JPH0733660A - Lipid metabolism improver - Google Patents

Abstract

PURPOSE:To obtain the medicine containing a (+)-antipode, etc., of a specific aminopyridine derivative as an active ingredient, having triglyceride(TG) or TG-rich lipoprotein-lowering action, low in toxicity and useful for preventing and treating arterial sclerosis. CONSTITUTION:An aminopyridine compound expressed by formula I (R<1> and R<2> are H, 1-6C alkyl or protecting group of amino group) (e.g. 2,5- diaminopyridine) is made to react with a compound of the formula R-NCS {R is formula II [R<3> is H or 1-6C alkyl; (m) is 1 or 2]} (e.g. optically active- end-2-norbornylisothiocyanate) in a solvent and as necessary, the reactinal product is oxidized with an antioxidant such as peracid to provide an (+)-antipode (salt) of an aminopyridine derivative expressed by formula III [Z is S or NCN; (n) is 0 or 1]. Then, this compound, which is used as an active ingredient, is blended with a carrier, vehicles, a diluent and the blend is prepared to provide the lipid metabolism improver for preventing and treating hyperlipemia, ischemic heart diseases, cerebrovascular diseases, pulpy arteriosclerosis, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel use of the (+)-enantiomer of an aminopyridine compound or its acid addition salt, and more specifically, to the (+)-aminopyridine compound having a specific structure described below. -The present invention relates to a lipid metabolism improving agent containing an antipode or an acid addition salt thereof as an active ingredient.

[0002]

[Prior Art / Problems to be Solved by the Invention]
It binds to apolipoprotein and is transferred as a lipoprotein. Lipoproteins are classified into chylomicron, VLDL (ultra-low-density lipoprotein), LDL (low-density lipoprotein), HDL (high-density lipoprotein), etc. according to their density, and each of them plays a role of lipid. Working on the transfer. Among them, LDL is said to be useful for supplying cholesterol and phospholipid to tissues, and HDL is effective for removing them from tissues. Abnormal lipid metabolism refers to abnormal metabolism of these lipoproteins, and causes hyperlipidemia, cerebral infarction, arteriosclerosis, ischemic heart disease and the like. In particular, hyperlipidemia has become a major problem in recent years due to changes in eating habits accompanying the spread of Western European lifestyles. Hyperlipidemia is either serum cholesterol or triglyceride (TG),
Alternatively, it refers to a condition in which both are increased. cholesterol,
TG exists in the blood as a complex with a protein (lipoprotein), and thus chylomicrons, VLDL, L
An increase in the blood content of lipoproteins such as DL is one of the indicators of this disease state.

The lipid metabolism improving agent has a blood lipid lowering action, specifically, a lowering action of TG and TG-rich lipoproteins (chylomicrons, VLDL, etc.) and, at the same time, a cholesterol pool and HD showing inverse correlation
It refers to one that raises L-C (high density lipoprotein cholesterol) to make lipid metabolism smooth.
Ion exchange resins, cholesterol synthesis inhibitors (HMG-CoA reduction inhibitors), probucol, clofibrate preparations, nicotinic acid preparations, etc. may be effective for hyperlipidemia, which is one of the pathologies of abnormal lipid metabolism. Known, these are all TG, chylomicron, VLDL, LD
This is due to the action of lowering L.

[0004] Today, the relationship between antihypertensive drugs and lipid metabolism is drawing attention. An antihypertensive drug refers to a drug that relieves vascular tone and lowers blood pressure in hypertension. Due to its mechanism, antihypertensive diuretics, β blockers, α ₁ blockers, calcium antagonists, angiotensin converting enzyme. Classified as an inhibitor. Among antihypertensive drugs, antihypertensive diuretics and β-blockers have been shown to adversely affect lipid metabolism.
[Glimm, RH, et al .: Am. J. Med., 87 (suppl 2A): 56-6
3, 1986], α ₁ blockers have been shown to have a lipid metabolism-improving effect [Glimm, RH, et al .: Am. J. Me.
d., 80 (suppl 2A): 62S-65S, 1989].

Therefore, in recent years, the problem of the present invention is that the diseases caused by abnormal lipid metabolism such as hyperlipidemia, cerebral infarction, arteriosclerosis, obesity and diabetes are regarded as problematic.
Focusing on the relationship between an antihypertensive drug and lipid metabolism, it is to find one having an excellent lipid metabolism action as a usefulness other than the antihypertensive action of the antihypertensive drug, and to provide it as a lipid metabolism improving agent without side effects.

By the way, it has already been found that the (+)-enantiomer of the aminopyridine compound described below is useful as a circulatory agent based on the mechanism of potassium ion channel opener, particularly as a therapeutic agent for hypertension ( Japanese Patent Application 4-
327013).

[0007]

Therefore, the inventors of the present invention relate to the (+)-enantiomer of an aminopyridine compound,
As a result of further research, it was found that the compound has a blood lipid lowering action, that is, a blood triglyceride, chylomicron, and VLDL lowering action, and is clinically useful as an agent for improving lipid metabolism. The present invention has been completed.

[0008]

That is, the lipid metabolism improving agent of the present invention has an active ingredient represented by the general formula (I):

[0009]

[Chemical 2]

(In the formula, R ¹ and R ² may be the same or different and each represents hydrogen, an alkyl group having 1 to 6 carbon atoms or a protecting group for an amino group, and R ³ represents hydrogen or 1 to carbon atoms. 6 is an alkyl group, Z is S or NCN, m
Is 1 or 2 and n is 0 or 1, and the (+)-enantiomer of the aminopyridine derivative [hereinafter also referred to as compound (I)] or its acid addition salt is used as an active ingredient. The present invention relates to a lipid metabolism improving agent.

The (+)-enantiomer of the aminopyridine derivative or the acid addition salt thereof used in the present invention has a strong action expression and low toxicity, and therefore is extremely effective and safe. It has a great feature in that it is expensive

In the general formula (I), with respect to R ¹ and R ² , alkyl having 1 to 6 carbon atoms may be straight or branched, and examples thereof include methyl group, ethyl group, propyl group, butyl group and pentyl. Group, hexyl group, t-butyl group and the like. Examples of the amino group protecting group include amino group protecting groups known per se, such as an acyl group (acetyl group, formyl group, benzoyl group, t-butoxycarbonyl group, etc.). ), A benzyl group, a phthalimido group, and the like. R
Regarding ³ , the alkyl group having 1 to 6 carbon atoms may be linear or branched, like the alkyl group of R ¹ or R ² , and the same examples are exemplified. In this specification, the (+)-enantiomer means an enantiomer that rotates to the right in the plane of vibration of the linearly polarized light ray of the sodium D line.

A typical method for synthesizing the compound (I) which is the active ingredient of the present invention is shown below. Synthesis method (a)

[0014]

[Chemical 3]

(Where R is

[0016]

[Chemical 4]

Is a group represented by R ¹ , R ² and R
³ is the same as above. ) A compound of general formula (II) is reacted with a compound of general formula (III). The reaction is usually performed in a solvent. As a solvent,
Any one can be used as long as it does not adversely affect the reaction, and examples thereof include a protic polar solvent such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, dichloromethane, dichloroethane, chloroform and tetrahydrofuran. Halogenated hydrocarbons such as carbon chloride, aromatic hydrocarbons such as benzene, toluene and xylene, heterocyclic compounds such as pyridine and piperidine, aprotic polar solvents such as dimethylformamide (DMF) and dimethylsulfoxide, etc. It is illustrated. The compound (III) is used in an amount of about 0.9 to 5 times mol, preferably about 1 to 3 times mol, of the compound (II). This reaction is carried out under a temperature condition of about 10 to 80 ° C., preferably about room temperature (that is, about 15 to 25 ° C.) and a reaction time of about 1 to 200 hours. Compound (III) can be prepared, for example, as shown below.
ML Moore et al, Org. Synth. III 599 (1955).

[0018]

[Chemical 5]

(In the formula, R and R ³ are the same as described above.) The amine derivative (IIIa) as a starting compound is a compound of T. Pol.
l et al, Tetrahedron. It is obtained by converting the carboxylic acid derivative described in Lett., 30 5595 (1989) into an amine derivative by the method described in JP-A-63-287794 or a method analogous thereto.

Synthesis method (b)

[0021]

[Chemical 6]

(In the formula, R, R ¹ and R ² are the same as above.)

First Step The first step of this reaction is a reaction for obtaining a carbodiimide compound of the general formula (IV) from a thiourea compound of the general formula (I-1). This reaction can be carried out by a conventional method for synthesizing a carbodiimide compound from a thiourea compound. For example, a method of reacting a thiourea compound with a metal oxide such as mercury oxide or lead oxide in the presence of sulfur as necessary, a thiourea compound and triphenylphosphine in the presence of carbon tetrachloride and triethylamine. It can be carried out by a reaction method or the like. The reaction is usually performed in a solvent. As the solvent, any one can be used as long as it does not adversely affect the reaction, for example, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ethers, ethers such as dioxane, Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as ethanol, pyridine and the like. The amount of the metal oxide or triphenylphosphine used is such that the reagent is about 0.9 times to about 2 times the mole of the thiourea compound (I-1), and preferably about the same mole to about 1.2 times the mole. Is good. The reaction is carried out under the temperature condition of room temperature (about 15 to 25 ° C.) to the boiling point of the solvent, preferably 30 to 60 ° C.
The reaction time is about 00 hours.

Second Step The second step is the carbodiimide compound (I
V) is reacted with cyanamide to obtain a compound of general formula (I-2). The reaction is usually performed in a solvent. As the solvent, any one can be used as long as it does not adversely affect the reaction, for example, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ethers, ethers such as dioxane, Examples thereof include alcohols such as ethanol and pyridine. The amount of cyanamide used is about 0.9 to 2 times mol, preferably about to 1.2 times mol, of the carbodiimide compound (IV). The reaction is preferably carried out in the presence of a basic substance such as diisopropylethylamine, and the reaction condition is 10 to 30.
For example, the temperature is about 1 to 50 hours.

Synthesis method (C)

[0026]

[Chemical 7]

(Wherein Z, R, R ¹ and R ² are the same as above)

First Step In the first step of this reaction, the compound of general formula (II) is reacted with the compound of general formula (V) to obtain the compound of general formula (VI). The reaction is usually performed in a solvent. As the solvent, any solvent can be used as long as it does not adversely influence the reaction. For example, the solvent described in the synthesis method (a) is exemplified, and particularly pyridine, dimethylformamide (DMF), ethanol and the like. The polar solvent and the like are preferably used. The compound (V) is used in an amount of about 0.9 to 5 times, preferably about 1 to 2 times the mol of the compound (II). Reaction is 10
~ 80 ° C, preferably about room temperature (i.e.
The reaction time is about 1 to 200 hours under a temperature condition of about 25 ° C.

Second Step In the second step, the compound of the general formula (VI) is reacted with the compound of the general formula (VII) to give a compound of the general formula (I-1) or (I-2). To obtain the compound. The reaction is carried out in a solvent or without solvent. When using a solvent,
Any solvent can be used as long as it does not adversely affect the reaction, and for example, polar solvents such as pyridine, dimethylformamide (DMF), ethanol and the like are preferably used. The compound (VII) is used in an amount of about 0.9 times to 10 times, preferably about 1 to 3 times the molar amount of the compound (VI). The reaction is carried out at a temperature of 10 to 90 ° C. for 1 to 100
The reaction time is about the time.

Synthetic method (d)

[0031]

[Chemical 8]

(In the formula, Z, R, R ¹ and R ² are the same as above.) The compound of the general formula (I-3) is obtained by subjecting the compound of the general formula (I-1) or (I-2) to an oxidation reaction. It is obtained by attaching to. The oxidation reaction is carried out in the presence of an oxidizing agent. The oxidation reaction is usually performed in a solvent. As the solvent, any solvent can be used as long as it does not adversely influence the reaction, for example, dichloromethane, dichloroethane,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride,
Alcohols such as methanol and ethanol, benzene,
Examples thereof include aromatic hydrocarbons such as toluene and xylene, and fatty acids such as acetic acid and propionic acid. Examples of the oxidizing agent used in the reaction include peracetic acid, perbenzoic acid, m-
Examples thereof include peracids such as chloroperbenzoic acid and hydrogen peroxide. The oxidizing agent is used in an amount of about 0.9 times to 2 times, preferably about 1 to 1.2 times the mol of the compound (I-1) or the compound (I-2). . The reaction is performed under ice cooling to under heating, preferably under ice cooling to about room temperature (1
The reaction time is about 1 to 10 hours under a temperature condition of about 5 to 25 ° C.

Regarding the general formula (I) in the present invention, R
^A compound in which ¹ and / or R ² is a protecting group for an amino group can be converted into a compound in which R ¹ and / or R ² is hydrogen by subjecting to a deprotection reaction by a method known per se. The means for removing the protective group varies depending on the type of the protective group, and specifically, it may be appropriately selected from a method of treating with an acid (for example, hydrochloric acid), an Ingemans method using hydrazine, and the like. The (+)-enantiomer of the aminopyridine compound, which is the active ingredient of the present invention, can be produced by optical resolution in addition to the above synthetic methods (a) to (d).

The compound (I) thus produced, which is the active ingredient of the present invention, can be isolated and purified by known means such as concentration,
By using extraction, chromatography, reprecipitation, recrystallization and the like as appropriate, the product can be collected in any purity.

Further, since the compound (I) which is the active ingredient of the present invention 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 a pharmacologically acceptable non-toxic salt,
For example, salts with inorganic acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.), salts with organic acids (acetate, succinate,
Maleate, fumarate, malate, tartrate, etc.) and the like.

The compound (I) and its acid addition salt, which are the active ingredients of the present invention, can be used to treat HDL-C (high density lipoprotein cholesterol) in mammals such as mice, rats, rabbits, dogs, cats and humans. With an increase,
Significant reductions in TG and TG-rich lipoproteins, chylomicrons, VLDL are observed. In addition, as one of its action mechanisms, blood LPL (lipoprotein lipase), H-TGL (hepatic triglyceride lipase)
Shows increased activity of.

The lipid metabolism improving agent containing the compound (I) of the present invention and an acid addition salt thereof as an active ingredient is a pharmaceutically acceptable additive (eg carrier, excipient, diluent, etc.). The necessary components can be appropriately mixed to prepare a pharmaceutical composition in the form of powder, granules, tablets, capsules, injections and the like, which can be orally or parenterally administered. An effective amount of the compound (I) of the present invention and its acid addition salt is incorporated in the above-mentioned preparation.

The dose varies depending on the administration route, symptoms, body weight or age of the patient, but when administered orally to an adult patient, for example, 0.05 to 50 mg / kg body weight / day,
Particularly, it is desirable to administer 1 to 20 mg / kg body weight / day in divided doses 1 to several times a day. When administered intravenously,
05-5 mg / kg body weight / day, especially 0.1-2 mg / kg body weight /
It is desirable to administer the drug in divided doses once to several times a day.

[0039]

EXAMPLES The present invention will be described in more detail below with reference to experimental examples, examples and reference examples, but these examples and experimental examples do not limit the present invention.

Experimental Example 1 Blood lipid improving action 1. Experimental animals Female Obese Zucker rats of 10 to 11 weeks of age were purchased (Charles River) and preliminarily reared for 1 week or more, and then subjected to the experiment. Obese Zucker rat is an autosomal recessive hereditary obese animal that exhibits hyperinsulinemia and hyperTGemia.

2. Reagents used Compound (I) obtained in Reference Example below was used. Further, among the antihypertensive drugs, prazosin, which is an α ₁ blocker which is clinically said to have a relatively high blood lipid improving effect, was used as a comparative drug. The dose of prazosin at this time was 5 mg / kg of compound (I) in SHR rats.
Dosage (1
(mg / kg / day) was set. The compound (I) was dissolved in physiological saline, and prazosin was dissolved in dimethylsulfoxide (DMSO), and then dissolved in physiological saline.
It was diluted to 00 times before use.

3. Measurement items Blood lipids are total cholesterol (TC), serum lipoprotein fraction [chylomicrons (Chy), VLDL, L
DL], high-density lipoprotein cholesterol (HDL
-C) was measured. The liver weight was also measured, and the drug administration group and the solvent administration group were compared.

4. Experimental method The drug dissolved in a solvent was orally administered to each rat at 10 ml / kg once a day for 2 weeks. The rats were fasted for 16 hours after the final administration to prevent a rapid rise in TG-rich lipoprotein immediately after feeding, after which the rats were killed by decapitation, and the exsanguinated blood was collected. After allowing the blood to coagulate by standing at 4 ° C. for 2 hours or more, the serum was separated by centrifugation at 1500 g for 15 minutes at 4 ° C. The TC in each serum was determined by the enzyme method [Yoshinori Toku, Kaburaya Fumio, Kato Shoji, Fujita Katsunari; Atherosclerosis 8, 737-743 (1981)], and TG was the method of Fossati et al. [Fossati P, Prencipe L; Clin. Chem. .28, 2077-20
80 (1982)], serum lipoprotein fraction is heparin-Ca
Turbidity method [Burstein M, Scholnick HR; Avanses in Li
pid Research, Vol.11 ed, New York: Academic Press,
p.81-83 (1973)], HDL-C is a sedimentation method [Burstein Me
al .; J. Lipid Res. 11, 583 (1970)]. In addition, the liver was removed and its weight was measured.

5. Results (i) TC compound (I) and prazosin had almost no effect (FIG. 1).

(Ii) TG In compound (I), TG was dose-dependently decreased, and in the 5 mg / kg / day administration group, it was significantly reduced to about half that of the solvent administration group. . On the other hand, α
In prazosin ₁ blocker, substantially no change was observed (Figure 2).

(Iii) Serum lipoprotein fraction (Chy,
VLDL, LDL) In compound (I), a significant decrease in TG-rich Chy and VLDL was observed in the 5 mg / kg / day administration group (Fig. 3), but no effect was observed in prazosin (Fig. 3). (Fig. 4).

(Iv) Heparin-aggregating lipoprotein (HPL) In general, the sum of Chy + VLDL + LDL, which is considered to be an index of “bad” cholesterol, is shown as HPL. As a result, Compound (I) significantly suppressed this by about 1/4. However, prazosin did not show such an effect (FIG. 5).

(V) 5 mg / kg of compound (I) in inverse correlation with the decrease in HDL-C TG
In the / day administration group, a significant increase in HDL-C was observed (Fig. 6).

(Vi) Liver weight In the 2 drug administration group, the liver weight was hardly affected (FIG. 7).

The effects of compound (I) and prazosin on blood lipids are summarized in Table 1.

[0051]

[Table 1]

The strong TG possessed by the compound (I)
It was also revealed that the lowering effect was exhibited by the administration of 5 mg / kg / day in a shorter administration period of 1 week (FIG. 8).

Experimental Example 2 Lipoprotein lipase (LPL) and hepatic triglyceride
Cerilipase (H-TGL) activity enhancing action 1. Experimental animals Females aged 10 to 11 weeks, similar to the above-mentioned lipid improving effect in blood
I bought Obese Zucker rats (Charles River),
After preliminarily breeding for 1 week or more, it was subjected to an experiment.

2. Reagents Compound (I) was found to have an effect of improving lipid metabolism in blood.
se (5 mg / kg / day, po) was administered.
The compound (I) was dissolved in physiological saline and used.

3. Measurement items Enzyme activity is measured for LPL and H-TGL present in blood and LPL activity that can be present in intestinal membrane adipose tissue,
A comparison was made between the solvent administration group and the drug administration group.

4. Experimental method Rats were orally administered with the solvent and compound (I) for 1 week. After administration on the 7th day, the rats were fasted for 16 hours, followed by administration of the solvent and compound (I), and 2 hours after that, 1000 units / kg of heparin was administered through the tail vein. 10 to 30 minutes after the administration of heparin, the rat was anesthetized with CO ₂ and whole blood was collected from the heart (EDTA as an anticoagulant 1 mg /
ml was used). Blood is rapidly 1,500g, 10
Min, centrifugation was performed at 4 ° C., and the obtained plasma (post-heparin plasma) was used for the experiment. The method for measuring the enzyme activity is the method of Yamada et al. [La Cossa, JC, Levy,
RJ, Windmueller, HG, Fredickson, DS; J. Lipi
d. Res. 13, 356 (1972)], using a ¹⁴ C-labeled substrate.

Preparation of adipose tissue extract Adipose tissue of the intestinal membrane was collected from the rat after blood collection, immediately frozen in liquid nitrogen, and sliced. 2m for 1g of fat
l Krebs-Ringer solution (500
IU / ml heparin-containing, pH 7.4) was added, 37
LPL extraction was performed in the tissue while shaking at 1 ° C for 1 hour. 0.15 ml of the extract was collected and used for the experiment.

Preparation of Substrate For 89 mg of triolein [0.444 ml of stock solution (1 g / 5 ml heptane)], 37 kBq of [ ¹⁴ C] triolein [stock solution (1.85 MBq / 5 ml)
Hexane) 0.1 ml] was added, and the solvent was distilled off under nitrogen. Here, 0.6% of 1% Triton X-100
1, 4% BSA / Tris-HCl (0.2M, pH
8.6) 0.6 ml, 0.2 M Tris-HCl (p
H8.6) (6.8 ml) was added, and the mixture was sonicated for 3 minutes under ice cooling to prepare a substrate emulsion (prepared before use).

Enzyme measurement 0.2 ml of substrate emulsion (2.5 μmol, 500
0 dpm), 0.15 ml of 4% BSA / Tri
s-HCl (0.2 M, pH 7.4) and 0.05 ml of rat serum (separately prepared) were mixed, and 0.15 ml of extract liquid from test plasma or fat was added thereto, and the mixture was incubated at 37 ° C for 1
The reaction was carried out with shaking for a time. The reaction was stopped with 2 ml of 3N sulfuric acid-isopropanol, 1 ml of water and 2 ml of hexane were added, and 10 μl of ³ H-oleic acid (300 nmol, 300 nmol, as an internal standard was added to calculate extraction efficiency.
30,000 dpm, prepared before use) was added. Extraction by shaking (200 rpm) for 15 minutes, collecting hexane fraction,
Further, the product was extracted with 1 ml of 0.1N KOH. The liquid layer was separated by standing for 1 hour or more, the aqueous layer was collected, 10 ml of scintillator (ACSII) was added, and the radioactivity was measured with a liquid scintillation counter to measure the enzyme activity. In addition to LPL, hepatic triglyceride lipase (H-
TGL) also exists. Therefore, in order to distinguish between the two, an anti-LPL monoclonal antibody (100 μg / ml, Oncogene
Sci.) Was reacted to inactivate LPL (20 μl antibody solution in 150 μl plasma, incubated for 1 hour at 4 ° C.), and post-heparin plasma was measured at the same time to separate enzyme activity. The enzyme activity was calculated by substituting the following formula

[0060]

[Equation 1]

In the post-heparin plasma, the total lipase activity and the lipase activity of the anti-LPL antibody-added plasma were measured, and the lipase activity of the anti-LPL antibody-added plasma was measured by H-TGL.
The remaining activity obtained by subtracting the lipase activity of anti-LPL antibody-added plasma from the activity and total lipase activity was expressed as LPL activity.

5. Results Obese Zucker r was obtained by continuous administration of compound (I) for 1 week.
The plasma LPL and H-TGL activities of at showed a significant increase. On the other hand, the LPL activity in adipose tissue showed almost no change between the solvent administration group and the compound (I) administration group (Fig. 9). In addition, Obes fasting Compound (I) for 16 hours
When a single dose was administered to e Zucker rat and the enzyme activity was measured 2 hours later, no change was observed in the LPL and H-TGL activities (FIG. 10). From this result, it was revealed that the LPL and H-TGL activity-enhancing effects of compound (I) were not observed in a single administration, but were first exhibited by continuous administration.

Experimental Example 3 Single-dose toxicity test using rat No death occurred even after oral administration of the compound (hydrochloride) of the present invention at 450 mg / kg.

Example 1 Tablet (1) Compound (I) 10 mg (2) Fine granules for direct compression No. 209 (manufactured by Fuji Chemical Co., Ltd.) 46.6 mg Magnesium aluminometasilicate 20% Corn starch 30% Lactose 50% (3 ) Crystalline cellulose 24.0 mg (4) Carboxymethyl cellulose calcium 4.0 mg (5) Magnesium stearate 0.4 mg (1), (3) and (4) are all passed through a 100 mesh sieve in advance. 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. Add (5) to the mixed powder which is homogenized and mixed for a short time (30 seconds), and press the mixed powder into a tablet (pestle:
6.3 mmφ, 6.0 mmR) to give tablets of 85 mg each. If necessary, the tablets may be coated with a commonly used gastric film coating agent (for example, polyvinyl acetal diethylaminoacetate) or an edible coloring agent.

Example 2 Capsule (1) Compound (I) 50 g (2) Lactose 935 g (3) Magnesium stearate 15 g The above ingredients were weighed and mixed evenly, and 200 mg each of the mixed powder was placed in a hard gelatin capsule. Filled.

Example 3 Injection (1) Compound (I) Hydrochloride 5 mg (2) Glucose 100 mg (3) Physiological saline 10 ml After filtering the above mixture with a membrane filter, sterilizing filtration was performed again and the filtration was performed. The liquid was aseptically dispensed into vials and filled with nitrogen gas to give an intravenous injection.

Reference Example 1 N- (6-amino-3-pyridyl) -N ''-cyano-
N '-(endo-2-norbornyl) guanidine (+) pair
Production of Palm Body (Compound I) and Hydrochloride thereof: (1) Optical activity-endo-2-norbornylisothiocyanate
Anate production

[0068]

[Chemical 9]

2.904 g of sodium hydroxide and 17 ml of water
Was dissolved in water, and 5.240 ml of carbon disulfide was added thereto under ice cooling. Under ice cooling, (2R)-(-)-endo-2-
When 8 g of norbornylamine was gradually added, white crystals were precipitated. After stirring at room temperature for 1 hour and at 70 ° C. for 1 hour, a further orange liquid was obtained. The temperature was returned to room temperature, 7.636 ml of ethyl chlorocarbonate was added dropwise, and the mixture was further stirred at room temperature for 1 hour to obtain a yellow liquid separated into two layers.
The oily substance deposited in the lower layer was taken out with a separating funnel, suspended in 20 ml of 20% aqueous sodium hydroxide solution, and vigorously stirred for 16 hours. 20 ml of water was added and extracted with hexane. After drying over magnesium sulfate, the solvent was distilled off, and column purification (hexane) was performed to obtain the desired product, optically active-endo-2-.
A white powder of norbornyl isothiocyanate was obtained. Yield: 5.109 g (46.5%)

(2) Optical activity-N- (6-amino-3-pyrone
Lysyl) -N '-(endo-2-norbornyl) thioure
Manufacturing of

[0071]

[Chemical 10]

4 g of 2,5-diaminopyridine hydrochloride was dissolved in 20 ml of dimethylformamide (DMF), and 3.655 g of the optically active endo-nor-2-norbornyl isothiocyanate obtained in the above (1) was added. Then, 6.125 ml of triethylamine was added. The mixture is stirred for 16 hours at room temperature, 80 ml of 5% aqueous potassium carbonate solution and 80 ml of water.
Was added and extracted with ethyl acetate. The solvent was distilled off, column purification (chloroform: methanol = 10: 1) and recrystallization from methylene chloride-methanol-diethyl ether were carried out, and the desired substance, optically active -N- (6-amino-3) was used.
A pale pink powder of -pyridyl) -N '-(endo-2-norbornyl) thiourea was obtained. Yield: 3.402 g (59.0%) Melting point: 173.0 to 174.0 ° C. ¹ H-NMR of the target substance is shown below. ¹ H-NMR (DMSO): 0.7-1.7 (7H, m), 1.8-2.1 (1H,
m), 2.1-2.25 (1H, m), 2.4-2.6 (1H, m), 4.2-4.45 (1
H, m), 5.77 (2H, brs), 6.40 (1H, d, J = 8.0Hz), 7.37
(1H, dd, J = 2.0, 8.0Hz), 7.55 (1H, brs), 7.77 (1H,
d, J = 2.0Hz), 8.84 (1H, brs) IR (KBr): 3500-3000, 2900, 2850, 1630, 150
0, 1530

(3) Optical activity-N- (6-amino-3-
Pyridyl) -N '-(endo-2-norbornyl) cal
Bodiimide production

[0074]

[Chemical 11]

The optically active N- (6-amino-3-pyridyl) -N '-(endo-2-norbornyl) obtained in the above (2) was placed in a 1-liter eggplant-shaped flask equipped with blue silica gel and a Dimroth condenser. ) Thiourea (29.7g, 1
A solution of 13.2 mmol) of ethanol (150 ml) -methylene chloride (150 ml) was added, and mercury oxide (49.0 g,
226.4 mmol) and sulfur powder (1.82 g, 56.
6 mmol) was added. The mixture was stirred under reflux for 15 hours, mercury oxide (20.0 g, 92.3 mmol) and sulfur powder (500 mg, 15.6 mmol) were further added, and the mixture was stirred under reflux for 2.5 hours. Insoluble matter was removed by filtration through Celite,
The filtrate was concentrated, leaving about 100 ml of ethanol to obtain an ethanol solution of the target compound.

(4) N- (6-amino-3-pyridyl)
-N "-cyano-N '-(endo-2-norbornyl) g
Method for producing (+) antipode of anidine

[0077]

[Chemical 12]

A 2-liter separate three-necked flask equipped with a nitrogen balloon was charged with the optically active -N- obtained in (3) above.
(6-Amino-3-pyridyl) -N '-(endo-2-
Norbornyl) carbodiimide (25.8 g, 113.
2 mmol of ethanol (200 ml) -methylene chloride (25
0 ml) solution and add cyanamide (5.23 g, 124.5 mmo)
l), diisopropylethylamine (9.9 ml, 56.
6 mmol) was added, and the mixture was stirred at room temperature for 18 hours, cyanamide (2.5 g, 59.5 mmol) was further added, and the mixture was stirred for 72 hours. The deposited material was filtered and recrystallized to obtain the desired product as white needle crystals. Yield: 22.5 g (74%) [α] _D = + 12.0 (c = 0.6 ethanol) Melting point: 184-185 ° C. ¹ H-NMR (DMSO): 0.9-1.6 (7H, m), 1.7- 2.05 (1
H, m), 2.05-2.2 (1H, brs), 2.3-2.45 (1H, m), 3.85-
4.1 (1H, m), 5.91 (2H, s), 6.43 (1H, d, J = 8.0Hz),
6.58 (1H, d, J = 4.0Hz), 7.21 (1H, dd, J = 2.0, 8.0Hz),
7.73 (1H, d, J = 2.0Hz), 8.46 (1H, s) IR (KBr): 3500-3000, 2900, 2850, 2150, 1600,
1500

(5) N- (6-amino-3-pyridyl)
-N "-cyano-N '-(endo-2-norbornyl) g
Process for producing anidine (+) enantiomer hydrochloride

[0080]

[Chemical 13]

N- (6-
Amino-3-pyridyl) -N "-cyano-N '-(endo-2-norbornyl) guanidine (+) enantiomer (21.
A solution of 9 g, 81.0 mmol) in methylene chloride (250 ml) -methanol (100 ml) was added, and under ice cooling, 4.74N.
Hydrochloric acid in ethanol (17.1 ml, 81.0 mmol)
Was gradually added dropwise. The mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure, the precipitated substance was collected by filtration, and dried at 78 ° C. for 6 hours with a vacuum pump to obtain a target white powder. Yield: 21.22 g (85%) [α] _D = +26.5 (C = 0.5 ethanol) ¹ H-NMR (DMSO): 0.9-1.7 (7H, m), 1.75-2.05 (1
H, m), 2.05-2.25 (1H, m), 2.35-2.50 (1H, m), 3.9-4.
2 (1H, m), 7.03 (1H, d, J = 10.0Hz), 7.44 (1H, d, J =
6.0Hz), 7.84 (1H, d, J = 10.0Hz), 7.98 (1H, s), 8.0-
8.4 (2H, brs), 9.31 (1H, brs) IR (KBr): 3600-2200, 2150

INDUSTRIAL APPLICABILITY The lipid metabolism-improving agent of the present invention exerts strong TG and TG-rich lipoprotein lowering action even after continuous administration for a short period of time and has low toxicity. Therefore,
It is useful for the prevention and treatment of diseases caused by abnormal lipid metabolism, such as hyperlipidemia, ischemic heart disease, cerebrovascular disease, atherosclerosis and the like.

[Brief description of drawings]

1] Total cholesterol (TC) of compound (I) and prazosin in fasted Obese Zucker Rats.
Show the effect on.

FIG. 2 shows the effect of compound (I) and prazosin on triglyceride (TG) in fasted Obese Zucker Rats.

FIG. 3 shows the effect of compound (I) on the serum lipoprotein fraction in fasted Obese Zucker Rats.

Figure 4: Praz in fasted Obese Zucker Rats
The effect of osin on the serum lipoprotein fraction is shown.

FIG. 5 shows the effect of compound (I) and prazosin on plasma heparin-aggregating lipoprotein (HPL) in fasted Obese Zucker Rats.

FIG. 6 shows the effect of compound (I) and prazosin on high-density lipoprotein-cholesterol (HDL-C) in fasted Obese Zucker Rats.

FIG. 7 shows the effect of compound (I) and prazosin on liver weight in fasted Obese Zucker Rats.

FIG. 8 shows the short-term effects of compound (I) on TC, TG, and HDL-C in fasted Obese Zucker Rats.

FIG. 9: Compound (I) in adipose tissue and postheparin plasma collected from fasted Obese Zucker Rats
2 shows the effect of azotin and prazosin on LPL and H-TGL activities.

FIG. 10 shows the effects of a single dose of Compound (I) on LPL and H-TGL activity in fasted Obese Zucker Rats.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kenji Nakamura Invited 2-25-1 Otani, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ and R ² may be the same or different and each is hydrogen, an alkyl group having 1 to 6 carbon atoms or a protecting group for an amino group, and R ³ is hydrogen or an alkyl group having 1 to 6 carbon atoms. A group, Z is S or NCN, and m is 1 or 2
, And n represents 0 or 1), a lipid metabolism-improving agent comprising an (+)-enantiomer of an aminopyridine derivative represented by the formula (1) or an acid addition salt thereof as an active ingredient.