JPH11286483A - Chroman derivative and ngf-producing inducer containing the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as a nerve growth factor-producing inducer which effectively acts in low concentration. SOLUTION: This compound is represented by formula I (R is a 1-20C alkyl or the like), e.g. racemic 5-hydroxy-2-methyl-2-(4-methyl-2-oxo-3-pentenyl)-7- chromanylmethylpalmitate. The compound of formula I is obtained by protecting two hydroxyl groups of a compound of formula II, carrying out reduction of ester group and halogenation at 4 position of benzene ring and carrying out esterification of hydroxyl group of the resultant compound with a carboxylic acid derivative and condensation of halogen group of the resultant compound with an α,β-unsaturated carbonyl compound and carrying out condensation of carbonyl carbon at 3 position on 3-oxobutyl group at 4-position of benzene ring with a 2-oxo-4-methyl-3-pentenylphosphonic acid derivative and further carrying out intramolecular ether bonding between one of the above protected groups and carbon at 3-position on 3, 7-dimethyl-5-oxo-3,6-octadienyl group at 4 position of benzene ring.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing NGF at a low concentration.
The present invention relates to a novel chroman derivative which exhibits a production inducing effect and is useful as a drug for preventing and treating brain dysfunction.

[0002]

2. Description of the Related Art Nerve growth factor (NG)
F) is abundant in the brain, especially in the hippocampus and cerebral cortex,
It is known that NGF mRNA levels are also high in this area. NGF is considered as an essential trophic factor for the survival and function of cholinergic neurons, suggesting that NGF may be used as a therapeutic agent for Alzheimer's disease in which degeneration and loss of the neurons is a major lesion. ing. However, NGF is a protein with a molecular weight of about 13,000,
Does not cross the blood-brain barrier. From this viewpoint, if a low-molecular compound that can cross the blood-brain barrier by peripheral administration and that promotes NGF production and secretion in the brain can be found, basal forebrain nucleus whose function has been reduced by these compounds It is expected to activate cholinergic neurons and improve brain dysfunction. Conventionally, for example, catechol derivatives,
It has been reported that dopamine derivatives, hydrocaffeic acid, substituted 1,4-benzoquinone derivatives and the like have NGF production and secretory effects. Therefore, various measures have been attempted to increase NGF secretion of various nerve cells and brain nerve cells.
For example, there is a test for inducing NGF secretion by a catechol compound. However, these compounds are not yet satisfactory in terms of potency and cytotoxicity.

[0003] On the other hand, the present inventor has proposed that the agaricaceae (Hydnacea)
e) isolating and extracting chroman derivatives present in the fruiting body of the genus Coricum erinaceum (Hericium erinaceum);
₂ (prostaglandin E ₂ ) production and NGF (nerve growth factor) production induction (JP-B-8-26010).

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel chroman derivative which effectively promotes NGF production at a low concentration, and a method for producing the same.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned drawbacks, synthesized a novel compound, a chroman derivative, and this chroman derivative can act on the brain at a low effective concentration. It revealed that. That is, the present invention relates to chemically synthesizing a novel chroman derivative. Further, by chemically synthesizing a novel chroman derivative, it is possible to obtain a larger amount of a chroman derivative in a higher yield than when it is extracted from a natural product. As a result, in experiments on cultured cells using this chroman derivative, compared to conventional NGF production and secretion agents,
The present inventors have found that this chroman derivative exhibits NGF production and secretion effects at a concentration of 0-fold or lower, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (X):

[0007]

Embedded image (Wherein R represents an alkyl group or an alkenyl group having 1 to 20 carbon atoms).

[0008] The present invention is also an NGF production inducer containing the above chroman derivative as an active ingredient. Further, the present invention is a method for producing the above chroman derivative.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION <1> Chromane Derivative of the Present Invention In the above general formula (X), R is an alkyl group or an alkenyl group. The alkyl group is, for example, a linear or branched alkyl group having 1 to 20 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, etc. It is preferably from 10 to 20. Alkenyl groups include, for example, ethenyl, 1-propenyl, 3-methyl-2-butenyl,
A hydrocarbon residue having 2 to 20 carbon atoms, such as 2,4-dimethyl-2,6-octadienyl;
It is preferably from 0 to 20.

Representative compounds represented by the general formula (X) include 5-hydroxy-2-methyl-2- (4-methyl-2-oxo-3-pentenyl) -7-chromanylmethyl palmitate, 5-hydroxy-2-methyl-2-
(4-methyl-2-oxo-3-pentenyl) -7-chromanylmethyl stearate, 5-hydroxy-2-methyl-2- (4-methyl-2-oxo-3-pentenyl) -7-chromanyl Methyl linoleate and the like.

<2> Method for producing chroman derivative of the present invention An example of a method for producing the chroman derivative of the present invention is shown below. As shown in FIGS. 1 and 2, the chroman derivative of the present invention can be produced by seven steps from step (A) to step (G).

3,5-Dihydroxybenzoic acid ester [compound (I)] which is a starting material for producing the chroman derivative of the present invention can be obtained by esterifying 3,5-dihydroxybenzoic acid by a conventional method. it can. In addition, 3,5-dihydroxybenzoic acid can be obtained by disulfonating benzoic acid and fusing it with alkali. The compound (I) is not particularly limited as long as it is an alkyl ester of 3,5-dihydroxybenzoic acid (—CO ₂ R), and methyl, ethyl, propyl or butyl ester (R: CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ ), etc., but methyl ester or ethyl ester is preferred from the viewpoint of reactivity.

[0013]

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Step (A) The compound (II) can be obtained by adding 2 to 10 equivalents of a protecting agent to the compound (I) to protect two hydroxyl groups. Here, the protecting agent refers to a protecting agent that protects two hydroxyl groups, is stable in a basic solvent, and is hydrolyzed by an acid to be eliminated. Specifically, those forming an ether bond, chlorotrimethylsilane, 3,4-dihydro-
Preferred are 2H-pyran, chloromethyl methyl ether and the like. As the solvent used for the reaction, benzene, toluene,
Aprotic solvents such as xylene, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, hexane, and ethyl acetate are preferred, and these are used as appropriate. The reaction is preferably performed at room temperature under ice-cooling. The compound (I) and the protective agent are preferably mixed little by little with stirring. As a reaction replenisher, pyridium P-toluenesulfonate (hereinafter referred to as “PP
It is preferred to add an acid catalyst such as "TS". Thereafter, the compound (II) is subjected to a post-treatment according to a conventional method.
Can be obtained.

[0015]

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Step (B) The compound (II) thus obtained is reduced with lithium aluminum hydride (LDA) to give the compound (II)
I) can be obtained. The reducing agent may be any as long as it can reduce a carboxylic acid ester to an alcohol, but lithium aluminum hydride is preferable. Compound (II) is dissolved or suspended in a dry solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF),
Next, 1 to 2 equivalents of lithium aluminum hydride is added to the compound (II), and the mixture is stirred at an appropriate temperature between 0 ° C. and the boiling point of the solvent for 1 hour to 12 hours to complete the reduction. . Thereafter, the compound (III) can be obtained by post-treatment according to a conventional method.

[0017]

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[0018] Step (C) thus obtained compound (III) Various halogenating agent (e.g., 1,2-dihalogenated ethane Y-CH ₂ -
CH ₂ —Y: Y represents a halogen group) to form a compound (I
V). This halogenation refers to chlorination, bromination, iodination, etc., with iodination being preferred. For iodination, various iodination agents can be used.
2 It is preferable to use diiodoethane or the like. As the solvent, a stable aprotic solvent such as benzene, diethyl ether, tetrahydrofuran, carbon tetrachloride, and hexane is preferable, and these are appropriately used. Further, it is preferable to add an alkyl lithium such as tert-butyl lithium [(CH ₃ ) ₃ CLi] or a tertiary amine such as tetramethylethylenediamine (TMEDA). The reaction is preferably carried out at a suitable temperature from -50 ° C to -80 ° C to reduce the generation of other by-products. The reaction time is preferably from 1 hour to 6 hours. Thereafter, the compound (IV) can be obtained by post-treatment according to a conventional method.

[0019]

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Step (D) Compound (V) can be obtained by reacting compound (IV) thus obtained with a carboxylic acid derivative. Here, the carboxylic acid derivative refers to a carboxylic acid, an acid halide, an acid anhydride, an amide, an ester, and the like, and it is preferable to use a carboxylic acid from the viewpoint of reactivity and the like. Carboxylic acid is _preferably linear and branched carboxylic acids having a carbon number of 1 to 21, acetic acid, other such butyric acid, palmitic acid (n =
16), stearic acid (n = 18) and the like, and also linoleic acid containing a double bond in a carbon bond. As for the ratio of the compound (IV) and the carboxylic acid derivative, it is preferable to add 1 to 10 equivalents of the carboxylic acid derivative to the compound (IV). As the solvent, aprotic solvents such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, hexane, and ethyl acetate are suitable, and these are used as appropriate. I do. In order to efficiently synthesize the ester, the reaction is preferably performed in a system in which 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC) are added. The reaction is preferably carried out under ice cooling to room temperature with stirring for 1 to 5 hours from the viewpoint of reaction efficiency.
After that, the compound is subjected to post-treatment
(V) can be obtained.

[0021]

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Step (E) The compound (VII) can be obtained by reacting the compound (V) obtained by the above method with 1 to 10 equivalents of the compound (VI). Compound (VI) is a compound that reacts with a halogen group in compound (V) to form a 3-oxobutyl group, and includes methyl vinyl ketone, 3-buten-2-ol, and the like. Vinyl ketone is preferred. If necessary, the reaction is carried out by appropriately adding an inert solvent such as dimethylformamide. It is also preferable to add a tertiary amine such as pyridine, triethylamine, diisopropylethylamine or the like as a reaction auxiliary as appropriate, and to add a reaction catalyst such as palladium acetate or triphenylphosphine (PPh ₃ ). From the viewpoint of reaction efficiency, the reaction is preferably performed after substituting with nitrogen or argon.
The reaction temperature may be from room temperature to 200 ° C.
The temperature is preferably from 0 ° C to 150 ° C. Reaction time is 1 hour ~
Preferably, it is 5 hours. Then, the compound (VII) can be obtained by post-treatment according to a conventional method.

[0023]

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[0024]

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Step (F) Compound (VII) thus obtained and 1 to 5 equivalents of compound (VIII) are combined with benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, diethyl ether , Tetrahydrofuran (T
Compound (IX) can be obtained by heating in a solvent such as HF), dioxane, acetonitrile or hexane at a temperature of 50 ° C to 100 ° C for 3 to 8 hours.
In order to perform this reaction regioselectively, the compound (V
III) is preferably a 2-oxo-4-methyl-3-pentenylphosphonic acid ester which is a phosphonic acid derivative, specifically, an alkyl ester of 2-oxo-4-methyl-3-pentenylphosphonic acid. (Meaning methyl ester or ethyl ester). For the reaction, it is preferable to use a strong base such as sodium hydride (NaH) or alkyllithium and a solvent such as anhydrous tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO) in an appropriate combination. The reaction system is preferably replaced with nitrogen or argon, and the reaction is preferably carried out under the condition of heated reflux. Thereafter, the compound (IX) can be obtained by post-treatment according to a conventional method.

[0026]

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[0027]

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Step (G) The compound (IX) thus obtained is dissolved or suspended in a solvent such as methanol, ethanol or isopropanol, and an appropriate amount of an acid catalyst such as hydrochloric acid is added thereto. By stirring at a temperature for 1 to 8 hours, compound (X) which is a novel chroman derivative of the present invention can be obtained.

<3> N containing a chroman derivative as an active ingredient
GF production inducer The chroman derivative represented by the general formula (X) of the present invention is NG
It can be used as an F production inducer. When this chroman derivative was administered to cultured cells, it showed NGF production inducing activity. Further, to show an effective NGF production inducing activity in cultured cells, it is necessary to use 10 to 400 μM of epinephrine, which has been conventionally reported, in cultured cells, whereas the chroman derivative of the present invention requires 0.3 to 400 μM. A similar effect was demonstrated using a concentration as low as 0.8 μM. That is, it was revealed that this chroman derivative exhibited NGF production inducing activity in an effective concentration region at least 10 times lower than that of the conventional NGF production inducing agent.

Furthermore, in order for a drug for preventing and treating cerebral dysfunction to act in the brain, the drug must pass through the blood-brain barrier and the like. It is understood that when a normal drug is administered, the drug is poorly transported under the influence of the blood-brain barrier and the like, and only a part of the administered drug is transferred to the brain and acts. Therefore, the chroman derivative of the present invention, which acts even at a low concentration to increase NGF activity, when administered to higher animals, is poorly translocated due to the effects of the blood-brain barrier and the like, and has a relatively small amount (cells). 0.3-0.8 μM in
NGF in the brain, even if only
It is understood that the concentration can be increased sufficiently. Also,
Chromane derivatives are structurally highly liposoluble, and are
It is presumed that the transfer to the brain is better than that of the F production inducer. Taken together, when this chroman derivative is administered to a higher animal, NG in the brain is obtained even in a relatively small amount.
It is presumed that F concentration is sufficiently increased, and as a result, it can effectively act as a therapeutic agent for preventing and treating the progression of central nervous system degenerative disease. In addition, since it acts at a low concentration, it is understood that side effects associated with administration such as cytotoxicity are relatively small.

Therefore, it is presumed that chroman derivatives or NGF-producing and secreting agents containing chroman derivatives can be effective agents for preventing and treating progression of central nervous system degenerative diseases, especially Alzheimer's disease and the like. The target disease includes Alzheimer's disease, diabetes, familial autonomic dysfunction, nerve fiber tumor, neuroblastoma, pheochromocytoma and the like.

When the compound of the present invention is used as an agent for preventing and treating the progression of central nervous system degenerative disease, it can be administered orally or parenterally according to a known method. When administered orally, 1 to 1 per adult per day
00 mg is divided into one or several times. For example, when administered as a tablet, granule, suspension, capsule, or the like, or parenterally, 0.1 to 10 mg is divided into one or several times. ,
For example, it can be administered as an infusion, suppository, or transfusion for infusion.

For example, in the case of tablets, crystalline cellulose, light silicic anhydride or the like is used as an adsorbent, and corn starch, lactose, calcium phosphate, stearic acid or the like is used as an activator. When used as an injection, it is used as an aqueous solution of the compound or a suspension aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, or the like, or an emulsion using a surfactant such as HCO-60. You can also.

[0034]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

[0035]

Example 1 Production of chroman derivative of the present invention An example of production of a chroman derivative of the present invention will be described with reference to FIGS. Step (A) [3,5-bis- (tetrahydropyranyl-2-oxo
B) Synthesis of methyl benzoate] 5.04 g (30 mmol) of methyl 3,5-dihydroxybenzoate and pyridium P-toluenesulfonate [PPTS, 0.23 g (0.9 mmol)] were placed in a dry 500 ml eggplant-shaped flask. The septum cap was attached. The system was replaced with argon, and 60 ml of anhydrous dichloromethane (CH ₂ Cl ₂ ) was added from a septum cap using a syringe. The solution was cooled on ice, and 8.2 ml (90 mmol) of 3,4-dihydro-2H-pyran was added dropwise with a syringe over 5 minutes with stirring. After returning to room temperature and stirring for 4 hours, 40 ml of 1.5N sodium hydroxide (NaOH) was added. After stirring, the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), and the solvent was distilled off.
It was used in the next reaction as a crude product of methyl (tetrahydropyranyl-2-oxy) benzoate.

Step (B) [3,5-bis- (tetrahydropi
Synthesis of Ranyl-2-oxy) -benzyl alcohol] A dry 200 ml three-necked flask was charged with lithium aluminum hydride [LAH, 2.28 g (60 mmol)], and a condenser with a drying tube and a septum cap were attached. . Further, 70 ml of anhydrous tetrahydrofuran (THF) was added to the flask, and the 3,5-bis- (tetrahydropyranyl-2
-Oxy) Methyl benzoate (crude product) containing anhydrous THF (50
ml) solution was dropped with a syringe from the septum cap over 20 minutes. After stirring at room temperature for 5 hours, 10 ml of water was added to the reaction solution.
3N NaOH (3 ml) was added dropwise, and the mixture was further stirred for 1 hour. After removing insolubles by filtration under reduced pressure, the filtrate was concentrated, and 100 ml of dichloromethane (CH ₂ Cl ₂ ) was added to the residue. The organic layer was washed with 20 ml of water and dried over anhydrous MgSO ₄ . And
The solvent was distilled off from the organic layer, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate =
1: 1) to give 3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl alcohol (colorless oil) 8.6
4 g (93% yield) was obtained.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.44-2.14 (m,
13H), 3.56-4.03 (m, 4H), 4.62 (s, 2H), 5.41 (d, J = 2.9Hz, 2
H), 6.71 (s, 3H)

Step (C) [4-Iodo-3,5-bis- (tetra
Hydropyranyl-2-oxy) -benzyl alcohol
Preparation] 3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl alcohol 2.
16 (7 mmol) was added and a septum cap was attached. The system was replaced with argon, and 50 ml of anhydrous ether was added via a septum cap with a syringe. This solution was cooled to −78 ° C. in a dry ice-acetone bath, and stirred at 1.0 mol / mol.
15 ml (15 mmol) of a hexane solution containing L of tert-butyllithium [(CH ₃ ) ₃ CLi] is added dropwise with a syringe over 15 minutes, and then 2.1 ml of tetramethylethylenediamine
(14 mmol) was added dropwise over 5 minutes. After the temperature was gradually raised to 0 ° C., the mixture was cooled to −50 ° C. in a dry ice-acetone bath, and 2.56 g of 1,2-diiodoethane [(ICH ₂ CH ₂ I)) was added.
(9 mmol)] in THF (15 ml) was added dropwise with a syringe.
After stirring for 1 hour, 100 ml of a saturated aqueous solution of sodium thiosulfate was added. The organic layer of the solution was separated, dried over anhydrous MgSO ₄ , and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate = 3: 2). 1.71 g (56% yield) of 4-iodo-3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl alcohol (colorless solid) was obtained.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.47-2.31 (m,
13H), 3.53-3.97 (m, 4H), 4.63 (s, 2H), 5.57 (d, J = 3.3Hz, 2
H), 6.76 (s, 2H)

Step (D) [4-Iodo-3,5-bis- (tetra
Hydropyranyl-2-oxy) -benzyl palmitate
Synthesis] In a dried 30 ml eggplant-shaped flask, 1.09 g (2.5 mmol) of 4-iodo-3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl alcohol, 0.77 g of palmitic acid (16.8 mmo)
l), 4-dimethylaminopyridine (DMAP) 0.03 g (0.25 mmol)
And a septum cap was attached. The system was replaced with argon, and 15 ml of anhydrous dichloromethane (CH ₂ Cl ₂ ) was added via a septum cap with a syringe. The solution was ice-cooled and stirred with dicyclohexylcarbodiimide (DCC, 0.
03 g (2.8 mmol)] in anhydrous dichloromethane [CH ₂ Cl ₂ (5
ml)] solution was added dropwise with a syringe over 5 minutes. Thereafter, the ice bath was removed, and after stirring at room temperature for 3 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained from the concentrated filtrate was purified by silica gel column chromatography (hexane-ether = 4: 1) to give 4-iodo-3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl 1.68 g of palmitate (colorless oil) was obtained (100% yield).

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.88 (t, J = 6.6
Hz, 3H), 1.25 (m, 24H), 1.53-2.28 (m, 14H), 2.23 (t, J = 7.5H
z, 2H), 3.56-3.96 (m, 4H), 5.03 (s, 2H), 5.55 (s, 2H), 6.73
(s, 2H)

Step (E) [4- (3-oxobutyl) -3,5-bi
S- (tetrahydropyranyl-2-oxy) -benzylpa
Synthesis of Lumitate] In a test tube with thread, add 4-iodo-3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl palmitate 0.67 g (1 mmo
l), methyl vinyl ketone 0.33 ml (4 mmol), triethylamine 0.55 ml (4 mmol), palladium acetate [Pd (OA
c) ₂ , 22 mg (0.1 mmol)], triphenylphosphine [P
Ph _3, placed 52 mg (0.2 mmol)], tighten the cap after purging with nitrogen, 120 ° C. using a block bath, and heated for 3 hours. After cooling, 10 ml of ether was added, and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ether). From the fraction of hexane-ether = 3: 1, 4- (3-oxobutyl) iodo-3,5-bis- (tetrahydropyranyl-
2-oxy) -benzyl palmitate (colorless oil) 0.31
g (yield 50%) was obtained.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.88 (t, J = 6.6
Hz, 3H), 1.25 (m, 24H), 1.52-2.06 (m, 14H), 2.16 (s, 3H), 2.3
3 (t, J = 7.5H, 2H), 2.64 (m, 2H), 2.97 (m, 2H), 3.57-3.94 (m, 4
H), 5.02 (s, 2H), 5.41 (s, 2H), 6.77 (s, 2H)

Step (F) [4- (3,7-dimethyl-5-oxo-
3,6-octadienyl) -3,5-bis- (tetrahydropyrani
Synthesis of l-2-oxy) -benzyl palmitate] A dry 30 ml eggplant-shaped flask was charged with 0.23 g (5.6 mmol) of 60% sodium hydride (NaH), and 2 ml of anhydrous tetrahydrofuran (THF) was added thereto. NaH was suspended in THF. Next, a solution of anhydrous THF (3 ml) containing 1.07 g (5.2 mmol) of dimethyl (2-oxo-4-methyl-3-pentenyl) -phosphonate was added dropwise with a syringe, followed by stirring at room temperature for 30 minutes. Furthermore, 4- (3-
Oxobutyl) -3,5-bis- (tetrahydropyranyl-2-
A solution of 2.95 g (4.7 mmol) of (oxy) -basil palmitate in anhydrous THF (4 ml) was added dropwise with a syringe. After the cooling tube was attached, the inside of the system was replaced with argon, and the system was heated under reflux for 5 hours. After cooling, 50 ml of ether was added to the reaction solution, which was then washed with 20 ml of water. After the reaction solution was dried over anhydrous MgSO ₄ , the solvent was distilled off. Then, the residue obtained from the reaction solution was purified by silica gel column chromatography (hexane-ether). From the hexane-ether = 3: 1 fraction, 4- (3,
7-dimethyl-5-oxo-3,6-octadienyl) -3,5-bis-
0.36 g (yield 11%) of (tetrahydropyranyl-2-oxy) -benzyl palmitate (light yellow oil) was obtained.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.88 (t, J = 6.6
Hz, 3H), 1.25 (m, 24H), 1.88 (s, 3H), 1.51-2.08 (m, 14H), 2.1
6 (s, 3H), 2.26 (s, 3H), 2.34 (t, J = 7.5Hz, 2H), 2.86 (m, 2H),
3.55-3.96 (m, 4H), 5.02 (s, 2H), 5.43 (d, J = 2.6Hz, 2H), 6.04
(m, 2H), 6.78 (s, 2H)

Step (G) [Racemic-5-hydroxy-2-methy
2- (4-methyl-2-oxo-3-pentenyl) -7-chromanyl
Synthesis of methyl palmitate] In a 10 ml eggplant-shaped flask, add 4- (3,7-dimethyl-5-oxo)
0.35 g (0.5 mmol) of -3,5-bis- (tetrahydropyranyl-2-oxy) -benzyl palmitate was added, and then 5 ml of isopropyl alcohol (i-PrOH) was added. Furthermore, 0.5 ml of 3N HCl was added to this solution, and the mixture was stirred at room temperature for 5 hours.
Then, after adding 20 ml of water to the reaction solution, dichloromethane was added.
The reaction product was extracted with [CH ₂ Cl ₂ (10 ml × 3)]. After the extracted organic layers were combined and dried over anhydrous MgSO ₄ , the solvent was distilled off. The residue obtained from the organic layer is subjected to silica gel column chromatography (hexane-ether = 2: 1).
0.20 g of racemic-5-hydroxy-2-methyl-2- (4-methyl-2-oxo-3-pentenyl) -7-chromanylmethyl palmitate (colorless oil) (76% yield) ).

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.88 (t, J = 6.2
Hz, 3H), 1.25 (m, 24H), 1.40 (s, 3H), 1.81-2.07 (m, 2H), 1.88
(s, 3H), 2.14 (s, 3H), 2.34 (t, J = 7.5Hz, 2H), 2.62 (m, 2H), 2.
65 (d, J = 13.5Hz, 1H), 2.75 (d, J = 13.5Hz, 1H), 4.96 (s, 2H),
6.10 (s, 1H), 6.35 (s, 1H), 6.41 (s, 1H)

[0048]

Example 2 N against mouse brain astroglial cells
Evaluation of GF production and secretion promoting effects Furukawa et al.'S method (Biochemical and Biophysical Reaserch
Comunications 136.55-63, 1986), 10 embryonic astroglial cells of the late fetal (19 days old) rat cortex
% Dulbecco's modified Eagle's medium (DM
EM) (1 to 2 weeks, medium change every 3 days), and when confluent, trypsin and EDTA
Processed. After dispersing the cells thereby, centrifugation was performed to remove the supernatant and suspend a part of the precipitate in a small amount of medium.
In another culture dish, the cells were seeded as secondary culture cells. The subcultured cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (medium exchange every 3 days for 1 to 2 weeks).
The culture was changed to Dulbecco's modified Eagle's medium (DEME) containing bovine serum albumin for several days. Thereafter, the medium was replaced with a medium containing various concentrations of the chroman derivative of the present invention, and cultured for 24 hours. After the culture, the medium was recovered, and the NGF concentration was measured by an enzyme immunoassay according to the method of Furukawa et al. (Journal of Neurochemistry, 40,734-744,1983). That is, the activity of inducing NGF production was evaluated using secondary culture cells after passage of primary culture cells for one generation.

Here, the chroman derivative added to the above medium was prepared as follows. The chroman derivative as the substance of the present invention was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 100 mg / ml, and this was used as a standard solution.
Next, DMSO was added to 1 volume (1 v / v) of this standard solution.
Was added to 2 volumes (2 v / v) to prepare a three-fold diluted solution (3 v / v) having a concentration of 33.3 mg / ml. Furthermore, by successively repeating the operation of three-fold dilution with DMSO, finally, sample solutions of various concentrations up to the seventh-stage diluted sample (0.05 mg / ml) were prepared. A total of eight (100, 33.3, 11.1, 3.7, 1.24, 0.41,
0.14, 0.05 mg / ml) were used in the experiments described below. An appropriate amount of each sample solution was added to a Dulbecco's modified Eagle's medium containing 0.5% bovine serum albumin so as to be diluted 1000-fold, and this was used as a test sample. That is, in a medium, 100 μg / ml to 0.0
Under conditions where chroman derivatives are present in the range of 5 μg / ml, N
The GF concentration was measured.

As a control, 100% DM
SO was added to Dulbecco's modified Eagle's medium containing 0.5% bovine serum albumin, and an appropriate amount was added so as to be diluted 1000-fold in the medium, and the NGF concentration was measured.

FIG. 3 shows the increase rate of the NGF concentration in the cultured cells to which the chroman derivative of the present invention was added.
The horizontal axis indicates the concentration in chroman-induced cultured cells. The results were shown as an increase rate of the NGF concentration in the cultured cells to which the chroman derivative was added, relative to the NGF concentration in the control culture medium cultured in a medium containing no test substance. From these results, the chroman derivative was added to the experimental cultured cells in a concentration of 0.1%.
When used at concentrations of 41 μg / ml and 0.14 μg / ml, the N concentration in experimental cultured cells was lower than that of the control.
GF concentration increased 1.9-fold. The NGF concentration of the control group cultured without administration of the chroman derivative was compared with the NGF concentration of the control group (control) cultured without administration of the chroman derivative.
As a result of performing a statistical test using the Duncan method with respect to the GF concentration, the chroman derivative was determined to be 0.1% at a risk factor of 5% or less.
When used at concentrations of 41 μg / ml and 0.14 μg / ml, a significant difference was observed (see asterisk (*) in FIG. 3).

[0052]

Comparative Example 1 As a positive control for a test compound, epinephrine, which has been known to have an NGF-producing effect, was also subjected to the same test at the same concentration as the chroman derivative.
When used so as to be μg / ml and 33 μg / ml, the NGF concentration in the experimental cultured cells was 1.
9 times.

[0053]

According to the present invention, a novel chroman derivative capable of effectively promoting NGF production at a low concentration can be provided. Furthermore, a method for producing this novel chroman derivative could be provided.

[Brief description of the drawings]

FIG. 1 is a diagram of the first half of a process for producing a chroman derivative.

FIG. 2 is a diagram illustrating the latter half of a process for producing a chroman derivative.

FIG. 3. NG in cultured cells to which chroman derivative was added
It is a figure which shows the increase rate of F density | concentration. An asterisk (*) indicates a statistically significant difference with a control with a risk ratio of 5% or less as a result of the Duncan's test.

Claims (3)

[Claims] 1. A chroman derivative represented by the following formula (X). (In the formula, R represents an alkyl group or an alkenyl group having 1 to 20 carbon atoms.) 2. An NGF production inducer comprising the chroman derivative according to claim 1 as an active ingredient. 3. The method for producing a chroman derivative according to claim 1, comprising the following steps. (A) a step of protecting two hydroxyl groups of 3,5-dihydroxybenzoic acid ester, (B) a step of reducing the ester group of the compound produced in step A to produce a benzyl alcohol compound, and (C) ) A step of halogenating the 4-position of the benzene ring of the compound produced in step B and (D) forming an ester bond between the hydroxyl group of the compound produced in step C and the carboxylic acid derivative to form a benzyl carboxylic ester (E) condensing the halogen group of the compound generated in step D with the αβ unsaturated carbonyl compound to form a 4- (3-oxobutyl) benzyl carboxylate compound, F) Derivation of the carbonyl carbon at the 3-position of the 3-oxobutyl group at the 4-position of the benzene ring of the compound produced in step E and 2-oxo-4-methyl-3-pentenylphosphonic acid To produce a 4- (3,7-dimethyl-5-oxo-3,6-octadienyl) benzylcarboxylic acid ester compound; and (G) any one of the compounds produced in the step F. An intramolecular ether bond is formed between the protecting group and the carbon at the 3-position of the 3,7-dimethyl-5-oxo-3,6-octadienyl group attached to the 4-position of the benzene ring to form 5-hydroxy-2. Producing methyl- (2-methyl-2-oxo-3-pentenyl-7-chromanylmethylcarboxylate).