JPH09118655A - Phenylethanolamine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a preventive and a therapeutic agent for diabetic, hyperglycemia and obesity, having no β1 and β2 -adrenergic activity, showing β3 -adrenergic activity, having no adverse effects such as increase in heart rate, bronchodilation, smooth muscle relaxation, etc. SOLUTION: This compound is shown by formula I [R1 is H or a halogen; R2 is H or a 1-4C alkyl; R3 to R5 are each H or a group of the formula OCH2 CO2 R6 (R6 is R2 ) and two or more of R3 to R5 are not H] or its salt such as N-[2-(2,4-dicarbomethoxymethoxy)phenyl-1-methylethyl]-2-hydroxy-(3-chl orophenyl) ethanamine. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III to give a compound of formula IV and reducing the compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phenylethanolamine derivative, a process for producing the same, and a preventive or therapeutic agent for diabetes, hyperglycemia and obesity in mammals containing them as an active ingredient.

[0002]

2. Description of the Related Art Diabetes is a condition in which utilization of glucose in a living body is insufficient. As a result, an increase in blood glucose level or chronic hyperglycemia occurs, which causes various complications. In the treatment of diabetes, how to normalize the blood glucose level is important. As one of the methods,
Insulin (a body hormone that controls blood sugar)
, Parenteral administration of drugs, oral administration of drugs and diet. By the way, diabetes refers to type I diabetes and
It is classified into two major forms of type II diabetes. Type I diabetes is due to insulin deficiency, which is basically ameliorated by insulin administration. Type II diabetes, on the other hand, is a non-insulin dependent type of diabetes that occurs even when insulin levels are normal or elevated. This means that the tissue's response to insulin is not normal. In the treatment of type II diabetes,
Oral administration of a drug that promotes insulin secretion or a drug that suppresses absorption of sugar contained in the diet, parenteral administration of insulin, and diet therapy are performed. However, these are not the fundamental treatment methods for diabetes, and are often accompanied by side effects and patient distress, and therefore there is a strong demand for the development of newer drugs that improve the pathological condition of diabetes. Furthermore, it is known that most type II diabetes is obesity, and it is considered that the onset of diabetes and obesity are closely related. Further, it is known that obesity-diabetic patients also improve diabetes by eliminating the obesity. Obesity is considered to be caused by the accumulation of fat in the living body, and it is necessary to consume the accumulated fat in order to improve obesity. Recently, obesity or diabetes has become a problem not only in humans but also in pets due to excessive nutrition and lack of exercise. Furthermore, in the case of breeding meat animals, it is desired to develop a method for reducing fat and increasing the amount of lean meat.

On the other hand, β ₁ , β ₂ and β ₃ subtypes are known for β-adrenergic receptors. Stimulation of β ₁ receptors primarily causes an increase in heart rate. β ₂
Receptor stimulation primarily causes bronchodilation and smooth muscle relaxation. Stimulation of the β ₃ receptor primarily promotes lipolysis (decomposing triglycerides in adipose tissue into glycerol and free fatty acids) and energy expenditure, which causes a reduction in fat mass. Therefore, compounds having β ₃ agonist activity are considered to have antiobesity activity. Furthermore, they have been reported to show antihyperglycemic activity in animal models of type II diabetes. These are β
₃ agonists have been shown to be useful in ameliorating obesity in mammals and eliminating diabetic hyperglycemic conditions in mammals. The β ₃ receptor is expressed in the digestive tract, skeletal muscle and the like. In the digestive tract, especially the intestinal tract, stimulation of β ₃ receptors is considered to be involved in relaxation of intestinal smooth muscle. This indicates that β ₃ agonists are useful as therapeutic agents for irritable bowel syndrome (IBS). The major β ₃ agonists currently known include, for example, the following.

That is, Einsworth et al.
The following formula (IX) in No. 5444

Embedded image And a carboxylic acid methyl ester thereof or a pharmaceutically suitable salt thereof. These compounds have antiobesity activity and antihyperglycemic activity. The carboxylic acid methyl ester has lipolytic activity (β ₃ ) in rats (Nature, 309, 163,
1984). The action on the β ₃ adrenergic receptor indicates that this kind of compound is useful as an antiobesity agent. Furthermore, compounds of this type have been reported to have antihyperglycemic activity in animal models of type II diabetes.
A drawback in treating diabetes or obesity with β ₃ agonists is their potential to stimulate other β receptors and their associated side effects. Examples of these include finger tremor due to β ₂ receptor stimulation and increase in heart rate due to β ₁ receptor stimulation. Although the carboxylic acid methyl ester has β ₃ agonistic activity, it also has β ₁ and β ₂ agonistic activities, and these are considered to cause side effects.

On the other hand, Bloom et al.
The following formula (X) in No. 320153

Embedded image (Wherein R represents carboxy or alkoxycarbonyl) or salts thereof are disclosed. These compounds have β ₃ selectivity, but 10 ^-4 M
Has a slight β ₂ -agonizing activity in.

Epstein et al. In JP-A-7-2831 have the following formula (XI)

Embedded image (Wherein R represents carboxy or alkoxycarbonyl) or salts thereof are disclosed. These compounds have β at a concentration of 10 ^-6 M or more.
Binding to β ₁ and β ₂ receptors is expected, and associated β ₁ and β ₂
Has operative activity.

Okuyama et al. In JP-A-7-112958, the following formula (XII)

Embedded image (In the formula, R ₇ and R ₈ are hydrogen, a halogen atom, (C _1-
C ₄₎ alkyl or (C ₁ -C ₄₎ alkoxy group, R ₉ represents a formula _{(XIII) -O-CR 10 R} 11 -CO 2 R 12 (XIII), R 10 is hydrogen, (C ₁ -C ₁₃₎ alkyl or aromatic ring, R ₁₁ and R ₁₂ is hydrogen or (C ₁ -C ₄₎
(Representing alkyl) are disclosed. These compounds were found to be β ₁ , β _{2 at} concentrations of 10 ^-6 M or higher.
It has agonistic activity and side effects are expected.

[0008]

Β ₃ agonists are useful as antiobesity agents, antidiabetic agents, or therapeutic agents for irritable bowel syndrome (IBS), while on the other hand, obesity, diabetes or IBS The number of patients tends to increase. However, the existing β ₃ agonists have a problem of side effects derived from β ₁ and β ₂ agonistic activities. Therefore, it is desired to develop a compound having β ₃ selective agonistic activity, which does not have β ₁ and β ₂ agonistic activity even at a higher concentration than existing β ₃ agonists.

[0009]

The present inventors have found that β ₁ , β ₂
Has no agonistic activity, has β ₃ agonistic activity, and
As a result of diligent research aimed at a compound having an antihyperglycemic effect in a type I diabetes model animal, the following general formula
The inventors have found that the phenylethanolamine derivative having the structure represented by (I) satisfies the above requirements and completed the present invention. That is, the compound of the present invention has β ₁ ,
It has almost no β ₂ -agonist activity, while it induces lipolysis in rat adipocytes (rat β ₃ -agonist activity)
Have an effect. Therefore, the compound of the present invention is a β ₃ selective agonist, and the compound of the present invention has an antihyperglycemic effect in a model animal of type II diabetes.

That is, the present invention has the general formula (I)

Embedded image (In the formula, R ₁ represents a hydrogen atom or a halogen atom, and R ₂
Represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group,
R ₃ , R ₄ and R ₅ are independently a hydrogen atom or —OCH ₂
CO ₂ R ₆ is represented, but two or more of R ₃ , R ₄ and R ₅ are not hydrogen, and R ₆ is hydrogen or (C ₁ -C
₄ ) Represents an alkyl), and a pharmaceutically acceptable salt thereof.

The present invention also relates to the prevention or treatment of diabetes, hyperglycemia and obesity in mammals containing the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. It also relates to agents. Examples of the halogen atom represented by R ₁ in the above general formula (I) of the present invention include fluorine, chlorine, bromine and iodine, and a (C ₁ -C ₄ ) alkyl group represented by R ₂ and R _6. Examples thereof include linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl. The compounds of the present invention have the general formula
Included are all optical isomers, stereoisomers, and metabolites and metabolic precursors of these compounds, which are possible due to the chemical structure represented by (I).

The compound represented by the general formula (I) of the present invention can be produced by various conventional methods, for example, the methods shown below. (a) General formula (II)

Embedded image (In the formula, R ₁ is as defined in the above general formula (I))
And the general formula (III)

Embedded image (Wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in the above general formula (I)) and reacted with the compound of the general formula (I
V)

Embedded image (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the above general formulas.
(As defined in (I)) (step A),
By reducing this compound (step B), the phenylethanolamine derivative represented by the above general formula (I) is produced.

Step A is a step for producing the compound having the above-mentioned general formula (IV), and is usually suitably carried out in the presence of a solvent. The reaction is carried out while removing the water produced by the Dean-Stark apparatus or in the presence of a dehydrating agent such as anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate, and molecular sieve. Be seen. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, methylene chloride, tetrahydrochloride. Carbon chloride, halogenated hydrocarbon such as 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol;
Sulfoxides such as dimethyl sulfoxide; sulfolane; or a mixed solvent thereof is preferably used. The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux.
The reaction time varies depending on the reaction reagent, reaction temperature, etc.
Usually 0.5 to 12 hours. It is preferably carried out under reflux with heating for 1 to 5 hours in a solvent of hydrocarbons or alcohols. More preferably, it is carried out by heating under reflux in benzene for 1 to 3 hours and dehydration.

The step B is a step of producing the above-mentioned general formula (I) and a step of reducing the compound having the above-mentioned general formula (IV). The reaction is usually carried out by reduction with a reducing agent or hydrogenation in the presence of a catalyst. Examples of the reducing agent used for the reduction of the compound of the general formula (IV) with a reducing agent include lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like. A metal hydride is used. The reaction is usually performed in the presence of a solvent. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used, for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, methylene chloride, tetrachloride. Carbon, halogenated hydrocarbon such as 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol;
Sulfoxides such as dimethyl sulfoxide; water; or a mixed solvent thereof is preferably used. Reaction is -78 ° C
To heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. Preferably in the presence of sodium borohydride or sodium cyanoborohydride in a solvent of alcohols for 1 hour to 5 hours,
It is carried out at 30 ° C to 50 ° C.

The catalytic hydrogenation reaction of the compound of general formula (IV) is carried out by reacting molecular hydrogen in the presence of a catalyst. As the catalyst used, a catalytic hydrogenation catalyst such as palladium-carbon, platinum oxide, or palladium hydroxide is preferably used. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used. For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; diethyl ether, diisopropyl ether, tetrahydrofuran. , Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; organic acid esters such as methyl acetate and ethyl acetate; organic acids such as acetic acid Or a mixed solvent thereof is preferably used. For the reaction, hydrogen gas at atmospheric pressure, or hydrogen gas at medium or high pressure, preferably 1 to 5 kg / cm ² of hydrogen gas is used. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. The reaction is preferably carried out using platinum oxide in an alcohol solvent, especially methanol or ethanol, under hydrogen gas at atmospheric pressure at 0 ° C. to 50 ° C. for 0.5 hours to 12 hours.
Done in time.

In some cases, the above steps A and B can be successively performed in the same container. That is, the general formula (I
The compound of general formula (I) can be produced by reacting the compound of I) with the compound of general formula (III) in a solvent in the presence of a catalyst under catalytic hydrogenation conditions. As the catalyst used, a catalytic hydrogenation catalyst such as palladium-carbon, platinum oxide, or palladium hydroxide is preferably used. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used. For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; diethyl ether, diisopropyl ether, tetrahydrofuran. , Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; organic acid esters such as methyl acetate and ethyl acetate; organic acids such as acetic acid Or a mixed solvent thereof is preferably used. For the reaction, hydrogen gas at atmospheric pressure, or hydrogen gas at medium or high pressure, preferably 1 to 5 kg / cm ² of hydrogen gas is used. The reaction is preferably carried out in an alcoholic solvent, especially methanol or ethanol, in the presence of acetic acid, with hydrogen oxide at atmospheric pressure using platinum oxide as catalyst, at 0 ° C. to 50 ° C. for 3 to 12 hours.

(B) General formula (V)

Embedded image Wherein R ₁ is as defined in general formula (I) above and general formula (VI)

Embedded image (Wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in the above general formula (I)) are reacted to give a phenylethanolamine derivative represented by the above general formula (I). Is manufactured.

In this reaction, inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; tertiary amines such as triethylamine and diisopropylethylamine; pyridines such as pyridine and 4-dimethylaminopyridine;
In the presence or absence of. This reaction is suitably carried out in the presence of a silylating agent such as trimethylsilylacetamide or chlorotrimethylsilane. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used, for example, benzene,
Hydrocarbons such as toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethylene and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; dimethyl Amides such as formamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; sulfoxides such as dimethyl sulfoxide; pyridine; or a mixed solvent thereof is preferably used. The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. Preferably in a dimethylsulfoxide solvent in the presence of trimethylsilylacetamide for 6 hours to 12 hours.
The time is 20 ° C. to 80 ° C.

(C) General formula (VII)

Embedded image (Wherein R ₁ is as defined in the above general formula (I), L represents a leaving group such as chlorine, bromine, iodine, and a sulfonate) and the general formula (VI)

Embedded image (In the formula, R ₂ , R ₃ , R ₃ , R ₄ and R ₅ are the above general formulas.
A compound of general formula (VIII)

Embedded image (Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined in the above general formula (I)) (Step C)
Then, it is reduced (step D) to produce the phenylethanolamine derivative represented by the above general formula (I).

Step C is a step for producing a compound having the above-mentioned general formula (VIII), which is an inorganic base such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate; a tertiary amine such as triethylamine or diisopropylethylamine;
It is carried out in the presence or absence of pyridines such as pyridine and 4-dimethylaminopyridine. The reaction is preferably carried out in the presence of a silylating agent such as trimethylsilylacetamide or chlorotrimethylsilane. Specific examples of the leaving group L represented by the above formula (VII) include chlorine, bromine,
Examples thereof include iodine, methanesulfonyloxy group, p-toluenesulfonyloxy group and the like. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used. For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; diethyl ether, diisopropyl ether, tetrahydrofuran. , Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof is preferably used. . The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. It is preferably carried out in sulfoxides, especially dimethyl sulfoxide, in the presence of trimethylsilylacetamide for 6 to 12 hours at a temperature of 20 ° C to 80 ° C.

Step D is a step of producing the compound of the above general formula (I), and a step of reducing the compound having the above general formula (VIII). The reaction is usually performed in the presence of a reducing agent,
Done. Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride and borane. The reaction is usually performed in the presence of a solvent,
The solvent is not limited as long as it does not affect the reaction, and any solvent may be used, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, etc. Amides; alcohols such as methanol, ethanol and isopropanol; sulfoxides such as dimethyl sulfoxide; water; or a mixed solvent thereof. The reaction is carried out at a temperature in the range from -78 ° C to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 12 hours. It is preferably carried out in the presence of sodium borohydride or sodium cyanoborohydride in a solvent of alcohols for 0.5 to 5 hours at a temperature of -30 ° C to 50 ° C.

The compound of formula (III) can be produced by various conventional methods, for example, the following methods. That is, the general formula (X
IV)

Embedded image (In the formula, R ₁₃ , R ₁₄ and R ₁₅ independently represent hydrogen or a hydroxyl group, but two or more of R ₁₃ , R ₁₄ and R ₁₅ are not hydrogen). Formula (XV) MCH ₂ CO ₂ R ₆ (XV) (In the formula, R ₆ is as defined in the above general formula (I), and M is a leaving group such as chlorine, bromine, iodine or a sulfonate ester. Represents the general formula (XVI)

Embedded image (Wherein R ₃ , R ₄ and R ₅ are as defined in the general formula (I) above) (step E)
(XVII) R ₁₆ NH ₂ (XVII) (wherein R ₁₆ represents C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl) and is reacted with the general formula (XVIII)

[0023]

Embedded image A compound having the formula: wherein R ₃ , R ₄ and R ₅ are as defined in general formula (I) above and R ₁₆ is as defined in general formula (XVII) above. After (F step),
General formula (XIX) R ₂ CH ₂ NO ₂ (XIX) (wherein R ₂ is as defined in the above general formula (I)) to give the general formula (XX)

Embedded image (Wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in the above general formula (I)) (step G), and reduction and hydrolysis are performed (step H). General formula (III)

Embedded image A compound represented by the formula (wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in the above general formula (I)) is produced.

Step E is a step for producing a compound having the general formula (XVI), and is usually suitably carried out in a solvent using a base. Examples of the base to be used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate; hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; or a mixture thereof. Examples of the ester represented by the general formula (XV) include methyl bromoacetate, ethyl bromoacetate, propyl bromoacetate, isopropyl bromoacetate, butyl bromoacetate, methyl chloroacetate, ethyl chloroacetate, methyl iodoacetate and ethyl iodoacetate. To be Moreover, an additive can be used for this reaction depending on the case. Examples of the additive used include lithium iodide, potassium iodide, sodium iodide, sodium chloride, potassium chloride, lithium chloride and the like. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used. For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; diethyl ether, diisopropyl ether, tetrahydrofuran. , Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; ketones such as acetone and methylethylketone; mixed solvents thereof are preferably used. The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 6 hours to 72 hours. Carbonates, preferably using ketones, especially methyl bromoacetate or ethyl bromoacetate in an acetone solvent,
Particularly in the presence of potassium carbonate, potassium iodide is used as an additive, and the mixture is heated at 20 ° C. or under reflux for 3 hours to 72 hours.
Done for hours.

Step F is a step for producing a compound having the above-mentioned general formula (XVIII), and is usually carried out in the presence or absence of a solvent in the presence of a primary amine represented by the general formula (XVII). Be seen. The reaction is carried out while removing water produced by a Dean-Stark apparatus or the like, or is carried out in the presence of anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate, molecular sieve and the like. The reaction is usually suitably carried out in the presence of solvent.

Examples of the amine represented by the general formula (XVII) include methylamine, ethylamine, butylamine and cyclohexylamine. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethylene, etc. Halogenated hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; dimethyl sulfoxide, etc. Sulfoxides; sulfolane; or a mixed solvent thereof is preferably used. The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 12 hours. It is preferably carried out under reflux with heating for 1 to 5 hours in a solvent of hydrocarbons. More preferably, heating under reflux in benzene for 1 to 3 hours,
It is done by dehydration.

Step G is a step for producing a compound having the above formula (XX), and usually in the presence or absence of a solvent,
It is carried out in the presence of acid. Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid, propionic acid and pivalic acid; sulfonic acids such as methanesulfonic acid, toluenesulfonic acid and camphorsulfonic acid. Examples of the nitro compound represented by the formula (XIX) include nitromethane, nitroethane, nitropropane and nitrobutane. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used, for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, methylene chloride, tetrachloride. Carbon, halogenated hydrocarbons such as 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; methanol, ethanol, isopropanol, etc. Alcohols; sulfoxides such as dimethyl sulfoxide; sulfolane; organic acids such as acetic acid and propionic acid; or a mixed solvent thereof is preferably used. The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time is the reaction reagent,
It depends on the reaction temperature, but usually 3 hours to 12 hours
Time. Preference is given to heating under reflux with organic acids, in particular acetic acid, with nitromethane or nitroethane for 1 to 5 hours.

Step H is a step for producing the compound having the general formula (III), and is usually carried out in the presence of a reducing agent. Examples of the reducing agent used include reducing metals such as iron powder, zinc powder and copper powder; tin chloride and the like. The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used. For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; diethyl ether, diisopropyl ether, tetrahydrofuran. ,
Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric acid triamide; alcohols such as methanol, ethanol, isopropanol; sulfoxides such as dimethyl sulfoxide; sulfolane; organic acids such as acetic acid and propionic acid; Water; or a mixed solvent thereof is preferably used.
The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 1 hour to 6 hours. It is preferably carried out in a mixed solvent of three kinds of alcohols, an organic acid and water, particularly a mixed solvent of methanol, acetic acid and water, in the presence of iron powder, under heating to reflux for 1 to 5 hours.

Of the compounds represented by the above general formula (I), the general formula (XXI)

Embedded image (In the formula, R ₁ and R ₂ are as represented by the above general formula (I), and R ₁₇ , R ₁₈ and R ₁₉ independently represent hydrogen or —OCH ₂ CO ₂ H, Two or more of R ₁₇ , R ₁₈ and R ₁₉ are not hydrogen)
General formula (XXII)

[0030]

Embedded image (In the formula, R ₁ and R ₂ are as shown in the above general formula (I), R ₂₀ , R ₂₁ and R ₂₂ independently represent hydrogen or —OCH ₂ CO ₂ R ₂₃ , R ₂₃ represents (C ₁ -C ₄ ) alkyl, but two or more of R ₂₀ , R ₂₁ and R ₂₂ may not be hydrogen), and may also be obtained by hydrolyzing a compound. The reaction is carried out by reacting with water in the presence of acid or base. When used under acidic conditions, the acids used include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid; organic acids such as acetic acid and propionic acid; sulfones such as methanesulfonic acid, toluenesulfonic acid and camphorsulfonic acid. Acids; or mixtures thereof. When carried out under basic conditions, examples of the base used include hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; carbonates such as potassium carbonate and sodium carbonate; and mixtures thereof. . The reaction is usually carried out in water, optionally mixed with another solvent. The solvent used is not limited as long as it does not affect the reaction, and any solvent may be used, for example, benzene, toluene, xylene, hexane,
Hydrocarbons such as heptane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; dimethyl sulfoxide, etc. Sulfoxides; sulfolane; organic acids such as acetic acid and propionic acid; or mixed solvents thereof are preferably used. The reaction is carried out at a temperature ranging from under ice cooling to under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to 24 hours. It is preferably carried out in the presence of hydrochloric acid or sulfuric acid in a mixed solvent of an alcohol, particularly methanol or ethanol, and water, under heating under reflux for 1 to 6 hours. Specific examples of the compound having the general formula (I) of the present invention include the compounds listed in the following table.

[0031]

[Table 1]

[0032]

[Table 2]

[0033]

[Table 3]

[0034]

[Table 4]

[0035]

[Table 5]

[0036]

[Table 6]

[0037]

[Table 7]

[0038]

[Table 8]

[0039]

[Table 9]

[0040]

[Table 10]

[0041]

[Table 11]

[0042]

[Table 12]

[0043]

[Table 13]

[0044]

[Table 14]

[0045]

[Table 15]

[0046]

[Table 16]

[0047]

[Table 17]

[0048]

[Table 18]

[0049]

[Table 19]

The compounds of the present invention represented by the general formula (I) and salts thereof have β ₃ agonistic activity, antihyperglycemic activity, obesity improving activity, and intestinal relaxing activity in mammals. Therefore, it is useful as a preventive and / or therapeutic drug for diabetes, hyperglycemia, obesity, irritable bowel syndrome (IBS), etc. in mammals including humans and pet animals, and in the case of breeding meat animals. , It is useful as a drug for reducing fat and increasing red meat portion.

The compounds of general formula (I) of the present invention may be administered in various forms. The dosage form includes, for example, oral administration by tablets, capsules, granules, powders, syrups, etc., or injections (intravenous, intramuscular, subcutaneous),
Parenteral administration such as drops and suppositories can be mentioned.
These various preparations are usually used in the technical field of pharmaceutical preparation such as excipients, binders, disintegrating agents, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, etc. It is possible to formulate with known auxiliary agents. The dose varies depending on the symptoms, age, body weight, and administration method, but usually, 0.01 mg to 2000 mg per day can be administered to an adult. No toxicity is observed within this range. Next, Examples for the synthesis of the compound of the present invention, Examples for the production of the raw material of the compound of the present invention, by the test examples for the physiologically active effect of the compound of the present invention, and the compound of the present invention The present invention will be described in more detail with reference to formulation examples as active ingredients. However, these examples, production examples, test examples, and formulation examples are for illustration only, and the present invention is not limited thereto. It goes without saying that this is not the case.

Example 1 N- [2- (2,4-dicarbomethoxymethoxy) phenyl-1-methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine

Embedded image 2- (3-chlorophenyl) -2-hydroxyethanamine 1.0 g (5.831 mmol) and 1-{(2,4-dicarbomethoxymethoxy) phenyl} propan-2-one 1.81 g (5.831 mmol) 20 ml of benzene solution
The mixture was heated under reflux for 1.5 hours while removing water produced by the Dean-Stark apparatus. The solvent was distilled off under reduced pressure, the residue was dissolved in 20 ml of methanol, 100 mg of platinum dioxide was added, and the mixture was stirred under a hydrogen stream at room temperature for 5 hours. The reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and methanol / ethyl acetate = 3 /
From the flow of 97 (v / v), N- [2- (2, 2,
1.40 g (52%) of 4-dicarbomethoxymethoxy) phenyl-1-methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine was obtained. mp 83-85.5 ° C; ¹ H NMR (CDCl ₃ ) δ 1.07 (d, J = 6.4
Hz, 1.5H), 1.08 (d, J = 6.3 Hz, 1.5H), 2.50-3.10 (m,
6H, 1H: D ₂ O substitution), 3.78 (s, 3H), 3.81 (s, 3H), 4.46
-4.70 (m, 5H), 6.32-6.45 (m, 2H), 6.97-7.06 (m, 1
H), 7.14-7.30 (m, 3H), 7.31-7.40 (m, 1H); ¹³ C NMR
(CDCl ₃ ) δ 20.5, 20.9, 37.3, 37.8, 52.3, 52.6, 53.
5, 54.0, 54.4, 64.9, 65.4, 70.7, 71.3, 100.2, 105.
26, 105.31, 121.7, 121.8, 123.9, 126.0, 127.3, 12
9.5, 131.7, 134.2, 145.00, 145.03, 156.6, 157.4, 1
69.2, 169.3 Further, the hydrochloride was prepared according to a conventional method. mp 45-49 ° C; ¹ H NMR (dimethyl sulfoxide d6-tetramethylsilane) δ1.14 (d, J = 6.8 Hz, 1.5H), 1.16
(d, J = 8.3 Hz, 1.5H), 2.57-2.68 (m, 1H), 3.00-3.60
(m, 4H), 2.50, 2.506, 2.511 (s × 3, 6H), 4.60-5.10
(m, 5H), 6.23-6.40 (br, 1H, D ₂ O substitution), 6.42-6.62
(m, 2H), 7.10 (dd, J = 2.4 Hz, 8.3 Hz, 1H), 7.24-7.55
(m, 4H), 8.60-8.82 (br, 1H, D ₂ O substitution), 9.01-9.31
(br, 1H, D ₂ O substitution); ¹³ C NMR (dimethyl sulfoxide d6)
δ 15.3, 16.1, 32.2, 32.8, 50.8, 51.8, 53.7, 53.
8, 64.7, 67.9, 99.9, 106.2, 117.77, 117.83, 124.7,
125.9, 127.7, 128.3, 130.2, 131.6, 131.7, 133.1,
144.3, 156.2, 156.3, 157.8, 169.1

Example 2 N- [2- (3,4-dicarbomethoxymethoxy) phenyl-1-methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine

Embedded image As in Example 1, 1-{(3,4-dicarbomethoxymethoxy) phenyl} propan-2-one to N- [2
-(3,4-Dicarbomethoxymethoxy) phenyl-1
-Methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine was obtained. Yield: 39% (yellow oil); ¹ H NMR (CDCl ₃ ) δ 1.05 (d,
J = 6.3Hz, 1.5H), 1.06 (d, J = 6.4 Hz, 1.5H), 1.30-1.95
(br, 2H, D ₂ O substitution), 2.50-2.67 (m, 3H), 2.80-2.92
(m, 1.5H), 2.96 (dd, J = 3.4 Hz, 12.2 Hz, 0.5H), 3.7
8 (s, 3H), 3.80 (s, 3H), 4.54 (dd, J = 3.4 Hz, 8.8 H
z, 0.5H), 4.60 (dd, J = 3.4 Hz, 8.3 Hz, 0.5H), 4.70
(s, 1H), 4.71 (s, 1H), 4.72 (s, 1H), 4.73 (s, 1H),
6.68-6.84 (m, 3H), 7.16-7.30 (m, 3H), 7.32-7.38
(m, 1H); ¹³ C NMR (CDCl ₃ ) δ 20.4, 20.7, 42.9, 43.
2, 52.2, 54.0, 54.1, 54.45, 54.52, 66.7, 71.1, 71.
6, 77.2, 115.4, 116.8, 123.3, 123.9, 125.9, 127.5,
130.0, 133.5, 133.6, 134.3, 144.7, 144.8, 146.51,
146.55, 147.7, 169.5, 169.6 Furthermore, the hydrochloride was obtained according to a conventional method. mp 35-38 ° C; ¹ H NMR (dimethyl sulfoxide d6-tetramethylsilane) δ1.11 (d, J = 6.8 Hz, 1.5H), 1.13
(d, J = 7.8 Hz, 1.5H), 2.45-2.65 (m, 2H), 2.99-3.60
(m, 3H), 3.70 (s, 6H), 4.79 (s, 2H), 4.82 (s, 2
H), 4.98-5.13 (m, 1H), 6.23-6.50 (br, 1H, D ₂ O substitution), 6.78 (d, J = 8.8 Hz, 1H), 6.82-6.92 (m, 2H), 7.
34-7.54 (m, 4H), 8.63-8.85 (br, 1H, D ₂ O substitution), 9.20
-9.40 (br, 1H, D ₂ O substitution); ¹³ C NMR (dimethyl sulfoxide d6) δ 14.7, 15.4, 37.3, 37.9, 50.5, 50.6, 51.
7, 54.9, 55.0, 65.4, 67.8, 68.0, 114.5, 115.6, 12
2.4, 124.7, 125.9, 127.4, 128.3, 130.0, 130.4, 13
3.2, 144.3, 146.1, 147.1, 169.2, 169.3

Example 3 N- [2- (2,4-dicarboxymethoxy) phenyl-1-methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine hydrochloride

Embedded image 1.85 g (3.974 mmol) of N- [2- (3,4-dicarbomethoxymethoxy) phenyl-1-methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine
Concentrated hydrochloric acid (0.60 ml, 5.961 mmol) was added to a methanol / water = 1/4 (v / v) 25 ml solution of the above, and the mixture was heated under reflux for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain N as a colorless amorphous solid.
-[2- (2,4-dicarboxymethoxyphenyl)-
1.80 g of 1-methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine was obtained. IR (KBr) ν max cm ^-1 3600-3300, 1739, 1598, 1517, 1
431, 1209, 1147, 1061, 791, 686; ¹ H NMR (dimethyl sulfoxide d6) δ 1.09 (d, J = 6.8 Hz, 1.5H), 1.11
(d, J = 8.3 Hz, 1.5H), 2.45-2.61 (brm, 1H), 3.06 (br
t, J = 10.7 Hz, 1H), 3.11-3.25 (brm, 2H), 3.31-3.46
(brm, 1H), 4.64 (s, 2H), 4.68 (s, 2H), 5.01-5.11
(brm, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.77-6.89 (m, 2
H), 7.30-7.48 (m, 3H), 7.49 (s, 1H); ¹³ C NMR (dimethyl sulfoxide d6) δ 14.7, 15.4, 37.4, 38.0, 50.
6, 50.7, 54.9, 55.0, 65.2, 65.3, 67.9, 68.0, 114.
1, 115.1, 121.9, 122.0, 124.7, 124.8, 125.9, 127.
7, 128.3, 130.0, 130.3, 133.1, 144.4, 146.2, 147.
3, 170.3, 170.4

Example 4 N- [2- (2,4,6-tricarbomethoxymethoxyphenyl) -1-methylethyl] -2-hydroxy- (3
-Chlorophenyl) ethanamine

Embedded image As in Example 1, 1- (2,4,6-tricarbomethoxymethoxyphenyl) propan-2-one was converted into N- [2
-(2,4,6-tricarbomethoxymethoxyphenyl)
-1-Methylethyl] -2-hydroxy- (3-chlorophenyl) ethanamine was obtained. Yield: 59% (pale reddish brown oil); ¹ H NMR (CDCl ₃ ) δ d
1.12 (d, J = 6.3 Hz, 1.5H), 1.13 (d, J = 6.3 Hz, 1.5
H), 2.55 (dd, J = 8.8 Hz, 11.7Hz, 0.5H), 2.64 (dd, J
= 9.3 Hz, 12.7 Hz, 0.5H), 2.71 (d, J = 5.9 Hz, 0.5H),
2.75 (d, J = 5.9 Hz, 0.5H), 2.80-3.10 (m, 3H), 3.78
(s, 6H), 3.81 (s, 3H), 4.50-4.70 (m, 1H), 4.56
(s, 2H), 4.60 (s, 2H), 4.62 (s, 2H), 6.01 (s, 1H),
6.03 (s, 1H), 7.08-7.30 (m, 3H), 7.36 (s, 1H) Further, according to a conventional method, hydrochloride was obtained and recrystallized from methanol / diethyl ether. mp 175-179 ° C; ¹ H NMR (dimethyl sulfoxide d6-tetramethylsilane) δ1.18 (d, J = 6.8 Hz, 1.5H), 1.19
(d, J = 7.8 Hz, 1.5H), 2.80-3.55 (m, 5H), 3.66 (s, 3
H), 3.68 (s, 3H), 3.70 (s, 3H), 4.70-4.90 (m, 6H),
4.95-5.10 (brm, 1H), 6.23 (s, 2H), 6.32 (brs, 1H,
Replace with heavy water), 7.35-7.48 (m, 3H), 7.49 (s, 0.5H),
7.51 (s, 0.5H), 8.74 (brs, 1H, replaced with heavy water), 9.01
(brs, 0.5H, replaced by heavy water), 9.20 (brs, 0.5H, replaced by heavy water); ¹³ C NMR (dimethyl sulfoxide d6) δ 15.8, 16.
4, 25.9, 50.6, 51.88, 51.92, 53.7, 64.8, 65.0, 67.
8,92.9, 106.1, 124.9, 126.1, 172.8, 130.4, 133.2,
144.3, 157.0, 157.1, 158.1, 169.11, 169.16, 169.24

Production Example 1 2,4-dicarbomethoxymethoxybenzaldehyde

Embedded image 2,4-dihydroxybenzaldehyde 10 g (72.4
Methyl bromoacetate (1 mmol) in 300 ml of acetone
4.4 ml (0.1520 mol), potassium carbonate 20.51 g
(0.1484 mol), 1.20 g of potassium iodide (7.2
40 mmol) was added and the mixture was stirred at room temperature for 16 hours. After the reaction solution was filtered, the filtrate was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with 100 ml of water and 100 ml of saturated saline, dried over magnesium sulfate and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate / hexane to obtain 16.88 g (83%) of yellow crystals of 2,4-dicarbomethoxymethoxybenzaldehyde. ¹ H NMR (CDCl ₃ ) δ 3.83 (s, 6H), 4.68 (s, 2H), 4.74
(s, 2H), 6.41 (d, J = 2.0 Hz, 1H), 6.53 (dd, J = 2.0
Hz, 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 10.39 (s,
1H)

Production Example 2 3,4-dicarbomethoxymethoxybenzaldehyde

Embedded image In the same manner as in Production Example 1, 3,4-dicarbomethoxymethoxybenzaldehyde was obtained from 3,4-dihydroxybenzaldehyde. Yield: 59% (pale yellow crystals); mp 96-97 ° C; ¹ H NMR (C
DCl ₃ ) δ 3.82 (s, 6H), 4.79 (s, 2H), 4.83 (s, 2H),
6.94 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H),
7.49 (dd, J = 2.0 Hz, 8.3 Hz, 1H), 9.85 (s, 1H)

Production Example 3 1-{(2,4-dicarbomethoxymethoxy) phenyl} -2-nitroprop-1-ene

Embedded image 2,4-dicarbomethoxymethoxybenzaldehyde 1
To a solution of 6 g (56.74 mmol) of benzene in 150 ml was added 9.1 ml of cyclohexylamine (79.43 mmol), and De
The mixture was heated under reflux for 1 hour while removing water produced by the an-Stark apparatus. The solvent was distilled off under reduced pressure, the residue was dissolved in 100 ml of acetic acid, 10.2 ml (0.1418 mol) of nitroethane was added, and the mixture was heated at 100 ° C. for 5 hours. The solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, water 100 ml, saturated saline solution 1
After washing with 00 ml, it was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give 1-{(2,4-dicarbomethoxymethoxy) as yellow crystals.
Phenyl} -2-nitroprop-1-ene 10.4 g
(54%) was obtained. mp 102-106 ° C; ¹ H NMR (CDCl ₃ ) δ 2.40 (d, J = 1.0
Hz, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 4.66 (s, 2H),
4.70 (s, 2H), 6.44 (d, J = 2.4 Hz, 1H), 6.53 (dd, J
= 2.4 Hz, 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 8.31
(s, 1H)

Production Example 4 1-{(3,4-dicarbomethoxymethoxy) phenyl} -2-nitroprop-1-ene

Embedded image In the same manner as in Production Example 3, 1-{(3,4-dicarbomethoxymethoxy) phenyl} -2-nitroprop-1-ene was obtained from 3,4-dicarbomethoxymethoxybenzaldehyde. Yield: 77% (yellow crystals); mp 110-113 ° C; ¹ H NMR (C
DCl ₃ ) δ 2.45 (s, 3H), 3.82 (s, 6H), 4.77 (s, 2H),
4.78 (s, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.99 (d, J =
2.0 Hz, 1H), 7.10 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 8.00
(s, 1H); ¹³ CNMR (CDCl ₃ ) δ 14.0, 52.3, 52.4, 66.
0, 66.7, 114.5, 117.5, 125.3, 126.5, 132.9, 146.8,
147.7, 149.4, 168.8, 169.1

Production Example 5 1-{(2,4-dicarbomethoxymethoxy) phenyl} propan-2-one

Embedded image 1-{(2,4-dicarbomethoxymethoxy) phenyl} -2-nitroprop-1-ene 10 g (29.50 m
mol) acetic acid / water / methanol = 3/2/1 (v / v)
Iron powder 8.24g (0.1475mol) in 120ml solution
Was added and the mixture was heated under reflux for 2 hours. To the reaction solution was added concentrated hydrochloric acid (10 ml) under ice-cooling, the mixture was stirred for 30 minutes, filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform / water and filtered through Celite. The filtrate is 100 ml of chloroform
It was extracted with × 3, washed with 100 ml of water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to obtain 1-{(2,4-dicarbomethoxymethoxy) phenyl} propan-2-one (5.66 g, 62%) as pale red crystals. mp 93-94.5 ° C; ¹ H NMR (CDCl ₃ ) δ 2.20 (s, 3H),
3.68 (s, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 4.60 (s,
2H), 4.61 (s, 2H), 6.38-6.50 (m, 2H), 7.06 (d, J =
(8.8 Hz, 1H)

Production Example 6 1-{(3,4-dicarbomethoxymethoxy) phenyl} propan-2-one

Embedded image In the same manner as in Production Example 5, 1-{(3,4-dicarbomethoxymethoxy) phenyl} -2-nitroprop-1-ene to 1-{(3,4-dicarbomethoxymethoxy) phenyl} propane-2- Got on. Yield: 77% (yellow oil); IR (film) νmax cm ^-1 175
4, 1740, 1721, 1510, 1439, 1203, 1147, 1069; ¹ H NMR
(CDCl ₃ ) δ 2.14 (s, 3H), 3.61 (s, 2H), 3.79 (s, 6
H), 4.71 (s, 2H), 4.72 (s, 2H), 6.73 (d, J = 2.0 Hz,
1H), 6.79 (dd, J = 2.0 Hz, 8.3 Hz, 1H), 6.85 (d, J =
(8.3 Hz, 1H)

Production Example 7 2- (3-chlorophenyl) -2-hydroxyethanamine

Embedded image 3-Chlorobenzaldehyde 33.6 ml (0.2970 mo
l) in 150 ml of methylene chloride, 47.4 ml of trimethylsilyl nitrile (0.3560 mol) and zinc iodide 1.
01 g (3.153 mmol) was sequentially added under ice cooling, stirred for 30 minutes, and then heated at 65 ° C. for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure, the residue was dissolved in 60 ml of diethyl ether, and 12.4 g (0.3%) of lithium aluminum hydride (LAH) was dissolved.
To a suspension of 27 mol) of diethyl ether in 100 ml was added dropwise over 60 minutes under ice cooling. After the dropping is completed, the reaction solution is added to 1.5
Heated to reflux for an hour. After cooling, aqueous ammonia (40
% W / v) 40% and 10% (w / v) sodium hydroxide aqueous solution 40 ml were carefully added, and the mixture was stirred for 5 hours and filtered through Celite. The filtrate was diluted with diisopropyl ether (100 ml x
After extraction with 3), the extract was washed with saturated brine (50 ml), dried over potassium carbonate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 35.7 g of 2- (3-chlorophenyl) -2-hydroxyethanamine as a pale red oil was obtained from a stream of methanol / ethyl acetate (1/9).
(70%). ¹ H NMR (CDCl ₃ ) δ 1.86-2.39 (brs, 3H, D ₂ O substitution), 2.
77 (dd, J = 7.8 Hz, 12.7 Hz, 1H), 3.00 (dd, J = 3.4 H
z, 12.3 Hz, 1H), 4.61 (dd, J = 3.9 Hz, 7.8 Hz, 1H),
7.10-7.36 (m, 4H)

Production Example 8 2,4,6-tricarbomethoxymethoxybenzaldehyde

Embedded image Similarly to Production Example 1, 2,4,6-tricarbomethoxymethoxybenzaldehyde was obtained from 2,4,6-trihydroxybenzaldehyde. Yield: 77% (pale orange crystals); mp 99-103 ° C; ¹ H NMR (CD
Cl ₃ ) δ 3.81 (s, 6H), 3.83 (s, 3H), 4.63 (s, 2H),
4.71 (s, 4H), 6.04 (s, 2H), 10.45 (s, 1H)

Production Example 9 1- (2,4,6-tricarbomethoxymethoxy) phenyl-2-nitroprop-1-ene

Embedded image In the same manner as in Production Example 3, 1-{(2,4,6-tricarbomethoxymethoxy) phenyl} -2-nitroprop- was prepared from 2,4,6-tricarbomethoxymethoxybenzaldehyde.
I got 1-ene. Yield: 26% (yellow crystals); mp 117-118 ° C; ¹ H NMR
(CDCl ₃ ) δ 1.56 (s, 3H), 3.80 (s, 6H), 3.83 (s, 3
H), 4.60 (s, 2H), 4.63 (s, 4H), 6.05 (s, 2H), 7.96
(s, 1H)

Production Example 10 1-{(2,4,6-tricarbomethoxymethoxy) phenyl} propan-2-one

Embedded image Similarly to Production Example 5, 1-{(2,4,6-tricarbomethoxymethoxy) phenyl} -2-nitroprop-1-ene to 1-{(2,4,6-tricarbomethoxymethoxy) phenyl} Propan-2-one was obtained. Yield: 51% (colorless needle crystals); mp 92-93 ℃; ¹ HN
MR (CDCl ₃ ) δ 2.20 (s, 3H) ,, 3.78 (s, 6H), 3.79
(s, 2H), 3.82 (s, 3H), 4.57 (s, 2H), 4.59 (s, 4H),
6.67 (s, 2H)

[0066] beta ₃ working effect of the beta ₃ agonism present invention in Test Example 1 Rats were measured by stimulatory effect on lipolysis of adipose cells. The fat mass of rat epididymis was cut and placed in a buffer solution having the following composition: 130 mM sodium chloride, 4.7 mM potassium chloride, 1.25 mM magnesium sulfate, 2.8 mM calcium chloride, 10 mM Hepes, 2.5 mM sodium dihydrogen phosphate, 1 g / l glucose, 1% fatty acid-free serum albumin (pH 7.6). All subsequent operations were performed in the above buffer solution. 5 g of tissue was transferred to a plastic bottle with 10 ml of buffer supplemented with 0.1% collagenase (Worthington Biochemical Corporation). The tissue was warmed at 37 ° C for about 75 minutes with gentle infiltration. The cell suspension was passed through a nylon mesh (# 100), washed three times with a double amount of buffer solution, and filtered through a nylon mesh again. The volume of the adipocytes was adjusted to 20% by using a buffer solution, and the experiment was performed. 0.1 ml of this cell suspension is added to vehicle or compound to 0.3 ml
Was added to a plastic test tube with buffer. 37
Warm with gentle shaking for 120 minutes at 0 ° C. The reaction solution was transferred to a centrifuge tube containing 50 ml of silicon oil (Shin-Etsu Chemical Co., Ltd.) with a specific gravity of 0.96 and a specific gravity of 0.96.
The reaction was stopped by removing adipocytes from the buffer by centrifuging at 00 × g for 1 minute. The amount of glycerol in the buffer solution produced by the hydrolysis of triglyceride was measured by the glycerol-3-phosphate-oxidase / p-chlorophenol method. 50 ml of the buffer solution was added to a 96-well plate having 0.2 ml of the evaluation mixture having the following composition and reacted at 37 ° C. for 15 minutes.
Absorbance at nm was measured: 50 mM Tris (pH 7.5),
5.4 mM p-chlorophenol, 250 mg / ml adenosine-5'-disodium triphosphate, 150 mg 4-
Aminoantipyrine, 250 U / L glycerol kinase, 500 U / L glycerol-3-
Phosphate oxidase, 1250 U / liter horseradish peroxidase. The molar EC50 value is the molar concentration of a compound that gives a 50% value of the maximum lipolytic activity of the compound itself.

[0067]

[Table 20] As is clear from Table 2, the compounds of the present invention showed excellent β ₃ agonistic activity.

Test Example 2 Heart Rate Elevating Action (β ₁ Agonist Activity) The heart was excised from a male guinea pig and the right atrium was separated.
The atrial sample was suspended in a Krebs-Henseleit solution at 37 ° C. in which a mixed gas (95% oxygen, 5% carbon dioxide) was aerated, and the load was set to 0.5 g. The contractile force was measured by a strain gague transducer, and the signal of heart rate was measured by a pulse meter. After the heart rate stabilized, the test compound was added cumulatively from a low dose and repeatedly until the response reached a maximum. Finally, the difference between the heart rate when adding 10 ⁶ M of isopreterenol and raising it and the difference before adding the test compound was 1
A dose-response curve was prepared as 00%. A comparison of the activity of compounds shows that the dose that causes 50% of its maximal response (EC
50).

[0069]

[Table 21] As is clear from Table 3, the compounds of the present invention do not have β ₁ agonist activity.

Test Example 3 Tracheal dilating action (β ₂ agonistic activity) A trachea was extracted from a male guinea pig and a spiral sample was prepared. The trachea specimen was suspended in a Krebs-Henseleit solution at 37 ° C, which was aerated with a mixed gas (95% oxygen, 5% carbon dioxide), and the load was set to 1.5 g. Tension is strain gague transd
It was measured by ucer. After the tension reached equilibrium, histamine 10 ⁻⁶ M was added to contract the trachea. After tension was stabilized, test compound was added cumulatively from low dose and repeatedly until maximal response was reached. Finally, ^10-6 M of isopreterenol was added, and the difference between the tension when the trachea was maximally relaxed and the tension before the test compound was added was 100%.
A dose-response curve was prepared as 50% of its maximum response
The dose (EC50) that caused

[0071]

[Table 22] As is clear from Table 4, the compounds of the present invention have no or very little β ₂ agonist activity. The compound of the above formula (I) of the present invention or a salt thereof has a β ₃ agonistic effect on mammals and leads to side effects β ₁
Alternatively, it has almost no β ₂ agonistic activity. Therefore, diabetes, hyperglycemia, obesity, IBS in mammals
And the like are useful as preventive and / or therapeutic agents.

Formulation Example 1 (Tablet) Compound of Example 1 (hydrochloride) 1 g Lactose 70 g Corn starch 8 g Crystalline cellulose 20 g Magnesium stearate 1 g Total 100 g The ingredients were uniformly mixed to give a powder for direct compression. This was molded into a tablet having a diameter of 6 mm and a weight of 100 mg with a rotary tableting machine to prepare 1000 tablets.

Formulation Example 2 (tablet) Compound of Example 2 (hydrochloride) 5 g Lactose 54 g Corn starch 25 g Crystalline cellulose 11 g Hydroxypropyl cellulose 3 g Light anhydrous silicic acid 1 g Magnesium stearate 1 g Total 100 g The ingredients were uniformly mixed, The powder was directly pressed. This was molded into a tablet having a diameter of 6 mm and a weight of 100 mg with a rotary tableting machine to prepare 1000 tablets.

Formulation Example 3 (Granule) A: Compound of Example 3 5 g Lactose 95 g Corn starch 50 g Crystalline cellulose 50 g B: Hydroxypropyl cellulose 10 g Ethanol 9 g After uniformly mixing the components of A, the solution of B is added. The mixture was kneaded, sized by extrusion granulation, and then dried at 50 ° C. in a dryer. Granules were prepared by sieving the dried particle size to 297 to 1460 μm, and the amount of one package was 200 mg.

Formulation Example 4 (Syrup) Compound of Example 3 1 g Sucrose 30 g D-sorbitol 70 w / v% 25 g Ethyl paraoxybenzoate 0.03 g Propyl paraoxybenzoate 0.015 g Flavor 0.2 g Glycerin 0.15 g 96 % Ethanol 0.5 g purified water appropriate amount total 100 ml sucrose, D-sorbitol, ethyl paraoxybenzoate,
Propyl paraoxybenzoate and the compound of Example 3 were dissolved in 60 g of purified water (warm water). After cooling, a solution of glycerin and ethanol in which the flavor was dissolved was added. Next, purified water was added to this mixture to make 100 ml.

Formulation Example 4 (Injection liquid) Compound of Example 2 (hydrochloride) 10.0 mg Sodium chloride 81.0 mg Sodium hydrogen carbonate 8.4 mg Distilled water for injection Suitable amount Total 10.0 ml Sodium hydrogen carbonate, sodium chloride and implementation The compound of Example 2 (hydrochloride) was added to distilled water and dissolved, and the total amount was 1
It was set to 0.0 ml.

Formulation Example 5 (Suppository) Compound of Example 2 (hydrochloride) 2 g Macrogol 4000 20 g Glycerin 78 g Total amount 100 g Glycerin was added to the compound of Example 2 (hydrochloride) and dissolved. Macrogol 4000 was added thereto, heated and dissolved, then poured into a suppository mold and cooled and solidified to give 1.5 g per one.
Suppositories.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C07C 69/712 C07C 69/712 Z 205/04 205/04 215/30 7457-4H 215 / 30 (72) Inventor Naoto Iwata 5-3 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Institute (72) Tamiko Hamada 5 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Prefecture 3-1 No. 1 Pharmaceutical Research Institute of Nisshin Seifun Co., Ltd. (72) Inventor Toshihiro Takahashi 5-3-1, Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd.

Claims (9)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ represents a hydrogen atom or a halogen atom, R ₂ represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group, and R ₃ , R ₄ and R ₅ are independently a hydrogen atom or —OCH. ₂
CO ₂ R ₆ but no two or more of R ₃ , R ₄ and R ₅ is hydrogen and R ₆ represents hydrogen or (C ₁ -C ₄ ) alkyl) Ethanolamine derivatives and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein R ₁ is a chlorine atom, and a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. A preventive or therapeutic agent for diabetes, hyperglycemia and obesity in a mammal, which comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. A compound represented by the general formula (II): (In the formula, R ₁ is as defined in the above general formula (I))
And a compound of the general formula (III): (Wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in the above general formula (I)) and reacted with a compound of the general formula (I
V) [Chemical 4] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the above general formulas.
A method for obtaining a compound according to claim 1, which comprises a compound of the above formula (I)) and reducing this compound to obtain a compound of the above general formula (I). 6. A compound represented by the general formula (V): Wherein R ₁ is as defined in formula (I) above and a compound of general formula (VI) From reacting with a compound of formula (wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in general formula (I) above) to obtain a compound of general formula (I) above A method for producing the compound according to claim 1. 7. A compound represented by the general formula (VII): Wherein R ₁ is as defined in general formula (I) above and L is a leaving group and a compound of general formula (VI) (Wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in the above general formula (I)) and reacted with the compound of the general formula
(VIII) [Chemical 9] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the above general formulas.
A compound of the formula (I) as defined above, and the compound is reduced to obtain a compound of the above general formula (I). 8. A meat quality improving agent for meat animals, comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 9. A meat quality improving agent for a meat animal, which comprises administering a meat quality improving agent for a meat animal containing the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient to the meat animal. Method.