The inventions relates to the compounds of formula (I) where: R is a hydrogen atom or a group selected from the (Cd- C)alkyl and (C-C)-cycloalkyl groups, optionally substituted by one or more groups independently selected from a fluorine atom, the (C-C)-cycloalkyl, (C-C)alkenyl, phenyl, (C-C)alkoxy, and hydroxy groups; the phenyl group being optionally substituted by one or more (C-C)alkoxy groups; R is a phenyl group optionally substituted by one or more substituants independently selected from halogen atoms, the (C-C)alkyl, (C-C)alkoxy, halo-(CC)alkyl, hydroxy, halo-(C-C)alkoxy, (C-C)alkyl-thio, and (C-C)alkyl-SO groups; R is one or more substituants selected from hydrogen atoms, halogen atoms, the halo-(C-C)alkyl, (C-C)alkyl, (C-C)cycloalkyl, (C-C)-cycloalkyl-(C-C)alkyl, (CC)alkoxy, (CC)alkyl-thio, and (C-C)alkyl-SO groups; in the form of a base or an addition salt to an acid. The invention further relates to the use thereof in therapy and to a method for synthesizing same.
DescriptionWO 20101119222 PCT/FR2010/050711 1 DERIVATIVES OF N-[(7-AZABICYCLO[2.2.1 ]HEPT-1 -YL)-ARYL METHYL]BENZAMIDE, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF 5 The present invention relates to N-[(7-azabicyclo[2.2.1 ]hept-1 -yl)-aryl methyl]benzamide derivatives, to the preparation thereof and to the therapeutic use thereof in the treatment or prevention of diseases involving Glyt1 glycine transporters. The compounds of the invention correspond to general formula (I) 10 R N R HN O 15 R2 in which: - R represents a hydrogen atom or a group chosen from the groups (C-C 6 )alkyl and (C3-C7)cycloalkyl, optionally substituted with one or more groups chosen, 20 independently of one another, from halogen atoms and (C 3
-C
7 )cycloalkyl, (Cr C4)alkenyl, phenyl, (C-C 6 )alkoxy and hydroxyl groups; the phenyl group being optionally substituted with one or more (C-C 6 )alkoxy groups; - R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen, independently of one another, from halogen atoms and (C 25 C 6 )alkyl, (C-C 6 )alkoxy, halo-(C-C 6 )alkyl, hydroxyl, halo-(C-C 6 )alkoxy, (C-C 6 )alkyl thio, (C-C 6 )alkyl-SO and (C 1
-C
6 )alkyl-SO 2 groups; - R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo-(C-C 6 )alkyl, (C-C 6 )alkyl, (C3-C7)cycloalkyl, (C 3
-C
7 )cycloalkyl(C
C
3 )alkyl, (C-C 6 )alkoxy, (C-C 6 )alkyl-thio, (C-C 6 )alkyl-SO and (C-C 8 )alkyl-SO2 30 groups; in the form of a base or of an addition salt with an acid. The compounds of formula (I) comprise an asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers, including racemic 35 mixtures, belong to the invention.
WO 20101119222 PCT/FR20101050711 2 The compounds of formula (1) can exist in the form of bases or of addition salts with acids. Such addition salts belong to the invention. 5 These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are of use, for example, for purifying or isolating the compounds of formula (I) also belong to the invention. In the context of the invention: 10 - the expression "Ct.C where t and z can take the values of 1 to 6" is intended to mean a carbon-based chain that can contain from t to z carbon atoms, for example the term "C 1
C
6 " is intended to mean a carbon-based chain that can contain from 1 to 6 carbon atoms; - the term "alkyl" is intended to mean a linear or branched, saturated aliphatic 15 group; for example, a C 1
-C
6 -alkyl group represents a linear or branched carbon based chain containing from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl; - the term "alkylene" is intended to mean a linear or branched, saturated divalent alkyl group; for example, a C 1 e-alkylene group represents a linear or branched, 20 divalent carbon-based chain containing from 1 to 6 carbon atoms, for example a methylene, ethylene, 1-methylethylene or propylene; - the term "alkoxy" is intended to mean an -0-alkyl group; - the term "hydroxyl" is intended to mean an -OH group; - the term "alkyl-thio" is intended to mean a sulphur atom substituted with an alkyl 25 group; - the term "halogen atom" is intended to mean a fluorine, a chlorine, a bromine or an iodine; - the term "halo-alkyl" is intended to mean an alkyl group in which one or more hydrogen atoms have been substituted with halogen. By way of example, 30 mention may be made of trifluoromethyl, trifluoroethyl or pentafluoroethyl groups; - the term "halo-alkoxy" is intended to mean an alkoxy group in which one or more hydrogen atoms have been substituted with halogen. Among the compounds of general formula (1) which are subjects of the invention, a 35 first group of compounds is constituted of the compounds for which: WO 20101119222 PCT/FR2010/050711 3 - R represents a hydrogen atom or a (C-C)alkyl or benzyl group; - Riand R 2 being as defined above. Among the compounds of general formula (I) which are subjects of the invention, a 5 second group of compounds is constituted by the compounds for which: - R 1 represents a phenyl group; - R and R 2 being as defined above. Among the compounds of general formula (I) which are subjects of the invention, a 10 third group of compounds is constituted of the compounds for which: - R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo-(C-C 6 )alkyl or (C-C 6 )alkyl groups; - R and R 1 being as defined above. 15 Among the compounds of general formula (I) which are subjects of the invention, a fourth group of compounds is constituted of the compounds for which: - R represents a hydrogen atom or a (Cl-C 6 )alkyl or benzyl group; - R, represents a phenyl group; - R 2 represents one or more substituents chosen from a hydrogen atom, halogen 20 atoms and halo-(C 1
-C
6 )alkyl or (C-C 6 )alkyl groups. Among the compounds of general formula (1) which are subjects of the invention, a fifth group of compounds is constituted of the compounds for which: - R represents a hydrogen atom or a methyl, ethyl or benzyl group; 25 - R 1 represents a phenyl group; - R 2 represents one or more substituents chosen from a hydrogen atom, a chlorine atom and methyl, ethyl or trifluoromethyl groups, in the form of a base or of an addition salt with an acid. 30 The combinations of groups one to five as defined above also belong to the invention. Among the compounds of general formula (1) which are subjects of the invention, mention may in particular be made of the following compounds: WO 2010/119222 PCT/FR2010/050711 4 *N-[(7-azabicyclo[2.2.1]hept-1-yi)phenylm6thyl](2-methyl-3 trifluoromethyl)benzamide; *N-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2,6-dichloro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; 5 *(-)-N-{(7-azabicyclo[2.2.1] hept-1 -yl)phenylmethyl](2,6-dich loro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; .N-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3-trifluoromethyl)benzamide, and the hydrochloride thereof; *2-chloro-N-[(7-ethyl-7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](3 10 trifluoromethyl)benzamide, and the hydrochloride thereof; *(+)-N-[(7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](2,6-dichloro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; u2-chloro-N-[(7-methyl-7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl}-3-trifluoromethyl benzamide, and the hydrochloride thereof; 15 *N-[(7-benzyl-7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl}-(2-methyl-3-trifluoro methyl)benzamide, and the hydrochloride thereof; *N-[(7-benzyl-7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](2-chloro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; *N-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3-ethyl)benzamide, and the 20 hydrochloride thereof. The compounds of the invention exhibit a particular activity as inhibitors of Glyti glycine transporters, in particular an improved activity and improved safety profile. 25 The compounds of general formula (1) can be prepared by means of a process illustrated by scheme 1 which follows: SCHEME I Y. 0 30 R NR I R 2 (Ill)
NH
2 (1)
(II)
WO 2010/119222 PCT/FR2010/050711 5 A diamine of general formula (1l), in which R and R, are as defined above, in particular when R represents a hydrogen atom or a phenylmethyl group, is coupled with an acid that is activated, for example via a mixed anhydride or an acid chloride 5 of general formula (111) in which Y represents a leaving group derived, for example, from benzotriazole, from acylurea or a halogen atom and R 2 is as defined above, using the methods known to those skilled in the art. The compounds of general formula (1) in which R represents a hydrogen atom can 10 also be prepared from compounds of general formula (1) in which R represents: - either a phenyimethyl group, by deprotecting the nitrogen by hydrogenolysis, - or an alkenyl group, preferably allyl group, by deprotecting the nitrogen, for example with a complex of palladium "zero" according to the methods known to those skilled in the art, 15 - or a dimethoxybenzyl group, by deprotecting using oxidation methods known to those skilled in the art. The compounds of general formula (1) in which R is other than a hydrogen atom can also be prepared from compounds of general formula (1) in which R represents a 20 hydrogen atom, either by alkylation of said compound of general formula (I) with a halide or mesylate of the RX type, in which R is as defined above and X is a mesylate or halogen, in the presence of an inorganic base, for example potassium carbonate in acetonitrile; or by means of an Eschweiler-Clarke reaction or reductive amination with a suitable aldehyde or a suitable ketone according to the methods 25 known to those skilled in the art; or with a suitable epoxide derivative, according to the methods known to those skilled in the art. The diamine of general formula (11) can be prepared by means of the process illustrated by scheme 2 for the amine of general formula (Ila) and for the amine of 30 general formula (Ilb) which follows: WO 2010/119222 PCTIFR2010/050711 6 SCHEME2 H N N N RLi N (VI)
CO
2 CH CN
H
2 N R 23H 2 N 1i (IV) (V) (Ila) (Ilb) 5 According to scheme 2, the ester of formula (IV) is converted to the nitrile of formula (V) by heating at the reflux of xylene in the presence of the previously formed complex of trimethylaluminium and of ammonium chloride, according to a method described in Synthetic Commun., 1982,12 (13), 989-993 and in Tetrahedron Lett., 10 1979, (51), 4907-4910. The nitrile of formula (V) is then reacted with the lithiated aromatic compound of general formula (VI), in which R, is as defined above, in an ethereal solvent such as tetrahydrofuran or ether, at low temperature, for example -70"C. An imine is thus obtained, which is reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol, so as to give the 15 amine of general formula (Ila). The amine (Ila) can be debenzylated by hydrogenation in the presence of a palladium catalyst, so as to give the deprotected amine of general formula (lIb). For the compounds of formulae (IV) and (V), the benzyl group could in particular be 20 replaced with another protective group, for example with an allyl group or a dimethoxybenzyl group, either: by debenzylating and then reprotecting, for example via an alkylation reaction with the appropriate electrophilic agent, for example an allyl bromide or a dimethoxybenzyl bromide, according to the methods known to those skilled in the 25 art; WO 2010/119222 PCT/FR2010/050711 7 - or according to the method described in Tetrahedron: Asymmetry, 2006 (17), 252-258 by replacing the benzylamine with allylamine or a dimethoxybenzylamine, in particular 2,4-dimethoxybenzylamine. 5 Moreover, the chiral compounds of general formula (1) corresponding to the S or R enantiomers can be obtained by separation of the racemic compounds by chiral column high performance liquid chromatography (HPLC), or could be obtained by resolving of the racemic amine of general formula (1l) using a chiral acid, such as dibenzoyltartaric acid, or by fractionated and preferential recrystallization of a 10 diastereoisomeric salt. The ester of formula (IV) is prepared according to a method described in Tetrahedron, 2002 (58), 10167-10171. The nitrile of formula (V) could also be prepared according to a method described in Tetrahedron: Asymmetry, 2006 (17), 252-258. 15 The lithiated derivatives of general formula (VI) can be prepared according to methods known to those skilled in the art. The acids and acid chlorides of general formula (ll) are commercially available or prepared by analogy with methods known to those skilled in the art. 20 The examples which follow illustrate the preparation of some compounds of the invention. In these examples: - the elemental microanalyses, the IR and NMR spectra and the chiral-column HPLC confirm the structures and the enantiomeric purities of the compounds obtained, 25 - For the NMR descriptions, "m" means multiplet, "s" singlet, "t" triplet, "d" doublet, "q" quadruplet, dxd means double doublet, txt means triple triplet, dxt means double triplet, etc., - The numbers indicated between parentheses in the titles of the examples correspond to those of the 1 column of the table given later, 30 - "decomp." means "decomposition", - The nomenclature used is the nomenclature according to the IUPAC (International Union of Pure and Applied Chemistry) recommendations.
WO 2010/119222 PCT/FR2010/050711 8 In the names of the compounds, the dash "-" is part of the word and the dash ris only used for the break at the end of a line; it should be deleted in the absence of a break and should not be replaced by a normal dash nor by a space. 5 Example I (Compound No. 4): N-[(7-Azabicyclo[2.2.1]hept-1 yl)phenylmethyl](2-chloro-3-trifluoromethyl)benzamide hydrochloride (1:1) 1.1. (7-Benzyl-7-azabicyclo2.2.1lheptane)-1-carbonitrile In a 250 ml three-necked flask under nitrogen, the complex of trimethylaluminium and 10 of ammonium chloride (approximately 0.67M), hereinafter referred to as complex A, is prepared by placing 1.5 g of dry ammonium chloride (28 mmol) in 30 ml of anhydrous toluene, adding thereto, after cooling, 15 ml of a 2N solution of trimethylaluminium in toluene (30 mmol), and leaving the mixture at ambient temperature until no more gas is given off. 15 In a 250 mi three-necked flask under nitrogen, fitted with a condenser, 1.27 g of methyl (7-benzyl-7-azabicyclo[2.2. 1 ]heptane)-1 -carboxylate (5.18 mmol) are placed. in 100 ml of anhydrous xylene. 20 ml of the complex A (13 mmol) are added dropwise and the mixture is refluxed overnight. 20 After cooling, the medium is acidified to pH 4-5 with a 1 N hydrochloric acid solution and is then extracted successively with ethyl acetate (100 ml) and then dichloromethane (100 ml). The organic phases are dried over sodium sulphate, filtered, combined, and then evaporated under reduced pressure. 25 The residue is purified by silica gel column chromatography, elution being carried out with a mixture of petroleum ether and ethyl acetate. 210 mg of (7-benzyl-7 azabicyclo[2.2.1]heptane)-1-carbonitrile are thus obtained in the form of an oil. 1 H NMR (200 MHz,CDC 3 ) S ppm 7.5 (m, 5H), 3.75 (s, 2H), 3.40 (m, 1H), 2.25 (m, 30 -2H), 2.0 (m, 4H), 1.4 (m, 2H). 1.2. (7-Benzyl-7-azabicyclo[2.2.11hept-1-vi)phenvimethylamine In a 50 ml three-necked flask under argon, 0.45 g of (7-benzyl-7 azabicyclo[2.2.1]heptane)-1-carbonitrile (2.12 mmol) is placed, at -70"C, in 15 ml of WO 2010/119222 PCT/FR20101050711 9 anhydrous tetrahydrofuran. 5.65 ml of a 0.75M solution (cyclohexane/ether) of phenyllithium (4.24 mmol) are added dropwise. The mixture is left at -70*C for two and a half hours and then hydrolysed at -20*C with 10 ml of water. 5 After extraction with ethyl acetate, the organic phase is concentrated under reduced pressure and the residue is then taken up in 20 ml of methanol. 0.40 g of sodium borohydride (10.6 mmol) is added thereto portionwise. The reaction medium is left to stir overnight at ambient temperature. After evaporation under reduced pressure, the residue is taken up with 25 ml of ether 10 and 25 ml of water. The medium is acidified with a 1 N hydrochloric acid solution and then extracted. The aqueous phase is basified with aqueous ammonia and then reextracted twice with 50 ml of dichloromethane. The organic phases are combined, dried over sodium sulphate, filtered, and evaporated under reduced pressure. The residue is purified by silica gel column chromatography, elution being carried out with 15 a mixture of dichioromethane and ammoniacal methanol. 0.5 g of (7-benzyl-7 azabicyclo[2.2.1]hept-1-yl)phenylmethylamine is thus obtained in the form of an oil which crystallizes. 'H NMR (400 MHz,CDCl 3 ) 5 ppm 7.56 -7.22 (m, 10H), 4.31 (s, 1H), 3.86 (d, J = 13.3 Hz, 1H), 3.37 (d, J = 13.3 Hz, 1H), 3.19 (t, J = 4.5 Hz, 1H), 2.23 (m, 1H), 2.00 (m, 20 1 H), 1.80-1.56 (m, 2H), 1.37 (m, 1 H), 1.22 -1.06 (m, 2H), 0.97 (m, 1 H). Mp = 87-88"C 1.3. (7-azabicyclo[2.2.1lhept-1-vl)phenylmethylamine In an autoclave, 0.5 g of (7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)phenylmethylamine 25 (1.71 mmol) in solution in 20 ml of ethanol and 3.4 ml of 1N hydrochloric acid in the presence of a spatula tip of palladium on carbon at 10% are placed under a pressure of 7 atmospheres of hydrogen at 50C for 6 hours. After the catalyst has been filtered off and the filtrate has been concentrated under reduced pressure, the .residue is taken up in 25 ml of dichloromethane and 25 ml of water basified with 30 aqueous ammonia. After extraction, the organic phase is dried over sodium sulphate, filtered, and evaporated under reduced pressure. 0.28 g of (7-azabicyclo[2.2.1]hept 1-yl)phenylmethylamine is thus obtained in the form of an oil which solidifies in the cold and which is used as it is in the next stage.
WO 2010/119222 PCT/FR2010/050711 10 1 H NMR (400 MHz,CDC 3 ) 6 ppm 7.36 -7.13 (m, 5H), 4.24 (s, IH), 3.49 (t, J = 4.8 Hz, IH), 1.74-1.15 (m, 8H). Mp = 62-63*C 1.4. N-[(7-azabicyclo(2.2.1 hept-1-yi)phenyImethyll(2-chloro-3-trifluoro 5 methyl)benzamide hydrochloride (1:1) In a 25 ml round-bottomed flask, 0.26 g of (2-chloro-3-trifluoromethyl)benzoic acid (1.19 mmol), 0.16g of hydroxybenzotriazole (1.19 mmol) and 0.23g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.19 mmol) are dissolved in 5 ml of dichloromethane and the mixture is stirred at ambient 10 temperature for 15 minutes. 0.2 g (1.0 mmol) of (7-azabicyclo{2.2.1]hept-1-yl)phenyl methylamine in solution in 2 ml of dichloromethane is added and the mixture is stirred at ambient temperature overnight. The reaction medium is then diluted with 2 ml of dichloromethane and then washed successively with water (3 ml), with 1 N sodium hydroxide (3 ml) and with a saturated 15 solution of sodium chloride (3 ml). The organic phase is dried over sodium sulphate, filtered, and evaporated under reduced pressure. The residue is purified by silica gel column chromatography, elution being carried out with a mixture of dichloromethane and ammoniacal methanol. 260 mg of N-[(7-azabicyclo[2.2.1 ]hept- 1 -yl)phenylmethyl](2-ch loro-3 20 trifluoromethyl)benzamide are thus obtained, said compound being salified in hydrochloride form by solubilisation of the base in ether, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure. 1H NMR (300 MHz, DMSO-d6) 6 ppm 9.52 (d, J = 9 Hz, 1H), 9.32 (m, 1H), 8.92 (m, IH), 7.96 (m, 2H), 7.65 (m, 1H), 7.55-7.30 (m, 5H), 5.69 (d, J = 9.1 Hz, IH), 4.07 (m, 25 1H), 2.30-0.65 (m, 8H). Mp = 146.5-147.5"C. Example 2 (Compound No. 5): 2-Chloro-N-[(7-ethyl-7-azabicyclo[2.2.1]hept-1 yl)phenylmethyl](3-trifluoromethyl)benzamide hydrochloride (1:1) 30 In a 25 ml round-bottomed flask fitted with a condenser, 95 mg of N-[(2 azabicyclo[2.1.1 ]hex-1 -yl)phenyimethyl](2-chloro-3-trifluoromethyl)benzamide (0.23 mmol) are placed in 2 ml of acetonitrile and 64 mg of potassium carbonate, to which 30 pl of iodoethane (0.36 mmol) are added. The reaction medium is stirred overnight at 45"C and then for 3 hours at 50"C and is then concentrated under WO 2010/119222 PCT/FR2010/050711 11 reduced pressure. The residue is then diluted with 10 ml of dichloromethane and then washed with water (5 ml). After extraction, the organic phase is dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, elution being carried out with a mixture 5 of dichloromethane and ammoniacal methanol. 90 mg of 2-chloro-N-[(7-ethy-7 azabicyclo[2.2.1]hept-1-yl)phenylmethyl](3-trifluoromethyl)benzamide are thus obtained, said compound being salified in hydrochloride form by solubilisation of the base in dichloromethane, addition of an excess of 1IN hydrochloric acid in ether, and then concentration under reduced pressure. 10 'H NMR (400 MHz,DMSO-d6) 8 ppm 10.29 (m, 1H), 9.48 (d, J = 9.1 Hz, 1H), 8.12 (m, J = 8 Hz, 1H), 7.94 (m, J = 7.6 Hz, 1H), 7.71-7.31 (m, 6H), 5.68 (d, J = 9.3 Hz, 1H), 4.21 (m, 1H), 3.41-3.03 (m, 2H), 2.39-1.15 (m, 11H). Mp = 189.5-191.5 0 C. 15 Example 3 (Compound No. 7): 2-Chloro-N-[(7-methyl-7-azabicyclo[2.2.1]hept-1 yl)phenylmethyl](3-trifluoromethyl)benzamide hydrochloride (1:1) In a 25 ml round-bottomed flask fitted with a condenser, 0.09 g of N-[(2 azabicyclo[2. 1.1 ]hex-1 -yl)phenylmethyl](2-chloro-3-trifluoromethyl)benzamide (0.22 mmol) and 2 ml of formaldehyde are placed in 2 ml of formic acid. The reaction 20 mixture is heated at 100 0 C for 72 hours. After cooling, the medium is hydrolysed, basified to pH 9 with aqueous ammonia, and then extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered, and evaporated under reduced pressure. 70 mg of 2-chloro-N-[(7-ethyl-7-azabicyclo[2.2. 1 ]hept-1 yl)phenylmethyl](3-trifluoromethyl)benzamide are thus obtained, said compound being 25 salified in hydrochloride form by solubilisation of the base in dichloromethane, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure. H NMR (400 MHz,DMSO-d6) 8 ppm 10.58 (m, 1H), 9.54 (d, J = 9.6 Hz, 1H), 8.26 (m, 30 J - 7.4 Hz, 1H), 7.97 (m, J =7.6 Hz, 1H), 7.75-7.33 (m, 7H), 5.71 (d, J = 9.4 Hz, 1H), 4.05 (m, 1H), 2.87 (m, 3H), 2.44-1.18 (m, 8H). Mp = 244-246"C. The other compounds listed in the table are obtained according to the methods WO 20101119222 PCT/FR2010/050711 12 described in Examples 1 to 3 using amines of general formula (Ila) or (ib), lithium compounds of general formula (VI), carboxylic acid derivatives of general formula (111) or alkylating agents that are appropriate. 5 Table 1 which follows illustrates the chemical structures of some compounds of the invention, In the "salts" column, "-" denotes a compound in the form of a base, "HCI" denotes a hydrochloride, the number between parentheses indicating the (acid:base) ratio; In the columns R, R 1 and R 2 : 10 - "Cl" stands for chlorine, - "CH 3 " stands for methyl, - "Ph" stands for phenyl, - "Rn" stands for benzyl, - "CF 3 " stands for trifluoromethyl, 15 - in the column "R 2 ", the number before the substituents indicates the position in general formula (I), - The compounds in the table are in the form of hydrochloride solvated with one or more molecules of water. Compounds No. 3 and 6 in Table 1 form a pair of enantiomers which are separated by 20 preparative HPLC, using a Chirobiotic" T2 5 pm column and a 100/0.1/0.05 methanol/triethylamine/acetic acid mixture as solvent. The absolute stereochemistry was determined by X-ray diffraction. Table 2 gives the physical properties, melting points and optical rotations of the 25 compounds of Table 1. In Table 2: - the column [aD20*C gives information on the result of analysis of the optical rotation of the compounds of the table at the wavelength of 589 nM and the temperature of 30 20*C. The solvent indicated between parentheses corresponds to the solvent used to carry out the measurement of optical rotation in degrees, and the letter "c" indicates the concentration of the solvent in g/100 ml. "N.A." means that the optical rotation measurement is not applicable, the column "m/z" gives information on the molecular ion (M+H*) or (Me) observed 35 by analysis of the products by mass spectrometry, either by LC-MS (liquid WO 2010/119222 PCT/FR2010/050711 13 chromatography coupled to mass spectroscopy) carried out on an Agilent LC MSD Trap instrument in positive ESI mode, or by direct introduction by MS (mass spectroscopy) on an Autospec M (EBE) instrument using the DCl-NH 3 technique or using the electron impact technique on a Waters GCT instrument. 5 TABLE 1 3 7 3 R'N 2 10 HN R2 No. R R 1
R
2 Salts stereochemistry 1 H Ph 2-CH 3 ,3-CF 3 - racemic HCI 2 H Ph 2,6-(CI) 2 ,3-CF 3 racemic (1:1) HCI Chiral 3 H Ph 2,6-(C) 2 ,3-CF 3 (1:1) levorotatory R HCI 4 H Ph 2-CI,3-CF 3 racemic (1:1) HCI 5 C2H 5 Ph 2-CI,3-CF 3 HCI racemic (1:1) HCI Chiral 6 H Ph 2,6-(CI) 2 ,3-CF 3 (1:1) dextrorotatoryS HCI 7 CH 3 Ph 2-CI,3-CF 3 racemic (1:1) Hl 8 Bn Ph 2-CH 3 ,3-CF 3 racemic ____________________(1:1) HCl 9 Bn Ph 2-C,3-CF 3 racemic (1:1) HCl 10 H Ph 2-CI,3-C 2
H
5 HCI racemic ___________ _____ __________________(1:1) WO 2010/119222 PCT/FR2010/050711 14 TABLE 2 LCMS No. Mp 0 C [aD] 20-C "H MH*' 1 62-63 N.A 389 2 210-211 N.A 443 3 185-186 -50.73 (MeOH, c=0.466 g/100 ml) 443 4 146.5-147.5 N.A 409 5 189.5-191.5 N.A 437 6 181.5-182.5 +34.41 (MeOH, c=0.732g/100 ml) 443 7 244-246 N.A 423 8 153-154 N.A 479 9 159.5-160.5 N.A 499 10 234.2-235.2 N.A 369 5 The compounds of the invention were subjected to a series of pharmacological tests which demonstrated their advantage as substances having therapeutic activities. Study of glycine transport in SK-N-MC cells expressing the native human transporter 10 gjyt1
[
1 4 C]glycine uptake is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native human transporter glyti, by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in a monolayer for 48 h in plates pretreated with 0.02% fibronectin. On the day of the 15 experiment, the culture medium is removed and the cells are washed with a Krebs HEPES ([ 4
-(
2 -hydroxyethyl)piperazine]-1-ethanesulphonic acid) buffer at pH 7.4. After preincubation for 10 min at 370C in the presence either of buffer (control batch), or of test compound at various concentrations, or of 10 mM glycine (determination of nonspecific uptake), 10 pM [ 1 4 C]glycine (specific activity 112 mCi/mmol) is then 20 added. The incubation is continued for 10 min at 37"C, and the reaction is stopped by means of 2 washes with a Krebs-HEPES buffer at pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 pl of liquid scintillant and WO 2010/119222 PCT/FR2010/050711 15 stirring for 1 h. The counting is performed on a Microbeta Tri-luxTm counter. The effectiveness of the compound is determined by means of the IC5o, which is the concentration of the compound which reduces by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control batch and the 5 batch which received the glycine at 10 mM. The compounds of the invention, in this test, have an IC50 of the order of 0.001 to 10 pM. Table 3 indicates some examples of IC5o results for compounds according to the 10 invention. TABLE 3 Compound IC.50 (pM) 1 0.038 2 0.003 3 0.023 4 0.027 6 0.0016 The results of the tests carried out on the chiral compounds of the invention and the racemates thereof in general formula (I) show that they are inhibitors of the glyt1 15 glycine transporter present in the brain. These results suggest that the compounds of the invention can be used for the treatment of cognitive and/or behavioural disorders associated with neurodegenerative diseases, with dementia; for the treatment of psychoses, in 20 particular of schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders; for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due 25 to alcohol abuse or to alcohol withdrawal, sexual behaviour disorders, eating disorders, migraine; pain; sleep disorders. The compounds according to the invention can therefore be used for the preparation WO 2010/119222 PCT/FR2010/050711 16 of medicaments, in particular medicaments which inhibit the glyt1 glycine transporter. Thus, according to another of the aspects of the invention, a subject thereof is medicaments which comprise a compound of formula (1), or an addition salt of the 5 latter with a pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of formula (I). A subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a 10 pharmaceutically acceptable base, salt or solvate, and as a mixture, where appropriate, with suitable excipients. Said excipients are chosen according to the pharmaceutical form and the method of administration desired. 15 The pharmaceutical compositions according to the invention may thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration. 20 The unit administration forms may be, for example, tablets, gel capsules, granules, powders, oral or injectable solutions or suspensions, patches or suppositories. For topical administration, ointments, lotions and collyria can be envisaged. Said unit forms contain doses so as to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the galenical form. 25 In order to prepare tablets, a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose or starch, and formulation additives such as binders (polyvinylpyrrolidone, hydroxypropyl methyl cellulose, etc.), flow agents such as silica, and lubricants such as magnesium stearate, stearic acid, 30 glyceryl tribehenate or sodium stearylfumarate, are added to the active ingredient, which may or may not be micronized. Wetting agents or surfactants such as sodium lauryl sulphate can also be added. The preparation techniques may be direct compression, dry granulation, wet granulation or the hot-melt process. 35 The tablets may be uncoated, sugar-coated, for example with sucrose, or coated with WO 2010/119222 PCT/FR2010/050711 17 various polymers or other suitable materials. They can be designed so as to allow rapid, delayed or sustained release of the active ingredient by virtue of polymer matrices or of specific polymers used in the coating. 5 In order to prepare gel capsules, the active ingredient is mixed with dry pharmaceutical carriers (simple mixing, dry or wet granulation, or the hot-melt process), or liquid or semi-solid pharmaceutical carriers. The gel capsules may be hard or soft, and optionally film-coated, so as to have a rapid, sustained or delayed activity (for example, for an enteric form). 10 A composition in the form of a syrup or an elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben or propylparaben as antiseptic, a flavour enhancer and a colorant. 15 The water-dispersible powders and granules can contain the active ingredient as a mixture with dispersing agents or wetting agents, or dispersing agents, such as polyvinylpyrrolidone, as well as with sweeteners and flavour-correcting agents. 20 For rectal administration, recourse is had to suppositories prepared with binders which melt at the rectal temperature, for example cocoa buffer or polyethylene glycols. For parenteral administration, use is made of aqueous suspensions, isotonic saline solutions or injectable sterile solutions comprising pharmacologically compatible 25 dispersing agents and/or wetting agents, for example propylene glycol or butylene glycol. The active ingredient can also be formulated in the form of microcapsules, optionally with one or more supports or additives, or else with a polymer matrix or with a 30 cyclodextrin (patches, sustained-release forms). The topical compositions according to the invention comprise a medium compatible with the skin. They can be provided in particular in the form of aqueous, alcoholic or aqueous-alcoholic solutions, of gels, of water-in-oil or oil-in-water emulsions having 35 the appearance of a cream or of a gel, of microemulsions or of aerosols, or else in the WO 2010/119222 PCTIFR2010/050711 18 form of vesicular dispersions containing ionic and/or nonionic lipids. These galenical forms are prepared according to the usual methods in the fields under consideration. By way of example, a unit administration form for a compound according to the 5 invention in tablet form can comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg 10 Maize starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg When given orally, the dose of active ingredient administered per day can reach 0.1 to 15 20 mg/kg, in one or more intakes. There may be particular cases where higher or lower dosages are appropriate; such dosages do not depart from the context of the invention. Depending on the usual practice, the dosage appropriate for each patient is determined by the physician according to the method of administration and the weight and response of said 20 patient. According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a 25 pharmaceutically acceptable salt thereof.
Claims (23)1. Compound of general formula (1) R'N: RI HN O R 2 5 in which: - R represents a hydrogen atom or a group chosen from the groups (C-C 6 )alkyl and (C 3 -C 7 )cycloalkyl, optionally substituted with one or more groups chosen, 10 independently of one another, from halogen atoms and (C 3 -C 7 )cycloalkyl, (C 2 C4)alkenyl, phenyl, (C-C 6 )alkoxy and hydroxyl groups; the phenyl group being optionally substituted with one or more (CI-C 6 )alkoxy groups; - R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen, independently of one another, from halogen atoms and (C 15 Ce)alkyl, (CrCe)alkoxy, halo-(C-C 6 )alkyl, hydroxyl, halo-(CCrCs)alkoxy, (C-C 6 )alkyl thio, (C-C 6 )alkyl-SO and (C-C 6 )alkyl-S0 2 groups; - R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo-(C -C 6 )alkyl, (C 1 -C 6 )alkyl, (C3-Cr)cycloalkyl, (C 3 -C7)cycloalkyl(C C 3 )alkyl, (C-C 6 )alkoxy, (C-Ce)alkyl-thio, (C-C 6 )alkyl-SO and (C-C 6 )alkyl-SO2 20 groups; in the form of a base or of an addition salt with an acid.
2. Compound of general formula (1) according to Claim 1, characterized in that *R represents a hydrogen atom or a (C-C 6 )alkyl or benzyl group; 25 R, and R 2 being as defined in Claim 1, in the form of a base or of an addition salt with an acid.
3. Compound of general formula (1) according to Claim 1, characterized in that WO 20101119222 PCT/FR2010/050711 20 R 1 represents a phenyl group; R and R 2 being as defined in Claim 1, in the form of a base or of an addition salt with an acid. 5
4. Compound of general formula (1) according to Claim 1, characterized in that R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo-(0 1 -C 6 )alkyl or (CI-Cs)alkyl groups; R and R 1 being as defined in Claim 1, in the form of a base or of an addition salt with an acid. 10
5. Compound of general formula (I) according to Claim 1, characterized in that R represents a hydrogen atom or a (C-Ce)alkyl or benzyl group; R 1 represents a phenyl group; R 2 represents one or more substituents chosen from a hydrogen atom, halogen 15 atoms and halo-(C-C 6 )alkyl or (C 1 -Cs)alkyl groups, in the form of a base or of an addition salt with an acid.
6. R represents a hydrogen atom or a methyl, ethyl or benzyl group; R, represents a phenyl group; 20 R 2 represents one or more substituents chosen from a hydrogen atom, a chlorine atom and methyl, ethyl or trifluoromethyl groups, in the form of a base or of an addition salt with an acid.
7. Compound according to Claim 1 or 2, characterized in that it is chosen from: 25 .N-[(7-azabicyclo[2.2.1]hept-1 -yl)phenylm6thyl](2-methyl-3 trifluoromethyl)benzamide; *N-[(7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](2,6-dichloro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; *(-)-N-[(7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](2,6-dichloro-3 30 trifluoromethyl)benzamide, and the hydrochloride thereof; *N-[(7-azabicyclo[2.2. 1]hept-1 -yl)phenylmethyl](2-chloro-3-trifluoromethyl)benzamide, and the hydrochloride thereof; *2-chloro-N-[(7-ethyl-7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](3 trifluoromethyl)benzamide, and the hydrochloride thereof; WO 2010/119222 PCT/FR20101050711 21 *(+)-N-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2,6-dichloro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; *2-chloro-N-[(7-methyl-7-azabicyclo[2.2.1]hept-1-yl)phenymethyl]-3-trifluoromethyl benzamide, and the hydrochloride thereof; 5 .N-[(7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl]-(2-methyl-3-trifluoro methyl)benzamide, and the hydrochloride thereof; -N-[(7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3 trifluoromethyl)benzamide, and the hydrochloride thereof; *N-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3-ethyl)benzamide, and the 10 hydrochloride thereof.
8. Process for preparing a compound of general formula (I) according to Claim 1, characterized in that a compound of general formula (II) RNR (ii) NH 2 15 in which R and R 1 are as defined according to Claim 1, reacts with a compound of general formula (Ill) Y 0 R 2 in which Y represents a leaving group or a halogen atom and R 2 is as defined according to Claim 1. 20
9. Compound of general formula (II) R'R (II) 25 NH 2 in which R and R 1 are as defined in Claim 1.
10. Medicament, characterized in that it comprises a compound of formula (I) WO 20101119222 PCT/FR2010/050711 22 according to any one of Claims 1 to 7, or an addition salt of this compound with a pharmaceutically acceptable acid.
11. Pharmaceutical composition, characterized in that it comprises a compound of 5 formula (1) according to any one of Claims 1 to 7, or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.
12. Use of a compound of formula (1) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of cognitive and/or behavioural 10 disorders associated with neurodegenerative diseases; with dementia.
13. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of psychoses, of schizophrenia (deficient form and productive form) and of acute or chronic extrapyramidal symptoms 15 induced by neuroleptics.
14. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of various forms of anxiety, panic attacks, phobias and obsessive-compulsive disorders. 20
15. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or alcohol 25 withdrawal, sexual behaviour disorders, eating disorders, and migraine.
16. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of pain. 30
17. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of sleep disorders.
18. Compound according to any one of Claims 1 to 7, for the treatment of cognitive and/or behavioural disorders associated with neurodegenerative diseases; with 35 dementia. WO 2010/119222 PCT/FR20101050711 23
19. Compound according to any one of Claims 1 to 7, for the treatment of psychoses, of schizophrenia (deficient form and productive form) and of acute or chronic extrapyramidal symptoms induced by neuroleptics. 5
20. Compound according to any one of Claims 1 to 7, for the treatment of various forms of anxiety, panic attacks, phobias and obsessive-compulsive disorders.
21. Compound according to any one of Claims 1 to 7, for the treatment of various 10 forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or alcohol withdrawal, sexual behaviour disorders, eating disorders, and migraine. 15
22. Compound according to any one of Claims 1 to 7, for the treatment of pain.
23. Compound according to any one of Claims 1 to 7, for the treatment of sleep disorders.
AU2010238409A 2009-04-14 2010-04-13 Derivatives of N-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Abandoned AU2010238409A1 (en) Applications Claiming Priority (3) Application Number Priority Date Filing Date Title FR0901809A FR2944284A1 (en) 2009-04-14 2009-04-14 N- (7-AZA-BICYCLO) 2.2.1! HEPT-1-YL) -LARYL-METHYL DERIVATIVES -BENZAMIDE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION FR09/01809 2009-04-14 PCT/FR2010/050711 WO2010119222A1 (en) 2009-04-14 2010-04-13 Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Publications (1) Family ID=41228015 Family Applications (1) Application Number Title Priority Date Filing Date AU2010238409A Abandoned AU2010238409A1 (en) 2009-04-14 2010-04-13 Derivatives of N-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Country Status (14) Families Citing this family (1) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title KR20160045182A (en) 2014-10-16 2016-04-27 íëìë차주ìíì¬ Gray cast iron for cylinder liner and method for manufacturing cylinder liner using the same Family Cites Families (4) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title FR2842804B1 (en) * 2002-07-29 2004-09-03 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION FR2861076B1 (en) * 2003-10-17 2006-01-06 Sanofi Synthelabo N-HETEROCYCLYMETHYLBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE WO2008065500A2 (en) * 2006-11-30 2008-06-05 Pfizer Products Inc. Heteroaryl amides as type i glycine transport inhibitors WO2009013535A1 (en) * 2007-07-23 2009-01-29 Astrazeneca Ab 2-azabicyclo(2.2.2)octane derivatives as modulators of the glycine transporter i receptorRetroSearch is an open source project built by @garambo | Open a GitHub Issue
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