CN1301259A - & alpha, -(1-piperazinyl) ocetamido arenecarboxylic acid derivatives as antidiabetic agents - Google Patents

Abstract

The invention relates to compounds of general formula (I). These compounds are useful in the treatment of diabetes.

Description

α-(1-piperazinyl)acetamidoarene carboxylic acid derivatives useful as antidiabetic agents

The present invention relates to novel α-(1-piperazinyl)acetamidoarene carboxylic acid derivatives useful in the treatment of diabetes.

Therefore, the subject of the present invention is the compound of general formula (I), its solvates and its pharmaceutically acceptable salts:

in:

Ar selected from

- a monocyclic, bicyclic or tricyclic aryl group having 6-14 carbon atoms,

- selected from pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolinyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyryl, diphenyl Heteroaryl of furyl, carbazolyl and benzothiazinyl,

The Ar may have 1-3 substituents selected from the group consisting of: C ₁ -C ₈ alkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl, C ₁ -C ₈ Alkoxy, (C ₃ -C ₈ ) cycloalkoxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkoxy, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ heteroaryl, (C ₆ -C ₁₄ ) heteroaryl (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) Aryl (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkyl (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl Oxy, (C ₆ -C ₁₄ )aryloxy(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy, (C ₆ -C ₁₄ ) Aryl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxy, (C ₁ -C ₆ )alkoxycarbonyl, carbamoyl, (C ₁ -C ₈ )alkylthio, (C ₁ -C ₈ )alkylsulfinyl, (C ₁ -C ₈ )alkylsulfonyl, sulfonyl amido, (C ₁ -C ₈ )alkylsulfonylamino, sulfamoyl, or (C ₁ -C ₈ )alkylcarbonylamino, or two of these substituents form methylenedioxy,

In the definition of Ar, 4-carboxyphenyl and substituted 4-carboxyphenyl are excluded,

R ₁ , R ₂ and R ₃ are independently selected from each other:

-A hydrogen atom,

-C ₁ -C ₈ alkyl or (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl,

-Cycloalkyl, (C ₃ -C ₈ )cycloalkyl(C _{1 -C 6 )alkyl, (C 3 -C 8} )cycloalkoxy ( _{C 1} -C ₆ ) containing 3-8 carbon atoms ) alkyl, or (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl,

-C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ heteroaryl, (C ₆ -C ₁₄ ) heteroaryl (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkyl(C ₆ -C ₁₄ )aryl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, or (C ₆ -C ₁₄ ) aryloxy (C ₁ -C ₆ ) alkyl,

A, B, C and D are =CH-, one or both of which may also be nitrogen atoms,

R ₄ , R ₅ and R ₆ are independently selected from:

-A hydrogen atom,

-C ₁ -C ₈ alkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl, C ₁ -C ₈ alkoxy, (C ₃ -C ₈ ) cycloalkoxy ( C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkoxy, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cyclo Alkyl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, C ₆ -C ₁₄ aryl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkyl(C ₆ -C ₁₄ )aryl, (C ₆ -C ₁₄ )aryloxy, (C ₆ -C ₁₄ )aryloxy(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy, or ( C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, halogen or trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro , amino, (C ₁ -C ₆ ) alkoxycarbonyl, carbamoyl, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₈ ) alkylsulfinyl, (C ₁ -C ₈ ) Alkylsulfonyl, sulfonylamino, (C ₁ -C ₈ )alkylsulfonylamino, sulfamoyl, or (C ₁ -C ₈ )alkylcarbonylamino, two of these groups can form methylene Dioxy or phenyl fused to the ring to which they are attached,

Each aryl group itself may also be substituted by 1-3 substituents selected from C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy, halogen or trifluoromethyl, trifluoromethoxy, Hydroxyl, Nitro and Amino.

Examples of aryl groups that may be mentioned are phenyl, α-naphthyl, β-naphthyl and fluorenyl.

The C ₁ -C ₈ alkyl group can be straight-chain or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.

Similarly, C ₁ -C ₈ alkoxy may be straight or branched. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy.

Halogen may be selected from fluorine, chlorine, bromine and iodine.

In the definitions of R ₁ , R ₂ and R ₃ , heteroaryl can be specifically defined as heteroaryl as defined in the definition of Ar.

The present invention also relates to tautomers, enantiomers, diastereomers and epimers of the compounds of general formula (I).

The compounds of general formula (I) have a carboxylic acid function and can be salified and thus exist in the form of base addition salts.

Examples of base addition salts of the compounds of general formula (I) include pharmaceutically acceptable salts such as sodium salts, potassium salts, calcium salts and other similar salts.

The compounds of general formula (I) can also be salified with amines to form pharmaceutically acceptable salts. For example, the compound of general formula (I) can be salified with glucosamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine .

The compound of the general formula (I) has a nitrogen atom, so it can form a mono-salt or a double-salt with an inorganic acid or an organic acid. Examples of acid addition salts of compounds of general formula (I) include pharmaceutically acceptable salts such as but not limited to hydrochloride, hydrobromide, sulfate, succinate, maleate, fumarate, apple salts or tartrates, and sulfonates such as mesylate, besylate or tosylate.

其中A、B、C、D、R₁、R₄、R₅和R₆定义同上，并且R₇是氢原子、C₁-C₆烷基或苄基，与通式(Ⅲ)卤代酰卤反应

其中R₂和R₃定义同上，Hal代表氯或溴原子，以生成通式(Ⅳ)化合物：其中A、B、C、D、R₁、R₂、R、R₄、R₅、R₆、R₇和Hal定义同上，并在碱性试剂，例如三乙胺存在下将通式(Ⅳ)化合物与通式(Ⅴ)化合物反应：其中Ar定义同上，以生成通式(Ⅵ)化合物：

其中Ar、A、B、C、D、R₁、R₂、R₃、R₄、R₅、R₆和R₇定义同上。The present invention also relates to processes for the preparation of compounds of general formula (I). The inventive method comprises, general formula (II) arylamine

Wherein A, B, C, D, R ₁ , R ₄ , R ₅ and R ₆ are as defined above, and R ₇ is a hydrogen atom, C ₁ -C ₆ alkyl or benzyl, and the haloacyl group of general formula (Ⅲ) halogen reaction

Wherein R ₂ and R ₃ are as defined above, Hal represents chlorine or bromine atom, to generate general formula (Ⅳ) compound: Wherein A, B, C, D, R ₁ , R ₂ , R, R ₄ , R ₅ , R ₆ , R ₇ and Hal are as defined above, and the general formula (Ⅳ ) compound reacts with general formula (Ⅴ) compound: Wherein Ar is as defined above, to generate general formula (Ⅵ) compound:

wherein Ar, A, B, C, D, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined above.

When R ₇ is an alkyl group, the compound of general formula (VI) can be hydrolyzed by conventional acidic or basic hydrolysis methods to generate the compound of general formula (I).

When R ₇ is benzyl, compounds of general formula (VI) can be hydrogenolyzed in the presence of a catalyst, such as palladium on carbon, to yield compounds of general formula (I).

Compounds of formula (II) and (V) are known compounds or can be prepared according to known methods.

Compounds of formula (II) are described, for example, in Organic Preparation and Procedures International, 13, 189, 1981.

The compound of formula (Ⅴ) can be prepared by the method of R. Ratouis et al. (J. Med. Chem., 8, 104, 1965) or Prelog et al.

For example, compounds of formula (VI) wherein R7 is alkyl may be hydrolyzed in the presence of a basic agent such as dilute sodium hydroxide.

The enantiomers of the compound of formula (I) can be separated by fractional recrystallization of the salt of the acid (I) with an optically active base in a solvent such as acetone, ethyl acetate or isopropanol, followed by conventional Methods Replace the salt with an optically active acid with an inorganic acid or an organic acid.

The compounds of the present invention are useful in the treatment of diabetes, especially non-insulin-dependent diabetes, because the compounds of the present invention have a hypoglycemic effect and are not toxic at active doses.

A further subject of the invention is therefore a pharmaceutical composition comprising an effective amount of a compound according to the invention.

The pharmaceutical composition of the present invention may be in a dosage form for parenteral, oral, rectal, transmucosal or transdermal administration.

The pharmaceutical compositions of the present invention may be in the form of injection solutions or suspensions for injection, or in multi-dose containers, or uncoated or coated tablets, sugar-coated tablets, capsules including hard gelatin capsules, pills, cachets. Capsules, powders, suppositories, capsules for rectal administration, solutions or suspensions in polar solvents for transdermal or transmucosal administration.

For solid dosage forms, suitable excipients for the administration are cellulose or microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starch, modified starch or lactose.

Cocoa butter or polyethylene glycol stearate are preferred excipients for rectal administration.

Water, aqueous, physiological or isotonic solutions are the most commonly used carriers for parenteral administration.

The dosage may vary within wide ranges depending on the indication being treated and the route of administration and on the age and weight of the patient.

The following examples illustrate the preparation of compounds of formula (I) and intermediates of formulas (II) and (IV). A-Example for the preparation of compounds of formula (II). Preparation of methyl 2-cyclohexylmethylamino-5-methoxybenzoate

In a 1 liter hydrogenation apparatus, 17.6 g of methyl 5-methoxyanthranilate, 11.8 g of cyclohexanecarbaldehyde and 2 g of 10% palladium on carbon (50% water) were added to 200 ml of methanol.

The apparatus was placed under a hydrogen atmosphere and stirred at room temperature for 3 hours.

300 mL of dichloromethane was added, the palladium on charcoal was removed by filtration, and the resulting filtrate was concentrated in vacuo.

The resulting oil was crystallized from a mixture of ethanol (200ml) and water (50ml) to give 25.4g of a yellow solid, melting at 58-60°C.

IR:(KBr)1683cm ^-1 (C=O),1528cm ^-1 (C=O)

¹ H NMR: (CDCl ₃ , 200 MHz) δ ppm: 1.06-1.64 (11H, m, cyclohexyl), 2.93 (2H, t, CH ₂ ), 3.68 (3H, s, OCH ₃ ), 3.78 (3H, s, OCH ₃ ), 6.56 (1H, d, phenyl proton), 6.96 (1H, dd, phenyl proton), 7.34 (2H, d+s, phenyl proton + NH)

B-制备式(Ⅳ)化合物的实施例制备4-氯-2-(氯乙酰氨基)苯甲酸The structural formula and characteristics of the compound of formula (II) are shown in Table I. Table I

B-Preparation of Examples of Compounds of Formula (IV) Preparation of 4-Chloro-2-(Chloroacetylamino) Benzoic Acid

With stirring, 25.5 ml of chloroacetyl chloride was added dropwise to 50 g of 2-amino-4-chlorobenzoic acid in 600 ml of dioxane, keeping the reaction mixture at 20°C.

It was then stirred at room temperature for 2 hours, after which 1200 ml of water were added. The desired product precipitated out and the mixture was stirred for 1 hour then filtered and the resulting solid was washed with water.

After drying, 60.7 g of 4-chloro-2-(chloroacetamido)benzoic acid with a melting point of 194-196° C. are obtained.

IR:1676cm ^-1 (C=O)

¹ H NMR: (d ₆ -DMSO.200 MHz) δ ppm: 4, 30 (2H, s, CH ₂ ), 71 (1H, d, phenyl proton), 77 (1H, d, phenyl proton), 8.5 (1H, s, phenyl proton), 11.75 (1H, s, NH), 1390 (1H, wide s, COOH) The structural formula and characteristics of the compound of formula (IV) are shown in Table II. Table II Table II (continued) C-Preparation of Examples of Compounds of Formula (II) Preparation of 4-chloro-2-{[4-(2-methoxyphenyl)-1-piperazinyl]acetamido}benzoic acid

15 g of 4-chloro-2-(chloroacetamido)benzoic acid were added to 11.6 g of 1-(2-methoxyphenyl)piperazine and 17 ml of triethylamine in 120 ml of DMF at room temperature with stirring.

The reaction mixture was stirred at room temperature for 48 hours, then 500 ml of water were added. Extraction was carried out with 3 x 300 ml dichloromethane. The solvent was evaporated in vacuo and the resulting solid redissolved in 300 mL of 2N aqueous sodium hydroxide. The solution was washed with 3 x 200 mL of ether, then the aqueous phase was acidified with acetic acid.

After filtration, 22.5 g of crude product were obtained as a crystalline solid. After recrystallization from dioxane, 21.1 g of 4-chloro-2-{4-(2-methoxyphenyl)-1-piperazinyl]acetamido}benzoic acid were obtained as a white solid, Its melting point is 218-220°C. IR: 1699cm ^-1 (C=O), 1673cm ^-1 (C=O) ¹ H NMR: (CF ₃ COOD), δ ppm: 4.25 (3H, s, OCH ₃ ), 4.65 (8H, wide s, 4 , CH ₂ ), 4.95 (2H, s, CH ₂ ), 7.5 (2H, m, phenyl proton), 7.6 (1H, d, phenyl proton), 7.90 (2H, m, phenyl proton), 8.50 ( 1H, d, phenyl proton), 8.75 (1H, s, phenyl proton) D-another way to prepare the compound of formula (I) to prepare 2-{[4-(4-fluorophenyl)-1-piperazine [yl]acetamido}-4,5-(methylenetrioxy)benzoic acid

Under stirring at room temperature, 15g of 2-(chloroacetamido)-4,5-(methylenedioxy)benzoic acid was added to 10.5g of 1-(4-fluorophenyl)piperazine and 16.2ml of triethylamine.

The reaction mixture was stirred at room temperature for 48 hours.

3.5ml of acetic acid was added and 150ml of water was added slowly. The acid crystallized out and was diluted with 300ml of water. The mixture was stirred for 30 minutes, filtered and the resulting solid washed with water.

After recrystallization from a dioxane/DMF mixture, 14.9 g of 2-{[4-(4-fluorophenyl)-1-piperazinyl]acetamido}-4,5-(methylenedi Oxy)benzoic acid, the melting point of this product is 254-256°C.

IR(KBr):1654cm ^-1 (C=O)

¹ H NMR: (CF ₃ COOD, 200 MHz) δ ppm: 4.40 (8H, s, pyrazinyl), 4.67 (2H, s, CH ₂ ), 6.05 (2H, s, O-CH ₂ -O) 7.30 (2H, t, phenyl proton), 7.65 (3H, m, phenyl proton), 7.90 (1H, s, phenyl proton)

The structural formula and characteristics of the compound of formula (I) are shown in Table III. Table III

The results of pharmacological experiments are given below. Study of antidiabetic activity in NOSTZ rats

The antidiabetic activity of orally administered compounds of formula (I) was determined using an experimental model of non-insulin-dependent diabetes induced in rats by streptozotocin.

This non-insulin-dependent diabetes model was obtained by injecting streptozotocin into neonatal rats (on the day of birth).

The diabetic rats used were 8 weeks old. The animals were maintained from the day of their birth until the day of the experiment in an animal room temperature-regulated at 21-22°C with a fixed cycle of light (7th to 19th) and dark (19th to 7th) . Feeding consisting of a maintenance diet, water and food was provided in such a way that the animals could ingest ad libitum, except for fasting (post-absorption state) 2 hours before testing when food was withdrawn.

The test product was orally administered to the rats on the day of the test. Two hours after the last administration of the product and 30 minutes after the animals were anesthetized with sodium pentobarbital (Nembutal), a 300 [mu]l blood sample was collected from the end of the tail.

The main results obtained are shown in Table IV. These results demonstrate the effectiveness of compounds of formula (I) in lowering blood sugar in diabetic animals.

The results are expressed as percent change in blood glucose on D4 (day 4 of treatment) compared to DO (before treatment).

Table IV compound 20mg/kg/day 200 mg/kg/day % Blood Glucose in D4 % Blood Glucose in D4 35 -12 -16 38 -6 -27 39 -15 -14 45 -9 -18 47 -16 -32 48 -20 -31 50 -17 -7 52 -14 -twenty one

Claims (10)

1. Compounds selected from compounds of formula (I), solvates and pharmaceutically acceptable salts thereof:

in: Ar selected from - a monocyclic, bicyclic or tricyclic aryl group having 6-14 carbon atoms, - selected from pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolinyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyryl, diphenyl Heteroaryl of furyl, carbazolyl and benzothiazinyl, The Ar may have 1-3 substituents selected from the group consisting of: C ₁ -C ₈ alkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl, C ₁ -C ₈ Alkoxy, (C ₃ -C ₈ ) cycloalkoxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkoxy, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ heteroaryl, (C ₆ -C ₁₄ ) heteroaryl (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) Aryl (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkyl (C ₆ -C ₁₄ ) aryl, (C ₆ -C ₁₄ ) aryl Oxy, (C ₆ -C ₁₄ )aryloxy(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy, (C ₆ -C ₁₄ ) Aryl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxy, (C ₁ -C ₆ )alkoxycarbonyl, carbamoyl, (C ₁ -C ₈ )alkylthio, (C ₁ -C ₈ )alkylsulfinyl, (C ₁ -C ₈ )alkylsulfonyl, sulfonyl amido, (C ₁ -C ₈ )alkylsulfonylamino, sulfamoyl, and (C ₁ -C ₈ )alkylcarbonylamino, or two of these substituents form methylenedioxy, In the definition of Ar, 4-carboxyphenyl and substituted 4-carboxyphenyl are excluded, R ₁ , R ₂ and R ₃ are independently selected from each other: -A hydrogen atom, -C ₁ -C ₈ alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, -Cycloalkyl, (C ₃ -C ₈ )cycloalkyl(C _{1 -C 6 )alkyl, (C 3 -C 8} )cycloalkoxy ( _{C 1} -C ₆ ) containing 3-8 carbon atoms )alkyl and (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, -C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ heteroaryl, (C ₆ -C ₁₄ ) heteroaryl (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkyl(C ₆ -C ₁₄ )aryl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl and (C ₆ -C ₁₄ )aryloxy(C ₁ -C ₆ )alkyl, A, B, C and D are =CH-groups, one or both of which may also be nitrogen atoms, R ₄ , R ₅ and R ₆ are independently selected from: -A hydrogen atom, -C ₁ -C ₈ alkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl, C ₁ -C ₈ alkoxy, (C ₃ -C ₈ ) cycloalkoxy ( C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkoxy, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cyclo Alkyl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, C ₆ -C ₁₄ aryl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkyl(C ₆ -C ₁₄ )aryl, (C ₆ -C ₁₄ )aryloxy, (C ₆ -C ₁₄ )aryloxy(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy, (C ₆ -C ₁₄ )aryl(C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, Amino, (C ₁ -C ₆ )alkoxycarbonyl, carbamoyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₈ )alkylsulfinyl, (C ₁ -C ₈ )alkane Sulfonyl, sulfonylamino, (C ₁ -C ₈ )alkylsulfonylamino, sulfamoyl and (C ₁ -C ₈ )alkylcarbonylamino, two of these groups can form methylenedioxy radicals or phenyl rings fused to the rings to which they are attached, Each aryl group itself may also be substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, halogen, trifluoromethyl, trifluoromethoxy, Hydroxyl, Nitro and Amino. 2. The compound of claim 1, wherein the essential component of the ring system is a phenyl ring. 3. The compound of claim 2, wherein at least one of R ₄ , R ₅ and R ₆ is C ₁ -C ₈ alkoxy, or two of these groups form methylenedioxy. 4. The method for preparing the compound of claim 1, comprising formula (II) arylamine

Wherein A, B, C, D, R ₁ , R ₄ , R ₅ and R ₆ are as defined above, and R ₇ is selected from hydrogen atom, C ₁ -C ₆ alkyl and benzyl, Reaction with haloacyl halide of formula (Ⅲ) Wherein R _{and R} are as defined above, and Hal is selected from chlorine and bromine, To generate the compound of formula (IV): Wherein A, B, C, D, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and Hal are as defined above, And in the presence of basic reagents, the compound of formula (IV) is reacted with the compound of formula (V):

where Ar is defined as above, To generate the compound of formula (Ⅵ):

Wherein Ar, A, B, C, D, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined above, And, when R is an alkyl _group , the compound is hydrolyzed to generate a compound of formula (I), and when _R7 is benzyl, the compound is hydrogenolyzed to give the compound of formula (I). 5. A pharmaceutical composition comprising an effective amount of the compound of claim 1. 6. A pharmaceutical composition comprising an effective amount of the compound of claim 2. 7. A pharmaceutical composition comprising an effective amount of the compound of claim 3. 8. A method for treating diabetes, comprising administering an effective amount of the compound of claim 1 to a human in need of treatment. 9. A method for treating diabetes, comprising administering an effective amount of the compound as claimed in claim 2 to a human in need of treatment. 10. A method for treating diabetes, comprising administering an effective amount of the compound of claim 3 to a human in need of treatment.