HK1050529B - Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses - Google Patents

Description

The present invention concerns amino derivatives of dihydro-1,3,5-triazine useful in the treatment of conditions associated with insulin resistance syndrome.

Amino derivatives of dihydro-1,3,5-triazine with hypoglycaemic properties have been described in JP-A-73 64 088 and JP-A-79 14 986.

Triazine compounds have also been described in JP54014986, JP48064088, J. Med. Chem. 6,4,1963, 370-378, J. Het Chem. 30,4,1993, 849-853 and US 3,287,366.

The present invention is intended to provide new compounds with improved properties.

The present invention thus concerns a compound of general formula (I): - What? in which: R1, R2, R3 and R4 are chosen independently from the groups: H-alkyl (C1-C20) possibly substituted by halogen, alkyl (C1-C5), alkoxy (C1-C5), cycloalkyl (C3-C8), alkenyl (C2-C20) possibly substituted by halogen, alkyl (C1-C5), alkoxy (C1-C5) heterocycloalkyl (C8-C8), alkoxy (C2-C20) possibly substituted by halogen, alkoxy (C1-C5) heterocycloalkyl (C8-C8), alkoxy (C1-C5) heterocycloalkyl (C8-C8), alkoxy (C2-C5) alcohol substitute possibly substituted by halogen, alkoxy (C1-C5) heterocycloalkyl (C1-C5) heterocycloalkyl (C2-C5) heterocycloalkyl (C1-C5) heterocycloalkyl (C1-C1) alcohol substitute possibly substituted by halogen, alkyl (C1-C1) alcohol substitute possibly substituted by halogen, alkyl (C1-C1-C4) cycloxy (C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C1-C4-C1-C1-C4-C1-C1-C1-C4-C1-C1-C4-C1-C1-C4-C1-C1-C4-C1-C4-C1-C1-C4-C1-C4-C1-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5), alkyl), alkyl (C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-C5-

R1 and R2 on the one hand and R3 and R4 on the other hand, which can form with the nitrogen atom a n-chain (n between 3 and 8) ring, whether or not containing one or more heteroatoms selected from N, O, S and possibly replaced by one or more of the following groups: amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-G5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxylethyl, R5 and R6 are chosen independently from the groups: -H-, alkyl (C1-C20) whether or not substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy,aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxymethyl,alkenyl (C2-C20) possibly substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), atkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy; aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxymethyl,alkylyl (C2-C20) possibly substituted by amino, hydroxy, thio, halogen, alkoxy (C1-C5), alkoxy (C1-C5), alkoxy (C1-C5), atkylthio (C1-C5), alkylamino (C1-C1-C5), cyc1-C1-C4, or haloksy (C1-C5), carboxy (C5-C5, hydroxy), trifluoroxy (C6-C5, hydroxy), trifluoroxy (C5-C5, hydroxy), alkoxy (C1-C1-C5, hydroxy), haloksyroxy (C1-C1-C4, hydroxy), carboxy (C1-C1-C5-C5, hydroxy), trifluoroxy (C1-C1-C4-C5, hydroxy), trioxyl, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, trioxyl, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy (C6-C5-C4-C5, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy,O, S and possibly substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoroethyl, carboxy, carboxymethyl or carboxymethyl-aryle (C6-C14) and possibly substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), oxyfluoroxy, cyboxymethyl, trioxymethyl, carboxy, carboxy, or halogen (C1-C1-C1-C1-C4), or possibly by alkylyl, hydroxy, carboxy, carboxy (C1-C1-C1-C5, hydroxy, carboxy, halogen, carboxy, hydroxy, carboxy, hydroxy, carboxy, hydroxy, halogen, carboxy, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen,

R5 and R6 which may form with the carbon atom to which they are attached a chain with m chainons (m between 3 and 8) whether or not containing one or more heteroatoms from N, O, S and possibly substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), atkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxv (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxymethyl, or which may form a polycyclic residue in C10-C30 with the carbon atom and possibly be replaced by an atom, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyetyl, the nitrogen atom of a heterocycloalkyl or heteroaryl group which can be replaced by an alkyl (C1-C5), cycloalkyl (C3-C8), aryl ((C6-C14), aryl ((C6-C14) alkyl ((C1-C5) or acyl ((C1-C6), provided that where R3 and R4 represent a hydrogen atom, R1 and R2 do not represent a hydrogen atom, and tautomeric, enantiomeric, diastereoisomeric and epimeric forms and pharmaceutically acceptable salts.

A m-chain cycle formed by R5 and R6 is in particular a saturated cycle such as a cyclohexyl, piperidinyl or tetrahydropyranyl group.

A polycyclic group formed by R5 and R6 means a polycyclic carbonate group which may be substituted and in particular a steroid residue.

A particular group of compounds of formula (I) is one in which R5 is hydrogen.

Another particular group of compounds of formula (I) is that in which R5 and R6 form a ring with m chainons (m between 3 and 8) with the carbon atom to which they are attached, including or without one or more heteroatoms selected from N, O, S and which may be substituted by one or more of the following groups: alkyl (C1-C5), amino, hydroxy, alkylamino ((C1-C5), alkoxyC1-C5), alkylt ((hioC1-C5); aryl ((C6-C14), aryl ((C6-C14) -alkoxy ((C1-C5). or form with the carbon atom a polycyclic C10-C30 residue whether or not substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoroethyl, carboxy, carboxymethyl or carboxyetyl.

Another particular group of compounds of formula (I) is that in which R5 and R6 are chosen independently from the groups: Alkyl (C1-C20) whether or not substituted by amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyetyl.

A more particular group of formula (I) compounds is one in which R1 and R2 are chosen independently from the groups specified above except for the hydrogen atom and R3 and R4 represent a hydrogen. More specifically, a preferred group of formula (I) compounds is one in which R1 and R2 are an alkyl group, advantageously methyl, and R3 and R4 represent a hydrogen.

The invention also relates to tautomeric, enantiomeric, diastereoisomeric and epimeric forms of compounds of general formula (I).

Compounds of general formula (I) have basic nitrogen atoms which can be monosalified or disalified by organic or mineral acids.

Compounds of general formula (I) may be prepared by reaction of a compound of general formula (II) - What? where R1, R2, R3 and R4 are defined as above, with a compound of general formula (III), (IV) or (V) - What? where R5 and R6 are defined as above and R7 is a methyl or ethyl group, in a polar solvent (e.g. ethanol or dimethyformamide) in the presence of an organic acid (e.g. camphor sulphonic acid) or mineral (e.g. hydrochloric acid).

Compounds of general formula (II) are biguanides whose synthesis is well known to all practitioners. For example, we cite some publications describing the synthesis of such compounds (FR 1537604, FR 2132396 ; K. H. Slotta and R. Tschesche, Ber., 1929(62b), 1398 ; S. L. Shapiro, V. A. Parrino, E. Rogow and L. Freedman, J. Org. Chem., 1959(81), 3725 ; S. L. Shapiro, V. A. Parrino, and L. Freedman, J. Org. Chem., 195981), 3728 ; S. L. Shapiro, V. A. Parrino, and L. Freedman, J. Org. Chem., 1959(81), 4636).

The compounds of the present invention are useful in the treatment of conditions associated with insulin resistance syndrome (Syndrome X). Insulin resistance is characterized by a reduction in insulin action (see Medical Press, 1997, 26(no.14), 671-677) and is involved in a significant number of pathological conditions, such as diabetes and particularly non-insulin-dependent diabetes (type II diabetes or NIDDM), dysleukemia, obesity, hypertension, and certain microvascular and macrovascular complications such as atherosclerosis, retinopathy and neuropathies.

For example, references to this subject are found in Diabetes, Vol. 37, 1988, 1595-1607; Journal of Diabetes and its complications, 1998, 12, 110-119; or Horm. Res., 1992, 38, 28-32.

In particular, the compounds of the invention have a strong hypoglycaemic activity.

Err1:Expecting ',' delimiter: line 1 column 192 (char 191)

Recent literature data clearly show the impact of AGEs on renal complications (Nephr. Dial. Transplant., 2000, 15 (suppl. 2). 7-11), on atherosclerosis, Alzheimer's disease and other neurodegenerative diseases (Glycoconj. J., 1998, 15(10), 1039-42 ; Brain Res., 2001, 888(2), 256). AGE formation may also play an important role in the pathogenesis of angiopathy, particularly in diabetics, as well as in senility (J. Neuropathol. 2000, Exp. Neurol., 5912), 1094).

The present invention therefore also concerns pharmaceutical compositions containing, as an active ingredient, a compound of the invention.

These pharmaceutical formulations are particularly intended for the treatment of diabetes, diseases caused by the formation of AGEs, such as kidney complications, atherosclerosis, angiopathy, Alzheimer's disease, neurodegenerative diseases and senility.

The pharmaceutical compounds of the invention may be presented in forms intended for parenteral, oral, rectal, permucus or percutaneous administration.

They will therefore be available as solutes or suspensions for injection or multi-dose vials, as tablets, blank or coated, dredges, capsules, capsules, pills, capsules, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, for permucous use.

The excipients suitable for such administration are cellulose or microcrystalline cellulose derivatives, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.

For parenteral use, water, aqueous solutes, physiological serum, isotonic solutes are the most convenient vehicles used.

The dosage may vary within large limits (0.5 mg to 1000 mg) depending on the therapeutic indication and route of administration, as well as the age and weight of the subject.

As an example, here are some biguanides of formula II used in the synthesis of formula I derivatives. - What? TABLEAU I

A		HCl	223-225
B		HCl	176-178
C		HCl	230-232
D		HCl	210-212
E		HCl	254-256
F		HCl	158-160
G		HCl	100-102

The following examples illustrate the preparation of formula I compounds.

The following paragraphs are added: Synthesis of 2-amino-3,6-dihydro-4-dimethylamino-6-ethyl-1,3,5-triazine hydrochloride

23 mL of propionaldehyde and 3.6 g of camphor sulphonic acid are added to a solution of compound A (25.7 g; 0.155 mol in 200 mL DMF). After 2 hours of reflux, the solvent is removed under vacuum and 100 mL of acetonitrile is added. The solid formed is exorcised and dried (21.9 g; 69%). F = 218 to 220°C The frequency range of the signal is defined as the frequency range of the signal at which the signal is transmitted. The following are the main parameters for the calculation of the frequency bands:

The following paragraphs shall apply: Synthesis of the hydrochloride of 2,4-bis-dimethylamino-3,6-dihydro-6-methyl-1,3,5-triazine

The solution of compound E (41.10 g, 0.212 mol) in 200 mL of absolute ethanol is then treated with 61 mL of acetal and 5 g of camphor sulfonic acid, which is then brought to the reflux for 72 hours and then concentrated. F = 200-202°C The frequency range of the frequency band is defined as the frequency range of the frequency band from the frequency range of the frequency band to the frequency range of the frequency band. The following information is provided for the purpose of the calculation of the frequency bands:

The characteristics of these and other compounds of formula I are given in Table II below: TABLEAU II

1		HCl	218-220	DMSO-d6 6.41, CH3 27.59, CH2 35.64, 2 CH3 60.75, CH 155.01, 156.67, 2 Cquaternaire
2		HCl	200-202	DMSO-d6 22.58, 37.75, 5 CH3 59.01, CH 156.34, 2 Cquaternaire
3			193-195	DMSO-d6 32.06, 37.40, 2 CH3 67.85, 158.16, 3 Cquaternaire
4		HCl	243-245	DMSO-d6 21.66, 25.19, 37.72, 3 CH2 37.89, 2 CH3 67.51, 156.83, 158.24, 3 Cquaternaire
5		méthanesulfo nate	174-176	DMSO-d6 34.31, 41.36, 44.79, 5 CH3 69.75, 160.30, 161.44, 3 Cquaternaire
6			138-140	DMSO-d6 28.04, CH2 30.84, 37:40, 3 CH3 42.06, 62.24, 2 CH2 70.00, 158.24, 158.69, 3 Cquaternaire
7		HCl	150-152	DMSO-d6 27.39, CH2 28.78, 39.14, 3 CH3 40.21, 61.30, 2 CH2 68.46, 156.48, 157.84, 3 Cquaternaire
8		HCl	124-126	DMSO 28.95, 38.65,2 CH3 42.77, CH2 69.75, Cquaternaire 115.93, CH2 149.12, CH 155.70. 156.16. 2 Cquaternaire
9		HCl	149-151	DMSO-d6 26.20, 32.39, 40.73, 6 CH3 46.16, CH 60.09, 158.83, 159.14, 3 Cquaternaire
10		HCl	239-241	DMSO-d6 37.78, 2 CH3 62.39, CH 126.66, 129.47, 5 CH 141.87, 156.52, 158.38, 3 Cquaternaire
11		HCl	221-223	DMSO-d6 37.23, 55.60, 3 CH3 61.88, CH 114.32, 127.66, 4 CH 133.17, 156.11, 157.86, 159.93, 4 Cquaternaire
12		HCl	251-253	DMSO-d6 37.75, 2 CH3 62.67, 116.16, 128.16, 5 CH 131.72, 156.64, 158.31, 158.88, 4 Cquaternaire
13			>260	DMSO-d6 39.55, 39.71, 2 CH3 65.92, 117.71, 130.17, 5 CH 131.72, 156.64, 158.31, 158.88, 4 Cquaternaire
14		furnarate	172-174	15.48, 29.33, 3 CH3 35.68, CH2 37.43, 2 CH3 65.71, Cquaternaire 135.47,2 CH 156.21, 156.63, 168.35, 4 Cquaternaire
15		HCl	250-252	DMSO-d6 28.74, 37.38, 6 CH3 66.53, 155.28, 3 Cquaternaire
16		HCI	183-185	DMSO-d6 32.62, 40.96, 5 CH3 69.37, 159.30, 160.19, 3 Cquaternaire
17		HCl	>260	DMSO-d6 22.78, 2 CH3 28.96, 2 CH2 40.13,2 CH3 42.73, 2 CH2 65.63, 155.42, 155.71, 3 Cquaternaire
18		HCI	229-231	DMSO-d6 22.97, 37.76, 3 CH3 58.59, CH 57.85, 159.39, 2 Cquaternaire
19		HCl	>260	Spectre succinct DMSO-d6 69.06, 159.78, 161.17, 3 Cquaternaire
21		carbonate	>140	DMSO-d6 20.51. CH3 24.73, 25.39, 2 CH2 39.98, 2 CH3 46.44, 47.91, 2 CH2 58.49, CH 154.58, 156.63, 160.61, 3 Cquaternaire
22		HCl	>260	DMSO-d6 21.18, 24.68, 3 CH2 27.26, CH3 37.00, 2 CH2 37.37, 2 CH3 67.12, 155.89, 156.86. 3 Cquaternaire
23		HCl	248-250	DMSO-d6 5.11, CH321.17, 24.70, 35.39, 37.04, 6 CH2 37.36, 2 CH3 67.09, 155.90, 156.21, 3 Cquaternaire
24		HCl	>260	Spectre succinct DMSO-d6 67.46, 68.80, 156.76, 157.47, 157.99, 159.14. 3 Cquaternaire 175.90, 176.11, COOH
25		HCl	>260	Spectre succinct DMSO-d6 64.87, 69.85, 2 CHOH 66.55, 154.91, 156.19, 3 Cquaternaire 173.75, COOH
26		HCl	91-93	DMSO-d6 25.76, 37.28, 3 CH3 43.28, CH2 64.27, CH 115.21, CH2 137.55, CH 159.79, 160.77. 2 Cquaternaire
27		HCl	>260	DMSO-d6 25.69, 27.25, 4 CH2 39.13, 2 CH3 67.25, Cquaternaire 70.01, CH2 72.50, CH 128.17, 128.34, 129.07, 5 CH 139.79, 156.81, 158.30, 3 Cquaternaire
28		HCl	>250	DMSO-d6 29.83, 34.4, 4 CH2 38.83, 2 CH3 66.17, CH 67.06, 156.25, 157.28, 3 Cquaternaire
29		carbonate	133-135	DMSO-d6 7.25, 26.81, 2 CH3 34.32, CH2 37.17, 2 CH3 68.59, 156.46, 157.71, 160.78, 4 C quaternaire
30		carbonate	140-144	8.68, 2CH3 34.54, 2 CH2 37.91, 2 CH3 74.98, 157.84, 159.14, 160.82, 4 Cquaternaire
31		HCl	207-209	DMSO-d6 22.50, 2 CH2 38.00, 2 CH3 39.78. 2 CH2 75.51, 157.18, 158.37, 3 Cquaternaire
32		carbonate	Se décompose	DMSO-d6 14.55, CH3 17.20, CH2 37.45, 2 CH3 39.00, CH2 62.43, CH 157.52, 159.04, 160.65, 3 Cquaternaire
33		HCl	>260	D20 37.90. 2 CH3 48.69, CH2 154.82, 156.33, 2 Cquaternaire
34		paratoluènesu lfonate	201-203	DMSO-d6 21.65, CH3 25.95, 26.07, 26.58, 26.89, 27.50, 5 CH2 37.56, 2 CH3 44.74, 66.56, 126.32, 129.08, 6 CH 138.99, 145.86, 158.18, 156.86, 4 Cquaternaire
35		HCl	157-159	DMSO-d6 29.10, 37.86, 4 CH3 65.90, 154.82, 156.33, 3 Cquaternaire
36		paratoluènesu lfonate	251-253	DMSO-d6 21.14, 37.26, 3 CH3 114.80, 120.70, 126.41, 132.12, CF3 125.82. 128.54, 4 CH 138.37, 145.49, 155.78, 157.18, 4 Cquaternaire
37		paratoluènesu lfonate	159-161	DMSO-d6 21.17, 36.95, 3 CH3 42.60, CH2 62.10, 126.86, 127.21, 128.55, 128.63, 130.32, 10 CH 135.14, 138.30, 145.67, 156.18, 157.44, 5 Cquaternaire
38		HCl	>260	DMSO-d6 37.41, 2 CH3 37.47, 62.73, 4 CH2 64.76, 156.35, 157.77, 3 Cquaternaire
39		HCl	>260	DMSO-d6 34.12, 2 CH2 38.63, 42.60, 3 CH3 48.72, 2 CH2 64.01, 156.11, 157.78, 3 Cquaternaire
41		paratoluènesulfonate	194-196	DMSO-d6 21.17, 37.03, 3 CH3 6037, CH 70.05, CH2 115.08, 121.60, 125.84, 128-54, 12995, 10 CH 138.28, 145.64, 156.40, 157.70, 158.45, 5 Cquaternaire
42		HCl	>260	DMSO-d6 24.12, 37.15, 5 CH3 39.90, Cquaternaire 68.39, CH 156.57, 158.10, 2 Cquaternaire
43		HCl	Se décompose	DMSO-d6 22.95, 23.05, 2 CH3 25.87, CH 36.94, 2 CH3 45.71, CH2 62.38, CH 157.15, 157.42, 158.34, 3 Cquaternaire
44		HCl	213-215	DMSO-d6 15.99, 17.12, 2 CH3 3457, CH 37.17, 2 CH3 65.68, CH 156.45, 158.12, 2 Cquaternaire
45		paratoluenesulfonate	217-219	DMSO-d6 21.17, CH3 22.53, 24.48, 25.30, 3 CH2 37.20, 2 CH3 40.07, 64.37, 2 CH 125.68, 125.83, 127.19, 128.61, 6 CH 138.53, 145.24, 156.06, 157.36, 4 Cquaternaire

The results of the pharmacological studies are given below.

Study of the anti-diabetic activity in rats

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

The non-insulin-dependent model of diabetes is obtained in rats by neonatal (birthday) injection of streptozotocin.

The animals were stabled from birth to the day of the experiment in a temperature controlled animal house of 21 to 22°C and subjected to a fixed cycle of light (7 to 19 h) and darkness (7 to 7 h). They were fed a maintenance diet, water and food were provided ab libitum, except for a 2-hour fast before the tests where the food was removed (post-absorptive state).

Rats are treated orally for one (J1) or four (J4) days with the test product. Two hours after half-administration of the product and 30 minutes after anesthesia of the animals with Pentobarbital sodium (Nembutal®), a 300 μL blood sample is taken from the tail end.

For example, the results obtained are summarised in Table III. These results show the effectiveness of formula (I) compounds in lowering blood glucose in diabetic animals. These results are expressed as a percentage of the change in blood glucose at J1 and J4 (number of treatment days) compared to J0 (before treatment). TABLEAU III

composés	20 mg/kg/J		200 mg/kg/J
	J1	J4	J1	J4
1	-7	-2	-13	-15
2	-11	-10	-12	-12
3	-10	-8	-18	-22
4	0	-1	-20	-10
7	-8	-11	-10	-16
15	-8	-9	-4	-5
17	-12	-8	-8	-14
18	-6	-4	-29	-28
19	-10	-6	-4	-14
21	-7	-2	-21	-24
22	-23	-16	-13	0
25	-4	-11	-7	-6
26	-6	-11	-14	-9
27	-14	-9	-12	-13
28	-4	-1	-4	-13
31	-5	-11	-3	-15
32	2	0	-22	-18
33	-7	-6	-9	-14
34	-5	-15	-6	-21
37	-7	-8	-10	-15
39	-6	-6	-4	-7
40	-8	-12	-18	-18
42	-5	-4	-26	-17
43	-4	-16	-12	-17
44	-7	-6	-22	-25

The study of the activity of anxiety

Err1:Expecting ',' delimiter: line 1 column 359 (char 358)

A 6.6 mg/ml solution of bovine albumin in a 0.2 M pH 7.4 phosphate buffer is incubated with 1 mM methylglyoxal in the presence or absence of a compound of the invention at a concentration of 10 mM. The incubation is carried out under sterile conditions at 37°C for 6 days. At the end of the incubation period, the quantity of ketamine is measured with a commercially available fructose dosing kit (kit FRA, product reference: 0757055, Roche S.A. products) as instructed by the manufacturer.

For example, the results obtained under the following experimental conditions are summarized in Table IV: fructosamine levels after incubation of albumin with methylglyoxal in the presence of the compounds (I) of the invention compared with fructosamine levels when albumin is incubated with methylglyoxal in the absence of the compounds (I) of the invention. - What? TABLEAU IV

Composés (I)	Baisse du taux de fructosamines (%)
1	62
10	80
11	89
12	90
13	95
18	69
33	79
34	64
36	66
37	65
40	66
43	68
45	67

Claims (14)

1. Compounds of the general formula (I) in which:

   R1, R2, R3, and R4 are independently selected from among the groups:

   - H,

   - (C1-C20) alkyl, optionally substituted by halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C3-C8) cycloalkyl,

   - (C2-C20) alkenyl, optionally substituted by halogen, (C1-C5) alkyl, (C1-C5) alkoxy,

   - (C2-C20) alkynyl, optionally substituted by halogen, (C1-C5) alkyl, (C1-C5) alkoxy,

   - (C3-C8) cycloalkyl, optionally substituted by (C1-C5) alkyl, (C1-C5) alkoxy,

   - (C3-C8) heterocycloalkyl bearing one or more heteroatoms selected from among N, O, S and optionally substituted by (C1-C5) alkyl, (C1-C5) alkoxy,

   - (C6-C14) aryl (C1-C20) alkyl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C6-C14) aryl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C1-C13) heteroaryl bearing one or more heteroatoms selected from among N, O, S and optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   R1 and R2 on the one hand and R3 and R4 on the other hand being capable of forming with the nitrogen atom a cycle with n chain links (n between 3 and 8) which may or may not comprise one or more heteroatoms selected from among N, O, S and optionally substituted by one or more of the following groups: amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5), (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, R5 and R6 are independently selected from among the groups:

   - H,

   - (C1-C20) alkyl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C2-C20) alkenyl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C2-C20) alkynyl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C3-C8) cycloalkyl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C3-C8) heterocycloalkyl bearing one or more heteroatoms selected from among N, O, S and optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C6-C14) aryl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   - (C6-C14) aryl (C1-C5) alkyl, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,

   R5 and R6 being capable of forming with the carbon atom to which they are attached a cycle with m chain links (m between 3 and 6) which may or may not comprise one or more heteroatoms selected from among N, O, S and optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, or being capable of forming with the carbon atom a C10-C30 polycyclic residue optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, the nitrogen atom of a heterocycloalkyl or heteroaryl group possibly being substituted by a (C1-C5) alkyl, (C3-C8) cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (C1-C5) alkyl, or (C1-C6) acyl group, it being understood that when R3 and R4 represent a hydrogen atom, R1 and R2 do not represent a hydrogen atom, together with the tautomeric, enantiomeric, diastereoisomeric and epimeric forms thereof and pharmaceutically acceptable salts.
2. Compounds of the formula (I) according to claim 1, in which R5 is hydrogen.
3. Compounds of the formula (I) according to claim 1, in which R5 and R6 form with the carbon atom to which they are attached a cycle with m chain links (m between 3 and 8) which may or may not comprise one or more heteroatoms selected from among N, O, S and optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, or form with the carbon atom a C10-C30 polycyclic residue, optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl.
4. Compounds of the formula (I) according to claim 1, in which R5 is a (C2-C20) alkyl group substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl.
5. A compound of the formula (I) according to claim 1 in which R5 and R6 are selected from among H and/or (C1-C20) alkyl groups optionally substituted by amino, hydroxy, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl.
6. Compounds of the formula (I) according to any one of claims 1 to 5 in which R1 and R2 are independently selected from among the groups specified in claim 1 with the exception of the hydrogen atom and R3 and R4 represent a hydrogen.
7. Compounds of the formula (I) according to claim 6, in which R1 and R2 are a methyl group and R3 and R4 represent a hydrogen.
8. Compounds of the formula (I) according to any one of claims 1 to 7, in which R1 and R2 are a methyl group, R3 and R4 represent a hydrogen atom, R5 represents a hydrogen atom and R6 represents a hydrogen atom and R6 represents a methyl group, together with the tautomeric, enantiomeric, diastereoisomeric and epimeric forms thereof, and pharmaceutically acceptable salts.
9. A method of preparing a compound according to claim 1 comprising the reaction of a compound of the general formula (II) in which R1, R2, R3 and R4 are defined as previously, with a compound of the general formula (III), (IV) or (V) in which R5 and R6 are defined as previously and R7 is a methyl or ethyl group, in a polar solvent in the presence of an organic or inorganic acid.
10. A pharmaceutical composition comprising, as active ingredient, a compound according to any one of claims 1 to 8.
11. Use of a compound according to any one of claims 1 to 8, for the manufacture of a medicine intended for the treatment of pathological conditions associated with insulin resistance syndrome.
12. Use of a compound according to any one of claims 1 to 8, for the manufacture of a medicine intended for the treatment of diabetes.
13. Use of a compound according to any one of claims 1 to 8, for the manufacture of a medicine intended for the treatment of pathological conditions due to the formation of AGEs.
14. Use of a compound according to any one of claims 1 to 8, for the manufacture of a medicine intended for the treatment of pathological conditions selected from among kidney complications, atherosclerosis, angiopathy, Alzheimer's disease, neurodegenerative diseases and senility.