HK1099552B - Derivatives of 1-piperazine- and 1-homopiperazine-carboxylates, preparation method thereof and use of same in therapeutics - Google Patents

Description

1-piperazine-and 1-homopiperazine-carboxylate derivatives, preparation and therapeutic use thereof

The present invention relates to 1-piperazine-and 1-homopiperazine (homopiperazine) -carboxylate derivatives, their preparation and their therapeutic use

The compounds of the invention correspond to the general formula (I)

Wherein

m represents an integer equal to 1 or 2;

R₁represents a group selected in particular from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothiophenyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, furopyridinyl, dihydrofuropyridinyl, thienopyridinyl, dihydrothienopyridinyl, imidazopyridinyl, and the likeA pyridyl group, an isothiazolopyridyl group,

these radicals being optionally substituted by one or more radicals R₃Substituted, R₃May be the same or different, or optionally substituted by a group R₄Substitution;

R₂is represented by the general formula CHR₅CONHR₆The group of (a) or (b),

R₃represents a halogen atom or a hydroxyl group, a cyano group, a nitro group, C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-sulfanyl radical, C_1-6-fluoroalkyl radical, C_1-6-fluoroalkoxy, -O- (C)_2-3-alkylene) -, -O- (C)_{1- 3}-alkylene) -O-, C_1-6-fluorosulfanylalkyl radical, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-3Alkylene, piperidinyl, benzyloxy, piperazinyl, pyrrolidinyl, morpholinyl, phenoxy, NR₇R₈，NHCOR₇，NHSO₂R₇，COR₇，CO₂R₇，CONR₇R₈，SO₂R₇Or SO₂NR₇R₈The radical(s) is (are),

R₄represents a group selected in particular from: phenyl, benzofuranyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, imidazopyrimidinyl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, imidazopyrimidinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl or isothiazolopyridyl;

radical R₄May be substituted by one or more radicals R₃Substituted, R₃Which may be the same or different from each other,

R₅represents a hydrogen atom or C_1-3-an alkyl group;

R₆represents a hydrogen atom or C_1-6-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-an alkylene group;

R₇and R₈Independently of each other, represents a hydrogen atom, C_1-3-alkyl or phenyl.

Among the compounds of general formula (I), a first subgroup of compounds consists of compounds which satisfy the following conditions:

m represents an integer equal to 1 or 2; and/or

R₁Represents a group selected in particular from: phenyl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, benzisoxazolyl, thienopyridyl, these radicals optionally being substituted by one or more radicals R₃Substituted, especially optionally by one or two radicals R₃Substituted, R₃May be the same or different; and/or

R₂Is represented by the general formula CHR₅CONHR₆A group of (a); and/or

R₃Represents a halogen atom, more particularly chlorine, bromine or fluorine, or a cyano group, C_1-6Alkyl, more particularly methyl, ethyl, n-propyl, isobutyl, C_1-6Alkoxy, more particularly methoxy, C_1-6-fluoroalkyl, more particularly CF₃，C_1-6-fluoroalkoxy, more particularly-OCH₂CF₃，-O-(C_2-3-alkylene) -, more particularly-O- (CH)₂)₃-, phenoxy; and/or

R₅Represents a hydrogen atom; and/or

R₆Represents a hydrogen atom or C_1-6-alkyl, more particularly methylAnd (4) a base.

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

m is equal to 1; and/or

R₁Represents a group selected in particular from: pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, these radicals optionally being substituted by radicals R₃Substitution; and/or

R₂Is represented by the general formula CHR₅CONHR₆A group of (a); and/or

R₃Represents a halogen atom, more particularly chlorine, or C_1-6Alkyl, more particularly methyl, ethyl, n-propyl, isobutyl, C_1-6Alkoxy, more particularly methoxy, C_1-6-fluoroalkyl, more particularly CF₃(ii) a And/or

R₅Represents a hydrogen atom; and/or

R₆Represents a hydrogen atom or C_1-6-alkyl, more particularly methyl.

Among the compounds of general formula (I), a third subgroup of compounds consists of compounds which satisfy the following conditions:

m represents an integer equal to 1 or 2; and/or

R₁Represents a group selected in particular from: phenyl, pyridyl, pyridazinyl, pyrimidinyl and thiadiazolyl,

these radicals being optionally substituted by radicals R₄Substitution; and/or

R₄Represents a group selected in particular from: phenyl, benzofuranyl, naphthyl; radical R₄May be substituted by one or more radicals R₃Substituted, R₃May be identical or different, more particularly by one or two radicals R₃Substituted, R₃May be the same or different; and/or

R₂Is represented by the general formula CHR₅CONHR₆A group of (a); and/or

R₃Represents a halogen atom, more particularly chlorine, bromine or fluorine, or a nitro group, C_1-6Alkyl, more particularly methyl, isopropyl, C_1-6Alkoxy, more particularly methoxy, ethoxy, C_1-6-fluoroalkyl, more particularly CF₃，C_1-6-fluoroalkoxy, more particularly OCF₃，-O-(C_1-3-alkylene) -O-, more particularly-O-CH₂-O-, benzyloxy; and/or

R₅Represents a hydrogen atom; and/or

R₆Represents a hydrogen atom or C_1-6Alkyl, more particularly methyl or ethyl, or C_3-7-cycloalkyl-C_1-3Alkylene, more particularly cyclopropyl-CH₂-。

Among the compounds of general formula (I), a fourth subgroup of compounds is constituted by compounds which meet the following condition:

m is equal to 1; and/or

R₁Represents a group selected in particular from: phenyl, pyridyl, pyridazinyl, pyrimidinyl,

these radicals being optionally substituted by radicals R₄Substitution; and/or

R₄Represents a group selected in particular from: phenyl, benzofuranyl, naphthyl; radical R₄May be substituted by one or more radicals R₃Substituted, R₃May be identical or different, more particularly by one or two radicals R₃Substituted, R₃May be the same or different; and/or

R₂Is represented by the general formula CHR₅CONHR₆A group of (a); and/or

R₃Represents a halogen atom, more particularly chlorine, bromine or fluorine, or a nitro group, C_1-6-alkyl, more particularly methylIsopropyl, C_1-6Alkoxy, more particularly methoxy, ethoxy, C_1-6-fluoroalkyl, more particularly CF₃，C_1-6-fluoroalkoxy, more particularly OCF₃，-O-(C_1-3-alkylene) -O-, more particularly-O-CH₂-O-, benzyloxy; and/or

R₅Represents a hydrogen atom; and/or

R₆Represents a hydrogen atom or C_1-6-alkyl, more particularly ethyl.

The compounds of formula (I) may include one or more asymmetric carbons. They may exist as enantiomers or diastereomers. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures thereof, form part of the present invention.

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

These salts are preferably prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for purifying or isolating the compounds of formula (I), also form part of the invention.

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

In the context of the present invention, the following definitions are used:

-C_t-zwhere t and z can assume values from 1 to 7, the carbon-based chain can contain from t to z carbon atoms, e.g. C_1-3Is a carbon-based chain that may contain from 1 to 3 carbon atoms,

-an alkyl group: saturated straight-chain or branched aliphatic radicals, e.g. C_1-3Alkyl represents a linear or branched carbon-based chain of1 to 3 carbon atoms, more particularly methyl, ethylA group of methyl, propyl or 1-methylethyl,

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

-a cycloalkyl group: cyclic alkyl radicals, e.g. C_3-5Cycloalkyl denotes a cyclic carbon-based group of 3 to 5 carbon atoms, more particularly cyclopropyl, cyclobutyl, cyclopentyl,

-an alkoxy group: -O-alkyl containing a saturated linear or branched aliphatic chain,

-a sulfanyl group: -S-alkyl containing a saturated linear or branched aliphatic chain,

-a fluoroalkyl group: an alkyl group in which one or more hydrogen atoms are substituted with fluorine atoms,

-a fluoroalkoxy group: alkoxy in which one or more hydrogen atoms are replaced by fluorine atoms,

-fluorosulfanylalkyl: alkylthio in which one or more hydrogen atoms are substituted by fluorine atoms,

-a halogen atom: fluorine, chlorine, bromine or iodine.

The compounds of the present invention can be prepared by various methods as illustrated in the following various reaction schemes.

Thus, the first preparation method (scheme 1) comprises: amines of the general formula (II) (wherein R₁And m is as defined for formula (I)) with a carbonate of formula (III) (wherein Z represents a hydrogen atom or a nitro group, R₂As defined by general formula (I) in a solvent such as toluene or dichloroethane at a temperature between 0 and 80 ℃.

Reaction scheme 1

The carbonates of the formula (III) can be prepared by any of the methods described in the literature, for example by means of the formula HOR₂Is reacted with phenyl chloroformate or 4-nitrophenyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine at a temperature between 0 ℃ and the reflux temperature of the solvent.

According to a second process (scheme 2), the compounds of formula (I) can be obtained by reacting an amine of formula (II) with a carbonate of formula (IIIa) (wherein Z represents a hydrogen atom or a nitro group, R₅As defined by general formula (I), R represents methyl or ethyl). Then, the general formula R is used₆NH₂The carbamate of formula (Ia) thus obtained is subjected to aminolysis (aminolyse) to convert it into a compound of formula (I), wherein R₆As defined by general formula (I). The aminolysis reaction may be carried out in a solvent such as methanol or a mixture of solvents such as methanol and tetrahydrofuran or methanol and dioxane.

Reaction scheme 2

The carbonates of formula (IIIa) can be prepared by any of the methods described in the literature, for example by the formula HOCHR₅The alcohol of COOR, wherein R represents methyl or ethyl, is reacted with phenyl chloroformate or 4-nitrophenyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine.

Wherein R is₁Is represented by C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3A group R of alkylene type₃Substituted or defined by the general formula (I)₄Substituted compounds of the formula (I) can also be prepared, for example, by reacting boronic acids with alkyl, cycloalkyl, aryl or heteroaryl radicals in the corresponding compounds of the formula (I) (where R is₁At the moment R should be introduced₃Or R₄Is substituted by chlorine, bromine, iodineAtom or substituted by a triflate group) by a Suzuki reaction.

For the compounds of the general formula (I), wherein R₁Is represented by C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3A group R of alkylene type₃Or a group R as defined by the general formula (I)₄Is substituted and R₂More particularly of the formula CHR₅CONHR₆The Suzuki reaction as described above may be carried out on a carbamate of the general formula (Ia) as defined above. General formula R as defined above₆NH₂The action of the amine of (a) on the carbamate thus obtained will give the compound of formula (I).

The compounds of formula (II), when their mode of preparation is not described, are commercially available or described in the literature, or may even be prepared according to the methods described therein or according to methods known to the person skilled in the art.

General formula R₆NH₂The amines of (a) are commercially available.

According to a further aspect of the invention, the subject of the invention is also compounds of the formula (Ia). These compounds are useful as intermediates in the synthesis of compounds of formula (I).

The following examples illustrate the preparation of certain compounds of the invention. These examples are not intended to limit the present invention, but are merely illustrative thereof. Microanalysis and IR and NMR and/or LC-MS spectroscopy (liquid chromatography coupled with mass spectrometry) were used to determine the structure and purity of the resulting compounds.

m.p. (° c) denotes the melting point in degrees celsius. The reference numbers in parentheses in the title of the examples correspond to the numbers in the first column of the following table:

example 1 (Compound 44)

2- (methylamino) -2-oxoethyl 4- { 4' - [ (trifluoromethyl) oxy ] -4-biphenyl } -1-piperazine carboxylate

[ (Phenoxycarbonyl) oxy ] acetic acid ethyl ester

32 ml (256mmol) of phenyl chloroformate are slowly added at room temperature to a solution of 25 g (240mmol) of ethyl glycolate and 55 ml (315mmol) of diisopropylethylamine in 500 ml of toluene. Stirring was continued at room temperature for 2 hours.

The salt formed was separated off and the filtrate was concentrated under reduced pressure.

53.7 g of oily product were obtained and used in the next step without further purification.

1.2.2- (ethoxy) -2-oxoethyl 4- (4-bromophenyl) -1-piperazinecarboxylate

A solution of 5.81 g (24.08mmol) of 1- (4-bromophenyl) piperazine and 6 g (26.76mmol) of ethyl [ (phenoxycarbonyl) oxy ] acetate obtained in step 1.1 in 50ml of toluene is heated at 80 ℃ for 12 hours.

The mixture was returned to room temperature, concentrated under reduced pressure and the residue thus obtained was then purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane of 20/80 and then 30/70.

This gives 7.75 g of pure product in the form of an oil which crystallizes at room temperature.

m.p.(℃)：80-82℃

1.3.2- (ethoxy) -2-oxoethyl 4- { 4' - (trifluoromethyl) oxy ] -4-biphenyl } -1-piperazine carboxylate

Under an inert atmosphere, 2 g (5.39mmol) of 2- (ethoxy) -2-oxoethyl 4- (4-bromophenyl) -1-piperazinecarboxylate obtained in step 1.2 suspended in 18 ml of1, 2-dimethoxyethane, 3.33 g (16.16mmol) of 4- (trifluoromethoxy) phenylboronic acid and 4.57 g (21.55mmol) of potassium phosphate hydrate were added. Then 0.62 g (0.54mmol) of tetrakis (triphenylphosphine) palladium was added. The reaction mixture was then held at about 80 ℃ for 12 hours.

It was concentrated under reduced pressure. The residue was treated with dichloromethane and water, the aqueous phase was separated off, extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane of 30/70.

1.65 g of product are obtained in the form of a white solid.

m.p.(℃)：112-116℃

1.4.2- (methylamino) -2-oxoethyl 4- { 4' - [ (trifluoromethyl) oxy ] -4-biphenyl } -1-piperazine carboxylate

7.10 ml (14.15mmol) of methylamine (2M) in tetrahydrofuran are added to a solution of 1.60 g (3.54mmol) of 2- (ethoxy) -2-oxoethyl 4- { 4' - [ (trifluoromethyl) oxy ] -4-biphenyl } -1-piperazinecarboxylate prepared in step 1.3 in 14 ml of methanol. Stirring was continued at room temperature for 12 hours.

After concentration under reduced pressure, the resulting residue was purified by chromatography on silica gel, eluting with 97/3 of a mixture of dichloromethane and methanol. A solid was obtained and recrystallized from a mixture of ethyl acetate and diisopropyl ether.

This gave 0.86 g of pure product in the form of a white solid.

LC-MS：M+H＝438

m.p.(℃)：187-189℃

¹H NMR(CDCl₃) δ (ppm): 2.90(d, 3H); 3.25(m, 4H); 3.70(m, 4H); 4.60(s, 2H); 6.10 (width s, 1H); 7.0(d, 2H); 7.30(d, 2H); 7.50(d, 2H); 7.60(d, 2H).

Example 2 (Compound 37)

2- (methylamino) -2-oxoethyl 4- [ 3' - (trifluoromethyl) -4-biphenyl ] -1-piperazinecarboxylate

2.1.2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate

5.93 g (29.4mmol) of 4-nitrophenyl chloroformate are added portionwise to a suspension of 2.62 g (29.4mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7mmol) of loaded diisopropylethylamine (Ps-DIEA from Argonaut, loading 3.56 mmol/g) in 250 ml of dichloromethane 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.

6 g of the product were obtained in the form of a pale yellow solid (purity estimated at 70%) and used in the following step without further purification.

2.2.2- (methylamino) -2-oxoethyl 4- (4-bromophenyl) -1-piperazinecarboxylate

1.17 g (4.85mmol) of 1- (4-bromophenyl) piperazine were added to a solution of 1.47 g (4mmol) of 2- (methylamino) -2-oxoethyl 4-nitrophenylcarbonate obtained in step 2.1 in 18 ml of1, 2-dichloroethane. The reaction mixture was heated at 65 ℃ for 2.25 hours.

The mixture was allowed to return to room temperature and then concentrated under reduced pressure. The oily yellow residue was treated in dichloromethane and washed successively with sodium hydroxide (1N), water, 5% aqueous citric acid, water and then brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. After washing with diisopropyl ether, 1.3 g of the product are obtained in the form of a white solid.

2.3. Synthesis of Palladium catalyst grafted onto Merrifield resin

Under an inert atmosphere, 54.6 ml (27.3mmol) of lithium diphenylphosphinate, sold at 0.5MTo a suspension of 5 g (3.5mmol) of Merrifield resin (Fluka, 200-400 mesh, crosslinked with 2% Divinylbenzene (DVB) at a loading of 0.7 mmol/g) in 50ml of anhydrous Tetrahydrofuran (THF). Orbital stirring was continued at room temperature for 24 hours, then 60 ml of acetone and 20 ml of water were added. The resin was filtered off and washed successively with water, acetone, THF/H₂The O (2/1) mixture was washed with THF, toluene, dichloromethane, and diethyl ether, and then dried in vacuo for 2 hours.

The resin suspension thus obtained was kept at 70 ℃ in 47 ml of ethanol and 23 ml of toluene for 24 hours. After filtration, the resin was washed sequentially with acetone, THF and diethyl ether. In total, this treatment was repeated four times to remove the soluble components of the polymer. The resin thus obtained was dried under vacuum for 2 hours.

0.18 g (0.16mmol) of tetrakis (triphenylphosphine) palladium were added to a 60 ml toluene suspension of the resin and the reaction mixture was kept at 95 ℃ for 24 h.

The mixture was allowed to cool to room temperature, the resin filtered off and washed successively with acetone, THF and then diethyl ether. 5.135 g of resin were obtained and used in the next step without further purification. 2.4.2- (methylamino) -2-oxoethyl 4- [ 3' - (trifluoromethyl) -4-biphenyl ] -1-piperazinecarboxylate

Step 2.2 suspended in 3 ml of toluene and 0.3 ml of ethanol was added 0.18 g (0.5mmol) of the resulting 2- (methylamino) -2-oxoethyl 4- (4-bromophenyl) -1-piperazinecarboxylate, 0.21 g (1.1mmol) of 3- (trifluoromethyl) phenylboronic acid and 0.16 g (1.5mmol) of sodium carbonate. Then 0.14 g (. about.10 mol%) of the supported palladium catalyst obtained in step 2.3 was added and orbital stirring was continued at 80 ℃ for 48 hours.

The mixture was brought to room temperature, the resin was filtered off, washed with dichloromethane and the filtrate was concentrated under reduced pressure.

The residue was taken up in 5ml of dichloromethane and washed with water and then with saturated aqueous sodium bicarbonate. The organic phase was filtered through a hydrophobic cartridge and the filtrate was concentrated under reduced pressure.

An oily residue is obtained which can be crystallized from diisopropyl ether.

0.15 g of white crystals are obtained.

LC-MS：M+H＝422

m.p.(℃)：129-130℃

¹H NMR(CDCl₃) δ (ppm): 2.95(d, 3H); 3.20-3.35(m, 4H); 3.65-3.80(m, 4H); 4.65(s, 2H); 6.05 (width s, 1H); 7.05(d, 2H); 7.50-7.60(m, 4H); 7.65-7.80(m, 2H)

Example 3 (Compound 76)

2- (methylamino) -2-oxoethyl 4- {5- [3- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate

3.1.1, 1-Dimethylethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate

29.2 g (157mmol) of1, 1-dimethylethyl 1-piperazine carboxylate, 37 g (157mmol) of 2, 5-dibromopyridine and 21.7 g (157mmol) of potassium carbonate suspended in 27 ml of dimethyl sulfoxide (DMSO) are added to the reaction vessel. The mixture was then heated at 150 ℃ for 21 hours.

The reaction mixture was returned to room temperature, treated with ethyl acetate and water, and then the insoluble material was separated by filtration. The aqueous phase was separated, extracted twice with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with 99/1 of a mixture of dichloromethane and methanol.

44 g of product are thus obtained in the form of a white solid.

m.p.(℃)：83-85℃

3.2.1- (5-bromo-2-pyridinyl) piperazine

To a solution of 18.60 g (54.40mmol) of1, 1-dimethyl-ethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate obtained in step 3.1, 100 ml of 1.4-dioxane was added 49 ml (272mmol) of hydrochloric acid in isopropanol at room temperature. The reaction mixture was then held at about 60 ℃ for 3 hours.

The mixture was concentrated to dryness under reduced pressure. The dihydrochloride salt obtained is taken up in 200 ml of dichloromethane and 200 ml of water, after which 10 g of sodium bicarbonate are added in portions with stirring. The phases were separated by settling, the aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure.

12 g of product are obtained in the form of a white solid.

m.p.(℃)：72℃

3.3.2- (ethoxy) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.2). Starting from 6 g (24.80mmol) of 1- (5-bromo-2-pyridinyl) piperazine obtained in step 3.2 and 10.88 g (48.52mmol) of ethyl [ (phenoxycarbonyl) oxy ] acetate prepared in step 1.1 of example 1, 6.70 g of the product are obtained in the form of an oil which crystallizes to a white solid after chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane of 15/85 then 30/70.

3.4.2- (ethoxy) -2-oxoethyl 4- {5- [3- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.3). Starting from 3 g (8.06mmol) of 2- (ethoxy) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazine-carboxylic acid ester obtained in step 3.3, 4.59 g (24.17mmol) of 3- (trifluoromethyl) phenylboronic acid, 6.84 g (32.23mmol) of potassium phosphate hydrate and 0.93 g (0.806mmol) of tetrakis (triphenylphosphine) palladium, 2.22 g of product are obtained in the form of a white solid after chromatography on silica gel, eluting with a mixture of 30/70 of ethyl acetate and cyclohexane.

3.5.2- (methylamino) -2-oxoethyl 4- {5- [3- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.4). Starting from 1.50 g (3.43mmol) of 2- (ethoxy) -2-oxoethyl 4- {5- [3- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate obtained in step 3.4 and 8.6 ml (17.15mmol) of methylamine in tetrahydrofuran (2M), 1.18 g of the product are obtained in the form of a white solid after chromatography on silica gel, eluting with 97/3 of a mixture of dichloromethane and methanol and then washing with diisopropyl ether.

LC-MS：M+H＝423

m.p.(℃)：158-160℃

¹HNMR(CDCl₃) δ (ppm): 2.90(d, 3H); 3.75 (broad s, 8H); 4.65(s, 2H); 6.05 (broad s, 1H); 6.75(d, 1H); 7.50-7.80 (multiplet, 5H); 8.50(d, 1H).

Example 4 (Compound 79)

2- (methylamino) -2-oxoethyl 4- {5- [4- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate

4.1.2- (ethoxy) -2-oxoethyl 4- {5- [4- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.3). Starting from 4 g (10.75mmol) of 2- (ethoxy) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazine-carboxylate obtained in step 3.3 of example 3, 5.50 g (28.96mmol) of 4- (trifluoromethyl) phenylboronic acid, 9.12 g (42.99mmol) of potassium phosphate hydrate and 1.24 g (1.07mmol) of tetrakis (triphenylphosphine) palladium, 2.78 g of product are obtained in the form of a white solid after chromatography on silica gel, eluting with a mixture of 30/70 of ethyl acetate and cyclohexane.

4.2.2- (methylamino) -2-oxoethyl 4- {5- [4- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.4). Starting from 2.77 g (6.33mmol) of 2- (ethoxy) -2-oxoethyl 4- {5- [4- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate obtained in step 4.1 and 15.80 ml (31.67mmol) of methylamine in tetrahydrofuran (2M), 1.69 g of the product are obtained in the form of a white solid after chromatography on silica gel, eluting with 97/3 of a mixture of dichloromethane and methanol and subsequent recrystallization from ethyl acetate.

LC-MS：M+H＝423

m.p.(℃)：206-209℃

¹H NMR(CDCl₃) δ (ppm): 2.90(d, 3H); 3.70 (broad s, 8H); 4.65(s, 2H); 6.05 (broad s, 1H); 6.75(d, 1H); 7.60-7.75(m, 4H); 7.80(dd, 1H); 8.50(d, 1H).

Example 5 (Compound 83)

2- (methylamino) -2-oxoethyl 4- (5- {4- [ (trifluoromethyl) oxy ] phenyl } -2-pyridyl) -1-piperazinecarboxylate

1.1.1, 1-Dimethylethyl 2- (methylamino) -2-oxoethyl 1, 4-piperazinedicarboxylate

A solution of 0.53 g (2.85mmol) of1, 1-dimethylethyl 1-piperazine carboxylate in 5ml of1, 2-dichloroethane is added dropwise at about 0 ℃ to a solution of 1.1 g (3mmol) of 2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate prepared in step 2.2 of example 2 in 10 ml of1, 2-dichloroethane cooled to 0 ℃. Stirring was continued at 0 ℃ for 1 hour, followed by stirring at room temperature for 3 hours.

The reaction mixture was concentrated under reduced pressure and the residue thus obtained was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane of 20/80. The gradient was gradually increased and elution was completed with ethyl acetate.

An oily residue is obtained which can be crystallized from diisopropyl ether.

0.61 g of product was obtained as a white solid and used in the next step without further purification.

5.2.2- (methylamino) -2-oxoethyl-1-piperazinecarboxylic acid ester hydrochloride

25ml of a 6N solution of hydrogen chloride in isopropanol are added to a solution of 2.68 g (8.9mmol) of 2- (methylamino) -2-oxoethyl-1, 1-dimethylethyl-1, 4-piperazinedicarboxylate obtained according to step 5.1 in 25ml of dichloromethane. Stirring was continued at room temperature for 1 hour.

The organic phase was removed by filtration through a hydrophobic cartridge and the acidic aqueous phase was concentrated under reduced pressure.

After crystallization from isopropanol, 2.05 g of the product was obtained as a white solid, which was used in the next step without further purification.

m.p.(℃)：167-169℃

5.3.2- (methylamino) -2-oxoethyl 4- (5-nitro-2-pyridinyl) -1-piperazinecarboxylate

1.84 g (11.6mmol) of 2-chloro-5-nitropyridine are added to a solution of 2.05 g (8.62mmol) of 2- (methylamino) -2-oxoethyl 1-piperazinecarboxylate hydrochloride and 3.85 ml (22.4mmol) of N, N-diisopropylethylamine in 55 ml of1, 2-dichloroethane obtained in step 5.2. The reaction mixture was kept at 70 ℃ for 5 hours.

The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue thus obtained was purified by chromatography on silica gel, eluting with 98/2 of a mixture of dichloromethane and methanol.

2.48 g of the product were obtained as a pale yellow solid and used in the next step without further purification.

5.4.2- (methylamino) -2-oxoethyl 4- (5-amino-2-pyridinyl) -1-piperazinecarboxylate

0.24 g of 10% palladium on activated carbon was added to a suspension of 0.64 g (1.98mmol) of 2- (methylamino) -2-oxoethyl 4- (5-nitro-2-pyridinyl) -1-piperazinecarboxylate prepared in step 5.3 in 90 ml of ethyl acetate. Stirring was continued at room temperature for 14 hours under a 60psi hydrogen atmosphere.

After filtering off the catalyst, the filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica, eluting with 98/2 of a mixture of dichloromethane and methanol.

0.47 g of product was obtained as a violet oil and used in the next step without further purification.

5.5.2- (methylamino) -2-oxoethyl 4- (5-iodo-2-pyridinyl) -1-piperazinecarboxylate

A solution of 0.16 g (2.2mmol) of sodium nitrite in 3.5 ml of water was slowly added to a solution of 0.47 g (1.5mmol) of 2- (methylamino) -2-oxoethyl 4- (5-amino-2-pyridinyl) -1-piperazinecarboxylate in 15 ml of aqueous sulfuric acid (0.33N) prepared in step 5.4, cooled to 0 ℃. Stirring was continued at about 0 ℃ for half an hour and 0.83 g (5mmol) of potassium iodide was added slowly. Stirring was continued at this temperature for half an hour and then the reaction mixture was held at 85 ℃ for 2 hours.

After cooling to room temperature, the reaction medium is basified to pH 14 by addition of saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed with 35% aqueous thiosulfite solution, water, brine and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by chromatography on silica gel, eluting with 98/2 of a mixture of dichloromethane and methanol.

After washing with diisopropyl ether, 0.35 g of the product is obtained in the form of a beige solid, which can be used in the next step without purification.

5.6.2- (methylamino) -2-oxoethyl 4- (5- {4- [ (trifluoromethyl) oxy ] phenyl } -2-pyridyl) -1-piperazinecarboxylate

The process was carried out as described in example 2 (step 2.4). Starting from 0.250 g (0.61mmol) of 2- (methylamino) -2-oxoethyl 4- (5-iodo-2-pyridinyl) -1-piperazinecarboxylate obtained in step 5.5, 0.51 g (2.44 mol) of 4- (trifluoromethoxy) phenylboronic acid, 0.61 g (. about.8 mol%) of the palladium catalyst on solid support prepared in step 2.1 of example 2, and 2.9 ml (7.32mmol) of aqueous sodium carbonate (2.5M) suspended in 12 ml of toluene and 3 ml of ethanol, 0.092 g of the product is obtained in the form of a white solid after chromatography on silica gel, elution with a mixture of 98/2 of dichloromethane and methanol, and then washing with diisopropyl ether.

LC-MS：M+H＝439

m.p.(℃)：188-190℃

¹H NMR(CDCl₃) (ppm): 2.90(d, 3H); 4.70 (broad s, 8H); 4.65(s, 2H); 6.05 (broad s, 1H); 6.75(dd, 1H); 7.30(d, 2H); 7.55(d, 2H); 7.75(dd, 1H); 8.45(dd, 1H).

Example 6 (Compound 63)

2- (methylamino) -2-oxoethyl 4- [5- (2-methylpropyl) -2-pyridinyl ] -1-piperazinecarboxylic acid ester

6.1.2- (methylamino) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.4). Starting from 2.20 g (5.91mmol) of 2- (ethoxy) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate obtained in step 3.3 of example 3 and 14.80 ml (29.55mmol) of methylamine in tetrahydrofuran (2M), the product is obtained after crystallization from diisopropyl ether in the form of a white solid.

6.2.2- (methylamino) -2-oxoethyl 4- [5- (2-methylpropyl) -2-pyridinyl ] -1-piperazinecarboxylate

0.88 g (2.47mmol) of 2- (methylamino) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate obtained in step 6.1, 0.33 g (3.22mmol) of isobutylboronic acid, 1.16 g (5.44mmol) of potassium phosphate hydrate and 0.07 g (0.25mmol) of tricyclohexylphosphine suspended in 11 ml of toluene were put together under an inert atmosphere. Then 0.028 g (0.12mmol) of palladium diacetate was added. The reaction mixture was then refluxed for 3 hours.

The mixture was allowed to cool to room temperature, then 15 ml of water and 15 ml of ethyl acetate were added. The salts were separated by filtration through a porous lake, the phases were separated by sedimentation, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After removal of the solvent by evaporation, the residue obtained is chromatographed on silica gel, eluting with 97/3 of a mixture of dichloromethane and methanol.

After crystallization from diisopropyl ether, 0.17 g of product is obtained in the form of a white solid.

LC-MS：M+H＝335

m.p.(℃)：127-129℃

¹H NMR(CDCl₃) δ (ppm): 0.90(d, 6H); 1.80(m, 1H); 2.35(d, 2H); 2.90(d, 3H); 3.60(m, 8H); 4.65(s, 2H); 6.10 (width s, 1H); 6.60(d, 1H); 7.35(dd, 1H); 8.0(d, 1H).

Example 7 (Compound 85)

2- (methylamino) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate

7.1.1, 1-Dimethylethyl 4- (3-pyridyl) -1-piperazinecarboxylate

7.07 g (44.74mmol) of 3-bromopyridine, 10 g (53.69mmol) of1, 1-dimethylethyl 1-piperazinecarboxylate, 6.02 g (62.64mmol) of sodium tert-butoxide and 0.836 g (1.34mmol) of (2, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl) (BINAP) suspended in 100 ml of toluene are introduced under inert atmosphere. Then 0.41 g (0.45mmol) of [ tris (dibenzylideneacetone) dipalladium ] (Pd2(dba)3) was added. The reaction mixture was then refluxed for 22 hours.

The mixture was allowed to cool to room temperature, the salt was isolated by filtration through glass fiber, and the filtrate was concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and 100 ml of water, the aqueous phase is separated off and extracted several times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue thus obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol of 98/2 and then 95/5.

9.80 g of product are obtained in the form of an oil which crystallizes at room temperature.

7.2.1, 1-Dimethylethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate

2.70 g (15.19mmol) of N-bromosuccinimide (NBS) were added portionwise to a solution of 4 g (15.19mmol) of1, 1-dimethylethyl 4- (3-pyridyl) -1-piperazinecarboxylate obtained in step 7.1 in 50ml of acetonitrile, cooled to about 0 ℃. Stirring was continued at 0 ℃ for 15 minutes and then at room temperature for 2 hours.

To the reaction medium were added 100 ml of aqueous sodium hydroxide (1M) and 100 ml of ethyl acetate. The aqueous phase was separated, extracted twice with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and the filtrate was concentrated under reduced pressure.

Thus 5.16 g of the product were obtained in the form of an orange-yellow solid and used in the next step without further purification.

7.3.1- (6-bromo-3-pyridinyl) piperazine

11.20 ml (150.77mmol) of trifluoroacetic acid are slowly added to a suspension of 5.16 g (15.08mmol) of the 1, 1-dimethylethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate obtained in step 7.2 in 70 ml of dichloromethane. Stirring was continued at room temperature for 16 hours.

The reaction mixture was concentrated under reduced pressure, and the residue was taken up in 40 ml of chloroform, followed by slow addition of 4 ml of aqueous sodium hydroxide solution (10M). The aqueous phase was separated and then extracted twice with chloroform. The organic phases were combined and washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the filtrate was concentrated under reduced pressure.

This gives 5.16 g of product in the form of an orange oil which crystallizes at room temperature. This product was used in the next step without further purification.

7.4.2- (ethoxy) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.2). Starting from 3.57 g (14.76mmol) of 1- (6-bromo-3-pyridinyl) piperazine obtained in step 7.3, and 3.97 g (17.71mmol) of ethyl [ (phenoxycarbonyl) oxy ] acetate prepared in example 1, step 1.1, chromatography on silica gel eluting with a mixture of 99/1 late 98/2 dichloromethane and methanol gives 3.75 g of the product as a yellow oil which crystallizes at room temperature.

7.5.2- (ethoxy) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.3). Starting from 1.28 g (3.43mmol) of 2- (ethoxy) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate obtained in step 7.4, 1.96 g (10.29mmol) of 3- (trifluoromethyl) phenylboronic acid, 2.91 g (13.72mmol) of potassium phosphate hydrate and 0.40 g (0.34mmol) of tetrakis (triphenylphosphine) palladium, 0.98 g of pure product is obtained in the form of an oil which crystallizes at room temperature after chromatography on silica gel eluting with a mixture of 35/65 ethyl acetate and cyclohexane.

7.6.2- (methylamino) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate

The method described in example 1 (step 1.4) was used. Starting from 0.60 g (1.37mmol) of 2- (ethoxy) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate obtained in step 7.5, and 3.40 ml (6.86mmol) of methylamine in tetrahydrofuran (2M), after chromatography on silica gel, eluting with a mixture of 98/2 and then 97/3 of dichloromethane and methanol, and then washing with diisopropyl ether, 0.36 g of the pure product is obtained in the form of a white solid.

LC-MS：M+H＝423

m.p.(℃)：146-150℃

¹H NMR(CDCl₃) δ (ppm): 2.90(d, 3H); 3.35(m, 4H); 3.80(m, 4H); 4.65(s, 2H); 6.05 (width s, 1H); 7.30(m, 1H); 7.65(m, 2H); 7.70(d, 1H); 8.10(d, 1H); 8.25(s, 1H); 8.45(d, 1H).

Example 8 (Compound 86)

2-amino-2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate

5.90 ml (41.40mmol) of ammonia in methanol (7N) were added to a solution of 0.30 g (0.69mmol) of 2- (ethoxy) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate obtained in example 7, step 7.5. in 6 ml of a mixture of 1/1 methanol and tetrahydrofuran. Stirring was continued at room temperature for 22 hours.

After concentration under reduced pressure, the residue obtained is purified by chromatography on silica, eluting with 96/4 of a mixture of dichloromethane and methanol, and then washed with diisopropyl ether.

0.19 g of pure product is obtained in the form of a yellow solid.

LC-MS：M+H＝409

m.p.(℃)：155-157℃

¹HNMR(CDCl₃) δ (ppm): 3.35(m, 4H); 3.75(m, 4H); 4.70(s, 2H); 5.50 (width s, 1H); 6.0 (width s, 1H); 7.30(m, 1H); 7.55(m, 2H); 7.70(d, 1H); 8.10(d, 1H); 8.25(s, 1H); 8.40(d, 1H).

Example 9 (Compound 66)

2- (methylamino) -2-oxoethyl 4- [6- (2-methylpropyl) -3-pyridinyl ] -1-piperazinecarboxylic acid ester

9.1.2- (methylamino) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate

The method described in example 1 (step 1.4) was used. Starting from 2.35 g (6.32mmol) of 2- (ethoxy) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate obtained in example 7, step 7.4, and 15.80 ml (31.61mmol) of methylamine in tetrahydrofuran (2M), chromatography on silica gel gave 1.779 g of product as a white solid after elution with 98/2 and then 97/3 of a mixture of dichloromethane and methanol.

m.p.(℃)：164℃

9.2.2- (methylamino) -2-oxoethyl 4- [6- (2-methylpropyl) -3-pyridinyl ] -1-piperazinecarboxylate

1.25 g (3.50mmol) of 2- (methylamino) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate prepared in step 9.1, and 0.12 g (0.17mmol) of dichlorobis (triphenylphosphine) palladium (Pd (PPh) suspended in 7 ml of tetrahydrofuran are introduced under an inert atmosphere₃)₂Cl₂) Then 17.50 ml (8.74mmol) of a solution of isobutyl zinc bromide in tetrahydrofuran (0.5M) were added. Stirring was continued at room temperature for 19 hours.

The reaction mixture was poured into 25mL of water and 25mL of ethyl acetate. The insoluble material was filtered off through glass fibers. The phases were separated by settling, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica, eluting with 95/5 of a mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether.

0.36 g of product is obtained in the form of a brown solid.

LC-MS：M+H＝335

m.p.(℃)：87-89℃

¹H NMR(CDCl₃) δ (ppm): 0.90(d, 6H); 2.05(m, 1H); 2.60(d, 2H); 2.90(d, 3H); 3.20(m, 4H); 3.70(m, 4H); 4.65(s, 2H); 6.05 (width s, 1H); 7.0-7.20(m, 2H); 8.25(d, 1H).

Example 10 (Compound 87)

2- (methylamino) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridazinyl } -1-piperazinecarboxylate

10.1.2- (ethoxy) -2-oxoethyl 4- (6-chloro-3-pyridazinyl) -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.2). Starting from 1.60 g (8.05mmol) of 3-chloro-6- (1-piperazinyl) pyridazine (J.Med.chem., 18, 2002, 4011. sup. 4017) and 1.99 g (8.86mmol) of ethyl [ (phenoxycarbonyl) oxy ] acetate prepared in example step 1.1, 1.70 g of the product are obtained in the form of a white solid after chromatography on silica gel, eluting with a mixture of 98/2 dichloromethane and methanol.

m.p.(℃)：149-151℃

10.2.2- (ethoxy) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridazinyl } -1-piperazinecarboxylate

The process was carried out as described in example 1 (step 1.3). Starting from 1.15 g (3.50mmol) of 2- (ethoxy) -2-oxoethyl 4- (6-chloro-3-pyridazinyl) -1-piperazinecarboxylate obtained in step 10.1, 1.99 g (10.49mmol) of 3- (trifluoromethyl) phenylboronic acid, 2.97 g (13.99mmol) of potassium phosphate hydrate and 0.40 g (0.35mmol) of tetrakis (triphenylphosphine) palladium, 0.67 g of pure product is obtained in solid form after chromatography on silica gel, elution with a mixture of ethyl acetate and cyclohexane of 35/65 and then 45/55.

m.p.(℃)：126-128℃

10.3.2- (methylamino) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridazinyl } -1-piperazinecarboxylate

The method described in example 1 (step 1.4) was used. Starting from 0.66 g (1.51mmol) of the 2- (ethoxy) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridazinyl } -1-piperazinecarboxylate obtained in step 10.2. and 3 ml (6.02mmol) of methylamine in tetrahydrofuran (2M), after chromatography on silica gel eluting with a mixture of 96/4 of dichloromethane and methanol and then washing with diisopropyl ether, 0.50 g of the product are obtained in the form of a white solid.

LC-MS：M+H＝424

m.p.(℃)：151-153℃

¹H NMR(DMSO)δ(ppm)：2.60(d，3H)；3.55(m，4H)；3.75(m，4H)；4.45(s，2H)；7.40(d，1H)；7.80(m，3H)；8.10(d，1H)；8.35(m，2H).

Example 11 (Compound 103)

2- (methylamino) -2-oxoethyl 4- (5- {4- [ (trifluoromethyl) oxy ] phenyl } -2-pyridyl) -1, 4-diazepan-1-carboxylate

11.1.1, 1-Dimethylethyl 4- (5-bromo-2-pyridinyl) -1, 4-diazepan-1-carboxylate

1.03 g (5mmol) of1, 1-dimethylethyl 1, 4-diazepan-1-carboxylate, 1.19 g (5mmol) of 2, 5-dibromopyridine and 0.7 g (5mmol) of potassium carbonate suspended in 0.90 ml of dimethyl sulfoxide (DMSO) are introduced into the reaction vessel. The mixture was heated at 150 ℃ for 22 hours.

The reaction mixture was returned to room temperature and taken up in ethyl acetate. The organic solution was washed with water then brine and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by chromatography on silica gel, eluting with a mixture of 99.5/0.5 of dichloromethane and methanol.

1.63 g of product are obtained in the form of an oil and can be used in the next step without further purification.

11.2.1- (5-bromo-2-pyridinyl) -1, 4-diazepane

To the 1.63 g (4.4mmol)1, 1-dimethylethyl 4- (5-bromo-2-pyridinyl) -1, 4-diazepan-1-carboxylate solution obtained in step 11.1 in 12 ml dioxane and 4 ml ethanol was added 6 ml isopropanol solution of hydrogen chloride (6N). The reaction mixture was maintained at 70 ℃ for 3 hours.

The mixture was allowed to return to room temperature and then concentrated under reduced pressure. After crystallization from acetone, 1.32 g of a white solid are obtained.

The crystals were taken up in 10 ml of dichloromethane and the reaction medium was basified to pH 14 by addition of 28% ammonia solution. The organic phase was recovered by filtration through a hydrophobic cartridge and the filtrate was concentrated under reduced pressure.

0.96 g of product was obtained in the form of an oil and was used in the next step without further purification.

11.3.2- (methylamino) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1, 4-diazepan-1-carboxylic acid ester

The process was carried out as described in example 1 (step 1.2). Starting with 0.95 g (3.70mmol) of 1- (5-bromo-2-pyridinyl) -1, 4-diazepan obtained in step 11.2, and 0.94 g (3.70mmol) of 2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate prepared in step 2.2 of example 2, was chromatographed on silica gel, eluting with a mixture of 30/70 of ethyl acetate and cyclohexane, then with a mixture of 95/5 of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.97 g of the product were obtained in the form of a white solid.

11.4.2- (methylamino) -2-oxoethyl 4- (5- {4- [ (trifluoromethyl) oxy ] phenyl } -2-pyridyl) -1, 4-diazepan-1-carboxylate

Into a Pyrex reactor were introduced 0.12 g (0.3mmol) of 2- (methylamino) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1, 4-diazepan-1-carboxylate prepared in step 11.3, 0.25 g (1.2mmol) of 4- (trifluoromethoxy) phenylboronic acid and 0.9 ml (1.8mmol) of aqueous sodium carbonate solution (2M) suspended in 3.5 ml of toluene and 0.8 ml of ethanol. Then 0.07 g (0.06mmol) of tetrakis (triphenylphosphine) palladium was added and after sealing the reactor it was maintained under microwave irradiation at 150 ℃ for 15 minutes.

The organic phase is recovered after separation of the phases by settling and the filtrate is concentrated under reduced pressure. The residue thus obtained was purified by chromatography on silica gel eluting with 30/70/5 of a mixture of ethyl acetate, cyclohexane and methanol.

After crystallization from diisopropyl ether, 0.078 g of product is obtained in the form of a white solid.

LC-MS：M+H＝452

m.p.(℃)：191-193℃

¹H NMR (DMSO) (ppm): 1.70-2.00(m, 2H); 2.55(d, 3H); 3.25-3.40(m, 2H); 3.40-3.90(m, 6H); 4.35(d, 2H); 6.75(d, 1H); 7.35(d, 2H); 7.70 (width d, 2H + NH); 7.80(dd, 1H); 8.45(d, 1H).

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," base "means the compound in the free base form, and" HCl "means the compound in the hydrochloride form. In the table, OMe represents methoxy group.

Under the column "m.p. (° c)" or M + H ", m.p. (° c) is the melting point of the compound in degrees celsius, and M + H is the value of the mass of the compound protonated by a hydrogen atom (mass of the compound +1) as determined by LC-MS (liquid chromatography-mass spectrometry).

TABLE 1

The compounds of the present invention were subjected to pharmacological tests to determine their inhibitory effect on the enzyme FAAH (fatty acid amidohydrolase).

Inhibitory Activity can be used in a Radioactive enzyme assay to use anandamide [ ethanolamine 1-³H](ethanolamine [1-³H]) Is demonstrated on the basis of the determination of (a). (Life sciences (1995), 56, 1999, 2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729, 734). Thus, the mouse brain (minus cerebellum) was removed and stored at-80 ℃. Membrane homogenates in 10mM Tris-HCl buffer (pH 8) containing 150mM NaCl and 1mM EDTA were prepared extemporaneously by homogenizing the tissue with a Polytron machine. The enzymatic reaction was then carried out in 70. mu.l of buffer containing bovine serum albumin without aliphatic acid (1 mg/ml). Different test compounds, anandamide [ ethanolamine 1-³H](specific activity 15-20Ci/mmol) was diluted to 10. mu.M with cold anandamide and membrane preparations (400. mu.g of fused tissue per run) were added sequentially. After 15 minutes at 25 ℃ the enzymatic reaction was quenched by addition of 140. mu.L chloroform/methanol (2: 1).The mixture was stirred for 10 minutes and then centrifuged at 3500g for 15 minutes. Liquid scintillation on ethanolamine [1-³H]An aliquot (30. mu.L) of the aqueous phase was counted.

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

Table 2 below shows the IC of the compounds according to the invention₅₀The value is obtained.

TABLE 2

Compound numbering	IC
		34	0.020μM
37	0.190μM
		43	0.044μM
44	0.007μM
		76	0.290μM
83	0.012μM

It can be seen that the compounds according to the invention have an inhibitory activity of the enzyme FAAH.

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

Thus, intraperitoneal (i.p.) administration OF PBQ (benzoquinone, 2mg/kg in 0.9% sodium chloride solution containing 5% ethanol) to 25 to 30 g heavy male OF1 mice resulted in abdominal elongation with an average twist or contraction OF 30 times over a period OF 5 to 15 minutes post injection. Test compounds were administered orally as a 0.5% suspension in tween 80 60 minutes or 120 minutes prior to PBQ administration. Under these conditions, the most effective compounds of the invention reduce the elongation induced by PBQ by 35 to 70% at doses ranging between 1 and 30 mg/kg.

Table 3 below shows the results of the analgesia test for some compounds according to the invention.

TABLE 3

Compound numbering	Number of elongations (%)
		37	-57(a)
44	-53(a)
		76	-47(a)

(a)1mg/kg p.o., 2 hours

The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyzes the hydrolysis of both endogenous derivatives of amides and of various fatty acid esters, for example N-arachidonoylethanolamide (anandamide), N-palmitoylethanolamide, N-oleoylethanolamide, oleamide or 2-arachidonylglycerol. These derivatives exert various pharmacological activities through interactions with, inter alia, cannabinoid and vanilloid receptors.

The compounds of the invention can block this degradation pathway and increase the tissue content of these endogenous substances. In this respect they may be used for the prevention and treatment of pathologies in which endogenous cannabinoids and/or any other substrate metabolized by the enzyme FAAH are involved. Mention may be made, for example, of the following diseases and disorders:

pain, particularly acute or chronic pain of the neurogenic type: migraine, neuropathic pain including forms associated with herpes viruses and diabetes; acute or chronic pain associated with inflammatory diseasesPain: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pain; vertigo; vomiting; nausea, especially for continuous chemotherapy; eating disorders, especially anorexia and extreme emaciation of different natures; neurological and psychiatric disorders: tremor, dyskinaesia, dystonia, spasticity, obsessive-compulsive behavior, Tourette's syndrome, all forms of depression and anxiety of any nature or origin, mood disorders, psychotic disorders; acute and chronic neurodegenerative diseases: parkinson's disease, Alzheimer's disease, senile dementia, huntington's chorea, lesions associated with cerebral ischemia and with cranial and bone marrow trauma; epilepsy; sleep disorders including sleep apnea; cardiovascular diseases, in particular hypertension, cardiac arrhythmias, arteriosclerosis, heart attacks, cardiac ischemia; renal ischemia; cancer: benign skin tumors, papilloma and cerebroma, prostate cancer, brain tumors (malignant glioma, medulloblastoma, neuroblastoma, tumors of embryonic origin, astrocytoma, ependymoma, oligodendritic glioma, vascular or fibroplex cancer, neuroepithelial tumors, pineal gland tumors, ependymoma, malignant meningioma, sarcoidosis, malignant melanoma, schwannoma); disorders of the immune system, in particular autoimmune diseases: psoriasis, lupus erythematosus, connective tissue disease,syndromes, ankylosing spondylitis, undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, diseases affecting the plasma cell line; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; parasitic, viral or bacterial infections: AIDS, meningitis; inflammatory diseases, in particular joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;osteoporosis; eye discomfort: ocular hypertension, glaucoma; lung diseases: diseases of the respiratory pathway, bronchospasm, cough, asthma, chronic bronchitis, chronic obstructive pulmonary disease, emphysema; gastrointestinal diseases: irritable bowel syndrome, inflammatory disorders of the bowel, ulcers, diarrhoea; urinary incontinence and bladder inflammation.

The use of a compound according to the invention in the form of a base, a pharmaceutically acceptable acid addition salt, a hydrate or a 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 relates to medicaments 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 pathologies mentioned above.

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

The excipients may be selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active ingredient of formula (I) above, or a suitable acid addition salt thereof, or a suitable solvate or hydrate thereof, may be administered to animals and humans in unit administration form in admixture with standard pharmaceutical excipients for the prevention or treatment of the above-mentioned disorders or diseases.

Suitable unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms. For topical application, the compounds according to the invention may be used in creams, ointments or lotions.

By way of example, a unit dosage 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

The unit dosage forms are dosed so that 0.01 to 20 mg of active principle is administered per kilogram of body weight per day in galenic form.

Higher or lower doses may be appropriate in particular cases, and such doses are also intended to be encompassed by the present invention. Conventionally, the dosage appropriate for each patient is determined by the physician according to the mode of administration, and the weight and sensitivity of the patient.

According to another aspect, the invention also relates to a method for treating the pathologies described above, comprising the administration of an effective dose of a compound according to the invention, of an addition salt thereof with a pharmaceutically acceptable acid, of a solvate or of a hydrate of said compound.

Claims (14)

1. A compound of formula (I)

Wherein

m represents an integer equal to 1 or 2;

R₁represents a group selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolineA group, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl, isothiazolopyridyl,

these radicals being optionally substituted by one or more radicals R₃Substituted, R₃May be the same or different, or optionally substituted by a group R₄Substitution;

R₂is represented by the general formula CHR₅CONHR₆The group of (a) or (b),

R₃represents a halogen atom or a hydroxyl group, a cyano group, a nitro group, C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-sulfanyl radical, C_1-6-fluoroalkyl radical, C_1-6-fluoroalkoxy, -O- (C)_2-3-alkylene) -, -O- (C)_1-3-alkylene) -O-, C_1-6-fluorosulfanylalkyl radical, C_3-7-cycloalkyl radical, C_3-7-cycloalkyl-C_1-3Alkylene, piperidinyl, benzyloxy, piperazinyl, pyrrolidinyl, morpholinyl, phenoxy, NR₇R₈，NHCOR₇，NHSO₂R₇，COR₇，CO₂R₇，CONR₇R₈，SO₂R₇Or SO₂NR₇R₈The radical(s) is (are),

R₄represents a group selected from: phenyl, benzofuranyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, imidazopyrimidinyl, benzothienyl, indolyl, benzoxazolyl, pyrazinyl, cinnolinyl, thiadiazolyl, thiazolinyl, thiaOxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, imidazopyrimidinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl, isothiazolo-pyridyl;

radical R₄May be substituted by one or more radicals R₃Substituted, R₃May be the same or different;

R₅represents a hydrogen atom or C_1-3-an alkyl group;

R₆represents a hydrogen atom or C_1-6-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-an alkylene group;

R₇and R₈Independently of each other, represents a hydrogen atom, C_1-3-alkyl or phenyl;

the compounds are in the form of bases or of addition salts with acids.

2. A compound of formula (I) according to claim 1, characterized in that:

m represents an integer equal to 1 or 2;

R₁represents a group selected in particular from: phenyl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, benzisoxazolyl and thienopyridyl, which radicals are optionally substituted by one or more radicals R₃Substituted, R₃May be the same or different;

R₂is represented by the general formula CHR₅CONHR₆A group of (a);

R₃represents a halogen atom or a cyano group, C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-fluoroalkyl radical, C_1-6-fluoroalkoxy, -O- (C)_2-3-alkylene) -, phenoxy;

R₅represents a hydrogen atom;

R₆represents a hydrogen atom or C_1-6-an alkyl group.

3. A compound of formula (I) according to claim 1 or 2, characterized in that:

m is equal to 1;

R₁represents a group selected in particular from: pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, which radicals are optionally substituted by radicals R₃Substitution;

R₂is represented by the general formula CHR₅CONHR₆A group of (a);

R₃represents a halogen atom, or C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-a fluoroalkyl group;

R₅represents a hydrogen atom;

R₆represents a hydrogen atom or C_1-6-an alkyl group.

4. A compound of formula (I) according to claim 1, characterized in that:

m represents an integer equal to 1 or 2;

R₁represents a group selected in particular from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl,

the radical being optionally substituted by a radical R₄Substitution;

R₄represents a group selected in particular from: phenyl, benzofuranyl, naphthyl; the group R₄May be substituted by one or more radicals R₃Substituted, R₃May be the same or different;

R₂is represented by the general formula CHR₅CONHR₆A group of (a);

R₃represents a halogen atom or a nitro group, C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-fluoroalkyl radical, C_1-6-fluoroalkoxy, -O- (C)_1-3-alkylene) -O-, benzyloxy;

R₅represents a hydrogen atom;

R₆represents a hydrogen atom or C_1-6-alkyl or C_3-7-cycloalkyl-C_1-3-an alkylene group.

5. Compounds of formula (I) according to claim 1 or 4, characterized in that:

m is equal to 1;

R₁represents a group selected in particular from: phenyl, pyridyl, pyridazinyl, pyrimidinyl,

the radical being optionally substituted by a radical R₄Substitution;

R₄represents a group selected in particular from: phenyl, benzofuranyl, naphthyl; the group R₄May be substituted by one or more radicals R₃Substituted, R₃May be the same or different;

R₂is represented by the general formula CHR₅CONHR₆A group of (a);

R₃represents a halogen atom or a nitro group, C_1-6-alkyl radical, C_1-6-alkoxy radical, C_1-6-fluoroalkyl radical, C_1-6-fluoroalkoxy, -O- (C)_1-3-alkylene) -O-, benzyloxy;

R₅represents a hydrogen atom;

R₆represents a hydrogen atom or C_1-6-an alkyl group.

6. A compound of formula (I) according to claim 1, selected from:

-2- (methylamino) -2-oxoethyl 4- { 4' - [ (trifluoromethyl) oxy ] -4-biphenyl } -1-piperazine carboxylate,

-2- (methylamino) -2-oxoethyl 4- [ 3' - (trifluoromethyl) -4-biphenyl ] -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- {5- [3- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- {5- [4- (trifluoromethyl) phenyl ] -2-pyridinyl } -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- (5- {4- [ (trifluoromethyl) oxy ] phenyl } -2-pyridyl) -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- [5- (2-methylpropyl) -2-pyridinyl ] -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate,

-2-amino-2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridinyl } -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- [6- (2-methylpropyl) -3-pyridinyl ] -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- {6- [3- (trifluoromethyl) phenyl ] -3-pyridazinyl } -1-piperazinecarboxylate,

-2- (methylamino) -2-oxoethyl 4- (5- {4- [ (trifluoromethyl) oxy ] phenyl } -2-pyridyl) -1, 4-diazepan-1-carboxylate.

7. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6, comprising the steps of:

an amine of the general formula (II),

wherein R is₁And m is as defined for formula (I) according to any one of claims 1 to 6, with a carbonate of formula (III),

wherein Z represents a hydrogen atom or a nitro group, R₂As defined by general formula (I) according to any one of claims 1 to 6.

8. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6, comprising the steps of: the carbamate of the general formula (Ia),

wherein m and R₁And R₅As defined by general formula (I) according to any one of claims 1 to 6, R represents methyl or ethyl,

by using the general formula R₆NH₂By aminolysis of an amine of (a) wherein R₆As defined in general formula (I) according to any one of claims 1 to 6.

9. A compound corresponding to formula (III) which is 2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate.

10. Corresponding to the compounds of the general formula (Ia),

wherein m and R₁And R₅As defined in formula (I) according to claim 1, R represents methyl or ethyl.

11. A medicament containing a compound of formula (I) according to any one of claims 1 to 6, in the form of its base or of a pharmaceutically acceptable acid addition salt.

12. Pharmaceutical compositions containing at least one compound of formula (I) according to any one of claims 1 to 6, in the form of a base or of a pharmaceutically acceptable acid addition salt, optionally with one or more pharmaceutically acceptable excipients.

13. Use of a compound of formula (I) according to any one of claims 1 to 6, in the form of a base or of a pharmaceutically acceptable acid addition salt, for the preparation of a medicament for the prevention or treatment of a condition involving endogenous cannabinoids and/or any other substrate metabolized by the enzyme FAAH.

14. Use of a compound of formula (I) according to any one of claims 1 to 6, in the form of a base or a pharmaceutically acceptable salt, for the preparation of a medicament for the prevention or treatment of: acute or chronic pain, vertigo, emesis, nausea, eating disorders, neurological and psychiatric conditions, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancer, immune system disorders, allergic diseases, parasitic, viral or bacterial infections, inflammatory diseases, osteoporosis, ocular discomfort, pulmonary discomfort, gastrointestinal diseases or urinary incontinence.