AU8798998A

AU8798998A - Alpha-(1-piperazinyl)acetamido arenecarboxylic acid derivatives as antidiabetic agents

Info

Publication number: AU8798998A
Application number: AU87989/98A
Authority: AU
Inventors: Donald D. Bierer; Gerard Botton; Liliane Doare; Micheline Kergoat; Didier Mesangeau; Gerard Patereau
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1998-06-08
Filing date: 1998-06-08
Publication date: 1999-12-30
Anticipated expiration: 2018-06-08
Also published as: UA56324C2; HUP0102006A2; KR20010052662A; JP2002517489A; SK18592000A3; AU748712B2; HUP0102006A3; EP1091947A1; CA2334558A1; RU2198881C2

Description

WO 99/64407 PCT/EP98/03431 a-(I-PPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS The present invention relates to new a-(1-piperazinyl)acetamido 5 arenecarboxylic acid derivatives which are useful in the treatment of diabetes. The subject of the present invention is thus compounds of general formula (I): COOH C 1

R

2 R 3 A B D 0 N~N 10 in which: Ar is selected from - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms, 15 - a heteroaromatic group selected from the pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, it being possible for the Ar group to carry 1 to 3 substituents selected from a C1-C8 alkyl, (C3-C8)cycloalkyl(C 1

-C

6 )alkyl, C1-C8 alkoxy, (C3 20 Cs)cycloalkyloxy(C-C 6 )alkyl, (C3-C8)cycloalkyl(Cl-C 6 )alkoxy(CC 6 )alkyl, (C3

C

8 )cycloalkyloxy, (C 3

-C

8 )cycloalkyl(C1C 6 )alkoxy, (C 1 -C6)alkoxy(C-C6)alkyl, C6-C14 aryl, C-C14 heteroaryl, (C 6

-C

1 4 )heteroaryl(C-C 6 )alkyl, (C-C 1 4 )aryl(0l-C 6 )alkyl;

(C

6 -Cl 4 )aryl(C-C 6 )alkyl(C 6

-C

4 )aryl, (C6-Cl)aryloxy, (C6-C14)aryloxy(C1-C 6 )alkyl,

(C

6 -Cl 4 )aryl(0 1

-C

6 )alkyloxy or (C6-C4)aryl(Cl-Ce)alkyloxy(Cr-C 6 )alkyl group, a 25 halogen, a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, (Cr-Cs)alkoxycarbonyl, carbamoyl, (Cr 1 C3)alkylthio, (C

C

8 )alkylsulphinyl, (C-C3)alkylsulphonyl, sulphoamino, (C SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 2

C

8 )alkylsulphonylamino, sulphamoyl or (CrC 8 )alkylcarbonylamino group, or two of these substituents forming a methylenedioxy group, the 4-carboxyphenyl and substituted 4-carboxyphenyl groups being excluded from the definition of Ar,

R

1 , R 2 and R 3 are selected, independently of one another, from: - a hydrogen atom, - a Cr1C8 alkyl or (C-C 6 )alkoxy(C-C 6 )alkyl group, - a cycloalkyl group containing from 3 to 8 carbon atoms, a (C3

C

8 )cycloalkyl(C-C 6 )alkyl group or a (C 3 -C3)cycloalkyloxy(C-C 6 )alkyl or (C3 i C 8 )cycloalkyl(C-C 6 )alkoxy(Cr-C 6 )alkyl group, - a C6-C14 aryl, C 6

-C

14 heteroaryl, (Ce-C 14 )heteroaryl(C 1

-C

6 )alkyl,

(C

6

-C

1 4)aryl(0 1

-C

6 )alkyl, (C 6

-C

1 )aryl(C-C 6 )alkyl(C 6

-C

1 )aryl, (C 6

-C

14 )aryl(Cj-C 6

)

alkoxy(0 1

-C

6 )alkyl or (C 6

-C

4 )aryloxy(C-C 6 )alkyl group, A, B, C and D are =CH- groups, it being possible for one or two of 15 them also to be a nitrogen atom,

R

4 , R 5 and R 6 are selected, independently of one another, from: - a hydrogen atom, - a C-C3 alkyl, (C3-C 8 )cycloalkyl(C-C 6 )alkyl, Cl-C alkoxy, (C3

C

8 )cycloalkyloxy(C-C 6 )alkyl, (C 3 -C3)cycloalkyloxy, (C 3

-C

8 )cycloalkyl(C 2 C 6 )alkoxy, (C 3

-C

8 )cycloalkyl(CrC 6 )alkoxy(C-C 6 )alkyl, (0 1 -C)alkoxy(C-C 6 )alkyl, C6-C14 aryl, (C 6

-C

4 )aryl(0 1

-C

6 )alkyl, (C6-Cl 4 )aryl(C-C 6 )alkyl(C 6 -Cl 4 )aryl, (C6

C

1 4 )aryloxy, (C 6

-C

1 4 )aryloxy(C 1

-C

6 )alkyl, (C6-C 4 )aryl(C-C 6 )alkoxy or (C6

C

14 )aryl(Cl-C 6 )alkyloxy(C-C 6 )alkyl group, a halogen or a trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino, (CI-C 6 )alkoxycarbonyl, 25 carbamoyl, (0 1

-C

6 )alkylthio, (Cl-C 8 )alkylsulphinyl, (CI-C3)alkylsulphonyl, sulphoamino, (CriCs)alkylsulphonylamino, sulphamoyl or (C 1 r C3)alkylcarbonylamino group, it being possible for two of these groups to form a methylenedioxy group or a phenyl ring condensed with the ring to which they are attached, 30 it being possible for the various aryl groups to be themselves substituted by 1 to 3 substituents selected from a C-Ce alkyl or C-C 8 alkoxy group, a halogen or a trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino group, SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/IEP98/03431 their solvates and their pharmaceutically acceptable salts. Mention may be made, as an example of the aryl group, of the phenyl, a-naphthyl, P-naphthyl and fluorenyl groups. The C1-C8 alkyl groups can be linear or branched. Mention may be made, as examples, of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and pentyl groups. The C1-Cs alkoxy groups can likewise be linear or branched. Mention may be made, as examples, of the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups. The halogens can be selected from fluorine, chlorine, bromine and iodine. The heteroaryl groups in the definition of R 1 , R 2 and R 3 may be defined in particular as defined for the heteroaromatic groups in the definition of Ar. 15 The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formula (1). The compounds of general formula (I) possess a carboxylic acid functional group and can be salified, then existing in the form of salts with bases. 20 Examples of salts with bases of the compounds of general formula (1) include the pharmacologically acceptable salts, such as the sodium salts. potassium salts, calcium salts and other salts of the same type. The compounds of general formula (1) can also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, 25 the compounds of general formula (1) could be salified with glucamine, N methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine. The compounds of general formula (1) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. 30 Examples of salts with acids of the compounds of general formula (I) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochloride, the hydrobromide, the sulphate, the succinate, maleate, fumarate, SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/IEP98/03431 4 malate or tartrate and the sulphonates, such as the methanesulphonate, the benzenesulphonate or the toluenesulphonate. The invention also relates to a process for the preparation of the compounds of general formula (I). A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (II):

COOR

7 R$ A N Rs - R6 in which A, B, C, D, R 1 , R 4 , R 5 and R 6 are as defined above and R 7 is a hydrogen atom, a C-C alkyl group or a benzyl group, with a haloacyl halide of general formula (III):

R

2

R

3 Hal Hal (Ill) 10 in which R 2 and R 3 are as defined above, Hal represents a chlorine or bromine atom, in order to form a compound of general formula (IV):

COOR

7 RR

R

2 R 3 AHal (V B D 0 RS R 6 i1 in which A, B, C, D, R 1 , R 2 , R 3 , R 4 , R 5 , R6, R 7 and Hal are as defined above, and the reaction of the compound of general formula (IV) with a compound of general formula (V): SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 H (V) ON A r in which Ar is as defined above, in the presence of a basic agent, such as triethylamine, in order to form the compound of general formula (VI):

COOR

7

R

1

R

2

R

3 R4

R

5 Ar in which Ar, A, B, C, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above. In the case where R 7 is an alkyl group, the compound of general formula (VI) can be hydrolysed by conventional acidic or basic means in order to to give the compound of general formula (1). In the case where R 7 is a benzyl group, the compound of general formula (VI) can be hydrogenolysed in the presence of a catalyst, such as palladium-on-charcoal, in order to give the compound of general formula (1). The compounds of formulae (11) and (V) are known compounds or 15 can be prepared according to known processes. Thus, compounds of formula (II) are described in Organic Preparation and Procedures International, 13, 189, 1981. The compounds of formula (V) can be prepared as described by R. Ratouis et al. (J. Med. Chem., 8, 104, 1965) or by Prelog et al. (Collection 20 Czechoslov. Chem. Communications, 6, 211, 1934). By way of example, the compound (VI), in which R 7 is an alkyl group, can by hydrolysed in the presence of a basic agent, such as dilute sodium hydroxide. SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 6 The enantiomers of the compounds of formula (1) can be separated by successive recrystallization of the salt of the acid (1) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol and then displacement from the salt into an optically active acid by an inorganic or organic 5 acid, according to a conventional method. The compounds according to the present invention can be used in the treatment of diabetes, in particular of non-insulin-dependent diabetes, because of their hypoglycaemic effect and of their absence of toxicity at the active doses. 10 Another subject of the present invention is thus pharmaceutical compositions comprising an effective amount of a compound according to the invention. The pharmaceutical compositions according to the invention can be presented in forms intended for parenteral, oral, rectal, permucosal or 15 percutaneous administration. They will thus be presented in the form of injectable solutions or suspensions, or multi-dose containers, in the form of uncoated or coated tablets, of sugar-coated tablets, of capsules, including hard gelatin capsules, of pills, of cachets, of powders, of suppositories or of rectal capsules, of solutions or of 20 suspensions, for percutaneous use in a polar solvent or for permucosal use. The excipients which are suitable for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms. 25 Cocoa butter or polyethylene glycol stearates are the preferred excipients for rectal use. Water, aqueous solutions, physiological solution or isotonic solutions are the most conveniently used vehicles for parenteral use. The dosage can vary within wide limits depending on the 30 therapeutic indication and the administration route, as well as the age and weight of the patient. SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/IEP98/03431 7 The following examples illustrate the preparation of the compounds of formula (1) and of the intermediates of formulae (11) and (IV). A - Example of the preparation of a compound of formula (II). i Preparation of methyl 2-cyclohexylmethylamino-5-methoxybenzoate 17.6 g of methyl 5-methoxyanthranilate, 11.8 ml of cyclohexanecarboxaldehyde and 2 g of 10% palladium-on-charcoal (50% water) are charged to 200 ml of methanol in a 1 litre hydrogenation apparatus. The apparatus is placed under a hydrogen atmosphere and i agitated at room temperature for 3 hours. 300 ml of dichloromethane are added, the palladium-on-charcoal is separated off by filtration and the filtrate obtained is concentrated under vacuum. The oil obtained crystallizes from an ethanol (200 ml) and water (50 ml) mixture to give 25.4 g of a yellow solid which melts at 58-600C. i IR: (KBr) 1683 cm-' (C=0), 1528 cm~ 1 (C=0) 1 H NMR: (CDC1 3 , 200 MHz) 6 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 (1 H, dd, phenyl proton), 7.34 (2H, d + s, phenyl proton + NH). The formulae and characteristics of the compounds of formula (1l) 20 have been combined in Table 1. SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 8 TABLE I Compound Structure M.p. in 0C (Kdfler) C02CH 3 58-60 N I "H

H

3 CO 2

CH

3 1 H NMR (200 MHz) C02CH 3 CDC1 3 6 PPM N 1.28 (t. 3H) H 3.20 (q, 2H)

H

3 CO 3.77 (s, 3H) Oil 3.88 (s,3H) 6.71 (d, 1H) 7.09 (dd, 1H) 7.28 (s, 1H) 7.50 (d, 1H) 3 COOH M.p. in 0C

NH

2 (Kofler) 147-149 0 B - Example of the preparation of a compound of formula (IV). Preparation of 4-chloro-2-(chloroacetamido)benzoic acid 25.5 ml of chloroacetyl chloride are added dropwise with stirring to 50 g of 2-amino-4-chlorobenzoic acid in 600 ml of dioxane, the reaction mixture being maintained at 200C. Stirring is then maintained for 2 hours at room temperature and then 1200 ml of water are added. The desired product precipitates, the mixture is stirred for one hour and then filtered and the solid obtained is washed with water. SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 9 After drying, 60.7 g of 4 -chloro-2-(chloroacetamido)benzoic acid are obtained, the melting point of which is 194-196*C. IR: 1676 cm-' (C=0) 'H NMR: (d 6 -DMSO, 200 MHz) 6 ppm: 4.30 (2H, s, CH 2 ), 7.1 (1H, d, 5 phenyl proton), 7.7 (1H, d, phenyl proton), 8.5 (1H, s, phenyl proton), 11.75 (1H, s, NH), 13.90 (1H, broad s, COOH). The formulae and characteristics of the compounds of formula (IV) have been combined in Table 11. 10 TABLE 11 Compound Structure M.p. in * C (Kafler) 001-H NH 1 Cl 194-196 0 Cl 2 COOH NH 182-184

H

3 CO OOH 3 NH Cl 236-238 0

H

3 CO

OCH

3 SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 10 TABLE II (continuation) Compound Structure M.p. in 0 C (Kofler) OOH 4 NH Cl1 180-182

H

3 CS COOH 5 NH CI 155-157

H

3 C COOiPr 6 C 6 3NH C l 83-85

H

3 C O COOH OI ~NH C 217-219 SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/IEP98/03431 1 -_ TABLE II (continuation) Compound Structure 'H NMR (200 MHz) CDC1 3 5 ppm

CH

3 0.99 (t, 3H) CO2CH3 3.35 (m, 1H) 8 N C 3.63 (d, 2H) Oil 3.89 (s+m,7H)

H

3 CO 0 7.12 (m, 2H) 7.40 (d, 1H) 1.05 (t, 3H) 1.57 (m, 6H) 9C2CH 2.81 (dd. 1H)

C

3 3.66 (s, 2H) N CI Oil 3.81 (s, 6H) 3.88 (dd, 1H)

H

3 CO 7.13 (m, 2H) 7.38 (d, 1 H) C - Example of the preparation of a compound of formula (11) Preparation of 4-chloro-2-{r4-(2-methoxVphenVl)-1-piperazinVllacetamido} benzoic acid 15 g of 4-chloro-2-(chloroacetamido)benzoic acid are added, with stirring and at room temperature, to 11.6 g of 1-(2-methoxyphenyl)piperazine and io 17 ml of triethylamine in 120 ml of DMF. The reaction mixture is kept stirring for 48 hours at room temperature and then 500 ml of water are added. Extraction is carried out with 3 , 300 ml of dichloromethane. The solvent is evaporated under vacuum and the solid thus obtained is taken up again in 300 ml of a 2N aqueous sodium 15 hydroxide solution. The solution is washed with 3 x 200 ml of diethyl ether and the aqueous phase is then acidified with acetic acid. A solid crystallizes to give, after filtration, 22.5 g of crude product. After recrystallization from dioxane, 21.1 g of 4 -chloro-2-{[4-(2-methoxyphenyl) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCTIEP98/03431 12 1-piperazinyl]acetamido}benzoic acid are obtained in the form of a white solid which melts at 218-220*C. IR: 1699 cm-' (C=0), 1673 cm- (C=0) 'H NMR: (CF 3 COOD), 5 ppm: 4.25 (3H, s, OCH 3 ), 4.65 (8H, broad s, 4 CH 2 ), 4.95 (2H, s, CH 2 ), 7.5 (2H, m, phenyl protons), 7.6 (1H, d, phenyl proton), 7.90 (2H, m, phenyl protons), 8.50 (1H, d, phenyl proton), 8.75 (1H, s, phenyl proton). D - Alternative form of the preparation of a compound of formula (1) i0 Preparation of 2-{f4-(4-fluorophenvl)-1-piperazinyll acetamido}-4,5-(methylenedioxy)benzoic acid 15 g of 2-(chloroacetamido)-4,5-(methylenedioxy)benzoic acid are added, with stirring and at room temperature, to 10.5 g of 1-(4 fluorophenyl)piperazine and 16.2 ml of triethylamine in 150 ml of DMF. 15 The reaction mixture is kept stirring for 48 hours at room temperature. 3.5 ml of acetic acid are added and 150 ml of water are slowly added. The acid crystallizes and is diluted with 300 ml of water. The mixture is stirred for 30 minutes and filtered and the solid obtained is washed with water. 20 After recrystallization from a dioxane/DMF mixture, 14.9 g of 2-{[4 (4-fluorophenyl)-1-piperazinyl]acetamido}-4,5-(methylenedioxy)benzoic acid are obtained, which product melts at 254-2560C. IR (KBr): 1654 cm-' (C=0) 'H NMR: (CF 3 COOD, 200 MHz) 6 ppm: 4.40 (8H, s, piperazinyl), 25 4.67 (2H, s, CH 2 ), 6.05 (2H, s, 0-CH 2 -0), 7.30 (2H, t, phenyl proton), 7.65 (3H, m, phenyl proton), 7.90 (1 H, s, phenyl proton). The formulae and characteristics of compounds of formula (1) have been combined in Table Ill. SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 13 TABLE III M.p. in 'H NMR Com- Structure *C (200 MHz) o ppm pound (Kdfler) d6-DMSO COOH 2.60 (s,4H) NH 3.10 (s,4H) N 185-187 3.20(s,2H) 0 N 3.70(s,3H) 6.80(q,4H) 7.10(t,1H) OCH. 7.55(t,1H) 8(d,1H) 8.7(d,1H)

CF

3 COOD COOH 4.25(s,8H) NH 4.65(s,2H) N 233-235 7.30(t,1H) 0 N 7.55(s,5H) 7.70(t, 1 H) 8.25(m,2H)

CF

3 COOD COOH 4.25(s,8H) 4.55(s,2H) NH N 248-250 7.10(d,1H) 7.50(s,5H) 0 N 8.05(d,1H) 8.30(s,1H)

CF

3 COOD COOH 4(s,3H) NH 4.5(s,8H) N241-243 4.8(s,2H) 0 N 7.2(d,2H) 7.4(d, 1 H) CI 7.65(d,2H)

OCH

3 8.25(d,1H) 8.60(s, 1 H) COOH

CF

3 COOD 4.20(s,8H) NH Y N 4.62(s,2H) 5 N > 265 7.20(d,1H) 0 7.55(s,4H) cl 8.10(d,1H) cl 8.35(s,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 14 M.p. in H NMR Com- Structure *C (200 MHZ) 6 ppm pound (Kbfler)

CF

3 COOD COOH 3.8(s,3H) NH 4.25(s,8H) 6 N 199-201 4.60(s,2H) 6 N OCH 3 7.20(m,4H) 7.5(m.1 H) C 8.15(d,1H) 8.40(s, 1 H)

CF

3 COOD COOH 4.60(d,8H) NH 4.90(s,2H) N F 238-240 7.50(m,3H) O N 7.85(m,2H) 8.35(d,1 H) Cl 8.65(s, I H)

CF

3 COOD COOH 4.10(s,8H) NH 4.45(s,2H) 8 N 244-246 7.05(d,3H) 0 N 7.45(m,2H) 7.95(d,1H) CI 8.20(s, 1 H) F

CF

3 COOD COOH 4.25(d,8H) NH N 4.60(s,2H) 9 | 191-193 7.15(d,1H) 9 O N CF3 7.75(m,4H) 8.1O(d,1H) CI 8.30(s,1H)

CF

3 COOD COOH 4.25(s,3H) NH 4.65(s,8H) 10 I NH N OCH 3 218-220 4.95(s,2H) 0 N 7.5(m,2H) 7.6(d,1 H) CI 7.9(m,2H) 8.5(d,1H) 8.75(s,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 15 M.p. in 'H NMR Com- Structure 0 C (200 MHZ) 6 ppm pound (Kbfler)

CF

3 COOD COOH 4.3(s,8H) 4.7(s,2H) 11 NH 260-262 7.25(t,1H) N 7.55(s,4H) 0 N 7.70(t,1 H) 8.25(m,2H) Ci

CF

3 COOD COOH 4.2(s,8H) NH 4.6(s,2H) N 249-251 7.2(m,3H) 12 0 N 7.6(m,3H) 8.15(m,2H) F CDC1 3 COOH 2.65(s,4H) NH 3.10(s,2H) N 174-176 3.20(s,4H) 0 N CF 3 7,00(m,7H) 8.65(d, 1 H) 10,00(s,1H) 11.8(s,1H)

CF

3 COOD COOH 3.85(s,3H) NH 4.30(s,8H) N 190-192 4.75(s,2H) O N OCH3 7.5(m,6H) 8.15(t,2H) COOH CDC13 COOH 2.74(s,3H) N H Y NF3.1 5(s,8H) 1N F 169-171 3.20(s,2H) O N 6.80(m,5H) 7.5(t, 1 H) 7.75(d, 1 H) 8.80(d,1H) 11.45(s,1H) 12.00(s,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 16 M.p. in 'H NMR Com- Structure *C (200 MHZ) C ppm pound (Kafler) CDC13 COOH 3.5(s,3H) N 3.75(s,8H) N OCH 3 217-219 4.29(s,2H) 16 N 6.65(d,2H) 6.85(t,1H) 7.10(m,3H) 7.75(t,2H) CF3COOD COOH 3.75(s,8H) NH 4.15(s,2H) N 190-192 6.75(m,1H) 17 N CI 7.00(m,5H) 7.60(m,2H) CF3COOD COOH 3.65(s,6H) NH 4.15(s,8H) N8>265 4.5(s,2H) 18 H CO N 7.55(s,5H) 3 7.65(s, 1 H)

OCH

3 7.85(s,1H)

CF

3 COOD COOH 3.75(s,6H) N 4.15(s,8H) 19 N >265 4.50(s,2H) 1 N 7.05(t,2H) H3CO 7.42 (m, 2 H)

OCH

3 7.55(s, 1 H) F 7.85(s,1H)

CF

3 COOD COOH 3.80(s,6H) NH T"_N4.1 5(s,8H) 20 N >265 4.50(s,2H) H COO N 7.40(s,4H) 3 CO 0 7.60(s, 1 H) CH3 C1 7.90(s,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 17 M.p. in 'H NMR Com- Structure *C (200 MHZ) 6 ppm pound (KofIer)

CF

3 COOD COOH 3.75(s,3H) NH 3.85(s,6H) 246-248 4.15(s,8H) 21 0 N 4.50(s,2H) H-CO 6.90(d,2H)

OCH

3 7.40(d,2H)

OCH

3 7.60(s,1H) 7.95(s,1 H) C F 3 000D COOH 3.80(s,9H) NH N OCH4.25(s,8H) 22 N 00 3 244-246 4.50(s,2H) 0 N 7,00(d,2H) H3CO 7.40(d,2H) CO OCH 3 7.60(s, 1H) 7.9 5(s, 1 H)

CF

3 COOD COOH 3.80(s,6H) N H N4.20 +4.35(2s,8H) N3 F 245-247 4.50(s,2H) 3 0 N7.20(q,2H) OCO 7.50(m,3H) OCH 3 7.95(s,1H)

CF

3 COOD COOH 3.75(s,6H) NH 4.10+4.20(2s,8H) 255-257 4.50(s,2H) 24 CO ON CF 7.60(M,5H) 300 7.85(s,1 H) OCH 7

CF

3 COOD COOH 3.80(s,6H) NH N 4.15(s,8H) >265 4.50(s,2H) H 0 NC 7.35(m,4H) 30 7.55(s,1 H) CH 3 8.85(s,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 18 M.p. in H NMR Com- Structure *C (200 MHZ) 6 ppm pound (Kofler)

CF

3 COOD COOH 3.70(s,3H) NH- 3.85(s,6H) 255-257 4.22(s,8H) 26 0 N ,, OCH, 45(,H

H

3 00 4.50(s,2H) 6.95(s,3H)

OH

3 7.35(t, 1 H) 7.55(s, 1 H) 7.88(s, 1 H)

CF

3 COOD COOH 4.15+4.17(2s,8H) NH 4.50(s,2H) 7 1257-259 7.1O(d,1H) 70 N C 7.40(m,4H) 8.00(d,1 H) Ci 8.25(s, 1 H) CF3COOD COOH 3.70(s,3H) NH 4.10(s,8H) 28 N239-241 4.50(s,2H) N 6.90(d,2H) 7.30(d,2H) 7.40(d, 1 H)

OCH

3 8.00(s,1H) 8.1O(d,1H)

CF

3 COOD COOH 4.15(s,8H) NH 4.55(s,2H) 29N >265 7.40(s+d,5H) 90 N 8.00(s,1H) 8.15(d,1H) Ci

CF

3 COOD 3.85(s,3H) NH N4.30(s,8H) 199-201 4.65(s,2H) 30 N OCH 3 7.15(m,3H) 7.55(m,2H) 8.15(s,1H) 8.30(d,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 19 M.p. in 'H NMR Com- Structure 0C (200 MHZ) 6 ppm pound (Kbfler)

CF

3 COOD COOH 4.30+4.50(2s,8H) NH N4.67(s,2H) 262-264 7.30(m,2H) 31 NH0 N 7.65(m,3H) 8.15(s,1H) 8.25(d,1H)

CF

3 COOD COOH 4.05(s,8H) NH 4.40(s,2H) 32 N 245-247 7.05(t,2H) 0 N 7.40(d,3H) CI 7.90(s.1H) F 8.05(d,1H)

CF

3 COOD COOH 4.25+4.40(2s,8H) NH 4.70(s,2H) N 213-215 7.55(d,1H) 33 N CF 3 7.80(m,4H) 8.15(s,1H) 8.25(d, 1 H)

CF

3 COOD COOH 3.80(s,3H) NH 4.20(s,8H) N OCH 3 203-205 4.45(s,2H) N 6.95(d,2H) CI 7.42(q,3H) 8.05(s+d,2H)

CF

3 COOD COOH 4.10(s,8H) NH 4.45(s,2H) 224-226 7.40(m,5H) C O0 CI 7.95(s,1H) 8.1O(d,1 H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 20 M.p. in 0 C 'H NMR Com- Structure (Kbfler) (200 MHZ) 6 ppm pound

CF

3 COOD COOH 4.20(s,8H) NH 4.50(s,2H) 36 0 N 238-240 5.85(s,2H) 0 N 7.45(s,6H) 0 7.80(s,1H) 0

CF

3 COOD COOH H 4.40(s,8H) N 4.67(s,2H) 37N 254-256 6.05(s,2H) 0 N 7.30(t,2H) 0 7.65(m,3H) o 7.90(s,1 H) F

CF

3 COOD COOH H 4.22(s,8H) N 4.57(s,2H) 38 | N >265 5.92(s,2H) 0 N 7.52(s,5H) 0 7.80(s,1H)

CF

3 COOD COOH 3.83(s,3H) NH 4.25(s,8H) 39N 236-238 4.59(s,2H) 0 N 6.0(s,2H) 0 7.13(d,2H) - O7.49(t,3H)

OCH

3 7.82(s,1H)

CF

3 COOD COOH 3.97(s,3H) NH 4.29(s,8H) 40 N OCH 3 257-259 4.59(s,2H) 0 N 6.06(s,2H) 0 \_ 7.15(d,2H) - O7.55(s,3H) 7.82(s, 1 H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 21 M.p. in 'H NMR Com- Structure C (200 MHZ) 6 ppm pound (Kofler)

CF

3 COOD COOH 4.23+4.38(2s,8H) NH 4.56(s,2H) N1 F 236-238 5.97(s,2H) 1 0 N 7.31 (m,2H) 0/ -7.55(m,3H) O 7.76(s, 1 H)

CF

3 COOD COOH 4.05+4.15(2s,8H) NH 4.35(s,2H) 42N 228230 5.75(s,2H) 0 N CF 3 7.30(s,1H) 0 7.60(m,5H) 0

CF

3 COOD COOH 4.00(s,8H) NH 4.37(s,2H) 43N 240-242 5.75(s,2H) 0 N CI 7.35(d,5H) 0 7.70(s, 1 H) 0

CF

3 COOD COOH 3.55(s,3H) NH N 198-2004.0(s,8H) 44 4-1 N 9-0 4.30(s,2H) 0 N OC 5.71(s,2H) 0 6.85(s,3H) 0 7.25(s,2H) 7.60(s, 1 H)

CF

3 COOD 4.05(s,3H) NH N4.42(s,8H) 45 188-190 4.78(s,2H) 0 N 7.45(d, 1 H) H H 3 7.72(s,5H) 7.93(s,1H) 8.30(d, 1 H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 22 Com- Structure M.p. in 'C 'H NMR pound (Kafler) (200 MHz)

CF

3 COOD COOH 3.75(s,3H) 4.20(s,8H) 46 NH N 197-199 4.50(s,2H) 7.10(m,3H) 0 N 7.50(t,2H) 3CO 7.70(s,1 H) 8.05(d,1H) F

CF

3 COOD (IOH 3.80(s,3H) 4.20(s,8H) NH 4.55(s,2H) 7.15(d,1H) 47 0 N 221-223 7.40(s,4H) 7.70(s,1H) 8.00(d,1H) a

CF

3 COOD COOH 3.85(d,6H) NH 4.25(s,8H) N 4.75(s,2H) X, 0 N 7.22(s,2H) 48 4 1 7 198-200 7.40(s,1H) 7.58(s,2H) O0H 3 7.82(s,1H) 8.20(s, 1 H)

CF

3 COOD COOH 3.75(s,3H) 49 NH 4.1 5(s,8H) 4oN 171-173 4.50(s,2H) 'N 0 N7.15(s, 1H) 70 ZNC 7.70(d,5H) 3 8.05(s, 1 H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 23 M.p. in OC H NMR Com- Structure (Kofler) (200 MHz) pound

CF

3 COOD COOH 3.65(s,3H) H 3.70(s,3H) 50 N OCH 3 200-202 4.12(s,8H) 1 0 N4.42(s,2H) 0 NO 7.00(d,2H) 7.10(d,1H) 7.40(m,2H) 7.65(s, 1 H) 8.00(d. 1 H)

CF

3 COOD COOH 3.72(s,3H) 4.25(d,8H) 51 N F 179-181 4.50(s,2H) 0 N 7.1 5(m,3H) 0 N 7.50(q,2H)

H

3 CO 7.65(d, 1 H) 8.00(d,1H)

CF

3 COOD COOH 3.88(s,3H) 3.96(s,3H) 52 NH N 177-179 4.34(s,8H) 4. 72 (s,2 H) 0 N OCH 7.20(m,1H) 3CO 7.39(dd,1 H) 7.62(m, 1 H) 7.88(s, 1 H) 8.22(d,3H)

CF

3 COOD COOH 3.95(s,3H) NH 4.40(s,8H) 53 N 4.70(s,2H) 5 0N7.30(d,1H) HCO N CI 182-184 7.60(m,3H) 7.85(s, 1 H) 8.25(d,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 24 M.p. in 'H NMR Com- Structure *C (200 MHz) pound (Kbfler) d 6 -DMSO COOH OH 3 2.42(d,4H) 3 2.90(s,2H) 210-212 3.10(s,4H) 54 N N 3.18(s,3H) 0 N 6.80(t, 1 H) S6.93(d,2H) 7.25(t,2H) 7.50(m,2H) 7.70(t, 1 H) 8.00(d,1H) d 6 -DMSO COOH OH 3 2.34(d,4H) 2.81 (s,2H) N ' N 226-227 3.00+3.10(2s,7H) 6.93(d,2H) 55 07.22(d,2H) 7.47(m,2H) C1 7.70(d,1H) 7.95(d,1H) d 6 -DMSO COOH OH 2.55(d,4H) 3.03(s,2H) N 3.25(d,7H) 56 N 7.25(m,3H) 0 N CF 3 193-195 7.60(m,3H) 7.82(t, 1 H) 8.12(d,1H) d 6 -DMSO 2.55(s,4H) 1 H 3 3.00(d,6H) N 3.25(s,3H) 3.80(s,3H) 0 N 208-210 7.00(s,4H) 7.65(m,2H) 7.82(d,1 H)

OCH

3 8.10(d,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCTIEP98/03431 25 M.p. in 00 'H NMR Corn- Structure (Kbfler) (200 MHz) pound d 6 -DMSO COOHCH 196198 2.1 5(s,4H)

IOHO

3 1619 2.65(s,2H) 58N' N 2.80(s,4H) 58 N 2.90(s,3H) N0 N 00aH 3 3.5 5(s, 3H) 3 6.20(t,3H) 6.85(t, 1H) 7.25(m,2H) 7.50(d, 1 H) _________ 7.75(d, 1 H) d 6 -DMSO COOH OH 2.5 5(s, 4H) 1 3 2.95(s,6H) N~ NOH 144-1 45 3.20(s,3H) 'r' NOCH 33.90(s,3H) 59 0 N 7.00(d,4H) 7.60(rn,2H) 7.80(d, 1 H) 8. 1 (d, 1H) C F 3 0000 COOH 2.38(s,3H) NH 3.77(s,3H) 60 Y- N 189-1 91 4.22(s,8H) 0 N 4.60(s,2H) Fl N N /7.05(d,2H) 14 3CS7.50(d,3H) N C 8.07(s, 1H) 0 3 8.15 (d, 1H) d 6 -DMSO COOH 2.50(s,3H) N H 2.83(s,4H) - ~ N 3.39(2s,6H) N. 0N 7.05(d,2H) 61 HCS- 214-216 7.43(d,2H) NC 7.66 (d d, 1 H) C1 7.96 (s, 1H) 8.79(d,2H) 1 2.20(s, 1 H) ____ ___ ____ ___ ____ ___ ____ ___ ____ ___ ____ ___ _ _ 1 3.80(s, 1 H) SUBSTIrTTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 26 M.p. in 'H NMR Com- Structure *C (200 MHz) pound (Kofler) d 6 -DMSO 0.75(t,3H) 1.24(m,2H) 62 N 167-169 1.58(q2H) 0 oN z2.94(s,6H) 3.50(s,3H) oH3 3.81 (t,2H) 6.71 (q, 4H) 7.05(dd, 1 H) 7.28(s, 1 H) 8.45(d,1H) 11.77(s,1H) 13.43(s, 1 H) d 6 -DMSO CCCH 0.83(t,3H) NH 1.32(m,2H) NH N 1.58(q,2H) NH N 0 2.60(s,4H) 03 0 Nzo 159-161 3.16+3.32(2s,6H) 63 se 2 Oc 3.88(t,2H) 6.87(d,2H) 7.10(d,3H) 7.3 5(d, 1H) 8.60(d, 1 H) 11.81(s,1H) 13.50(s,1H) d 6 -DMSO S1.62(m,8H) 2.64(s,4H) NH187-189 3.20+3.28(2s,6H) N 14.75(s, 1 H) 0 N 6.86(d,2H) 7.13(m,3H) 7.39(s, 1 H) ci 8.56(d,1H) 10.1 5(s, 1 H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 27 M.p. in OC 'H NMR Com- Structure (Kofler) (200 MHz) pound d 6 -DMSO 1.51 (m,8H) 2.52(s,4H) NHN 7'' N 2.98(s,6H) 0 3.50(s,3H) 65 O 171-173 4.60(s,1H) 6.60(q,4H) 6.98(dd,1H) 7.28(s, 1 H) 8.45(d,1H) 11.77(s,1H) 13.43(s, 1 H) d 6 -DMSO 1.35(m,11H) 2.56(s,4H) 66 2.84(m,3H) COOH 3.12(s,4H) N 236-238 4.90(s+m,4H) N 6.92(d,2H) 0 N 7.28(m,4H) H 3C 7.46(d,1H) d 6 -DMSO 1 .00(m,5H) 1 .66(m,6H) 67 COOH2.49(s,4H) COOH2.90(m,7H) N 209-211 3.73(s,3H) 3.85(s+m,4H) 6.83(q,4H) 7.24(q,2H) 00H 3 7.40(s,1H) d 6 -DMSO 1.54(d,6H) NH 3.00(s,4H) 68 CHi 3 ~N 218-220 3.50(s,6H) 4.67(m, 1 H) 0 N 7.05(d,2H) 6 7.35(d,3H) 7.74(d,1H) C I 8.98(s,1H) 12.00(s,1 H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 28 M.p. in *C 'H NMR Com- Structure (KcIfler) (200 MHz) pound d 6 -DMSO CO0H 1.20(d,6H) 2.79(s,4H) CH ~ N 132-134 3.13(s,4H) 3.20(s,2H) 69 N3.62(s,3H) 4.37(m,1H) OCH- 4.94(s,1H) 6.60(d,2H) 6.79(d,2H) 7.00(dd, 1 H) 7.43(s, 1 H) 8.56(d, 1 H) 11.88(s,1H) d 6 -DMSO CH 1.05(t,3H) COOH 2.50(s4H) r161-163 3.OO(s,2H) 7 0 NN N 70N- 'N 3.2 0(s, 5H) 3.92(m+s,4H) 3CO 6.94(d,2H) H7.28(m,4H) C1 ~ 7.47(s, 1H) 13.62(s large, 1 H)

CF

3 COOD COCH rOH 3 3.58 s, N 3.79 s, 18H 71 N 3.92 m, H o6 r 0 N 150-152 6.83(d,2H)

OCH

3 7. 1O(s,2H) 7.28(d,2H) 7.58(s,1H) SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 29 Com- M.p. in *C 'H NMR pound Structure (Kofler) (200 MHz)

CF

3 COOD COOH 3.90(s,3H) 4.41 (s,8H) 72 NH N 261-263 4.75(s,2H) 7.13(d,2H) 7.45(m,4H) 7.88(m,2H) 8.64(s,1 H) 8.90(s,1H)

CF

3 COOD COOH 4.40(s,8H) 4.77(s,2H) N H 7.67(s+m,6H) 7.92(m,2H) 30 N > 265 8.68(s,1H) 8.92(s,1H) C1 Results of the pharmacological studies will be given hereinbelow. Study of the anti-diabetic activity in the NOSTZ rat The anti-diabetic activity of the compounds of formula (1) by the oral route was determined with respect to an experimental model of non-insulin io dependent diabetes induced in the rat by streptozotocin. The non-insulin-dependent diabetes model is obtained in the rat by a neonatal (the day of birth) injection of streptozotocin. The diabetic rats used are 8 weeks old. The animals are kept, from the day of their birth to the day of the experiment, in an animal house at a 15 temperature regulated from 21 to 220C and subject to a fixed cycle of light (from 7 h to 19 h) and of darkness (from 19 h to 7 h). Their feeding consisted of a maintenance diet, water and food was supplied "ad libitum", except for fasting for 2 hours before the test when the food is withdrawn (post-absorptive state). SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/IEP98/03431 30 The rats are treated orally during the day with the test product. Two hours after the final administration of the product and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal=), a 300 pl blood sample is taken from the end of the tail. The main results obtained are combined in Table IV. These results show the effectiveness of the compounds of formula (1) in decreasing glycaemia in the diabetic animals. These results are expressed as percentage of change in glycaemia at D4 (4 days of treatment) in comparison with DO (before treatment). 10 TABLE IV Compound 20 mg/kg/d 200 mg/kg/d Glycaemia at D4 Glycaemia 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 SUBSTITUTE SHEET (Rule 26)

Claims

1. A compound selected from the compounds of the formula (I): COOH R, R

2 R

3 R 0) 0CD NAr in which: Ar is selected from - mono-, bi- or tricyclic aryl having from 6 to 14 carbon atoms, - a heteroaromatic group selected from the pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, 1o benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, it being possible for the Ar group to carry 1 to 3 substituents selected from C1C8 alkyl, (C 3 -C 8 )cycloalkyl(C-C 6 )alkyl, C1C8 alkoxy, (C 3 C 8 )cycloalkyloxy(C-C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C-C 6 )alkoxy(C-C 6 )alkyl, (C 3 C3)cycloalkyloxy, (C 3 -C 8 )cycloalkyl(C-C 6 )alkoxy, (C 1 -C 6 )alkoxy(Cl-C 6 )alkyl, C6 15 C 14 aryl, C6-C14 heteroaryl, (C 6 -C 14 )heteroaryl(C-C 6 )alkyl, (C 6 -C 14 )aryl(Cr C 6 )alkyl, (C 6 -C 4 )aryl(0 1 -C 6 )alkyl(C 6 -C 1 )aryl, (C 6 -C 14 )aryloxy, (C 6 -C 4 )aryloxy(Cl C 6 )alkyl, (C 6 -C 14 )aryl(C 1 -C 6 )alkyloxy, (C6-C 4 )aryl(C 1 -C 6 )alkyloxy(0 1 -C 6 )akyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (Cl-C 6 )alkoxycarbonyl, carbamoyl, (C-C3)alkylthio, (C-C 8 )alkylsulphinyl, (Ci 20 C 8 )alkylsulphonyl, sulphoamino, (CI-C 8 )alkylsulphonylamino, sulphamoyl and (Cr-C 8 )alkylcarbonylamino, or two of these substituents forming methylenedioxy,

4-carboxyphenyl and substituted 4-carboxyphenyl being excluded from the definition of Ar, R 1 , R 2 and R 3 are selected, independently of one another, from: 25 - hydrogen, - CrC8 alkyl, (CI-Ce)alkoxy(Cr-C 6 )alkyl group, SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 32 - cycloalkyl containing from 3 to 8 carbon atoms,(C 3 Cs)cycloalkyl(Cl-C 6 )alkyl,(C 3 -Cs)cycloalkyloxy- (Cl 1 C 6 )alkyl and (C3 C 8 )cycloalkyl(0 1 -C 6 )alkoxy(C 1 C 6 )- alkyl, - C6-C14 aryl, C6-C14 heteroaryl, (C 6 -C 1 4 )heteroaryl(Cl-C 6 )alkyl, (C6 C 1 4 )aryl(C-C 6 )alkyl, (C-C 4 )aryl(C-C 6 )alkyl(C 6 -C)aryl, (C 6 -C 4 )aryl(Cr-C 6 ) alkoxy(C-C 6 )alkyl and (C 6 -Cl 4 )aryloxy(C 1 -C 6 )alkyl, A, B, C and D are =CH- groups, it being possible for one or two of them also to be a nitrogen atom, R 4 , R 5 and R 6 are selected, independently of one another, from: 10) - hydrogen, - CrC8 alkyl, (C 3 -C 8 )cycloalkyl(CC 6 )alkyl, C1C8 alkoxy, (C3 C 8 )cycloalkyloxy(CrC 6 )alkyl, (C 3 -C 8 )cycloalkyloxy, (C 3 -C 8 )cycloalkyl(C Ce)alkoxy, (C 3 -C 8 )cycloalkyl(Cl-C-)alkoxy(Cl-C 6 )alkyl, (C-C)alkoxy(CrC 6 )alkyl, C6-C14 aryl, (C 6 -C 1 4 )aryl(0 1 -C 6 )alkyl, (Ce-Cl 4 )aryl(0 1 -C 6 )alkyl(C 6 -C 4 )aryl, (C6 15 C 1 4 )aryloxy, (C 6 -C 4 )aryloxy(Cr-C 6 )alkyl, (C 6 -Cl 4 )aryl(Cr-C-)alkoxy, (C6 C 14 )aryl(Cr-C 6 )alkyloxy(CC 6 )alkyl, halogen, trifluoro- methyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino, (C-C 6 )alkoxycarbonyl, carbamoyl, (C C 6 )alkylthio, (Cr 1 C 8 )alkylsulphinyl, (Cr-C 8 )alkylsulphonyl, sulphoamino, (C C 8 )alkylsulphonylamino, sulphamoyl and (CrC 8 )alkylcarbonylamino, it being 20 possible for two of these groups to form methylenedioxy or phenyl ring condensed with the ring to which they are attached, it being possible for the various aryl groups to be themselves substituted by 1 to 3 sub'stituents selected from C1-C8 alkyl, Cr-Cs alkoxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino, 25 their solvates and their pharmaceutically acceptable salts. 2. A compound as claimed in Claim 1, in which the base component of the ring system SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 33 A1& R4--to- || R <C )D R R5 is a phenyl ring. 3. A compound as claimed in Claim 2, in which at least one of the R4, R 5 and R 6 groups is C1-C8 alkoxy or two of these groups form methylenedioxy. 4. A process for the preparation of a compound according to Claim 1, comprising the reaction of an aromatic amine of the formula (II): COOR 7 xR$ A N ' H B D(1 fCN R5 in which A, B, C, D, R 1 , R 4 , R 5 and R 6 are as defined above and R 7 is selected from hydrogen, C-C alkyl and benzyl, io with a haloacyl halide of the formula (III): R 2 R 3 Hal Hal in which R 2 and R 3 are as defined above, Hal is selected from chlorine and bromine, in order to form a compound of the formula (IV): COOR 7 R 1 R 2 R 3 Hal O) B D 0 IRS R6 15 SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/IEP98/03431 34 in which 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 the reaction of the compound of the formula (IV) with a compound of the formula (V): H N ) (V) N \ Ar in which Ar is as defined above, in the presence of a basic agent, in order to form the compound of the formula (VI): COOR 7 R 1 R 2 R 3 A 4 - (VD) B D 0 N Rf C< Ar R 5 Ar in which Ar, A, B, C, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined i0 above, and, in the case where R 7 is alkyl, the hydrolysis of this compound in order to form a compound of formula (I), and, in the case where R 7 is benzyl, the hydrogenolysis of this compound in order to form a compound of formula (1). 15 5. A pharmaceutical composition comprising an effective amount of a compound as claimed in Claim 1.

6. A pharmaceutical composition comprising an effective amount of a compound as claimed in Claim 2.

7. A pharmaceutical composition comprising an effective amount of a 20 compound as claimed in Claim 3.

8. A method for the treatment of diabetes which comprises administering to a human in need thereof an effective amount of a compound as claimed in Claim 1. SUBSTITUTE SHEET (Rule 26) WO 99/64407 PCT/EP98/03431 35

9. A method for the treatment of diabetes which comprises administering to a human in need thereof an effective amount of a compound as claimed in Claim 2.

10. A method for the treatment of diabetes which comprises administering to a human in need thereof an effective amount of a compound as claimed in Claim 3. SUBSTITUTE SHEET (Rule 26)