HK1101284B - Derivatives of alkylpiperazine-and alkylhomopiperazine-carboxylates, preparation method thereof and use of same as faah enzyme inhibitors - Google Patents

Description

Alkylpiperazine-and alkylpiperazine-carboxylate derivatives, method for the production thereof and use thereof as FAAH enzyme inhibitors

The present invention relates to alkylpiperazine-and alkylpiperazine carboxylate derivatives, their preparation and their use in therapy.

Known are phenyl alkyl carbamate, dioxane-2-alkyl carbamate and 1-piperazine-and 1-homopiperazine-carboxylate derivatives, described in documents WO 2004/067498A, WO 2004/020430 a and WO 2005/070910, respectively, which are FAAH enzyme (fatty acid amide hydrolase) inhibitors.

There is still a need to find and develop products that inhibit the FAAH enzyme. The compounds of the invention meet this object.

The compounds of the present invention have the general formula (I)

Wherein

n represents an integer of1 or 2;

p represents an integer of1 to 7;

a is selected from one or more groups of X, Y and/or Z;

x represents optionally substituted by one or two C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-a methylene group substituted with an alkylene group;

y represents optionally substituted by one or two C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3C substituted by alkylene groups₂-an alkenylene group; or C₂-an alkynylene group;

z represents a group of the formula:

o represents an integer of1 to 5;

r and s represent integers and are defined such that r + s is a number from 1 to 5;

g represents a single bond, an oxygen or sulfur atom or SO, SO₂C ═ O or ch (oh) groups;

R₁represents optionally substituted by one or more R₅And/or R₆Radical substituted R₄A group;

R₄represents a group selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, benzhydryl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, quinazolinyl, quinoxalyl, 2, 3-diazanaphthylA group of cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indanyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzooxadiazolyl, benzothiadiazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl;

R₅represents a halogen atom or a cyano group, a nitro group, C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy, C_1-6-sulfanyl radical, C_1-6-fluoroalkyl, C_1-6-fluoroalkoxy radical, C_1-6Fluorosulfanyl, NR₇R₈、NR₇COR₈、NR₇CO₂R₈、NR₇SO₂R₈、COR₇、CO₂R₇、CONR₇R₈、SO₂R₇、SO₂NR₇R₇R₈or-O- (C)_1-3Alkylene) -O groups;

R₆represents phenyl, phenoxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, R or R₆The radicals being optionally substituted by one or more identical or different R₅Substituted by groups;

R₇and R₈Independently of one another, represents a hydrogen atom or C_1-6Alkyl, or forms with the atom bearing them, chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azaAnd a ring of piperazine, optionally substituted by C_1-6-alkyl or benzyl substitution;

R₂represents a hydrogen atom or C_1-6-an alkyl group;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3-an alkyl group.

Thus, in the context of the present invention, the compounds of the general formula (I) may comprise two or more identical or different a groups.

In the compounds of general formula (I), the first subgroup of compounds consists of the following compounds:

n represents an integer of1 or 2;

p represents an integer of1 to 7;

a is selected from one or more groups of X and/or Y;

x represents optionally substituted by one or two C_1-6A methylene group substituted with an alkyl (more specifically, methyl) group;

y represents C₂An alkenylene group or C₂-an alkynylene group;

g represents a single bond, an oxygen atom or a C ═ O group;

R₁represents optionally substituted by one or more R₅And/or R₆Radical substituted R₄A group;

R₄represents a group selected from phenyl, naphthyl, benzhydryl, quinolyl, indolyl, pyrazolyl, isoxazolyl, pyrimidinyl, thiazolyl;

R₅represents a halogen atom (more particularly chlorine, fluorine, bromine or iodine) or a cyano group, C_1-6Alkyl (more particularly methyl, isopropyl or tert-butyl), C_1-6Alkoxy (more specifically methoxy), C_1-6Fluoroalkyl (more specifically trifluoromethyl), C_1-6-fluoroalkoxy (more specifically trifluoromethoxy), or-O- (C)_1-3Alkylene) -O group (more specifically-OCH₂O-)；

R₆Represents phenyl, naphthyl or benzyloxy;

R₂represents a hydrogen atom or C_1-6-an alkyl group;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-an alkyl group.

Among the compounds of general formula (I), the second subgroup of compounds consists of the following compounds:

n represents an integer of 1;

p represents an integer of1 to 4;

a is selected from one or more groups of X and/or Y;

x represents optionally substituted by one or two C_1-6A methylene group substituted with an alkyl (more specifically, methyl) group;

y represents C₂-an alkynylene group;

g represents a single bond or an oxygen atom;

R₁represents optionally substituted by one or more R₅And/or R₆Radical substituted R₄A group;

R₄represents a group selected from phenyl, naphthyl or isoxazolyl;

R₅represents a halogen atom (more particularly chlorine or fluorine) or a cyano group, C_1-6Alkoxy (more specifically methoxy), C_1-6-fluoroalkyl (more specifically trifluoromethyl);

R₆represents a phenyl group;

R₂represents a hydrogen atom or C_1-6-an alkyl group;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3-an alkyl group.

Among the compounds of general formula (I), the third subgroup of compounds consists of the following compounds: n, p, A, X, Y, Z, o, R, s, G, R₁、R₄、R₅、R₆、R₇And R₈As defined in general formula (I) or in the subgroups defined above;

R₂represents a hydrogen atom;

R₃represents a hydrogen atom or C_1-6Alkyl (more specifically methyl), C_3-7Cycloalkyl (more particularly cyclopropyl) or C_3-7-cycloalkyl-C_1-3-alkyl group (more specifically-CH)₂-cyclopropyl).

Among the compounds of general formula (I), the following compounds may be mentioned:

-2- (methylamino) -2-oxo (oxo) ethyl 4- (2-biphenyl-3-ylethyl) -piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- (2-biphenyl-4-ylethyl) -piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- [2- (1-naphthyl) ethyl ] -piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- {2- [3- (4-chlorophenyl) -isoxazol-5-yl ] ethyl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- {2- [5- (4-chlorophenyl) -isoxazol-3-yl ] ethyl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- (3-biphenyl-3-ylpropyl) -piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- (3-biphenyl-4-ylpropyl) -piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- (3-biphenyl-3-yl-1, 1-dimethylpropyl) piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (3' -chlorobiphenyl-3-yl) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (4' -chlorobiphenyl-3-yl) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (3' -methoxybiphenyl-3-yl) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (4' -methoxybiphenyl-3-yl) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (3' -chlorobiphenyl-4-yl) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (4' -chlorobiphenyl 4-yl) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (2-naphthyl) propyl ] -piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- {3- [5- (4-chlorophenyl) -isoxazol-3-yl ] propyl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- {3- [3- (4-chlorophenyl) -isoxazol-5-yl ] propyl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [4- (3-chlorophenyl) butyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [4- (4-chlorophenyl) butyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- {4- [3- (trifluoromethyl) -phenyl ] butyl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- {4- [4- (trifluoromethyl) phenyl ] butyl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- {4- [4- (trifluoromethyl) phenyl ] but-3-yn-1-yl } piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [5- (3-chlorophenyl) pent-4-yn-1-yl ] piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- [5- (2, 4-dichlorophenyl) pent-4-yn-1-yl ] piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- [5- (2, 5-dichlorophenyl) pent-4-yn-1-yl ] piperazine-1-carboxylic acid ester

-2- (methylamino) -2-oxoethyl 4- [5- (3, 4-dichlorophenyl) pent-4-yn-1-yl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [5- (3-chloro-4-fluorophenyl) pent-4-yn-1-yl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (2-chlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (3-chlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (4-chlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (2, 3-dichlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (2, 4-dichlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (2, 5-dichlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (2, 6-dichlorophenoxy) propyl ] piperazine-1-carboxylate

-2- (methylamino) -2-oxoethyl 4- [3- (3, 5-dichlorophenoxy) propyl ] piperazine-1-carboxylate.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may exist as enantiomers or diastereomers. The compounds of the general formula (I) may also exist in the form of cis (Z) or trans (E) stereoisomers. These stereoisomers, enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, are part of the present invention.

The compounds of formula (I) may be present in the form of base or acid addition salts. Such addition salts form part of the present invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids used, for example, for the purification or isolation of the compounds of formula (I) are likewise part of the invention.

The compounds of formula (I) may be in the form of hydrates or solvates, i.e. in association or combination with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the present invention.

In the context of the present invention, terms have the following meanings:

-C_t-z(wherein t and z may take values of1 to 7) is a carbon chain which may have from t to z carbon atoms; e.g. C_1-3Is a carbon chain which may have 1 to 3 carbon atoms;

-alkyl is a linear or branched saturated aliphatic group; e.g. C_1-6-alkyl represents a linear or branched carbon chain of1 to 6 carbon atoms, more specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl;

-alkylene is a linear or branched saturated divalent alkyl group; e.g. C_1-3Alkylene represents a linear or branched divalent carbon chain of1 to 3 carbon atoms, more particularly methylene, ethylene, 1-methylethylene, propylene;

-cycloalkyl is a cyclic alkyl group; e.g. C_3-7Cycloalkyl represents a cyclic carbonyl group of 3 to 7 carbon atoms, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;

-alkenylene is a divalent unsaturated aliphatic radical having 2 carbon atoms, more particularly ethylene;

-C₂-alkynylene is a-C ≡ C-group;

-alkoxy is-O-alkyl with a straight or branched saturated aliphatic chain;

alkylthio is-S-alkyl with a straight or branched saturated aliphatic chain;

-fluoroalkyl is an alkyl group in which one or more hydrogen atoms have been replaced by fluorine atoms;

-fluoroalkoxy is an alkoxy group in which one or more hydrogen atoms have been replaced by fluorine atoms;

a fluoroalkylthio group is an alkylthio group in which one or more hydrogen atoms have been replaced by fluorine atoms; and

-the halogen atom is fluorine, chlorine, bromine or iodine.

The compounds of the invention can be prepared according to different methods, as illustrated by the following schemes.

Thus according to the first method (scheme 1), the compounds of formula (I) can be reacted with amines of formula (IV) (wherein R is₁G, A, p and n are as defined in formula (I)) with a carbonate of formula (IIIa) (in which V represents a hydrogen atom or a nitro group, R₂As defined in formula (I) and R represents methyl or ethyl). The carbamate ester of the formula (II) thus obtained is then obtained by using the formula R₃NH₂Amine (wherein R is₃As defined in formula (I) to a compound of formula (I). The aminolysis reaction may be carried out in a solvent such as methanol or ethanol or in a mixture of solvents such as methanol and tetrahydrofuran.

Scheme 1

Another method (scheme) for obtaining the compounds of formula (I)FIG. 2) comprises piperazine or homopiperazine derivatives of the general formula (VII) wherein PG represents a protecting group such as t-butyloxycarbonyl (Boc) and carbonates of the general formula (IIIb) wherein V represents a hydrogen atom or a nitro group and R represents₂And R₃As defined in general formula (I), and then deprotecting the resulting compound in, for example, a solution of hydrochloric acid in a solvent such as isopropanol. By reaction with a derivative of the general formula (VI), followed by conversion of the thus obtained carbamate-amide of the general formula (V) to a compound of the general formula (I), wherein R₁G, p and A are as defined in formula (I) and W represents a chlorine, bromine or iodine atom or a methanesulphonate or toluenesulphonate group. The N-alkylation reaction may be carried out in a solvent such as acetonitrile or toluene in the presence of a base such as potassium carbonate or diisopropylethylamine.

Flow chart 2

Compounds of the general formulae (I), (II) and (IV) (wherein R₁Representing groups of the aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type) can also be prepared by corresponding compounds of the general formula (I), (II) or (IV) in which the group R should be introduced₆At position R of₄Substituted by a chlorine, bromine, iodine atom or a triflate group) with aryl-or heteroaryl-boronic acid derivatives according to the Suzuki reaction conditions (chem. rev.1995,952457-2483), or with aryl-or heteroaryl-trialkylstannane derivatives according to Stille reaction conditions (Angew. chem. int. Ed., 1986,25504-524).

The carbonates of the formulae (IIIa) and (IIIb) can be prepared by any of the methods described in the literature, for example by means of the alcohols HOCHR of the respective formulae in the presence of a base, for example triethylamine or diisopropylethylamine₂COOR (wherein R represents methyl or ethyl) or HOCHR₂CONHR₃(wherein R is₃As defined in formula (I), with chloromethylAcid phenyl ester or 4-nitrophenyl chloroformate.

When compounds of the formulae (IV), (VI) and (VII) and of the formula R are not described₃NH₂In the preparation of the amines of the general formulae (IV), (VI) and (VII) and of the general formula R₃NH₂The amines of (a) are commercially available or described in the literature or can be prepared according to various methods described in the literature or known to the person skilled in the art.

According to a further aspect of the invention, the invention likewise provides compounds of the general formulae (II) and (V). These compounds are useful as intermediates in the synthesis of compounds of formula (I).

The examples which follow illustrate the preparation of some of the compounds of the invention. These examples are not intended to be limiting and merely illustrate the invention. Microanalysis, IR and NMR spectroscopy and/or LC-MS (liquid chromatography coupled with mass spectrometry) determine the structure and purity of the resulting compound.

m.p. (° c) denotes melting point in degrees celsius.

The numbers indicated in parentheses in the title of the examples correspond to the numbers in the first column of the following tables.

Example 1 (Compound 85)

Trans-4- (3-phenylprop-2-en-1-yl) piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

1.1. Trans-4- (3-phenylprop-2-en-1-yl) piperazine-1-carboxylic acid 2- (ethoxy) -2-oxoethyl ester

A solution of 1.40g (6.93mmol) trans-1-cinnamyl piperazine and 1.74g (7.76mmol) ethyl { [ (phenoxy) carbonyl ] oxy } acetate (J.Med.chem., 1999, 42, 277-290) in 15ml toluene was heated at 80 ℃ overnight. It is evaporated to dryness and the residue is taken up in 50ml of ethyl acetate. Washed 2 times with 20ml of water and 1 time with 10ml of saturated aqueous sodium chloride solution. Dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (50/50) followed by ethyl acetate to give 0.814g of product as a pale yellow oil.

1.2. Trans-4- (3-phenylprop-2-en-1-yl) piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

0.8g (2.4mmol) of the 2- (ethoxy) -2-oxoethyl trans-4- (3-phenylprop-2-en-1-yl) piperazine-1-carboxylate obtained in step 1.1 are dissolved in 10ml of a 2M solution of methylamine (20mmol) in methanol. The solution was reacted at room temperature for 1.5 hours and then evaporated to dryness. The residue was chromatographed on silica gel, eluting with ethyl acetate then a mixture of ethyl acetate and methanol (90/10). 0.548g of a white powder was obtained. Melting Point (. degree. C.): 109-111.

LC-MS：M+H＝318

¹H NMR(DMSO-d₆): δ (ppm): 7.80 (width s, 1H); 7.50-7.15(m, 5H); 6.55(d, 1H); 6.25(td, 1H); 4.40(s, 2H); 3.40(m, 4H); 3.10(d, 2H); 2.60(d, 3H); 2.40(m, 4H)

Example 2 (Compound 99)

4- {3- [3- (trifluoromethyl) phenyl) prop-2-yn-1-yl } -1, 4-diaza-1-carboxylic acid 2-amino-2-oxoethyl ester

2.1.4- {3- [3- (trifluoromethyl) phenyl]Prop-2-yn-1-yl } -1, 4-diaza-1-Formaldehyde

1.28g (10mmol) of1, 4-diazaA mixture of-1-formaldehyde and 0.33g (11mmol) of paraformaldehyde in 13ml of dioxane was heated at 80 ℃ until a homogeneous solution was obtained. A solution of 1.70g (10mmol) of 3-trifluoromethylphenylacetylene in 7ml of dioxane and 1.81g (10mmol) of copper diacetate was added. The mixture was heated at 80 ℃ for 4 hours. It was cooled to room temperature and diluted with 75ml of ethyl acetate. The organic phase is washed with 25ml of 30% ammonia solution followed by saturated aqueous sodium chloride solution. Dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using 98/2/0.2 followed by 96/4/0.4 and 94/6/0.6 mixtures of dichloromethane, methanol and 30% aqueous ammonia to give 2.67g of a yellow oil.

2.2.4- {3- [3- (trifluoromethyl) phenyl]Prop-2-yn-1-yl } -1, 4-diaza

2.63g (8.48mmol) of 4- {3- [3- (trifluoromethyl) phenyl ] obtained in step 2.1]Prop-2-yn-1-yl } -l, 4-diaza-1-Formaldehyde was dissolved in 7.5ml of methanol. 3.5ml of 35% aqueous sodium hydroxide solution (30mmol) were added and the mixture was heated under reflux for 3 hours. It was cooled to room temperature. Diluted with 20ml of water and 75ml of dichloromethane. The phases were separated and the aqueous phase was extracted 2 times with 25ml dichloromethane. The organic phase is washed with 25ml of water and then with 25ml of saturated aqueous sodium chloride solution. Drying over sodium sulphate and evaporation to dryness gave 2.25g of a red oily product, which was used as such in the following step.

2.3.4- {3- [3- (trifluoromethyl) phenyl]Prop-2-yn-1-yl } -1, 4-diaza-1-carboxylic acid 2- (ethoxy) -2-oxoethyl ester

2.25g (7.95mmol) of 4- {3- [3- (trifluoromethyl) phenyl ] obtained in step 2.2]Prop-2-yn-1-yl } -1, 4-diazaAnd 2.68g (11.9mmol) of { [ (phenoxy) carbonyl]A solution of ethyl oxy } acetate in 10ml of toluene was heated at 60 ℃ overnight. 5g of silica (silica) are added and the mixture is evaporated to dryness. The residue was chromatographed on silica gel using 60/40, then 40/60 of a mixture of cyclohexane and ethyl acetate, then ethyl acetate to give 2.42g of product as an orange oil.

2.4.4- {3- [3- (trifluoromethyl) phenyl]Prop-2-yn-1-yl } -1, 4-diaza-1-carboxylic acid 2-amino-2-oxoethyl ester

0.77g (1.87mmol) of 4- {3- [3- (trifluoromethyl) phenyl ] obtained in step 2.3]Prop-2-yn-1-yl } -1, 4-diaza-1-Carboxylic acid 2- (ethoxy) -2-oxoethyl ester was dissolved in 14ml of a 7M solution of ammonia (98mmol) in methanol. The solution was reacted at room temperature overnight, then 2g of silica were added and evaporated to dryness. The residue was chromatographed on silica gel using 97/3/0.3 followed by 95/5/0.5 and 93/7/0.7 mixtures of dichloromethane, methanol and 30% aqueous ammonia. Followed by recrystallization from a mixture of ethyl acetate and diisopropyl ether to give 0.57g of white crystals.

Melting Point (. degree. C.): 102-104

LC-MS：M+H＝384

¹H NMR(CDCl₃)δ(ppm)：7.70(s，1H)；7.55(m，2H)；7.45(d, 1H); 6.15 (width m, 1H); 5.50 (width m, 1H); 4.65(s, 2H); 3.65(m + s, 6H); 2.85(m, 4H); 1.95(m, 2H).

Example 3 (Compound 130)

4- {2- [ (4-chlorophenyl) -oxy ] ethyl } piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

3.1.4-Nitrophenyl and 2- (methylamino) -2-oxoethyl carbonate

To a suspension of 2.62g (29.4mmol) of 2-hydroxy-N-methylacetamide and 16.5g (58.7mmol) of supported (supported ee) diisopropylethylamine (Ps-DIEA from Argonaut, loading 3.56mmol/g) in 250ml of dichloromethane were added 5.93g (29.4mmol) of 4-nitrophenylchloroformate in small portions at room temperature. Orbital stirring was continued for 16 hours at room temperature. The resin was filtered off and washed with 150ml dichloromethane and the filtrate was concentrated under reduced pressure. 6g of the product are obtained as a pale yellow solid, which is used as such in the following step.

3.2.1, 1-Dimethylethyl and 2- (methylamino) -2-oxoethylpiperazine-1, 4-dicarboxylate

To a solution of 1.1g (3mmol) of the 4-nitrophenyl and 2- (methylamino) -2-oxoethyl carbonate prepared in step 3.1, in 10ml of1, 2-dichloroethane cooled to 0 ℃ at about 0 ℃ is added dropwise a solution of 0.53g (2.85mmol) of1, 1-dimethylethyl piperazine-1-carboxylate in 5ml of1, 2-dichloroethane. Stirring was continued at 0 ℃ for 1 hour and then at room temperature for 3 hours.

The mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 20/80 of a mixture of ethyl acetate and cyclohexane, followed by a gradually increasing gradient and finally with ethyl acetate. The effluent was triturated in diisopropyl ether to give 0.61g of product as a white solid, which was used as such in the following step.

3.3. Piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester hydrochloride

To a solution of 2.68g (8.9mmol) of the 1, 1-dimethylethyl and 2- (methylamino) -2-oxoethylpiperazine-1, 4-dicarboxylate obtained in step 3.2 in 25ml of dichloromethane were added dropwise a solution of 25ml of 6N hydrochloric acid in isopropanol. Stirring was continued at room temperature for 1 hour. The organic phase was separated by filtration through a hydrophobic cartridge and concentrated under reduced pressure. Trituration in isopropanol afforded 2.05g of product.

Melting Point (. degree. C.): 167 deg.C and 169 deg.C

3.4.4- {2- [ (4-chlorophenyl) oxy ] ethyl } piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

A solution of 0.073g (0.3mmol) of 2- (methylamino) -2-oxoethyl ester hydrochloride piperazine-1-carboxylic acid prepared in step 3.3, 0.13g (0.9mmol) of potassium carbonate and 0.069g (0.29mmol) of 1- (2-bromoethoxy) -4-chlorobenzene in 3ml of acetonitrile was heated at 85 ℃ for 16 hours. After cooling to room temperature, the inorganic components are filtered off through a column containing the glass raw material and diatomaceous earth. The cartridge was rinsed with acetone and the filtrate was concentrated under reduced pressure. Chromatography on silica gel eluting with 95/5 mixtures of dichloromethane and methanol followed by crystallization from diisopropyl ether afforded 0.089g of the product as a white solid.

LC-MS：M+H＝356

Melting point: 159 ℃ plus 161 DEG C

¹H NMR(CDCl₃) δ (ppm): 7.25(dd, 2H); 6.85(dd, 2H); 6.05 (width s, 1H); 4.60(s, 2H); 4.10(t, 2H); 3.55(m, 4H); 2.90(d, 3H); 2.85(t, 2H); 2.60(m, 4H).

Example 4 (Compound 25)

4- (2-Naphthalen-2-ylethyl) -piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

To a solution of 0.13g (0.75mmol) of 2-naphthalen-2-ylethanol and 0.19ml (1.13mmol) of diisopropylethylamine in 7.5ml of dichloromethane cooled to 0 ℃ was added 0.07ml (0.9mmol) of methanesulfonyl chloride. Stirring was continued for 0.5 hour in a cooled state and then for 2 hours at room temperature. The solution was concentrated under reduced pressure.

The residue was taken up in 5ml of acetonitrile and 0.12g (0.5mmol) of 2- (methylamino) -2-oxoethyl ester hydrochloride piperazine-1-carboxylic acid prepared as in example 3.3 and 0.20g (1.5mmol) of potassium carbonate were added. The mixture was heated at 70 ℃ for 16 hours. After cooling to room temperature, it was concentrated under reduced pressure. The residue was suspended in dichloromethane and washed with saturated sodium bicarbonate solution and then with water. The organic phase was recovered by filtration over a hydrophobic membrane and concentrated under reduced pressure. Chromatography on silica gel eluting with 95/5 mixtures of dichloromethane and methanol followed by crystallization from diisopropyl ether afforded 0.069g of the product as a white solid.

LC-MS：M+H＝356

Melting point: 135 ℃ of 133-

¹H NMR(CDCl₃) δ (ppm): 7.85(m, 3H); 7.65(s, 1H)7.55-7.30(m, 3H); 6.05 (width s, 1H); 4.60(s, 2H); 3.55(m, 4H); 3.05-2.65(m, 7H); 2.55(m, 4H).

Example 5 (Compound 50)

4- (3-Biphenyl-3-yl-1, 1-dimethylpropyl) piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester hydrochloride

5.1.1- (2, 2-dimethylpropionyl-4- (1, 1-dimethylprop-2-yn-1-yl) piperazine

0.756g (6mmol) of1, 1-dimethylprop-2-yn-1-yl acetate (J.Org.chem.1994, 59, 2282-. The mixture was heated to reflux for 3 hours. After cooling to room temperature, 100ml of ethyl acetate, 10ml of a 1N aqueous sodium hydroxide solution and 2ml of 30% aqueous ammonia were added. The organic phase is separated off and washed 2 times with 10ml of water and then with 10ml of saturated aqueous sodium chloride solution. Dried over sodium sulfate and evaporated to dryness. The product was chromatographed on silica gel using 85/15, then eluting with a mixture of 75/25 and 65/35 of cyclohexane and ethyl acetate to give 1.19g (4.71mmol) of the product as a pale yellow solid.

Melting point: 106 ℃ to 109 DEG C

5.2.1- (3-Biphenyl-3-yl- [1, 1-dimethylprop-2-yn-1-yl) -4- (2, 2-dimethylpropionyl) piperazine

1.05g (4.5mmol) of 3-bromobiphenyl and 0.9g (3.6mmol) of 1- (2, 2-dimethylpropionyl) -4- (1, 1-dimethylpropan-2-yn-1-yl) piperazine prepared in step 5.1, 0.75ml (5.38mmol) of triethylamine and 0.028g (0.11mmol) of triphenylphosphine were dissolved in 8ml of tetrahydrofuran. Under an argon atmosphere, 0.126g (0.18mmol) of bis (triphenylphosphine) palladium dichloride complex was added. The mixture was stirred for 15 minutes, then 0.014g (0.07mmol) of cuprous iodide was added. The mixture was stirred at room temperature for 4 hours and then at 60 ℃ overnight. After cooling to temperature, it was diluted with 25ml of ethyl acetate and filtered on filter paper. The solid was washed 4 times with 10ml ethyl acetate. 4g of silica were added to the filtrate and evaporated to dryness. The residue was chromatographed on silica gel using 90/10, then eluting with a mixture of 80/20 and 70/30 of cyclohexane and ethyl acetate to give 0.90g (2.22mmol) of the product as an orange oil.

1, 1-Dimethylethyl ester of 4- (3-biphenyl-3-yl-1, 1-dimethylpropyl) piperazine-1-carboxylic acid

0.87g (2.15mmol) of 1- (3-biphenyl-3-yl-1, 1-dimethylprop-2-yn-1-yl) -4- (2, 2-dimethylpropanoyl) piperazine prepared in step 5.2 are dissolved in a mixture of 5ml methanol and 15ml ethyl acetate. 0.2g of platinum oxide was added and the mixture was stirred under a 40psi hydrogen atmosphere for 6 hours. Filter on filter paper and rinse the filtered product 3 times with 10ml ethyl acetate. 2g of silica were added to the filtrate and evaporated to dryness. The residue was chromatographed on silica gel using 90/10, then eluting with a mixture of 85/15 and 80/20 of cyclohexane and ethyl acetate to give 0.36g (0.88mmol) of the product as a colorless oil.

5.4.1- (3-Biphenyl-3-yl-1, 1-dimethylpropyl) -piperazine

0.65ml (8.4mmol) of trifluoroacetic acid are added to 0.35g (0.86mmol) in step

5.3. To a solution of1, 1-dimethylethyl 4- (3-biphenyl-3-yl-1, 1-dimethylpropyl) piperazine-1-carboxylate prepared in (1) in 5ml of dichloromethane. The mixture was stirred for 2 hours, then 0.65ml of trifluoroacetic acid was added. Stirring is continued for a further 2 hours, then diluted with 10ml of1, 2-dichloroethane and evaporated to dryness. The residue was taken up in a mixture of 50ml of dichloromethane and 20ml of 15% aqueous sodium hydroxide solution. The phases were separated and the aqueous phase was extracted 2 times with 20ml dichloromethane. The organic phase is washed with 10ml of water and then with 20ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to give 0.25g (0.81mmol) of product as a yellow oil.

5.5.4- (3-Biphenyl-3-yl-1, 1-dimethylpropyl) piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester hydrochloride

A solution of 0.25g (0.81mmol) of 1- (3-biphenyl-3-yl-1, 1-dimethylpropyl) piperazine prepared in step 5.4 and 1.5g (1.22mmol) of ethyl { [ (phenoxy) carbonyl ] oxy } acetate was heated at 60 ℃ overnight and then evaporated to dryness. The residue was dissolved in a mixture of 4ml of 2M methylamine (8mmol) in tetrahydrofuran and 2ml of methanol. The solution was left to react overnight, then 1g of silica was added and the mixture was evaporated to dryness. The residue was chromatographed on silica gel using 98/2, then 96/4 and 94/6 of a mixture of dichloromethane and methanol to give 0.23g (0.54mmol) of the product as a colorless gum.

The product was dissolved in 5ml of ethyl acetate and 1ml of 5N hydrochloric acid in isopropanol was added. The mixture was evaporated to dryness. The residue was taken up in 15ml of hot ethyl acetate. The solid is filtered off, washed 2 times with 3ml of ethyl acetate and dried to yield 0.215g (0.46mmol) of the product as a white powder.

LC-MS：M+H＝424

Melting point: 212 ℃ in 216 ℃ (decomposition)

¹H MMR(CDCl₃) δ (ppm): 12.50 (width s, 1H); 7.55(d, 2H)7.40(m, 6H); 7.20(d, 1H); 6.05 (width s, 1H); 4.60(s, 2H); 4.30-4.10(m, 4H); 3.55 (width d, 2H); 3.05-2.75(m + d, 5H); 2.15(m, 2H); 1.70(s, 8H).

Example 6 (Compound 29)

4- {2- [3- (4-chlorophenyl) isoxazol-5-yl ] ethyl } piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

6.1.2- [3- (4-chlorophenyl) isoxazol-5-yl ] ethanol

1.63ml (11.58mmol) of triethylamine are added dropwise to a solution of 1.18ml (15.57mmol) of but-4-yn-1-ol and 2.0g (10.52mmol) of 4-chloro-N-hydroxyphenylcarboxyimino (imidoyl) chloride (J.Med.chem.1998, 41, 4556-66) in 30ml of dichloromethane, cooled with an ice bath. The mixture was reacted at room temperature overnight. 50ml of dichloromethane were added and the mixture was washed 2 times with 50ml of water and then with 50ml of saturated aqueous sodium chloride solution. After drying over sodium sulfate, the system was evaporated to dryness. The residue was chromatographed on silica gel using 80/20 and then 70/30 of a mixture of cyclohexane and ethyl acetate to give 1.1g (4.91mmol) of the product as a white solid.

Melting point: 65-67 deg.C

2- (methylamino) -2-oxoethyl 6.2.4- {2- [3- (4-chlorophenyl) isoxazol-5-yl ] ethyl } piperazine-1-carboxylate

To a solution of 0.100g (0.447mmol) of 2- [3- (4-chlorophenyl) isoxazol-5-yl ] ethanol prepared in step 6.1. and 0.082ml (0.47mmol) of diisopropylethylamine in 5ml of dichloromethane was added 0.036ml (0.469mmol) of methanesulfonyl chloride. The mixture was stirred at room temperature for 4 hours, and then washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. Concentrated under reduced pressure. The residue was taken up in 5ml of acetonitrile and 0.107g (0.45mmol) of 2- (methylamino) -2-oxoethyl ester hydrochloride piperazine-1-carboxylic acid prepared as in example 3.3 and 0.186g (1.35mmol) of potassium carbonate were added. The mixture was heated at 75 ℃ for 16 hours. After cooling to room temperature, it was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water and then with saturated aqueous sodium chloride solution. The mixture was evaporated and the residue was chromatographed on silica gel, eluting first with dichloromethane and then with 90/10 of a mixture of dichloromethane and methanol. 0.054g (0.132mmol) of the product was obtained as a white solid.

LC-MS：M+H＝407

Melting point: 130 ℃ C. and 132 ℃ C

¹H NMR(DMSO-d₆) δ (ppm): 7.85(d, 2H); 7.75 (not decomposed, 1H); 7.55(d, 2H); 6.85(s, 1H); 4.40(s, 2H); 3.40(m, 4H); 2.95(t, 2H); 2.70(t, 2H); 2.55(d, 3H); 2.40(m, 4H).

Example 7 (Compound 52)

4- [3- (3' -chlorobiphenyl-3-yl) propyl ] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

7.1.3- (3-bromophenyl) propan-1-ol

To a suspension of 1.84g (8mmol) of 3- (3-bromophenyl) propionic acid and 0.91g (24mmol) of sodium borohydride in 20ml of THF, cooled to 0 deg.C, 3.2ml (25mmol) of trifluoroborane-ethyl ether complex are added in small portions. Stirring was continued for 1 hour in the cooled state and then for 16 hours at room temperature. The reaction mixture was cooled to 0 ℃ and neutralized to pH 7-8 by addition of 1N aqueous sodium hydroxide solution. Concentrated under reduced pressure and the residue was transferred to water. It was extracted with dichloromethane and dried over sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure. 1.62g (7.53mmol) of oily product are obtained, which are used as such in the following step.

7.2.4- [3- (3-bromophenyl) propyl ] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

To a solution of 1.57g (6.7mmol) of 3- (3-bromophenyl) propan-1-ol prepared in step 7.1. and 1.73ml (10.1mmol) of diisopropylethylamine in 38ml of dichloromethane cooled to 0 deg.C was added 0.63ml (8.14mmol) of methanesulfonyl chloride. Stirring was continued for 0.5 hour in a cooled state and then for 2 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was then suspended in 35ml of acetonitrile. 1.34g (5.35mmol) of 2- (methylamino) -2-oxoethyl ester hydrochloride piperazine-1-carboxylic acid prepared according to example 3.3 and 2.2g (16mmol) of potassium carbonate were added. The mixture was heated at 75 ℃ for 16 hours. After cooling to room temperature, it was concentrated under reduced pressure and the residue was transferred to water. Extracted with ethyl acetate and dried over sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure. The product was chromatographed on silica gel, eluting with 98/2 of a mixture of dichloromethane and methanol. Crystallization from diisopropyl ether gave 0.84g (2.10mmol) of white crystals.

7.3.4- [3- (3' -chlorobiphenyl-3-yl) propyl ] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester

To a suspension of 0.14g (0.35mm1ol) of 2- (methylamino) -2-oxoethyl 4- [3- (3-bromophenyl) propyl ] piperazine-1-carboxylate prepared in step 7.2. in a mixture of 4ml of toluene and 0.6ml of ethanol were added 0.08g (0.07mol) of tetrakis (triphenylphosphine) palladium complex, 1.05ml (2.1mmol) of 2M aqueous sodium carbonate solution and 0.22g (1.4mmol) of 3-chlorobenzeneboronic acid. The mixture was heated to 150 ℃ for 5 minutes under microwave irradiation and the organic phase was recovered by filtration on a cartridge containing the glass starting material and containing celite and sodium sulfate. The cartridge was washed with toluene and the filtrate was concentrated under reduced pressure. The product was purified by chromatography on silica gel eluting with a mixture of ethyl acetate and methanol 90/10. The effluent was then transferred to n-heptane to yield 0.086g (0.18mmol) of product as white crystals.

LC-MS：M+H＝430

Melting point: 82-85 deg.C

¹H NMR δ (ppm): 7.35(m, 8H); 6.05 (width s, 1H); 4.6(s, 2H); 3.55(m, 4H); 2.85(d, 3H); 2.75(t, 2H); 2.45(m, 6H); 1.9(m, 2H).

Table 1 below illustrates the chemical structures and physical properties of some of the compounds according to the present invention. In the column "base or salt", the "base" denotes the compound in the free base form and the "HCl" denotes the compound in the hydrochloride form.

TABLE 1

Numbering	R	G	[A]	n	R	R	m.p. (. degree. C.) (or M + H)	Alkali or salt
									1.	2-F-phenyl	Key with a key body	CH	1	H	CH	196-200	HCl
2.	2-Cl-phenyl	Key with a key body	CH	1	H	CH	212-217	HCl
									3.	3-F-phenyl	Key with a key body	CH	1	H	CH	161-166	HCl
4.	3-I-phenyl	Key with a key body	CH	1	H	CH	(418)	Alkali
									5.	3-Cl-phenyl	Key with a key body	CH	1	H	CH	203-207	HCl
6.	4-Cl-phenyl	Key with a key body	CH	1	H	CH	112-115	HCl
									7.	4-CHO-phenyl	Key with a key body	CH	1	H	CH	155-159	HCl
8.	4- (phenyl CH)O) -phenyl	Key with a key body	CH	1	H	CH	172-178	HCl
									9.	4-(CH)CH-phenyl	Key with a key body	CH	1	H	CH	104-108	HCl
10.	3-phenyl	Key with a key body	CH	1	H	CH	111-114	HCl
									11.	4-phenyl	Key with a key body	CH	1	H	CH	173-179	HCl
12.	Naphthalen-1-yl	Key with a key body	CH	1	H	CH	143-145	Alkali
									13.	Naphthalen-2-yl	Key with a key body	CH	1	H	CH	184-186	HCl
14.	Phenyl radical	Key with a key body	(CH)	1	H	CH	167-169	Alkali
									15.	3-Br-phenyl	Key with a key body	(CH)	1	H	CH	(384)	Alkali

Numbering	R	G	[A]	n	R	R	m.p. (. degree. C.) (or M + H)	Alkali or salt
									16.	4-Br-phenyl	Key with a key body	(CH)	1	H	CH	(384)	Alkali
17.	4-CHO-phenyl	Key with a key body	(CH)	1	H	CH	124-126	Alkali
									18.	3-phenyl	Key with a key body	(CH)	1	H	CH	118-120	Alkali
19.	4-phenyl	Key with a key body	(CH)	1	H	CH	148-150	Alkali
									20.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	H	125-127	Alkali
21.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	CH	109-112	Alkali
									22.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	CHCH	113-115	Alkali
23.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	Cyclopropyl group	125-127	Alkali
									24.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	CH-cyclopropyl group	113-115	Alkali
25.	Naphthalen-2-yl	Key with a key body	(CH)	1	H	CH	133-135	Alkali
									26.	Naphthalen-2-yl	Key with a key body	(CH)	2	H	H	115-119	Alkali
27.	Indol-3-yl	Key with a key body	(CH)	1	H	CH	121-123	Alkali
									28.	3- (4-Cl-phenyl) -1H-methyl-pyrazol-5-yl	Key with a key body	(CH)	1	H	CH	141-143	Alkali
29.	3- (4-Cl-phenyl) isoxazol-5-yl	Key with a key body	(CH)	1	H	CH	130-132	Alkali
									30.	5- (4-Cl-phenyl) isoxazol-3-yl	Key with a key body	(CH)	1	H	CH	146-148	Alkali
31.	6- (4-Cl-phenyl) pyrimidin-4-yl	Key with a key body	(CH)	1	H	CH	132-134	Alkali
									32.	1, 1-diphenylmethyl	Key with a key body	(CH)	1	H	CH	86-88	Alkali
33.	Phenyl radical	Key with a key body	(CH)	1	H	CH	315-317	HCl
									34.	3-Cl-phenyl	Key with a key body	(CH)	1	H	CH	85-87	Alkali
35.	4-Cl-phenyl	Key with a key body	(CH)	1	H	CH	115-117	Alkali
									36.	3-Br-phenyl	Key with a key body	(CH)	1	H	CH	(398)	Alkali
37.	4-Br-phenyl	Key with a key body	(CH)	1	H	CH	(398)	Alkali
									38.	3-CN-phenyl	Key with a key body	(CH)	1	H	CH	107-109	Alkali
39.	3-CF-phenyl radical	Key with a key body	(CH)	1	H	CH	98-100	Alkali
									40.	4-CF-phenyl radical	Key with a key body	(CH)	1	H	CH	85-87	Alkali
41.	2-Cl, 4-Cl-phenyl	Key with a key body	(CH)	1	H	CH	103-105	Alkali
									42.	2-Cl, 5-Cl-phenyl	Key with a key body	(CH)	1	H	H	128-130	Alkali
43.	2-Cl, 5-Cl-phenyl	Key with a key body	(CH)	1	H	CH	121-123	Alkali
									44.	Pyrimidin-2-yl	Key with a key body	(CH)	1	H	CH	103-105	Alkali
45.	Pyrimidin-5-yl	Key with a key body	(CH)	1	H	CH	116-118	Alkali
									46.	Thiazol-2-yl	Key with a key body	(CH)	1	H	CH	83-85	Alkali
47.	2-phenyl	Key with a key body	(CH)	1	H	CH	(396)	Alkali
									48.	3-phenyl	Key with a key body	(CH)	1	H	CH	99-101	Alkali
49.	4-phenyl	Key with a key body	(CH)	1	H	CH	110-113	Alkali
									50.	3-phenyl	Key with a key body	(CH)-C(CH)	1	H	CH	212-216	HCl
51.	4-phenyl	Key with a key body	(CH)-	1	H	CH	101-103	Alkali

Numbering	R	G	[A]	n	R	R	m.p. (. degree. C.) (or M + H)	Alkali or salt
												C(CH)
52.	3- (3-Cl-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	82-85	Alkali
									53.	3- (4-Cl-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	136-138	Alkali
54.	3-(3-CHO) phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	(426)	Alkali
									55.	3-(4-CHO) phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	135-137	Alkali
56.	3- (3-CN-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	152-154	Alkali
									57.	3- (4-CN-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	137-139	Alkali
58.	4- (3-Cl-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	101-103	Alkali
									59.	4- (4-Cl-extract) -phenyl	Key with a key body	(CH)	1	H	CH	125-128	Alkali
60.	4-(3-CHO) phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	97-100	Alkali
									61.	4-(4-CHO) phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	128-130	Alkali
62.	4- (3-CN-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	108-110	Alkali
									63.	4- (4-CN-phenyl) -phenyl	Key with a key body	(CH)	1	H	CH	148-150	City (a city)
64.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	CH	104-106	HCl
									65.	Naphthalen-2-yl	Key with a key body	(CH)	2	H	CH	110-112	Alkali
66.	3- (4-Cl-phenyl) -1H-methyl-pyrazol-5-yl	Key with a key body	(CH)	1	H	CH	157-159	Alkali
									67.	5- (4-Cl-phenyl) isoxazol-3-yl	Key with a key body	(CH)	1	H	CH	125-127	Alkali
68.	3- (4-Cl-phenyl) isoOxazol-5-yl	Key with a key body	(CH)	1	H	H	132-134	Alkali
									69.	3- (4-Cl-phenyl) isoxazol-5-yl	Key with a key body	(CH)	1	H	CH	108-110	Alkali
70.	3- (naphthalen-2-yl) isoxazol-5-yl	Key with a key body	(CH)	1	H	CH	71-73	Alkali
									71.	1, 1-bis- (4-F-phenyl) methyl	Key with a key body	(CH)	1	H	CH	(446)	Alkali
72.	3-Cl-phenyl	Key with a key body	(CH)	1	H	CH	103-105	Alkali
									73.	4-Cl-phenyl	Key with a key body	(CH)	1	H	CH	120-122	Alkali
74.	3-CN-phenyl	Key with a key body	(CH)	1	H	CH	127-129	Alkali
									75.	3-CF-phenyl radical	Key with a key body	(CH)	1	H	CH	98-100	Alkali

Numbering	R	G	[A]	n	R	R	m.p. (. degree. C.) (or M + H)	Alkali or salt
									76.	4-CF-phenyl radical	Key with a key body	(CH)	1	H	CH	129-131	Alkali
77.	Pyrimidin-2-yl	Key with a key body	(CH)	1	H	CH	141-143	Alkali
									78.	Pyrimidin-5-yl	Key with a key body	(CH)	1	H	CH	114-116	Alkali
79.	Thiazol-2-yl	Key with a key body	(CH)	1	H	CH	93-95	Alkali
									80.	Naphthalen-1-yl	Key with a key body	(CH)	1	H	CH	90-92	Alkali
81.	Naphthalen-2-yl	Key with a key body	(CH)	1	H	CH	109-111	Alkali
									82.	2-phenyl	Key with a key body	(CH)	1	H	CH	92-94	Alkali
83.	3-phenyl	Key with a key body	(CH)	1	H	CH	97-99	Alkali
									84.	Phenyl radical	Key with a key body	CH＝CHCH(E)	1	H	H	115-117	Alkali
85.	Phenyl radical	Key with a key body	CH＝CHCH(E)	1	H	CH	109-111	Alkali
									86.	3-Cl-phenyl	Key with a key body	C≡CCH	1	H	CH	114-116	Alkali
87.	4-Cl-phenyl	Key with a key body	C≡CCH	1	H	CH	127-129	Alkali
									88.	3-CF-phenyl radical	Key with a key body	C≡CCH	1	H	CH	131-133	Alkali
89.	4-CF-phenyl radical	Key with a key body	C≡CCH	1	H	CH	125-127	Alkali
									90.	3-CN-phenyl	Key with a key body	C≡CCH	1	H	CH	134-140	Alkali
91.	Pyrimidin-2-yl	Key with a key body	C≡CCH	1	H	CH	137-139	Alkali
									92.	Pyrimidin-5-yl	Key with a key body	C≡CCH	1	H	CH	151-153	Alkali
93.	Thiazol-2-yl	Key with a key body	C≡CCH	1	H	CH	111-113	Alkali
									94.	Naphthalen-1-yl	Key with a key body	C≡CCH	1	H	CH	131-134	Alkali
95.	Naphthalen-2-yl	Key with a key body	C≡CCH	1	H	CH	(366)	Alkali
									96.	2-phenyl	Key with a key body	C≡CCH	1	H	CH	(392)	Alkali
97.	3-phenyl	Key with a key body	C≡CCH	1	H	CH	125-127	Alkali
									98.	4-phenyl	Key with a key body	C≡CC(CH)	1	H	CH	137-139	Alkali
99.	3-CF-phenyl radical	Key with a key body	C≡CCH	2	H	H	102-104	Alkali
									100.	3-CF-phenyl radical	Key with a key body	C≡CCH	2	H	CH	92-94	Alkali
101.	3-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	115-117	Alkali
									102.	4-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	141-143	Alkali
103.	3-CF-phenyl radical	Key with a key body	C≡C(CH)	1	H	CH	93-95	Alkali
									104.	4-CF-phenyl radical	Key with a key body	C≡C(CH)	1	H	CH	142-144	Alkali
105	3-CN-phenyl	Key with a key body	C≡C(CH)	1	H	CH	144-146	Alkali
									106.	Pyrimidin-2-yl	Key with a key body	C≡C(CH)	1	H	CH	120-122	Alkali
107.	Pyrimidin-5-yl	Key with a key body	C≡C(CH)	1	H	CH	159-161	Alkali
									108.	Thiazol-2-yl	Key with a key body	C≡C(CH)	1	H	CH	103-105	Alkali
109.	Naphthalen-1-yl	Key with a key body	C≡C(CH)	1	H	CH	99-101	Alkali
									110.	Naphthalen-2-yl	Key with a key body	C≡C(CH)	1	H	CH	140-142	Alkali
111.	2-phenyl	Key with a key body	C≡C(CH)	1	H	CH	(406)	Alkali
									112.	3-phenyl	Key with a key body	C≡C(CH)	1	H	CH	102-104	Alkali
113.	3-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	79-81	Alkali
									114.	4-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	126-128	Alkali
115.	2-F, 4-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	131-133	Alkali
									116.	2-Cl, 4-F-phenyl	Key with a key body	C≡C(CH)	1	H	CH	133-135	Alkali
117.	2-Cl, 4-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	133-135	Alkali
									118.	2-Cl, 5-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	110-112	Alkali

Numbering	R	G	[A]	n	R	R	m.p. (. degree. C.) (or M + H)	Alkali or salt
									119.	3-Cl, 4-Cl-phenyl	Key with a key body	C≡C(CH)	1	H	CH	119-121	Alkali
120.	3-Cl, 4-F-phenyl	Key with a key body	C≡C(CH)	1	H	CH	98-100	Alkali
									121.	Phenyl radical	O	(CH)	1	H	CH	233-235	Alkali
122.	2-Cl-phenyl	O	(CH)	1	H	H	90-92	Alkali
									123.	2-Cl-phenyl	O	(CH)	1	H	CH	184-186	HCl
124.	2-CN-phenyl	O	(CH)	1	H	CH	109-111	Alkali
									125.	3-Cl-phenyl	O	(CH)	1	H	H	＞300	HCl
126.	3-Cl-phenyl	O	(CH)	1	H	CH	105-107	Alkali
									127.	3-CN-phenyl	O	(CH)	1	H	CH	141-143	Alkali
128.	4-F-phenyl	O	(CH)	1	H	CH	134-136	Alkali
									129.	4-Cl-phenyl	O	(CH)	1	H	H	115-117	Alkali
130.	4-Cl-phenyl	O	(CH)	1	H	CH	159-161	Alkali
									131.	4-CN-phenyl	O	(CH)	1	H	H	145-147	Alkali
132.	4-CN-phenyl	O	(CH)	1	H	CH	138-140	Alkali
									133.	4-(CH)C-phenyl	O	(CH)	1	H	CH	111-113	HCl
134.	4-CF-phenyl radical	O	(CH)	1	H	H	104-106	Alkali
									135.	4-CFO-phenyl	O	(CH)	1	H	H	96-98	Alkali
136.	4-CFO-phenyl	O	(CH)	1	H	CH	93-96	Alkali
									137.	2-Cl, 3-Cl-phenyl	O	(CH)	1	H	H	136-138	Alkali
138.	2-Cl, 3-Cl-phenyl	O	(CH)	1	H	CH	132-134	Alkali
									139.	2-Cl, 4-Cl-phenyl	O	(CH)	1	H	H	178-180	Alkali
140.	2-Cl, 4-Cl-phenyl	O	(CH)	1	H	CH	102-104	Alkali
									141.	3-Cl, 4-Cl-phenyl	O	(CH)	1	H	CH	128-130	Alkali
142.	3-Cl, 4-Cl-phenyl	O	(CH)	1	H	H	126-128	Alkali
									143.	3-Cl, 5-Cl-phenyl	O	(CH)	1	H	CH	111-113	Alkali
144.	3-CF，5-CF-phenyl radical	O	(CH)	1	H	CH	137-139	Alkali
									145.	3，4-(OCHO) -phenyl	O	(CH)	1	H	CH	139-141	Alkali
146.	3-phenyl	O	(CH)	1	H	H	120-122	HCl
									147.	3-phenyl	O	(CH)	1	H	CH	143-145	HCl
148.	4-phenyl	O	(CH)	1	H	H	238-240	Alkali
									149.	4-aryl-phenyl	O	(CH)	1	H	CH	130-132	Alkali
150.	Naphthalen-1-yl	O	(CH)	1	H	H	116-118	Alkali
									151.	Naphthalen-1-yl	O	(CH)	1	H	CH	135-137	Alkali
152.	Naphthalen-2-yl	O	(CH)	1	H	H	88-90	Alkali
									153.	Naphthalen-2-yl	O	(CH)	1	H	CH	118-120	Alkali
154.	Quinolin-6-yl	O	(CH)	1	H	H	203-205	Alkali
									155.	Quinolin-6-yl	O	(CH)	1	H	CH	126-128	Alkali
156.	Quinolin-8-yl	O	(CH)	1	H	CH	99-101	Alkali
									157.	Phenyl radical	O	(CH)	1	H	CH	103-105	Alkali
158.	2-Cl-phenyl	O	(CH)	1	H	CH	119-121	Alkali
									159	3-Cl-phenyl	O	(CH)	1	H	CH	95-97	Alkali
160.	4-Cl-phenyl	O	(CH)	1	H	CH	116-118	Alkali
									161.	2-Cl, 3-Cl-phenyl	O	(CH)	1	H	CH	110-112	Alkali

Numbering	R	G	[A]	n	R	R	m.p. (. degree. C.) (or M + H)	Alkali or salt
162.	2-Cl, 4-Cl-phenyl	O	(CH)	1	H	CH	115-117	Alkali
									163.	2-Cl, 5-Cl-phenyl	O	(CH)	1	H	CH	134-136	Alkali
164.	2-Cl, 6-Cl-phenyl	O	(CH)	1	H	CH	100-102	Alkali
									165.	3-Cl, 5-Cl-phenyl	O	(CH)	1	H	CH	121-123	Alkali
166.	Phenyl radical	C＝O	(CH)	1	H	CH	141-143	Alkali
									167.	4-Cl-phenyl	C＝O	(CH)	1	H	CH	172-174	Alkali
168.	Phenyl radical	C＝O	(CH)	1	H	CH	110-112	Alkali

The compounds of the invention are subjected to pharmacological tests which determine their inhibitory effect on the FAAH enzyme (fatty acid amide hydrolase).

In the measurement of anandamide ([1-³H]Ethanolamine) hydrolysis product ([1-³H]Ethanolamine) was tested in a radioimmunoassay (Life Sciences (1995), 56, 1999) 2005 and Journal of Pharmacology and experimental therapeutics (1997), 283, 729) 734). Thus, the mouse brain (except for cerebellum) was removed and stored at-80 ℃. When in use, by adding in Polytron thin film homogenates were prepared by homogenizing tissues in a solution of 10mM Tris-HCl buffer (pH 8) containing 150mM NaCl and 1mM EDTA. The subsequent enzymatic reaction was carried out in 70. mu.l of a buffer containing bovine serum albumin without fatty acids (1 mg/ml). Continuously, various concentrations of test compound were added, and anandamide was diluted to 10. mu.M with cold anandamide [1-³H ethanolamine](specific activity: 15-20Ci/mmol) and film preparations (400. mu.g frozen tissue per assay). After 15 minutes, the enzyme reaction was stopped at 25 ℃ by adding 140. mu.l of chloroform/methanol (2: 1). The mixture was stirred for 10 minutes and then centrifuged at 3500g for 15 minutes. Counting of the content [1-³H]An aqueous aliquot (30. mu.l) of ethanolamine.

Under these conditions, most of the active compounds according to the invention exhibit an IC of between 0.001 and 1. mu.M₅₀Values (concentration of control enzyme activity inhibiting 50% FAAH).

Table 2 below shows the IC's of some compounds according to the invention₅₀。

TABLE 2

Compound numbering	IC
		21	0.072μM
48	0.050μM
		49	0.032μM

It can thus be seen that the compounds according to the invention have an inhibitory effect on the FAAH enzyme.

The in vivo activity of the compounds of the invention was evaluated in an analgesia assay.

Thus, intraperitoneal (i.p.) administration OF PBQ (2mg/kg benzoquinone in 5% ethanol in 0.9% sodium chloride) to male OF1 mice weighing 25-30g caused abdominal extension with an average OF 30 twists or contractions during the 5-15 min post-injection period. Tween 80 suspension at 0.5% of test compound was administered either orally (p.o.) or intraperitoneally (i.p.) 60 min or 120 min before PBQ administration. Under these conditions, most of the effective compounds of the present invention reduced the number of PBQ-induced stretches by 35-70% in the dose range of 1-30 mg/kg. For example, compounds 49 and 69 in the table reduced the number of PBQ-induced stretches by 43% and 47%, respectively, at a dose of 10mg/kg at 120 minutes.

FAAH enzymes (Chemistry and Physics of Lipids, (2000), 108, 107-21) catalyze the hydrolysis of endogenous derivatives of amides and esters of various fatty acids, such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, N-oleoylethanolamide, oleamide, or 2-arachidonylglycerol. These derivatives exert various pharmacological activities through interactions, especially with cannabinoids and vanilloid receptors.

The compounds of the invention block these degradation pathways and increase the tissue level of these endogenous substances. They are useful in the prevention and treatment of such conditions, including endocannabinoids and/or any other substrate metabolized by the FAAH enzyme. The following diseases and conditions may be mentioned, for example: pain, especially acute or chronic neurogenic pain: migraine, neuropathic pain, including forms associated with herpes viruses and diabetes; acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pain; dizziness, emesis, nausea, especially dizziness, emesis, nausea after chemotherapy; eating disorders, especially anorexia and various cachexia; neurological and psychiatric disorders: shaking, movement disorders, dystonia, rigidity, obsessive-compulsive behaviour, Tourette's syndrome, depression and anxiety of any kind and cause, mood disorders, psychosis; acute and chronic neurodegenerative diseases: parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, and cerebral ischemia and with cranial and bone marrow trauma related damage; epilepsy; sleep disorders, including sleep apnea; cardiovascular diseases, in particular hypertension, arrhythmia, arteriosclerosis, heart attack, cardiac ischemia; renal ischemia; cancer: benign cutaneous tumors, papilloma and brain tumors, prostate tumors, brain tumors (glioblastoma, medullary epithelioma, medulloblastoma, neuroblastoma, embryonal carcinoma of origin, astrocytoma, ependymoma, oligodendroglioma, plexus tumors, neuroepithelioma, epiphysoma, ependymoma, malignant meningioma, sarcoma, malignant melanoma, schwannoma); diseases of the immune system, in particular autoimmune diseases: psoriasis, lupus erythematosus, connective tissue disease or collagen disease, sjogren's syndrome, ankylosing spondylitis, undifferentiated spondyloarthritis, behcet's disease, hemolytic autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis, proteinoid degeneration, graft rejection, diseases affecting plasma cell lines; allergic diseases: acute or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; parasitic, viral or bacterial infectious diseases; AIDS, meningitis; inflammatory diseases, especially joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; osteoporosis; eye diseases: ocular hypertension, glaucoma; pulmonary disorders: respiratory tract diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic airway obstruction, emphysema; gastrointestinal tract diseases: irritable bowel syndrome, enteritis, ulceration, diarrhea; urinary incontinence and cystitis.

The use of a compound according to the invention in the form of a base, a pharmaceutically acceptable salt, hydrate or solvate for the manufacture of a medicament for the treatment of the above mentioned pathologies forms an integral part of the present invention.

The invention also provides a medicament comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt, or a hydrate or solvate of a compound of formula (I). These medicaments are useful in therapy, in particular in the treatment of the above mentioned pathologies.

According to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising at least one compound according to the present invention as an active ingredient. These pharmaceutical compositions comprise an effective dose of a compound according to the invention, or of a pharmaceutically acceptable acid addition salt or hydrate or solvate of said compound, and optionally one or more pharmaceutically acceptable excipients.

The excipients are selected from the usual excipients, according to the pharmaceutical form to be administered and the desired mode, as is well known to the person skilled in the art.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of the above general formula (I), or the appropriate acid addition salts, solvates or hydrates, can be administered in single dose administration, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above-mentioned conditions or diseases.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, chewable gums and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular and intranasal administration and for administration by inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration. The compounds according to the invention can be applied topically as creams, ointments or lotions.

For example, a single dosage administration form of a compound according to the invention in the form of a tablet may comprise the following components:

compound according to the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl-methylcellulose 2.25mg

Magnesium stearate 3.0mg

Depending on the form of the medicament, said single-dose form contains daily doses of 0.01-20mg of active principle per kg of body weight.

Higher or lower doses are appropriate in particular cases; such dosages are also within the scope of the present invention. According to the usual practice, the dosage appropriate for each patient is determined by diagnosis according to the method of administration, the body weight and the response of said patient.

According to another aspect of the present invention there is also provided a method of treatment of a pathology as described above, which method comprises administering an effective dose of a compound according to the present invention, an addition salt thereof with a pharmaceutically acceptable acid, or one of a solvate or hydrate of said compound.

Claims (12)

1. A compound of formula (I) in the form of a base or acid addition salt

Wherein

n represents an integer of1 or 2;

p represents an integer of1 to 7;

a is selected from one or more groups of X, Y and/or Z;

x represents an arbitraryOptionally one or two C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-a methylene group substituted with an alkylene group;

y represents optionally substituted by one or two C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3C substituted by alkylene groups₂-an alkenylene group; or C₂-an alkynylene group;

z represents a group of the formula:

o represents an integer of1 to 5;

r and s represent integers and are defined such that r + s is a number from 1 to 5;

g represents a single bond, an oxygen or sulfur atom or SO, SO₂C ═ O or ch (oh) groups;

R₁represents optionally substituted by one or more R₅And/or R₆Radical substituted R₄A group;

R₄represents a group selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, benzhydryl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, quinazolinyl, quinoxalyl, 2, 3-naphthyridinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indanyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzooxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, Thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl;

R₅represents a halogen atom or a cyano group, a nitro group, C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy, C_1-6-sulfanyl radical, C_1-6-fluoroalkyl, C_1-6-fluoroalkoxy radical, C_1-6Fluorosulfanyl, NR₇R₈、NR₇COR₈、NR₇CO₂R₈、NR₇SO₂R₈、COR₇、CO₂R₇、CONR₇R₈、SO₂R₇、SO₂NR₇R₈or-O- (C)_1-3Alkylene) -O groups;

R₆represents phenyl, phenoxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, R or R₆The radicals being optionally substituted by one or more identical or different R₅Substituted by groups;

R₇and R₈Independently of one another, represents a hydrogen atom or C_1-6Alkyl, or forms with the atom bearing them, chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azaPiperazine ring, optionally substituted by C_1-6-alkyl or benzyl substitution;

R₂represents a hydrogen atom or C_1-6-an alkyl group;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3-an alkyl group.

2. A compound of formula (I) according to claim 1, in the form of a base or acid addition salt, characterized in that

n represents an integer of1 or 2;

p represents an integer of1 to 7;

a is selected from one or more groups of X and/or Y;

x represents optionally substituted by one or two C_1-6Substituted by alkyl groupsA methylene group;

y represents C₂An alkenylene group or C₂-an alkynylene group;

g represents a single bond, an oxygen atom or a C ═ O group;

R₁represents optionally substituted by one or more R₅And/or R₆Radical substituted R₄A group;

R₄represents a group selected from phenyl, naphthyl, benzhydryl, quinolyl, indolyl, pyrazolyl, isoxazolyl, pyrimidinyl, thiazolyl;

R₅represents a halogen atom or a cyano group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6-fluoroalkyl, C_1-6-fluoroalkoxy, or-O- (C)_1-3Alkylene) -O groups;

R₆represents phenyl, naphthyl or benzyloxy;

R₂represents a hydrogen atom or C_1-6-an alkyl group;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3-an alkyl group.

3. A compound of formula (I) according to claim 1 or 2, in the form of a base or acid addition salt, characterized in that

n represents an integer of 1;

p represents an integer of1 to 4;

a is selected from one or more groups of X and/or Y;

x represents optionally substituted by one or two C_1-6An alkyl group-substituted methylene group;

y represents C₂-an alkynylene group;

g represents a single bond or an oxygen atom;

R₁represents optionally substituted by one or more R₅And/or R₆A group-substituted R4 group;

R₄represents a group selected from phenyl, naphthyl or isoxazolyl;

R₅represents a halogen atom or a cyano group, C_1-6Alkoxy radical, C_1-6-a fluoroalkyl group;

R₆represents a phenyl group;

R₂represents a hydrogen atom or C_1-6-an alkyl group;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3-an alkyl group.

4. Compounds of formula (I) according to claims 1 or 2, characterized in that

R₂Represents a hydrogen atom;

R₃represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-an alkyl group.

5. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, which process comprises the preparation of a compound of formula (I) by using the general formula R₃NH₂In which R is₃A step of converting the carbamate-ester compound of the general formula (II) as defined in the general formula (I)

Wherein R is₁、R₂G, A, p and n are as defined in general formula (I) in any one of claims 1 to 4, and R represents methyl or ethyl.

6. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, which process comprises reacting a compound of formula R with₁-G-[A]_pReaction of derivatives of the formula (VI) in which R₁G, p and A are as defined for formula (I) and W represents a chlorine, bromine or iodine atom, or a methanesulfonate or toluenesulfonate group, a step of converting the carbamate-amide of formula (V)

Wherein R is₂、R₃And n is as defined in general formula (I) according to any one of claims 1 to 4.

7. A compound of the general formula (II),

wherein R is₁、R₂G, A, p and n are as defined in formula (I) in claim 1, and R represents methyl or ethyl.

8. A compound of the general formula (V),

wherein R is₂、R₃And n is as defined in general formula (I) of claim 1.

9. A compound of formula (I) according to claim 1 or 2 for use as a medicament in the form of a base or an acid addition salt.

10. Pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 4, in the form of a base or of an acid addition salt, and optionally one or more pharmaceutically acceptable excipients.

11. Use of a compound of formula (I) according to any one of claims 1-4 in the manufacture of a medicament for the prevention or treatment of a condition in which endocannabinoid and/or any other substrate metabolized by the FAAH enzyme is implicated, in the form of a base or acid addition salt.

12. Use of a compound of formula (I) according to any one of claims 1 to 4 in the form of a base or acid addition salt for the preparation of a medicament for the prevention or treatment of acute or chronic pain, dizziness, emesis, nausea, eating disorders, neurological and psychiatric disorders, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancer, disorders of the immune system, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular disorders, pulmonary disorders, gastrointestinal diseases or urinary incontinence.