WO2005030721A1

WO2005030721A1 - Piperidine derivative

Info

Publication number: WO2005030721A1
Application number: PCT/JP2004/014563
Authority: WO
Inventors: Tomio Yamakawa; Shinichi Yoshida; Kaoru Hara; Heinojo Yamasaka; Kazushiro Yamaguchi
Original assignee: Nippon Chemiphar Co., Ltd.
Priority date: 2003-09-30
Filing date: 2004-09-28
Publication date: 2005-04-07

Abstract

Disclosed is a piperidine derivative represented by the general formula (I) below or a salt thereof. Also disclosed is an antioxidant containing such a compound or a salt thereof as an active constituent. (I) (In the formula, R1 represents an alkyl group having 1-8 carbon atoms or the like; R2 represents a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkylcarbonyl group having 2-8 carbon atoms or the like; and R3 and R4 may be the same or different and represent alkyl groups having 1-8 carbon atoms or the like.)

Description

Piperidine derivatives Technical field

The present invention relates to piperidine derivatives having an antioxidant effect. Background art

It is well known that compounds having a funolic hydroxyl group have an antioxidant effect. For example, synthetic antioxidants represented by natural phenols such as tocopherols, flavonoids, and gallic acids, and heptylhydroxytoluene (BHT).

And many other compounds have been reported.

Amines also have an antioxidant effect, and various amino acids, p-phenylenediamine and the like are known to have an antioxidant effect.

It is also known that both phenols and amines act as a radioactive inhibitor | J (frEraladicalsengaven) which suppresses the chain reaction of autoxidation.

Therefore, these compounds having an antioxidant effect are used not only as additives for a drug substance containing a drug substance that is easily oxidized, but also for diseases related to oxidative stress, for example, dementia, inflammation, ischemic disease, carcinogenesis. It is considered as a potential therapeutic or prophylactic drug.

However, almost no antioxidants having such phenols and amines in the same molecule are known. This is probably due to the difficulty of synthesis and possibly the phenolic hydroxyl group being relatively unstable under basic conditions. As a compound having a structure similar to the piperidine derivative of the present invention, probucol known as a therapeutic agent for hyperlipidemia (US Pat. No. 3,576,883, hereinafter referred to as Patent Document 1). And N-methyl-4-piperidonebis (3,5-dibutyltin-4-hydroxypheninole) mercaptol (WO 91/01 1124, hereinafter referred to as Patent Document 2). No. Patent Document 2 is antioxidant Based on the finding that BHT or BHA having antimicrobial activity has an antiviral effect, bis (dialkylphenol) mercaptonore (or mercaptal) is provided as an antiviral agent. 5-g-t-ptyl-4-hydroxyphene-mercaptol has an antiviral effect but has strong cytotoxicity and is mentioned as an unfavorable example. Note that Patent Document 2 does not disclose specific data indicating that this compound has an antioxidant effect. The present inventors aimed at providing a piperidine derivative having phenols and amines in the same molecule and having an antioxidant effect, and intended to provide an acetyl-41- (3,5-di-one) A patent application has been filed with respect to 4-buty-noray 4-hydroxydreno-1,4-hydroxy-1, trans-1,6-dimethylbiperidine (WO 03/997788, hereinafter referred to as Patent Document 3). The compound described in Patent Literature 3 has 3,5-di-t-peti / le4-hydroxyhydrinolethio and a hydroxyl group at the 4-position of piperidine, but the compound of the present invention has a 3,5-diene It has two t-butyryl 4-hydroxy phenols. Disclosure of the invention

An object of the present invention is to provide a piperidine derivative having phenols and amines in the same molecule and having an antioxidant action.

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

(In the formula, is an aralkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an aralkyl group (the carbon number of the aryl group is 6 to 1 0 represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms;

R ₂ is a hydrogen atom, an aralkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an aralkyl group (the aryl group has 6 to 10 carbon atoms; The alkyl moiety has 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, or an alkyl group having 2 to 8 carbon atoms.

And R ₃及Pi 1 ₄ are the same or different and may be alkyl groups having 1 to 8 carbon atoms, a 3 to 8-membered cycloalkyl group, 1 of 3 halogen atoms carbon atoms is substituted with 1-8 Alkyl group, alkyl group having 1 to 8 carbon atoms, aralkyl group substituted with alkoxy group having 1 to 8 carbon atoms (aryl moiety has 6 to 10 carbon atoms, and alkyl moiety has 1 to 4 carbon atoms) Or an aryl group having 6 to 10 carbon atoms. )

And a salt thereof.

The present invention also relates to an antioxidant containing the piperidine derivative represented by the above general formula (I) or a salt thereof as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described in detail.

In Piperi derivative represented by the above general formula (I), the alkyl group having a carbon number 1-8 of to R _4, Mechinore group, Echiru group, propyl group, i - propyl group, heptyl group, i one heptyl Group, t-butyl group, pentyl group or hexyl group.

Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R _{1 to} R ₄ include methyl substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom. Group, ethyl group, propyl group, i-propyl group, butyl group or t-butyl group, preferably trifluoromethyl group, 2-chloroethyl group, 2-bromoethyl group or 2-phenyl / rhoethyl group. And the like.

Ararukiru group to R ₄ (the number of carbon atoms of Arinore portion is 6-1 0, the number of carbon atoms in the alkyl moiety content is 1-4) as the benzyl group or the like is phenethyl group. Examples of the aryl group having 6 to 10 carbon atoms of R ₄ to R ₄ include a phenyl group and a naphthyl group. +

Examples of the anorecoxy group / reponyl group having 2 to 8 carbon atoms for R ₂ include a methoxy group / repoxy group or an ethoxycarbyl group.

Examples of the alkylcarbon group having 2 to 8 carbon atoms for R ₂ include an acetyl group and a propionyl group.

Examples of the 3- to 8-membered cyclic alkyl group of R 3 and R ₄ include a cyclic pentyl group and a cyclic hexyl group.

Examples of the C 1-8 alkyl group substituted with a C 1-8 alkyl group of R ₃ and R ₄ include a methoxy group, an ethoxy group, a propyloxy group, an i-propyloxy group and a butyloxy group. Group, i-butyloxy group, t-butyloxy group, methyl group, ethyl group, propyl group, i-propyl group substituted by pentyloxy group or hexyloxy group, i-propyl group, butyl group, i-butyl group, t-butyl group And a pentyl group or a hexyl group.

(1) The piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein is a C 1-8 alkyl group represented by the above general formula (I) Piperidine derivatives or salts thereof are preferred.

(2) The piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein is a C 1 to C 3 alkyl group represented by the above general formula (I) Piperidine derivatives or salts thereof are preferred.

(3) The piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R ₃ and R ₄ are an alkyl group having 1 to 8 carbon atoms. The piperidine derivative represented by I), the piperidine derivative according to the above (1) or (2), or a salt thereof is preferable.

(4) The piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R ₃ and R ₄ are both t-butyl groups.

)), Or the piberidine derivative described in (1) or (2) above, or a salt thereof. (5) Further, the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), and represented by the above general formula (I) wherein R ₂ is a hydrogen atom. The piperidine derivative, or the piperidine derivative according to any one of the above (1) to (4), or a salt thereof is preferred.

The salt of the piperidine derivative represented by the above general formula (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic acid such as hydrochloric acid or sulfuric acid, or a salt of citric acid or tartaric acid. And salts with organic acids. The 2- and 6-positions of the piperidine ring have a trans configuration. Next, a method for synthesizing the piperidine derivative represented by the above general formula (I) will be described. For example, trans-1,6-dimethyl-4,4-bis-[(3,5-di-t-butyl-4-hi) [Droxy) phenylsulfael] piperidine can be obtained by the following synthetic scheme.

 That is, 2,6-dimethyl-4-oxopiperidine-13,5-dicarboxylic acid ester was obtained from 1,3-diacetone carboxylate, acetoaldehyde and ammonia, and then hydrolyzed and decarboxylated to obtain 2,2-dimethyl-4-oxopiperidine. 6-Dimethyl 4-obtains xopiperidine. After protecting the nitrogen atom of the piperidine ring with Boc, etc. in step ヽ, this is combined with 2,6-zyt-butynol 4-mercaptophenol in an organic solvent such as porcine orifice, and boron trifluoride dimethyl ether. By reacting in the presence of an acid catalyst such as a complex, a mixture of a trans form and a cis form is obtained. Further, the trans-form can be separated from this mixture by gel chromatography.

The raw material trans 2,6-dimethyl-14-oxopiperidine can be obtained, for example, by the following synthesis route.

Other piperidine derivatives represented by the above general formula (I) can also be obtained by a similar synthesis method.

Tables 1 to 12 show examples of typical compounds of the present invention thus obtained.

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£ 9S 0 contract Zdf / e :) d [Table 2]

[Table 3]

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[Table 6]

[Table 7]

[Table 9]

vD O oifcIdAV

[Table 11]

[Table 1 2]

Next, the pharmacological effect (antioxidant effect) of the compound of the present invention will be described.

The antioxidant action of the compound of the present invention was confirmed by measuring the lipid peroxidation inhibitory action of rat liver microsomes. (References)

Aruoma 0. I. et al. (1990) An evaluation of the antioxidant and potential pro-oxidant properties of food additives and of trolox c, vitamin E and probucol. Free Rad. Res. Comms. 10, 143-157. As described in Example 2, the compound of the present invention suppressed lipid peroxidation of rat liver micromouth liposomes at a concentration of 100 μmo 1 ZL.

Therefore, since the compound of the present invention has an excellent antioxidant activity, it can be used as an additive for a preparation containing a drug substance that is easily oxidized. It is also expected to be a therapeutic or prophylactic agent for diseases related to oxidative stress, such as dementia, inflammation, ischemic disease, and carcinogenesis.

Furthermore, the compound of the present invention can also be used as an antioxidant added for the purpose of maintaining the quality of foods, an antioxidant for plastics for preventing deterioration of plastics due to oxygen in the air, and the like. When the compound of the present invention is used for diseases associated with oxidative stress, it can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.

For formulation, it can be produced in the form of tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by a usual method in the technical field of formulation.

These preparations use conventional excipients, disintegrants, binders, lubricants, pigments, diluents, and the like. Here, excipients include lactose, D-mannitol, crystalline cellulose, glucose, etc., disintegrants include starch, carboxymethylcellulose calcium (CMC-C a), and lubricants. , Magnesium stearate, talc, and the like, and binders include hydroxypropyl cellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP). The dose of the compound of the present invention is usually about 0.1 mg / day to 100 mg / day in an injection for adults. mg, orally administered lmg to 2000mg per day, but can be increased or decreased depending on age, symptoms, etc. Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Example 1

Synthesis example

(1) 2,6-Dimethyl-4-oxopiperidine (cis, 1, lance mixture)

1,3-Acetone dicarboxylic acid getyl estenolate (12.5 mL, 68.8 mmo1) and acetoaldehyde (4.3 mL, 82.2 mmol) were dried in ether (1 40 mL). ), Cooled to 115 ° C, and blown ammonia gas for 3.5 hours with stirring. Stirring was further continued for 1 hour, acetoaldehyde (4.3 mL, 82.2 mmo 1) was added, the temperature was raised to 0 ° C, and nitrogen gas was blown for 1 hour. After stirring at 0 ° for 23 hours, water (40 mL) was added, and the mixture was extracted with ether (20 mL, 1 OmL). The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol Z-mouth form = 1/50) to give 9.97 g of 2,6-dimethinole-1-4-oxopiperidine-13 , 5-Dicanolevonic acid gentinolester (crude) was obtained as a pale brown oil.

To this crude product (8.97 g) was added 2 mol / L aqueous sodium hydroxide solution (53.8 mL), and the mixture was stirred at room temperature for 15 hours, and then concentrated with hydrochloric acid (13.4 mL) under ice-cooling. Was added and the mixture was refluxed for 33 hours. After cooling to room temperature, 4 mol 1 ZL sodium hydroxide aqueous solution was added until the pH became 9, and sodium chloride was added until it became saturated. After extraction with dichloromethane (5 OmL × 4), drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methanol / chloroform = 1/20) to give 1.06 g (yield 14%, cis: trans = 2: 1 mixture) of the title compound. Was obtained as a light brown oil. (Cis)

¹ H NMR (CD C 1a, 40 OMH z): δ = 1.21 (6H, d, J =

Hz), 2.03 (1H, d, J = 13Hz), 2.07 (1H, d, J = 1

H z), 2.33 (1 H, d, 14 H z), 2.33 (1 H, d, 14 H z)

2.91-3.1 (2H, m)

(Trance)

^{_{1 H NMR (CD C 1 3}} , 40 OMH z): δ = 1. 1 7 (3 H, d, J = 6 H z), 2. 1 2 (0. 5 H, dd, J = 1 H z , 14 Hz), 2.14 (0.5 H, dd, J = 1 Hz, 14 Hz), 2.48 (0.5 H, dd, 1 Hz, 14 H) z), 2.49 (0.5 H, dd, l Hz, 14 Hz), 3.5—3.6 (1 H, m)

(2) 2,6-Dimethyl-4-oxopiperidine-11-potolevonic acid t-butyl ester (cis, trans mixture) 2,6-Dimethyl-4-oxopiperidine obtained by the above method (1. 20 g, 9.43 mmo1 [cis: trans = 2: 1 mixture]) in dioxane (15 mL), water (3 mL) and lmol / L aqueous sodium hydroxide solution (9.5 ml), and di-t-butyl dicarbonate (2.29 g, 10.5 mmol) was added, followed by stirring at room temperature for 5 hours. Further, 4mo1 ZL sodium hydroxide aqueous solution (1.1 mL) and di-tert-butyl dicarbonate (1.00 g, 4.58 mmo1) were added, and the mixture was stirred at room temperature for 19 hours, and then depressurized. The lower solvent was distilled off, and the mixture was extracted with ethyl acetate (20 mL × 3). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate hexane = 1/2, methanol mouth opening form = 1/10). 1.70 g (yield 79%, cis: trans = 10: 9 mixture) of the title compound was obtained as a colorless oil. (Cis)

¹ H NMR (CDC 1340 0 MHz): 6 = 1.28 (6 H, d, J = 7 Hz), 1.49 (9 H, s), 2.27 (2 H, dd , J = 3 Hz, 15 Hz), 2.72 (2 H, d, 7 Hz, 15 Hz), 4.7-4.8 (2 H, m)

(Trance)

1 H NMR (CD C 13 40 OMH z): 5 = 1.25 (5.4 H, d, J = 6 Hz), 1.50 (81 H, s), 2.37 ( 1.8 H, dd, J = 2 Hz, 18 Hz), 2.85 (1.8 H, d, 6 Hz, 18 Hz), 4.3-4.4 (1 .8 H, m)

(3) trans-1,6-dimethyl-4,4-bis _ [(3,5-dibutylbutyno-4-hydroxy) pheninoles refinore] piperidine 2,6-dimethynole-1-oxo Lysine-1-carboxylic acid t-butyl ester (700 mg, 3.08 mmo 1 [cis: trans = 1: 1 mixture]) and 2,6-di-t-butyltin 4-mercaptophenol ( 1. 3 1 g, 5.49 mm o 1) was added to dry black-mouthed form (10 mL). Boron trifluoride getyl ether complex (0.77 mL, 6.08 mm o) was added under ice cooling. 1) was added dropwise, and the mixture was stirred for 2 hours and then at room temperature for 14 hours. The reaction solution was purified by silica gel column chromatography (methanol / mouth opening form = 1/10) to give 38 mg (yield 2.1%) of the title compound as pale yellow crystals.

¹ H NMR (CD C 13, 400 MHz): 5 = 1.26 (6H, d, J = 6 Hz), 1.43 (18 H, s), 1.46 (18 H, s), 1.6-1.9 (4H, m), 3.7-3.8 (2H, m), 5.43 (1H, s), 5.46 (1H, s) ), 7.34 (2H, s), 7.53 (2H, s) Example 2

Lipid peroxidation inhibitory action

(Test method)

The reaction was performed in 1 mL of a reaction solution containing the following reagents.

(1) 0. 5 mL phosphate-buffered saline (4 mm o 1 ZL N a 2 HP0 4

/ N a H ₂ P〇 ₄ , 0.15 mo 1 / LNa C 1, H 7.4),

(2) 0.25 mg microsomal protein (rat liver microsome ¹ )),

(3) F e C 1 3 (1 00 xmo l / L),

( ⁴ ) The compound of the present invention described in Example 1 (100 / xmol ZL),

(5) Ascorbic acid (100 jumo1 / L) The peroxidation reaction was started by adding ascorbic acid and incubated at 37 ° C for 2 hours. Peroxides were measured by the thiobarbituric acid (TBA) method. That is, the reaction solution is 0,

After heating at 100 ° C for 15 minutes in the presence of 1% (W / V) and 0.5 mL of 2.8% (W / V) trichloroacetic acid, the chromogen was extracted with butanol. The absorbance of the organic layer at 532 nm was measured.

(References)

1) Quin 丄 an GJ et al. (1988) Action of lead (II) and aluminum (III) ions on iron-stimulated lipid peroxidation in liposomes, erythrocytes and rat liver microsomes.Biochira.Biophys.Acta 962, 196-200.

(Result)

The compound of the present invention described in Example 1 at 100 μπιο1 ZL concentration almost completely inhibited the lipid peroxidation of rat liver microsomes stimulated with ascorbic acid in the presence of iron ions.

Claims

Claims The following general formula (I),

(I)

(Wherein, is an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an aralkyl group (the aryl group has 6 to 10 carbon atoms, The alkyl moiety has 1 to 4) carbon atoms or an aryl group having 6 to 10 carbon atoms,

R ₂ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an aralkyl group (the aryl group has 6 to 10 carbon atoms, The alkyl portion has 1 to 4 carbon atoms, represents an aryl group having 6 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, or an alkylcarbol group having 2 to 8 carbon atoms,

And R ₃ and R ₄ may be the same or different, and may be an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having a 3 to 8 membered ring, and a 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Alkyl group and aralkyl group having 1 to 8 carbon atoms substituted with an alkyl group and an alkoxy group having 1 to 8 carbon atoms (the aryl group has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 4 carbon atoms) Or an aryl group having 6 to 10 carbon atoms. )

Or a salt thereof.

2. The piperidine derivative or a salt thereof according to claim 1, wherein 2 R, is an alkyl group having 1 to 8 carbon atoms.

The piperidine according to claim _{1, wherein} 3 R ₁ is an alkyl group having 1 to 3 carbon atoms. Derivatives or salts thereof.

4. The piperidine derivative according to any one of claims 1 to 3, wherein R 3 and R ₄ are an alkyl group having 1 to 8 carbon atoms, or a salt thereof.

5. The piperidine derivative according to claim 1, wherein R ₃ and R ₄ are both t-butyl groups, or a salt thereof.

6. The piperidin derivative according to any one of claims 1 to 5, wherein R ₂ is a hydrogen atom, or a salt thereof.

7. An antioxidant comprising the piperidine derivative according to any one of claims 1 to 6 or a salt thereof as an active ingredient.