FR2640970A1 - "Z"-1-Phenyl-2-(aminomethyl)cyclopropanecarboxamide derivatives and their therapeutic application - Google Patents

Abstract

The invention relates to new derivatives of general formula I: in which: R represents hydrogen or a group where R3, R4, R5 and R6 are not simultaneously hydrogen atoms and where R3 represents: - hydrogen; - a linear or branched alkyl or hydroxyalkyl group containing from 1 to 4 carbon atoms; - an aryl, arylalkyl or heteroarylalkyl group such as phenyl or 3-indolylmethyl, these groups being optionally hydroxylated, such as hydroxyphenyl or 3-(5-hydroxyindolyl), R4, R5 and R6 represent, independently of each other, hydrogen or a linear or branched alkyl radical containing from 1 to 4 carbon atoms, R1 and R2, which are identical or different, represent a linear or branched alkyl radical containing from 1 to 4 carbon atoms. The derivatives of general formula I are used alone or in combination with other active principles to prepare medicaments which can be used in the treatment of the central nervous system.

Description

The present invention, carried out at the PIERRE FABRE Research Center, relates to novel "Z" phenyl-1-aninomethyl-2-cyclopropane carboxamide derivatives, their preparation and their application in human therapy.

dans laquelle
R R représente l'hydrogène ou un groupement

ou R3, R4, R5' R6 ne sont pas simultanément des atomes d hydrogène et ou .R3 représente :
- l'hydrogène ,
- un groupement alcoyle ou hydroxy alcoyle linéaire ou ramifié
comportant de 1 à 4 atones de carbone,
- un groupe en aryle, erylalcoyle ou hétéro arylalcoyle tel que
phényl, indolyl-3 méthyl. éventuellement hyroxylés tels que
hydroxyphényl ou (hydroxy-5 indolyl)-3
.R4, R5, R6 représentent indépenda@ment les uns des autres l'hydrogène ou un radical alcoyl linéaire ou ramifié Comportant de 1 à 4 atones de carbone.The compounds of the present invention have the general formula I

in which
RR represents hydrogen or a group

or R3, R4, R5 'R6 are not simultaneously hydrogen atoms and or R3 represents:
- hydrogen,
a linear or branched alkyl or hydroxy alkyl group
with 1 to 4 carbon atoms,
a group of aryl, erylalkyl or heteroarylalkyl, such as
phenyl, 3-indolylmethyl. possibly hyroxylated such as
hydroxyphenyl or (5-hydroxy-indolyl) -3
R 4, R 5, R 6 independently of one another represent hydrogen or a linear or branched alkyl radical having 1 to 4 carbon atoms.

R 1 and R 2, which may be identical or different, represent a linear or branched alkyl radical containing from 1 to 4 carbon atoms.

In addition, the present invention covers, in the case of compounds having an asymmetric carbon at the R group, the "d" derivatives. "1" and the racemic mixtures as well as the therapeutically acceptable organic or mineral salts of the compounds of the invention
The preferred compounds of the present invention are those for which
R1 and R2 represent the ethyl radical. By way of non-limiting examples, mention may be made more particularly of the following compounds - 2-phenyl-2-formamidomethyl-NN diethyl cyclopropane carboxamide 1-2-phenyl-1 (D-valinylaminomethyl) -2 NN diethyl cyclopropane carboxamide, hydrochloride 2-Z phenyl-1 - [(α-dimethyl glycyl) aminomethyl] -2NN diethylcyclopropane carboxamide 3 -Z phenyl-1 (L tryptophanylaminomethyl) -2NN diethylcyclopropane carboxamide, fumarate 4 -Z phenyl-1 ( sarcosinyl aminomethyl) -2 NN diethylcyclopropane carboxamide, - hydrochloride 5-Z phenyl-1 - ((N, N-dimethyl glycyl) aminomethyl] 2 N N diethyl cyclopropane carboxamide, oxalate 6-Z phenyl-1 (L valinyl aminomethyl) -2 NN diethyl cyclopropane carboxamide fumarate 7-Z phenyl-1 (L-alanyl aminomethyl) -2 NN diethyl cyclopropane carboxamide 8-Z phenyl-1 (L phenyl glycyl aminomethyl) -2 NN diethyl cyclopropane carboxaeide, hydrochloride 2
The present invention also relates to the preparation of the compounds of formula I according to one of the following processes, starting from corresponding "Z" -phenyl-1-aminomethyl-2-cyclopropane carboxamide II obtained according to known methods.

2) Les composés de formule I dans lesquels R est différent de H peuvent être obtenus å partir des composés II
a) par couplage avec un amine acide N protégé et activé sous des for es telles que chlorure d'acide ou anhydride sixte puis déprotection pour régénérer la fonction amine terminale.On pourra choisir parmi les formes de protections, à titre d'exemple
- les dérivés phtaloyl, pouvant etre déprotégés par hydrazinolyse,
- les dérivés butyloxycarbonyl déprotégés Dar l'acide trifluoroacétique,
- les dérivés benzyloxycarbonyl @éprotégés par hydrogénolyse
b) par réaction avec un halogénure d'o halogénoacyle III puis traitement par une amine IV

1) The compounds of formula I, wherein R = H can be obtained by treating with fornicic acid in the presence of a dehydrating agent such as dicyclohexylcarbodiimide in an organic solvent such as chloroform

2) The compounds of formula I wherein R is other than H can be obtained from compounds II
a) by coupling with a protected and activated N-amine acid under such forms as acid chloride or anhydride sixth and then deprotection to regenerate the amine terminal function. We can choose among the forms of protections, for example
phthaloyl derivatives, which can be deprotected by hydrazinolysis,
the butyloxycarbonyl derivatives deprotected with trifluoroacetic acid,
the benzyloxycarbonyl derivatives which have been hydrogenolysis-challenged
b) by reaction with a haloacyl halide III and then treatment with an amine IV

the substituents R 1, R 2, R 3, R 4 and R 5 having the same meaning as above
R6 has the same meaning as above or represents a benzyl radical which can be removed by hydrogenolysis to give the secondary amine (R6 = H)
- X and X 'identical or different represent a halogen atom such as bromine or chlorine.

The invention will be described hereinafter in more detail by way of the following nonlimiting examples
Example 1 "Z" phenyl-1 formamidomethyl-2 NN diethyl cyclopropane carboxamide 1
In the solution of 3.3 g (0.016 mol) of dicyclohexyl carbodiimide and 30 cm of anhydrous chloroform, with stirring in an ice bath, 16 cm3 (0.032 mol) of chloroformic solution of 2M formic acid are added dropwise.

To the white suspension obtained. add dropwise the solution of 1.97 g (0.008 sole) of "Z" phenyl-1-aminosethyl-2NN diethyl cyclopropane carboxamide and 20 cm3 of anhydrous chloroform. After stirring overnight at room temperature the solvent is removed under vacuum.

The residue is taken up in ether and the insoluble matter is filtered. The expected product crystallizes by concentration of the ether solution.

Weight i 1.5 g (68%)
TLC (silica Merck GF 254) Rf = 0.53 (chloroform-methanol-ammonia 90-9-1).

Example 2 "Z" phenyl-1 (sarcosinylaminomethyl) -2 NN diethyl cyclopropane carboxamide
8.47 g (0.03 mol) of 2-phenyl-2-aminomethyl-NN diethylcyclopropane carboxamide hydrochloride, 9.75 cm3 (0.07 mol) of triethylamine and 80 cm of anhydrous THF under stirring were suspended in the suspension. on an ice bath, drop the solution of 2.65 cc (0.03 mole) of chloroacetyl chloride and 10 cm3 of anhydrous THF. After stirring overnight at room temperature, the T1IF is removed under vacuum and the residue is taken up in ethyl acetate, washed with dilute hydrochloric acid. After drying over Na2SO4 and filtration, the solvent is removed in vacuo. The residual oil is purified on silica gel using 1% chloroform methanol as eluent. After crystallization from isopropyl ether, 5.12 g (53%) of "Z" phenyl-1-chloroacetylaminoiethyl-2NN diethylcyclopropane carboxamide is obtained.

Melting point: 112-114 C. IR (KBr): 1665. 1610 cm-1 (CO).

TLC (Merck Silica GF 254) Rf t 0.56 (toluene 70, dioxane 25, acetic acid 5).

The addition of 2.5 g (0.0077 mol) of "Z" 1-phenyl-2-chloroacetylaminomethyl-NN diethyl cyclopropane carboxamide, 1 g (0.0082 mol) N methylbenzylamine, 1.4 g (0.01 mol) K 2 CO 3 and 20 cm3 of anhydrous methyl ethyl ketone is kept under reflux with stirring for 5 hours.

After return to room temperature. the suspension is filtered and the water-meres are brought to dryness under vacuum. The residue obtained is extracted with dilute hydrochloric acid. The aqueous solution is washed with ether, basified with NaOH (C) and extracted with ethyl acetate.

After washing with water, drying over Na 2 SO 4 and filtering, the solvent is removed in vacuo and the residue is purified on silicagel using chloroform with 1 ml of eluent methanol.

The deprotection of the benzyl group is carried out by hydrogen in an ethanolic medium (acidic pH) in the presence of palladium on carbon.

After removal of the catalyst and usual treatment, the product is isolated as hydrochloride.

Weight: 1.8 g (59%)
TLC (silica GF Merck 254) Rf = 0.33 (chloroform 90 - methanol 9 - NH 4 OH).

Example 3 - Z phenyl-1 (L valinylaminosethyl) -2 NN diethylcyclopropane carboxamide. fumarate 7
In the solution of 4.9 g (0.0225 mol) of N-tertbutoxycarbonyl-L-valine, 4.12 cm3 (0.0375 mol) of N-methyl morpholine and 100 cm3 of anhydrous THF, with stirring on an ice-bath, introduce dropwise 2.55 g (0.021 mol) of isoprenyl chloroformate. To the suspension obtained, 4.25 g (0.015 mole) of "Z" -hydrochloride-1-phenyl-2-aminomethyl-NN diethylcyclopropane carboxamide (prepared according to patent FR 2,581,059) are added and the suspension obtained is stirred for 15 hours at room temperature. The THF is removed in vacuo, the residue is taken up in ethyl acetate, washed with water, with N HCl, with water, with 5N CO 3 NaH and then with water. After drying over Na2SO4 and filtration, the solvent is removed in vacuo and the residual oil is purified on silica gel using hexane / ethyl acetate (70/30) as eluent.

The oily residue obtained after removal of the solvent in vacuo is treated with 15 cm3 of trifluoroacetic acid for 4 hours at 25 ° C.

The trifluoroacetic acid is removed under vacuum and the residue is taken up in water. The aqueous solution alkalinized with NaOH (C) is extracted with ethyl acetate. After drying over Na2O4, filtration and solvent removal under vacuum, the residue is isolated under strong fumarate (ethanol-ether).

Weight: 2.77 g (40%) NCC (Merck GF 254 silica) Rf 0.51 (butanol-acetic acid-water 6-2-2).

Example 4
Z phenyl-1 (L-alanyl aminomethyl) -2 NN diethyl cyclopropane carboxamide 8
In the suspension of 4.25 g (0.015 mole) of "Z" phenyl-1-aminomethyl-2NN diethyl cyclopropane carboxamide hydrochloride, 4.9 cx3 (0.035 mole) of triethylamine and 50 cm3 of anhydrous THF with stirring on a bath of ice, dropwise drop the solution of 3.56 g (0.015 mole) of phthaloyl L alanyl chloride and 15 cc of anhydrous THF.

After stirring overnight at room temperature, the THF is removed under vacuum. The residue is taken up in water, extracted with ethyl acetate, washed with 0.5N HCl, with water, dried over Na 2 SO 4, filtered and dried to dryness in vacuo.

The residual oil obtained is refluxed for 1 hour 45 in the presence of 1.5 cm (0.03 mol) of hydrazine hydrate and 70 cm 3 of ethanol. The ethanol is removed under vacuum and the crystalline mass is treated with 60 cm 3 of N HCl for 1 hour at room temperature. After filtration, the water-creatures are alkalinized with NaOH and extracted with ethyl acetate. After drying over Na 2 SO 4, filtration and removal of the solvent in vacuo, the oil obtained is crystallized from iso ether.

Weight: 3.5 g (73 X)
TLC (silica Nerck GF 254) R f = 0.68 (CHCl 3: 80, MeOH: 18, NH 4 OH: 2)
Example 5 "Z" phenyl-1 (L tryptophanyl aminomethyl) -2 NN diethyl cyclopropane carboxamide, fumarate 4
The solution of 8.4 g (0.0146 mol) of "Z" phenyl-1 (N Benzyloxy carbonyl
2-tryptophanylaminomethyl) NN diethyl cyclopropane carboxamide (prepared according to the technique described in Example 3) and 100 cm3 of methanol is hydrogenolysed at atmospheric pressure and ambient temperature for 15 hours in the presence of 0.5 g of Pd / C at 10 ° C. %. After filtration of the catalyst and removal of the solvent, the product is purified on silica gel (chloroform / methanol as eluent) and isolated in the form of fumarate (ethanol-ether).

Weight: 4.48 g (56%)
TLC (Merck GF 254 silica) Rf = 0.59 (chloroform-methanol: 50-50).

The products, object of the invention and obtained according to the examples described above, are characterized by their spectroscopic properties, their elemental analysis and physicochemical properties summarized in Table I.

Table I

<tb> N <SEP> Formula <SEP> crude <SEP> PF <SEP> IR (KBr) <SEP>(&alpha;) D20 <SEP> (C. <SEP> solvent)
<tb> Mass <SEP> Molecular <SEP> (C) <SEP> C = O (cm-1)
<tb> 1 <SEP> C16H22N2O2 <SEP> 106-107 <SEP> 1600
<tb> 274.36 <SEP> 1665
<tb> 2 <SEP> C20H32ClN3O2 <SEP> 154-156 <SEP> 1600 <SEP> + <SEP> 33.6 <SEP> (2 <SEP>% <SEP> water)
<tb><SEP> 381.95 <SEP> 1665
<tb> 3 <SEP> C19H29N3O2 <SEP> 103-105 <SEP> 1610
<tb> 331.45 <SEP> 1660
<tb> 4 <SEP> C30H36N4O6 <SEP> 140-150 <SEP> 1600
<tb> 548.65 <SEP> 1665 <SEP> + <SEP> 12.4 <SEP> (2 <SEP>% <SEP> ethanol)
<tb> 1700
<tb> 1 <SEP> 5 <SEP> 1 <SEP> C18H28ClN3O2 <SEP> 1158-160 <SEP>#<SEP><SEP> 1605 <SEP> l <SEP> l <SEP>
<tb> 353.9 <SEP> 1665
<tb> 6 <SEP> C21H31N3O6 <SEP> Amorphous <SEP> 1600
<tb> 421.48 <SEP> 1665
<tb> | <SEP> 7 <SEP> C24H35N306 <SEQ> 1124-126 <SEP> 1 <SEP> 1610 <SEP> I
<tb> I <SEP> I <SEP> 461.57 <SEP> I <SEP> 1 <SEP> 1665 <SEP>#<SEP><SEP> -2.5 <SEP> (2 <SEP>% <SEP> water) <SEP> I
<tb> I <SEP> I <SEP> I <SEP> I <SEP> 1700 <SEP> 1 <SEP> I
<tb> I <SEP> 1 <SEP> 1 <SEP> | <SEP> I
<tb> 8 <SEP> C18H27N3O2 <SEP> 92-96 <SEP> 1605 <SEP> -7.5 <SEP> (2% <SEP> water)
<tb> I <SEP>#<SEP><SEP> 317.42 <SEP> 1 <SEP> 1 <SEP><SEP> 1660 <SEP> 1 <SEP> I
<tb> 9 <SEP> C23H30ClN3O2 <SEP> 175-180 <SEP> 1600 <SEP> +4.8 <SEP> (2 <SEP>% <SEP> water)
<tb> 415.97
<Tb>
experiments
Pharmacological experiments have shown remarkable antidepressant properties.

Hereinafter, the results obtained with certain products of the present invention are compared by way of example with imiprAmine on the Quinton yohimbine test (Br. J. Pharmacol.

1963, 21, 56) in mice.

The ED50 values correspond to the oral dose that kills half of the animals that received a sublethal dose of yohimbine (25 mg / kg).

DE50 (mg / kg)
1 1.9
3 2.9
4 7.2
6 8
7 3.45
8 3.1
imipramine 7
Therapeutic applications
Given their pharmacological properties, the compounds of the present invention can be used in the treatment of various diseases of the central nervous system and more particularly depression and anxiety.

Pharmaceutical preparations containing these active ingredients can be administered orally.

 It is also possible to combine other pharmaceutically active and therapeutically acceptable active ingredients.

Claims (12)

claims 1 - As new chemical compounds, derivatives of "Z" phenyl-1-aminomethyl-2-cyclopropane carboxamides corresponding to the general formula I:

 in which - R represents hydrogen or a grouping

 or R3, R4, R5, R6 are not simultaneously hydrogen atoms and where R3 represents  - hydrogen,  a linear or branched alkyl or hydroxy alkyl group  having 1 to 4 carbon atoms,  an aryl, arylalkyl or hetero arylalkyl group, such as  phenyl, 3-indolyl, possibly hyroxylated, such as  hydroxyphenyl or (5-hydroxy-indolyl) -3. R4, R5 and R6 independently of one another represent hydrogen or a linear or branched alkyl radical containing from 1 to 4 carbon atoms - R1 and R2, which may be identical or different, represent a linear or branched alkyl radical having from 1 to 4 carbon atoms; carbon atoms their therapeutically acceptable organic or inorganic salts and, in the case of compounds having an asymmetric carbon at R, the derivatives "d", "1" or the racemic mixture. 2 - A compound according to claim 1 characterized in that R1 and R2 are ethyl groups. 3 - A compound according to claims 1 and 2 characterized in that it is selected from - 2-phenyl-2-formamidomethyl NN diethyl cyclopropane carboxamide 1 - 2-phenyl-2 (D-valinylaminomethyl) -2 NN diethyl cyclopropane carboxamide, hydrochloride 2 1-phenyl-1 E (dimethyl glycyl) aminomethyl-2 NN diethyl cyclopropane carboxamide 3-2-phenyl-1 (L-tryptophanyl aminomethyl) -2 NN diethyl cyclopropane carboxamide, fumarate 4-Z phenyl-1 (sarcosinyl aminomethyl) -2NN diethyl cyclopropane carboxamide, hydrochloride 5-Z phenyl-1 E (N, N-dimethyl glycyl) aminomethyl] 2 N N diethyl cyclopropane carboxamide, oxalate 6-Z phenyl-1 (L valinyl aminomethyl) -2 N N diethyl cyclopropane carboxamide, fumarate 7-Z phenyl 1 - (L-alanyl aminomethyl) -2 N N diethyl cyclopropane carboxamide 8-Z phenyl-1 (L phenyl glycyl aminomethyl) -2 NN diethyl cyclopropane carboxamide, hydrochloride 2 4 - A process for the preparation of chemical compounds according to one of claims 1 , 2, 3 and wherein R = H, characterized in that a "2-phenyl-1-aminomethyl-NN dialkyl cyclopropane carboxamide is treated with formic acid in the presence of a dehydrating agent. 5 - A process for the preparation of the chemical compounds according to one of claims 1, 2 and 3 and wherein R is different from H, characterized in that one treatment a "Z" phenyl-1 amino-2-ethyl NN dialkyl cyclopropane carboxamide with a protected and activated N-amino acid, and deprotecting the N-terminal function. 6 - A preparation method according to claim 5 characterized in that the amino acid is protected by a butyloxycarbonyl group and the deprotection carried out by treatment with trifluoroacetic acid. 7 - A method of preparation according to claim 5 characterized in that the amino acid is protected by a benzyloxycarbonyl group and the deprotection carried out by hydrogenolysis. 8 - A method of preparation according to claim 5 characterized in that the amino acid is protected by a phthaloyl group and the deprotection carried out by treatment with hydrazine. 9 - A method of preparation according to claim 5 characterized in that the amino acid can be activated under strong acid chloride or mixed anhydride. - A process for the preparation of the chemical compounds according to one of claims 1, 2 and 3 and wherein R is different from H, characterized in that one treated with a "Z" phenyl-1-aminomethyl-2NN dialkyl cyclopropane carboxamide with a haloalkyl halide III

  then by an amine IV, the substituents R1, R2, R3, R4, R5, R6 having the same meaning as in claim 1 and R6 may further represent a benzyl radical which can be removed by catalytic hydrogenation. X and X 'identical or different represent a halogen such as chlorine or bromine. 11 - As new drugs useful in human therapy, the compounds according to one of claims 1, 2 and 3. 12 - As new drugs useful in the treatment of disorders of the central nervous system, the compounds according to one of claims 1, 2 and 3. 13 - Pharmaceutical compositions characterized in that they contain as active ingredient at least one derivative according to claims 1, 2 and 3, associated with a pharmaceutically acceptable carrier.