FR2763334A1 - Piperazino alkyl anthranilic acid amide - Google Patents

Abstract

Piperazino alkyl anthranilic amides of formula (I), their salts and solvates, are new; where Ar = 6 - 14C mono- bi- or tricyclic aryl, or heteroaryl selected from pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl, or benzothiazinyl, all of these groups being optionally substituted by 1 - 3 groups selected from 1-8C alkyl or alkoxy, 3-8C cycloalkyl 1-6C alkyl, 3-8C cycloalkyloxy 1-6C alkyl, 3-8C cycloalkyl 1-6C alkoxy 1-6C alkyl, 3-8C cycloalkyloxy, 3-8C cycloalkyl 1-6C alkoxy, 1-6C alkoxy 1-6C alkyl, 6-14C aryl, 6-14C heteroaryl, 6-14C heteroaryl 1-6C alkyl, 6-14C aryl 1-6C alkyl, 6-14C aryl 1-6C alkyl 6-14C aryl, 6-14C aryloxy, 6-14C aryloxy 1-6C alkyl, 6-14C aryl 1-6C alkoxy, 6-14C aryl 1-6C alkoxy 1-6C alkyl, halogen, CF3, CF3O, CN, OH, NO2, NH2, COOH, 1-6C alkoxy carbonyl, carbamoyl, 1-8C alkylthio, 1-8C alkylsulphinyl, 1-8C alkylsulphonyl, sulphoamino, 1-8C alkyl sulphonyl amino, sulphamoyl, 1-8C alkyl carbonylamino, or two of these substituents may form a methylene dioxy group, with the exclusion from the definition of Ar of 4-carboxy phenyl and substituted 4- carboxy phenyl; R1, R2, and R3 = H, 1-8C alkyl, 1-6C alkoxy 1-6C alkyl, 3-8C cycloalkyl, 3-8C cycloalkyl 1-6C alkyl, 3-8C cycloalkyloxy 1-6C alkyl, or 3-8c cycloalkyl 1-6C alkoxy 1-6C alkyl, 6-14C aryl, 6-14C heteroaryl, 6-14C heteroaryl 1-6C alkyl, 6-14C aryl 1-6C alkyl, 6-14C aryl 1-6C alkyl 6-14C aryl, 6-14C aryl 1-6C alkoxy 1-6C alkyl, 6-14C aryloxy 1-6C alkyl, A, B, C, and D = =CH-or one or two of them may be =N-, R4, R5, and R6 = 1-8C alkyl or alkoxy, 3-8C cycloalkyl 1-6C alkyl, 3-8C cycloalkyloxy 1-6C alkyl, 3-8C cycloalkyl 1-6C alkoxy 1-6C alkyl, 1-6C alkoxy 1-6C alkyl, 6-14C aryl, 6 - 14C aryl 1-6C alkyl, 6-14C aryl 1-6C alkyl 6-14C aryl, 6-14C aryloxy, 6-14C aryloxy 1-6C alkyl, 1-14C aryl (sic) 1-6C alkoxy, 6-14C aryl 1-6C alkoxy 1-6C alkyl, halogen, CF3, CF3O, CN, OH, NO2, NH2, 1-6C alkoxy carbonyl, carbamoyl, 1-6C alkylthio, 1-8C alkylsulphinyl, 1-8C alkylsulphonyl, sulphoamino, 1-8C alkyl sulphonyl amino, sulphamoyl, 1-8C alkyl carbonyl amino, or two of these substituents may form a methylene dioxy group, or a phenyl ring condensed to the ring to which they are attached, the various aryl groups may themselves be substituted by 1-3 substituents selected from 1-8C alkyl or alkoxy, halogen, CF3, CF3O, OH, NO2, and NH2.

Description

The present invention relates to novel o- (1-

  piperazinyl) acetamidoarylcarboxylic acid which are useful in the

diabetes treatment.

  The subject of the present invention is thus compounds of general formula (I):

COOH R1 R2 R3

  Wherein Ar is selected from - a mono, bi or tricyclic aryl group having 6 to 14 carbon atoms, - a heteroaromatic group selected from pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyrranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl, the Ar group having 1 to 3 substituents selected from C 1 -C 8 alkyl, cycloalkyl (C 3 -C 8) alkyl (C 1 -C 6) alkoxy

  C1-C8; cycloalkyl (C3-C8) oxyalkyl (C1-C6), cycloalkyl (C3-C8) alkoxy (C1-

  C6) (C1-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C1C6) alkoxy, (C1-C6) alkoxy (C1-C6) (C1-C6) alkyl, (C6-C14) aryl; C6-C14 heteroaryl;

  heteroaryl (C6-C14) alkyl (C1-C6), aryl (C6-C14) alkyl (C1-C6) aryl (C6-

  C14) alkyl (C1-C6) aryl (C6-C14), aryl (C6-C14) oxy, aryl (C6C14) oxyalkyl (C1-

  C6), aryl (C6-C4) alkyl (C1-C6) oxy, aryl (C6-C14) alkyl (C1-C6) oxyalkyl (C1-

  06), halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (C1-C8) alkylsulfinyl, alkyl ( C1-C8) alkylsulfonyl,

  sulfoamino, alkyl (C1-C8) sulfonylamino, sulfamoyl, alkyl (C1-

  C8) carbonylamino, or two of these substituents forming a methylenedioxy group, 4-carboxyphenyl and substituted 4-carboxyphenyl groups

  being excluded from the definition of Ar.

  R 1, R 2 and R 3 are chosen independently of each other 10 from: - a hydrogen atom, - a C 1 -C 8 alkyl group, - (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, - a cycloalkyl group comprising from 3 to to 8 carbon atoms, a cycloalkyl (C3-C8) alkyl group (C1-C6), a group

  cycloalkyl (C3-C8) oxyalkyl (C1-C6) or cycloalkyl (C3-C8) alkoxy (C1-

  C6) (C1-C6) alkyl, - C6-C14 aryl, C6-C14 heteroaryl,

  heteroaryl (C6-C14) alkyl (C1-C6), aryl (C6-C14) alkyl (C1-C6), aryl (C6-

  C14) (C1-C6) alkyl (C6-C14) aryl, (C6-C14) aryl (C1-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryloxy (C1-C6) alkyl, A , B, C, D are = CH- groups, one or two of them may also be a nitrogen atom, R4, Rs, R8 are chosen independently of each other from: - a hydrogen atom,

  a C1-C8 alkyl group; cycloalkyl (C3-C8) alkyl (C1-

  C6), C1-C8 alkoxy; cycloalkyl (C3-C8) oxyalkyl (C1-C6), cycloalkyl (C3-

  C8) oxy, cycloalkyl (C3-C8) alkoxy (C1-C6), cycloalkyl (C3-C8) alkoxy (C1-

  C6) (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryl, (C6-C6) aryl

  C14) (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14) aryl, (C6C14) aryl,

  aryl (C6-C14) oxyalkyl (C1-C6), aryl (C1-C14) alkoxy (C1-C6), aryl (C6-

  C14) (C1-C6) alkyloxy-(C1-C6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, carboxy, hydroxy, nitro, amino,

  (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylthio, alkyl (C1-

  C8) sulfinyl, (C1-C8) alkylsulfonyl, sulphoamino, (C1-C8) alkyl -

  sulfonylamino, sulfamoyl, alkyl (C1-C8) carbonylamino; two of these groups being able to form a methylenedioxy group or a phenyl ring condensed with the nucleus to which they are attached, the different aryl groups which may themselves be substituted with 1 to 3 substituents chosen from a C 1 -C 8 alkyl and alkoxy group; C1-C8, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro and amino,

  solvates and pharmaceutically acceptable salts thereof.

  Examples of aryl groups are groups

  phenyl, α-naphthyl, β-naphthyl, fluorenyl.

  The C1-C8 alkyl groups may be linear or branched. Examples include methyl, ethyl,

  propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl.

  C1-C8 alkoxy groups can likewise be linear or branched. Examples include methoxy, ethoxy,

  propoxy, isopropoxy, butoxy, isobutoxy.

  The halogens can be chosen from fluorine, chlorine,

bromine and iodine.

  The invention also relates to the tautomeric forms, enantiomers, diastereoisomers and epimers of

general formula (1).

  The compounds of general formula (I) possess a carboxylic acid function and can be salified, thus presenting

  in the form of salts with bases.

  Examples of base salts of the compounds of the general formula (I) include pharmacologically acceptable salts such as sodium salts, potassium salts, calcium salts and the like.

salts of the same type.

  The compounds of general formula (I) may also be salified with amines to form pharmaceutically acceptable salts. By way of example, the compounds of general formula (I)

  may be salified with glucamine, N-methylglucamine, N, N-

  dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine

or lysine.

  The compounds of general formula (I) have basic nitrogen atoms and can be monosalified or disalified by inorganic or organic acids. Examples of salts with acids, compounds of general formula (1) include pharmaceutically acceptable salts such as, and not limited to, hydrochloride, hydrobromide, sulfate, succinate, maleate, fumarate, malate, tartrate and sulphonates like methane

  sulfonate, benzenesulfonate, toluenesulfonate.

  The invention also relates to a process for the preparation of the compounds of general formula (1). A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (II): COOR7xR N> sD A

R44 DR1

  wherein A, B, C, D, R1, R4, R5, R6 are as defined

  previously and R7 is a hydrogen atom, a C4 alkyl group,

C6 or a benzyl group.

  with a haloacyl halide of the general formula (III):

R2 R3

  Hal (I) in which R2 and R3 are as defined above, Hal represents a chlorine or bromine atom, to form a compound of general formula (IV) COOR7

R R2 R3

  RA Hal (V) 4, wherein A, B, C, D, R 1, R 2, R 3, R 4, R 5, R 6, R 7 and Hal are as previously defined, and the reaction of the compound of the general formula (IV) with a compound of general formula (V): H

N M

  Wherein Ar is as defined above, in the presence of a basic agent such as triethylamine to form the compound of the general formula (VI): ## STR2 ## In which Ar, A, B, C, D, R1, R2, R3, R4, Rs, R6 and R7 are

as defined previously.

  In the case where R 7 is an alkyl group, the compound of general formula (VI) may be hydrolysed by conventional means,

  acid or basic, to give the compound of general formula (I).

  In the case where R 7 is a benzyl group, the compound of general formula (VI) may undergo hydrogenolysis in the presence of a catalyst such as palladium on carbon, to give the compound of

general formula (I).

7 2763334

  The compounds of formulas (II) and (V) are compounds

  known 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 can be prepared as described by R. Ratouis et al. (J. Med Chem 8, 104, 1965) or Prelog et al.

  al. (Collection Czechoslov Chem Communications, 6, 211, 1934).

  By way of example, the compound (VI), in which R 7 is an alkyl group, can be hydrolyzed in the presence of a basic agent such as

than diluted soda.

  The separation of the enantiomers of the compounds of formula (I) can be carried out by successive recrystallization of the salt of the acid (I) with an optically active base in solvents such as acetone, ethyl acetate and isopropanol. and then moving the salt to optically active acid by a mineral or organic acid, according to a conventional method. The compounds according to the present invention can be

  used in the treatment of diabetes, including non-insulin-dependent diabetes

  dependent because of their hypoglycemic effect and their lack of

toxicity at active doses.

  The subject of the present invention is therefore also pharmaceutical compositions comprising, as active ingredient, a

compound according to the invention.

  The pharmaceutical compositions according to the invention may be presented in forms intended for administration by the route

  parenteral, oral, rectal, permucous or percutaneous.

  They will therefore be presented in the form of injectable solutes or suspensions or multi-dose vials, in the form of naked or coated tablets, coated tablets, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules. , solutions or suspensions, for percutaneous use in a solvent

polar, for permucous use.

  Suitable excipients for such administrations are cellulose derivatives or microcrystalline cellulose, alkaline earth carbonates, magnesium phosphate, starches,

  modified starches, lactose for solid forms.

  For rectal use, cocoa butter or stearates of

  polyethylene glycol are the preferred excipients.

  For parenteral use, water, aqueous solutes, physiological saline, isotonic solutes are the most

conveniently used.

  The dosage may vary within the important limits depending on the therapeutic indication and the route of administration, as well as

than the age and weight of the subject.

  The following examples illustrate the preparation of

  compounds of formula (I) and intermediates of formulas (II) and (IV).

  A - Example of preparation of compound of formula (11l).

  Preparation of 2-cyclohexylmethylamino-5-methoxy

  methyl benzoate 17.6 g of methyl 5-methoxyanthanilate, 11.8 ml of cyclohexanecarboxaldehyde and 2 g of 10% palladium on carbon are charged to a 1 liter hydrogenator.

  (50% wet) in 200 ml of methanol.

  It is placed under a hydrogen atmosphere and stirred at

  room temperature for 3 hours.

  300 ml of dichloromethane are added, the palladium on charcoal is filtered off and the filtrate obtained is concentrated in vacuo. The resulting oil crystallizes from ethanol (200 ml) and water (50 ml) to give 25.4 g of a yellow solid which melts at 58-60 ° C. IR: (Kbr) 1683 cm -1 C = O) 1528 cm -1 (C = O) 1 H NMR (CDCl 3 200 MH 2)? Ppm 1.06-1.64 (11H, m, cyclohexyl), 2.93 (2H, t, CH 2), 3.68 ( 3H, s, OCH3), 3.78 (3H, s, OCH3), 6.56 (1H, d, phenyl proton), 6.96 (1H, dd, phenyl proton), 7.34 (2H, d +

s, proton phenyl + NH).

  Table I summarizes the formulas and

  characteristics of the compounds of formula II.

TABLE I

  Compose Structure Pf in C (Kofler) 58-60 -i Co 2CH 3N-: N11H H3CO NMR 1H (200 MHz) CDCl3 5 ppm

1CO2CH3 CH3

  N 1.28 (t, 3H) o 2X FH 3.20 (q, 2H) H GO 3.77 (s, 3H) H. 3CO Oil 3.88 (s, 3H) 6.71 ((d, 1H) 7.09 (dd, 1H) 7.28 (s, 1H) i 7.50 (d, 1H) mp COOH (Kofler)

5 N NH 2 147-149

o

  B - Example of Preparation of Compound of Formula (IV)

  Preparation of 4-chloro-2 (chloroacetamido) acid

  benzodfque To 50 g of 2-amino-4-chloro-benzoic acid, in 251 ml of chloroacetyl chloride, 25.5 ml of chloroacetyl chloride are added dropwise with stirring while maintaining the reaction medium at 20 ° C. in 600 ml of dioxane. Then stirring is continued for 2 hours at room temperature, and then 1200 ml of water are added. The desired product is precipitated, stirred for one hour and then filtered and the solid obtained is washed with water. After drying, 60.7 g of 4-chloro-2-chloroacetamido) benzoic acid are obtained, mp 194-196 C. IR: 1676 cm -1 (C = O) 1 H NMR: (DMSO / d 6 200 MHz) ompm 4.30 (2H, s, CH 2), 7.1 (1H, d, phenyl proton), 7.7 (1H, d, phenyl proton), 8.5 (1H, s, proton

  phenyl), 11.75 (1H, s, NH), 13.90 (1H, brs, COOH).

  Table II lists the formulas and

  characteristics of the compounds of formula (IV).

TABLE 11

  Compose Structure PfcnC (Kofre COOH 51NH (f C 194-196 * 0 and COOH N O o2 H. CU C 182-184 fiCo HsCO-COOH 3.-Coo 236-238 HsCO OCHs COOH 4- H. N If A180-182

"H CS

  H3 Cs6OF NH0A q 155-157 coopi, H, 3C., O o COOiP * 26 | -Dhc '"ftCI 83-85

6

ooe

HC

COOIIII oCl 217-219

13 2763334

  TABLE II (cont.) 1H NMR (200MHz) Compose Structure cI 3s Pp0M CH'c HI 99 (t.3H) CO> CH (C3 35 (m1H) N3 63 (d.2H) 8 c 4 3 N Oil3.89 (s * m, 7H) HCO 7. 12 ((m, 2H) 7 40 (d.1H) 1.05 (m.SH> 1.57 (m, 6H) CO CH3? J3 2.81 (dd , 1H) 9 C SANCHC Oil 3.66 (s, .2H 9 3.81 (s, 6)> ci 3.88 (dd, 1H) H, CO O 7.13 (m, 2H, 38d, 1H) C - Example of preparation of compound of formula (I)

  Preparation of 4-chloro-2H14- (2-methoxypyldienyl) -acid

  1-piperazinylacetamidolbenzoic acid To 11.6 g of 1- (2-methoxyphenyl) piperazine and 17 ml of triethylamine in 120 ml of DMF is added with stirring and

  room temperature 15 g of 4-chloro-2-chloroacetylamido acid

  benzoic. The reaction medium is stirred for 48 hours at room temperature and then 500 ml of water are added. It is extracted with 3 x 300 ml of dichloromethane. The solvent is evaporated under vacuum and the solid thus obtained is taken up in 300 ml of a 2N aqueous sodium hydroxide solution. Washed with 3 x 200 ml of diethyl ether

  then the aqueous phase is 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) -1-piperazinyl] acetamido} -benzoic acid is obtained in the form of a white solid which melts at 218 ° C. IR: 1699 cm -1 (C = O), 1673 cm -1 (C = O) 1 H NMR: (CF 3 COOD) δ ppm 4.25 (3H, s, OCH 3) 4.65 (8H, brs) , 4 CH 2), 4.95 (2H, s, CH 2), 7.5 (2H, m, phenyl protons), 7.6 (1H, d,] 0 phenyl proton), 7.90 (2H, m, phenyl protons), 8.50 (1H, d, proton

  phenyl), 8.75 (1H, s, phenyl proton).

  D - Variant of preparation of compound of formula (I)

  Preparation of 24 [4- (4-fluorophenyl) -1-acid

  To 10.5 g of 1- (4-fluorophenyl) piperazine and 16.2 ml of triethylamine in 150 ml of DMF was added, with stirring and stirring, to 10.5 g of 1- (4-fluorophenyl) piperazine.

  room temperature, 15 g of 2- (chloroacetamido) -4,5-

  methylenedioxy-benzoic acid. The reaction medium is kept under stirring for 48 hours.

hours at room temperature.

  3.5 ml of acetic acid are added and ml of water is slowly added. The acid crystallizes and is diluted with 300 ml of water. Stir 30

  minutes, the mixture is filtered and the solid obtained is washed with water.

  After recrystallization from a dioxane / DMF mixture,

  14.9 g of 2 - {[4- (4-fluorophenyl) -1H-piperazinyl) acetamido} is obtained.

  methylenedioxybenzoic acid which melts at 254-256 C. IR (Kbr): 1654 cm -1 (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, proton)

  phenyl), 7.65 (3H, m, phenyl proton), 7.90 (1H, s, phenyl proton).

  Table III lists the formulas and

  characteristics of compounds of formula (I).

TABLE III

  Pf in CRMN 1H Compound Structure f efl C NMR 1H (Kofier) (200 MHz 8 ppm DMBO-d6

2.60 (8.4H)

COOH, 3.10 (<, 4H)

  NH 3.20 (a, 2H) 1N 3. 70 (s, 3H> 1H <oN 186-187 6.80 (q.4H)? .10 (t, H) T.766 (t, 1H) OCH, B < d, iH 8.T (d, 1H) 8.?(d, lH)

CF 3 COO

COOH 4.26 (I, 8H

  7.30 (t, 1H 2 [ON233-236 7.65is, SH 7.70 (t, 1H 8.26 (m2H)

CF3COOD

4.t8 (Sesh

COOH 4.65, IH

  AoNHzN T7.10 (dH 3 (CN 248-260 7.60d, H 8. 30 (s, 1H) CI

CF3COOD

  4 (s, H) COOH 4.SiSH) NHN 4.B (s.2H) 7.2 (d, 2H 4 - N241-243 7.4 (d, 1IH 7.65 (d.2H) ci 8. 2 (d, IH ) COCH3 8.60 (s, 1H)

CFSCOOD

  COOH 4.20 (s, 8H) 4.62 (s, 2H) NH NH NH-N 7.20 (d, 1H) 10 NI 266 7.65 (s, 4H) N Nssv, 81.0 (d, 1H) Cl C 18.36 (s, 1H) ciC (HZ't ") 9Z S (H) oz9 LN H (H8 9Sk t HOOO (H-isi) g9g

(H P) 9- '

(Hi'W> 6L 10

(H LP) S 1Z-1 L) OA0

  (Hr'e) 9 '. 'HOO J'LH N Hg'9) 99't' HC'UG S) 9fH OHOOO

G OODUI

aooocio _.

{HJ'P10L'81Nl 0

(H I ') 9' 1B

(HL'P) OT9

OOOOSAO

[H I'P] 98 '

[HZ'8] 9 'H

  [H'iP) ST'lP HOO 300cot-4H S'S) 99'8 lo CI'P) 9C, - "9 1l 1 [H9P) gZ't HOOO

GOOD: -13

  (HI, '*) 0 $' g HI'P) 901. l H'lw) grL Hl'W) 9I 'Z

<HC'ú8 I. 1.6 II

  wt, w) ozz tO-6 [H: Do-N) o to HZ '[) 09t NP H'p) sgjt, N-J H N t') 8c 'HOOO wdd 9 tzmw OOZ) (Pel) Q) eJlo ^ Saodwoo

<H NWH 'BOO Id.

<HIPJSV9 = 0L I

  ## EQU1 ## where: ## EQU1 ## where: ## STR2 ## in C NMR 1 COMPOS6 Structure Compos6Structure (KOfler) (2zoo0 MHz) S ppm

COOH CF3COOD

  NH 4.2 (s, CH) -NH _s-N-4.6 {s, 2H 7.2 (mSH) 12 N 249-251 7.B (m, 3H) 1 2 7. S (m, sN) 8. 16 (m, 2H F CDCl3 OOH L2.656 (s, 4H) NH N 3.10 (s, 2H) 13 o IN \ CF 174-176 73.20 (s, 4H) 13 o LI'I orS 74-7 7.00 ( m, 7H) 8.66 (d, 1H), 00 (s, 1H) 11.8 (s, 1HJ)

COOH CF3COOD

  NH NH 4.30 (s, 6H 14 O. N OCH 190-192 i .6 (m6H 7.6 (m, H 111.1 8.16 (t, 2H CDCl3!

COOHNZ2.74 { "3H

COOH H F $ 3.20 (s, 1H

(6 0 N 169-171 6.0 (, IH)

  | I 1 7.?t(d,1H) 8.80 (d.1 H) 11.45 (s, 1H) 1 2.00 (s, 1H) CDCl3

COOH CI

  COOH 3.6 (s, 3H) NH N 76OCHS.T6 (sSH) -4N OCH 4.29 (8, 2H) 16 o N 217-219 6.66 (d, 2H) O L .... N. 6.85 ( t, HR) 7.10 (m, 3H) 7.76 (t, 2H)

CF3COOD

  COOH 3.75 (s, 8H) NH 14 N4 (s, 2H) 17O1 N C 190-192. 700 (m, 6H) LD nf7.60 (m, 2H) Compos6Structure "Ptf in CRMN 1H Composite Structure (Kofier) (200 MHz) 8 ppm

COOH CF3COOD

  COOH.66 (s, 6H) NH-, 4.16 (s, 8H) II 0 N> 266 4.6 (>, ZH) 18 No> 266? 66 (s, 6H) H CO H, coff i 7.86 (s) , 1H)

CF3COOD

  COOH 3.16 (8, s6H 4.16 <e, OH 19.01 -oN> 2B65 4.60 (s, 2H 19 CoN> 27.06 (t.2H) HC TC 7.42 (m, 2H OCH, F 7.65 (s, 1H )

HH3C3 7OT.60 (I, 1H

CFJC0OOD

  00H3 i7.90 (14IH 3.80 (s, 6H O [4NH-.f "iNt -" 6.1 ("

4.16C (,, 8

20.co. o>, ,, OCH, 7 r. 60 (SiH

At COOHCFJCOO

COOH $ 3. (rs, 9H NH 4.25 (s, 8H)

21 I 1 I N 24-246 4.60 (.H

  HCO Cz 83t.90 (d.2H OCHS OCH 7.40 (HH 2 OCHS OCH I 7.60 ($, 1H 7.96 (s, IH

CF3COOD

  COOH S.80 (s, 9H) 4.26 (s, 8H) NH N OCH 4.60 (s, 2H) ON 23 ..... N 244-246 7.00 (d7H) Haco 7.40 (d, 2H) OCH3 7.60 (s, 1H) CH, 7.16 (s, 1H)

_ CH3CF3COOD

  3. $ 0 (s, 6H) 4.20 +4.36 (2s, 8H) _ / NH -NF 4.60 (s, 2H) 23 N llllI ll 245-247 7.20 (q, 2H) HSCO i LN 7.60 (mSH) Pf in oC 1H NMR Compound Structure (Kofler) (200 MHz) 8 ppm

COOH CF3COO 0

N H N3.76 (8.6H>

4.10 + 4.20 (28,8H

  24 c N CF, 255-267 4.60 (, 26H) H3co 3 7.6o (m.EH) "sCO" OCH, 7.88 (s, 1H)

00011H CFSCOOD

  NCOOH $ 3.8o (8.6H) NH₂N8 4.16 (s, 8H) N.O. > 264.60 (,, 2H) 2HSCO <. << C bo c 26 7. 36 (m, 4H HCO 7.55 (s, 1H] -CH, 8.685 (8.1 H

CF 3 COO

3.T70 (s, SH COOH 3.8s6H 4.22 (sOH)

26 N OCH 266-267. H

  CH 3, 8 L (1H, 1H, 1H (T.

! CFSCOOD

COOH 4.16 + 4.17 (2, SH

  Nil 4.50 (s, 2 N, N, NH, IrTN 7.1 O (d, 1H 27 N 1 N c 267-269 7.40 (m, 4H LD f O N u <Xr8.00 (d, 1H))

CI NC 8.26 (8.1H)

CF3COOD

COOH 3.70 (., $ H)

NH 4.10 (9.8H>

  ## STR1 ## ) 8.1 0 (d, 1 H)

CF3COOD

  COOH 4.16 (s, BH) 4.66 (s, 2H) 7.40 (8 + d, 6H) 29 N. ON> 265 S.00 (s dH) 29 ci Cl -gnl B.1 6 (d, 1H) CI Compound Structure Pf in C NMR H (Kofler) (200 MHz) 6 ppm co o1 H CF $ SCOOD NH 4. $ O (e, OH N OCH 199-201 7.16 (m, 3JH Cl '?. $$ (m , 2H 6.16 (s, 1H 8.30 (d, 1 Hi

COOH CF3COO

  I 4.3O + 4.50 <2s.SH NH l <NF 4.67 (s, 2H 31 - .. W ol NN 262-264 7.30 (n, 2H ci? .66 (m, 3H IU 68.16 (s, 1H S.25 <d, 1 H

COOH CF.0

  32 c, o 246-247.0t ci 7..N. ..40 (d, $ H

7.0O <$, I

F -8.06 (d, 1H

CF3COOD

  COOH 4.254.40 (b, SH N H 4.7 O. (., N 7.66 (d, 1H) 33 NH "L N CF3 213-2156 7.0 (m, 4H) 86.26 {d, 1H)

CFSCOOD

COOH 3.80 (s, 3H)

NH 4 .4.20 (o, 8H.

* 0011 NOCH 3 4.45 (s, 2H> 34c0 $ J IN s203-206 6.96 (d, 2H Cl1 7.42 (q, 3H) 8.06 (s $ d, 2H

CF3COOD

  COOH 4.10 (s, 8H) NH 4.46 (s, 2H) 7.40 (m, 6H) 224-226 7.96 (s, 1H) CH 2 O 8.10 (d 1H Pf on C Conmpostructure (K6flor) (200M, > l) e, ppm

COOH 4F3OOH

36 N N 238-240

CF3COOD

  COOH 4.40 (s, 8H) 3> N7Il 6 4.67 (s, 2H 36 O 2438-256 6.06 (s, 2H 7.66 (m, 3t- <oF <1 7.90 (s, 1H

CF3COOP

OOH 01

  4.22 (s, 6H 4.67 (s, 2f3> O264-256 N6.30 (t, 2H 38O LI'-IN> 266 -.66 (m, $ H, O0 'F 7.90 (s, 1H

CFSCOO

COH

3.83 <8.3

  ## STR6 ##

\ Xochi

CFSCOOD

  ## STR00006 ## wherein: ## STR1 ## wherein: ## STR1 ## 7.66 (s, 3H) OCHsO 7.82 (9s, 1H)

CF3COOD

  COH 4.23 ± 4.38T2s ($, 8H NC H 4.62 (s, 2H) <2 NF 6.97 (s, 2H) 41 o0 N v 236-238 77 s1 (m, 2H) kO 7. (s, 1A) 3ooD / Compos6 Pf in IC Compound Structure n H NMR (Kofler) (200 MHz) s ppm

CF3COOD

COOH 4.06 + 4.16 (2s, BH)

NH 4.35 (9.2H)

  N-f'N 6.76 (s, 2H) 42 | Y N CF 228-230 7.30 (s, 1H) O..CF3 7.60 (m, 6H) \ o

CF3COOD

  COOH 4,600 (s, SH N H- / '"i.O1 (-SN HifN 4.37 (s.2H) 44> 0 N. <OCM3 198Nc24-2006.76 (s1,2H) o LJ T.3Z5d, 6H) O o ... / c7.670 (s, 1H

HC-O 7.26, H

COOH CF3COOD

  3.6O (s, 3H COONH SA4.oo (s, 8H) 46 'NSo4.188-190 60 (s, 2H> CO NT.48 <d, IH) 47 198-200 6.7 <t (, .5) 7.8 S (s, 1H) 7. 60 (d.H)

COH CFSCOOD

COOH 3.TB (sSH) 4.06 (s, 3H)

NHN 4A2 (., $ H)

  46 0 N 188-199 4.7e (s, 2H) 47, / o N 218-223 7. 14 (6 (d, 1H H 3 Co 7.40 (S, 4H 3 C0 i> J7.93 (t, 1H) 8.30 ( d, H>

CF3COOD

COOH 3.76 ($, 3H)

NH 4.20 ($, $ H>

  4.6% (m, 3H> H Co 7.60 (t, 2H), m.p.

7.70 (<, IH)

$ 8.0 (d, H)

CF3COOD

COOH 3.80 (8.3H)

  4.65> (s, 2H) .beta.LN 221-223 .16 (d, 11H) H3 Co 7.40 (8.4H) (Hk'w) OZ-1zr (FFZ8 s) -LZ Zr [Hg'S) tú't H HOOO

(HS'S) 96 '

(HC'9) gg'S

O OOOOJ

aoosss0

1H 'P) O9'A

  (HS'C) 91. JIo'Z (HZ's) O9't. ## EQU1 ## ## STR2 ## ## STR2 ##

(HI.'P) OO'8

[Hvas) glS'Z

[HIP] 0 1 '-O "O OOSH

  ## STR1 ## where ## STR2 ## where ## STR2 ## .4o) HNO (H'S) Og't, (Hó'e) gZ'ó HOOS

[H I.'S] 0Z-'9

(H'8) Z8-'HSO

  (HZ'S) gg'ZZ-6 [vnN oot: H [HZ'9) 9gz'I HN X (HO'O) gZ't HsFp) sB-t S looo uudd 9 (zHW OOZ) (JeugN) H t NW ## STR1 ## Compound Pf in C N1 Composite Structure (KOf C NMR 1H (Kt $ f1er) (200 MHz) at ppm

CF3COOD

00H s3.96 (, 3H> NH 4.40 (s, 8H)

4.70 (8,2H

  53 HN 3 182-184 7.30 (d, HH 3 CO 3 O (m, 3H) H 3, T7, 86 (s, 1H) 8.256 (d, 1H DM80-d 2.42 (d, 4H COOH CH) 2.90 (s, 2H) 3.10 (s, 4Hrv K NNI 3.18 (s, 3H 54I) 6. $ 0 (t, 1 tH 54 W 0 N 210-212 6.0 (d, 1H) 6.g (d, 2 T.25 (t, 2H 7.60tm.2H /.70 (tH 8.00 (d, 1H DM80 Z. 34 (d, 4H COOH (He L1O (s, ZH) - I N 3.00 + 3.10 (23, TH7 22s-227 z.93 (d, 2H 7.4 / (m, RH) s. 7. 70 (d, 1H, T.96 (d, 1H, DMO8-d6 CoOH, 2.65 (d, 4H) COOH (Ha S.03 (s, 2H) NN 3.25 (d, TH) 56 3-CCF 193-195 S.26 (m, 3H) 0 o .... v..N CF, 7.60 (m, 3H) 7.82 (t, 1H) 8.12 (d, 1H) DMSO-d6G. OOH CH, 2.66 (s, 4H) COOH (CH3 3.00 (d, 6H) N N.26 (s, 1H)> 571 (920 N 208-210 T3.80 (s)) , 3H)

OCH 208-210.87.00 (9,411)

  T.66 (m, 2H) 7.82 (d, 1H) 8.10 (d, 1H) Pfen C NMR 1H Compound Structure (Kflern (0 MH) ppm (Kaffier) (0 HP DM8BO-d6 16 (s, 4H) CO 2.65 ($, 2H)

COO H C: H. 3 C H

N 2.90 (8.3H)

  (???????? S3.66 (8.3H) 58. N OCH3, 196-198 6.20 (t.3H 6.86 (tlHi 7.26 (m, 2H) T.60 (d, 11H) 7. 76 (d, lH) DM8046-d

2.6 $ (, 4H

  COOH H1 2.96 (s, 6H) I S.20 (s, SH) NN OCH 3.90 (s, 3H-59 'N 144-146 7.00 (d, 4H vvO1, N T.60 (m, 2H) 7. 80 {d, t H) 8.10 (d.1H

CF3COOD

L3; (s, 3H) COOH 3.T <s, 3H 4. $ s, .2H]

6 -0N1 4.0O (, 2)

  | 3 NG N 189-191? .0 {d, 3H] I T.60 (d, 3H) 8.07 (s, 1H) OCHs B.16 (d, tH) DM8O-d 2.60 (s, 3H) 2.83 (s) , 4H]

COOH S3.39 (2.6H)

  NH 7.05 (d 2 H) - fN 7.43 (d, 2H) 61 O 4 N 214-216 7.66 (dd, 1H) H cS 7. 96 (s, 1H) ci 2L J 8.T9 (d, 2H) cI 12.20 ( s, 1H) 1 3. 80 (slH) Compound Structure Keln C 1H NMR (Kofer) (200 MHz) 8 ppm

DMB-0 6

  0.76 (t, 3H) 1.24 (m, 2H, 1.68 (q, 2H) COOH

NH 2.62 (6.4H)

  COOH 2.94 (s, 6H) ≤ 3.60 (s, 3H, 62, n, 3, N, 167-169, 3.81 (t, 2H, HIC, OO, N, 6.71 (q, 4H) v 7.06, dd. 7.28 (s, 1H) 8.46 (d, 1H) tl.77 (s, 1H) 1.43 (s, 1H) DM80-d6 0.83 (t, SH) 1.32 (m, 1H); 2H) 1.68 (q, 2H) COOK 2.60 (s, 4H) 3.16 + S.sub.2 (2s, 6H) 63. NHN, 3.88t, 2H) 63H s Co-Li-1 and 69-161 71dH 7. 36 ( d, 1H, 1H (d, 1H, 1H, 8H, s, 1H, 1H, s, 1H) DM80-d 1.62 (m, BH) COOH 2.64 (s, 4H) NHI X3..28 (2s, 6H) NH_Nj - 4.76 (s, 1H) 64 <v-k0 o N 187-189 6.86 (d, 2H) 0 1.13 (m, 3H) 7.39 (sH) Cl 8.66 (d, 1H) 10.16 (s, 1 H) DMSO-d6 1.61 (m, 8H) COOH 2.62 (s, 4H)

NH 29 (.H

  1H 3.60 (s, 3H) 4.60 (s, 1H) -o, 171-173 4 60 (q, 1H) 6.98 (dd, 11H) OCH, 7.28 (s, 1H) 8.46 (d, 1H) 11.77 (, 1tl) _________________________________ I 3.4 3.s, 1 1.) Pf in CR MN t H Compound Structure Ptfl eC NMR 6p (Kofier) (200 MHfi) f ppm DMBQOd6 1.36 (m, 1 1 H 2.66 ( ## STR3 ## ) this

DMSO-6

1.00 (m, SH) 1.66 (m, 6H)

COOH 2.49 (, 4H

  N 2.0 <m, H) 67 NOH 3 N209-211 3.7s, 3H COOH 3.7 (,, Hs) 3. e (s + m, 4H) I7..NH'- IN 6.83 (qm1H) 68O 7.2 ( q, SH) OCHS T.40 (olH) CDCl3 68 l, HsClo] O lowNsn 218-220 T. $ 4 (d, H)

- = COON

  8.96 (s, 1H) δ 2.0067 (m, 1H 68 NN218-220 7.36 (d, 3H) 8. $ (d, 1H) 12.00 (st H) DM O O-d6 1.20 (d, 6H) 2.70 ( s, 4H) 3. 13 (s, 4H) COOH 3.20 (s, 2H) COON H S.62 (s, 3H) CHS Nf N 4.37 (m, 1H) 69 OH N 132-134 4.94 (s, 1H) H3C o 6.60 (d, 2H) Ht3C OT (6.789 (d, 2H) OCH, 7.00 (dd, 1H)

7.43 (.1 1H)

8.66 (d, 1H)

11.S8 (.1U H

  Pfeon C NMR 1H Compound Structure Pt in C 1H NMR (K6fler) (200 MHz) 6 ppm

DM80-6

  1.05 (t, 3H) CH $ s 2.60 (s, 4H) OOH r 3.00 (s, 2H) -Ir'1 N - '- l 3.20 (s, 6H) j IN 161-163 3.92 (m * s, 4H O L .... N 6.94 (d, 2H) HC 3Co 7.28 (m, 4H ccl 7T.47 (s, 1H) 13.62 (bs, 1H)

CFSCOOD

CH $ 3.68.,

COOH 3 /, 18H

  3.92 m, 1 <71I N 160-162 6.83 (d, 2H) 71 CO o N7.10 (s.2H) HsCO T ll. 7.28 (d, 2H) OCH $ 7.68 (s, 1H) Cf3COOD 00H 3.9O (s, 3H) NOOH 4.41 (s, SH) 4.76 (s.2H) 72 'o IIN 261-263 71 (m (m, 4H) I <1T7.88 (m, 2H) OCH 3 8.64 (s, 1H) 8.90 (s, 1H)

CFSCOOD

4.40 (s, 8H)

4.77 (8,2H)

  NH -N. 7.67 (s + m, 6H) 73I3OI> 28 78.96Z (m, ZH) 73 0 N> 266 8.68 (sIH)

8.92 (, 1 H)

  The results of the pharmacological studies will be given below. Study of Antidiabetic Activity in the NOSTZ Rat The antidiabetic activity of the compounds of the formula I was determined orally on an experimental model of non-diabetic diabetes.

  insulin-dependent, induced in the rat by streptozotocin.

  The non-insulin-dependent diabetes model is obtained in the rat by a neonatal injection (the day of birth) of

Streptozotozine.

  The diabetic rats used are 8 weeks old. Stabulation of the animals is carried out, from the day of their birth to the day of the experiment, in a temperature-regulated animal house of 21 to 22 C, and subjected to a fixed cycle of light (from 7 am to 19 pm) and of darkness (from 7 pm to 7 am). Their diet consisted of a maintenance diet, water and food were provided "ad libitum", with the exception of fasting 2

  hours before testing o food is removed (postabsorptive state).

  The rats are treated orally during the day with the product to be tested. Two hours after the last administration of the product and 30 minutes after anesthesia of animals with Pentobarbital sodium (Nembutal), a blood sample of 300 μl is taken at the end.

of the tail.

  Table IV summarizes the main results obtained.

  These results show the effectiveness of the compounds of formula I for

  to lower blood sugar levels in diabetic animals.

31 2763334

  These results are expressed as a percentage change in blood glucose on Day 4 (4 days of treatment) compared to Day 0 (before treatment).

TABLE IV

Compound 20 mg / kg / day

%%

  o0 ____________ Glucose at D4 Glucose at D4

-12 -16

38 -6 -27

39 -15 -14

-9 -18

47 -16 -32

48 -20 -31

50 -17 7

52 -14 -21

Claims (5)

  1. Compounds of general formula (I): COOH R1 R2 R3 B D O   Wherein Ar is selected from - a mono, bi or tricyclic aryl group having 6 to 14 carbon atoms, - a heteroaromatic group selected from pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyrranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl, the Ar group being able to carry 1 to 3 substituents selected from a C 1 -C 8 alkyl, cycloalkyl (C 3 -C 8) alkyl group (C1- C6) alkoxy   C1-C8; cycloalkyl (C3-C8) oxyalkyl (C1-C6), cycloalkyl (C3-C8) alkoxy (C1-   C6) (C1-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C6) cycloalkyl (C1C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryl; C6C14 heteroaryl;   heteroaryl (C6-C14) alkyl (C1-C6), aryl (C6-C14) alkyl (C1-C6) aryl (C6-   C14) (C1-C6) alkyl, (C6-C14) aryl, (C6-C14) aryloxy, (C6Cl4) aryloxyalkyl (C1-C14)   C6), aryl (C6-C14) alkyl (C1-C6) oxy, aryl (C6-C14) alkyl (C1-C6) oxyalkyl (C1-   C6), halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (C1-C8) alkylsulfinyl, alkyl ( C1-C8) alkylsulfonyl,   sulfoamino, alkyl (C 1 -C 8) sulfonylamino, sulfamoyl, alkyl (Cl-   C8) carbonylamino, or two of these substituents forming a methylenedioxy group, the 4-carboxyphenyl and 4-substituted carboxyphenyl groups being excluded from the definition of Ar. R1, R2 and R3 are chosen independently of one another from: - an atom of hydrogen, - (C1-C8) alkyl, (C1-C6) alkoxy (C1-C6) alkyl, - a cycloalkyl group having from 3 to 8 carbon atoms, a cycloalkyl (C3-C8) alkyl group (C1-C6) -C6), a group   cycloalkyl (C3-C8) oxyalkyl (C6-C6) or cycloalkyl (C3-C8) alkoxy (C4-   C6) (C -C) alkyl, - (C6-C14) aryl, (C6-C14) heteroaryl,   heteroaryl (C6-C14) alkyl (C1-C6), aryl (C6-C14) alkyl (C1-C6), aryl (C6-   C14) (C1-C6) alkyl, (C6-C4) aryl, (C6-C14) aryl (C1-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryl, (C1-C6) alkyl, (C1-C6) alkyl, , B, C, D are = CH- groups, one or two of them may also be a nitrogen atom, R4, R5, R6 are chosen independently of each other from: - a hydrogen atom,   a C1-C8 alkyl group; cycloalkyl (C3-C8) alkyl (C1-   C6), C1-C8 alkoxy; cycloalkyl (C3-C8) oxyalkyl (C1-C6), cycloalkyl (C3-   C8) oxy, cycloalkyl (C3-C8) alkoxy (C1-C6), cycloalkyl (C3-C8) alkoxy (C1-   C6) (C1-C6) alkyl, (C1-C6) alkoxy (C0-C6) alkyl, (C6-C14) aryl, (C6-C6) aryl   C14) (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14) aryl, (C6C14) aryl,   aryl (C6-C14) oxyalkyl (C1-C6), aryl (C1-C14) alkoxy (C1-C6), aryl (C6-   C14) (C1-C6) alkyloxy-(C1-C6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, carboxy, hydroxy, nitro, amino,   (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylthio, alkyl (C1-   C8) sulfinyl, (C1-C8) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl, (C1-C8) alkylcarbonylamino; two of these groups may form a methylenedioxy group or a phenyl ring condensed with the ring to which they are attached, the different aryl groups may themselves be substituted with 1 to 3 substituents selected from a C 1 -C 8 alkyl group, alkoxy group; C1-C8, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro and amino, solvates and pharmaceutically acceptable salts thereof acceptable.   2. Compounds of formula I according to claim 1 wherein the base ring of the ring A R44-e ", ' R "5 R5 is a phenyl ring.   Compounds according to claim 2, wherein at least one of R4, R5 and Re is a C1-C8 alkoxy group or two of these   groups form a methylenedioxy group.   4. Process for the preparation of compounds according to claim 1, comprising the reaction of an aromatic amine of general formula (II): COOR7, R1 +: N-H R4 B DP   in which A, B, C, D, R1, R4, R5, R6 are as defined   previously and R7 is a hydrogen atom, a C4 alkyl group,   C6e or a benzyl group. with a haloacyl halide of the general formula (III): R2 R3   Half Hal (III) or wherein R2 and R3 are as previously defined, Hal represents a chlorine or bromine atom, to form a compound of general formula (IV); OOR7 R1 R2 R3 R44 Hal (IV) B D O R5 R6   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 the reaction of the compound of the general formula (IV) with a compound of the general formula (V) ): H N> (V)   Ar in which Ar is as defined above, in the presence of a basic agent such as triethylamine to form the compound of general formula (VI): COOR7] Rl1 R2 R3 DELIGHTED) R4 B D O   Wherein Ar, A, B, C, D, R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as previously defined, and, in the case where R 7 is an alkyl group, the hydrolysis of this compound to form a compound of formula 1, and, in the case where R 7 is a benzyl group, the hydrogenolysis of this compound to form a compound of formula I. 5. A pharmaceutical composition comprising, as a   active ingredient, a compound according to any one of claims 1 to 3.