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

1. Field of the Invention

The present invention relates to amine-containing derivatives of dihydro-1,3,5-triazine which are useful in the treatment of pathological conditions associated with the insulin-resistance syndrome.

2. Description of the Related Art

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

The aim of the present invention is to provide novel compounds having improved properties.

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

in which:

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

H, (C1-C20)alkyl substituted or otherwise with halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C8)cycloalkyl, (C2-C20)alkylene substituted or otherwise with halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C2-C20)alkyne substituted or otherwise with halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C8)cycloalkyl substituted or otherwise with (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen from N, O, S and substituted or otherwise with (C1-C5)alkyl, (C1-C5)alkoxy, (C6-C14)aryl(C1-C20)alkyl substituted or otherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C8)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C6-C14)aryl substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl, (C1-C13)heteroaryl carrying one or more heteroatoms chosen from N, O, S and substituted or otherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C8)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

it being possible for R1 and R2, on the one hand, and R3 and R4, on the other hand, to form with the nitrogen atom an n-membered ring (n between 3 and 8) comprising or otherwise one or more heteroatoms chosen from N, O, S and being capable of being substituted with one or more of the following groups: amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

R5 and R6 are chosen independently from the groups:

H,

(C1-C20)alkyl substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

(C2-C20)alkylene substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

(C2-C20)alkyne substituted or otherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C8)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

(C3-C8)cycloalkyl substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

(C3-C8)heterocycloalkyl carrying one or more heteroatoms chosen from N, O, S and substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

(C6-C14)aryl substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

(C1-C13)heteroaryl carrying one or more heteroatoms chosen from N, O, S and substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

(C6-C14)aryl(C1-C5)alkyl substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

it being possible for R5 and R6 to form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8) comprising or otherwise one or more heteroatoms chosen from N, O, S and being capable of being substituted with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

or being capable of forming with the carbon atom a C10-C30 polycyclic residue substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl,

it being possible for the nitrogen atom of a heterocycloalkyl or heteroaryl group to be substituted with a (C1-C5)alkyl, (C3-C8)cycloalkyl, (C6-C14)aryl, (C6-C14)aryl(C1-C5)alkyl or (C1-C6)acyl group,

with the exclusion of the compounds of formula I in which:

a—R1=H, R2=H, R3=H, R5=CH3, R6=CH3 and R4=phenethyl, phenoxyethyl, 2-phenylthioisopropyl or benzyl;

b—R1=H, R2=H, R3=H or CH3, R4=H, methyl, butyl or phenethyl, R5=H or ethyl and R6 is 3-methyl-5-isoxazolyl, 5-methyl-3-isoxazolyl, 3-methyl-5-pyrazolyl or (5-methyl-3-isoxazolyl)methyl,

c—R1, R2, R3 and R4 represent a hydrogen atom,

as well as the tautomeric, enantiomeric, diastereoisomeric and epimeric forms and the pharmaceutically acceptable salts.

The expression m-membered ring formed by R5 and R6 is understood to mean in particular a saturated ring such as a cyclohexyl, piperidinyl or tetrahydropyranyl group.

The expression polycyclic group formed by R5 and R6 is understood to mean an optionally substituted carbon-containing polycyclic group and in particular a steroid residue.

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

Another particular group of compounds of formula (I) is that in which R5 and R6 form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8) comprising or otherwise one or more heteroatoms chosen from N, O, S and being capable of being substituted with one or more of the following groups: (C1-C5)alkyl, amino, hydroxyl, (C1-C5)alkylamino, (C1-C5)alkoxy, (C1-C8)alkylthio, (C6-C14)aryl, (C6-C14)aryl(C1-C5)alkoxy,

or form with the carbon atom a C10-C30 polycyclic residue substituted or otherwise with amino, hydroxyl, 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, carboxyl, carboxymethyl or carboxyethyl.

Another particular group of compounds of formula (I) is that in which R5 and R6 are chosen independently from the groups:

(C1-C20)alkyl substituted or otherwise with amino, hydroxyl, thio, halogen, (C1-C25)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.

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

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

The compounds of general formula (I) possess basic nitrogen atoms which may be monosalified or disalified with organic or inorganic acids.

The compounds of general formula (I) may be prepared by reacting a compound of general formula (II)

in which R1, R2, R3 and R4 are as defined above, with a compound of general formula (III), (IV) or (V)

in which R5 and R6 are as defined above and R7 is a methyl or ethyl group, in a polar solvent (for example ethanol or dimethylformamide) in the presence of an organic acid (for example camphorsulphonic acid) or of an inorganic acid (for example hydrochloric acid).

The compounds of general formula (II) are biguanides whose synthesis is routine to every person skilled in the art. We will cite for example 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., 1959 (81), 3728; S. L. Shapiro, V. A. Parrino and L. Freedman, J. Org. Chem., 1959 (81), 4636).

The compounds according to the present invention are useful in the treatment of pathological conditions associated with the insulin-resistance syndrome (X syndrome).

Insulin-resistance is characterized by a reduction in the action of insulin (cf. Presse Médicale, 1997, 26 (No. 14), 671-677) and is involved in a large number of pathological states, such as diabetes and more particularly non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslatupidaemia, obesity, high blood pressure, as well as certain microvascular and macrovascular complications such as atherosclerosis, retinopathies and neuropathies.

In this regard, reference may be made for example to Diabètes, 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 high hypoglycaemic activity.

The compounds according to the present invention can also be used to treat chronic complications which are in particular due to the formation of “advanced glycosylation end-products” noted AGEs which are derived from the glycoxidation reaction between glucose, its oxidation derivatives and the amino functional groups of proteins, including the so-called Maillard reactions for glycation of glyoxal for example.

Indeed, recently published 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). The formation of AGE may also play an important part in the pathogenesis of angiopathy, in particular in diabetics, and also in senility (J. Neuropathol. Exp. Neurol., 2000, 59 (12), 1094).

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

These pharmaceutical compositions are particularly intended for treating diabetes, pathological conditions due to the formation of AGEs, such as, in particular, renal complications, atherosclerosis, angiopathy, Alzheimer's disease, neurodegenerative diseases and senility.

The pharmaceutical compounds according to the invention may be provided in forms intended for administration by the parenteral, oral, rectal, permucosal or percutaneous route.

They will therefore be provided in the form of injectable solutions or suspensions or multidose vials, in the form of uncoated or coated tablets, sugar-coated tablets, capsules, gelatin capsules, pills, cachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, for permucosal use.

The excipients which are suitable for such administrations are the derivatives of cellulose or of microcrystalline cellulose, the alkaline-earth carbonates, magnesium phosphate, starches, modified starches, lactose for the solid forms.

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

For parenteral use, water, aqueous solutions, physiological saline, isotonic solutions are the vehicles most conveniently used.

The dosage may vary within wide limits (0.5 mg to 1 000 mg) according to the therapeutic indication and the route of administration, as well as the age and weight of the subject.

By way of example, here are a few biguanides of formula II used in the synthesis of derivatives of formula I.

The following examples illustrate the preparation of the compounds of formula I.

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 camphorsulphonic acid are added to a solution of compound A (25.7 g; 0.155 mol) in 200 ml of DMF. After refluxing for 2 hours, the solvent is removed under vacuum and 100 ml of acetonitrile are added. The solid formed is drained and dried (21.9 g; 69%).

m.p.=218-220° C.

1 H NMR (DMSO-d6, 200 MHz): 1.10 (t, 3H); 1.80 (m, 2H) 3.20 (s, 6H); 4.83 (m, 1H); 7.57 (m, 2H); 8.65 (s, 1H); 8.90 (s, 1H)

13 C NMR (DMSO-d6, 50 MHz): 6.41 (CH3); 27.59 (CH2); 35.64 (CH3); 60.75 (CH); 155.01 (C═N); 156.67 (C═N)

Synthesis of 2,4-bisdimethylamino-3,6-dihydro-6-methyl-1,3,5-triazine hydrochloride

61 ml of acetal and 5 g of camphorsulphonic acid are added to a solution of compound E (41.10 g; 0.212 mol) in 200 ml of absolute ethanol. The whole is heated under reflux for 72 hours and then concentrated. The crude material is triturated with acetonitrile and the solid formed is drained and then recrystallized from acetonitrile. 24 g (51.5%) of a solid are obtained.

m.p.=200-202° C.

1 H NMR (DMSO-d6, 200 MHz): 1.34 (d, 3H); 3.02 (s, 6H) 4.72 (m, 1H); 4.83 (m, 1H); 8.80 (s, 2H)

13 C NMR (DMSO-d6, 50 MHz): 22.59 (CH3); 37.76 (CH3); 59.02 (CH); 156.35 (C═N)

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

Results of pharmacological studies will be given below.

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

The non-insulin-dependent diabetes model is obtained in rats by neonatal injection (on the day of birth) of streptozotocin.

The diabetic rats used were 8 weeks old. The animals were kept, from the day of their birth to the day of the experiment, in an animal house at a controlled temperature of 21 to 22° C. and subjected to a fixed cycle of light (from 7 am to 7 pm) and darkness (from 7 pm to 7 am). Their diet consisted of a maintenance diet, water and food were provided “ab libitum”, with the exception of the 2 hours of fasting preceding the tests when the food is withdrawn (postabsorptive state).

The rats were treated by the oral route for one (D1) or four (D4) days with the product to be tested. Two hours after the last administration of the product and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal a), 300 μl of blood sample are collected from the end of the tail.

By way of example, results obtained are assembled in Table III. These results show the efficacy of the compounds of formula (I) in reducing glycaemia in the diabetic animals. These results are expressed as a percentage variation of glycaemia at D1 and D4 (number of days of treatment) relative to D0 (before the treatment).

The compounds (I) are also capable of inhibiting the so-called Maillard reactions by “capturing effect” on the α-dicarbonyl-containing derivatives such as glyoxal—this is the antiglycation effect. This Maillard reaction inhibiting effect of the compounds according to the invention was studied in vitro by assaying ketamines (“fructosamines”) produced during the incubation of albumin with methylglyoxal in the presence or otherwise of a compound of formula (I) according to the invention.

A solution of bovine albumin at 6.6 mg/ml in 0.2 M phosphate buffer, pH 7.4, is incubated with 1 mM methylglyoxal in the presence or otherwise of a compound according to 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 ketamines is measure with a commercially available fructosamine assay kit (“FRA” kit, product reference: 0757055, Roche S. A. products) according to the manufacturer's instructions.

By way of example, results obtained under these experimental conditions are assembled in Table IV: level of fructosamine after incubation of the albumin with the methylglyoxal in the presence of compounds (I) according to the invention in relation to the level of fructosamine when albumin is incubated with methylglyoxal in the absence of the compounds (I) according to the invention.