JP2002114763A - Indole long-chain alcohol and medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an indole long-chain alcohol (I) having excellent nerve growth-stimulating activity, antioxidative effect and antitumor effect, and useful as a preventing and curing agent for brain diseases such as dementia and malignant tumors such as brain tumor. SOLUTION: The indole long-chain alcohol expressed by the following general formula (I) (wherein, R1, R2, R3 and R4 are each H, methyl, acetyl or hydroxyl; and n is 0-20), and a medicine containing the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention has excellent nerve growth promoting action, strong antioxidant action and antitumor action, and is an agent for preventing and treating malignant tumors such as brain diseases or brain tumors represented by dementia. Long-chain alcohol useful as a pharmaceutical and a medicine containing the same.

[0002]

2. Description of the Related Art Alzheimer's dementia is mainly caused by degeneration and loss of cholinergic neurons. Currently, the treatment uses cholinesterase inhibitors or muscarinic receptor agonists. However, these drugs symptomatically improve the degree of dementia, but do not stop or slow the progression of the condition. Attempts have also been made to administer nerve growth factor (NGF) into the brain and use it to treat Alzheimer's dementia. NGF is expected to suppress the degeneration of neurons and stop or delay the progress of dementia from the nerve growth effect.However, since the molecular weight of the protein is 12,000, it cannot pass through the blood-brain barrier. Limited. Therefore, it is not practical as a treatment for humans. Therefore, a low-molecular-weight compound that can pass through the blood-brain barrier exhibiting an NGF-like effect and a compound that enhances NGF synthesis in the brain can be expected as an effective therapeutic drug for Alzheimer's dementia. Based on this idea, NG
Attempts have been made to find substances that promote and enhance the production of F. Until now, long-chain aliphatic alcohols such as n-hexacosanol have been
It has been demonstrated that it has nerve growth factor promotion in vitro and that it can cross the blood-brain barrier in vivo (Japanese Patent Application Laid-Open
4-502167).

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a compound which can be orally administered and easily migrates into the brain, and which can extend neurites or activate NGF synthesis and secretion in the brain. Is to provide.

[0004]

The present inventors have synthesized a long-chain alcohol derivative having an indole skeleton and examined the pharmacological action of the derivative. As a result, the indole long-chain alcohol represented by the following general formula (I) was obtained. It has excellent nerve growth promoting action, strong antioxidant action and antitumor action, and is found to be useful as a preventive / therapeutic agent for brain diseases such as dementia or malignant tumors such as brain tumors, and completes the present invention. Reached.

That is, the present invention provides the following general formula (I)

[0006]

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Wherein R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom, a methyl group, an acetyl group or a hydroxyl group;
Represents an integer of 0 to 20). The present invention also provides a medicine containing a compound represented by the general formula (I) as an active ingredient. Further, the present invention provides a nerve growth promoting agent containing a compound represented by the general formula (I) as an active ingredient. The present invention still further provides a preventive / therapeutic agent for dementia and / or malignant tumor comprising a compound represented by the general formula (I) as an active ingredient.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (I), R ¹ , R ² , R ³
And R ⁴ include the groups described above, and particularly preferably a hydrogen atom. n is a number from 0 to 20;
Is preferred, 6 to 16 is more preferred, and 8 to 14 is particularly preferred.

The compound (I) of the present invention may exist in the form of a hydrate. The compound may have various isomers, and these isomers are also included in the present invention.

The compound (I) of the present invention can be produced, for example, according to the following reaction formula.

[0011]

Embedded image

(Wherein, Ar represents an aromatic hydrocarbon group;
¹ and X ² represent a halogen atom, R ⁵ represents a protecting group for a hydroxyl group, and R ¹ , R ² , R ³ , R ⁴ and n are the same as described above.

That is, the compound (B) is obtained by reacting the indole-3-carboxaldehyde (A) with the arylsulfonyl halide, and the compound (C) is reacted with the compound (B) to obtain the compound (D). When hydrogen is added thereto, the protecting group for the hydroxyl group is eliminated to obtain the compound (E), and the protecting group for the amino group is eliminated to obtain the compound (I) of the present invention.

The arylsulfonyl halide includes p
-Methoxybenzenesulfonyl chloride and the like. The reaction between the indole-3-carboxaldehyde (A) and the arylsulfonyl halide is preferably performed at room temperature in the presence of an alkali such as sodium hydroxide.

The hydroxyl-protecting group (R ⁵ ) in the compound (C) used in the Wittig reaction is preferably a group capable of leaving by a hydrogenation reaction, for example, a benzyl group. The Wittig reaction is preferably performed by reacting compound (C) with n-butyllithium, then reacting potassium t-butoxide, and then reacting compound (B).

The hydrogenation reaction of compound (D) is preferably carried out, for example, by reacting hydrogen in the presence of a palladium catalyst. Next, in the elimination reaction of the arylsulfonyl group, it is preferable to use, for example, amalgam hydroxide and sodium hydrogen phosphate.

The compound (I) of the present invention thus obtained is
It has excellent nerve growth promoting action, strong antioxidant action and antitumor action, and because it is a small molecule, it crosses the blood-brain barrier, so it is a brain disease represented by dementia in animals including humans or It is useful as a prophylactic / therapeutic agent for malignant tumors such as brain tumors.

The medicament of the present invention may be administered orally or parenterally.
(Intramuscular, subcutaneous, intravenous, suppository, etc.). In the case of preparing an oral preparation, excipients, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added, and then tablets, coated tablets, granules, Capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. As an excipient, for example, lactose, corn starch, sucrose, glucose, sorbitol,
Crystalline cellulose and the like, as a binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl starch, polyvinylpyrrolidone and the like. Disintegrants include, for example, starch, agar,
Gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica,
Hardened vegetable oils and the like are permitted to be added to pharmaceuticals as coloring agents, and cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used as flavoring agents. In these tablets, the granules may be sugar-coated, gelatin-coated or any other appropriate coating as needed.

The dose of the medicament of the present invention varies depending on the target disease, administration route, symptoms, body weight and the like.
The compound (I) of the present invention is usually 0.001 per day per adult.
The dose is in the range of 1 to 1000 mg, preferably 0.1 to 100 mg, and a single dose is administered once a day or divided into 2 to 4 times.

[0020]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 3-indolecarboxaldehyde (1.003 g,
(6.91 mmol) was dissolved in 20 mL of dry dichloromethane, and sodium hydroxide (410 mg, 10.24 mmol) was added. After standing at room temperature for 15 minutes, 4-methoxybenzenesulfonyl chloride (2.112 g, 10.22
mmol) and left at room temperature again for 12 hours. Then 100 mL of ammonium chloride was added, and 3
Extracted times. The organic solvent phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallize the residue,
1- (4-Methoxybenzenesulfonyl) -3-indolecarboxaldehyde was obtained as pearl pink crystals.

Melting point: 138-139 ° C. ¹ H-NMR (200 MHz),: 3.81 (s, 3H, H-9); 6.94 (d, J
= 9.1 Hz, 2H, H-3 ", 5"); 7.32-7.45 (m, 2H, H-5,6);
7.91 (d, J = 9.1 Hz, 2H, H-2 ", 6"); 7.87-7.96 (m, 1
H, H-4); 8.23 (s, 1H, H-2), 8.25 (dd, J = 6.9 Hz,
J = 2.7 Hz, 1H, H-7); 10.09 (s br, 1H, H-8) ¹³ C-NMR (50 MHz),: 55.81 (C-9); 113.25 (C-7); 114.
94 (C-3 ", 5"); 122.26 (C-3); 122.60 (C-4,6); 125.01
(C-5); 126.27 (C-2 ", 6"); 128.63 (C-3 '); 129.61 (C
-7 '); 135.23 (C-1 "); 136.24 (C-2); 164.54 (C-4");
185.34 (C-8)

Reference Example 2 15-dissolved in 10 mL of tetrahydrofuran (THF)
A solution of benzyloxypentadecyltriphenylphosphonium bromide (755 mg, 1.14 mmol) was added dropwise to n-butyllithium (0.8 mL, 1.20 mmol as a 1.5 M solution in hexane) at -78 ° C under an argon gas atmosphere. . After reacting at room temperature for 15 minutes, the mixture was cooled to 0 ° C and potassium t-butoxide (131 mg, 1.16 mmol) was added. The solution was left at room temperature for 15 minutes, again at -78 ° C.
1- (4-methoxybenzenesulfonyl) -3-
Indole carboxaldehyde (307 mg, 0.97
mmol) in THF was added slowly. The mixture was allowed to stand at -78 ° C for 1 hour and then at 0 ° C for 1.5 hours. Add 50 mL of ammonium chloride and add ethyl ether 6
Extraction was performed three times with 0 mL. Wash the organic solvent phase with saline,
Dried and concentrated over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to give 3- (16-benzyloxyhexadecenyl) -1- (4-methoxybenzenesulfonyl) indole as a white solid.

¹ H-NMR (200 MHz), δ: 1.26 (s br, 20H,
H-12 to H-21); 1.46-1.65 (m, 4H, H-11, 22); 2.32
(m, 2H, H-10); 3.47 (t, J = 6.6 Hz, 2H, H-23); 3.7
7 (s, 3H, H-25); 4.51 (s, 2H, H-24); 5.82 (dt, J =
11.1 Hz, J = 6.9 Hz, 1H, H-9); 6.40 (d, J = 11.1 H
z, 1H, H-8); 6.86 (d, J = 8.7 Hz, 2H, H-3 ", 5"); 7.
21-7.36 (m, 7H, H-2 '"to H-6'", H-5,6); 7.51 (s, 1
H, H-2); 7.53 (d, J = 6.9 Hz, 1H, H-4); 7.82 (d, J
= 8.7 Hz, 2H, H-2 ", 6"); 7.99 (d, J = 7.6 Hz, 1H, H
-7) ¹³ C-NMR (50 MHz), δ: 26.35 (C-10); 29.83 (C-11 to
C-22); 55.75 (C-25); 70.70 (C-23); 72.99 (C-24); 1
13.74 (C-7); 114.56 (C-9); 117.58 (C-3 ", s5"); 11
9.41 (C-3); 119.71 (C-5); 123.31 (C-4); 123.58 (C-
6); 124.92 (C-2 ", 6"); 127.61 (C4 '"); 127.74 (C-
3 '", 5'"); 128.49 (C-2 '", 6'"); 129.18 (C-8); 129.90
(C-3 '); 131.25 (C-7'); 134.79 (C-1 "); 135.02 (C-
2); 138.92 (C-1 '"); 163.92 (C-4")

In the same manner as in Reference Examples 1 and 2, 3- (10
-Benzyloxydecenyl) -1- (4-methoxybenzenesulfonyl) indole (70% yield), 3- (1
2-benzyloxidedecenyl) -1- (4-methoxybenzenesulfonyl) indole (87% yield) and 3
-(14-benzyloxytetradecenyl) -1- (4
-Methoxybenzenesulfonyl) indole (yield 88
%).

Reference Example 3 3- (16-benzyloxyhexadecenyl) -1-
(4-methoxybenzenesulfonyl) indole (53
0 mg, 0.86 mmol) in 25 mL of ethanol,
(5%) (50%) added to palladium on activated carbon
mg). The mixture was left under a hydrogen pressure of 1 atm and room temperature for 3 hours. After filtering the mixture, the mixture was extracted with ethyl ether, and the organic solvent phase was concentrated under reduced pressure. Residue is flash
Purification by chromatography gave 3- (16-hydroxyhexadecyl) -1- (4-methoxybenzenesulfonyl) indole as a white solid (417 mg, 92%).
As obtained.

¹ H-NMR (200 MHz), δ: 1.26 (s br, 24H,
H-10 to H-21); 1.62 (m, 4H, H-9,22); 2.63 (t, J =
7.4 Hz, 2H, H-8); 3.64 (t, J = 6.4 Hz, 2H, H-23);
3.77 (s, 3H, H-24); 6.85 (d, J = 8.8 Hz, 2H, H-3 ",
5 "); 7.25 (m, 2H, H-5,6); 7.29 (s, 1H, H-2); 7.47
(d, J = 6.6 Hz, 1H, H-4); 7.79 (d, J = 8.8 Hz, 1H,
H-2 ", 6"); 7.97 (d, J = 7.6 Hz, 1H, H-7) ¹³ C-NMR (50 MHz), δ: 24.93 (C-21); 25.80 (C-9); 2
8.94 (C-20); 29.70 (C-10 to C-19); 32.87 (C-8); 5
5.63 (C-24); 63.14 (C-23); 113.81 (C-7); 114.36 (C
-9); 119.54 (C-3 ", 5"); 122.64 (C-4); 122.89 (C-6);
123.66 (C-3); 124.50 (C-5); 128.99 (C-2 ", 6"); 12
9.99 (C-3 '); 131.31 (C-7'); 134.85 (C-1 "); 135.44
(C-2); 163.60 (C-4 ")

In the same manner as in Reference Example 3, 3- (10-hydroxydecyl) -1- (4-methoxybenzenesulfonyl) indole (92% yield), 3- (12-hydroxydodecyl) -1- (4 -Methoxybenzenesulfonyl) indole (92% yield) and 3- (14-hydroxytetradecyl) -1- (4-methoxybenzenesulfonyl) indole (93% yield) were obtained.

Example 1 3- (16-hydroxyhexadecyl) -1- (4-methoxybenzenesulfonyl) indole (400 mg,
0.72 mmol) was dissolved in 20 mL of dry methanol, and disodium hydrogen phosphate (205 mg, 1.44 mmol) and amalgam chloride (6%, 4 g) were added at 0 ° C. under argon gas. The mixture was left at room temperature for 12 hours, added with 50 mL of ammonium chloride, and extracted three times with 60 mL of ethyl acetate with disodium hydrogen phosphate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to give 3- (16-hydroxyhexadecyl) indole (Compound 1) as a white solid (204 mg, 75%).

Melting point: 79-80 ° C. ¹ H-NMR (200 MHz), δ: 1.27 (sbr, 24H, H-10 to H-2)
1); 1.57 (m, 2H, H-22); 1.72 (m, 2H, H-9); 2.76
(t, J = 7.6 Hz, 2H, H-8); 3.64 (t, J = 6.4 Hz, 2H,
H-23); 6.97 (s, 1H, H-2); 7.15 (m, 2H, H-5,6); 7.3
5 (d, J = 7.6 Hz, 1H, H-4); 7.62 (d, J = 7.6 Hz, 1
H, H-7); 7.93 (s br, 1H, H-1) ¹³ C-NMR (50 MHz), δ: 25.30 (C-21); 25.89 (C-9); 2
9.83 (C-10 to C-20); 30.32 (C-8); 32.97 (C-22); 6
3.26 (C-23); 111.15 (C-7); 117.38 (C-3); 119.15 (C
-4,6); 121.12 (C-5); 121.94 (C-2); 127.79 (C-3 ');
136.52 (C-7 ') IR (KBr): 3416 (s br, OH, NH); 3049 (w, = CH); 2
916, 2849 (s, CH); 1638, 1618 (m, C = C); 1474, 145
7 (m, CH); 1061 (w, CO); 741 (m, CH) UV (acetonitrile): λmax: 203 nm (ε 18864); 222
nm (ε 27571); 281 nm (ε 5880) MS (EI): 357.3 (M +, 37); 144.2 (C10H10N, 4); 130.3
(C9H8N, 100)

The following compounds were obtained in the same manner as in Example 1.・ 3- (2-hydroxyethyl) indole (liquid)
(Compound 2) 3- (10-hydroxydecyl) indole (melting point 5
3- (11-hydroxyundecyl) indole (melting point 60-61 ° C) (compound 4) 3- (12-hydroxydodecyl) indole (melting point 66-67 ° C) (compound 5) · 3- (14-hydroxytetradecyl) indole (melting point 72-73 ° C) (compound 6)

Test Example 1 (Effect on Neurite Outgrowth and Remaining Neurons) This test was carried out according to the method of Ryu et al.
yclohexenonic Long Chain Fatty Alcohols on Neurite
Outgrowth. Study on Structure-Activity Relationsh
ip. C. Girlanda-Junges, F. Keyling-Bilger, G. Schm
itt & B. Luu Tetrahedron, 1998, 54, 7735-7748). Compound 1 was added to primary cultured fetal rat neurons at 10-6 and 10
-7 M was applied and cultured for 3 days. As shown in FIG.
The ratio of the above neurons was higher in the group to which Compound 1 was administered than in the group to which no compound was administered. Therefore, it was revealed that Compound 1 has a strong neurite outgrowth action.

Test Example 2 (Prevention of Hemolysis by Free Radicals in Human Blood) This test was performed according to the method of D. Blache. FASEB J.
(Glucose and free radicals impair the antioxidant
properties of serum albumin, E. Bourdon, NLoreau &
D. Blache. FASEB J. 1999, 13, 233-244). The time required for 50% hemolysis (HT50) was measured and the extent of prolongation was graphed compared to that of the non-administration group. Also, vitamin E
Was used as a positive control. As a result, as shown in FIG. 2, the compounds of the present invention (Compound 1, Compound 2 and Compound 4) prolonged HT50 and exhibited a preventive action against hemolysis. In particular, compound 4 showed a strong hemolytic prevention effect.

Test Example 3 (Induction of differentiation and apoptosis of neuroblastoma cells) Human neuroblastoma cells Lan-1 (Lan-1: muscarinic M1 and M2 receptors coupled to intracellular Ca ²⁺ are present. Neuroblastoma cells) were used to examine the proliferation, differentiation, and induction of apoptosis of the compound of the present invention. As shown in Table 1, the compounds of the present invention (Compound 1, Compound 3, and Compound 4) showed a stronger differentiation-inducing or apoptosis-inducing effect than proliferation of neuroblastoma cells.

[0035]

[Table 1]

[0036]

The compound (I) of the present invention has an excellent nerve growth promoting action, antioxidant action and antitumor action and is useful as a preventive / therapeutic agent for brain diseases such as dementia and malignant tumors such as brain tumors. It is.

[Brief description of the drawings]

FIG. 1 is a graph showing the effect of the compound of the present invention on neurite outgrowth.

FIG. 2 is a graph showing the preventive effect of the compound of the present invention on hemolysis caused by free radicals in human blood.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shoji Yamada 1-26-11, Midori, Sumida-ku, Tokyo Meiji Dairy Products Pharmaceutical Division (72) Inventor Yukie Suma 1-26-11, Midori, Sumida-ku, Tokyo Meiji Dairies Corporation Pharmaceutical Division (72) Inventor Hirohito Suzuki 1-26-11 Midori, Sumida-ku, Tokyo Meiji Dairies Corporation Pharmaceutical Division F-term (reference) 4C086 AA01 AA02 AA03 BC13 MA01 MA04 NA14 ZA16 ZB26 ZC37 4C204 BB01 CB03 DB15 EB02 FB01 GB01 GB03 GB15 GB26

Claims (4)

[Claims] 1. The following general formula (I): (Wherein, R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom, a methyl group, an acetyl group or a hydroxyl group, and n represents a number of 0 to 20). 2. A medicament comprising the compound according to claim 1 as an active ingredient. 3. A nerve growth promoting agent comprising the compound according to claim 1 as an active ingredient. 4. A preventive / therapeutic agent for dementia and / or malignant tumor comprising the compound according to claim 1 as an active ingredient.