WO2003099788A1 - Piperidine derivatives - Google Patents

Abstract

Piperidine derivatives represented by the general formula (I) or salts thereof, and antioxidants containing the same as the active ingredient: (I) wherein R1, R2, R3 and R4 are each hydrogen, alkyl having 1 to 8 carbon atoms, or the like; R5 is alkylcarbonyl having 2 to 8 carbon atoms, or the like; and R6 and R7 are each alkyl having 1 to 8 carbon atoms, or the like.

Description

 Description Piperidine derivative

 Technical field

 The present invention relates to a piberidine derivative having an antioxidant effect. Background art

 It is well known that compounds having a phenolic hydroxyl group have an antioxidant effect. Numerous compounds have been reported, for example, natural phenols represented by tocopherols, flavones, and gallic acids, and synthetic antioxidants represented by butylhydroxytoluene (BH-cho).

 Amines also show an antioxidant effect, and various amino acids such as 4-amino-p-diphenylamine are known to have an antioxidant effect.

 Furthermore, it is also known that both phenols and amines act as a radical force inhibitor that suppresses the chain reaction of autoxidation (frEradadicacalscavenger).

 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. Compounds having a similar structure to the piperidine derivative of the present invention include Probucol '(U.S. Pat. No. 3,576,883) known as a therapeutic agent for hyperlipidemia. N-methyl-4 having antiviral activity -Piperidone bis (3,5-di-tert-butyl-1-hydroxyphenyl) mercaptol (WO 91/01124), and the like, but the piperidine derivative of the present invention is clearly different from these. Structurally different. 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):

(Wherein, R ¹ , R ² , R ³ and R ⁴ may be the same or different, a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and a carbon number substituted with 1 to 3 haegen atoms. Represents an alkyl group having 1 to 8 carbon atoms, an aralkyl group (the aryl moiety 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;

R ⁵ 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 moiety 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 alkylcarbonyl group having 2 to 8 carbon atoms;

And R ⁶ and R ⁷ may be the same or different and may have 1 to 8 carbon atoms, a 5- to 8-membered ring-opening alkyl group, and 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkyl group, an alkyl group having 1 to 8 carbon atoms, an aralkyl group substituted with an alkoxy group having 1 to 8 carbon atoms (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 4 carbon atoms) ) Or represents 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.

 Furthermore, the present invention relates to the use of a piperidine derivative represented by the above general formula (I) or a salt thereof as an antioxidant. BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described in detail.

In the piperidine derivative represented by the above general formula (I), the alkyl group of ¹ to! ^ ⁷ having 1 to 8 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl, i- A butyl group, a t-butyl group, a pentyl group or a hexyl group.

Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R ¹ ! ^ ⁷ 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, isopropyl group, butyl group or t-butyl group, preferably trifluoromethyl group, 2-chloroethyl group, 2-bromoethyl group or 2-phenylenoethyl group. Can be

1 ~! Examples of the aralkyl group of ^ ⁷ (the carbon number of the aryl part is 6 to 10 and the carbon number of the alkyl part is 1 to 4) include a benzyl group and a phenethyl group.

Examples of the aryl group having 1 to ¹⁷ carbon atoms of 6 to 10 include a phenyl group and a naphthyl group.

Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms for R ⁵ include a methoxy canoleponinole group and an ethoxycarbonyl group.

Examples of the alkylcarbonyl group having 2 to 8 carbon atoms for R ⁵ include an acetyl group and a propionyl group. '

Examples of the 5- to 8-membered cycloalkyl group of R ⁶ and R ⁷ include a cyclopentyl group and a cyclohexyl group.

Examples of the C 1-8 alkyl group substituted with a C 1-8 alkoxy group represented by R ⁶ and R ⁷ include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butynoleoxy group, and a Butynoleoxy group, T-tinoleoxy group, Pentinole Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group, which are substituted with an oxy group or a hexyloxy group.

(1) The piperidine derivative of the present invention is a piberidine derivative represented by the above general formula (I), wherein ^one of R ¹ and R ² is other than a hydrogen atom, the other is a hydrogen atom, and A piperidine derivative represented by the above general formula (I) wherein one of R ³ and R ⁴ is other than a hydrogen atom and the other is a hydrogen atom, or a salt thereof is preferable.

(2) Further, the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), and ^one of R ¹ and R ² is an alkyl group having 1 to 8 carbon atoms. A piperidine derivative represented by the above general formula (I), wherein the other is a hydrogen atom, and one of R ³ and R ⁴ is an alkyl group having 1 to 8 carbon atoms, and the other is a hydrogen atom. Or its salt is preferable.

(3) The piperidine derivative of the present invention includes the piperidine derivative described in (1) above, wherein the alkyl group having 1 to 8 carbon atoms of R ¹ , R ² and R ³ and R ⁴ is in the trans configuration of the piperidine ring. Its salts are preferred.

The piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R ⁵ is an alkylcarbonyl group having 2 to 8 carbon atoms. The piperidine derivative to be used, or the piperidine derivative according to any of the above ① to ③, or a salt thereof is preferred.

The piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R ⁶ and R ⁷ are an alkyl group having 1 to 8 carbon atoms.

The piperidine derivative represented by (I), the piberidine derivative according to any one of the above (1) to (4), or a salt thereof is preferred.

Further, the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R ⁶ and R ⁷ are both t-butyl groups. The piperidine derivative described above, the piperidine derivative according to any one of the above items 1 to 4, or a salt thereof is preferable. The piperidine derivative represented by the above general formula (I) has R ¹ , R ² , R ³ and R ^4. Except for the case where they are identical, they have an asymmetric carbon atom at the 4-position of the piperidine ring, and when R ¹ and R ² are not the same or R ³ and R ⁴ are not the same, , Has an asymmetric carbon atom at the 6-position.

 Accordingly, the piperidine derivative represented by the above general formula (I) of the present invention includes an optically active substance and a racemic form.

 Further, 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 citric acid Alternatively, a salt with an organic acid such as tartaric acid may be used. Next, a method for synthesizing the piperidine derivative represented by the above general formula (I) will be described.

The reaction between the carbonyl compound represented by the general formula (a) and the mercaptophenol represented by the general formula (b) can be performed in a solvent that does not participate in the reaction such as methanol under acidic conditions (such as hydrochloric acid gas). it can. The carbonyl compound represented by the general formula (a) as a raw material can be obtained, for example, by the following synthesis route. ; BuLi, Mel

M Me

また、 原料である （b) で表される R⁶ , R⁷ が t一プチル基の化合物は、 例 えば、 以下の合成ルートで得ることができる。

Further, a compound in which R ⁶ and R ⁷ represented by (b), which are raw materials, are t-butyl groups can be obtained, for example, by the following synthesis route.

【表 1】 _C showing representative compounds of the present invention compounds obtained by thus Table 1-3

【table 1】

[Table 2]

[Table 3]

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

 The antioxidant effect of the compound of the present invention was confirmed by measuring the lipid peroxidation inhibitory effect 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. Coraras. 10, 143-1 & 7. As described in Example 2, the compound of the present invention inhibited lipid peroxidation of rat moon dried microsomes at a concentration of 10 mo1 / L.

 Therefore, since the compound of the present invention has an excellent antioxidant effect, 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 food, 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 manufactured into 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, pudose, etc. Disintegrants include starch, carboxymethylcellulose calcium (CMC-C a), etc., and lubricants Is magnesium stearate, talc, etc., and the binding agent is hydroxypropyl senorelose (HP C), gelatin, polybutylpyrrolidone (PVP) and the like. The amount of the compound used as an additive and the amount administered when used for diseases related to oxidative stress is usually about 0.1 mg to 100 mg of the compound of the present invention by injection as a parenteral injection, and 1 dose per day for oral administration. The daily dose is between lmg and 200mg, but it can be increased or decreased depending on age, symptoms, etc. Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Example

 Example 1 (Synthesis example)

 (1) trans-1-1-acetyl-2,6-dimethinoleviperidin-14-one trans-1,6-dimethyl-biperidine-14-one 31 Omg (purity 89.2%, 2 217 mmo1) and triethylamine (0.4 mL, 2.87 mmo1) were dissolved in dry dichloromethane (2 mL), and the mixture was dissolved in ice-cooled acetyl chloride (0.2 mL, 2.81 mmo1). A solution of dry dichloromethane (1 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform: 100-100) to give 31 Omg (purity 95.6%, yield 83%) of the title compound. Obtained as a colorless oil.

_{^{1 H NMR (CDC 1 3,}} 400MHz)

 5 = 1.2-1.4 (6H, br)

 2.20 (3H, s)

 2.44 (2H, d d, J = 2 Hz 18 Hz)

 2.8-3.0 (2 H, b r)

 4.2-4.3 (1 H, br)

4. 7-4. 8 (1 H, br). (2) 1-acetinole 4- (3,5-di-t-butyl-4-hydroxyphenylthio) 1-4-hydroxy-1-trans-2,6-dimethylbiperidine Trans-11-acetyl-2,6-dimethyl Piperidine-one-one (15 Omg, purity 95.6%, 0.85 mmo1) and 3,5-di-tert-butylphenylenol 4-hydrodroxythiophenol (63 4 mg, 2. Add 66 mm o 1) to the hydrochloric acid gas / methanol solution (3 mL), and add 60-65. The mixture was stirred with C for 15 hours and 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ethyl hexanoacetate = 1/1 / 1-n-form and methanol nox-oral form = 1/1000) to obtain 330 mg ( The title compound (yield 98%) was obtained as a pale yellow oil.

¹ H NMR (CD C 13, 400 MHz)

δ = 1.2-1. 3 (6 H, m)

 1. 4 3 (1 8 Η, s)

 1. 8— 2. 1 (3 H, b r)

 2.4-2.8 (4 H, m)

 3. 4—3.6 (1 H, b r)

 4. 2—4.5 (1 H, b r)

 5.30 (1 H, s)

 6. 0—6.3 (1 H, b r)

 7.26 (2H)

MS (m / z): 4 7 (M ⁺ )

Example 2 (lipid peroxidation inhibitory action)

(Test method) The reaction was performed in 1 mL of a reaction solution containing the following reagents.

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

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

0.2 5 mg microsomal protein (rat liver microsome ¹ )),

 F e C 1 3 (1 0 0 z m o 1 / L),

 The compound of the present invention described in Example 1 (10 and 100 μπιο 1 / L),

 Ascorbic acid (100 μm o 1 / 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 was heated at 100 ° C for 15 minutes in the presence of 0.5% of 1% (/ V) 0.5% and 0.5 mL of 2.8% (WZV) trichloroacetic acid. Was extracted with butanol, and the absorbance of the organic layer at 532 nm was measured.

(References)

 1 Quinlan G. J. et al. (1988) Action of lead (II) and aluminum (I II) ions on iron-stimulated lipid peroxidation in liposomes, erythrocytes and rat liver microsomes. Biochira. Biophys.

(Result)

 The test compound completely inhibited lipid peroxidation of rat liver microsomes stimulated with ascorbic acid in the presence of iron ions at concentrations of 10 and 100 jLimo 1 / L.

Claims

1. The following general formula (I), of

Enclosure (In the formula, R ¹ , R ² , R ³ and R ⁴ may be the same or different, a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Represents an alkyl group or an aralkyl group (the aryl moiety 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. R ⁵ 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 moiety has 1 to 4 carbon atoms), represents an aryl group having 6 to 10 carbon atoms, an anolekoxycarbonyl group having 2 to 8 carbon atoms, or an alkylcarbonyl group having 2 to 8 carbon atoms, R ⁶ and R ⁷ may be the same or different and may have 1 to 8 carbon atoms, a 5- to 8-membered ring-opening alkyl group, and 1 to 3 carbon atoms substituted with 1 to 3 halogen atoms. Alkyl group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms substituted with alkoxy group having 1 to 8 carbon atoms, and aranolequinole group (the carbon number of the aryl portion is 6 to 10, and the carbon number of the alkyl portion is 1 to 4) or represents an aryl group having 6 to 10 carbon atoms. ') Or a salt thereof. 2. One of R ¹ and R ² is other than a hydrogen atom, the other is a hydrogen atom, and 2. The piperidine derivative or a salt thereof according to claim 1, wherein one of R ³ and R ⁴ is other than a hydrogen atom, and the other is a hydrogen atom. 3. One of R ¹ and R ² is an alkyl group having 1 to 8 carbon atoms, the other is a hydrogen atom, and one of R ³ and R ⁴ is an alkyl group having 1 to 8 carbon atoms, 2. The piperidine derivative or a salt thereof according to claim 1, wherein the other is a hydrogen atom. 4. The piperidine derivative or a salt thereof according to claim ³ , wherein the alkyl group having 1 to 8 carbon atoms of R ¹ , R ² and R ³ and R ⁴ is in a trans configuration of a piperidine ring. 5. The piperidine derivative or a salt thereof according to any one of claims 1 to 4, wherein R ⁵ is an alkylcarbonyl group having 2 to 8 carbon atoms. 6. The piperidine derivative or a salt thereof according to any one of claims 1 to 5, wherein R ⁶ and R ⁷ are an alkyl group having 1 to 8 carbon atoms. 7. The piperidine derivative or a salt thereof according to any one of claims 1 to 5, wherein R ⁶ and R ⁷ are both t-butyl groups. 8. An antioxidant comprising the piperidine derivative or a salt thereof according to any one of claims 1 to 7 as an active ingredient. 9. Use of the piperidine derivative or a salt thereof according to any one of claims 1 to 7 as an antioxidant.