JPH05239088A - Cycloartenol derivative or its salt and ameliorant of cerebral function comprising the same - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as an ameliorant of cerebral function for treating motor dysfunction, intelligent dysfunction, etc., caused by cerebral hemorrhage, cerebral infarction, subarachnoidal hemorrhage, transient cerebral ischemic attack, etc., due to its manifestation of excellent antihypoxic action. CONSTITUTION:The objective compound of formula I [R<1> is residue of monosaccharides, disaccharides, etc., or R<2>CO (R<2> is dialkylamino, alkoxy, etc.)] or its salt, e.g. 3-cycloartenyl ethyl carbonate. This compound is obtained by a method for subjecting, e.g. a carboxylic acid of the formula R<3>COOH (R<3> is R<2> other than alkylamino) and cycloartenol of formula II to esterifying reaction in the presence of a base such as pyridine or reacting phosgene of the formula COCl2 or trichloromethyl formate of the formula ClCOOCCl2 with the cycloartenol of formula II in the presence of a base such as pyridine, then reacting the produced cycloartenyl chloroformate with an alcohol or an amine of the formula R<4>H (R<4> is alkoxy, alkylamino, etc.), etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cycloartenol derivative having an excellent anti-hypoxic effect or a salt thereof and a brain function improving agent containing the same.

[0002]

2. Description of the Related Art In recent years, as the number of elderly people increases, the number of patients with various cerebral dysfunction represented by cerebral ischemia such as motor dysfunction and cerebrovascular dementia is increasing. The causes of these diseases are mainly cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient cerebral ischemic attack, decrease in cerebral blood flow caused by cerebrovascular disorder, lack of oxygen in blood, hypoglycemia, etc. It is thought to be due to metabolic disorders. From these viewpoints, attention has recently been focused on agents that improve the above-mentioned cerebral dysfunction by protecting the brain from ischemia and hypoxia, that is, agents that improve anti-hypoxia.

[0003]

However, conventional cerebral function-improving agents have problems that they do not show sufficient drug effects upon oral administration and that they have many side effects. Therefore, an object of the present invention is to provide a novel compound having an excellent anti-hypoxic effect and useful as a brain function improving agent.

[0004]

Under the circumstances, as a result of intensive studies by the present inventors, various derivatives of cycloartenol, a kind of trimethylsteroid contained in plants, have excellent anti-hypoxic action. It was found that there is something, and the present invention has been completed.

That is, the present invention has the following general formula (1):

[0006]

[Chemical 2]

[Wherein R ¹ represents a residue or a group R ² CO- selected from monosaccharides, disaccharides and uronic acids (wherein R ² has a dialkylaminoalkyl group or a substituent) An alkoxy group, a nitrogen-containing heterocyclic group which may have a substituent or an alkylamino group which may have a substituent))] or a salt thereof. It is a thing.

The present invention also provides a brain function improving agent containing the cycloartenol derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the general formula (1), examples of the monosaccharide represented by R ¹ include various pentoses and hexoses such as xylose, glucose, fructose, mannose, galactose and fucose. Disaccharides include sucrose, maltose, lactose, cellobiose,
Examples thereof include trehalose. Examples of uronic acid include glucuronic acid and iduronic acid. In addition, these monosaccharides, disaccharides and uronic acids may have their hydroxyl groups and carboxyl groups protected with an acyl group such as an acetyl group and a toluyl group or an alkyl group such as a methyl group and an ethyl group.
Among these sugars, a particularly preferable example is a glucopyranosyluronic acid-1-yl group in which a hydroxyl group and a carboxyl group may be protected.

The dialkylaminoalkyl group represented by R ² is a diC ₁ -C ₅ alkylamino C ₁ -C ₅ alkyl group such as dimethylaminoethyl group, dimethylaminomethyl group, diethylaminoethyl group, dimethylaminopropyl group, Examples thereof include a diethylaminopropyl group and a diisopropylaminoethyl group.

The alkoxy group which may have a substituent represented by R ² may be substituted with a halogen atom, an amino group, an alkylamino group, a dialkylamino group or a trialkylammonium group, a hydroxy group and the like. Good C
It includes ₁ -C ₅ alkoxy group. Preferred examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a chloroethoxy group, a bromoethoxy group, an iodoethoxy group, a dimethylaminoethoxy group, a diethylaminoethoxy group and a triethylaminoethoxy group.

As the nitrogen-containing heterocyclic group which may have a substituent represented by R ² , an alkyl group, an alkylamino group, a cyclic alkylamino group, an alkylaminocarbonylamino group and the like may be substituted. Included are well saturated or unsaturated 1-2 nitrogen containing 6 membered heterocyclic groups.
Specific examples thereof include aromatic groups such as pyridyl group, pyrimidyl group and triazinyl group; saturated heterocyclic groups such as piperidyl group, piperidinopiperidyl group, piperazinyl group, alkyl-substituted piperazinyl group and alkylaminocarbonylmethylpiperazinyl group. Groups.

R²May have a substituent represented by
The alkylamino group is C₁~ C _FiveAlkyl group of 1
And an amino group having two or more bonded to each other.
Groups include halogen atoms, hydroxy groups, heterocycles,
It may be substituted with a luamino group or the like. Specifically, meth
Ruamino group, ethylamino group, isopropylamino group,
Dimethylamino group, diethylamino group, chloroethyl group
Mino group, iodoethylamino group, hydroxyethylami
Group, hydroxypropylamino group, di (hydroxyme
Tyl) -2-hydroxyethylamino group, dimethylamido
Noethylamino group, diethylaminoethylamino group, N
-(2-Methyltetrahydrofurfuryl) -N-methyl
-Amino group, 4- (isopropylaminocarbonylmethyl)
L) piperazinyl-1-ethylamino group, 4-[(1-
Pyrrolidinyl) carbonylmethyl] piperazinyl-1-
Examples thereof include an ethylamino group.

The salt of the cycloartenol derivative (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, inorganic acid salts such as hydrochloride, sulfate and nitrate; methanesulfone Acid salt, ethane sulfonate,
Organic acid salts such as acetates; quaternary ammonium salts formed from alkyl halides, alkylsulfates, arylsulfonic acids and the like can be mentioned.

The cycloartenol derivative of the present invention or a salt thereof can be produced, for example, by any of the following methods.

[0016]

[Chemical 3]

[In the formula, R ³ represents a dialkylaminoalkyl group, an alkoxy group which may have a substituent or a nitrogen-containing heterocyclic group which may have a substituent]

That is, the cycloartenol derivative (1a) is produced by reacting the carboxylic acid (2) or its reactive derivative with cycloartenol (3).

Examples of the reactive derivative of the carboxylic acid (2) include acid halides. The above reaction is carried out by a conventional esterification reaction, for example, in the presence of a base such as pyridine or N, N-dimethylaniline, in a solvent or without a solvent.

[0020]

[Chemical 4]

[In the formula, R ⁴ represents an alkoxy group which may have a substituent, a cyclic amino group which may have a substituent or an alkylamino group which may have a substituent]

That is, phosgene or trichloromethyl chloroformate (TCF) is reacted with cycloartenol (3) to form cycloartenyl chloroformate (4), which is then reacted with alcohols or amines (R ⁴ H ) Is reacted to produce a cycloartenol derivative (1b).

The reaction of phosgene or trichloromethyl chloroformate with cycloartenol (3) is carried out in the presence of a base such as pyridine or N, N-dimethylaniline according to a conventional method, and cycloartenyl chloroformate is used. The reaction of the mate (4) with the alcohol or amine (R ⁴ H) is preferably carried out in the presence of a base of pyridine or N, N-dimethylaniline salt.

[0024]

[Chemical 5]

[In the formula, R ⁵ represents an alkyl group which may have a substituent]

That is, the cycloartenol derivative (1c) is produced by reacting the isocyanates (5) with the cycloartenol (3).

The reaction between the isocyanates (5) and cycloartenol (3) is carried out by heating in an inert solvent such as an alkyl halide or an aromatic compound.

[0028]

[Chemical 6]

[In the formula, R ⁶ represents a residue selected from monosaccharides, disaccharides and uronic acids, and X represents a halogen atom]

That is, the cycloartenol derivative (1d) is produced by reacting the saccharide (6) with the cycloartenol (3). This reaction is preferably carried out in an aromatic compound solvent such as toluene in the presence of silver acetate or the like. As the saccharide (6), it is preferable to use a compound in which a hydroxyl group and / or a carboxyl group is protected.
In such a case, the protecting group can be removed by hydrolysis, hydrogenolysis or the like after the above reaction.

[0031]

[Chemical 7]

[In the formula, R ⁷ represents an alkylene group or an alkyleneoxy group, X represents a halogen atom, and Y represents an optionally substituted alkylamino group or an optionally substituted group. Indicates a cyclic amino group]

That is, the cycloartenol derivative (1f) is produced by reacting the halide of the cycloartenol derivative (1e) with an amine.
This reaction is preferably carried out by heating in an inert solvent such as benzene.

When the cycloartenol derivative (1) obtained as described above contains a tertiary amino group, it is reacted with an alkyl halide, alkyl sulfuric acid, aryl sulfonic acid or the like. Thus, a quaternary ammonium salt can be obtained.

The cycloartenol derivative (1) or a salt thereof thus obtained has an excellent anti-hypoxic effect and is highly safe, so that it is associated with various cerebral ischemia-related movement disorders, senile dementia and the like. It is useful as a therapeutic agent for

The cycloartenol derivative (1) or a salt thereof can be administered orally or parenterally, and the brain function improving agent of the present invention can be administered in various dosage forms such as powders and granules. Orally administrable agents such as agents, tablets, dragees and capsules; subcutaneous, intramuscular or intravenous injections; suppositories and the like.

The above-mentioned preparation is carried out by the cycloartenol derivative (1) or a salt thereof alone or the cycloartenol derivative (1) or a salt thereof and an excipient, a filler, a binder, a wetting agent, a disintegrating agent, a surface active agent. It can be produced by appropriately combining and formulating agents, lubricants, dispersants, buffers, preservatives, flavoring agents, perfumes, coating agents and the like.

The dose of the brain function-improving agent of the present invention thus obtained varies depending on the symptoms, administration route, etc., but is generally 50 to 5 as cycloartenol derivative (1) or its salt in adults. 1,000 mg / day, preferably 10
The dose is 0 to 2,000 mg / day, and it is usually preferable to administer this in 3 to 4 divided doses per day.

[0039]

EFFECTS OF THE INVENTION Since the compound (1) of the present invention or a salt thereof has an excellent anti-hypoxic effect, exercise caused by cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient cerebral ischemic attack, cerebrovascular disorder, etc. It is useful as a therapeutic agent for functional disorders and intellectual dysfunction.

[0040]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 Preparation of 3-Cycloartenyl Ethyl Carbonate 5.0 g of cycloartenol (1
1.7 mmol) is dissolved and ethyl chlorocarbonate 4.
5 g (41.5 mmol) was added dropwise, and after completion, the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and extracted with chloroform,
The extract was washed successively with diluted hydrochloric acid and water and dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, the resulting residue was hot-extracted with acetonitrile to remove the insoluble matter, the extract was allowed to cool, and the precipitated crystals were collected by filtration to give crude crystals. The crude crystals were purified by silica gel chromatography (chloroform solvent) and recrystallized from acetonitrile to obtain a pure product of the title compound. Yield 4.4 g (75% yield) mp 113.0-114.0 ° C IRν _max ^KBr cm ⁻¹ : 2970, 2940, 2880, 1745, 1265, 102
0, 1010, 980, 790 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.35 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.72 to 2.38 (48H, m), 4.17 (2H, q, J = 7Hz), 4.15
~ 4.59 (1H, m), 4.87 ~ 5.28 (1H, m)

Example 2 Preparation of 2-chloroethyl 3-cycloartenyl carbonate The procedure of Example 1 was repeated except that 2-chloroethyl chlorocarbonate was used instead of ethyl chlorocarbonate to give the title compound in a yield of 56%. Obtained. mp 93.5-95.5 ° C IRν _max ^KBr cm ^-1 : 2940, 2860, 1745, 1270, 1250, 960,
925 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.35 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.74 to 2.32 (45H, m), 3.76 (2H, t, J = 6Hz), 4.34
(2H, t, J = 6Hz), 4.21 ~ 4.57 (1H, m), 4.89 ~ 5.24 (1H, m)

Example 3 Preparation of 3-Cycloartenyl 2-iodoethyl carbonate 2.4 g (4.5 mmol) of 2-chloroethyl 3-cycloartenyl carbonate was dissolved in 50 ml of acetone and 15 g (9 mmol) of potassium iodide was added. In addition, 2 at room temperature
The reaction was carried out for 4 hours and then under heating under reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the crude crystal obtained by distilling off the solvent under reduced pressure was recrystallized from acetonitrile to obtain the title compound. Yield 1.2 g (75% yield) mp 102.5-104.5 ° C IRν _max ^KBr cm ^-1 : 2970, 2940, 2870, 1740, 1265, 965,
930

Example 4 Preparation of 3-cycloartenyl 2-dimethylaminoethyl carbonate hydrochloride (1) To 90 ml of anhydrous chloroform was added 6.0 g (30 mmol) of trichloromethyl chloroformate (TCF), and ice was added thereto. 3 ml of pyridine was added dropwise under cooling. Then, a solution of 6.4 g (15 mmol) of cycloartenol in 45 ml of chloroform was added dropwise, and after completion, stirring was continued for 2 hours under ice cooling, and then the reaction solution was concentrated under reduced pressure to obtain cycloartenyl chloroformate. This cycloartenyl chloroformate was dissolved in 90 ml of chloroform without purification and added dropwise to a solution of 9 ml of 2-dimethylaminoethanol in 60 ml of chloroform under ice cooling. After completion of dropping, the mixture was stirred overnight at room temperature, the reaction solution was washed with water four times, and then dried over anhydrous magnesium sulfate. Then, 9.1 g of the residual oily substance obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (solvent chloroform / methanol) and crystallized from acetonitrile to obtain the free base of the title compound as white crystals. Yield 5.7 g (yield 70.4%) mp 86-87.5 ° C IRν _max ^KBr cm ^-1 : 2970, 2880, 2780, 1735, 1285, 127
0, 980, 960, 800 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.33 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.70 to 2.20 (45H, m), 2.28 (6H, s), 2.59 (2H, t, J
= 6Hz), 4.20 (2H, t, J = 6Hz), 4.05 ~ 4.59 (1H, m), 4.92 ~ 5.
30 (1H, m) (2) 4.6 g of the base of the title compound was dissolved in a mixed solution of 45 ml of acetone and 4 ml of chloroform, and 0.8 ml of concentrated hydrochloric acid was added to the solution.
ml was added, and the precipitated crystals were collected by filtration and washed with acetone to obtain 3-cycloartenyl 2-dimethylaminoethyl carbonate hydrochloride. Yield 4.2 g (Yield 91.3%) mp 209 ° C. (decomposition) IRν _max ^KBr cm ⁻¹ : 2940, 2860, 2650, 1740, 1270, 965 ¹ H-NMR (60 MHz, CDCl ₃ ) δ: 0.33 ( 1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.70 to 2.50 (45H, m), 2.94 (6H, d, J = 4Hz), 3.30
~ 3.70 (2H, m), 4.25 ~ 4.50 (1H, m), 4.50 ~ 4.80 (2H, m),
4.90 ~ 5.25 (1H, m), 5.42 ~ 5.80 (1H, m)

Example 5 2- (3-Cycloartenyloxycarbonyloxy)
Production of ethyltrimethylammonium iodide 1.1 g (2 mmol) of 3-cycloartenyl 2-dimethylaminoethyl carbonate was dissolved in 40 ml of acetone, 0.2 ml of methyl iodide was added under ice cooling, and the mixture was stirred overnight. The precipitated crystals were collected by filtration and washed with acetone to obtain 1.2 g (yield 85%) of the title compound as yellow powdery crystals. mp 228 ℃ (decomposition) IRν _max ^KBr cm ^-1 : 2940, 2870, 1740, 1475, 1380, 128
0, 1265, 1040, 970, 955, 940 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.35 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.72 ~ 2.33 (45H, m), 3.59 (9H, s), 4.02 ~ 4.82
(5H, m), 4.94 ~ 5.30 (1H, m)

Example 6 Preparation of cycloartenol 3-dimethylaminopropionate Cycloartenol 10.0 in 100 ml of methylene chloride.
g (23 mmol), 3-dimethylaminopropionate hydrochloride 5.4 g (36 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride 9.5 g (56 mmol).
Was added, and 10.0 g (127 mmol) of pyridine was added dropwise. After completion, stirring was continued overnight at room temperature, and the reaction solution was added to saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 15.0 g of crude crystals. The crude crystals were purified by silica gel chromatography (solvent chloroform / methanol) to obtain a pure product of the title compound. Yield 12.5 g (yield 95%) mp 79.0-87.0 ° C. IRν _max ^KBr cm ⁻¹ : 2970, 2930, 2850, 1730, 1280, 125
5, 1215, 1130, 1030, 990 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.32 (1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.72 ~ 2.15 (45H, m), 2.21 (6H, s), 2.41 ~ 2.65
(4H, m), 4.40 ~ 4.72 (1H, m), 4.89 ~ 5.21 (1H, m)

Example 7 Preparation of 2- (3-cycloartenyloxycarbonyl) ethyltrimethylammonium methylsulfate 1.1 g of cycloartenol 3-dimethylaminopropionate was dissolved in 50 ml of acetone and 1 ml of dimethyl sulfate was added. Stir overnight. The precipitated crystal was collected by filtration and washed with acetone to obtain 0.8 g of the title compound (yield 67%). mp 206.0 to 210.0 ° C IRν _max ^KBr cm ^-1 : 2940, 2860, 1730, 1470, 1375, 122
0, 1190, 1060,1010, 980, 740 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.33 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.71 to 2.22 (45H, m), 2.73 to 3.11 (2H, m), 3.29
(9H, s), 3.63 (3H, s), 3.56 ~ 3.91 (2H, m), 4.18 ~ 4.73 (1
H, m), 4.89-5.27 (1H, m)

Example 8 Preparation of 2- (3-cycloartenyloxycarbonyl) ethyldimethylethylammonium ethylsulfate The title compound was prepared in the same manner as in Example 7 except that diethylsulfate was used instead of dimethylsulfate. Obtained in a yield of 64%. mp 207.0 ° C (decomposition) IRν _max ^KBr cm ^-1 : 2950, 2870, 1730, 1280, 1265, 120
0, 1020, 920, 775 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.35 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.74〜2.23 (51H, m), 2.68〜3.17 (4H, m), 2.91
(6H, s), 3.26 ~ 3.60 (2H, m), 4.02 (2H, q, J = 7Hz), 4.32 ~
4.70 (1H, m), 4.81 ~ 5.17 (1H, m)

Example 9 3- (3-Cycloartenyloxycarbonyl) -1-
Manufacture of methylpyridinium iodide (1) Manufacture of cycloartenol nicotinic acid ester 27.1 g of nicotinic acid (0.
22 mol), 85.3 g of cycloartenol (0.20 m
ol) and 2-chloro-1,3-dimethylimidazolinium chloride (84.5 g, 0.50 mol) were added, pyridine (79.0 g, 1.00 mol) was added dropwise under ice cooling, and after completion, 68 hours at room temperature. It was stirred. Water was added to the reaction solution and extracted with chloroform. The extract solution was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, acetonitrile was added to the obtained residue, and the precipitated crystals were collected by filtration to obtain 102.0 g (yield 96%) of the title compound. mp 170.5 to 171.0 ° C. (2) To 700 ml of acetone, 5.0 g (9.4 mmol) of cycloartenol nicotinic acid ester and 8 ml of methyl iodide were added, and the mixture was heated under reflux for 9.5 hours. After cooling, the solvent was concentrated under reduced pressure and the obtained crystalline residue was recrystallized from isopropyl alcohol / dichloromethane to obtain 4.7 g (yield 75%) of the title compound. mp 220.0 ℃ IRν _max ^KBr cm ^-1 : 2940, 2870, 1725, 1640, 1595, 130
0, 1205, 1185, 1120, 970 ¹ H-NMR (60MHz, CDCl ₃ / MeOH-d ₄ ) δ: 0.43 (1H, d, J = 4Hz),
0.69 (1H, d, J = 4Hz), 0.80〜2.24 (45H, m), 4.60 (3H, s), 4.7
9 ~ 5.29 (2H, m), 8.28 (1H, t, J = 8Hz), 8.99 (1H, d, J = 8Hz),
9.27 (1H, d, J = 8Hz), 9.36 (1H, s)

Example 10 3- (3-Cycloartenyloxycarbonyl) -1-
Preparation of ethylpyridinium ethylsulfate 5.0 g (9.4 mmol) of cycloartenol nicotinate and 5 ml of diethylsulfate in 50 ml of chloroform.
Was added and the mixture was heated under reflux for 14 hours. After allowing to cool, the solvent was concentrated under reduced pressure, acetonitrile was added to the residue, and the crystals were collected by filtration. The crystals were further purified by silica gel chromatography (solvent chloroform / methanol) to obtain 0.3 g (yield 5%) of the title compound. mp 229.0 ° C (decomposition) IRν _max ^KBr cm ^-1 : 2930, 2860, 1720, 1640, 1225, 118
0, 1025, 920 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.38 (1H, d, J = 4Hz), 0.62 (1H,
d, J = 4Hz), 0.70 to 2.21 (51H, m), 3.95 (2H, q, J = 7Hz), 4.51
~ 5.26 (4H, m), 8.27 (1H, t, J = 8Hz), 8.81 (1H, d, J = 8Hz),
9.22 (1H, s), 9.52 (1H, d, J = 8Hz)

Example 11 Preparation of 1-O- (3-cycloartenyl) -2,3,4-tri-O-acetyl-D-glucopyranosideuronic acid methyl ester 7.2 g of cycloartenol in 170 ml of toluene ( 1
7 mmol), 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranoside uronic acid methyl ester 19.7 g (50 mmol) and silver carbonate 2
4.8 g (73 mmol) was added, and stirring was continued at room temperature for 66 hours in the dark. Then, the reaction solution is filtered through Celite, washed with toluene, and the residue obtained by concentrating the wash solution under reduced pressure is subjected to silica gel chromatography (solvent chloroform / methanol).
Purification was carried out to obtain 9.5 g of crystals. This crystal was recrystallized twice from ethanol to give a pure product of the title compound.
1 g (yield 49%) was obtained. mp 196 ° C (decomposition) IRν _max ^KBr cm ^-1 : 2930, 2850, 1750, 1435, 1370, 121
5, 1170, 1040 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.31 (1H, d, J = 4Hz), 0.54 (1H,
d, J = 4Hz), 0.66 ~ 2.30 (45H, m), 2.01 (9H, s), 3.00 ~ 3.38
(1H, m), 3.23 (3H, s), 3.89 ~ 4.15 (1H, m), 4.50 ~ 4.73 (1
H, m), 4.89-5.37 (4H, m)

Example 12 Preparation of 1-O- (3-cycloartenyl) -D-glucopyranosideuronic acid 2.4 g (93% 56 mmol) of sodium hydroxide was dissolved in a mixed solution of 1.6 l of ethanol and 0.6 l of water. Then, 3.0 g (4 mmol) of 1-O- (3-cycloartenyl) -2,3,4-tri-O-acetyl-D-glucopyranosideuronic acid methyl ester was added thereto, and the mixture was stirred at room temperature overnight. did. Then, after distilling off most of ethanol under reduced pressure, dilute hydrochloric acid was added to make the mixture acidic, and crystals were collected by filtration and washed with water to give 2.3 g.
To obtain crude crystals of. The crude crystals were dissolved in dimethylformamide,
The solution was added to acetonitrile and the precipitated crystals were collected by filtration and washed with acetonitrile to give 1.7 g of the pure product of the title compound (yield 7
1%) was obtained. mp 196.0 ° C (decomposition) UV λ _max ^EtOH nm: 202.4 (ε4800) IR ν _max ^KBr cm ⁻¹ : 3380, 2930, 2860, 1720, 1440, 137
5, 1160, 1085, 1040, 1010 ¹ H-NMR (60MHz, DMSO-d ₆ ) δ: 0.35 (1H, d, J = 4Hz), 0.53 (1
H, d, J = 4Hz), 0.62 to 2.42 (45H, m), 2.84 to 4.40 (6H, m), 4.5
5 to 5.90 (5H, m)

Example 13 Preparation of 4- (1-piperidino) -1-piperidinecarboxylic acid cycloartenol ester To 90 ml of anhydrous chloroform was added 6.0 g (30 mmol) of trichloromethyl chloroformate (TCF). 3 ml of pyridine was added dropwise under ice cooling. Then, a solution of 6.4 g (15 mmol) of cycloartenol in 45 ml of chloroform was added dropwise, and after completion, stirring was continued for 2 hours under ice cooling, and then the reaction solution was concentrated under reduced pressure to obtain cycloartenyl chloroformate. This chloroformate was dissolved in 90 ml of chloroform without purification, and 5.0 g (30 mmol) of 4-piperidinopiperidine and 10 ml of triethylamine were added dropwise to 60 ml of chloroform under ice cooling. After completion of dropping, the mixture was stirred under ice cooling for 2 hours, and further stirred overnight at room temperature. Water was added to the reaction solution to separate the organic layer, and the organic layer was washed with water and the solvent was distilled off under reduced pressure to obtain a brown viscous residue. Acetonitrile was added to this residue, and the precipitated crystals were collected by filtration to obtain 10.0 g of yellow-brown crude crystals. The crude crystal was purified by silica gel chromatography (solvent chloroform / methanol) and recrystallized from ethanol / acetonitrile to give a pure product of the title compound as 4.5.
g (yield 49%) was obtained. mp 137.0 ℃ IRν _max ^KBr cm ^-1 : 2925, 2850, 1690, 1270, 1240, 120
0, 1100, 1020 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.32 (1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.74 to 2.30 (55H, m), 2.30 to 3.02 (8H, m), 3.90
~ 4.62 (2H, m), 4.87 ~ 5.24 (1H, m)

Example 14 Preparation of N- (2-methyltetrahydrofurfuryl) -N-methylcarbamic acid cycloartenol ester N- (2-Methyltetrahydrofurfuryl) -N was used instead of 4-piperidinopiperidine. The same operation as in Example 13 was carried out except using -methylamine to obtain the title compound in a yield of 69%. mp 135.0 ° C IRν _max ^KBr cm ⁻¹ : 2920, 2850, 1680, 1190, 1105, 103
5, 980 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.33 (1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.72 ~ 2.31 (52H, m), 2.98 (3H, s), 3.22 ~ 3.43
(2H, m), 3.63 ~ 3.93 (2H, m), 4.19 ~ 4.63 (1H, m), 4.84 ~
5.20 (1H, m)

Example 15 Preparation of 4- (isopropylcarbamoylmethyl) -1-piperazinecarboxylic acid cycloartenol ester Example 1 except that N- (isopropylcarbamoylmethyl) piperazine was used in place of 4-piperidinopiperidine.
The same operation as in 3 was carried out to obtain the title compound with a yield of 48%. mp 176.0 ℃ IRν _max ^KBr cm ^-1 : 3370, 2920, 2850, 1690, 1675, 123
0, 1125, 1065,995, 965 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.34 (1H, d, J = 4Hz), 0.60 (1H,
d, J = 4Hz), 0.71 to 2.20 (61H, m), 2.31 to 2.66 (4H, m), 2.98
(2H, s), 3.32 ~ 3.68 (4H, m), 3.88 ~ 4.66 (2H, m), 4.87 ~
5.24 (1H, m), 6.50 ~ 7.00 (1H, m)

Example 16 Preparation of N- [1,1-di (hydroxymethyl) -2-hydroxyethyl] carbamic acid cycloartenol ester Tris (hydroxymethyl) aminomethane is used in place of 4-piperidinopiperidine. Otherwise by performing the same operations as in Example 13, the title compound was obtained in a yield of 64%. mp 223.8 ° C. IRν _max ^KBr cm ⁻¹ : 3300, 2920, 2850, 1680, 1280, 112
0, 1035 ¹ H-NMR (60MHz, CDCl ₃ / MeOH-d ₄ ) δ: 0.38 (1H, d, J = 4Hz),
0.64 (1H, d, J = 4Hz), 0.77〜2.25 (45H, m), 3.70 (6H, s), 4.2
2 ~ 4.67 (1H, m), 4.88 ~ 5.31 (1H, m)

Example 17 Preparation of N- (3-hydroxypropyl) carbamic acid cycloartenol ester The same operation as in Example 13 was carried out except that 3-hydroxypropylamine was used in place of 4-piperidinopiperidine 67. The title compound was obtained in a yield of%. mp 151.5 ℃ IRν _max ^KBr cm ^-1 : 3370, 2920, 2850, 1680, 1260, 113
0, 1040, 985 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.32 (1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.70 ~ 2.35 (47H, m), 2.81 ~ 3.86 (5H, m), 4.19
~ 4.62 (1H, m), 4.87 ~ 5.27 (2H, m)

Example 18 Preparation of N- (2-chloroethyl) carbamic acid cycloartenol ester Cycloartenol 50.0 in 500 ml of chloroform.
g (117 mmol) and 25.0 g (237 mmol) of 2-chloroethyl isocyanate and dissolve at 40-60 ° C. for 49
Heated to reflux for hours. After allowing to cool, 30 ml of methanol was added and the mixture was stirred at room temperature for 1 hour, then the solvent was distilled off under reduced pressure, acetonitrile was added to the residue obtained, and crystals were collected by filtration to give crude crystals of the title compound. The crude crystals were purified by reprecipitation using chloroform / acetonitrile to give a pure product of the title compound.
2.8 g (yield 85%) was obtained. mp 128.0-130.0 ° C IRν _max ^KBr cm ^-1 : 3350, 2930, 2875, 2855, 1690, 126
5, 1245, 1145,985 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.32 (1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.72 ~ 2.35 (45H, m), 3.35 ~ 3.75 (4H, m), 4.29
~ 4.63 (1H, m), 4.88 ~ 5.25 (2H, m)

Example 19 N- [2- [4- (isopropylcarbamoylmethyl)
Preparation of -1-piperazinyl] ethyl] carbamic acid cycloartenol ester dihydrochloride (1) N- (2-chloroethyl) in 500 ml of benzene
Carbamic acid cycloartenol ester 30.0g
(56 mmol) and 30.0 g (162 mmol) of N- (isopropylcarbamoylmethyl) piperazine were added, 46
Heated to reflux for hours. After allowing to cool, water was added to the reaction solution to separate the organic layer, and the organic layer was washed with water and dried over anhydrous sodium sulfate.
Next, the yellow-brown oily residue obtained by distilling off the solvent under reduced pressure was washed with acetonitrile to obtain 37 g of crude crystals. The crude crystals were purified by silica gel chromatography (solvent chloroform / methanol) to give 25.0 g of the free base of the title compound.
(Yield 65%) was obtained. Amorphous IR ν _max ^KBr cm ^-1 : 3320, 2930, 2860, 2810, 1715, 166
5, 1245, 1160, 1130, 990 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 0.31 (1H, d, J = 4Hz), 0.59 (1H,
d, J = 4Hz), 0.77〜2.22 (51H, m), 2.31〜2.70 (10H, m), 2.96
(2H, s), 3.11 ~ 3.47 (2H, m), 3.89 ~ 4.30 (1H, m), 4.30 ~
4.67 (1H, m), 4.90-5.27 (2H, m), 6.75-7.06 (1H, m) (2) 5.0 g (7 mmol) of the free base of the title compound was dissolved in 50 ml of acetone, and 5 ml of concentrated hydrochloric acid was added. The precipitated crystals were collected by filtration and washed with acetone to remove the dihydrochloride of the title compound from 4.5.
g (yield 85%) was obtained. mp 217.0 ° C (decomposition) IRν _max ^KBr cm ^-1 : 3350, 2920, 2850, 2540, 1700, 167
0, 1255, 1150, 1100, 990 ¹ H-NMR (60MHz, CDCl ₃ / MeOH-d ₄ ) δ: 0.37 (1H, d, J = 4Hz),
0.61 (1H, d, J = 4Hz), 0.74〜2.21 (51H, m), 3.18〜5.28 (17H,
m)

Example 20 Preparation of N- (2-diethylaminoethyl) carbamic acid cycloartenol ester hydrochloride The same procedure as in Example 19 was carried out except that diethylamine was used in place of N- (isopropylcarbamoylmethyl) piperazine. The compound was obtained in a yield of 47%. mp 250.0 ° C (decomposition) IRν _max ^KBr cm ^-1 : 3460, 3220, 2940, 2860, 2620, 171
0, 1275, 1250, 1155, 990 ¹ H-NMR (60MHz, CDCl ₃ / MeOH-d ₄ ) δ: 0.32 (1H, d, J = 4Hz),
0.59 (1H, d, J = 4Hz), 0.71〜2.28 (51H, m), 2.97〜3.72 (8H,
m), 4.22-4.59 (1H, m), 4.90-5.24 (1H, m), 6.64-6.91 (1
H, m)

Example 21 Preparation of N- [2- [4-[(1-pyrrolidinyl) carbonylmethyl] -1-piperazinyl] ethyl] carbamic acid cycloartenol ester dihydrochloride Preparation of N- (isopropylcarbamoylmethyl) piperazine 1-[(1-pyrrolidinyl) carbonylmethyl] instead
The title compound was obtained in a yield of 31% by the same procedure as in Example 19 except that piperazine was used. mp 247.0 ° C (decomposition) IRν _max ^KBr cm ^-1 : 3400, 2920, 2850, 2640, 1700, 165
0, 1250, 1100 ¹ H-NMR (60MHz, CDCl ₃ / MeOH-d ₄ ) δ: 0.37 (1H, d, J = 4Hz),
0.62 (1H, d, J = 4Hz), 0.78〜2.40 (49H, m), 3.25〜5.30 (20
H, m)

Test Example 1 Anti-hypoxic effect (oral administration) (1) Experimental animal Four-week-old Jcl: ICR male mice (CLEA Japan, Inc.) were purchased and used at 5 weeks of age and a weight of 27 to 34 g. did. (2) Test substance 1) Dose 250, 50 for cycloartenol derivative or its salt
Three doses of 0 and 1,000 mg / kg were set, and each was orally administered to the mouse in a volume of 10 ml / kg 30 minutes before the start of the experiment. The control group was similarly administered with 5% gum arabic solution. 2) Preparation method Cycloartenol derivative or its salt is 5% of the preparation volume.
The mixture was placed in a mortar together with an amount (0.5 g if 10 ml was prepared) in a mortar and mixed well, and then water for injection was gradually added to suspend the mixture, and the volume was adjusted to 1,000 mg / 10 ml / kg. This suspension is diluted 500 times to 2
Two doses of 50 mg / 10 ml / kg were prepared. (3) Experimental method According to the method of Tobe et al., 30 × 20 × 20 having an exhaust port
100% N ₂ and 100% O ₂ were mixed (96: 4) in a cm chamber at a flow rate, aerated at a flow rate of about 10 L / min, and replaced with air in the container to generate a low oxygen state. Thirty minutes after the start of aeration, four mice were placed in the chamber at the same time, and the time (seconds) until respiratory arrest was measured. During the experiment, the mixed gas of N ₂ + O ₂ was replenished at a constant flow rate, and the experiment was continued for 3 or 4 times with gas bubbling for about 5 minutes. After venting the gas for a minute, the experiment was continued. Mice that survived for 10 minutes or more were regarded as surviving mice, and the survival time was calculated as 600 seconds when calculating the average survival time. (4) Results From the average survival time thus obtained, the survival rate was calculated with the control group set to 100, and the results are shown in Table 1.

[0063]

[Table 1]

Test Example 2 Anti-hypoxic effect (intraperitoneal administration) (1) Experimental animal 5 week-old Slc: ICR male mice (Japan SLC, Inc. were purchased, 5-6 weeks old, weight 28-) (2) Test substance 1) Dose The cycloartenol derivative or its salt was 31.25,
Three doses of 62.5 or 125 mg / kg were intraperitoneally administered to mice in a volume of 10 ml / kg 30 minutes before the start of the experiment. Also,
A 5% gum arabic solution was similarly administered to the control group. 2) Preparation method Cycloartenol derivative or its salt is 5% of the preparation volume.
The mixture was placed in a mortar together with an amount (0.5 g if 10 ml was prepared) in a mortar and mixed well, then water for injection was gradually added to suspend the mixture, and the volume was adjusted to 125 mg / 10 ml / kg. This suspension is diluted 62.5 and 3 by double dilution.
Two doses of 1.25 mg / 10 ml / kg were prepared. (3) The experiment was conducted in the same manner as in Test Example 1 and the results shown in Table 2 were obtained.

[0065]

[Table 2]

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[Procedure amendment]

[Submission date] May 29, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0061

[Correction method] Change

[Correction content]

Example 21 Preparation of N- [2- [4-[(1-pyrrolidinyl) carbonylmethyl] -1-piperazinyl] ethyl] carbamic acid cycloartenol ester dihydrochloride Preparation of N- (isopropylcarbamoylmethyl) piperazine 1-[(1-pyrrolidinyl) carbonylmethyl] instead
The title compound was obtained in a yield of 31% by the same procedure as in Example 19 except that piperazine was used. mp 247.0 ° C. (decomposition) IRν _max ^KBr cm ⁻¹ : 3400, 2920, 2
850, 2640, 1700, 1650, 1250, 1
100 ¹ H-NMR (60 MHz, CDCl ₃ / MeOH-d
₄ ) δ: 0.37 (1H, d, J = 4Hz), 0.62
(1H, d, J = 4Hz), 0.78 to 2.40 (49
H, m), 3.25 to 5.30 (20H, m) Example 22 Preparation of 3-cycloartenyl methyl carbonate Cycloartenol 2 was added to 250 ml of methylene chloride.
0.0 g (46.9 mmol) and methyl chlorocarbonate 1
8.0 g (187 mmol) was dissolved, and 9.5 g (120 mmol) of pyridine was added dropwise to this solution under ice cooling.
Then, the mixture was stirred for 96 hours while cooling with water, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was washed successively with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 25.0 g of an oily residue. The residue was purified by silica gel chromatography (solvent n-hexane / chloroform), and recrystallized from acetonitrile to give a pure product of the title compound. Yield 5.0 g (yield 22%) mp 144.0 ° C. (white scaly) IRν _max ^KBr cm ⁻¹ : 2930,2870,1
745, 1445, 1275, 980, 945 ¹ H-NMR (60 MHz, CDCl ₃ ) δ: 0.33
(1H, d, J = 4Hz ), 0.60 (1H, d, J =
4 Hz), 0.72 to 2.20 (45 H, m), 3.7
5 (3H, s), 4.23 to 4.51 (1H, m),
4.89-5.25 (1H, m) Example 23 Preparation of 3-cycloartenyl n-propyl carbonate
Cycloartenol 10.0g in concrete pyridine 100ml
(23.4 mmol) is dissolved and the solution is cooled under ice-cooling.
N-Propyl carbonate 12.0 g (93.5 mmol)
Was dripped. Then, after stirring at room temperature for 65 hours, water is added to the reaction solution.
Was added and extracted with methylene chloride. The extract is diluted hydrochloric acid and water
Sequentially washed with, dried over anhydrous magnesium sulfate, and dissolved under reduced pressure.
The medium was distilled off to obtain 15.2 g of a reddish brown oily substance. This oil
Silica gel chromatography (solvent n-hexa
(Chloroform / chloroform) and then acetonitrile
Crystallization from the above yielded a pure product of the title compound. Yield 6.3g (yield 52%) mp 74.0 ° C This product shows liquid crystal properties (monotro.
Transition point 66.9 ° C.) IRν _max ^KBr cm ⁻¹ : 2970, 2940, 2
860, 1740, 1265, 970, 960 ¹ H-NMR (60 MHz, CDCl ₃ ) δ: 0.31
(1H, d, J = 4Hz), 0.60 (1H, d, J =
4Hz), 0.74 to 2.30 (50H, m), 4.0
4 (1H, t, J = 6.5 Hz), 4.22 to 4.56
(1H, m), 4.89-5.22 (1H, m) Example 24 Preparation of cycloartenol dimethylaminoacetic acid ester Cycloartenol 10.
0 g (23 mmol), N, N-dimethylglycine hydrochloride 5.2 g (purity 95% 35 mmol) and 2-chloro.
B-1,3-Dimethylimidazolinium chloride 9.
5 g (56 mmol) was added, and 10.0 g (1
27 mmol) was added dropwise. After completion, stir at room temperature for 4 days
Then, the reaction solution was saturated with an aqueous sodium hydrogen carbonate solution.
The organic layer was separated. After washing the organic layer with water,
After drying with gnesium, the solvent was distilled off under reduced pressure to give 14.0 g.
A yellowish brown viscous oil was obtained. The oil is then converted to silica.
Purified by gel chromatography (solvent chloroform)
And crystallized from acetonitrile to give the pure title compound.
I got the goods. Yield 5.2 g (yield 44%) mp 69.1 ° C IRv _max ^KBr cm ^-1 : 2920,2870,1
725, 1450, 1375, 1185, 1070, 9
80 ¹ H-NMR (60 MHz, CDCl ₃ ) δ: 0.32
(1H, d, J = 4Hz), 0.59 (1H, d, J =
4 Hz), 0.72 to 2.24 (45 H, m), 2.3
5 (6H, s), 3.15 (2H, s), 4.48-
4.80 (1H, m), 4.90 to 5.25 (1H,
m) Example 25 Preparation of 3-cycloartenyloxycarbonylmethyltrimethylammonium iodide 4.0 g (7.8 mmol) of cycloartenol dimethylaminoacetic acid ester was dissolved in 140 ml of acetone to give 9.1 g (64 g) of methyl iodide. .3 mmol) was added and the mixture was left for 3 days. The precipitated crystals were collected by filtration and washed with acetone to obtain the title compound. Yield 5.1 g (yield 100%) mp 240.5 ° C. (decomposition) IRν _max ^KBr cm ⁻¹ : 2930, 2860,1
735, 1460, 1400, 1375, 1260, 1
220,1200,995 ¹ H-NMR (60 MHz, CDCl ₃ / DMSO-d
₆ ) δ: 0.38 (1 H, d, J = 4 Hz), 0.60
(1H, d, J = 4Hz), 0.79 to 2.32 (45
H, m), 3.44 (11H, s), 4.52 to 4.8.
9 (1H, m), 4.92 to 5.26 (1H, m) Example 26 Cycloartenol 4-dimethylaminobutanoic acid S
Preparation of tellur 10. Cycloartenol in 100 ml of methylene chloride.
0 g (23 mmol), 4-dimethylaminobutanoate
Acid salt 6.0 g (purity 98% 35 mmol) and 2-q
Lolo-1,3-dimethylimidazolinium chloride
9.5 g (56 mmol) was added, and pyridine 10.0 g
(127 mmol) was added dropwise. After completion, stir at room temperature for 3 days
Stirring is continued, and then the reaction solution is saturated aqueous sodium hydrogen carbonate solution.
The mixture was added to the liquid and the organic layer was separated. The organic layer is washed with water and then anhydrous sulfuric acid
Dry over magnesium and evaporate the solvent under reduced pressure to 13.0.
g of red oil was obtained. This oil is a silica gel chroma
Purification by chromatography (solvent chloroform / methanol)
And crystallized from acetonitrile to give the pure title compound.
I got the goods. Yield 7.0 g (yield 56%) mp 74.1 ° C IRv _max ^KBr cm ^-1 : 2910,2870,2
760, 1720, 1445, 1375, 1220, 1
190,1130,980,960 ¹ H-NMR (60 MHz, CDCl ₃ ) δ: 0.33
(1H, d, J = 4Hz), 0.60 (1H, d, J =
4 Hz), 0.74 to 2.11 (47 H, m), 2.2
2 (6H, s), 2.18 to 2.59 (4H, m),
4.42 to 4.75 (1H, m), 4.91 to 5.27
(1H, m) Example 27 3- (3-Cycloartenyloxycarbonyl) propyi
Preparation of trimethylammonium iodide Cycloartenol 4-dimer was added to 140 ml of acetone.
Cylaminobutanoic acid ester 4.0 g (7.4 mmo
l) was dissolved, and 9.1 g (64.3 mmo) of methyl iodide was dissolved.
1) was added and left overnight. The precipitated crystals are collected by filtration and washed with acetone.
Purification gave the title compound. Yield 5.1 g (yield 100%) mp 261.9 ° C (decomposition) IRv _max ^KBr cm ^-1 : 2925, 2855,1
725, 1470, 1375, 1295, 1180, 9
65 ¹ H-NMR (60 MHz, CDCl ₃ / DMSO-d
₆ ) δ: 0.38 (1H, d, J = 4Hz), 0.60
(1H, d, J = 4Hz), 0.77 to 2.10 (47
H, m), 2.48 (2H, t, J = 6 Hz), 3.2
2 (9H, s), 3.63 (2H, t, J = 6Hz),
4.40 to 4.79 (1H, m), 4.95 to 5.31
(1H, m)

Front page continued (72) Inventor Masaaki Saito 751 Hiraga, Inba-mura, Inba-gun, Chiba Prefecture (72) Inventor Shinya Murata Nishinoharu-cho, Nishi-Kasugai-gun, Aichi Kuninotsubo Saijo Yashiki 51 Amano Pharmaceutical Co., Ltd. Central Research Institute (72) Inventor Takashi Nagao 3-634-42, Kamiyama-cho, Funabashi, Chiba Maison 102 Kamiyama 102 (72) Inventor Chiho Tsurumi Nishiharu Town, Nishikasugai-gun, Aichi Kunotsubo Nishijoya 51 Central Research Laboratory, Amano Pharmaceutical Co., Ltd.

Claims (2)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents a residue or a group R ² CO- selected from monosaccharides, disaccharides and uronic acids (wherein R ² is a dialkylaminoalkyl group or an alkoxy group which may have a substituent). Group, a nitrogen-containing heterocyclic group which may have a substituent or an alkylamino group which may have a substituent)]] or a salt thereof. 2. A brain function improving agent comprising the cycloartenol derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.