JPH08225450A - Lipid oxidation suppressor - Google Patents

Abstract

PURPOSE: To provide a suppressor having an oxidation inhibiting action to lipid, especially low-density lipoprotein and exceedingly low-toxicity, and useful for curing and prevention of senescence, carcinogenesis and diabetes, etc., by including a compound having a specific structure as an active component. CONSTITUTION: This suppressor contains a dihydropyridine derivative of formula I [R1 -R3 are each an alkyl or an alkoxyalkyl, etc.; R4 and R5 are each H or a halogen, etc., R4 and R5 are not simultaneously H; X is a vinylene or azomethine; A is an alkylene; B is -N(R6 )(R7 ) or formula II (R6 -R8 are each H or an aralkyl, etc.; Ar is an aryl or pyridyl; (n) is 0-2)] or its salt as an active component. As the compound of the formula I, 2-[p-(4- benzohydrylpiperazino)phenyl] ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate, etc., is preferable. A dose of the active component is preferably 1-20mg/human/day in a case of orally administrating to an adult patient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a lipid oxidation inhibitor containing a dihydropyridine derivative having a specific structure described below or an acid addition salt thereof as an active ingredient.

[0002]

The dihydropyridine derivative (I) described below is known to have a calcium channel antagonistic action.

By the way, in a living body, lipids are denatured by various mechanisms. Among them, the ones due to oxidation reaction are important. Whether this lipid oxidation (denaturation) causes oxidative damage in the living body, or merely the result, has not been sufficiently clarified. However,
The relationship between this lipid oxidation and various diseases has been discussed. Examples of these diseases include aging, carcinogenesis, diabetes, hyperlipidemia, arteriosclerosis, heart disease, lung disease (ARDS, pneumonia, asthma), renal disease (nephrotic syndrome, renal failure, glomerulonephritis), liver disease, Gastrointestinal diseases, autoimmune diseases, eye diseases (retinopathy, cataract) and the like are mentioned, and it is considered that oxidized low density lipoprotein (hereinafter referred to as LDL) plays an important role. Oxidized LDL has been shown to be produced in the intima and present in the lesion. Oxidized LD
L shows chemotaxis to monocytes in the bloodstream, attracts monocytes to the blood vessel wall, differentiates them into macrophages, and suppresses migration when they become macrophages. Oxidized LDL is taken up by macrophages via scavenger receptors, CD36, etc., and causes cells to foam. Further oxidation L
DL has cytotoxicity, enhances secretion of cytokines and growth factors from vascular endothelial cells and macrophages,
It is believed to progress the lesion. Therefore, if lipid oxidation can be suppressed, it is useful for prevention or treatment of these diseases.

An object of the present invention is to provide a novel medicinal use of the dihydropyridine derivative (I) described below, that is, a use as a lipid oxidation inhibitor.

[0005]

As a result of intensive studies, the present inventors have found that the dihydropyridine derivative or its acid addition salt has a lipid oxidation inhibitory effect, and have completed the present invention. .

The present invention has the general formula

[0007]

Embedded image

[Wherein R ₁ , R ₂ and R ₃ are the same or different and are alkyl, cycloalkyl or alkoxyalkyl, and R ₄ and R ₅ are the same or different and are hydrogen atom, halogen, nitro and halogenated alkyl, A group represented by alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ₄ and R ₅ are not hydrogen atoms at the same time), and X is vinylene or azomethine. , A is alkylene, B is —N (R ₆ ) (R ₇ ), or

[0009]

[Chemical 4]

(R ₆ , R ₇ and R ₈ are the same or different and each is a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar is aryl or pyridyl, and n is 0 or an integer of 1 or 2, respectively. Represents a group represented by

The present invention relates to a lipid oxidation inhibitor containing a dihydropyridine derivative [hereinafter referred to as dihydropyridine derivative (I)] represented by or an acid addition salt thereof (usually, a pharmacologically acceptable acid addition salt) as an active ingredient.

In particular, in the above, R ₁ , R ₂ and R
₃ is the same or different alkyl, R ₄ is a hydrogen atom, R
Particularly preferably, ₅ is nitro, alkyl halide or cyano, R ₆ and R ₇ are the same or different and are alkyl, aralkyl or aryl, R ₈ is aryl, Ar is aryl and n is 1.

The dihydropyridine derivative (I) and its acid addition salt used in the present invention are particularly effective and highly safe because they have a particularly mild action expression and a long duration and their toxicity is extremely low. It has a great feature in that.

The symbols used in this specification will be described below. The alkyl represented by R ₁ , R ₂ and R ₃ may be linear or branched, and is preferably lower alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. are mentioned, and especially C1
The thing of -4 is preferable. Further, a lower cycloalkylalkyl having 3 to 6 carbon atoms (for example,
Cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, etc.).

The cycloalkyl represented by R ₁ , R ₂ and R ₃ is preferably lower cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The alkoxyalkyl represented by R ₁ , R ₂ and R ₃ is preferably one having a total carbon number of 3 to 7, such as methoxyethyl, ethoxyethyl,
Propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl and the like can be mentioned.

The substituents represented by R ₄ and R ₅ may be the same or different and may be substituted at any position on the ring, but especially at the 2-position with respect to the bonding position with the dihydropyridine ring. Or / and those at the 3rd position are preferred.

The halogen represented by R ₄ and R ₅ includes each atom of fluorine, chlorine, bromine and iodine,
Particularly, a fluorine atom or a chlorine atom is preferable. Examples of the alkyl and cycloalkyl represented by R ₄ and R ₅ include those exemplified above for R _{1 to} R ₃ .

The alkoxy represented by R ₄ and R ₅ is preferably a lower alkoxy having 1 to 3 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy and isopropoxy.

The alkylthio represented by R ₄ and R ₅ preferably has 1 to 3 carbon atoms, and examples thereof include methylthio, ethylthio, propylthio and isopropylthio.

The alkoxycarbonyl represented by R ₄ and R ₅ preferably has 2 to 4 carbon atoms, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like.

The halogen of the halide is also the same as above, and the alkyl halides represented by R ₄ and R ₅ are those in which a part of hydrogen atoms thereof are halogenated [eg (CF ₃ ) ₂ CHCH ₂ —, CF ₃ CH ₂ —, etc.] or all hydrogen atoms are halogenated (trifluoromethyl, etc.). Also,
The halogenated alkoxy may be one in which a part of the hydrogen atoms is halogenated or may be one in which all the hydrogen atoms are halogenated. The alkyl halide and the halogenated alkoxy each have 1 to 6, preferably 1 to 4 carbon atoms.

The alkyl in the alkylsulfonyl and alkylsulfinyl represented by R ₄ and R ₅ is the same as those exemplified for R _{1 to} R _3, that is, the alkyl having 1 to 1 carbon atoms.
And 6 (preferably having 1 to 4 carbon atoms).

R ₄ is preferably a hydrogen atom, and R ₅ is preferably cyano, nitro or alkyl halide (particularly trifluoromethyl).

R₆, R₇And R₈Archi indicated by
And R is cycloalkyl ₁~ R₃Illustrated by
Some of them are listed.

Examples of aralkyl include phenyl C _1-3 alkyl such as benzyl, α-phenylethyl, β-phenylethyl, γ-phenylpropyl and the like. Examples of aryl include phenyl and naphthyl.

These aromatic rings may have the same or different substituents at arbitrary positions. Examples of the substituents include those exemplified as R ₄ and R ₅ above.

Examples of pyridyl include 2-pyridyl, 3-pyridyl and 4-pyridyl, which may have the substituents exemplified as R ₄ and R ₅ .

The alkylene represented by A is preferably a linear or branched one having 2 to 4 carbon atoms, specifically, ethylene, trimethylene, tetramethylene, 1,2.
-Dimethyl ethylene and the like.

Examples of the aryl and pyridyl represented by Ar include those exemplified above for R ₆ , R ₇ and R ₈ and may have the same substituents.

It is the 4-position substituent of dihydropyridine.

[0032]

Embedded image

In the ring represented by, X is vinylene (-
CH = CH-) means a benzene ring, and azomethine (-CH = N-) means a pyridine, which may be bonded to the 4-position of dihydropyridine at any position thereof.

The substituents R ₄ and R ₅ may be substituted at any of the ortho, meta and para positions with respect to the carbon atom bonded to the 4-position of the dihydropyridine, preferably the ortho position and / or the meta position. Is replaced by.

Specific examples of the dihydropyridine derivative (I) and its acid addition salt include the compounds shown in Table 1 below and their acid addition salts.

[0036]

[Table 1]

The dihydropyridine derivative (I) and its acid addition salt are more preferably 2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl.
2,6-dimethyl-4- (3-nitrophenyl) -1,
4-dihydropyridine-3,5-dicarboxylate,
2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4- (4-cyano-2-pyridyl) -1,4-dihydropyridine-
Examples include 3,5-dicarboxylate and acid addition salts thereof.

The dihydropyridine derivative (I) can be produced by subjecting an arbitrary portion and a residual portion constituting the dihydropyridine derivative (I) to a method known per se, particularly a dehydration ring closure reaction.

Specifically, JP-A-63-107975, JP-A-63-112560, JP-A-63-
225356, JP-A-58-201765, JP-A-63-99042, and JP-A-63-15.
It is manufactured using the manufacturing method described in JP-A No. 2351 and JP-A No. 61-260064.

The dihydropyridine derivative (I) thus produced can be collected in an arbitrary purity by appropriately using known separation and purification means such as concentration, extraction, chromatography, reprecipitation and recrystallization.

Since the dihydropyridine derivative (I) has a basic group, it can be converted into an acid addition salt by a known means. The salt is not particularly limited as long as it is pharmacologically acceptable, and for example, a salt with an inorganic acid (hydrochloride, hydrobromide, phosphate, sulfate, etc.), a salt with an organic acid. (Acetate, succinate, maleate, fumarate, malate, tartrate) and the like.

[0042]

According to the present invention, the dihydropyridine derivative (I) and its acid addition salt have extremely low toxicity and have an action of inhibiting lipid, particularly LDL, oxidation. Therefore, for example, aging, carcinogenesis, diabetes, hyperlipidemia, arteriosclerosis,
Treatment and prevention of heart disease, lung disease (ARDS, pneumonia, asthma), renal disease (nephrotic syndrome, renal failure, glomerulonephritis), liver disease, gastrointestinal disease, autoimmune disease, eye disease (retinopathy, cataract), etc. Useful for.

When the dihydropyridine derivative (I) and its acid addition salt are used as the above-mentioned pharmaceuticals, pharmacologically acceptable additives (eg carrier, excipient, diluent, etc.)
Etc. are mixed appropriately with the pharmaceutically necessary ingredients, powder, granules,
The pharmaceutical composition can be orally or parenterally administered in the form of tablets, capsules, syrups, injections and the like.

An effective amount of the dihydropyridine derivative (I) and its acid addition salt is added to the above-mentioned preparation. The dose varies depending on the administration route, symptoms, patient weight or age, etc., but when administered orally to an adult patient, for example, 0.1 to 100 mg / human / day, particularly 1 to 20 mg / human / day. It is desirable to administer 1 to several times a day. In the case of intravenous administration, 0.1-300 μg / human / day,
Particularly, it is desirable to administer 5 to 100 μg / human / day in 1 to several times a day.

[0045]

EXAMPLES In order to explain the present invention in more detail, examples and experimental examples will be given, but the present invention is not limited thereto. Regarding ¹ H-NMR measurement, CDCl ₃ was used unless otherwise specified.

The inhibitory effect on lipid oxidation of dihydropyridine derivative (I) or its acid addition salt was tested in the following experimental examples.

[Test Drug] Compound 2 (compound of the present invention), nicardipine (control drug) and nilvadipine (control drug) described below were used.

Experimental Example 1 ¹²⁵ I-LDL was incubated at 37 ° C. for 2 hours in the presence of 10 μM copper sulfate.
It was oxidized by keeping it warm for 4 hours. At this time, the effects of the compound of the present invention and nicardipine (10 μM) were examined. The reaction solution was applied to agarose gel electrophoresis. At this time, the mobility of ¹²⁵ I-LDL without the oxidation treatment 0, ¹²⁵ and oxidized I
-The mobility of LDL was set to 1, and the change in the mobility was used as an index of lipid oxidation. Table 2 shows the results.

[0049]

[Table 2]

Experimental Example 2 Human aorta-derived endothelial cells and ¹²⁵ I-LDL were oxidized by incubating at 37 ° C. for 24 hours. At this time, the compound of the present invention, nicardipine and nilvadipine (10 μm
The effects of M) were examined.
The reaction solution was applied to agarose gel electrophoresis. At this time, it is not oxidized with human aortic endothelial cells
The mobility of ¹²⁵ I-LDL is 0 and the oxidized ¹²⁵ I-L
The mobility of DL was set to 1, and the change in the mobility was used as an index of lipid oxidation. The results are shown in Table 3.

[0051]

[Table 3]

The above sample was applied to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). As a result, with ¹²⁵ I-LDL (unoxidized) and the compound of the present invention, a single band of apoprotein B-100 was observed in the region of molecular weight 200,000 daltons. However, with ¹²⁵ I-LDL (oxidized), nicardipine and nilpadipine, the band disappeared almost completely, and it was speculated that the apoprotein was degraded by the oxidation reaction.

From these results, the compound of the present invention
It was found to inhibit the oxidative reaction of the endothelial cells.

Reference Example 2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-
Synthesis of dicarboxylate (Compound 1) and its hydrochloride salt (Compound 2):

In a 100 ml eggplant-shaped flask, 3-nitrobenzaldehyde (1.144 g, 7.57 mmol), acetoacetic acid [p
-(4-Benzhydrylpiperazino) phenyl] ethyl (3.464 g, 7.59 mmol) and methyl 3-aminocrotonate (873 mg, 7.58 mmol) were added, isopropanol (12 ml) was added, and a Dimroth condenser was added. It was attached and heated under reflux for 16 hours. The reaction solvent was distilled off under reduced pressure, and the residue was obtained by column chromatography [silica gel, chloroform: methanol (45: 1)] and column chromatography [silica gel, ethyl acetate: n-hexane (2: 3)]. The crude product was purified by high performance liquid chromatography to obtain 2.503 g of the title compound 1 (yield 48%).

IR ν _max ^KBr cm ⁻¹ : 1680, 1520 ¹ H-NMR δ: 8.06 (1H, t, J = 2Hz), 7.97 (1H, ddd,
J = 8; 2; 1Hz), 7.1-7.6 (12H), 7.03 (2H, d, J = 8.6H
z), 6.80 (2H, d, J = 8.6Hz), 6.02 (1H, s), 5.07 (1H,
s), 4.26 (1H, s), 4.22 (2H, t, J = 7Hz), 3.64 (3H,
s), 3.15 (4H, dd, J = 5; 4.7Hz), 2.81 (2H, t, J = 7H
z), 2.55 (4H, dd, J = 5; 4.7Hz), 2.33, 2.28 (3H, s respectively)

This compound 1 (2.124 g, 3.16 mmol) was added to
It was put in a 200 ml eggplant-shaped flask and a septum rubber was attached. After adding methylene chloride (100 ml) to the flask and dissolving the contents, while introducing hydrogen chloride gas, at room temperature,
Stir for 30 minutes. The precipitated crystals are collected by filtration and the title compound 2 is
2.22 g was obtained.

IRν _max ^KBr cm ^-1 : 2450, 1680, 1525,
1350. ¹ H-NMR δ: 13.72 (1H, brs), 8.05-7.9 (6H), 7.
82, 7.26 (4H, A ₂ B, J = .6Hz), 7.6-7.3 (8H), 6.28 (1H,
s), 5.2-5.05 (2H), 5.01 (2H, s), 4.27 (2H, t, J = 6.
5Hz), 4.3-4.1 (2H), 3.66 (3H, s), 3.65-3.45 (4H),
2.95 (2H, t, J = 6.5Hz), 2.36, 2.33 (3H, s respectively)

Example 1: Tablet (1) Compound 2 10 g (2) Fine granules for direct compression No.209 (manufactured by Fuji Chemical Co., Ltd.) 110 g Magnesium aluminometasilicate 20% Corn starch 30% Lactose 50% (3) Crystalline cellulose 60g (4) CMC calcium 18g (5) Magnesium stearate 2g

(1), (3) and (4) are all 100
Pass through a sieve of mesh. Each of (1), (3), (4) and (2) is dried to reduce the water content to a constant value, and then mixed in the above-mentioned weight ratio using a mixer. (5) was added to the mixed powder which was made uniform in quality and mixed for a short time (30 seconds), and the mixed powder was tabletted to give 200 mg tablets each.

If desired, the tablets may be coated with a gastric film-coating agent (eg polyvinyl acetal diethylaminoacetate) or an edible coloring agent which is usually used.

Example 2: Capsule (1) Compound 2 50 g (2) Lactose 930 g (3) Magnesium stearate 20 g The above ingredients were weighed and mixed uniformly, and 200 mg of the mixed powder was packed in a hard gelatin capsule. Each was filled.

Example 3: Injection (1) Compound 2 5 mg (2) Glucose 100 mg (3) Physiological saline 10 ml The above mixture was filtered through a membrane filter and then sterilized again, and the filtrate was sterilized. The solution was dispensed into a vial, filled with nitrogen gas, and then sealed to give an intravenous injection.

Example 4 20.1 g of Compound 2 was mixed with unsaturated fatty acid monoglyceride ("Exel O-95R" manufactured by Kao Corporation) and polyoxyethylene sorbitan monooleate ("TO-10" manufactured by Nikko Chemical Co., Ltd.).
M ”) mixture (1: 1) (650 g) and dissolved at 40 ° C.,
The mixture was stirred to obtain a non-micelle type solution. The solution thus obtained
600 g and 370 g of magnesium aluminometasilicate (“Neucillin US ₂ ” manufactured by Fuji Chemical Industry Co., Ltd.) were mixed with a stirring granulator. In addition, croscarmellose sodium A type 3
0 g was mixed and stirred, and 250 ml of purified water was added for granulation. Then, dry in a ventilated dryer at 40 ° C for 17 hours, 42 to 200 me.
Sift through sh to prepare 550 g of fine granules for capsule filling.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/495 ACJ A61K 31/495 ACJ ACS ACS ACV ACV ADN ADN ADP ADP ADU ADU AGZ AGZ 31/455 ABL 31/455 ABL C07D 211/90 C07D 211/90 401/04 211 401/04 211 // (C07D 401/04 211: 90 213: 84)

Claims (1)

[Claims] 1. A compound of the general formula [Wherein R ₁ , R ₂ and R ₃ are the same or different and each represents an alkyl, a cycloalkyl or an alkoxyalkyl,
R ₄ and R ₅ are the same or different and each represents a hydrogen atom, halogen, nitro, halogenated alkyl, alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ₄ And R ₅ are not simultaneously hydrogen atoms), X is a group represented by vinylene or azomethine, A is alkylene, and B is
Is -N (R ₆ ) (R ₇ ), or (R ₆ , R ₇ and R ₈ are the same or different and each is a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar is aryl or pyridyl,
n represents a group represented by 0 or an integer of 1 or 2, respectively)], and a lipid oxidation inhibitor comprising a dihydropyridine derivative represented by the formula [3] or an acid addition salt thereof as an active ingredient.