FR2485008A1 - PROCESS FOR THE PRODUCTION OF N- (4 PYRIDYLMETHYL) -BENZAMIDES, COMPOUNDS OBTAINED AND APPLICATION AS DRUGS - Google Patents

Abstract

N- (4-PYRIDYLMETHYL) -BENZAMIDES OF FORMULA: (CF DRAWING IN BOPI) IN WHICH X AND Y, IDENTICAL OR DIFFERENT, EACH REPRESENT A HYDROGEN ATOM, OR A HALOGEN, HYDROXYL, NITRO OR ALKIFER GROUP 1 TO 4ATOMS OF CARBON, ALCOXY WITH 1 TO 4ATOMS OF CARBON, ALKYLTHIO WITH 1 TO 4ATOMS OF CARBON, DIALKYLAMINO WITH 1 TO 4ATOMS OF CARBON, ACYLAMINO WITH 1 TO 4ATOMS OF CARBON, SULFONYLAMENETHINYFLUONYLAMINYFUONYLAMINO, PHUONYLAMENHINO OUENOMYLAMINO. SAID COMPOUNDS ARE VERY POWERFUL NEUROLEPTIC AGENTS.

Description

The invention relates to a process for the industrial production of N- (4-

  pyridylmethyl) benzamides which are

  very powerful neuroleptic agents making them particularly

  interesting in therapeutics. The invention also relates to

  the compounds in question and their application as medicinal products. These compounds correspond to the formula:

O CONH-CH Q N

y Y

  where X and Y, identical or different, represent each

  each a hydrogen atom, a halogen, hydroxyl, nitro, linear or branched alkyl group with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms, carbon atoms, acylamino

  with 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoro-

methyl or phenylsulfonylamino.

  The method of the invention comprises the following operations:

  1. reaction of a substituted acid of formula

O 9 COOH

  X and Y have the above meanings with a 4-aminomethylpyridine of formula:

12 N-CH2 N.

  in the presence of a condensing agent in a suitable solvent

  and at a temperature between -80 C and the boiling point

the solvent itself;

  2. elimination of solid secondary products by

  after completion of the reaction; 3. evaporation of the solvent to dryness; 4. crystallization in a suitable solvent of the residue

formed by the desired product.

  Here are some examples that illustrate

  the invention without limiting it.

EXAMPLE I (X = 3-CH 3, Y = 5-CH 3)

  A mixture of 7.5 g (0.05 mole) of 3,5-dimethylbenzoic acid

  zoic acid, 5.4 g (0.05 mole) of 4-aminomethylpyridine and 100 ml

  Methylene chloride is introduced into a two-necked flask.

  bulbs with a capacity of 250 ml equipped with a thermometer, a calcium chloride tube, an ice bath and a magnetic stirrer. When the mixture is at 2 ° C., a solution of 10.3 g (0.05 mol) is added portionwise and with stirring.

  of dicyclohexylcarbodiimide in 25 ml of methylene chloride.

  Stirring is maintained between 0 and 5 C for 2 hours and the temperature is then allowed to rise to room temperature, allowing the reaction to proceed overnight with stirring. The dicyclohexylurea formed is filtered and washed

  with two 25 ml portions of methylene chloride each.

  The filtrate waters and the washings are evaporated to dryness and the solid residue is crystallized from ethyl acetate. N- (4-pyridylmethyl) -3,5-dimethylbenzamide

  has a melting point of 105-106 C.

Analysis Calculated for C15H16N20

C, 74.97; H, 6.71; NOT; 11.65

Find

C, 74.85; H, 6.70; N: 11.65

EXAMPLE 2 (X = 3-CH 3, Y = H)

  The operation is the same as in the previous example, but 0.05 mol of m-toluic acid and acetonitrile are used.

  as a solvent. Melting point = 104-105 ° C (dimethylformamide-water).

Analysis Calculated for C14H14N20

C, 74.31; H, 6.23; N: 12.38

Find

C, 74.50; H, 6.19; N: 12.35

  EXAMPLE 3 (X = 4-Butyl, Y = H) Same operation as in Example 1 using 0.05 mole of 4-tert-butylbenzoic acid and tetrahydrofuran

  as a solvent. Melting point: 129-130 ° C (benzene).

Analysis Calculated for C17H20N20

C, 76.08; H, 7.51; N: 10.44

Find

C, 75.81; H, 7.24; N: 10.15

EXAMPLE 4 (X = 4-CH 3 S, Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-thiomethoxybenzoic acid. Fusion point:

-152 C (ethanol-water).

Analysis Calculated for C14H14N20S

  C, 65.10; H, 5.46; N, 10.84; S: 12.41

Find

  C, 65.19; H, 5.23; N, 10.61; S: 12.21

EXAMPLE 5 (X = Y = H)

  Operation identical to that of example 1 using

  0.05 moles of benzoic acid. Melting point: 114-116 ° C (ethanol)

  water). Calculated Analysis for Cr3H13N2O

C, 73.58; H, 5.66; N: 13.20

Find

C, 73.23; H, 5.71; N: 13.40

EXAMPLE 6 (X = 4-CH 3, Y = H)

  Operation identical to that of example 1 using

  0.05 moles of p-toluic acid. Melting point: 130-131 ° C (water).

Calculated for C14H14N2O

C, 74.31; H, 6.23; N: 12.38

Find

C, 74.09; H, 6.22; N: 12.21

EXAMPLE 7 (X = 2-CH 3, Y = H)

  Operation identical to that of example 1 using

  0.05 sol of o-toluic acid. Melting point: 146-148 ° C (water).

Analysis Calculated for C14H14N2O

C, 74.31; H, 6.23; N: 12.38

Find

C, 74.08; H, 6.31; N: 12.49

EXAMPLE 8 (X = 4-OCH 3, Y = H)

  Operation identical to that of example 1 using

  0.05 moles of anisic acid. Melting point: 138-140 ° C (water).

Analysis Calculated for C14H14N2O2

C, 69.57; H, 5.85; N: 11.45

Find

C, 69.40; H, 5.80; N: 11.56

EXAMPLE 9 (X = 4-OH; Y = H)

  Operation identical to that of Example 1 using 0.05 moles of 4-hydroxybenzoic acid. Melting point: 260 ° C (dimethylformamide-water). Analysis Calculated for C13H12N2O2

C, 68.40; H: 5.29; N: 12.27

Find

C, 68.46; H, 5.15; N: 12.14

EXAMPLE 10 (X = 4-NO 2, Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-nitrobenzoic acid. Melting point: 198-200 ° C (ethanol-water). Analysis Calculated for C13H11N303

C, 60.69; H, 4.31; N: 16.33

Find

C, 60.42; H, 4.18; N: 16.06

EXAMPLE 11 (X = 4-N (CH 3) 2; Y = H)

  Operation identical to that of Example t using 0.05 mole of 4-dimethylaminobenzoic acid. Fusion point:

  206-207 C (dimethylformamide-water). -

Analysis Calculated for C15H17N30

C, 70.56; H, 6.71; N: 16.45

Find

C, 70.31; H, 6.48; N: 16.22

EXAMPLE 12 (X = 4-CH3CONH, Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-acetylaminobenzoic acid. Fusion point:

233-235 C (water).

Analysis Calculated for C15H15N302

C, 66.89; H, 5.61; N: 15.60

Find

C, 66.70; H, 5.34; N: 15.48

EXAMPLE 13 (X = 4-SO 2 NH 2; Y = H)

  Operation identical to that of Example 1 using 0.05 moles of 4-sulfamoylbenzoic acid. Melting point: 235-237 ° C

(water).

Analysis Calculated for C13H113N303S

  C, 53.60; H, 4.49; N, 14.42; S: 10.90

Find

  C, 53.74; H, 4.61; N, 14.61; S: 10.64

EXAMPLE 14 (X = 4-C6H5; Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-phenylbenzoic acid. Melting point: 193-194 ° C (methanol-water). Analysis Calculated for C19H16N20

C, 79.14; H, 5.59; N: 9.71

Find

C, 79.10; H, 5.74; N: 9.59

EXAMPLE 15 (X = 4-C1; Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-chlorobenzoic acid. Melting point: 133-134 ° C (dimethylformamide-water). Analysis Calculated for C13H11N2OC1 C: 63.31; H, 4.46; N, 11.36; Cl, 14.36 Found C, 63.29; H, 4.61; N, 11.12; Cl: 14.44 EXAMPLE 16 (X = 3-Cl; Y = H) Same operation as in Example 1 using 0.05 moles of 3-chlorobenzoic acid Melting point: 88-90 ° C

(Ethanol-water).

  Analysis Calculated for C13H11N2OC1 C: 63.31; H, 4.46; N, 11.36; Found: 14.36 Found C, 63.19; H, 4.51; N, 11.16; Cl: 14.63

EXAMPLE 17 (X = 2-C1; Y = H)

  Operation identical to that of Example 1, using 0.05 mole of 2-chlorobenzoic acid. Melting point: 98-99 ° C (ethanol-water). Analysis Calculated for C13H11N2OCl C: 63.31; H, 4.46; N, 11.36; Found: 14.36 Found C, 63.12; H, 4.56; N, 11.16; Cl: 14.46

EXAMPLE 18 (X = Y = 3,5-C12)

  Operation identical to that of Example 1 using 0.05 moles of 3,5-dichlorobenzoic acid. Melting point: 144-146 ° C (dimethylformamide-water). Analysis Calculated for C13H10N2OC12 C: 55.51; H, 3.55; N, 9.96; Cl: 25.26 Found C-55.42; H, 3.36; N: 10.07; Cl: 25.54

EXAMPLE 19 (X = 4-F; Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-fluorobenzoic acid. Melting point: 88-90 ° C

  (ethyl acetate-petroleum ether).

Analysis Calculated for C13H11N20F

C, 67.82; H, 4.85; N: 12.17

Find

C, 67.73; H, 4.79; N: 11.89

EXAMPLE 20 (X = 4-CF 3, Y = H)

  Operation identical to that of Example 1 using 0.05 mole of 4-trifluoromethylbenzoic acid. Fusion point:

167-169 ° C (methanol).

Analysis Calculated for C14H11N2OF3

C, 60.00; H, 3.92; N: 10.00

Find

C, 60.27; H, 4.25; N: 10.05

EXAMPLE 21 (X = 4-C6H5-SO2NH, Y = H)

  Operation identical to that of example 1 using

  0.05 mole of 4-phenylsulfonylaminobenzoic acid. Point of departure

  180-181 ° C (ethyl acetate).

Analysis Calculated for C19H17N303S

  C, 62.11; H, 4.66; N, 11.43; S: 8.72

Find

  C, 62.22; H, 4.60; N, 11.45; S: 8.96

2-485008

PHARMACOLOGICAL STUDIES

  The product of Example 1 presented a spectrum of

  pharmacological activity similar to that of neuroleptics,

  characterized by a reduction in the motile activity

  a loss of reactivity as the dose is increased and by cataleptic immobilization at even higher doses. It is for this reason that the measure

  chosen to compare the effectiveness of the products of the examples

  above was the decrease in motile activity at a normal

  for all of them.

acute toxicity

  Swiss I.C.R. mice were used. albino.

  The products were administered intraperitoneally and the observation time was 72 hours, after which the mortality rate was evaluated in the different batches, the M 50

  calculated from these data. The results obtained

  are shown in the following table.

  Product of Example DL. <(I.p.) Mg / kg

1,266

2,271

3,114.7

4,259.3

417.8

6,364.4

7,510

8,345.7

9 1 277.7

350

he 300

12 333.8

13 1 314.1

---

16,219

17 ---

  Product of the example DL o (i.p.) Mg / kg

18,113

19,339.1

---

21> 1,500

Reduced motile activity

  Swiss I.C.R. mice were used. albino. Professionals-

  Drugs were administered intraperitoneally at a dose of 72 mg / kg, standard measurements of motile activity having been made beforehand. Fresh motile activity measurements are taken 30 minutes after dosing.

  products and the comparison of the control measures makes it possible

  ler the percentage reduction of motile activity. All measurements were performed with an automatic actinometer provided by Panlab using at least six measurements

  controls for each product and six measurements after administration.

  of the product and calculating the decrease in motile activity

  from the difference between the corresponding averages.

  The results obtained are shown in the following table.

  % reduction in motile activity at the product of the example dose of 72 mg / kg (i.p.)

1 99.6

2 97.5

3 97.5

4 87.6

----

6 56.3

7 90.4

8 72.9

9 98.3

85.1

11.93.6

12 99.8

13.90.2

14 ----

95.3

  Example Product -% reduction in motile activity at 72 mg / kg (i.p.) 99.2 97.6 98.7

  The invention thus provides novel compounds

  drugs, especially neuroleptics.

  Routes of administration are not critical and can

  vary according to the nature of the cases to be treated. The intraperitoneal route

  Ne is suitable. The dosage depends on the severity of the

  disease-or disorder to be treated, as well as the selected compound.

  For the purpose of application, the new compounds can be used in pharmaceutical compositions with conventional vehicles suitable for administration. The formulation

  such compositions are within the reach of those skilled in the art.

Claims (8)

  1. Process for the industrial production of N- (4-   pyridylmethyl) -benzamides of the general formula: CONH-CH2 wherein X and Y, which may be identical or different, each represent a hydrogen atom, or a halogen, hydroxyl, nitro, linear or branched alkyl group with 1 to 4 carbon atoms,   alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms   carbon monoxide, dialkylamino with 1 to 4 carbon atoms, acylamino with 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoromethyl or phenylsulfonylamino, characterized in that: 1. a substituted acid of general formula is reacted: COOH   X y COOH Y o X and Y have the above meanings, with 4 aminomethylpyridine of formula: H2N-CH2 N   in the presence of a condensing agent in a suitable solvent   and at a temperature between -80 C and the boiling point   the solvent itself; 2. Solid secondary products are removed by filtration after completion of the reaction; 3. the solvent is evaporated to dryness; and 4. the residue formed by the desired product is crystallized a suitable solvent.   2. Method according to claim 1, characterized in that   dicyclohexylcarbodiimide is used as the densation.   3. Method according to one of claims 1 or 2, characterized   in that the solvent used is methylene chloride, acetonitrile, or tetrahydrofuran.   4. Method according to any one of the claims   1 to 3, characterized in that the substituted acid is the acid   3,5-dimethylbenzoic acid, m-toluic acid, 4-tert-butyl-   benzoic acid, 4-thiomethoxybenzoic acid, benzoic acid, ptoluic acid, o-toluic acid, anisic acid, acid   4-hydroxybenzoic acid, 4-nitrobenzoic acid, 4-dimethylacid   minobenzoic acid, 4-acetylaminobenzoic acid, 4-sulfamoyl   benzoic acid, 4-phenylbenzoic acid, 4-chlorobenzoic acid, 3-chlorobenzoic acid, 2-chlorobenzoic acid,   3,5-dichlorobenzoic acid, 4-fluorobenzoic acid, 4-tri-   fluoromethylbenzoic acid, or 4-phenylsulfonylaminobenzoic acid.   5. N- (4-pyridylmethyl) benzamides of the general formula: ONH-CH2 N   Wherein X and Y, which may be identical or different, each represents a hydrogen atom, or a halohydroxyl, nitro, linear or branched alkyl group with 1 to 4 carbon atoms, alkoxy group with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms, acylamino   with 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoro-   methyl or phenylsulfonylamino, provided that X and Y can not be   not be simultaneously methyl in positions 3 and 5.   6. Compounds obtained by the process according to any one that claims 1 to 4.   7. Application as medicaments of the compounds of   claim 5 or claim 6.   8. Neuroleptic drugs containing any one of   compounds of claims 6 or 7.