JPH0820536A - Novel prenyl 6-3c compound derivative - Google Patents

Abstract

PURPOSE:To obtain the new prenyl 6-3C compound derivative useful for the therapy of various diseases caused by the disorders of cholinergic nerve cells. CONSTITUTION:The CH2CH=CH2,-CH2CH2CH3; R<2> is H, 2-4C acyl; R<3> is H, 1-4C alkyl 2-4C alkyl, 2-4C acyl). The compound is obtained e.g. by extracting the epigeal part of Illicium tashiroi Maxim with methanol, ethanol, etc., concentrating the extract under vacuum, and subsequently isolating the compound from the obtained first extract by various methods using the physicochemical properties of the objective compound. The compound is useful for the therapy of senile dermentia including Alzheimer's disease; cerebrovascular dementia accompanied by cerebral hemorrhage (cerebral hemorrhage, cerebral infarction), cerebral arteriosclerosis, etc.; dysmnesia accompanied by head injury, encephalitis aftereffect, cerebral palsy, etc.; and further for the therapy of peripheral neuropathy.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to prenyl C, which is useful for treating various diseases caused by disorders of cholinergic neurons.
_6- C ₃ compound derivatives.

[0002]

2. Description of the Related Art Shikimi (Illicium anistatum) has long been known as a poisonous plant for whole trees. As its toxic components, sesquiterpene anisatin (II) and neoanisatin (III) of the following formulas were isolated and their structure was determined [Y. Hir
ata et al. , Tetrahedron, 2
4 , 199, 1255 (1968)] and was revealed to be a typical neurotoxin.

[0003]

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[0004] On the other hand, Illicium tashiroi Maxi that grows naturally in the Yaeyama Islands
m) is considered a variant of Shikimi,
Yakushijin et al. [K. Yakushijin
et al. , Chem, Pharm. Bull. , 3
2 (1), 11 (1984)] in formula (IV)-
A compound represented by (VIII) has been found.

[0005]

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Further, as a result of scrutinizing the chemical components of Yaeyamashikimi, the present inventors have found that the compounds represented by the formulas (IX) to (XIII) [Y. Fukuyama et a
l. , Tetrahedron, 48 (28), 584.
7 (1992); Phytochemistry, 3
1 , 3975 (1992)] and rat fetal brain-derived cultured neurons, and stimulates neurite outgrowth to increase acetylcholine synthase (hereinafter abbreviated as “ChAT”) activity, isodonianin (XIV) [Y. Fuknyama eta
l. , Planta Med. , 59 , 181 (199
3)] is isolated and the structure is determined.

[0007]

[Chemical 4]

Thus, although the physiologically active substance contained in Yaeyamashikimi is of great pharmaceutical interest, its components have not yet been sufficiently clarified.

[0009]

[Means for Solving the Problems] As a part of researches on physiologically active components from natural products, the present inventors have focused their attention on such Yaeyamashikimi, and as a result, have novel prenyl C ₆ -C ₃ compounds. The present inventors have found that the derivative can be a drug for improving memory disorders in senile dementia including Alzheimer's disease by activating ChAT activity in cholinergic neurons, and completed the present invention. That is, the gist of the invention is the following general formula (I)

[0010]

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(In the above general formula, R¹Is -CH₂CH =
CH₂Or -CH₂CH₂CH₃Represents R²Is hydrogen
Atom or C₂~ C_FourRepresents an acyl group of R³Is hydrogen
Child, C ₁~ C_FourAlkyl group or C₂~ C_FourThe acyl
Represents a group) prenyl C represented by₆-C₃Compound derivative
Exist in.

The present invention will be described in detail below. Examples of the C _{2 to} C ₄ acyl group represented by R ² and R ³ in the above general formula (I) include an acetyl group, a propionyl group and a butyryl group, and a C _{1 to} C ₄ alkyl group represented by R ^3. Are, for example, methyl group, ethyl group, n-propyl group, i-
Examples thereof include propyl group, n-butyl group, i-butyl group, t-butyl group and the like. Specific examples of preferred compounds represented by the above general formula (I) are shown below.

[0013]

[Table 1]

Next, a method for producing the compound of the present invention will be described. The compound of the present invention is extracted and isolated as shown below. That is, the compound of the present invention of general formula [I] is extracted and isolated from Yaeyamashikimi. The above extraction and isolation are carried out, for example, as follows. First, the aerial part of Yaeyamashikimi is extracted with a solvent such as methanol and ethanol, and the extract is concentrated under reduced pressure to obtain a primary extract. Then, the physicochemical properties of the target compound are extracted from the extract. Collect the target product by various methods used. Collection of the target substance is a conventional method, for example, a method utilizing a difference in distribution ratio between two liquid phases,
It can be carried out by a method utilizing a difference in adsorption affinity for an adsorbent such as silica gel, activated carbon, an ion exchange resin, Sephadex, or a combination of these methods. As a preferable collection method, the primary extract is distributed between two liquid phases such as water and ethyl acetate, the organic layer is concentrated under reduced pressure, and the concentrated liquid is subjected to silica gel chromatography, for example, methylene chloride, ethyl acetate, methanol. After elution with a suitable solvent such as the mixed solvent of, the eluate was concentrated under reduced pressure, and the concentrated solution was repeatedly purified by silica gel chromatography, followed by reverse phase HPLC.
The method of purification can be exemplified.

The obtained compound is a derivative in which R ¹ is a propyl group by a well-known reduction reaction, a derivative in which R ³ is a hydrogen atom by a well-known demethylation reaction, or an alkyl derivative by a well-known alkylation reaction. Further, they can be respectively converted into acyl derivatives by a well-known acylation reaction. When the compound of the present invention is used as a therapeutic agent,
Alternatively, it is administered in combination with a pharmaceutically acceptable carrier. Its composition is determined by the solubility of the compound, chemical characteristics, administration route, administration schedule and the like. For example, granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups,
It may be orally administered in the form of emulsion, suspension, liquid or the like, or may be intravenously, intramuscularly or subcutaneously administered as an injection.

It is also possible to prepare powder for injection and adjust it before use. A pharmaceutical organic or inorganic solid or liquid carrier or diluent suitable for oral, enteral, parenteral or topical administration can be used with the compounds of the present invention. Examples of the excipient used when producing the solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, that is, emulsions, syrups, suspensions, solutions and the like, contain a commonly used inert diluent such as water or vegetable oil. In addition to an inert diluent, this formulation may include auxiliary agents such as wetting agents, suspension auxiliary agents,
Sweetening agents, aromatic agents, coloring agents, preservatives and the like may be included. Liquid formulations may be included in capsules of absorbable material such as gelatin. Examples of the preparation for parenteral administration, that is, the solvent or suspending agent used for producing an injection or the like include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. The preparation method may be a conventional method.

When used by oral administration, the clinical dose is generally 1 for the compound of the present invention for adults.
The daily dose is 1 to 1000 mg, preferably 1 to 100 m
Although it is g, it is more preferable to appropriately increase or decrease depending on the age, medical condition, symptom, and presence or absence of simultaneous administration. The above-mentioned daily dose of the compound of the present invention may be administered once a day or at a suitable interval of 2 times a day.
Alternatively, it may be administered in three divided doses or intermittently. When used as an injection, the daily dose of the compound of the present invention for an adult is 0.1 to 100 mg, preferably 0.1 to 50 mg.

[0018]

EFFECTS OF THE INVENTION Since the compound of the present invention activates ChAT activity in cholinergic neurons, senile dementia including Alzheimer's disease; cerebrovascular dementia associated with stroke (cerebral hemorrhage, cerebral infarction), cerebral arteriosclerosis, etc .; head It is considered to be useful for treating memory disorders associated with partial trauma, encephalitis sequelae, cerebral palsy, etc., and also for treating peripheral neuropathy such as diabetic neuropathy and alcoholic neuropathy.

[0019]

EXAMPLES The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto unless it exceeds the gist thereof.

Example Compounds 2 (16R form) and (2
Isolation of (16S body) Yaeyamashikimi (Illic) collected at Omotodake, Ishigaki Island
2k above ground level of ium tashiroi Maxim)
After drying and pulverizing g, it was extracted in methanol (40 liters) at room temperature for 18 days. After filtering the methanol extract, the methanol was distilled off under reduced pressure to obtain a primary extract (276 g). Water was added to this primary extract to suspend it, and the mixture was extracted 5 times with ethyl acetate. Then, the ethyl acetate extract was concentrated to dryness under reduced pressure to obtain a secondary extract (117 g).

The secondary extract (117 g) was subjected to silica gel chromatography (Kiselgel 60, 70-230 manufactured by Merck & Co., Inc.).
mesh, 1 kg), methylene chloride (4 liters), methylene chloride-ethyl acetate (4: 1, v / v, 4
Liter), ethyl acetate-methanol (9: 1, v /
v, 4 liters), and fractions 1 to 1
Fractionated into 4. Fraction 3 (15 g) was subjected to silica gel chromatography (Kiselgel 60, 70 manufactured by Merck & Co., Inc.).
-230 mesh, 400 g), methylene chloride (500 ml), methylene chloride-ethyl acetate (4: 1,
(v / v, 500 ml), methylene chloride-ethyl acetate (1: 1, v / v, 500 ml), ethyl acetate-methanol (9: 1, v / v, 1 liter), and elute sequentially,
Fractions 15-20 were fractionated. Fraction 18
(8.8 g) was again subjected to silica gel chromatography (Wakogel C-300, 500 g, manufactured by Wako Pure Chemical Industries, Ltd.), and methylene chloride-ethyl acetate (9: 1, v / v, 500 ml).
Elution was carried out and fractionation was carried out into fractions 21 to 30. Fraction 24 (130 mg) was subjected to high performance liquid chromatography [column: Cosmosil 5C18AR (φ10 × 250.
mm]; solvent: methanol: water = 7: 3, 2.0 ml /
min; detection: UV254 nm] retention time 67 minutes and 7
3 minutes was collected to obtain Compound 2 (16R isomer) (6 mg) and 2 (16S isomer) 6 mg) as colorless oils.

Physical Data of Compound 2 (16R Form) Colorless oily substance, [α] _D ²⁰ -177.5 (c0.1, CH)
Cl ₃ ). ν _max ^FT cm ⁻¹ : 3463, 3077, 16
51,1493. λ _max ^EtOH nm (ε): 243 (92
00), 301 (3960). High resolution EI-MS: 4
54.1964 [M] ⁺ , calcd. 454.199
_{2 for C 26 H 30 O 7} . EI-MS m / z (re
l. int. ): 454 [M] ⁺ (100), 191
(88), 180 (40). ¹ H NMR (400 MH
z, CDCl ₃ ) δ: 1.11 (3H, s, H-1
4), 1.36 (3H, s, H-13), 2.18 (1
H, ddJ = 12.2, 11.2 Hz, H-10β),
2.34 (1H, dd, J = 11.2, 5.9Hz, H
-10α), 2.43 (1H, dd, J = 12.2,
5.9 Hz, H-11), 2.53 (1H, dd, J =
15.9, 6.3 (Hz, H-7), 3.01 (1H,
d, J = 4.4 Hz, H-3), 3.09 (1H, dd
J = 15.9, 9.0 Hz, H-7), 3.25 (2
H, dd, J = 7.8, 1.2 Hz, H-7 '), 3.
74 (3H, s, OCH ₃ ), 5.00 (1H, dd,
J = 18.2, 2.0 Hz, H-9 ′), 5.02 (1
H, dd, J = 13.7, 2.0 Hz, H-9 '),
5.19 (1H, dd, J = 18.2, 1.5Hz, H
-9), 5.23 (1H, dd, J = 11.5, 1.5
Hz, H-9), 5.56 (1H, s, H-15α),
5.60 (1H, s, H-6), 5.70 (1H, s,
H-15β), 5.89 (2H, m, H-8, 8 '),
5.99 (1H, d, J = 4.4Hz, H-16),
6.45 (1H, s, H-6 '), 6.59 (1H,
s, H-3 '). ¹³ C NMR (100 MHz, CDC
l ₃ ) δ: 29.1 (C-13), 30.5 (C-1)
4), 33.9 (C-7 '), 34.2 (C-7), 3
4.8 (C-10), 46.7 (C-11), 55.9.
(C-3), 56.5 ( OCH 3), 58.5 (C-
2), 72.1 (C-12), 86.1 (C-4), 9
4.6 (C-6 '), 99.4 (C-6), 100.0
(C-15), 108.9 (C-16), 109.8.
(C-3 '), 115.3 (C-9'), 120.5
(C-9), 121.0 (C-4 '), 133.2 (C
-8), 137.1 (C-8 '), 140.6 (C-
2 '), 145.5 (C-1'), 152.2 (C-
5 '), 173.8 (C-5), 199.9 (C-
1).

Physical Data of Compound 2 (16S Form) Colorless oily substance, [α] _D ²⁰ -187.0 (c0.57, C)
HCl _3). ν _max ^FT cm ⁻¹ : 3441, 3076, ¹
645, 1493. λ _max ^EtOH nm (ε): 235 (6
900), 298 (3170). High resolution EI-MS:
454.2013 [M] ⁺ , calcd. 454.19
_{92 for C 26 H 30 O 7} . EI-MS m / z (r
el. int. ): 454 [M] ⁺ (100), 191
(90), 180 (29). ¹ H NMR (400 MH
z, CDCl ₃ ) δ: 1.11 (3H, s, H-1
4), 1.36 (3H, s, H-13), 2.18 (1
H, dd, J = 12.2, 11.2 Hz, H-10
β), 2.35 (1H, dd, J = 11.2, 5.6H
z, H-10α), 2.43 (1H, dd, J = 12.
2,5.6 Hz, H-11), 2.51 (1H, dd,
J = 15.4, 5.9 Hz, H-7), 3.02 (1
H, d, J = 4.4 Hz, H-3), 3.10 (1H,
dd, J = 15.4, 9.0 Hz, H-7), 3.26
(2H, dd, J = 6.6, 1.5Hz, H-7 '),
_{3.73 (3H, s, OCH 3} ), 5.00 (1H, d
d, J = 15.9, 1.5 Hz, H-9 ′), 5.01
(1H, dd, J = 12.7, 1.5Hz, H-
9 '), 5.19 (1H, dd, J = 19.8, 1.5
Hz, H-9), 5.23 (1H, dd, J = 11.
2,1.5 Hz, H-9), 5.56 (1H, s, H-
15α), 5.60 (1H, s, H-6), 5.70.
(1H, s, H-15β), 5.89 (2H, m, H-
8,8 '), 5.98 (1H, d, J = 4.4Hz, H
-16), 6.46 (1H, s, H-6 '), 6.59
(1H, s, H-3 '). ¹³ C NMR (100 MH
z, CDCl ₃ ) δ: 29.1 (C-13), 30.5
(C-14), 33.9 (C-7 '), 34.2 (C-
7), 34.8 (C-10), 46.7 (C-11),
55.9 (C-3), 56.5 (OCH 3), 58.5
(C-2), 72.1 (C-12), 86.1 (C-
4), 94.8 (C-6 '), 99.4 (C-6), 1
00.0 (C-15), 108.9 (C-16), 10
9.5 (C-3 '), 115.3 (C-9'), 12
0.5 (C-9), 121.0 (C-4 '), 133.
2 (C-8), 137.2 (C-8 '), 140.2
(C-2 '), 145.9 (C-1'), 152.2
(C-5 '), 173.6 (C-5), 200.0 (C
-1).

[0024]

[Chemical 6]

Test Example Effect on acetylcholine synthase (choline acetyltransferase; ChAT) activity of cultured septal corneal neurons derived from postnatal rat The primary culture method of septal neuron from postnatal rat is the method of Hatanaka et al. H. Ha
tanaka et al. Dev. Brain Res. 39 , 8
5-95, 1988). That is, 1
The septal area was removed from the brain of a 4-day-old rat, cut into small pieces, and enzymatically (D
The cells were dispersed by papain treatment in the presence of Nase I) and mechanically (pipetting). The isolated cells thus obtained were seeded on a 48-well plate in which astroglial cells had been grown on a sheet at about 5 × 10 ⁵ cells / cm ² , and 5% quasi-fetal bovine serum and 5% non-mobilized bovine serum. Was cultured in a DF medium (containing an equal amount of Dulbecco's modified Eagle medium and Ham's F12 medium). Astroglial cells were prepared from the cerebral cortex of rat embryo E20, propagated for several generations, and then used. The day after the start of culturing, the test compound was replaced with the same medium containing a predetermined concentration, and after culturing for 1 week, the cells were added with 5 mM containing 0.1% Triton X-100.
It was disrupted by sonication in Tris-HCl buffer.
This was used as a crude enzyme preparation, [ ¹⁴ C] acetylcoenzyme A (0.3 KBq) was added, and the mixture was incubated at 37 ° C. for 1 hour. After the reaction was stopped, the produced [ ¹⁴ C] acetylcholine was extracted into a toluene scintillator and measured with a liquid scintillation counter. Control group ChA
The T activity value is usually about 1.5 pmol / min / culture hole, and the ChAT activity of the test compound is shown as a ratio (%) when the activity value of the control group is 0. The test results are shown in Table 2 below.

[0026]

[Table 2]

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[Procedure amendment]

[Submission date] August 23, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0026

[Correction method] Change

[Correction content]

[0026]

[Table 2]

Claims (1)

[Claims] 1. The following general formula (I):(In the above general formula, R¹Is -CH₂CH = CH₂Or
-CH₂CH₂CH₃Represents R²Is a hydrogen atom or C
₂~ C_FourRepresents an acyl group of R³Is a hydrogen atom, C ₁~ C
_FourAlkyl group or C₂~ C_FourRepresents the acyl group of
Prenyl C represented₆-C₃Compound derivative.