JPH066580B2 - Abietamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an abietamide derivative which exhibits an excellent cholesterol-lowering effect and is useful for the prevention and treatment of arteriosclerosis.

More specifically, the present invention relates to an abietamide derivative represented by the following general formula [I].

However, R is hydrogen, alkyl, phenyl, or -CH ₂ CO
Represents OR ¹ (R ¹ represents hydrogen or lower alkyl), Represents a single bond or a double bond.

(Prior Art) As a compound similar to the compound of the present invention, the present inventors have already applied for a patent for N- (2,6-dimethylphenyl) = Δ ⁸ -dihydroabietamides (JP-A-51- 026864
issue). This compound inhibits absorption of exogenous cholesterol from the intestinal tract but not cholesterol biosynthesis.

(Problems to be Solved by the Invention) The present inventors have a novel structure, low toxicity, inhibition of absorption of exogenous cholesterol from the intestinal tract, and inhibition of cholesterol biosynthesis or catabolism. Further studies were carried out with the aim of obtaining compounds having an action of promoting excretion.

(Means for Solving the Problems) The inventors of the present invention have conducted extensive studies in accordance with the above object, and as a result, found that the compound represented by the general formula [I] described above is a compound suitable for this object. It arrived and completed this invention.

The compound according to the present invention is a novel compound which has not been described in the literature, and its chemical structure is characterized in that the amide residue contains a thiazole ring.

In the formula, the alkyl represented by R and R ¹ is preferably a linear or branched lower alkyl having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl and n-.
Butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned.

The compound of the present invention comprises Δ ⁸ -dihydroabietic acid ([I
I]) or dehydroabietic acid ([III]) (hereinafter, these are collectively referred to as “resin acid”) and various amines corresponding thereto can be produced to condense.

This amidation reaction can be carried out by a method known per se, and a method in which a reactive derivative of [II] or [III], for example, an acid anhydride or an acid halide is appropriately reacted is used. When using an acid halide, the reaction is carried out in a commonly used solvent (eg, aromatic hydrocarbons such as toluene and benzene, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane, acetonitrile, N. In an aprotic polar solvent such as N, N-dimethylformamide), preferably a base (eg, an inorganic base such as sodium hydrogen carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, N, N-dimethylaniline, toluethylamine) In the presence of (such as an organic base), it is usually carried out at -10 to 100 ° C, preferably -5 to 10 ° C.

The reaction time varies depending on the kind of the resin acid halide or amine, the reaction temperature, etc., but is usually 1 to 72 hours. The amount of the amine used is 1 to 1.5 mol per 1 mol of the resin acid halide. An equimolar amount of sodium hydride or potassium hydride may be added to accelerate the reaction and improve the yield.

The target compound [I] thus obtained can be isolated and purified by a means known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography and the like. You can

The raw material compound (II) used in the present invention can be easily prepared by a known method (see J.Org, Chem. 34 , 1550 (1969)) from a mixture mainly composed of Δ8 ⁽¹⁴⁾ -dihydroabietic acid [VII]. It can be manufactured. Such a mixture containing Δ8 ⁽¹⁴⁾ -dihydroabietic acid [VII] as a main component is pulstophosphoric acid [I
V], levopimaric acid [V], abietic acid [VI] or pine resin can be obtained by catalytic reduction.

The starting compound [III] can be obtained from a commercially available disproportionated rosin according to a known method (see J. Org, Chem. 31 , 4246 (1967)). Various amines as the other raw material are commercially available or can be produced by known methods.

When the compound of the present invention is administered as a pharmaceutical, the compound of the present invention is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5% to 90%.
%, And is administered to animals including humans.

As the carrier, one or more liquid, solid, or semisolid diluents, fillers, and other auxiliaries for formulation are used.
The pharmaceutical composition is preferably administered in dosage unit form. The compound of the present invention can be administered orally, intratically, locally or rectally. It goes without saying that the dosage form is suitable for these administration methods, for example, various oral preparations, injections, suppositories, and the like. For example, oral administration is particularly preferable.

The dose as a therapeutic agent for arteriosclerosis is preferably adjusted in consideration of the patient's condition such as age and weight, administration route, nature and degree of disease, etc. 0.5 ~ 5.0g per day as the effective amount of
Is used, and a range of 1 to 2 g is generally used. In some cases, lower doses may be sufficient and, conversely, higher doses may be required. 2 to 1 day
It can be administered in three divided doses.

(Examples) The present invention will be described in more detail below with reference to Examples and Test Examples of the compounds of the present invention, but the present invention is not limited thereto.

Example 1 N- (4-methylthiazol-2-yl) dehydroabietamide 29.54 g of dehydroabietic acid, dehydroabietic acid chloride obtained from 25 g of oxalic acid chloride in 100 ml of methylene chloride in the presence of 10.12 g of triethylamine. React with 15.06 g of 2-amino-4-methylthiazole at room temperature for 3 days. The reaction solution is washed twice with 50 ml of 5% hydrochloric acid, further washed with water, dried over anhydrous magnesium sulfate and filtered.
Methylene chloride was distilled off from the filtrate under reduced pressure to obtain a pale brown oily substance. This is subjected to silica gel column chromatography and eluted with benzene. Benzene was distilled off from the eluate under reduced pressure to obtain a colorless oily substance. Vacuum dried colorless powder 1
3.5 g was obtained.

IR ▲ ν ^KBr _max ▼ (cm ^-1 ): 3340 (NH), 1620 (CO) Elemental analysis value: C ₂₄ H ₃₂ N ₂ O (molecular weight 396.59) Calculated value (%): C 72.69 H 8.13 N 7.06 Measured value (%): C 72.32 H 7.98 N 7.15 Similarly, the following compounds were obtained.

Example 2 N- (thiazol-2-yl) -Δ ⁸ -dihydroabietamide: oily substance. IR ▲ ν ^film _max ▼ (c
m ⁻¹ ) 1620 Elemental analysis value: C ₂₃ H ₃₄ N ₂ OS (molecular weight 386.59) Calculated value (%): C 71.46 H 8.86 N 7.25 Measured value (%): C 71.71 H 9.03 N 7.31 Example 3 N- ( 4-methyl-2-yl) - [delta ⁸ - dihydroabietic data bromide: oil _{^{IR ▲ ν film max ▼ (cm}} -1) 1620 elemental _{analysis: C 24 H 36 N 2 OS} ( molecular weight 400.60) calculated ( %): C 71.95 H 9.06 N 6.99 Found (%): C 72.03 H 9.15 N 7.11 Example 4 N- (thiazol-2-yl) dehydroabietamide: oily substance. IR ▲ ν ^film _max ▼ (cm ^-1 ) 1620 Elemental analysis value: C ₂₃ H ₃₀ N ₂ OS (molecular weight 382.56) Calculated value (%): C 72.21 H 7.90 N 7.32 Measured value (%): C 72.51 H 8.05 N 7.52 Example 5 N- (4-phenylthiazol-2-yl)
Dehydroabietamide: oily substance. IR ▲ ν ^film _max ▼
(cm ^-1 ) 1623 Elemental analysis value: C ₂₉ H ₃₄ N ₂ OS (molecular weight 458.66) Calculated value (%): C 75.94 H 7.47 N 6.11 Actual value (%): C 76.02 H 7.52 N 6.09 Example 6 N- (4-ethoxycarbonylmethyl-2-yl) - [delta ⁸ - dihydroabietic data bromide: mp 106 to 108 ° C..

Elemental analysis value: C ₂₇ H ₄₀ N ₂ O ₃ S (molecular weight 472.68) Calculated value (%): C 68.61 H 8.53 N 5.93 Measured value (%): C 68.50 H 9.10 N 6.05 Example 7 N- (4-carboxyl Methylthiazole-2
-Yl)-[Delta] ⁸ -dihydroabietamide: melting point 217-219 [deg.] C.

Elemental analysis value: C ₂₅ H ₃₆ N ₂ O ₃ S (molecular weight 444.63) Calculated value (%): C 67.53 H 8.16 N 6.30 Measured value (%): C 67.08 H 8.35 N 6.14 The usefulness of the compound of the present invention is shown below. The result of the pharmacological test shown is shown.

(1) Effects in cholesterol-loaded rats (HCD
Test) Test method: Four-week-old male Wistar rats were used as one group, and a high-cholesterol diet containing 0.03% of the test compound was allowed to freely feed for 3 days, blood was collected after overnight fasting, and total serum cholesterol level (TC) Was measured. The group fed the high cholesterol diet without the test compound was used as a control group, and the group fed a normal synthetic diet was used as a normal group. The serum TC increase suppression rate (%) of the test compound was calculated by the following formula.

The results are shown in Table 1.

(2) Effect on Triton-induced hyperlipidemia mice (Triton test) Test method: Male ICR mice of 9 weeks old were grouped into 6 to 9 mice, and Triton WR-1339 dissolved in physiological saline was 500 mg / kg.
It was administered via the tail vein and induced hyperlipidemia.

Saline was intravenously administered to the normal group. Immediately 0.5%
Test compound suspended in methylcellulose (MC) solution
Oral administration was performed at 0 mg / kg. The group to which the 0.5% MC solution was administered was used as a control group. After 24-hour fasting, decapitated blood was collected, and the TC value of the obtained serum was measured. The serum TC increase suppression rate (%) of the test compound was calculated by the following formula.

The results are shown in Table 1.

As is clear from the table, the compounds of the present invention show effectiveness in the HCD test loaded with cholesterol and the Triton test in which cholesterol biosynthesis is enhanced.

(3) Acute toxicity test method: 6-week-old male STD-ddY mice were fasted for 24 hours and then used.

A 0.5% suspension of the test compound in methylcellulose was orally administered, and then the animals were observed under a normal condition for 1 week for general symptoms and appearance of death. The compound of the present invention showed no particular symptoms and 2 g / kg. I didn't see any deaths.

(Effects) As is clear from the above, the compound of the present invention is not only highly toxic and exhibits an absorption inhibitory effect on exogenous cholesterol, but also exhibits a cholesterol biosynthesis inhibitory effect or a catabolic excretion promoting effect. It is useful for the prevention and treatment of broader hyperlipidemia.

Claims (1)

[Claims] 1. An abietamide derivative represented by the following general formula [I]. However, R is hydrogen, alkyl, phenyl, or -CH ₂ CO
Represents OR ¹ (R ¹ represents hydrogen or lower alkyl), Represents a single bond or a double bond.