KR100440607B1 - Pregnan glycoside compounds and preventives and remedies of neurodegenerative disease containing them as active ingredients - Google Patents

Abstract

The present invention relates to a pregnan glycoside compound having an AChE inhibitory activity of formula (I), extracted and separated from white rice, and a prophylactic and therapeutic agent for degenerative cerebral nervous system disease containing the same as an active ingredient:

(I)

Wherein R ₁ is hydrogen or a hydroxy group,

R ₂ is ,

or

, to be.

Description

Pregnan glycoside compounds and preventives and remedies of neurodegenerative disease containing them as active ingredients

The present invention is a Pregnane Glycosides compound having an acetylcholinesterase (AChE) inhibitory activity of the following formula (I), extracted from white rice, and a degenerative neurological disease containing the same as an active ingredient. It relates to the prevention and treatment of.

(I)

Wherein R ₁ is hydrogen or a hydroxy group,

R ₂ is ,

or

, to be.

Alzheimer's disease is a representative degenerative neurological disorder involving symptoms such as memory loss, language, spatial perception and judgment disorders. Various theories have been published one after another on the cause or progress of the disease, but it is not yet clear. However, in the brain of Alzheimer's disease, various neurological systems involving various neurotransmitters are damaged, the most serious of which is cholinergic nerve damage. In addition, this cholinergic damage has been reported to be deeply linked to learning, memory loss and cognitive decline in Alzheimer's disease patients. The pathology of Alzheimer's disease as described above is called "Cholinergic Hypothesis in Alzheimer's disease" and based on this, the development of therapeutic agents has been actively conducted to improve damaged cholinergic nerves. In order to improve damaged cholinergic nerves, a synthetic precursor of acetylcholine (ACh), a cholinergic neurotransmitter (ACh precursor), a cholinergic receptor agonist, or ACh degradation There is a method of maintaining the concentration of ACh at the synapse by administering an AChE inhibitor. However, agonists of cholinergic receptors have a disadvantage in that they are easily hydrolyzed in vivo, and in practice, methods using an AChE inhibitor are mainly used. Indeed, all drugs developed for the treatment of Alzheimer's disease and approved by the FDA are AChE inhibitors such as tacrine, donepezil, and rivastigmin. Among them, compounds derived from natural products include physostigmin (Physostigma venesosum ), galanthamin ( Galanthus nivalis ), and huperzine A ( Huperzia serrata ).

These AChE inhibitors have the effect of improving degradation of cognitive function by preventing the breakdown of ACh and maintaining the concentration of ACh.However, problems such as hepatotoxicity, short half-life or low bioavailability have been raised. We are working hard to develop new AChE inhibitors that act on AChE and have fewer side effects.

Accordingly, the present inventors were able to confirm that the extract of white rice showed a significant inhibitory activity while searching for AChE inhibitory activity in natural products to find a substance that can improve the symptoms of Alzheimer's disease by inhibiting the decomposition of ACh. .

White rice is the root of Cynanchum atratum Bunge, a perennial herb that belongs to Asclepiadaceae , and is used for the treatment of women's diseases, stroke, diuresis and edema in oriental medicine. White flowers are about 60cm high, with hairs distributed throughout, stems are straight, leaves are opposite, and oval. The flower is black purple and blooms in May-July, and the fruit is doldol, and when it opens, the seeds with white cotton come out. It is wild throughout the country and geographically distributed in Japan, Manchuria, and China.

The components of the rice are 13,14: 14,15-disecopregnane type skeletons, such as glaucogenin-A, -C, glaucoside-C, -H, Cynatratoside-A, -B, -C, -D, -E, -F and 14,15-secopregnane type skeletons of atratogenin-A, -B Cinajapogenin-A and atratoside-D have been reported as the backbones of attratoside-A, -B, -C and 14,15-seco-18-nor-pregnan types. .

However, no substance having AChE inhibitory activity in white rice has yet been reported.

Accordingly, the present inventors have conducted a long study to isolate a substance having AChE inhibitory activity from white rice, and found that the novel pregnan glycoside compound according to the present invention has significant AChE inhibitory activity and completed the present invention.

An object of the present invention is to provide a pregnan glycoside compound having a structure of formula (1) and a pharmaceutical preparation containing the same as an active ingredient.

The present invention provides a pregnan glycoside compound of formula (I), which is extracted and separated from white rice ( Cynanchum atratum ).

(I)

Wherein R ₁ is hydrogen or a hydroxy group,

R ₂ is ,

or

, to be.

The present invention also provides an agent for the prevention and treatment of neurodegenerative diseases of the brain, which comprises the above-mentioned Fregnan glycoside compound of formula (I) as an active ingredient.

The present invention extracts white rice with C _1-4 alcohol, or is suspended again with water and fractionated with n -hexane, and then the aqueous layer is partitioned with EtOAc or n- BuOH, or column chromatography to prepare the white rice extract Provide a method.

In another aspect, the present invention provides an agent for the prevention and treatment of degenerative cerebral nervous system diseases such as Alzheimer's disease, the white rice extract as an active ingredient.

Hereinafter, the present invention will be described in more detail with an example of the extraction process of white rice.

The white rice is seasoned and then ultrasonically extracted with MeOH to give a total methanol extract. In addition to this procedure, the methanol extract was suspended in water, fractionated with n -hexane, and the aqueous layer was further partitioned with EtOAc to obtain an EtOAc fraction. In addition to the water layer fraction with n -BuOH n -BuOH obtain a fraction and water fraction. In addition, the EtOAc fraction of the white rice was subjected to silica gel column chromatography several times and recrystallized to obtain the compounds 1 to 4 of the present invention. Compounds 1 to 4 are substances reported for the first time in nature, and their physicochemical and spectroscopic properties are described in the following Examples.

In addition, the prophylactic and therapeutic activity of the degenerative cerebral nervous system disease of the white rice extract and the compounds 1 to 4 isolated and purified therefrom was determined by measuring the acetylcholinesterase inhibitory activity by the method of the following experimental example.

As a result, the white rice extract of the present invention and the compounds 1 to 4 isolated therefrom showed acetylcholinesterase inhibitory activity.

The white rice extract or compounds 1 to 4 of the present invention may be formulated by a method known in the pharmaceutical art, and may be prepared by pharmaceutically or a pharmaceutically acceptable pharmaceutical agent by mixing with itself or a pharmaceutically acceptable carrier, excipient, etc., For example, it may be formulated as an injection, a liquid, a syrup, a tablet, a capsule, and the like, and the compounds 1 to 4 of the present invention may be converted into pharmaceutically acceptable inorganic or organic salts by conventional pharmaceutical methods. They can also be administered orally or parenterally.

The dosage of the white rice extract or compounds 1 to 4 of the present invention is appropriately selected depending on the absorption rate, excretion rate, active age and weight, sex and condition of the patient, the severity of the disease to be treated, etc. 10 mg to 5000 mg may be administered 1 to 3 times daily.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for illustrative purposes of the present invention and are not intended to limit the protection scope of the present invention.

Example 1 White Rice Extract and Fraction

15 kg of white rice was prepared and then ultrasonically extracted with 80% MeOH to obtain 3 kg of total methanol extract. It was suspended in water and partitioned with n -hexane, and then the aqueous layer was partitioned with EtOAc to obtain 581 g of EtOAc fraction. In addition to the water layer fraction with n -BuOH n -BuOH to give a fraction and water fraction.

Example 2 Isolation of AChE Inhibitory Active Components from White Rice Extract

(1) Compound 1 (cinnazapogenin - A 3- O- α-L-cymar pyranosyl- (1 → 4) -β-D-digitoxopyranosyl- (1 → 4) -β-L-sima Separation of ropyranoside)

The EtOAc fraction of white rice was partitioned into 15 fractions by silica gel column chromatography ( n -hexane → n -hexane: EtOAc → EtOAc → EtOAc: MeOH → MeOH). The 11th fraction was again subjected to silica gel column chromatography ( n -hexane: EtOAc (4: 1)-> EtOAc: MeOH-> MeOH) and divided into 12 subfractions, and 6 subfractions were again subjected to silica gel column chromatography. ( n -hexane: EtOAc: MeOH = 50: 50: 3) was divided into 16 subfractions, and then 6 subfractions were again subjected to reverse phase silica gel column chromatography (MeOH: H ₂ O ₂ = 1: 1). After dividing into 14 small fractions, 10 fractions were RP-HPLC with a mixed solvent of H ₂ O: MeOH: AcCN = 45: 5: 50 to separate Compound 1 (62.6 mg) having R _t 17.7 min. . This material showed blue fluorescence at UV long wavelength (365 nm) and developed black in anisealdehyde-H ₂ SO ₄ color reagent.

Compound 1:

White powder, C ₄₀ H ₆₀ O ₁₃ ,

R _f : 0.27 ( n -hexane: EtOAc: MeOH = 5: 5: 1),

IR λ _max (KBr): 3444 (-OH), 2932 (-OH), 1715 (-C = O), 1653 (-C = C-), 1058 (-CO-), 756 cm ^-1 ,

Positive FABMS ( m / z ): 771 [M + Na] ⁺ , 749 [M + H] ⁺ , 605 [M + H-144] ⁺ , 475, 331,

¹ H NMR (300MHz, C ₅ D ₅ N): 1.05 (3H, s, H-19), 1.28-1.43 (9H, m, H-6 ', 6'',6'''), 2.18 (3H , s, H-21), 3.38 and 3.60 (each 3H, s, OMe × 2), 5.07, 5.20 and 5.23 (each 1H, H-1 ', 1'',1'''), 5.41 (1H, br d, J = 4.1 Hz, H-6), 6.48 (1H, d, J = 2.0 Hz, H-16), 7.49 (1H, d, J = 2.0 Hz, H-15) ppm,

¹³ C NMR: Tables 1, 3,

Chemical structure:

(One)

(2) Compound 2 (cinnazapogenin - A 3- O- α-L-cymaropyranosyl- (1 → 4) -β-D-digitoxopyranosyl- (1 → 4) -β-D-ol Isolation of Leandropyranoside)

Seven fractions out of twelve subfractions obtained in the separation of Compound 1 were subjected to silica gel column chromatography ( n -hexane: EtOAc: MeOH = 50: 50: 3), and divided into fifteen subfractions. The subfraction was again subjected to silica gel column chromatography ( n -hexane: EtOAc: MeOH = 50: 50: 3), divided into 18 subfractions, and 18 fractions were H ₂ O: MeOH: AcCN = 50: 5 : Compound 2 (68.9 mg) having R _t 16.6 min was isolated by reverse phase-HPLC with a mixed solvent of 45. This material was colored black in the anisealdehyde-H ₂ SO ₄ color reagent.

Compound 2:

White powder, C ₄₀ H ₆₀ O ₁₃ ,

R _f : 0.26 ( n -hexane: EtOAc: MeOH = 5: 5: 1),

IR λ _max (KBr): 3444 (-OH), 2932 (-OH), 1716 (-C = O), 1653 (-C = C-), 1059 (-CO-), 750 cm ^-1 ,

Positive FABMS ( m / z ): 749 [M + H] ⁺ ,

¹ H NMR (400 MHz, CDCl ₃ ): 1.14 (3H, s, H-19), 1.26-1.35 (9H, m, H-6 ', 6'',6'''), 2.19 (3H, s, H-21), 3.43 (6H, s, -OMe × 2), 4.53 and 5.02 (each1H, br d, J = 8.5 Hz, H-1 ', 1''), 4.93 (1H, d, J = 3.7 Hz, H-1 '''), 6.22 (1H, d, J = 1.5 Hz, H-16) ppm,

¹³ C NMR: Tables 1, 3,

Chemical structure:

(2)

(3) Compound 3 (13-hydroxycynajapojenin-A 3- O- β-D-cymaropyranosyl- (1 → 4) -α-L-diginopyranosyl- (1 → 4) -β-D-cymaropyranoside)

Seven fractions out of twelve subfractions obtained in the separation of Compound 1 were subjected to silica gel column chromatography ( n -hexane: EtOAc: MeOH = 50: 50: 3), and divided into fifteen subfractions. The subfraction was again subjected to silica gel column chromatography ( n -hexane: EtOAc: MeOH = 50: 50: 3), divided into 18 subfractions, and fraction 13 of the fraction was H ₂ O: MeOH: AcCN = 52: 4: RP-HPLC with 44 mixed solvents isolated Compound 3 (42.3 mg) with R _t 14.7 min. This material showed blue fluorescence at UV long wavelength (365 nm) and developed black in anisealdehyde-H ₂ SO ₄ .

Compound 3:

White powder, C ₄₁ H ₆₂ O ₁₄ ,

R _f : 0.15 ( n -hexane: EtOAc: MeOH = 5: 5: 1),

IR λ _max (KBr): 3445 (-OH), 2933 (-OH), 1715 (-C = O), 1653 (-C = C-), 1058 (-CO-), 752 cm ^-1 ,

Positive FABMS ( m / z ): 802 [M + H + Na] ⁺ , 780 [M + H ₂ ] ⁺ , 762 [M + H ₂ -H ₂ O] ⁺ , 618 [762-144] ⁺ , 474, 330,

¹ H NMR (300 MHz, CDCl ₃ ): 0.88 (3H, s, H-19), 1.20-1.28 (9H, m, H-6 ', 6'',6'''), 2.06 (3H, s, H-21), 3.38, 3.39, 3.40 (each 3H, s, -OMe × 3), 4.67 (1H, br d, J = 8.2 Hz, H-1 '''), 4.74 (1H, br d, J = 8.0 Hz, H-1 '), 4.95 (1H, d, J = 3.2 Hz, H-1''), 5.39 (1H, br d, H-6), 6.36 (1H, d, J = 2.0 Hz , H-16), 7.25 (1H, d, J = 2.0 Hz, H-15) ppm,

¹³ C NMR: Tables 2, 3,

Chemical structure:

(3)

(4) Isolation of Compound 3 a

Compound 3 (8mg) dissolved in MeOH, 0.1N H₂SO₄Acid was hydrolyzed, neutralized with 0.4N NaOH, concentrated and partitioned with EtOAc. EtOAc layer was purified by silica gel column chromatography (nHexane: EtOAc: MeOH = 50: 50: 1)₂O: MeOH: AcCN = 60: 5: RP-HPLC with a mixed solvent of R_tCompound 3 with 8.8 mina(2.6 mg) was isolated.

Compound 3a:

White powder, C ₂₀ H ₂₆ O ₅ ,

¹ H NMR (300 MHz, C ₅ D ₅ N): 0.93 (3H, s, H-19), 1.81 (2H, m, H-11), 2.17 (3H, s, H-21), 2.40 (1H, dd, J = 12.9, 4.9 Hz, H-1b), 3.81 (1H, dd, H-2b), 5.43 (1H, br d, J = 4.9 Hz, H-6), 6.68 (1H, d, J = 2.0 Hz, H-16), 7.52 (1H, d, J = 1.7 Hz, H-15) ppm,

¹³ C NMR: Table 2

(5) Compound 4 (13-hydroxycinnapogenin-A 3- O- α-L-cymaropyranosyl- (1 → 4) -β-D-digitoxopyranosyl- (1 → 4)- β-L-cymaropyranoside)

Compound 4 (42.3 mg) having R _t 16.9 min was isolated during the compounding process. This material developed black in anisealdehyde-H ₂ SO ₄ .

Compound 4:

White powder, C ₄₀ H ₆₀ O ₁₄ ,

R _f : 0.18 ( n -hexane: EtOAc: MeOH = 5: 5: 1),

IR λ _max (KBr): 3444 (-OH), 2932 (-OH), 1715 (-C = O), 1653 (-C = C-), 1056 (-CO-), 754 cm ^-1 ,

Positive FABMS ( m / z ): 765 [M + H] ⁺ , 747 [M + HH ₂ O] ⁺ , 603, 473, 329,

¹ H NMR (300 MHz, CDCl ₃ ): 0.88 (3H, s, H-19), 1.18-1.24 (9H, m, H-6 ', 6'',6'''), 2.06 (3H, s, H-21), 3.38, 3.43 (each 3H, s, -OMe × 2), 4.71 (1H, br d, J = 8.0 Hz, H-1 '''), 4.82 (1H, br d, J = 8.0 Hz, H-1 '), 4.88 (1H, d, J = 4.0 Hz, H-1``), 5.39 (1H, br d, H-6), 6.36 (1H, d, J = 1.7 Hz, H -16), 7.25 (1H, d, J = 1.7 Hz, H-15) ppm,

¹³ C NMR: Tables 2, 3,

Chemical structure:

(4)

Table 1. Non-sugar Part of Compounds 1 and 2¹³C-NMR chemical shifts (100 MHz)

CarbonNo. 1 (C ₅ D ₅ N) 2 (CDCl ₃ ) Cynajapogenin-A (C ₅ D ₅ N) One 45.1 44.3 46.2 2 69.8 69.7 72.5 3 85.0 86.5 76.5 4 37.4 37.4 40.6 5 138.6 137.9 140.1 6 121.2 121.5 120.8 7 25.6 25.3 25.8 8 51.7 51.8 52.2 9 45.2 45.4 45.6 10 38.5 38.5 39.4 11 25.1 25.2 25.5 12 33.5 33.6 34.0 13 47.6 47.9 47.9 14 209.2 209.3 209.3 15 139.9 139.9 139.9 16 111.7 110.7 112.0 17 117.7 116.4 117.9 18 - - - 19 19.6 19.8 20.2 20 148.0 147.9 148.0 21 11.6 11.8 11.9

Table 2. Non-sugar Part of Compounds 3 and 4¹³C-NMR chemical shifts (100 MHz)

CarbonNo. 3 (C ₅ D ₅ N) (CDCl ₃ ) 4 (CDCl ₃ ) 3 a (C ₅ D ₅ N) One 45.1 44.3 44.3 45.9 2 69.3 69.7 69.6 72.1 3 84.8 86.4 86.3 76.2 4 37.2 37.4 37.4 40.2 5 138.6 138.3 138.3 139.7 6 121.2 120.8 120.6 121.2 7 25.5 25.1 25.0 25.5 8 52.1 52.5 52.4 52.3 9 42.7 42.0 42.0 42.8 10 39.5 39.4 39.3 39.6 11 22.1 21.9 21.8 22.2 12 38.5 38.6 38.5 39.2 13 76.0 75.5 75.3 76.0 14 212.8 213.5 213.5 212.9 15 140.6 140.6 140.5 140.5 16 110.2 109.5 109.4 110.2 17 120.9 119.5 119.4 120.2 18 - - - - 19 19.5 19.9 19.8 19.8 20 Overlap 149.4 149.3 Overlap 21 12.5 12.7 12.6 12.5

Table 3. ¹³ C-NMR chemical shifts of sugars of Compounds 1-4

CarbonNo. One 2 3 4 L-cym D-ole D-cym L-cym c-1 ' 97.5 98.5 97.9 97.4 c-2 ' 36.7 36.4 34.3 35.5 c-3 ' 77.6 78.9 77.0 76.8 c-4 ' 82.6 82.1 81.7 82.1 c-5 ' 69.1 71.4 69.3 69.0 c-6 ' 17.9 18.1 18.1 17.8 -OMe 58.6 56.8 57.1 58.2 D-dig D-dig L-dgn D-dig c-1 '' 100.1 99.8 101.0 99.5 c-2 '' 38.2 36.9 31.6 36.7 c-3 '' 68.6 68.7 72.2 68.2 c-4 '' 80.6 79.3 74.2 79.2 c-5 '' 67.4 67.5 67.0 67.4 c-6 '' 18.1 18.0 17.5 17.8 -OMe - - 55.7 - L-cym L-cym D-cym L-cym c-1 '' ' 98.2 97.4 99.1 98.2 c-2 '' ' 32.0 30.9 33.0 30.9 c-3 '' ' 76.3 75.0 77.6 75.0 c-4 '' ' 72.4 71.9 73.9 71.9 c-5 '' ' 67.0 65.8 71.1 65.9 c-6 '' ' 18.2 17.8 18.0 18.1 -OMe 56.6 56.3 57.2 56.3

Experimental Example 1 Screening of Acetylcholinesterase Inhibitory Activity of White Rice Extract

AChE Inhibitory Activity Measurement

AChE inhibitory activity was determined by application of Elman's method (Ellman GL, Courtney KD, Andres V., Featherstone, RM. (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol . 7: 68 75). AChE was homogenized with phosphate buffer (0.1 M, pH 8.0) to 4.3 units / ml. The color reagent was prepared by homogenizing DTNB 39.6 mg and NaHCO ₃ 15 mg with 0.1 M phosphate buffer (pH 8.0). Phosphate buffer (0.1 M, pH 8.0), a color developing reagent and a sample were added to the Eppendorf tube, and AChE was added to make the final volume 900 μl, followed by preincubation at 25 ° C. for 5 minutes. Acetylthiocholine iodide, a substrate of AChE, was added to a final concentration of 0.2 mM, incubated for 3 minutes at 25 ° C, and neostigmine bromide was added to a final concentration of 0.1 mM to terminate the reaction. I was. UV absorbance was measured at 412 nm. Under the same conditions, only the AChE was not added to the blank test, and the phosphate buffer solution was added as the sample amount without the sample as a control.

Preparation of Sample Solution

Each sample was dissolved in DMSO and diluted with phosphate buffer (0.1 M, pH 8.0). The concentration of DMSO was such that the final concentration was less than 1% so as not to affect the activity of AChE.

Statistical processing

Statistical significance review consisted of variation from control as a "one way ANOVA" test. When the P value was less than 5%, it was determined to be statistically significant.

Experiment result

When the AChE inhibitory activity was measured at the concentration of 100 μg / ml of each fraction, the total extract was 72%, the n -hexane fraction was 82%, the EtOAc fraction was 86%, the n- BuOH fraction was 78%, and the water fraction was 19%. Inhibitory activity was shown. The EtOAc fraction of white rice showed the best activity.

Experimental Example 2 Screening of Acetylcholinesterase Inhibitory Activity of Compounds 1 to 4

The compounds 1 to 4 were searched for acetylcholinesterase inhibitory activity as in Experimental Example 1, and the results are shown in Table 4 below.

Table 4. IC ₅₀ Values for Compounds 1-4.

compound IC ₅₀ (μM) One 152.9 2 34.4 3 8.2 4 52.3

As shown in Table 4, it was found that Compounds 1 to 4 have inhibitory activity against AChE, and Compound 3 showed the strongest AChE inhibitory activity.

Experimental Example 3 Acute Toxicity Test

1. Oral administration

ICR-based mice (28 ± 6g) and Sprague Dawley (250 ± 12g) rats were divided into 5 groups of 15 rats each, and the compounds 1 to 4 of the present invention were 250, 500, 725, 1000 and 5000 mg, respectively. Two weeks after oral administration at / kg, no toxicity was observed in all five groups, and no symptoms were apparent in the control group.

2. Intraperitoneal administration

ICR mice (25 ± 5g) and Sprague doll rats (250 ± 12g) were divided into 5 groups of 10 mice each, and the compounds 1 to 4 of the present invention were dosed at 125, 250, 500, 725 and 1000 mg / kg, respectively. After 24 hours of intraperitoneal administration, no toxicities were observed in all 5 groups, and no symptoms were apparent in the control group.

From the above results, it was confirmed that the compound of the present invention was not acutely toxic.

Next, the present invention will be described in more detail as formulation examples.

Formulation Example 1

Compound 3 100 mg

Appropriate sterile distilled water for injection

pH adjuster

Compound 3 is dissolved in distilled water for injection, adjusted to pH 7.6 with a pH adjuster, and then the total amount is 2 ml, followed by filling into a 2 ml ampoule and sterilizing to prepare an injection.

Formulation Example 2

Compound 2 2mg

Appropriate sterile distilled water for injection

pH adjuster

Compound 2 is dissolved in sterile distilled water for injection, adjusted to pH 7.2 with a pH adjuster, the total amount is 2 ml, and then filled into 2 ml ampoules to prepare an injection.

Formulation Example 3

Compound 3 200 mg

Lactose 100mg

Starch 100mg

Magnesium stearate proper amount

The above components are mixed and tableted according to a conventional method for producing tablets to produce tablets.

Formulation Example 4

Compound 4 10 mg

Lactose 100mg

Starch 50mg

Magnesium stearate proper amount

The above components are mixed and tableted according to a conventional method for producing tablets to produce tablets.

Formulation Example 5

Compound 3 100 mg

Lactose 50mg

Starch 50mg

Talc 2mg

Magnesium stearate appropriate amount

The capsules are prepared by mixing the above components and filling gelatin capsules according to a conventional method for preparing capsules.

Formulation Example 6

Compound 2 5mg

Lactose 100mg

Starch 93mg

Tackle 2mg

Magnesium stearate proper amount

The capsules are prepared by mixing the above components and filling gelatin capsules according to a conventional method for preparing capsules.

Formulation Example 7

Compound 3 1000mg

20 g of sugar

20 g of isomerized sugar

Lemon flavor

Add 100 ml of purified water

The above components are mixed according to a conventional method for preparing a liquid, and filled into 100 ml of brown bottle and sterilized to prepare a liquid.

Formulation Example 8

Compound 4 100 mg

20 g of sugar

20 g of isomerized sugar

Lemon flavor

Add 100 ml of purified water

The above components are mixed according to a conventional method for preparing a liquid, and filled into 100 ml of brown bottle and sterilized to prepare a liquid.

As can be seen from the above, since the Fregnan glycoside compound of the formula (I) according to the present invention has a significant AChE inhibitory activity, it can be usefully used as a prophylactic and therapeutic agent for degenerative brain neurological diseases such as Alzheimer's disease. .

Claims (5)

Pregnane glycoside compound having the structure of formula (I) (I) Wherein R ₁ is hydrogen or a hydroxy group, R ₂ is , or , to be. The compound of claim 1 selected from the group consisting of: , And A prophylactic and therapeutic agent for degenerative cerebral nervous system diseases comprising the pregnan glycoside compound of claim 1 as an active ingredient. delete C _1-4 alcohol extract of white rice comprising the pregnan glycoside compound of claim ₁ or n -hexane fraction, ethyl acetate fraction or n- BuOH fraction of the C _1-4 alcohol extract as an active ingredient. Prevention and treatment.