cerebral infarction aftereffects, and a cerebral metabolism activator, such as a therapeutic agent for senile dementia and a therapeutic agent for traumatic brain injury. Its dosage form is
Examples include parenteral administration such as subcutaneous injection and intramuscular injection, as well as oral administration.

When used as a preparation for oral administration, excipients such as sugars and cellulose preparations, binders such as starches, pastes, and methylcellulose commonly used in preparations,
Additives such as disintegrants may also be included. The dosage varies depending on symptoms, age, etc., but for example, when orally administered to adults, it can be administered once or in divided doses within the range of 0.1-100 sP per day.

Next, a more detailed description will be given with reference examples and examples.

The physicochemical properties of the compounds mentioned in the Examples are listed in Tables 4 to 6 at the end of the Examples.

Reference Example 1a Glyseolic acid dimethyl ester Glyseolic acid Too # was mixed with 100wt of dimethylformamide
Dissolve in water and keep under water cooling. To this, 1.0~j, 2.0 to 1d diethyl ether. A solution containing rrmol of diazomethane is added under stirring until it becomes yellow (colored),
Let react for 10 minutes. After the reaction is completed, acetic acid is added until the color of the reaction solution is decolored, and the mixture is dried under reduced pressure. Add methanol to dissolve and filter. FW was dried under reduced pressure and recrystallized from water to obtain the target compound 54011P.

UV spectrum: λmax (methanol): 25
11 nm (g=1ssoo) nmr spectrum (δin DM80-dd): I
! 1.37, IH.

8, 8.33. IH,B (2-or8-H)
; 6.53. 1)(.

B (1'-H); li, 06. IH, dd(
λG, 6.0) (3'-H);&12. IH,
d(Fo) (5'-H); tso, IH.

d(&O) (2/ -H); 4,66, IH
,8(7'-H).

Reference Example 1b Compound 10 f of Reference Example 1a was converted into an eggplant-shaped kolben.
1', dissolved in 15011tK of pyridine, added 33ml of acetic anhydride under water cooling, and allowed to react at room temperature for 2 hours. After the reaction, 15 Jt of water was added under ice cooling, and the solvent was distilled off under reduced pressure to dryness. The residue was dissolved in 400 ml of methylene chloride, 400 Wt of 1N hydrochloric acid, and 400 ml of water.

Wash with 400 liters of water, and then 4. Extract twice with the chimekoshin. j4-A The six layers were collected, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. During distillation, the title compound precipitated as crystals &70ft
-I got it.

υV spectrum: λmax <methanol): 25
7nm (ε: 1710O) nmr spectrum (δfnDM130-d6):
a, 3B, IH, B.

8.23. IH, 8 (2-Ore-H); L8g
, IH, 51(1'-H); 6.31. IH, dd
(λG, 6.0) (3'-H); 5.17. IH,
d.

(λG) (5'-H); 5.66, IH, d (6,0
) (2'-H); 5.73°IH, 8 (7'-H).

Reference Example 2 Compound 1.82F of Reference Example 1 was dissolved in an 80% acetic acid aqueous solution, and 2.55 f of IJum was added thereto, and the mixture was sealed and left for 16 hours. At this point T
Since there was still some starting material left in the LO, add 111 nitrous acid (IJ) and leave it for 3 hours. The residue obtained by distilling off the solvent under reduced pressure is dissolved in acetone, and the operation of adding toluene and distilling off is repeated three times.

Dissolve the residue in water-chloroform, and remove the organic layer with hydrogen carbonate. Wash with an aqueous solution of IJ and saturated brine, dry over magnesium sulfate, and then evaporate the solvent to obtain a light brown glassy substance. This is purified using silica gel chromatography, dissolved in a small amount of acetone, benzene is added and left to stand, and the white crystals formed are collected. The target compound 1.2BI was obtained as fine white crystals.

UV spectrum: λmaz (50% methanol aqueous solution)
:243nm (g=12700), 2411nm (
sh) (12500), 275nm(sh) (4
3◎a).

nmr spectrum (δinDM80-d6): &34.
IH, 8, 1m. 18゜IH, 8(2-Ore-H
) ;6.88. IH,! 9(1'-H); 6.1
3. IH.

dd(λG, 6.0)(3/-H);5.22. I
H, d, (elephant 0) (S'-H); s, sz, IH,
a, (j, o) (2I-H); 5.73. IH,s
(r'-H).

Reference Example 3 6-Disamino-6-hydroxyglyseolic acid Glyseolic acid 5.31jF was heated and dissolved in an 80% acetic acid aqueous solution, allowed to cool to room temperature K, and then sodium nitrite s, soy was added and the mixture was replaced with nitrogen. Then, seal the bottle tightly and leave it for 18 hours. The operation of adding ethanol to the residue obtained by distilling off the solvent under reduced pressure and distilling it off is repeated until the acetic acid odor disappears. Dissolve the residue in 50ml of water, adjust the pH to 1.0IC using concentrated hydrochloric acid under water cooling, leave it in the refrigerator for 16 hours, collect the precipitated solid, wash with a small amount of water, and recrystallize from water-acetone. to obtain the title compound of 1.66 f. The mother liquor is concentrated to further obtain crude crystals of K 2.201.

Recrystallization was performed in the same manner to obtain 1.2 g of the target compound.

UV spectrum: λmax (water): 247nm (
g=11800).

270nm (sh) (g=3700).

nnr spectrum (δ1nDM80-d6): IL
33. IH, 8°8.1? , IH,8(2-Ore
-H); 6.5G, IH, 8(1'-H);
188, IH, dd, (3,0,6,0)(3'-
H);L12. IH, d(3,0)(5'-H)
;457. IH, d(6,0) (2'-H); 4
．． 50. IH, 8(7'-H).

Example 1 After heating and stirring at 50°C for 20 minutes, the solvent was distilled off under reduced pressure, and the operation of adding and distilling off acetone and toluene was repeated three times. Water 30s? After separating the organic layer, add 30 tons of 5% sodium bicarbonate water and 30 g of water again.
After washing with 30 g of saturated saline and drying with magnesium sulfate, the solvent was distilled off under reduced pressure for 7 traps, and the resulting caramel-like product was purified using silica gel column chromatography using 3% methanol-methylene chloride as a developing solution. From the U'V absorption peak obtained, 210 cm of the title compound was obtained.

Example 2 After heating and stirring at 50°C for 20 minutes, the solvent was distilled off under reduced pressure, and the operation of adding acetone and toluene and distilling off was repeated three times, and the residue was 5% ethyl acetate.
Dissolve in 30ml of sodium bicarbonate water, separate the organic layer, and add 5% hydrogen carbonate again)IJum water 30st, water 30ml
d. After washing with 30 d of saturated brine and drying over magnesium sulfate, the solvent was distilled off under reduced pressure for 7 consecutive days. 1.06N of the title compound was obtained from the next peak.

Example 3 Compound 512# of Example 2 was dissolved in acetone 10-,
80% acetic acid 10- was added, stirred at room temperature for 4 hours and 20 minutes, the solvent was distilled off under reduced pressure, the remaining 1 Gm of water was dissolved in 20 m of ethyl acetate, the pH was brought to 1 with -normal hydrochloric acid, and impurities were removed. leave

The organic layer was further washed with 204ml of saturated brine and 20ml of 5% sodium bicarbonate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure for 70 minutes. % methanol-methylene chloride was used as a developing solution to separate and purify the title compound 129.
The cape was obtained as a colorless caramel-like substance.

Example 4 υ Compound 80η of Example 3 was added to (L2 normal sodium hydroxide solution) and sonicated for about 10 minutes until it became a clear solution, left as it was for 2 hours, and purified using -acetonitrile-water as a developing solvent. Then, the main peak was lyophilized to obtain 57wl1 of the title compound as a white powder.

Example 5a 1) Put 4 g of the compound of Reference Example 2 into a two-headed colben, attach a cooling pipe, and replace the mixture with nitrogen gas. To this mixture, 4% hydrogen chloride-acetic acid was added and heated at 80°C. After reacting for 2 hours, the solvent was distilled off under reduced pressure, and the residue was extracted three times with toluene and methylene chloride, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with 1% methanol-methylene chloride to obtain the title compound 270η.

鄄) Compound 600q of Reference Example 2 was extracted three times using a pressure-resistant catalytic reduction device. The methylene chloride layer is collected, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure to dryness. The residue was subjected to silica gel column chromatography, eluted with 3% methanol-methylene chloride, and the solvent was distilled off. From K,
The title compound 28q was obtained.

I) The compound soo q of Reference Example 2 is placed in a two-headed colben, and the atmosphere is replaced with nitrogen gas. To this, add acetic acid and acetic anhydride in a ratio of 4:1.
1001d of the mixture was added and dissolved, followed by extraction with trifluoromethane sulfate while cooling with water. The oil layer was collected, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, first with methylene chloride,
The sugar derivative was eluted, then 1% methanol-methylene chloride, then 5% methanol-methylene chloride, and after evaporation of the solvent, the title compound 129119 was obtained.

Example 5b 500 mg of the compound of Reference Example 2 was placed in a two-headed colben and purged with nitrogen gas. To this was added 100 mt of a mixture of acetic acid and acetic anhydride in a ratio of 4:1 and dissolved, and after drying over trifluoromethanesulfonic acid dianhydride magnesium sulfate under water cooling, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with methylene chloride, 1% methanol-methylene chloride, then 5% methanol-methylene chloride, and after distilling off the solvent, the title compound 64 was obtained.

Example 6a Compound 4f of Reference Example 2 was placed in a two-headed Kolben, a cooling tube was attached, and the mixture was replaced with nitrogen gas. To this was added 40 tIe of 4% hydrogen chloride-acetic acid, heated at 80°C, and purified using methylene chloride to obtain the title compound 2. I got Oy.

Example 6b Zeol acid 500 q of the compound of Reference Example 2 is added to 10% hydrobromic acid-acetic acid, the mixture is tightly capped, and the mixture is treated with ultrasound for about 30 minutes to dissolve and left at room temperature for 64 hours. The operation of distilling off the solvent under reduced pressure, adding acetone and toluene to the residue, and distilling off the residue is repeated three times. Add 30xl of ethyl acetate to the resulting residue and perform ultrasonic treatment to remove insoluble matter. Dissolve this in 30 g of ethyl acetate (5% aqueous sodium bicarbonate) and separate the layers. The organic layer is washed with 20 g of saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Purification by column chromatography on silica gel gave 50 Mg of the title compound as a white powder lyophilized from benzene.

Example 7 1) Compound soo 119 of Example 6a and AIBN (
z2'-azobisisobutyronitrile) was placed in a two-headed colben, and the atmosphere was replaced with nitrogen. This is K.

Add and dissolve 20 ml of nitrogen-substituted benzene.

Furthermore, 3.1 ml of n-butyltin hydride was added using a syringe, and the mixture was refluxed with stirring. The residue was chromatographed at about 2 hours, eluted with 3% methanol-methylene chloride, and evaporated under reduced pressure to obtain 350η of the title compound.

l) The compound BOOη of Reference Example 2 was placed in a pressure-resistant catalytic reduction container, 70 μm of acetic acid and 600 μm of platinum oxide were added thereto, and the mixture was reacted at 5 ops for 6 hours in a Parr catalytic reduction apparatus. After the reaction, nitrogen is collected, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to dryness. Shirikage the remainder/
1/column chroma) with K, elute with 70% benzene-acetone, and distill off the solvent to obtain the title compound s.
oMg was obtained.

Example 8 - Dihydro-glyseolic acid The compound aso WIg of Example T was placed in an eggplant-shaped colben, and 20 g of 1N aqueous sodium hydroxide solution was added under water cooling.
Add J, dissolve and leave at room temperature for 2 hours.

After the reaction, the pH was adjusted to 1 with hydrochloric acid under water cooling, and the pH was adjusted to RP-1.
8 reverse phase column chromatography, 3% acetonitrile-0
, 3% acetic acid-water and freeze-drying to obtain the title compound 140819.

Example 9a 500η of the compound of Reference Example 2 was placed in a two-headed colben, and the mixture was replaced with nitrogen. Add anhydrous methanol to dissolve and cool on ice. Next, a solution of carbon tetrachloride (approximately 56 mmol) containing 11.05% chlorine is added. The reaction will be completed in 2 minutes under water cooling, so add sodium bisulfite and
After decomposing the chlorine, the solvent is distilled off under reduced pressure. The residue was dissolved in methylene chloride, subjected to silica gel column chromatography, eluted with 1% methanol-methylene chloride, and the solvent was distilled off under reduced pressure to obtain the title compound 412#.

Example sb Lugriseolic acid dimethyl ester H 300 Mg of the compound of Reference Example 2 is placed in an eggplant-shaped colben, and methanol 30- is added and dissolved.

While cooling with water, add 600 μm of N-promsuccinimide and return to room temperature. N-promsuccinimide dissolves to form a homogeneous solution. Stir at room temperature for 10 minutes and remove hydrogen sulfite) IJ
After drying the reaction solution with colorless cum, the solvent is dried under reduced pressure. The residue was diluted with methylene chloride and subjected to silica gel column chromatography, eluted with 3% methanol-methylene chloride, and the solvent was distilled off under reduced pressure to obtain the title compound 130.
η was obtained.

East Example 10 1.5 g of the compound of Reference Example 3 was placed in an eggplant Kolben, dissolved in a 2N aqueous sodium hydroxide solution, and cooled on ice. To this was added 258 mt of bromine saturated water under water cooling. The reaction was completed after stirring at 0°C for 40 minutes. The residue was dissolved in water, adjusted to pH 1 with 1N hydrochloric acid, and subjected to BP-8 reverse phase column chromatography. First, after desalting with a large amount of water, the title compound was eluted with 5% methanol-water and freeze-dried. 2 g of the title compound were obtained.

Example 11a Griseolic acid SO* is placed in an eggplant-shaped colben, dissolved in a 2N aqueous sodium hydroxide solution, and cooled on ice. While stirring under water cooling, the mixture is neutralized with chlorine-saturated water and freeze-dried. Dissolve the residue in water and adjust the pH to 1 with 1N hydrochloric acid.
P-8 - Perform reverse phase column chromatography, elute with 2% acetonitrile-0.3% acetic acid-97.7% water, and freeze-dry to obtain the title compound 1G! 'i got it.

Example 11b 2.271 glyseolic acid was dissolved in 80 slC of a 2N aqueous sodium hydroxide solution, cooled with ice water, and saturated bromine water 112 was poured over about 5 minutes, followed by stirring for 30 minutes. Excess bromine was decomposed by adding 5 molar aqueous sodium bisulfite solution at pH t-
Adjust to 2 or 3 and leave in the refrigerator overnight. The resulting crystals were separated by P and 1.6 g of the title compound was obtained as yellow needle-shaped crystals.

Example 11C Liglyseolic acid 10f was added to 2N sodium hydroxide solution 2
Dissolve the solution to 64 ml, and dropwise add a 0.5 molar iodine-methanol solution at 15° C. or lower while cooling with water. Crystals begin to precipitate when 2/3 of the amount is added. 15 hours later, water 700
Add 1 m of sodium bisulfite and dissolve, add 2 ml of sodium hydrogen sulfite, and add saturated hydrogen carbonate).
After leaving the mixture at 5°C overnight, the precipitated crystals were collected, washed with water, washed with n-hexane, and dried to obtain 1λOg of the target compound.

Example 12a Compound 2 of Example 11b. Asy was heated and dissolved in 150g of 1M acetate buffer with pH 4.0, allowed to cool to room temperature, poured with 120g of saturated bromine water, and left as it was for 6 hours, and the starting material disappeared with TI and O. Make sure that
Excess bromine was decomposed by adding 2.67 N of sodium bisulfite as a solid, and concentrated hydrochloric acid was added to reduce the pH to 2.3.
The solvent was concentrated to dryness under wave pressure, the residue was dissolved in as little water as possible, the pH was adjusted to -2.3, and the mixture was left in the refrigerator overnight. The resulting solid was collected and recrystallized from water to obtain the desired compound λ21.

Example 12b 160g of bromine water? Add '. Using a PH meter,
Add sodium bicarbonate and adjust the pH to 40.
Leave at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the operation of adding and distilling off with ethanol was repeated until the acetic acid odor became strong. The resulting residue was dissolved in 50 Il of water, and PHt" L3 K was dissolved using 3N hydrochloric acid under water cooling. Adjust.

The solid was allowed to stand for 3 hours under water cooling, and the precipitated solid was removed from P and dried to obtain the title compound of 1.9f.

Example 13 Example a Compound 300119 of example t2a was dissolved in dimethylformamide 8yd and diphenyldiazomethane 419
Dissolve q in ethanol 2- and add. After stirring at room temperature for 3 hours and confirming that the starting material was gone by TLO,
Excess diphenyldiazomethane is destroyed using acetic acid. When the solvent was distilled off under reduced pressure and ether was added to the residue, which was then rubbed, it turned into a powder. P was removed from this powder and recrystallized from ethanol to obtain 380η of the title compound as pale yellow crystals. Ta.

Example 14 Benzhydryl ester 1.97 f of the compound of Example 13 was placed in a two-head eggplant-shaped 7 flask, 20 m of pyridine was added to the bottom in a nitrogen stream, nitrogen gas was passed through it for 5 minutes, and hydrogen sulfide gas was heated to Vc3 under water cooling.
After replacing the inside of the flask with nitrogen gas for 0 minutes, seal the flask tightly and leave it at room temperature for 30 hours. Excess hydrogen sulfide gas is removed by passing nitrogen gas through the reaction solution for 1 hour at room temperature, and the solvent is distilled off under reduced pressure. Repeat the process of adding ethanol to the residue and distilling it off. The residue was 30 d of ethyl acetate.

Dissolve in 20w1 of water and separate. The organic layer was reduced to 0. Dry over IN-anhydrous magnesium sulfate and remove the solvent under reduced pressure to obtain a residue of 1.69 F. This was separated and purified using a silica gel prepacked column manufactured by Merck & Co., Ltd. using methylene chloride containing 2% methanol as a developing solvent, and the main beak was freeze-dried from benzene to obtain the title compound 1.201.

Example 15 1.69 F of the compound of Example 14 was added to 20 ml of A7
80% acetic acid 20w1. and zinc powder
, 1.31 and stir vigorously at room temperature. After 5 hours, 1.3 f of zinc powder was added and stirred for 24 hours. After washing with 20 m of saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was separated and purified using silica gel prepacked column chromatography manufactured by Merck Co., Ltd. using methylene chloride containing 3% methanol as a developing agent.
The title compound was obtained.

Example 16 Compound 130q of Example 15 is suspended in 1st of anisole, and 1d of trifluoroacetic acid is added and dissolved while cooling with water.

After standing for 30 minutes, toluene was added and distilled off, acetone-toluene was added to the residue, and the operation of distilling off was repeated. Dissolve in a small amount of acetone and pour into n-hexane with stirring to form a powder. This was dissolved in saturated hydrogen carbonate (IJ) plum solution, adjusted to pH 2.3 with IN-hydrochloric acid, separated and purified using a reversed-phase Brevara column-Ram Rp-8, and freeze-dried to obtain 50η of the target compound.

Example 1 T -274 knees, ←--*Trout 1m 16 at room temperature
Add m to λN-sodium meth4site.

Then, let it react in ultrasonic cleaning for about 4 hours. Distill the solvent under direct pressure, make the residue into an aqueous solution with pH 1.5 using IN-Sakaki and sodium bicarbonate, add the same amount of acetone, add diphenyldiazomethane and stir until no more foaming occurs. and converts it into benzhydryl. Excess diphenyldiazomethane was decomposed by adding acetic acid, and the solvent was distilled off under reduced pressure. The resulting residue was mixed with 30 d of ethyl acetate and 2 d of water.
Dissolve the organic layer in Q, IN-m, water, 5
% sodium bicarbonate water and saturated saline solution (2°), the organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was methylene chloride containing 3% methanol as a developing agent.

Example 18 8-Methoxyglyseolic Acid Dipenzhydryl Ester Compound 410* of Example 17 is dissolved in 80% acetic acid, and zinc powder Q and 6 f are added thereto at room temperature, followed by vigorous stirring at room temperature. After 3 hours, o and sy of zinc powder were further added, and the mixture was further stirred at Vc for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 30 ml of ethyl acetate and 20 dK of normal hydrochloric acid (L1) to remove insoluble matter. The organic layer was washed with 20 sJ each of water, 5% sodium bicarbonate and saturated brine, and diluted with anhydrous sulfuric acid. Dry with magnesium. The residue obtained by distilling off the solvent under reduced pressure was separated and purified using a silica gel prepacked column manufactured by Merck Co., Ltd. using methylene chloride containing 50% methanol as a developing solvent to obtain the title compound 85m+9. I got it.

Example 1s B-methoxy-glyseolic acid 32m9 of the compound of Example 18 was dissolved in 0.3d of anisole, and 0.311t of trifluoroacetic acid was added under water cooling.
Incubate for 10 minutes at room temperature. After repeating the operation of adding toluene and distilling off the solvent, adding acetone-toluene and distilling it off, adjust the pH to 2.3 with a small amount of 7cetone-hydrochloric acid, and drain with water using a reverse phase preparatory column Rp-8. The target compound 1B cape was obtained by freeze-drying.

Example 20 Add 624q of rum and 2.49N of potassium iodide and stir. Leave on an ultrasonic cleaner under water cooling for 3 hours. What is the pH of the reaction by adding sodium bicarbonate? Adjust to 2.2 and leave in the refrigerator overnight. Collect the resulting solid,
Recrystallization from water gave 0.63 g of the title compound as yellowish-white crystals.

Example 21 Dissolve the solution in 2 d of sodium hydroxide, add acetic acid OJ- to it, add 345 ml of sodium nitrite under a nitrogen stream, seal it, and leave it in the refrigerator. After 20 hours, 345η of sodium nitrite was added and the mixture was left to stand for an additional 27 hours. Add 345 cape sodium nitrite again and add 1
After standing for 7 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in water to adjust the pH to -1.0. This aqueous solution was separated and purified using a prepacked column RP-8f manufactured by Merck & Co., Ltd. using water containing 10% acetonitrile as a developing solvent, and the peak of the main product was lyophilized to obtain the title compound 78η.

Example 22 The organic layer was separated, washed with water, dried over magnesium sulfate, the solvent was distilled off, and crystals of the target compound were obtained from acetone.

Example 23 Compound 720 of Example 22 was dissolved in dimethylformamide, 1421"9 of sodium azide was added, and 80
Heat at ℃ for 7 hours. The solvent is distilled off, the residue is dissolved in ethyl acetate and water, the organic layer is separated, washed with water, dried over magnesium sulfate, and the solvent is distilled off. The residue was separated and purified using silica gel chromatography, and crystallized from methylene chloride.
76η was obtained.

Example 24 1 d of water is added to the compound 150IIy of Example 23, and 10 Jl/of a pyridine solution containing hydrogen sulfide at a concentration of about 1 molar is added while substituting with nitrogen, which immediately foams and dissolves. Seal tightly and leave at room temperature overnight. The solvent was distilled off and the residue was separated using silica gel chromatography to obtain 110.

Example 25 10011 g of the compound of Example 24 was dissolved in 1#t of anisole, and while cooling with water, 11111 g of trifluoroacetic acid was added. Add and leave at room temperature for 10 minutes. The operations of adding toluene, distilling off the solvent, and distilling off with acetone-toluene are repeated. Residue 1: Dissolved in acetone and added to n-hexane with stirring to form a powder. This was dissolved in a saturated solution of hydrogen carbonate, adjusted to pH 3 with 1N hydrochloric acid, and drained with water using a reversed phase preparator.

Fractions of the target product were collected and lyophilized to obtain 44.

Example 26a 5'α-promo 4'α-hydroxy-47,71 ester Compound 3h3y of Example 11b was treated with acetone 100 resistant,
Dissolve in 20sj of water, adjust to pH around 1 with concentrated hydrochloric acid,
Add diazomethane dissolved in acetone,
Stir at room temperature. After the reaction is completed, the reaction mixture is ace-dried and then distilled off.
Dissolve in a small amount of acetone.

Add to n-hexane with stirring to make powder, strain t-F
The target compound &751 was obtained by crystallization from benzene and a small amount of methanol.

Example 26b Ester Compound of Example 11c Using Example 26a and Example 26c Compound of Example 11b 1ft-tetrahydrofuran 40
After adding 3.19 g of 1-methyl-3-p-)lyl triazene, 10 g of water was added. Add.

It becomes a clear solution in about 10 minutes. After 3 hours, p-toluenesulfonic acid 1,1f was added, and the reaction mixture was further reacted at room temperature for 4 hours, and then left overnight at 5°C. The solvent is distilled off, the mixture is dissolved in ethyl acetate and water, and the organic layer is separated, washed with water, dried over magnesium sulfate, and as the solvent is distilled off, crystals are precipitated.

P was removed from this to obtain 3.46 ft- of the target compound. Further, the mother liquor was concentrated, dissolved in a small amount of acetone, and poured into n-hexane with stirring to obtain 0.241 as a powder.

Example 26d The same procedure as Example 26C was carried out using the compound zo y of Example 11c to obtain 1.1 g of the target compound.

Example 27a 1 g of the compound of Example 10 was placed in an eggplant-shaped colben, and T
1 (F100g/, water is added and dissolved, and the pH is adjusted to 1 using 1N hydrochloric acid. To this, diphenyldiazomethane is added while stirring until the red color no longer disappears. Stirring is carried out at room temperature for 3 hours. After that, the solvent was dried under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with 3% methanol and 87% methylene chloride, and the solvent was distilled off to obtain Compound 970119 of title 1.

Example 27b Compound 13 f of Example 10 was added to eggplant colben, dissolved by adding 800s+J of THF and 200w1 of water.
As it heats up, it foams vigorously. Add until foaming stops,
Add an excess amount, totaling 75 g.

If this continues, a considerable amount of the 7-methyl compound remains, so one reaction is completed by gradually acidifying the solution to pH 1 using 1N hydrochloric acid. The solvent was distilled off under reduced pressure, and the residue was dissolved in 500gJ of methylene chloride, and diluted with 3◎OWl of 1N hydrochloric acid.
After washing twice, the hydrochloric acid layer was back-extracted twice with 300-methylene chloride, the oil layer was collected, and after drying over anhydrous magnesium sulfate,
The residue was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with 3% methanol-97% methylene chloride, and the solvent was distilled off to obtain the title compound 6.32.

Example 28a Compound o of Example 26c was suspended in 5 pft of pyridine 20- and added with 1.411 s/l of benzoyl chloride under water cooling.
If you add 'i, it becomes clear immediately. Stir overnight at room temperature.

After the solvent was distilled off, water was added and the mixture was distilled off, the organic layer was separated, washed with water, and then dried over magnesium sulfate, and the solvent was distilled off. , crystallized from a small amount of ethyl acetate and ethanol to give 0.58jl
The desired compound was obtained.

Example 28b 12 g of the compound of Example 26d was added to pyridine 15011tK.
Suspend and add 6.98w1 of benzoyl chloride while cooling with water. The ingredients will melt in about an hour. After stirring overnight at room temperature, the solvent is distilled off. After adding water and evaporating, add ethyl acetate and saturated hydrogen carbonate to the residue, separate the organic layer, and wash with water. After drying over magnesium sulfate, the solvent was distilled off, dissolved in a small amount of ethyl acetate, and crystallized by adding ethanol to obtain the target compound 3.24 f.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a hydroxyl group protecting group,
are the same or different and represent a hydrogen atom or a protecting group for a carboxyl group, R_5 represents a hydrogen atom, a halogen atom, an acyloxy group, or an alkoxy group, R_6 represents a hydrogen atom or a halogen atom, or R_5 and R_
6 together form a double bond or R_2
and R_5 may be combined to form a single bond, and A has the formula ▲ Numerical formula, chemical formula, table, etc. ▼ group (wherein R_7 is an optionally substituted amino group or a substituted (R_8 represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted mercapto group, a cyclic amino group, an azide group, or a halogen atom.) show. However, the case where R_8 represents a hydrogen atom and R_5 and R_6 together form a double bond is excluded. ] A glyceolic acid derivative and a pharmacologically acceptable non-toxic salt thereof.