JPH02174779A - 3,7-dioxabicycle(3,3,0)octane derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1, R5 and R6 are H or alkyl; R3 is H, halogen or alkoxycarbonyl; R2 and R4 are H, halogen, carboxy, CN, NO2, NH2, alkyl, alkenyl, acyl, acyloxy, alkylthio, etc.; R2 and R4 may independently form a naphthalene ring together with R3: R1-R4 are not H at the same time). EXAMPLE:cis-2,6-Bis(m-fluorophenyl)-3,7-dioxabicyclo[3,3,0]octane-4,8- dione. USE:Agent for improving cerebral circulation and metabolism, agent for activating cerebral metabolism and remedy and preventive for senile dementia. PREPARATION:A compound of formula II (R3' is R3; R2' and R4' are R2 and R4 excluding carboxy, NH2, etc.) is made to react with a compound of formula III (R5' and R6, are R5 and R6; R7 is trisubstituted alkylsilyl) in the presence of an aldol condensation reaction accelerator and the obtained compound of formula VI is treated with an acid to obtain the corresponding compound of formula I.

Description

[Detailed Description of the Invention] [Background of the Invention] Industrial Application Field The present invention provides novel 3,7
- Dioxabicyclo[3,3,3,0)octane derivatives and their production method.

Conventional Technology With the arrival of an aging society, strokes, cerebral infarctions, and senile dementia caused by cerebrovascular disorders or decreased energy metabolism have become major social problems, and various drugs have been developed to address these issues. (Unexamined Japanese Patent Publication No. 55-17329,
(See Publications No. 59-219223 and No. 56-158713).

The present applicant has also reported that the known 2,6-diphenyl-3,7 dioxabisic O (3,3,07 octane derivative) has an effect on improving cerebral circulation and metabolism (Japanese Unexamined Patent Application Publication No. 1983-1999).
30416).

However, the 3゜7-dioxabicyclo[3,3,3,O)octane derivatives known to date are few and only have limited substituents, and their pharmacological effects are unknown. Almost never reported.

[Summary of the invention]

Abstract The present inventors synthesized various derivatives of 3,7-dioxabicyclo[3,3,3,0)octane with the aim of developing compounds that have clinically useful effects on improving cerebral circulation and metabolism. However, by discovering a new compound having an excellent effect on improving cerebral circulation and metabolism, we have completed the present invention.

That is, the present invention relates to a novel 3,7-dioxabicyclo[3,3,3,0)octane derivative or a salt thereof;
,3,3,0) octane derivative is represented by the following formula (I).

[Wherein, R1, R5 and R6 may be the same or different and represent a hydrogen atom or a lower alkyl group, R3 represents a hydrogen atom, a halogen atom or a lower alkoxycarbonyl group, and R2 and R4 represent a hydrogen atom, a halogen atom or a lower alkoxycarbonyl group, and R2 and R4 are , which may be the same or different from each other and may include a hydrogen atom, a halogen atom, a carboxy group, a cyano group, a nitro group, an amino group,
a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylamino group, a lower acyl group, a lower acylamino group, a lower acyloxy group, a lower alkylthio group, or a group -CONRR [where, R9 and Rlo may be the same or different and represent a hydrogen atom or a lower alkyl group. However, R9 and Rlo are both 5~
It may form a 6-membered ring, and the ring may contain -NR- (R□□ represents hydrogen or a lower alkyl group) -〇- or -8- as a ring constituent atom. ], or R2 and R4 may each form a naphthalene ring together with R3 (provided that R1, R2, R3
, and R4 are hydrogen atoms at the same time). ]
The present invention also relates to a method for producing this new compound (I), and the method for producing O includes the following steps (a) to (b).
, consisting of (a) to (c) or (a) to (d);
is the most important characteristic.

(B) A compound represented by the following general formula (■) and a compound reduced by the general formula CN) are reacted in the presence of -H or multiple aldol condensation reaction accelerators to form -soft formula (V).
To obtain a compound represented by

82' R4 may be the same or different and may be a hydrogen atom, a halogen-based T1 cyano group, a nitro group, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a mono- or di-lower alkylamino group, a lower an acyl group, a lower acylamino group, a lower acyloxy group, a lower alkylthio group, or a group -CONRR (where R and Rlo may be strongly the same or different and represent a hydrogen atom or a lower alkyl group). However, R9 and Rlo may both form a 5- to 6-membered ring, and in the chain ring, the ring constituent atoms are -NR1° (R11 represents a hydrogen atom or a lower alkyl group), -〇-, or -S-] may form a naphthalene ring (in the formula C, R1 represents a hydrogen atom or a lower alkyl group, and R'3 represents a hydrogen atom, a halogen atom, or a lower alkoxycarbonyl group). group, excluding cases where R2 and atoms are present). General formula (wherein, R5 and R6 represent a hydrogen atom or a lower alkyl group, and R7 represents a tri-substituted lower alkylsilyl group)
.

(In the formula, R1, R2, R3, R4, R5, R6 and R
The definition of 7 is as above) (b) Process (b)
Compound (V) obtained in step (c) is treated with an acid, (in the formula, the definitions of R1, R2, R3, R4, R5, and R6 are as described above). Subjecting the compound to a treatment step selected from reduction treatment, hydrolysis treatment, or a combination of both.

(d) When the treatment step of step (c) is a hydrolysis treatment, subjecting the compound obtained by the step to an esterification treatment step.

The present invention also provides a 3,7-dioxabicyclo[3,3,3,0)octane derivative represented by the following formula (II) or
This relates to the manufacturing method of the salt, and this manufacturing method is as follows:
It is characterized by consisting of ~(d).

R and Rlo may be the same or different and represent a hydrogen atom or a lower alkyl group. However, R
and Rlo may both form a 5- to 6-membered ring, and the chain ring includes -NR- (R-1 represents a hydrogen atom or a lower alkyl group), -〇-, or −
8-], or R2 may be very different, and the hydrogen atom or lower may be the same or different, and may be a hydrogen atom, a halogen atom, a carboxy group, or a cyano group. , nitro group, amino group,
Lower alkyl group, lower alkenyl group, halo lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
mono- or di-lower alkylamino group, lower acyl group,
A lower acylamino group, a lower acyloxy group, a lower alkylthio group, or a group -CONRR (wherein may form a naphthalene ring (.)) (a) Represented by the following general formula (■)' The compound and the compound represented by the general formula (■)' are mixed in a ratio of 0.01 to 5 to the compound (■)'.
Reaction in the presence of 0 mole percent of one or more aldol condensation reaction accelerators to obtain a compound of formula (V)'.

R2# [wherein R1 may or may not be a hydrogen atom or a lower alkyl group, and may be a hydrogen atom, a halogen atom, a cyano group, a nitro group, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, lower alkoxy group, mono- or di-lower alkylamino group, lower acyl group, lower acylamino group, lower acyloxy group, lower alkylthio group,
or the group -CONRR (where R9 and Rlo may be the same or different and represent a hydrogen atom or a lower alkyl group; however, Ro and Rlo together form a 5- to 6-membered ring; The chain ring may contain -N R1l- (R11 represents a hydrogen atom or a lower alkyl group) -0- or -8- as ring constituent atoms, or R2 and R3, R3 and R4
And R4 and R5 may each form a naphthalene ring. ] (In the formula, R6 and R7 may be the same or different and represent a hydrogen atom or a lower alkyl group,
R8 represents a tri-substituted lower alkylsilyl group. ) (In the formula, the definitions of R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above.) (B) The compound (V) obtained in step (A) is treated with an acid. The general formula and definition of R7 are as described above. ) to obtain a compound represented by

(c) Subjecting the compound obtained in step (b) to a treatment step selected from reduction treatment, hydrolysis treatment, or a combination of both.

(d) When the treatment step of step (c) is a hydrolysis treatment, subjecting the compound obtained in that step to an esterification treatment step.

Furthermore, the present invention provides 3,7-thioxabicyclo[3,3
, O] It relates to a method for selectively producing stereoisomers in octane derivatives (I) or (II), and this production method includes 3,7 dioxapinchloro(3, 3,0) Among octane derivatives, treating a compound in which the substituent at the 2.6 position is trans, or a mixture of a compound in which the substituent at the 2,6 position is cis and a compound in which the substituent is trans, with sulfuric acid. 3,7-dioxabicyclo[3
,3,3,O)octane derivatives, the substituent at position 2.6 is cis.

Effects of the Invention The compound represented by the general formula (I) and its salt according to the present invention are all new compounds, and have a remarkable effect on improving brain metabolism.

That is, compound [I] has an ameliorating effect on energy deficiency associated with brain aging, and is extremely useful as an agent for improving cerebral circulation and metabolism, an agent for activating cerebral metabolism, and an agent for treating and preventing senile dementia.

Furthermore, according to the production method of the present invention, the 3,7 dioxabicyclo(3,3,0)octane derivative (I) and its salt can be reliably provided by easy means.

Although the production method according to the present invention involves both new and known compounds, it is possible to use a small amount of an aldol condensation reaction accelerator, which has the advantage of being able to carry out the reaction under milder conditions. It has industrial advantages.

Further, according to the present invention, desired stereoisomers can be selectively produced.

[Detailed description of the invention]

3.7-Shioxapinchloro[3,3,0]octane derivative The compound according to the present invention is represented by the following general formula (I), and the definitions of R1 to R6 in the formula are as described above.

In the present invention, the term "lower" used to identify organic groups or compounds is a group or compound having up to 7 carbon atoms, preferably 4, most preferably 1 or 2 carbon atoms. Therefore, the lower alkyl group used in the general formula (I) according to the present invention is, for example, a methyl group, the lower alkoxy group is, for example, a methoxy group, an ethoxy group, an isopropoxy group, and the lower alkoxycarbonyl group is, for example, a methoxy group. Examples include carbonyl groups.

Examples of the halogen atom include fluorine, bromine, and chlorine. Examples of halo lower alkyl groups include trifluoromethyl groups.

Examples of the mono- or di-lower alkylamino group include ethylamino group and dimethylamino group.

Examples of the lower acyl group include an acetyl group, a propionyl group, and a benzoyl group.

Examples of the lower acylamino group include N-acetylamino M and N-acetylmethylamino group.

Examples of lower alkylthio groups include methylthio and ethylthio groups.

Examples of the group -CONR9R1o include the groups -CONHCH3 and -CON(C13)2.

The compounds according to the invention can form pharmacologically acceptable acid addition salts. As an acid addition salt,
Examples include mineral acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid, and mineral acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, and tartaric acid. .

In addition, the compound represented by - soft formula (I) is dextrorotatory (+
) and levorotatory (-), or a mixture thereof, and cis and trans stereoisomers due to substituents at the 2 and 6 positions exist, and the present invention includes both of them.

Usefulness of Compound (I)/Medicine The compound represented by soft formula (I) and its salts according to the present invention can be used as a cerebral circulation and metabolism modifier, a brain metabolism activator, a treatment for senile dementia, and a salt thereof, as described above. r. Can be used as a preventive agent. Although these drugs can be used as they are, they are preferably applied by injection, oral administration, mucosal application, etc., and are usually mixed with appropriate excipients, binders, diluents, adjuvants, etc. for the preparation, and made into powders. It is formulated and used as granules, tablets, capsules, syrups, and injections by conventional methods. Further, other drugs may be mixed as necessary.

The dosage may be adjusted depending on age, body weight, symptoms, etc., but for adults it is normal to administer 1 dose per day as a 3.7-dioxabicyclo[3,3,3,0)octane derivative.
About 0-g to 10-g, more preferably 50-g
It is about ~10g.

3.7-Shioxabicyclo[3,3,0]octa Novel compound 3,7 represented by the following general formula (I) according to the present invention
-dioxabicyclo[3,3,3,0)octane derivative (as described above) In formula C, R0 to R6 are defined as above],
The following steps (a) to (b), (a) to (c) or (
As mentioned above, it can be produced by steps (a) to (d).

Step-(a) A compound represented by the following general formula (III) and a general formula (I
V) is reacted with the compound represented by V) in the presence of one or more aldol embroidery reaction accelerators to form -soft formula (V).
To obtain a compound represented by

R-1 (wherein R6 and R7 may be the same or different and are a hydrogen atom or a lower alkyl group, and R
8 is a tri-substituted lower alkylsilyl group. ) The definitions of R7 and R8 are as described above. ) Solvents used in this reaction include solvents inert to the reaction,
Examples include carbon tetrachloride, chloroporum, dichloromethane, diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, benzene, toluene, xylene, and a mixed solvent thereof.

Examples of aldol condensation reaction accelerators include aluminum chloride, tin chloride, zinc chloride, zinc bromide, titanium tetrachloride, titanium tetraisopropoxide, trifluoroboronic acid ether, tetrabutylammonium fluoride, and trifluoroacetic acid. Examples include trimethylsilyl, tert-butyldimethylsilyl trifluoroacetate, trimethylsilyl trifluoromethanesulfonate, and tert-butyldimethylsilyl trifluoromethanesulfonate. Furthermore, a combination of two or more of these substances may be used. Examples of such combinations include combinations of titanium tetraisopropoxide and titanium tetrachloride, titanium tetraisopropoxide and trimethylsilyl trifluoromethanesulfonate, and the like.

The amount of aldol condensation reaction accelerator can be set arbitrarily, for example, 0.01 to 20% relative to compound (III).
An amount of 0 mole percent can be used. Each is used in an amount of about 0.01 to 50 mol percent, preferably 0.1 to 1.20 mol percent, based on compound (m).

The reaction is carried out at a temperature ranging from -79°C to the reflux temperature of the solvent used, especially when the reaction promoter is present in a small amount (0.01% relative to compound (III)).
~50 mol percent), 10°C to 30°C
It can be carried out under mild conditions in the temperature range of .

Step-(b) Treating the compound (V) obtained in step (a) with an acid (in the formula,
R□, R'2, R'3, R'4% R'5, R'6, R7
The definition of is as described above. ) to obtain a compound represented by

Examples of the solvent used in the reaction include aromatic hydrocarbon organic solvents such as benzene and toluene. Examples of acids include mineral acids and organic acids, with mineral acids being preferred. Preferred examples of mineral acids include hydrochloric acid,
Examples include sulfuric acid and nitric acid. The amount of acid is the compound (III
) or (V) in a range of 5 to 200 weight percent. Further, the reaction is carried out in a range from room temperature to the heating reflux temperature of the solvent used.

! 2t'i-<c): Subjecting the compound obtained in step (b) to a treatment step selected from reduction treatment, hydrolysis treatment, or a combination of both.

Examples of the reduction treatment include treatment with a metal such as zinc or iron in hydrochloric acid.

Furthermore, examples of the hydrolysis treatment include treatment with an acid, such as sulfuric acid.

Step 1-(d) During step (c), subjecting the compound obtained by the hydrolysis treatment to an esterification treatment step.

The esterification treatment can be carried out by a commonly used method, for example, treating a carboxylic acid with an alcohol in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, or para-toluenesulfonic acid, or treating a carboxylic acid with thionyl chloride, oxalyl chloride, etc. Examples include converting it into an acid chloride and then treating it with alcohol.

The lower alkyl group used in the general formula (I) in the present invention includes, for example, a methyl group, and the lower alkoxy group includes, for example, a methoxy group, an ethoxy group, an isopropoxy group,
Examples of lower alkoxycarbonyl groups include methoxycarbonyl groups.

Examples of the halogen atom include fluorine, bromine, and chlorine. Examples of halo lower alkyl groups include trifluoromethyl groups.

Examples of the mono- or di-lower alkylamino group include ethylamino group and dimethylamino group.

Examples of the lower acyl group include an acetyl group, a propionyl group, and a benzoyl group.

Examples of the lower acylamino group include N-acetylamino group and N-acetylmethylamino group.

Examples of lower alkylthio groups include methylthio and ethylthio groups.

Examples of the group -CONR9R, . include groups -CONHCH3, -CON (CH3)2, and organic acid salts such as oxalic acid and tartaric acid.

The present invention also provides 3,7- represented by the following general formula (n).
This is a method for producing a cyoxysabicyclo[3,3,0]octane derivative or a salt thereof, which includes the following steps (a) to (b),
Consisting of (a) to (c) or (a) to (d),
The characteristics are mentioned above.

Can be mentioned.

Furthermore, in the production method according to the present invention, pharmacologically acceptable acid addition salts can be formed.

Examples of acid addition salts include mineral acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, etc. (each substituent in the formula The definition of is as described above.) (a) The following general formula (
The compound represented by (■)' and the compound represented by the general formula (■)' are mixed in the presence of one or more aldol condensation reaction accelerators in an amount of 0.01 to 50 mol percent based on the compound (■)'. to obtain a compound represented by the soft formula (V)'.

Rj'(m)' (The definitions of each substituent in the formula are as described above.) (B) The compound (V) obtained in step (a) is treated with an acid to form the general formula (in the formula The definitions of each substituent are as described above.) (■
)′ to obtain a compound represented by

(c) Subjecting the compound obtained in step (b) to a treatment step selected from reduction treatment, hydrolysis treatment, or a combination of both.

(d) When the treatment step of step (c) is a hydrolysis treatment, subjecting the compound obtained in that step to an esterification treatment step.

This invention is a method for producing a compound represented by formula (n) other than that represented by formula (I), which is basically the same as the method for producing compound (I) described above, but with the step (I). ), a small amount of aldol condensation reaction accelerator, i.e. compound (
m)' is used in an amount of 0.01 to 50 mole percent. Therefore, in this case, the reaction can be carried out under milder conditions as described above.

Specific examples of compounds to which the production method of the present invention is applied are disclosed in Japanese Patent Application No. 174367/1982 (Japanese Patent Application No. 3041/1983)
Publication No. 6).

In addition, the compounds represented by soft formulas (I) and (■) are optical isomers such as dextrorotatory (+) and levorotatory (-), or mixtures thereof, or cis-isomers with a substituent at the 2.6-position. and trans stereoisomers exist; however, the present invention includes methods for producing either compound.

In particular, in the above reaction step (a), when multiple types of catalysts are used in combination (for example, titanium tetraisopropoxide and titanium tetrachloride, titanium tetraisopropoxide and trimethylsilyl trifluoromethanesulfonate, only the cis form is used). Of course, it also includes methods for selectively obtaining or selectively producing these stereoisomers.

The present invention also provides a compound in which the substituents at the 2 and 6 positions of the 3,7-dioxabicyclo(3,3,0) octane derivative represented by the soft formula (I) or (II) are trans,
Alternatively, by treating a mixture of a compound in which the substituent at the 2.6-position is cis and a compound in which the substituent is trans with sulfuric acid, the 2゜6 The present invention provides a method for selectively producing stereoisomers, which is characterized by converting the compound into a compound having a cis substituent.

The sulfuric acid treatment is carried out in an aromatic hydrocarbon-based white organic solvent such as benzene, toluene, or xylene, and the amount of sulfuric acid is 3.7%.
-Dioxabicyclo[3,3,0)octane derivatives can be used in the range of 5 to 20 C1ffi percent. Further, the reaction is carried out in a range from room temperature to the heating reflux temperature of the solvent used.

Experimental Examples Example 1 8.2 g of metafluorobenzaldehyde and 12.5 g of 2゜5-bis(trimethylsiloxy)furan were dissolved in 150 ml of dichloromethane, and stirred in a water-cooled oven to prepare trimethylsilyl trifluoromethanesulfonate (0.054 M 20 ml of dichloromethane solution was added. After 3 days after returning to room temperature,
The mixture was neutralized by adding an aqueous sodium hydrogen carbonate solution, and extracted with chloroform.

The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered.
Concentrated. Dissolve the residue in 200ml of benzene to 97%
3 ml of sulfuric acid was added, and the mixture was heated and refluxed.

After 10 minutes, add sodium bicarbonate aqueous solution to neutralize.
Extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated.

When diisopropyl ether was added to the residue, crystals were precipitated. This was taken and dried under reduced pressure to obtain 7.4 g of a mixture of cis and trans forms (yield: 68%).

The cis-isomer and trans-isomer were each separated and purified using silica gel chromatography (eluent: chloroform). The physicochemical properties of the obtained compound are shown in Table-2.

Examples 2 to 18 According to the same method as in Example 1-1, appropriate starting compounds were used to react, and compound V3 (Hymer compound) shown in Table 21 was synthesized.

Example-19 rate 100%).

Example-21 3.6 g of cis-2,6-bis(metanitrophenyl)3.7-thioxabicyclo[3,3,0]octane was suspended in 36 ml of concentrated hydrochloric acid, and 4.3 g of tin was added and heated. It refluxed. After 45 minutes, the mixture was returned to room temperature and neutralized with an aqueous solution of sodium bicarbonate. The precipitated solid was collected, washed successively with water, ethanol, and diisopropyl ether, and dried under reduced pressure to obtain 3.0 g of the desired product (yield 98%).

cis-2,6-bis(methacyanophenyl)-3,7-
Dioxabicyclo[3,3,3,0)octane-4,8
- 2 g of dione was added to a sulfuric acid aqueous solution (97% sulfuric acid: water - 1: 1
), and the mixture was stirred and heated to reflux. After 20 minutes, the reaction solution was added to ice water, and the precipitated crystals were collected in a furnace and thoroughly washed with water. This was dried under reduced pressure to obtain 1.5 g of the target product (yield: 68%).

Implementation N-22 trans-2,6-bis(metanitrophenyl) 3.7
-dioxabicyclo[3,3,3,O)octane 4.8
Using 3.7 g of -dione as a raw material, the same procedure as in Example 19 was carried out to obtain 3.2 g of the target product (cys-2,6-(methacarboxyphenyl)-3,7-thioxabicyclo[3
,3,0]octane-4,8-dione was suspended in 100 ml of tetrahydrofuran, and thionyl chloride 6
The mixture was added to 100 ml of methanol containing 100 g of the product under water-cooling and stirring.

This was returned to room temperature, stirred overnight, and concentrated, and the residue was neutralized by adding an aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. When diisopropyl ether was added to the residue, crystals were precipitated.

This was taken out and dried under reduced pressure to obtain 1.4 g of the target product (
yield 65%).

Example-23 Cis-2,6-(methacarboxyphenyl)3,7-dioxabicyclo[3,3,3,O)octane-4,8-
Using dione as a raw material, the same procedure as in Example 22 was carried out to obtain the desired product.

Table of physicochemical properties of the compounds of Examples 19 to 23
Shown in 3.

Manufacturing method of Example 24-1 7 g of benzaldehyde and 12.5 g of 2.5-bis(trimethylsiloxy)furan were dissolved in 150 ml of dichloromethane, and 5 ml of trimethylsilyl trifluoroacetate (0,054 M dichloromethane solution) was added dropwise while stirring under water cooling. . The temperature was returned to room temperature, and after 16 hours, the mixture was neutralized with an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated.

The concentrated residue was dissolved in 200 ml of benzene, 3 ml of 97% sulfuric acid was added, and the mixture was heated under reflux. After 15 minutes, the temperature was returned to room temperature, neutralized with an aqueous sodium bicarbonate solution, and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was recrystallized from isopropyl alcohol. A mixture of approximately equal amounts of cis and trans isomers was obtained in a yield of 6.7 g (yield 69%). Than this,
The cis isomer was isolated and purified using silica gel column chromatography.

Manufacturing method of Example 25-2 10.6 g of benzaldehyde and 21 g of 2,5-bis(trimethylsiloxy)furan were dissolved in dichloromethane at 150 g.
In addition to the above solution, 40 ml of tert-butyldimethylsilyl trifluoromethanesulfonate (0,038 M dichloromethane solution) was added dropwise while stirring and cooling with water. After 2 hours, the mixture was neutralized with an aqueous sodium bicarbonate solution and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. Dissolve the residue in 200ml of benzene,
9 ml of 97% sulfuric acid was added and heated to reflux. After 10 minutes, the temperature was returned to room temperature, neutralized with an aqueous sodium bicarbonate solution, and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated.

The residue was recrystallized from isopropyl alcohol.

A mixture of approximately equal amounts of cis isomer and trans isomer was obtained with a yield of 16.3sr (yield 55%). From this, the cis isomer was isolated and purified using silica gel chromatography.

Example-26 Production method-3 Trans-2,6-diphenyl-3,7-dioxabicyclo[3,3,3,0)octane-4,8-dione 1 g
: Dissolved in 70ml of benzene, 9796 sulfuric acid 0.2
ml was added and heated to reflux. After 20 minutes, an aqueous sodium hydrogen carbonate solution was added to neutralize the mixture, and the mixture was extracted with chloroform.

The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. Crystallized from diisopropyl ether. This was weighed and dried to obtain a cis isomer with an yield of 0.9 g.

Production method of Example-27-4 Cis-2,6-diphenyl-3,7-dioxabicyclo[3,3,0]octane-4,8-dione and trans-
2,6-diphenyl-3,7-dioxabicyclo[3,
3,3,0) octane in approximately the same amount as the mixture lug was dissolved in 300 ml of benzene, 3 ml of 97% sulfuric acid was added, and the same operation as in Example 26 was carried out to obtain the cis-isomer 7.8
I got g.

Example-28 Production method-5 2.7 g of benzaldehyde, 5 g of 2,5-bis(trimethylsiloxy)furan, and 0.25 g of titanium tetraisopropoxide were added to 25 ml of dichloromethane, and 10 ml of trimethylsilyl trifluoromethanesulfonate was added under water cooling and stirring. (0.18M dichloromethane solution) was added dropwise. The temperature was returned to room temperature, and after 64 hours, the mixture was neutralized with sodium hydrogen carbonate solution.

Insoluble matter was filtered off, and the filtrate solution was extracted with chloroform.

The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. Dissolve the residue in 50 ml of benzene,
% sulfuric acid was added thereto, and the mixture was heated to reflux. After 15 minutes, the temperature was returned to room temperature, neutralized with an aqueous sodium bicarbonate solution, and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. This was crystallized from diisopropyl ether. This was collected by filtration and dried under reduced pressure to obtain 2.2 g of the desired cis-isomer (yield: 59%).

Effect on cerebral glucose uptake rate in 4 cases SPE, ddY
Male strain mice (4 weeks old, weight 18-20r) were preliminarily housed in an animal house for a certain period of time, and then healthy mice weighing around 25 g were used in this experiment. In addition, before the experiment [1st 5:20 p.m.
The animals were fasted from 0:00 am until 10:00 am on the day of the experiment.

Scopolamine (2 sg/kg) was injected subcutaneously into the above-mentioned mice, and 30 minutes later, the test compound suspended in 0.5% CMC (carbomethoxycellulose) was administered at 100 g/kg.
g Orally administered. After another 30 minutes, 0.3 MBq/kg of 2-deoxyglucose (I-14C) was administered into the tail vein (
8 μCi/kg), and 10 minutes later, blood was collected by cutting the carotid artery, and the whole thickness was also removed. Blood is at 3000 rpm
The plasma was centrifuged for 5 minutes, and the radioactivity of the resulting plasma was determined using a liquid scintillation counter. In addition, after solubilizing all layers, 7111 determination of radioactivity was performed. In addition, the effect of promoting 14c uptake into the brain is due to brain '4C (dpm/g)
Judgment was made by determining the ratio of activity to plasma 14C (d pm/ml).

The test results are shown in Table 1, and significant activity was observed in the compounds of Examples 1 (cis form), 4 (cis form), 9 (lance form), and 11 (cis form).

Claims (1)

[Claims] 1. A novel 3,7-dioxabicyclo[3,3,0]octane derivative or a salt thereof represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1, R_5 and R_6 may be the same or different and represent a hydrogen atom or a lower alkyl group, and R_3 is a hydrogen atom or a halogen Represents an atom or lower alkoxycarbonyl group, R_2 and R_4
may be the same or different and include a hydrogen atom, a halogen atom, a carboxy group, a cyano group, a nitro group, an amino group, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxycarbonyl group, Mono- or di-lower alkylamino group, lower acyl group, lower acylamino group, lower acyloxy group, lower alkylthio group, or group -CONR_9R_1_0 [where R_
9 and R_1_0 may be the same or different and represent a hydrogen atom or a lower alkyl group. However, R_9 and R_1_0 may both form a 5- to 6-membered ring, and the ring has -NR_
1_1- (R_1_1 represents a hydrogen atom or a lower alkyl group) may contain -O- or -S-], or R_2 and R_4 may each form a naphthalene ring with R_3 ( However, R_1,
(except when R_2, R_3, and R_4 are hydrogen atoms at the same time). ] 2. Represented by the general formula (I) according to claim 1, characterized in that it consists of the following steps (a) to (b), (a) to (c), or (a) to (d). A method for producing a 3,7-dioxabicyclo[3,3,0]octane derivative or a salt thereof (the definitions of each substituent in the formula are the same as those described in claim 1). (a) A compound represented by the following general formula (III) and a compound represented by the general formula (IV) are reacted in the presence of one or more aldol condensation reaction promoters, and the general formula (V
) to obtain the compound shown. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R_1 represents a hydrogen atom or a lower alkyl group, R'_3 represents a hydrogen atom, a halogen atom, or a lower alkoxycarbonyl group, and R'_2 and R_4 may be the same or different and include a hydrogen atom, a halogen atom, a cyano group, a nitro group, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a mono- or di-lower alkylamino group, a lower acyl group, Lower acylamino group, lower acyloxy group, lower alkylthio group, or group -CONR_9R_1_0 [where R_9 and R
_1_0 may be the same or different and represent a hydrogen atom or a lower alkyl group. However, R_9 and R_1_0 may both form a 5- to 6-membered ring, and the ring includes -NR_1_1-(
R_1_1 represents a hydrogen atom or a lower alkyl group),
-O- or -S-), or R'_2 and R'_4 may each form a naphthalene ring together with R'_3 (provided that R_1,
(except when R'_2, R'_3, and R'_4 are hydrogen atoms at the same time). ] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R'_5 and R'_6 represent a hydrogen atom or a lower alkyl group, and R_7 represents a tri-substituted lower alkylsilyl group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R_1, R'_2, R'_3, R'_4, R_
5. The definitions of R_6 and R_7 are as described above) (b) The compound (V) obtained in step (a) is treated with acid to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ ( VI) (In the formula, R_1, R'_2, R'_3, R'_4, R_
5 and R_6 are as defined above). (c) Subjecting the compound obtained in step (b) to a treatment step selected from reduction treatment, hydrolysis treatment, or a combination of both. (d) When the treatment step of step (c) is a hydrolysis treatment, subjecting the compound obtained by the step to an esterification treatment step. 3. 3,7- represented by the following general formula (II), characterized by consisting of the following steps (a) to (b), (a) to (c), or (a) to (d) A method for producing a dioxabicyclo[3,3,0]octane derivative or a salt thereof (excluding parts that overlap with claim 2). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R'_1, R'_6 and R'_7 may be the same or different and represent a hydrogen atom or a lower alkyl group, R'_2, R'_3, R'_4 and R'_5 may be the same or different and are a hydrogen atom, a halogen atom, a carboxy group, a cyano group,
Nitro group, amino group, lower alkyl group, lower alkenyl group, halo lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, mono- or di-lower alkylamino group, lower acyl group, lower acylamino group, lower acyloxy group, lower alkylthio group or group -CONR_
9R_1_0 [Here, R_9 and R_1_0 may be the same or different and represent a hydrogen atom or a lower alkyl group. However, R_9 and R_1_0
may form a 5- to 6-membered ring, and the ring is
As a ring constituent atom, -NR_1_1- (R_1_1 represents a hydrogen atom or a lower alkyl group), -O- or -
may contain S-], or R'_2
and R'_3, R'_3 and R'_4, and R'_4 and R'
Both of _5 may form a naphthalene ring. ). ] (a) A compound represented by the following general formula (III)′ and a compound represented by the general formula (IV)′ are combined into a compound (
III) reacting in the presence of one or more aldol condensation reaction accelerators in an amount of 0.01 to 50 mole percent relative to ', to obtain a compound represented by general formula (V)'. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R′_1 represents a hydrogen atom or a lower alkyl group, and R″_2, R″_3, R″_4 and R″_5 are the same as each other. hydrogen atom, halogen atom, cyano group, nitro group, lower alkyl group, lower alkenyl group, halo-lower alkyl group, lower alkoxy group, mono- or di-lower alkylamino group, lower acyl group, lower Acylamino group, lower acyloxy group, lower alkylthio group, or group -CONR_9R_1_0 [Here, R_9 and R_1_0 may be the same or different and represent a hydrogen atom or a lower alkyl group. However, R_9 and R_1_0 may both form a 5- to 6-membered ring, and the ring includes -NR_1_1- (R_1_1 represents a hydrogen atom or a lower alkyl group), -O-, or -S-] or R″_
2 and R″_3, R″_3 and R″_4, and R″_4 and R
``_5 may each form a naphthalene ring.] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IV)' (In the formula, R'_6 and R'_7 may be the same or different. (V)' (In the formula, R'_1, R''_2 , R″_3, R″_4, R″
The definitions of _5, R'_6, R'_7 and R_8 are as described above. ) (B) Compound (V) obtained in step (A) is treated with acid to form a ▲Numerical formula, chemical formula, table, etc.▼(VI)′ ″_3, R″_4, R
``_5, R'_6 and R'_7 are defined as above.) (c) The compound obtained in step (b) is subjected to reduction treatment, hydrolysis treatment, or a combination of both. (d) When the treatment step of step (c) is a hydrolysis treatment, the compound obtained in that step is subjected to an esterification treatment step. 4. Claim 1 or 3 General formula (I) or (
II) 3,7-dioxabicyclo[3,3,
0] Among octane derivatives, by treating a compound in which the substituents at positions 2 and 6 are trans, or a mixture of a compound in which the substituents at positions 2 and 6 are cis and trans, with sulfuric acid, The 3,7-dioxabicyclo[3,3,0]octane derivative represented by general formula (I) or (II) is characterized by being converted into a compound in which the substituents at the 2 and 6 positions are cis. , a method for selectively producing stereoisomers.