ITRM20060090A1 - NEW COMPOUNDS CPT INHIBITORS AT LEVEL OF THE SNC AS ANTI-DIABETIC AND OR ANTI-BESIDE DRUGS - Google Patents

Description

The present invention describes a new class of compounds having an inhibitory action of carnitine palmitoyl transferase (CPT) at the level of the central nervous system (CNS).

The published international patent application W099 / 59957 describes and claims a class of butyric acid derivatives with CPT1 inhibition activity. An example of such compounds is R-4-trimethylammonium-3- (tetradecylcarbamoyl) -amino-butyrate (ST 1326).

It has recently been shown that the inhibition of the hepatic isoform of CPT1 (CPT1L) in the hypothalamus, carried out experimentally by means of ICV administration, is able to significantly and consistently decrease, in terms of entity and duration of the effect, consumption. of food and gluconeogenesis (Nature Medicine, 2003, 9 (6), 756-761). In confirmation of these data, a brain-liver circuit involved in glucose homeostasis has recently been demonstrated (Celi Metabolism 2005, vol. 1, 53-61). This property has also been reported using the compound ST1326.

In international patent application W02004 / 071458 it is shown that food intake and glucose production can be regulated by modulating the levels of the enzyme LC-Co-A (long-chain fatty acyl-Co-A) in the hypothalamus. In particular, it is shown that the intracerebroventricular injection (ICV) of ST1326 significantly inhibits food intake and glucose production in treated animals (rats).

In the literature there are data of weak activity on CPT1, more marked for the muscular form, of antiangine molecules such as trimetazidine, perexillin and amiodarone (Pharmacol. Research vol. 44, n. 2, 2001; Biochem. Pharmacol, vol. 52, 2, 1996). The action of these drugs seems to take place, at least in part by promoting a shift in cellular metabolism in the myocardium that leads to the preferential use of glucose by decreasing the oxidation of fatty acids by inhibiting the activity of CPT1.

The subject of this patent is therefore new inhibitors of CPT1, derivatives of trimetazidine and perexylline, preferentially selective for the hepatic form of CPT1 (CPT1L) abundantly expressed also in the brain, with structural characteristics different from those of the inhibitors object of the previous application W099 / 59957 and of the Italian co-pending patent application No. RM2005A000090 more appropriate to the passage of the BBB.

These compounds are able to inhibit CPT1 at the hypothalamic level and therefore bring about a reduction in food consumption and gluconeogenesis and as drugs they are therefore useful for the treatment of obesity and / or diabetes.

The present invention responds to this need and relates to new inhibitors having general formula (I):

where is it:

A is a monovalent group selected from the comprising group

linear or branched C1-C15 alkyl, saturated or unsaturated optionally substituted with an aryloxy group in turn substituted with halogen or alkyl or alkoxy (C-1-C10); ; n is selected from 0, 1, 2 and 3;

R and R ', equal or different from each other, are selected from the group comprising H, C1-C8 alkyl, C1-C8 alkoxy, nitro, halogen;

R1 is selected from H and -CH2-CH (C5-C6 cycloalkyl) 2

X is selected from CH2, NR2;

R2 is chosen from the group comprising () -

- q

R3, R4 and R5, the same or different from each other, are selected from the group comprising H, OH, halogen, C1-C4 alkoxy, linear or branched C-1-C4 alkyl; or R3 and R4 together form an alkylidene (C1-C4) -dioxy group;

Y is chosen from (

q is chosen from 1, 2 and 3;

m is chosen between 0 and 1;

and its pharmaceutically acceptable salts.

Depending on the meaning of the radicals A, R, R ', R1, R2, R3, R4, R5, and Y, the compounds of formula (I) may have one or more chiral centers. In these cases, for the purposes of the present invention it is specified that each of the products of formula (I) can exist both as a ceramic mixture R / S and as separate isomeric forms R and S.

The compounds of formula (I) can also exist salified with pharmaceutically acceptable acids.

Pharmaceutically acceptable salts of the compounds of formula (I) preferred according to the present invention are for example the salts obtained by adding pharmaceutically acceptable acids, such as hydrochloride, hydrobromide, sulphate or bisulfate, phosphate or acid phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate and paratoluenesulfonate.

Compounds of formula (I), which do not contain a net positive or negative charge, are expected to be more efficient in passing the blood brain barrier.

A is preferably equal to and R and R 'are preferably different with R = H and R' = alkyloxy group; n is preferably = 0

When X is NR2, R1 is preferably = H and R2 preferably = CH2PhR3, R4, R5 with R3 R4 and R5 preferably methoxy.

When X = CH2, R1 is preferably = -CH2-CH (cycloalkylC5-C6) 2

m is preferably equal to 0. When m is different from 0, Y is preferably = (CH2) q-O and q is = 2.

Particularly preferred are the following compounds:

2- [4- (2,3,4 trimethoxybenzyl) piperazine-1-yl] ethyl- (2-phenylethyl) carbamate (ST3473); 2- [2- (2,2dicyclohexylethylpiperidin-1-yl] ethyl (4-butylphenyl) carbamate (ST3348);

4-benzyl-N- (2-phenylethyl) -1 -carboxamide-piperazine (ST3340);

4-benzyl-N- (4-fluorobenzyl) -1-carboxamide-piperazine (ST3344); 4-benzyl-N- (2,4-dichlorophenyl) -1-carboxamide-piperazine (ST3342);

4-benzoyl-N- (4-ethylphenyl) -1 -carboxamide-piperazine (ST3343);

4-benzoyl-N- (2-phenylethyl) -1-carboxamide-piperazine (ST3341);

4-benzoyl-N- (4-fluorobenzyl) -1 -carboxamide-piperazine (ST3345);

2- (2,2-dicyclohexylethyl) - N- (4-chlorophenyl) -1-carboxamide-piperidine (ST3346);

2- (2, 2-diicycloesis letyl) - N- (4-butylphenyl) -1 -carboxamide-piperidine (ST3347);

2- (2,2-dicyclohexylethyl) - N- (4-fluorobenzyl) -1 -carboxamide-piperidine (ST3349); 4-benzoyl-N- (4-chlorophenyl) -1 -carboxamide-piperazine (ST3350);

4-benzoyl-N- (2,4-dichlorophenyl) -1 -carboxamide-piperazine (ST3351);

2- (2,2-dicyclohexylethyl) - N- (2-phenylethyl) -1 -carboxamide-piperidine (ST3410);

2- (2,2-dicyclohexylethyl) - N- (4-ethylphenyl) - 1 -carboxamide-piperidine (ST3411);

2- (2, 2-dicyclohexylethyl) - N- (4-heptyloxyphenyl) -1 -carboxamide-piperidine (ST3412); 2- (2, 2-dicyclohexylethyl) - N- (4-methoxybenzyl) -1 -carboxamide-piperidine (ST3413); 2- (2, 2-dicyclohexylethyl) - N- (4-nitrophenyl) -1 -carboxamide-piperidine (ST3415);

4- [bis (4-fluorophenyl) methyl] -N- (2-phenylethyl) -1 -carboxyamide-piperazine (ST3416); 4- [bis (4-fluorophenyl) methyl] -N- (2-ethylphenyl) -1-carboxyamide-piperazine (ST3417); 4- [bis (4-fluorophenyl) methyl] -N- (4-heptyloxyphenyl) -1 -carboxyamide-piperazine (ST3418); 4- [bis (4-fluorophenyl) methyl] -N- (4-chlorophenyl) -1 -carboxyamide-piperazine (ST3419); 4- [bis (4-fluorophenyl) methyl] -N- (4-methoxybenzyl) -1-carboxyamide-piperazine (ST3420);

4- (1,3-benzodioxole-5-methyl) -N- (2-phenylethyl) -1 -carboxyamide-piperazine (ST3421); 4- (1,3-benzodioxole-5-methyl) -N- (4-ethylphenyl) -1 -carboxyamide-piperazine (ST3422); 4- (1,3-benzodioxole-5-methyl) -N- (4-heptyloxyphenyl) -1-carboxyamide-piperazine (ST3423);

4- (1,3-benzodioxole-5-methyl) -N- (4-methoxybenzyl) -1-carboxyamide-piperazine (ST3424);

4- (1,3-benzodioxole-5-methyl) -N- (4-chlorophenyl) -1-carboxyamide-piperazine (ST3425);

4- (1,3-benzodioxole-5-methyl) -N- (4-nitrophenyl) -1-carboxyamide-piperazine (ST3426);

4- (2,3,4-trimethoxybenzyl) -N- (4-heptyloxyphenyl) -1-carboxyamide-piperazine (ST3428);

4- (2,3,4-trimethoxybenzyl) -N- (2-phenylethyl) -1-carboxiamide-piperazine (ST3519); 4- (2,3,4-trimethoxybenzyl) -N- (4-ethylphenyl) -1-carboxyamide-piperazine (ST3520); 4- (2,3,4-trimethoxybenzyl) -N- (4-nitrophenyl) -1-carboxiamide-piperazine (ST3521); 4- (2,3,4-trimethoxybenzyl) -N- (4-methoxybenzyl) -1-carboxyamide-piperazine (ST3522); And

4- (2, 3, 4-trimethoxybenzyl) -N- (4-chlorophen I) - 1 -carboxyamide-piperazine (ST3414). The compounds of general formula (I) can be prepared using reactions known in the state of the art and can also be prepared with parallel chemistry using a suitable reactor consisting of several reaction tubes in each of which a reaction with different reactants is set up but in the same conditions of temperature and inert atmosphere.

An example of synthesis is represented in the following Scheme A.

Scheme A

When m is 0 there is the attack of the isocyanate on the amine; the solvents used are preferably low boiling and chlorinated such as dichloromethane. The reaction temperature is comprised between 20 and 40 ° C, preferably 25 ° C. The reaction time is between 1 and 18 hours, preferably 2 hours.

When m is different from 0 and Y = (CH2) q-O there is the attack of the isocyanate on the hydroxyl group; the solvents used are preferably high boiling such as toluene. The reaction temperature is comprised between 50 and 140 ° C, preferably 120 ° C. The reaction time is between 5 and 30 hours, preferably 24 hours. All reactions are carried out in an inert gas flow, preferably argon. In each reaction one of the two reagents is present in excess of 0.5 moles with respect to the default reagent, the excess reagent is eliminated through the use of polystyrene "scavenger" resins. Isocyanate is preferably used in excess of to the amine and / or alcohol, and the aminomethyl polystyrene resin allows the elimination of excess.

The compounds of formula (I) have CPT1 inhibitory activity. This activity makes it possible to use them in the treatment and / or prevention of obesity, hyperglycemia, diabetes and associated disorders, such as diabetic retinopathy, diabetic neuropathy and cardiovascular disorders.

The compounds of formula (I) are also used in the prevention and / or treatment of cardiac disorders such as CHF (congestive heart failure).

The inhibitory action of the compounds of formula (I) occurs mainly on the hepatic isoform of CPT1 and, in particular, also in the hypothalamus.

A further object of the present invention are pharmaceutical compositions containing one or more compounds of formula (I) described above in combination with pharmaceutically acceptable excipients and / or diluents.

The compositions in question can, together with the compounds of formula (I), contain known active principles.

The pharmaceutical compositions according to the present invention can be adapted for oral, parenteral, rectal, transdermal and intranasal administration.

The oral form includes capsules, lozenges, granules, powders, syrups and elixirs.

Parenteral forms include solutions or emulsions.

The dosage of the compounds of the present invention varies according to the type of compound used, the route of administration and the degree of development of the disease to be treated. Generally an effective dosage is between 0.1 and 100 mg / kg. The invention also includes the use of compounds of formula (I) for the preparation of drugs with hypoglycemic and anti-obesity action.

A further aspect of the invention is a process for the preparation of pharmaceutical compositions characterized by mixing one or more compounds of formula (I) with suitable excipients, stabilizers and / or pharmaceutically acceptable diluents.

Another object of the present invention is the method for treating a mammal affected by hyperglycemia, diabetes, obesity and associated disorders, as reported above, comprising the administration of a therapeutically effective amount of the compound of formula (I).

The present invention is illustrated by means of the following non-limiting examples.

EXAMPLES

Example 1

Synthesis of 2- [4- (2.3.4 trimethoxybenzyl) piperazin-1-yl] ethyl- (2-phenylethyl) carbamate

Synthesis of the intermediate 1- (2-hydroxyethyl) -4- (2.3.4 trimethoxybenzyl) piperazine

K2CO3 (0.376 g; 2.72 mmol) and the mixture of reaction was left at T = 50 ° C for 24 hours. After cooling, K1 was added in catalytic quantities (0.022 g) and bromoethanol (0.056 g; 0.45 mmoles). The reaction was left at 40 ° C for 24 hours under magnetic stirring. After this time the reaction mixture was filtered and evaporated under reduced pressure. The crude obtained was purified by silica gel chromatography using chloroform / methanol 97/3 as eluent. 0.087 g of product were obtained with a yield of 60%. TLC silica gel with eluent CH2CI2 / MeOH 8/2 Rf = 0.38. ESI-MS m / z 350 [M + K] <+ 1> H-NMR (CD2CI2,300 MHz) δ 7.00 (1H, d), 6.70 (1H, d), 3.85 (3H, s), 3.80 (6H, s), 3.50 (2H, t), 3.40 (2H, s), 2.65 (2H, m), 2.50 (8H, m).

Synthesis of 2- [4- (2.3.4 trimethoxybenzyl) piperazin-1-yl] ethyl- (2-phenylethyl) carbamate ST3473

Phenylethylisocyanate (0.026 g; 0.179 mmol). The reaction mixture was left at 130 ° C under reflux for 24 hours under continuous magnetic stirring. The reaction crude was purified with the polystyrene resin sulfuryl chloride (0.032 g; capacity 1.52 mmol / g) in the presence of triethylamine (4.9 mg, 5 μL, 0.048 mmoles). The reaction was left for one hour at room temperature under slow magnetic stirring. After this time the amino methyl resin (0.056 g; 2.7 mmol / g) was added to the filtrate and the mixture was left for 2 hours at room temperature under slow magnetic stirring.

After this time the mixture was filtered and the solvent evaporated under reduced pressure. The solid treated with ethyl acetate and the solution separated from the precipitate. The collected solution was evaporated under reduced pressure and 0.042 g of the product were obtained as oil, with a yield of 77.2%. <1> H-NMR (CD2Cl2, 300 MHz) δ 7.3 (5H, m), 7 , 0 (1H, d), 6.6 (1H, d), 4.1 (2H, t), 3.85 (3H, s), 3.84 (6H, s), 3.4 (4H, s + t), 2.8 (2H, t), 2.5 (2H, t), 2.4 (8H, brt + brs). HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 0.7ml / min, U.V. 220nm, retention time: 5.3min, ESI-MS m / z 458 [M + H] <+>, 480 [M + Na] <+>, 496 [M + K] <+> Example 2

Synthesis of 2- [2- (2.2dicyclohexylethylpiperidin-1-yl] ethyl (4-butylphenyl) carbamate (ST3348)

Synthesis of intermediate 2- (2,2dicyclohexylethyl) -1- (2-hydroxyethyl) piperidine

N (Et) 3 (0.075 g; 0.733 mmol, 0.103 ml), K1 in catalytic quantities (0.020g; 0.120mmol) and bromoethanol (0.110g; 0.880mmol, 0.057ml). The reaction was left at T = 50 ° C for 24 hours under magnetic stirring. After this time the reaction mixture was filtered and evaporated under reduced pressure. Once the presence of the starting product 2- (2,2 dicyclohexylethyl) piperidine was still observed, the resin methyl isocyanate polystyrene (80 mg; 1.84 mmol / g) in 5 ml of anhydrous dichloromethane was added to the reaction crude, the suspension was left for 2 hours at room temperature, subsequently the mixture was filtered and evaporated under reduced pressure. 0.100 g of the solid product were obtained with a yield of 43%. P.f. 134.5 ° C-135.5 ° C. <1> H-NMR (CDCI3, 300 MHz) δ 4.2 (1 H, t), 3.80 (2H, m), 3.00 (2H, m), 2.70 (3H, m), 2.00-1.00 (31 H, m) .TLC silica gel with eluent CH30H / CH2CI2 90/10, Rf = 0.24. ESI-MS m / z: 322 [M + H] <+> Synthesis of 2- [2- (2.2dicyclohexylethylpiperidin-1] yl1ethyl (4-butylphenes) carbamate ST3348 A 0.161 g (0.501 mmol) of 2 (2,2dicyclohexylethyl ) -1- (2-hydroxyethyl) piperidine dissolved in 5 ml of toluene 4-butylphenylisocyanate (0.131 g; 0.752 mmol) was added. The reaction mixture was brought to 130 ° C and left under reflux for 24 hours under magnetic stirring After this time the amino methyl polystyrene resin (0.186g, 2.7mmol / g) was added to the reaction mixture, the mixture was left for two hours at room temperature under slow magnetic stirring. At the end of this time it was filtered and evaporated under reduced pressure. 0.234g of oily product were obtained with a yield of 94%. TLC silica gel with eluent CH3OH / CH2CL290 / 10, Rf = 0.74; <1> H-NMR (CDCI3300 MHz) δ 7, 35 (2H, d), 7.15 (2H, d), 4.30 (2H, brs), 3.20 (2H, brm), 2, 8-2, 6 (3H, m), 2.50 (2H, t), 1.90-0.90 (38H, m); HPLC Symmetry Column C-18 (3.5μm) 4.6x75mm, T = environment, phase mobile CH3CN / H2O 0.1% ac. formic in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1 ml / min, U.V. 220nm, retention time 11, 2 min. EI-MS m / z 497 [M + H] <+>

Example 3

Synthesis of 4-benzyl-N- (2-phenylethyl) -1-carboxamide-piperazine ST3340

The product was obtained starting from 0.030 g (0.185 mmol) of 4-benzyl piperazine and 0.041 g (0.277 mmol) 2-phenylethyl isocyanate in 2 ml of anhydrous CH2CI2. The reaction mixture was left for 2 hours under stirring at room temperature under Argon flow. After this time, 0.068 g of amino methyl polystyrene resin (2.7 mmoles / g) was added to the solution and the mixture was left for 2 hours under gentle stirring at room temperature and under Argon flow. At the end of this time the mixture was filtered and the solution evaporated under a nitrogen flow. 0.048g of product were obtained (yield 80%) ESI-MS m / z 346 [M + Na] <+>, <+> HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = environment, phase mobile CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 9.1min ,.

Example 4

Synthesis of 4-benzyl-N- (4-fluorobenzyl) -1-carboxamide-piperazine ST3344

The compound of example 4 was prepared as described in example 3 starting from 4-benzyl piperazine and 4-fluorobenzyl isocyanate to give 0.048 g of product (yield 79%)

ESI-MS m / z 328 [M + H] <+>,. HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 0.7 ml / min, U.V. 220 nm, retention time: 8.77 min ,.

Example 5

Synthesis of 4-benzyl-N- (2,4-dichlorophenyl) -1-carboxamide-piperazine ST3342

The compound of example 5 was prepared as described in example 3 starting from 4-benzyl piperazine and 2,4-dichlorophenyl isocyanate to give 0.060 g of product (yield 88%)

ESI-MS m / z 364 [M + H] <+>, <+>. HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1 ml / min, U.V. 220 nm, retention time: 7.1 min ,.

Example 6

Synthesis of 4-benzoyl-N- (4-ethylphenyl) -1-carboxamide-piperazine ST3343

The compound of example 6 was prepared as described in example 3 starting from 4-benzoyl piperazine and 4-ethylphenyl isocyanate to give 0.032 g of product (yield 60%)

ESI-MS m / z 360 [M + Na] <+>,. HPLC Column Luna C-18 (3.5μm) 4.6x250 mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 0.7 ml / min, U.V. 220 nm, retention time: 8.79min ,.

Example 7

Synthesis of 4-benzoyl-N- (2-phenylethyl) -1-carboxamide-piperazine ST3341

The compound of example 7 was prepared as described in example 3 starting from 4-benzoyl piperazine and 2-phenylethyl isocyanate to give 0.040 g of product (yield 75.2%)

ESI-MS m / z 360 [M + Na] <+> ,. HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 0.7ml / min, U.V. 220nm, retention time: 7.1min ,.

Example 8

Synthesis of 4-benzoyl-N- (4-fluorobenzyl-1-carboxamide-piperazine ST3345

The compound of example 8 was prepared as described in example 3 starting from 4-benzoyl piperazine and 4-fluorobenzyl isocyanate to give 0.044 g of product (yield 82%)

ESI-MS m / z 363 [M + Na] <+>,. HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 0.7 ml / min, U.V. 220 nm, retention time: 6.8min,

Example 9

Synthesis of 2- (2.2-dicyclohexylethyl) - N- (4-chlorophenyl) -1-carboxamide-piperidine ST3346

The compound of example 9 was prepared as described in example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 4-chlorophenyl isocyanate to give 0.040 g of product (yield 46%)

ESI-MS m / z 453 [M + Na] <+> ,. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H20 0.1% ac. formic in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1 ml / min, U.V. detector 220nm, retention time: 23.6min,

<1> H-NMR (CDCI3200 MHz) δ 7, 4-7, 2 (4H, d + d), 6.3 (1H, brs), 4.2 (1H, m), 3.9 (1H, m), 3.0 (1H, t), 1.90-0.90 (31H, m).

Example 10

Synthesis of 2- (2,2-dicyclohexylethyl) - N- (4-butylphenyl) -1-carboxamide-piperidine ST3347

The compound of example 10 was prepared as described in example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 4-butylphenyl isocyanate to give 0.065 g of product (yield 80%)

ESI-MS m / z 453 [M + H] <+>, 475 [M + Na] <+>, HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O 0.1% formic acid in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 30.2min ,.

<1> H-NMR (CDCI3200 MHz) δ 7, 4-7, 2 (4H, d + d), 6.3 (1H, brs), 4.2 (1H, m), 3.9 (1H, m), 3.0 (1H, t), 2.5 (2H, t), 1.90-0.90 (38H, m).

Example 11

Synthesis of 2- (2.2-dicyclohexylethyl) - N- (4-fluorobenzyl) -1-carboxamide-piperidine ST3349

The compound of example 11 was prepared as described in example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 4-fluorophenyl isocyanate to give 0.035 g of product (yield 91%)

ESI-MS m / z451 [M + Na] <+>. HPLC Symmetry Column C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H20 0.1% TFA in linear gradient of 20 min . from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 13.4min, <1> H-NMR (CDCI3200 MHz) δ 7.3 (2H, d) 7.0 (2H, t), 4.4 (2H, brs), 1.90 -0.90 (31 H, m).

Example 12

Synthesis of 4-benzoyl-N- (4-chlorophenyl) -1-carboxamide-piperazine ST3350

The compound of Example 12 was prepared as described in Example 3 starting from 4-benzoyl piperazine and 4-chlorophenyl isocyanate to give 0.054g of product (yield 100%). ESI-MS m / z 366 [M + Na] <+>, <+>. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O 0.1% ac formic in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220 nm, retention time: 7.9min ,. <1> H-NMR (CDCI3200 MHz) δ 7.4 (5H, m) 7.3 (4H, m), 3, 9-3, 4 (8H, m).

Example 13

Synthesis of 4-benzoyl-N- (2.4-dichlorophenyl) -1-carboxamide-piperazine ST3351.

The compound of example 13 was prepared as described in example 3 starting from 4-benzoyl piperazine and 2,4-dichlorophenyl isocyanate to give 0.063 g of product (yield 90%)

ESI-MS m / z 400 [M + Na] <+>, HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 0.7ml / min, U.V. 220nm, retention time: 9.7min ,.

Example 14

Synthesis of 2- (2.2-dicyclohexylethyl) - N- (2-phenylethyl) -1-carboxamide-piperidine ST3410 The compound of Example 14 was prepared as described in Example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 2-phenylethyl isocyanate to give 0.060 g of product (yield 85%)

ESI-MS m / z 453 [M + H] <+>, 447 [M + Na] <+> HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O 90 / 10 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 6.24min ,.

Example 15

Synthesis of 2- (2,2-dicyclohexylethyl) - N- (4-ethylphenyl) -1-carboxamide-piperidine ST3411 The compound of example 15 was prepared as described in example 3 starting from 2- (2,2- dicyclohexylethyl) piperidine and 4-ethylphenyl isocyanate to give 0.061g of product (yield 86%).

ESI-MS m / z 447 [M + Na] <+>. HPLC Symmetry Column C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O 90/10 (v / v), pH = as it is, flow = 1ml / min, U.V. detector 220nm, retention time: 7.34min ,.

Example 16

Synthesis of 2- (2,2-dicyclohexylethyl) - N- (4-heptyloxyphenyl) -1-carboxamide-piperidine ST3412

The compound of example 16 was prepared as described in example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 4-heptyloxyphenyl isocyanate to give 0.052g (yield 61%).

ESI-MS m / z 533 [M + Na] <+>. HPLC Column Symmetry C-18 (3,5μm) 4,6x75mm, T = environment, mobile phase CH3CN / H20 90/10 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 18.15min,

Example 17

Synthesis of 2- (2,2-dicyclohexylethyl) - N- (4-methoxybenzyl) -1-carboxamide-piperidine ST3413

The compound of example 17 was prepared as described in example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 4-methoxybenzyl isocyanate to give 0.025g of product (yield 34%).

ESI-MS m / z 463 [M + Na] <+>. HPLC Symmetry Column C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O 90/10 (v / v), pH = as it is, flow = 1ml / min, U.V. detector 220 nm, retention time: 4.6min,

Example 18

Synthesis of 2- (2,2-dicyclohexylethyl) - N- (4-nitrophenyl) -1-carboxamide-piperidine ST3415

The compound of example 18 was prepared as described in example 3 starting from 2- (2,2-dicyclohexylethyl) piperidine and 4-nitrophenyl isocyanate to give 0.032g of product (yield 43%).

ESI-MS m / z, 442 [M + H] <+>, HPLC Symmetry Column C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H20 90/10 (v / v), pH = as it is, flow = 1ml / min, U.V. detector 220 nm, retention time: 5.1 min,

Example 19

Synthesis of 4- [bis (4-fluorophenyl) methyl] -N- (2-phenylethyl) -1-carboxiamide-piperazine ST3416

The compound of example 19 was prepared as described in example 3 starting from 4- (bis (4-fluorophenyl) methyl) piperazine and 2-phenylethyl isocyanate to give 0.066g of product (yield 91%)

ESI-MS m / z 436 [M + H], 458 [M + Na] <+> HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220 nm, retention time: 17.5min,

Example 20

Synthesis of 4- [bis (4-fluorophenyl) methyl] -N- (2-ethylphenyl) -1-carboxyamide-piperazine ST3417

The compound of example 20 was prepared as described in example 3 starting from 4- (bis (4-fluorophenyl) methyl) piperazine and 2-ethylphenyl isocyanate to give 0.063g of product (yield 87%)

LC-MS: ESI-MS m / z 436 [M + H] <+>. HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min . from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 205-380nm, retention time: 19.2min ,.

Example 21

Synthesis of 4- [bis (4-fluorophenyl) methyl-N- (4-heptyloxyphenyl) -1-carboxiamide-piperazine ST3418

The compound of example 21 was prepared as described in example 3 starting from 4- (bis (4-fluorophenyl) methyl) piperazine and 4-heptyloxyphenyl isocyanate to give 0.061 g of product (yield 70%)

LC-MS: ESI-MS m / z 522 [M + H] <+>. HPLC Column Luna C-18 (3.5pm) 4.6x250mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min . from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 205-380nm, retention time: 24.07min,

Example 22

Synthesis of 4- [bis (4-fluorophenyl) methyl] -N- (4-chlorophenyl) -1 -carboxyamide-piperazine ST3419

The compound of example 22 was prepared as described in example 3 starting from 4- (bis (4-fluorophenyl) methyl) piperazine and 4-chlorophenyl isocyanate to give 0.025g of product (yield 34%)

ESI-MS m / z 442 [M + H] <+>. HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = environment, mobile phase CH3CN / H20 70/30 (v / v), pH = as it is, flow = 0.7ml / min, U.V. 254nm, retention time: 22.4min,

Example 23

Synthesis of 4- [bis (4-fluorophenyl) methyl] -N- (4-methoxybenzyl) -1 -carboxyamidepiperazine ST3420

The compound of example 23 was prepared as described in example 3 starting from 4- (bis (4-fluorophenyl) methyl) piperazine and 4-methoxybenzyl isocyanate to give 0.039g of product (yield 52%)

LC-MS: ESI-MS m / z 452 [M + H] <+>. HPLC Column Luna C-18 (3.5pm) 4.6x250mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min . from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 205-380nm, retention time: 16.2min,

Example 24

Synthesis of 4- (1.3-benzodioxol-5-methyl) -N- (2-phenylethyl) -1-carboxyamide-piperazine ST3421

The compound of example 24 was prepared as described in example 3 starting from 4- (1, 3-benzodioxol-5-methyl) piperazine and 2-phenylethyl isocyanate to give 0.053g of product (yield 86%)

ESI-MS m / z 368 [M + H] <+>, 390 [M + Na] <+>. HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H20 in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 15.4min ,.

Example 25

Synthesis of 4- (1,3-benzodioxol-5-methyl) -N- (4-ethylphenyl) -1-carboxiamide-piperazine ST3422

The compound of example 25 was prepared as described in example 3 starting from 4- (1,3-benzodioxolo-5-methyl) piperazine and 4-ethylphenyl isocyanate to give 0.053g of product (yield 86%)

ESI-MS m / z 368 [M + H] <+> 390 [M + Na] <+>. HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 17.3min

Example 26

Synthesis of 4- (1.3-benzodioxol-5-methyl) -N- (4-heptyloxyphenyl) -1-carboxyiamidepiperazine ST3423

The compound of example 26 was prepared as described in example 3 starting from 4- (1,3-benzodioxolo-5-methyl) piperazine and 4-heptyloxyphenyl isocyanate to give 0.062g of product (yield 82%)

ESI-MS m / z 454 [M + H] <+>, 476 [M + Na] <+>. HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 23.9min,

Example 27

Synthesis of 4- (1,3-benzodioxol-5-methyl) -N- (4-methoxybenzyl) -1-carboxyiamidepiperazine ST3424

The compound of example 27 was prepared as described in example 3 starting from 4- (1,3-benzodioxolo-5-methyl) piperazine and 4-methoxybenzyl isocyanate to give 0.050g of product (yield 78%)

LC-MS: ESI-MS m / z 384 [M + H] <+>. HPLC Column Luna C-18 (3.5μm) 4.6x250mm, T = ambient, mobile phase CH3CN / H20 in linear gradient of 20 min . from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 205-380nm, retention time: 10.35min,

Example 28

Synthesis of 4- (1,3-benzodioxol-5-methyl-N- (4-chlorophenyl) -1-carboxyiamidepiperazine ST3425

The compound of example 28 was prepared as described in example 3 starting from 4- (1,3-benzodioxole-5-methyl) piperazine and 4-chlorophenyl isocyanate to give 0.052g of product (yield 83%)

ESI-MS m / z 374 [M + H] <+> HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 17min,

Example 29

Synthesis of 4- (1,3-benzodioxol-5-methyl) -N- (4-nitrophenyl) -1-carboxyiamidepiperazine ST3426

The compound of example 29 was prepared as described in example 3 starting from 4- (1,3-benzodioxolo-5-methyl) piperazine and 4-nitrophenyl isocyanate to give 0.041 g of product (yield 64%)

ESI-MS m / z 385 [M + H] <+> HPLC Symmetry C-18 column (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O in linear gradient of 20 min. from 10/90 to 80/20 (v / v), pH = as it is, flow = 1ml / min, U.V. 220 nm, retention time: 16.2min,

Example 30

Synthesis of 4- (2,3,4-trimethoxybenzyl) -N- (4-heptyloxyphenyl) -1-carboxiamide-piperazine ST3428

The compound of example 30 was prepared as described in example 3 starting from 4- (2,3,4-trimethoxybenzytes) piperazine and 4-heptyloxyphenyl isocyanate to give 0.082g of product (yield 75%)

ESI-MS m / z 500 [M + H] <+> HPLC Symmetry Column C-18 (3.5μm) 4.6x75mm, T = ambient, mobile phase CH3CN / H2O 70/30 (v / v), pH = as it is, flow = 1ml / min, U.V. 220nm, retention time: 5.06min, TLC silica gel with eluent CHCL3 / CH3OH 99/1, Rf = 0.22

Example 31

Synthesis of 4- (2.3.4-trimethoxybenzyl) -N- (2-phenylethyl) -1 -carboxyamide-piperazine ST3519

The compound of example 31 was prepared as described in example 3 starting from 4- (2,3,4-trimethoxybenzyl) piperazine and 2-phenylethyl isocyanate to give 0.030 g of product (yield 90%)

ESI-MS m / z 414 [M + H] <+>, 436 [M + Na] <+>. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = environment, mobile phase CH3CN / H2O 60/40 (v / v), pH = as it is, flow = 0.75ml / min, U.V. 220nm, retention time: 2.7min, Example 32

Synthesis of 4- (2.3.4-trimethoxybenzyl) -N- (4-ethylphenyl) -1-carboxyamide-piperazine ST3520

The compound of Example 32 was prepared as described in Example 3 starting from 4- (2,3,4-trimethoxybenzyl) piperazine and 4-ethylphenyl isocyanate to give 0.032g of product (yield 96%)

ESI-MS m / z 414 [M + H] <+> 436 [M + Na] <+>. HPLC Column Symmetry C-18 (3,5μm) 4,6x75mm, T = environment, mobile phase CH3CN / H2O 60/40 (v / v), pH = as it is, flow = 0,6ml / min, U.V. 220nm, retention time: 3.6min,

Example 33

Synthesis of 4- (2,3,4trimethoxybenzyl) -N- (4-nitrophenyl) -1-carboxyamide-piperazine ST3521

The compound of example 33 was prepared as described in example 3 starting from 4- (2,3,4-trimethoxybenzyl) piperazine and 4-nitrophenyl isocyanate to give 0.030g; 0.074mmoles of product (yield 91%). ESI-MS m / z 430 [M + Na] <+>. HPLC Column Symmetry C-18 (3,5μm) 4,6x75mm, T = environment, mobile phase CH3CN / H2O 60/40 (v / v), pH = as it is, flow = 0,6ml / min, U.V. 220nm, retention time: 3.0min,

Example 34

Synthesis of 4- (2,3,4-trimethoxybenzyl) -N- (4-methoxybenzyl) -1 -carboxyamidepiperazine ST3522

The compound of example 34 was prepared as described in example 3 starting from 4- (2,3,4-trimethoxybenzyl) piperazine and 4-methoxybenzyl isocyanate to give 0.033g of product (yield 85%)

ESI-MS m / z 430 [M + H] <+> 452 [M + Na] <+>. HPLC Column Symmetry C-18 (3,5μm) 4,6x75mm, T = environment, mobile phase CH3CN / H2O 60/40 (v / v), pH = as it is, flow = 0,6ml / min, U.V. 220 nm, retention time: 2.4min, Example 35

Synthesis of 4- (2,3,4-trimethoxybenzyl) -N- (4-chlorophenyl) -1 -carboxyamide-piperazine ST3414

The compound of example 35 was prepared as described in example 3 starting from 4- (2,3,4-trimethoxybenzyl) piperazine and 4-chlorophenyl isocyanate to give 0.033g of product (yield 83%)

ESI-MS m / z 420 [M + H] <+>, 442 [M + Na] <+>. HPLC Column Symmetry C-18 (3.5μm) 4.6x75mm, T = environment, mobile phase CH3CN / H2O 60/40 (v / v), pH = as it is, flow = 0.75ml / min, U.V. 220nm, retention time: 2.7min, DETERMINATION OF THE PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS

FORMULA (I)

Test 1: Determination of the inhibitory activity of CPT

Inhibition of CPT was evaluated on fresh mitochondrial preparations obtained from liver or heart of normally fed Fischer rats; mitochondria taken from the liver or heart are suspended in 75 mM sucrose buffer, 1 mM EGTA, pH 7.5. 100 μl of a mitochondrial suspension, containing 50 μΜ of [<14> C] palmitoyl-CoA (specific att. 10000 DPM / mole) and 10 mM of L-carnitine, are incubated at 37 ° C in the presence of scalar concentrations ( 0-3 mM) of product concerned.

Reaction time: 1 minute.

The IC50 is then determined.

Test 2: Determination of oleate-stimulated β-hydroxybutyrate production The synthesis of β-hydroxybutyrate indicates CPT activity. In fact, the production of ketone bodies, terminal products of mitochondrial beta-oxidation, is linked to the activity of CPT.

Preparations of hepatocytes obtained according to the described technique are used Venerando R. et al. (1994) Am. J. Physiol. 266: C455-C461]

Hepatocytes are incubated at 37 ° C in KRB bicarbonate buffer at pH 7.4, 6 mM glucose, 1% BSA in an O2 / CO295 / 5% atmosphere at a concentration of 2.5 x 10 <6> cells / ml. After a pre-incubation of 40 min. with the compound to be tested at different concentrations, the first series of samples (Tomin) is taken and the oleate is added (1 mM final in KRB BSA 1.4%). After 20 min the second sampling is made (T20min)

Test 3: B-hydroxy butyrate in the serum of treated rats

Fischer rats, fed normally, are fasted for 24 hours and subsequently treated with the compounds under examination. One hour after treatment, the animals are sacrificed and the serum concentrations of β-hydroxy butyrate are determined.

Other Tests

The ability of these compounds to pass the blood brain barrier in rats or mice after oral or intravenous administration is measured on brain homogenates using HPLC-MS techniques.

Furthermore, the evaluation of food consumption after oral or intravenous administration is determined on rats with access to free or timed food, for acute or fasted administration.

Finally, the lowering of blood glucose by oral or intracerebroventricular administration is measured in diabetic mice, for example db / db mice.

Claims (47)

CLAIMS 1. Compounds in the racemic form (R, S) or in their enantiomeric forms R and S, and their pharmacologically acceptable salts, having the structure described by formula (I): where is it: A is a monovalent group selected from the comprising group saturated or unsaturated linear or branched C1-C15 alkyl, optionally substituted with an aryloxy group, in turn optionally substituted with halogen or alkyl or alkoxy (C1-C10); n is selected from 0, 1, 2 and 3; R and R ', the same or different from each other, are selected from the group comprising H, C1-C8 alkyl, C1-C8 alkoxy, nitro, halogen; R1 = H, -CH2-CH (C5-C6 cycloalkyl) 2 X is selected from CH2, NR2; R2 is selected from the group comprising CH- (PhR3, R4, R5) 2, -CH2PhR3, R4, R5, -COPhR3, R4, R5, - (CH2) q-S-PhR3, R4, R5, -CH2COheterocycle (C5-C6) , CO heterocycleC5-C6, - (CH2) SCH3, -CH2cycloalkyl; R3, R4 and R5, the same or different from each other, are selected from the group comprising H, OH, halogen, C1-C4 alkoxy, linear or branched C1-C4 alkyl; or R3 and R4 together form an alkylidene (C1-C4) -dioxy group; Y is selected from (CH2) q-O and (CH2) qNH; q is chosen from 1, 2 and 3; m is chosen between 0 and 1. 2. Compounds according to claim 1, where A is the group, where R is H, R 'is methoxy and n is 0. Compounds according to claim 1, where X is NR2, R2 is the group -CH2PhR3, R4, R5 and R3, R4, R5, equal to each other, are methoxy. 4. Compounds according to claim 3, where X is CH2, R1 is the -CH2CH (cycloalkylC5-C6) 2 group and m is 0. 5. Compounds according to claims 3 or 4, where m is 1, Y is the (CH2) q-O group and q is 2. 6. A compound according to claim 1 which is 2- [4- (2,3,4 trimethoxybenzyl) piperazin-1-yl] ethyl- (2-phenylethyl) carbamate. 7. A compound according to claim 1 which is 2- [2- (2,2dicyclohexylethylpiperidin-1 -yl] ethyl (4-butylphenyl) carbamate. 8. A compound according to claim 1 which is 4-benzyl-N- (2-phenylethyl) -1-carboxamide-piperazine. 9. A compound according to claim 1 which is 4-benzyl-N- (4-fluorobenzyl) -1-carboxamide-piperazine. 10. A compound according to claim 1 which is 4-benzyl-N- (2,4-dichlorophenyl) -1-carboxamide-piperazine. 11. Compound according to claim 1 which is 4-benzyl-N- (4-ethylphenyl) -1-carboxamide-piperazine. The compound according to claim 1 which is 4-benzoyl-N- (2-phenylethyl) -1-carboxamide-piperazine. 13. Compound according to claim 1 which is 4-benzoyl-N- (4-fluorobenzyl) -1-carboxamide-piperazine. The compound according to claim 1 which is 2- (2, 2-dicyclohexylethyl) - N- (4-chlorophenyl) -1-carboxamide-piperidine. Compound according to claim 1 which is 2- (2,2-dicyclohexylethyl) - N- (4-butylphenyl) -1-carboxamide-piperidine. 16. Compound according to claim 1 which is 2- (2,2-dicyclohexylethyl) - N- (4-fluorobenzyl) -1-carboxamide-piperidine. 17. Compound according to claim 1 which is 4-benzoyl-N- (4-chlorophenyl) -1-carboxamide-piperazine. 18. A compound according to claim 1 which is 4-benzoyl-N- (2,4-dichlorophenyl) -1 -carboxamide-piperazine. 19. Compound according to claim 1 which is 2- (2, 2-dicycloesis letyl) - N- (2-phenylethyl) -1-carboxamide-piperidine. 20. A compound according to claim 1 which is 2- (2,2-dicyclohexylethyl) - N- (4-ethylphenyl) -1-carboxamide-piperidine. 21. Compound according to claim 1 which is 2- (2,2-dicyclohexylethyl) - N- (4-heptyloxyphenyl) -1-carboxamide-piperidine. 22. Compound according to claim 1 which is 2- (2,2-dicyclohexylethyl) - N- (4-methoxybenzyl) -1-carboxamide-piperidine. 23. Compound according to claim 1 which is 2- (2,2-dicyclohexylethyl) - N- (4-nitrophenyl) -1-carboxamide-piperidine. 24. Compound according to claim 1 which is 4- [bis (4-fluorophenyl) methyl] -N- (2-phenylethyl) -1-carboxiamide-piperazine. 25. Compound according to claim 1 which is 4- [bis (4-fluorophenyl) methyl] -N- (2-ethylphenyl) -1-carboxyamide-piperazine. 26. Compound according to claim 1 which is 4- [bis (4-fluorophenyl) methyl] -N- (4-heptyloxyphenyl) -1-carboxiamide-piperazine. 27. Compound according to claim 1 which is 4- [bis (4-fluorophenyl) methyl] -N- (4-chlorophenyl) -1-carboxyamide-piperazine. 28. Compound according to claim 1 which is 4- [bis (4-fluorophenyl) methyl] -N- (4-methoxybenzyl) -1-carboxyamide-piperazine. 29. Compound according to claim 1 which is 4- (1,3-benzodioxol-5-methyl) -N- (2-phenylethyl) -1-carboxyamide-piperazine. 30. A compound according to claim 1 which is 4- (1,3-benzodioxol-5-methyl) -N- (4-ethylphenyl) -1-carboxyamide-piperazine. 31. A compound according to claim 1 which is 4- (1,3-benzodioxole-5-methyl) -N- (4-heptyloxyphenyl) -1-carboxyamide-piperazine. 32. Compound according to claim 1 which is 4- (1,3-benzodioxole-5-methyl) -N- (4-methoxybenzyl) -1-carboxyamide-piperazine. 33. A compound according to claim 1 which is 4- (1,3-benzodioxole-5-methyl) -N- (4-chlorophenyl) -1-carboxyamide-piperazine. 34. A compound according to claim 1 which is 4- (1,3-benzodioxol-5-methyl) -N- (4-nitrophenyl) -1-carboxiamide-piperazine. 35. Compound according to claim 1 which is 4- (2,3,4-trimethoxybenzyl) -N- (4-heptyloxyphenyl) -1-carboxyamide-piperazine. 36. A compound according to claim 1 which is 4- (2,3,4-trimethoxybenzyl) -N- (2-phenylethyl) -1-carboxiamide-piperazine. 37. A compound according to claim 1 which is 4- (2,3,4-trimethoxybenzyl) -N- (4-ethylphenyl) -1-carboxyamide-piperazine. 38. Compound according to claim 1 which is 4- (2,3,4-trimethoxybenzyl) -N- (4-nitrophenyl) -1-carboxiamide-piperazine. 39. Compound according to claim 1 which is 4- (2,3,4-trimethoxybenzyl) - N- (4-methoxybenzyl) -1-carboxyamide-piperazine. 40. A compound according to claim 1 which is 4- (2,3,4-trimethoxybenzyl) -N- (4-chlorophenyl) -1-carboxyamide-piperazine. 41. Compounds according to claims 1 to 40, for use in therapy. 42. Pharmaceutical composition containing as active principle one or more of the compounds according to claims 1 to 40 in association with pharmaceutically acceptable excipients and / or diluents. 43. Use of the compounds according to claims 1 to 40 for the preparation of a medicament for the treatment of pathologies linked to a hyperactivity of carnitine palmitoyl transferase. 44. Use according to claim 43, for the prevention and treatment of obesity, hyperglycemia, diabetes and related diseases, and congestive heart failure. 45. Process for the preparation of the compounds according to claims 1 to 40. 46. Process according to claim 45 in accordance with the following Scheme A 47. Process for the preparation of the pharmaceutical compositions according to claim 42 comprising the mixing of one or more compounds according to claims 1 to 40 with pharmaceutically acceptable excipients and / or diluents.