KR20010052662A - α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS - Google Patents

Abstract

The present invention relates to compounds of formula (I). Such compounds are useful for the treatment of diabetes.

Description

(1-PIPERAZINYL) ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS AS ANTI-DIABETIC AGENTS <br> <br> <br> Patents -

The present invention relates to novel? - (1-piperazinyl) acetamidoarenecarboxylic acid derivatives useful for the treatment of diabetes.

Accordingly, the subject of the present invention are compounds of formula (I), solvates thereof and pharmaceutically acceptable salts thereof:

[Wherein:

Ar is selected from

- a mono-, non-or tricyclic aryl group having from 6 to 14 carbon atoms,

Pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazyl groups A heterocyclic group,

Ar groups are C ₁ -C ₈ alkyl, (C ₃ -C ₈₎ cycloalkyl (C ₁ -C ₆₎ alkyl, C ₁ -C ₈ alkoxy, (C ₃ -C ₈₎ cycloalkyloxy (C ₁ -C ₆ (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyloxy, (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 aryl (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₎ aryloxy, (C ₆ -C ₁₄₎ aryloxy (C ₁ -C ₆₎ alkyl, (C ₆ -C ₁₄₎ aryl (C ₁ -C ₆₎ alkyloxy or (C ₆ -C ₁₄₎ aryl (C ₁ -C ₆₎ alkyloxy (C ₁ -C ₆₎ alkyl group, methyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, (C ₁ -C ₈ ) alkoxycarbonyl, carbamoyl, (C ₁ -C ₈ ) alkylthio, (C ₁ -C ₈ ) alkylsulfinyl, (C ₁ -C ₈ ) alkylsulfonyl, (C ₁ -C ₈₎ alkylsulfonyl 2 of the unexposed, sulfamoyl, or (C ₁ -C ₈₎ alkylcarbonylamino group, or may have 1 to 3 substituents selected from, or the substituent dog and form a methylenedioxy,

4-carboxyphenyl and substituted 4-carboxyphenyl groups are excluded from the definition of Ar;

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

- a hydrogen atom,

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

- alkyl group, a cycloalkyl having 3 to ₈ (C ₃ -C 8) cycloalkyl (C ₁ -C ₆₎ alkyl group or (C ₃ -C ₈₎ cycloalkyloxy (C ₁ -C ₆₎ alkyl or (C ₃ -C ₈₎ cycloalkyl (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ alkyl group,

- 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 group;

A, B, C and D are = CH- groups, and one or both of them may be a nitrogen atom;

R ₄ , R ₅ and R ₆ are each 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₎ cycloalkyloxy (C ₁ -C ₆₎ alkyl, (C ₃ -C ₈₎ cycloalkyloxy, (C ₃ -C ₈₎ cycloalkyl (C ₁ -C ₆₎ alkoxy, (C ₃ -C ₈₎ cycloalkyl (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₎ alkyloxy (C ₁ -C ₆₎ alkyl group, a halogen or a trifluoromethyl methyl, 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, alkylsulfonyl amino, (C ₁ -C ₈₎ alkylsulfonylamino, sulfamoyl or (C ₁ -C ₈₎ alkyl-carbonyl group (these Two of the groups R may form a phenyl ring or a methylenedioxy condensed with the ring to which they are attached);

Multiple aryl groups are themselves substituted with 1 to 3 substituents selected from C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy groups, halogen or trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino groups Can be].

Examples of aryl groups include phenyl, alpha -naphthyl, beta -naphthyl and fluorenyl groups.

The C ₁ -C ₈ alkyl group may be linear or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.

The C ₁ -C ₈ alkoxy group may also be linear or branched. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.

The halogen may be selected from fluorine, chlorine, bromine or iodine.

The heteroaryl group in the definitions of R ₁ , R ₂ and R ₃ can be defined in particular as defined for the heteroaromatic group in the definition of Ar.

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

The compounds of formula I have carboxylic acid functional groups and may exist in the form of salts with salified bases.

Examples of salts with bases of the compounds of formula I include pharmacologically acceptable salts such as sodium salts, potassium salts, calcium salts and other salts of the same type.

The compounds of formula I may also be chlorinated with amines to form pharmaceutically acceptable salts. For example, the compounds of formula I may be chlorinated with glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compounds of formula (I) possess basic nitrogen atoms and can be mono- or di-chlorinated with inorganic or organic acids. Examples of salts with acids of the compounds of formula I include pharmaceutically acceptable salts such as, but not limited to, hydrochloride, hydrobromide, sulfate, succinate, maleate, fumarate, maleate or tartrate and sulfonates such as methane Sulfonates, benzenesulfonates or toluenesulfonates.

The present invention also relates to a process for the preparation of compounds of formula (I). The preparation method according to the present invention comprises reacting an aromatic amine of the formula (II) with a haloacyl halide of the formula (III) to form a compound of the formula (IV) and a compound of the formula (IV) in the presence of a basic agent, With a compound of formula V to form a compound of formula VI: &lt; RTI ID = 0.0 &gt;

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above and R ₇ is a hydrogen atom, a C ₁ -C ₆ alkyl group or a benzyl group,

Wherein R ₂ and R ₃ are as defined above,

Hal represents a chlorine or bromine atom]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and Hal are as defined above,

Wherein Ar is as defined above,

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 &lt; ₇ &gt; is an alkyl group, the compound of formula (VI) may be hydrolyzed by conventional acidic or basic methods to give a compound of formula (I).

When R &lt; ₇ &gt; is a benzyl group, the compound of formula (VI) can be hydrolyzed in the presence of palladium on a catalyst, e.g., charcoal, to produce a compound of formula (I).

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

Thus, compounds of formula II are described in [Organic Preparation and Procedures International, 13, 189, 1981].

Compounds of formula V may be prepared according to the methods of R. Ratouis et al. [J. Med. Chem., 8, 104, 1965] or Prelog et al. [Collection Czechoslov. Chem. Communications, 6, 211, 1934, incorporated herein by reference.

For example, compounds of formula (VI) wherein R &lt; ₇ &gt; is an alkyl group may be hydrolyzed in the presence of a basic agent such as, for example, dilute sodium hydroxide.

The enantiomers of the compounds of formula (I) may be obtained by successive 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 conversion of the salt Lt; / RTI &gt; to an optically active acid.

The compounds according to the invention can be used for the treatment of diabetes, in particular non-insulin-dependent diabetes, due to their hypoglycemic effect and non-toxicity in active doses.

Thus, another subject of the present invention is a pharmaceutical composition comprising an effective amount of a compound according to the present invention.

The pharmaceutical composition according to the present invention may be provided in the form of parenteral, oral, rectal, permucosal or transdermal administration.

Thus, the pharmaceutical compositions may be in the form of injectable solutions or suspensions, or in the form of multi-dose containers, in the form of uncoated or coated tablets, in the form of sugar-coated tablets, in capsules containing hard gelatine capsules, In the form of solutions, suspensions, powders, suppositories or rectal capsules, transdermal applications in polar solvents or mucosal transdermal applications.

Suitable cosmetics for such administration are cellulose or derivatives of microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starch, modified starches for solid form or lactose.

Cocoa butter or polyethylene glycol stearate are preferred formulations for rectal use.

Water, aqueous solutions, physiological solutions or isotonic solutions are the most convenient excipients for parenteral use.

The dosage may vary within a wide range depending on the age and weight of the patient as well as the therapeutic adaptation and administration route.

The following examples illustrate the preparation of intermediates of formula (I) and intermediates of formula (II) and (IV).

A - Preparation of the compound of formula (II)

Preparation of methyl 2-cyclohexylmethylamino-5-methoxybenzoate

To 200 mg of methanol in a 1 L hydrogenation apparatus was added 17.6 g of methyl 5-methoxyanthranilate, 11.8 mL of cyclohexanecarboxaldehyde and 2 g of 10% palladium on charcoal (50% water).

The device was placed under a hydrogen atmosphere and shaken at room temperature for 3 hours.

300 ml of dichloromethane was added, palladium on charcoal was separated off by filtration, and the obtained filtrate was concentrated in vacuo.

The oil obtained is crystallized from a mixture of 200 ml of ethanol and 50 ml of water to give 25.4 g of a yellow solid which is melted at 58-60 &lt; 0 &gt; C.

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

_{^{1 H NMR: (CDCl 3,}} 200 MHz) δppm: 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, phenylproton), 6.96 (1H, dd, phenylproton), 7.34 (2H, d + s, phenylproton + NH).

The formulas and characteristics of the compounds of formula (II) are shown together in Table I.

B - Preparation of the compound of formula IV

Preparation of 4-chloro-2- (chloroacetamido) benzoic acid

While maintaining the reaction mixture at 20 占 폚, 25.5 ml of chloroacetyl chloride is added dropwise to 50 g of 2-amino-4-chlorobenzoic acid in 600 ml of dioxane with stirring.

Then continue stirring at room temperature for 2 hours, then add 1200 ml of water. The desired product precipitates, the mixture is stirred for 1 hour, then filtered and the resulting solid is washed with water.

After drying, 60.7 g of 4-chloro-2- (chloroacetamido) benzoic acid is obtained, the melting point of which is 194-196 占 폚.

IR: 1676 cm &lt; ^-1 &gt; (C = O)

_{^{1 H NMR: (d 6 -DMSO}} , 200 MHz) δppm: 4.30 (2H, s, CH 2), 7.1 (1H, d, phenyl proton), 7.7 (1H, d, phenyl proton), 8.5 (1H, s , Phenyl protons), 11.75 (1H, s, NH), 13.90 (1H, br s, COOH).

The formulas and characteristics of the compounds of formula IV are shown together in Table II.

C - Preparation of the compound 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 are added at room temperature to 11.6 g of 1- (2-methoxyphenyl) piperazine and 17 ml of triethylamine in 120 ml of DMF with stirring .

The reaction mixture is continuously stirred at room temperature for 48 hours and then 500 ml of water are added. Extract with 3 x 300 mL of dichloromethane. The solvent is evaporated in vacuo and the solid so obtained is redissolved in 300 ml of a 2N aqueous sodium hydroxide solution. The solution is washed with 3 x 200 ml of diethyl ether and the aqueous layer is acidified with acetic acid.

The solid crystallizes to yield 22.5 g of crude product after filtration. After recrystallization from dioxane, 21.1 g of 4-chloro-2- {[4- (2-methoxyphenyl) -1-piperazinyl] acetamido} benzoic acid was obtained as a white solid &Lt; / RTI &gt;

^{IR: (KBr) 1699 cm -1} (C = O), 1673 cm -1 (C = O)

_{^{1 H NMR: (CF 3 COOD}} ) δppm: 4.25 (3H, s, OCH 3), 4.65 (8H, br s, 4 CH 2), 4.95 (. 2H, s CH 2), 7.5 (2H, m, phenyl (Proton), 7.6 (1H, d, phenylproton), 7.90 (2H, m, phenylproton), 8.50 (1H, d, phenylproton), 8.75

D - Alternative forms of the preparation of compounds of formula (I)

Preparation of 2 - {[4- (4-fluorophenyl) -1-piperazinyl] -acetamido} -4,5- (methylenedioxy) benzoic acid

15 g of 2- (chloroacetamido) -4,5- (methylenedioxy) benzoic acid were added to a solution of 10.5 g of 1- (4-fluorophenyl) piperazine and 150 mg of 16.2 ml Is added to triethylamine.

The reaction mixture is continuously stirred at room temperature for 48 hours.

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

After recrystallization from a dioxane / DMF mixture, 14.9 g of 2 - {[4- (4-fluorophenyl) -1-piperazinyl] acetamido} -4,5- (methylenedioxy) , And the product is melted at 254-256 占 폚.

IR: (KBr) 1654 cm &lt; ^-1 &gt; (C = O)

_{^{1 H NMR: (CF 3 COOD}} , 200 MHz) δppm: 4.40 (8H, s, piperazinyl), 4.67 (2H, s, CH 2), 6.05 (. 2H, s O-CH 2 -O), 7.30 (2H, t, phenylproton), 7.65 (3H, m, phenylproton), 7.90 (1H, s, phenylproton).

The chemical formulas and characteristics of the compounds of formula I are shown together in Table III.

Results of pharmacological studies will be provided below.

Study of anti-diabetic activity in NOSTZ rats

The anti-diabetic activity of the compounds of formula I by the oral route was determined on an experimental model of non-insulin-dependent diabetes induced in mice by streptozotocin.

Non-insulin-dependent diabetes models are obtained by neonatal (birthday) injection of streptozotocin in rats.

The diabetic rats used are eight weeks old. Animals were housed in an animal house at a temperature controlled from 21 to 22 占 폚 from their birthday to the experiment and applied to a fixed light-dark cycle (light: 7 to 19 hours, darkness: 19 to 7 hours). Their diet consisted of a maintenance diet and provided "unlimited" water and food except fasting (post-absorption phase) for 2 hours before the test was interrupted.

Rats were orally treated on the day of the test product. A 300 μl blood sample was taken from the tail end for 2 hours after the final administration of the product and 30 minutes after the animal was anesthetized with pentobarbital (Nembutal).

The main results obtained are shown together in Table IV. These results show the efficacy of compounds of formula I in reducing glycaemia in diabetic animals.

These results are expressed as a percentage change in glicerism in D4 (4 days of treatment) compared to DO (before treatment).

compound 20 mg / kg / d 200 mg / kg / d % Glicaeemia at D4 % Glicaeemia at D4 35 -12 -16 38 -6 -27 39 -15 -14 45 -9 -18 47 -16 -32 48 -20 -31 50 -17 -7 52 -14 -21

Claims (10)

A compound selected from the compounds of formula (I), their solvates and pharmaceutically acceptable salts thereof: [Chemical Formula 1] [Wherein: Ar is selected from Mono-, non-or tricyclic aryl having from 6 to 14 carbon atoms, Pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazyl groups A heterocyclic group, Ar groups are C ₁ -C ₈ alkyl, (C ₃ -C ₈₎ cycloalkyl (C ₁ -C ₆₎ alkyl, C ₁ -C ₈ alkoxy, (C ₃ -C ₈₎ cycloalkyloxy (C ₁ -C ₆ (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyloxy, (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 aryl (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₎ (C ₆ -C ₁₄ ) aryloxy, (C ₆ -C ₁₄ ) aryloxy (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkyloxy, ₆ -C ₁₄₎ aryl (C ₁ -C ₆₎ alkyloxy (C ₁ -C ₆₎ alkyl, methyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, carbamoyl, (C ₁ -C ₈₎ alkylthio, (C ₁ -C ₈₎ alkylsulfinyl, (C ₁ -C ₈₎ alkylsulfonyl, alkylsulfonyl amino, (C ₁ -C ₈₎ alkylsulfonylamino, Sulfamoyl and (C ₁ -C ₈ ) alkylcarbonylamino, or two of these substituents may be methylenedioxy, 4-carboxyphenyl and substituted 4-carboxyphenyl are excluded from the definition of Ar; R ₁ , R ₂ and R ₃ are each independently selected from - Hydrogen, - C ₁ -C ₈ alkyl, (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ alkyl group, - cycloalkyl having 3 to _8, (C ₃ -C 8) cycloalkyl (C ₁ -C ₆₎ alkyl, (C ₃ -C ₈₎ cycloalkyloxy (C ₁ -C ₆₎ 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, and one or both of them may be a nitrogen atom; R ₄ , R ₅ and R ₆ are each independently selected from - Hydrogen, - C ₁ -C ₈ alkyl, (C ₃ -C ₈₎ cycloalkyl (C ₁ -C ₆₎ alkyl, C ₁ -C ₈ alkoxy, (C ₃ -C ₈₎ cycloalkyloxy (C ₁ -C ₆₎ alkyl, (C ₃ -C ₈₎ cycloalkyloxy, (C ₃ -C ₈₎ cycloalkyl (C ₁ -C ₆₎ alkoxy, (C ₃ -C ₈₎ cycloalkyl (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₎ alkyloxy (C ₁ -C ₆₎ alkyl, methyl, halogen, trifluoromethyl , trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino, (C ₁ -C ₆₎ alkoxycarbonyl, carbamoyl, (C ₁ -C ₆₎ alkylthio, (C ₁ -C ₈ (C ₁ -C ₈ ) alkylsulfonyl, sulfamoyl, (C ₁ -C ₈ ) alkylsulfonylamino, sulfamoyl and (C ₁ -C ₈ ) alkylcarbonylamino Dog Are attached may form a fused ring with the phenyl ring or methylenedioxy); The various aryl groups may themselves be substituted with one to three substituents selected from C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino have]. The compound according to claim 1, wherein the basic component of the following ring system is a phenyl ring: . The method of claim 2, wherein, R _4, R ₅ and R ₆ at least one of the groups C ₁ -C ₆ alkoxy or such groups of two are each the compound forms a methicillin alkylenedioxy. A process for preparing a compound according to claim 1, which process comprises reacting an aromatic amine of formula (II) with a haloacyl halide of formula (III) to form a compound of formula (IV) With a compound of formula V to form a compound of formula VI wherein R ₇ is alkyl, then hydrolyzing the compound of formula VI to form a compound of formula I, and when R ₇ is benzyl, , Hydrolyzing a compound of formula (VI) to form a compound of formula (I) &Lt; RTI ID = 0.0 & Wherein R ₇ is selected from hydrogen, C ₁ -C ₆ alkyl, and benzyl. The compounds of formula (I), wherein A, B, C, D, R ₁ , R ₄ , R ₅ and R ₆ are as defined above, (III) Wherein R ₂ and R ₃ are as defined above, Hal is selected from chlorine and bromine. (IV) Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and Hal are as defined above, (V) Wherein Ar is as defined above, (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. A pharmaceutical composition comprising an effective amount of a compound claimed in claim 1. A pharmaceutical composition comprising an effective amount of a compound claimed in claim 2. A pharmaceutical composition comprising an effective amount of a compound as claimed in claim 3. A method of treating diabetes comprising administering to a human in need thereof an effective amount of a compound claimed in claim 1. A method of treating diabetes comprising administering to a human in need of treatment an effective amount of a compound claimed in claim 2. A method of treating diabetes comprising administering to a human in need of treatment an effective amount of a compound claimed in claim 3.