SG174434A1 - Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics - Google Patents

Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics Download PDF

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SG174434A1
SG174434A1 SG2011066867A SG2011066867A SG174434A1 SG 174434 A1 SG174434 A1 SG 174434A1 SG 2011066867 A SG2011066867 A SG 2011066867A SG 2011066867 A SG2011066867 A SG 2011066867A SG 174434 A1 SG174434 A1 SG 174434A1
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compound
hex
azabicyclo
phenyl
methyl
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SG2011066867A
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Genevieve Estenne-Bouhtou
Abdel-Kader Mafroud
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Sanofi Sa
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Priority claimed from FR0901219A external-priority patent/FR2943056A1/en
Priority claimed from FR0901810A external-priority patent/FR2944283B1/en
Application filed by Sanofi Sa filed Critical Sanofi Sa
Publication of SG174434A1 publication Critical patent/SG174434A1/en

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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description

DERIVATIVES OF N-[(2-AZA-BICYCLO[2.1.1JHEX-1-YL)-ARYL-)METHYL]-
HETEROBENZAMIDE, PREPARATION THEREOF AND APPLICATION OF SAME IN
THERAPEUTICS : ~The present invention relates to N-[(2-azabicyclo[2.2.1]hex-1-yl)(aryl)methyl}- heterobenzamide derivatives, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving glycine transporters GlyT1.
The compounds of the invention correspond to the general formula 0) a
N 4)
N 0 (Het)—R, in which: -- R represents a hydrogen atom or a group chosen from {C;-Cgalkyl, (Cs-C7)cyclo- ‘alkyl, benzyl or allyl groups which is optionally substituted by one or more groups chosen, independently of one another, from halogen atoms or (Cs-C;)cycloaikyl, (C4-Cslalkyl, (C4-Cs)alkoxy or hydroxyl groups; : - Ry represents a phenyl or naphthyl group which is optionally substituted by one or more substituents chosen, independently of one another, from halogen atoms or (Ci-Co)alkyl, (Ci-Colalkoxy, halo(Ci-Cglalkyl, hydroxyl, halo(C4-Cg)alkoxy, (Cs- :
GCgalkylthio, (C4-Ce)alkyl-SO or (C4-Cg)alkyl-SO, groups; - Het represents a heteroaryl group; - Ry represents one or more substituents chosen from the hydrogen atom, halogen atoms or halo{C4-Cs)alkyl, (C+-Cg)alkyl, (Cs-Cr)oycloalkyl, (Cs-Cr)eycloalkyl(C4-Cs)alkyl, (C1-Ce)alkoxy, benzyl, (C-Ce)alkylthio, (C1-Ce)alkyl-SO or (C4-Ce)alkyl-SO- groups; inthe form of the base or of an addition salt with an acid.
The compounds of formula (I) comprise an asymmetric carbon atom. They can thus exist in the form of enantiomers. These enantiomers, including racemic mixtures,
N come within the scope of the invention.
The compounds of formula (I) can exist in the form of bases or of addition salts with acids. Such addition salts come within the scope of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids, for example for use in the purification or isolation of the compounds of formula (I), also come within the invention. : : In the context of the invention: - - CC, where t and z can take the values from 1 fo 6, is understood to mean a carbon chain which can have from t to z carbon atoms; for example, C-Cs is understood to mean a carbon chain which can have from 1 to 6 carbon atoms; - alkyl is understood to mean a saturated, linear or branched, aliphatic group; for example, a (C4-Cs)alkyl group represents a linear or branched carbon chain of 1 to
I 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl or hexyl; - alkoxy is understood to mean an —O-alkyl group; - hydroxyl is understood to mean an —OH group; - allyl is understood to mean a {CH.)-CH=CH, group; - alkylthio is understood to mean a sulphur atom substituted by an alkyl group; - halogen atom is understood to mean a fluorine, a chlorine, a bromine or an iodine; - haloalkyl is understood to mean an alkyl group, one or more hydrogen atoms of which have been replaced by a halogen. Mention may be made, by way of examples, of the trifluoromethyl, trifluoroethyl or pentafluoroethyl groups; - heteroaryl group is understood to mean a 5- or 10-membered hetero-aromatic mono- or bicyclic group comprising from 1 fo 3 heteroatoms chosen from nitrogen, oxygen and sulphur. Mention may be made, as examples of heteroaryl group, of the pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, : : 30 pyrazine, pyridazine, friazine, indole, isoindole, benzimidazole, indazole, indolizine, benzofuran, isobenzofuran, benzothiophene, benzo[cjthiophene, pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine, pyrrolopyridazine, imidazopyridazine,
pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine, pyrrolotriazine, imidazotriazine, pyrazolotriazine, friazolotriazine, tetrazolotriazine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine, isoxazolatriazine, oxadiazolopyridine, oxadiazolopyrimidine, oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine, benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, : isothiazolopyrazine, isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine, | thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine, benzothiazole, benzisothiazole, benzothiadiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine, pyrimidotriazine, - pyrazinopyrazine, pyrazinopyridazine, pyrazinofriazine, pyridazinopyridazine or pyridazinotriazine groups.
Among the compounds of general formula (I) which are subject-matters of the invention, a first group of compounds is composed of the compounds for which: - R represents a hydrogen atom, a benzyl group or an allyl group; : - Ry, Het and R; being as defined above, “in the form of the base or of an addition salt with an acid.
Among the compounds of general formula (I) which are subject-matters of the invention, a second group of compounds is composed of the compounds for which: - Ry represents a phenyl or a naphthyl group which is optionally substituted by one or more groups chosen, independently of one another, from halogen atoms or (Cs- : 30 GCylalkyl, (C4-Cs)alcoxy or halo(C4-Cg)alkyl groups; - R,Hetand R; being as defined above, . in the form of the base or of an addition salt with an acid.
Among the compounds of general formula (I) which are subject-matters of the invention, a third group of compounds is composed of the compounds for which:
: - Het represents an indole, thiophene or pyridine group; - R, Ry and R; being as defined above, in the form of the base or of an addition salt with an acid.
Among the compounds of general formula (I) which are subject-matters of the invention, a fourth group of compounds is composed of the compounds for which: - Rj represents one or more substituents chosen from the hydrogen atom, halogen atoms or halo(C,-Cg)alkyl, benzyl or (C-Cs)alkylthio groups; - R, R; and Het being as defined above, . in the form of the base or of an addition salt with an acid.
Among the compounds of general formula (I} which are subject-matters of the invention, a fifth group of compounds is composed of the compounds for which: - R represents a hydrogen atom, a benzyl group or an allyl group; - Rj represents a phenyl or naphthyl group which is optionally substituied by one or more substituents chosen, independently of one another, from halogen atoms or (C4-Cs)alkyl, (C1-Cg)alcoxy or halo{C-Cg)alkyl groups; - Het represents an indole, thiophene or pyridine group; - Ry represents one or more substituents chosen from the hydrogen atom, halogen atoms or halo(C4-Cg)alkyl, benzyi or (C4-Cg)alkylthio groups; in the form of the base or of an addition salt with an acid.
Among the compounds of general formula (I) which are subject-matters of the invention, a sixth group of compounds is composed of the compounds for which: - R represents a hydrogen atom, a benzyl group or an allyl group; - Ry represents a phenyl or naphthyl group which is optionally substituted by one or more substituents chosen, independently of one another, from the fluorine atom or methyl, methoxy or trifluoromethyl groups; - Het represents an indole, thiophene or pyridine group; - Ro represents one or more substituents chosen from the hydrogen atom, bromine or chlorine atoms or trifluoromethyl, methylthio or benzyl groups; . in the form of the base or of an addition salt with an acid.
The combinations of the groups one to six above also come within the scope of the invention.
Mention may in particular be made, among the compounds of general formula (1) which are subject-matters of the invention, of the following compounds: N-{(2-Allyl-2-azabicyclo[2.1. 1}hex-1-yl{phenyl)methyl}-4,5-dibromothiophene-2- carboxamide; :
N-[(2-Azabicyclo[2.1.1]hex-1-yi)(phenyl)methyi]-4,5-dibromothiophene-2-carboxamide;
N-{(2-Azabicyclo[2.1.1]hex-1-yI)(phenyl)methyi]-2,5-dichiorothiophene-3-carboxamide; (+)-N-[(2-Azabicyclo[2.1.1ihex-1-yI){(phenyl)methyl]-4,5-dibromothiophene-2- carboxamide, and its hydrochioride; (-}-N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyi]-4,5-dibromothiophene-2- : carboxamide, and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl){4-fluorophenyl)methyl]-3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide; N-(2-Azabicyclo[2.1.1]hex-1-yl} phenyl)methyl]-2-(methylsulfanyl)nicotinamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yI}(phenylmethyl]-3-chioro-4-(trifluoromethyl)pyridine-2- - carboxamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)}(phenyl)methyi]-1-benzyl-1H-indole-4-carboxamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(naphth-2-yl)methyi]-3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide, and its hydrochloride; -. N-f(2-Azabicyclo[2.1.1]hex-1-yl)(naphth-2-yl)methyl]-2-(methylsulfanyl) nicotinamide, and its hydrochloride;
N-f(2-Azabicyclo[2.1.1]hex-1-y1){3-methoxyphenyl)methyl}-3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide, and its hydrochloride; N-[(2-Azabicyclof2.1.1]hex-1-yI)(3-methoxyphenyl)methyl]-2- (methylsulfanyl)nicotinamide, and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl){ m-tolyl)methyi}-2-(methylsulfanyl)nicotinamide, and its hydrochloride;
N-[(2-Azabicycio[2.1.1}hex-1-yl)}(3-(trifluoromethyl)phenyl)methyl]-3-chioro-4- : (trifluoromethyl)pyridine-2-carboxamide, and its hydrochloride;
N-[(2-Azabicycio[2.1.1}hex-1-yl)(m-tolyl)methyl}-3-chloro-4-(trifluoromethyl pyridine-2- carboxamide, and its hydrochloride; (+)-N-[(2-Allyl-2-azabicyclo[2.1.1]hex-1-yl){phenyl)methyl]-4,5-dibromothiophene-2- carboxamide; (-}N-[(2-Aliyl-2-azabicyclo[2.1.1]hex-1 -yl)}{phenyl)methyl}-4,5-dibromothiophene-2-
carboxamide;
N-[(2-Benzyl-2-azabicyclo[2.1.1]hex-1 ~yl)(3-(trifluoromethyl)phenyl)methyi]-3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide, and its hydrochloride;
N-[(2-Benzyl-2-azabicyclo[2.1.1thex-1-yl}{(phenyi)methyl]-2,5-dichlorothiophene-3- carboxamide, and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-3,6-dichloropyridine-2-carboxamide, and its hydrochloride; Co
N-{(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-3-chloro-5-(trifluoromethyt)pyridine-2- _ carboxamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl){(phenyl)methyl}-6-chloro-3-(trifluoromethyl)pyridine-2- carboxamide. :
The compounds of the invention exhibit a specific activity as inhibitors of glycine transporters GlyT1, in particular an improved activity profile and an improved safety profile.
The compounds of general formula (1) can be prepared by a process illustrated by the following Scheme 1: : SCHEME 1
Y. 0 } R, = (Hn
GP R; r NH, 0 (1)
A diamine of general formula (ll), in which R and R, are as defined above, in particular when R represents a hydrogen atom or an allyl group, is coupled with an activated acid, for example an acid activated via a mixed anhydride or an acid chloride, of general formula (lll), in which Y represents a leaving group derived, for example, from benzotriazole or acylurea or a halogen atom and R; is as defined above, using oo methods known to a person skilled inthe art.
The compounds of general formula (I) in which R represents the hydrogen atom can also be prepared from compounds of general formula (1) in which R represents:
- either protective group which can be deprotected by hydrogenolysis, : - or an allyl group, by deprotecting the nitrogen, for example with a palladium(0) complex, according to methods known to a person skilled in the art.
The compounds of general formula (I) in which R is other than the hydrogen atom can also be prepared from compounds of general formula (I) in which R represents a - hydrogen atom either by alkylation of the 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 mesylate or : halogen, in the presence of an inorganic base, for example potassium carbonate in acetonitrile; or by a reaction of Eschweiler-Clarke type or a reductive amination with an appropriate aldehyde or an appropriate ketone, according to methods known to a person skilled in the art; or with an appropriate epoxide derivative, according to methods known to a person skilled in the art.
The compounds of general formuia (I} in which the R, group is a phenyl group substituted by a hydroxyl can be obtained from the corresponding compound of general formula (1) substituted by a methoxy, using methods known to a person skilied in the art.
The diamine of general formula (il) can be prepared by processes illustrated by the following Scheme 2, for the amine (lla), and the following Scheme 3, for the amines (b)and (llc)
: . SCHEME 2 orl od o
NO N N
0 N N —_— oON_.0— H 3 (Vh (Iv) Vv)
O .
NO Pn R.Li 2 el 8 et
N
7 OR va . Pl \ ! ©
N oH cH
Xy CH : 2 x) \ (IX) (VII)
R, \ : / NH
N 2
CH, : (la)
The ester (IV) is converted to the amide (V) by heating the trimethylaluminium complex and the appropriate amine, such as morpholine, at reflux of the solvent, such as toluene. The amine (V) can be deprotected by using a lithium compound of phenyliithium type in a solvent, such as tetrahydrofuran, at low temperature, for example at -70°C. An N-allylation is subsequently carried out using allyl bromide in ’ 10 the presence of a base, such as potassium carbonate, in a solvent, such as acetonitrile, at ambient temperature, in order to obtain the compound (VII). The morpholine amide of formula (VII) can be reacted with the lithiated aromatic compound of general formula (VIII), in which R, is as defined above, in an ethereal solvent, such as ether or tetrahydrofuran, at low temperature. A ketone of general formula (IX) is thus obtained and is reacted with O-benzylhydroxylamine hydrochloride, at reflux of pyridine, in order to obtain a Z/E mixture of oxime of general formula (X).
The oxime (X) is subsequently reduced at reflux of the ether by lithium aluminium - hydride, in order to provide the diamine of formula (fla).
SCHEME 3
R,
CN a “NRL J NH, SA : . - J NH, 1 (VII) H (lic) (Xi) 1)
According to Scheme 3, a nitrile of formula (XI) is reacted with the lithiated aromatic . compound of general formula (VII), 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 and is reduced with a reducing agent, such as sodium borohydride, in a protic solvent, such as methanol, to give the amine of general formula (lib). The amine (lib) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide the deprotected amine (llc). :
Furthermore, the chiral compounds of general formula (I) corresponding to the S or R enantiomers can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column or might be obtained by resolution of the racemic amine of general formula (11) by use of a chiral acid, such as dibenzoyltartaric acid, or by the fractional and preferential recrystaliization of a diastereoisomeric salt.
The ester of formula (IV) is prepared according to a method described in J. Org. Chem., 2003, 9348-9355.
The nitrile of formula (Xl!) is prepared according to a method described in Tetrahedron: : Asymmetry, 2006 (17), 252-258.
The lithiated derivatives of general formula (VIII) can be prepared according to methods known {o a person skilled in the art.
The acids and acid chlorides of general formula (lll) are available commercially or are ) prepared by analogy to methods known to a person skilled in the art. ~The examples which will follow illustrate the preparation of some compounds of the invention. In these examples: ~~ the elemental microanalyses, the IR and NMR spectra and chiral column HPLC confirm the structures and the enantiomeric purities of the compounds obtained, - for the NMR descriptions, “m” means multiplet, “s” singlet, "t" triplet, "d" doublet, "gq" ae quartet, “dxd” double doublet, “bt” triple triplet, “dxt” double triplet, and the like, - the numbers shown befween brackets in the titles of the examples correspond to those in the 1° column in Table 1, - "decomp." means "decomposition", - for the compounds in the salt form, the figures between brackets indicate the (base:acid) ratio, -*ee” means enantiomeric excess, - the nomenclature employed is the nomenclature according to the IUPAC (International Union of Pure and Applied Chemistry) recommendations.
In the names of the compounds, the hyphen “-” forms part of the word and the “underiine” symbol “_” is used only for the break at the line end; it is to be omitted in the absence of a break and should be replaced neither by an ordinary hyphen nor by a space.
Example 1 (compound No. 1): N-[(2-Allyi-2-azabicyclo[2.1.1]hex-1- yl)(phenyl)methyl}-4,5-dibromothiophene-2-carboxamide 1.1 (2-Benzoyl-2-azabicyclo[2. 1.1]hex-1-y}{morpholin-4-ylYmethanone 10 ml of morpholine (115 mmol) are added dropwise to a solution of 29 ml of 2N trimethylaluminium (58 mmol) in 200 ml of anhydrous toluene in a 500 ml three- necked flask under argon and the mixture is heated at 60°C for 15 minutes. A solution of 20g of ethyl 2-benzoyl-2-azabicyclo[2.1.1]hexane-1-carboxylate (77.1 mmol) in 190 mi of anhydrous toluene is transferred via a tube into the reaction medium, which is subsequently heated at reflux overnight. After cooling, the mixture is carefully hydrolysed with 60 ml of water while stirring. The precipitate formed is filtered off on
Celite® and then rinsed with dichioromethane. The filtrate is evaporated under reduced pressure.
The residue obtained is triturated from ether. 18.35g of (2-benzoyl2- azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone are thus obtained in the form of a dark beige solid. : 'H NMR (400 MHz, dg-DMSO) & ppm 7.69 (d, J = 8 Hz, 2H), 7.56-7.45 (m, 3H), 3.76 (d, J = 7.7 Hz, 1H), 3.64-3.26 (m, 9H), 2.73 (t, J = 2.7 Hz, 1H), 2.10 (m, 2H), 1.97 (m, 1H), 1.52 (m, 1H).
M.p.: 176-177°C 1.2. (2-Azabicyclo[2.1. 1lhex-1-yvi)}{morpholin-4-y)methanone 10 g of (2-benzoyl-2-azabicyclof2.1. t]hex-1-yl)(morpholin-4-yl)methanone (compound obtained according to stage 1.1) (33.3 mmol) are placed in 400 mi of anhydrous tetrahydrofuran at -70°C in a 11 three-necked flask under argon. 50 ml of 0.8M phenyllithium (cyclohexane/ether) (40 mmol) are added dropwise and the solution obtained is left stirring at -70°C for 1 h.
Hydrolysis is carried out with 100 ml of water and the mixture is allowed to return to . ambient temperature. After extracting, the organic phase is concentrated and then the residue is taken up in ether. This ethereal phase is poured into the preacidified aqueous phase. After extracting, the aqueous phase is basified with aqueous ammonia and then extracted with dichloromethane (3 x 200 ml). The organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. 5.2 g of (2-azabicyclo]2.1.1]hex-1-yi)(morpholin-4-yl)methanone are thus obtained in the form of a dark beige solid. : 'H NMR (400 MHz, d-DMSO) 8 ppm 3.71 (m, 2H), 3.55 (m, 4H), 3.44 (m, 2H), 2.87 (s, 2H), 2.89 (broad s, 1H), 2.60 (t, J = 2.9 Hz, 1H), 1.84 (m, 2H), 1.43 (m, 2H).
M.p.: 97.5-98°C 1.3. {2-Allyl-2-azabicyclof2.1. 1]hex-1-yl){ morpholin-4-yi imethanone 7.4 g of (2-azabicyclo[2.1.1]hex-1-yl}morpholin-4-yl)methanone (compound obtained - according to stage 1.2) (37.7 mmol) are placed in 100 mi of acetonitrile and 10.4 g of potassium carbonate (75.4 mmol) in a 500 ml round-bottomed flask. A solution of - 3.9 ml of allyl bromide (45.2 mmol) is added dropwise to this suspension. The reaction medium is stirred overnight at ambient temperature and then concentrated under reduced pressure.
The residue is dissolved in 100 mi of dichloromethane. The organic phase is washed
: with water, dried over sodium sulphate, filtered and then evaporated under reduced pressure. 8.9 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl))methanone are thus obtained in the form of an ail.
HNMR (400 MHz, ds-DMSO) 8 ppm 5.85 (m, 1H), 5.24 (m, 1H), 5.08 (m, 1H), 3.78 (broad t, J = 4.7 Hz, 2H), 3.54 (m, 4H), 3.44 (m, 2H), 3.05 (broad d, J = 5.7 Hz, 2H), 2.69 (broad s, 2H), 2.56 (broad t, J = 3 Hz, 1H), 1.83 (m, 2H), 1.68 (m, 2H). 1.4. (2-Allvi-2-azabicyclof2.1. 1]hex-1-vi)(phenyl)methanone 3.2g of (2-allyl-2-azabicycio[2.1.1]hex-1-yl)}{morphoiin-4-yl)methanone (compound obtained according to stage 1.3) (13.5 mmol) are placed in 70 ml of tetrahydrofuran at -70°C in a 250 ml three-necked flask under argon. 16.2 ml of 1M phenyliithium (cyclohexane/ether) are run in dropwise and the mixture is left at -70°C for one hour.
After hydrolysis with 20 ml of water, the mixture is allowed to return to ambient temperature. After evaporating the solvent under reduced pressure, the residue is taken up in ethyl acetate. After extracting, the organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of petroleum ether and ethyl acetate. 2g of (2-allyl-2-azabicyclo[2.1.1]hex-1- yl)phenyl)methanone are thus obtained in the form of an oil. : *H NMR (400 MHz, ds-DMSQ) ppm 8.28 (m, 2H), 7.64 (txt, J = 7.3 and 1.4 Hz, 1H), 7.52 (m, 2H), 5.73 (m, 1H}, 5.20 (m, J = 17 and 2 Hz, 1H), 5 (m, J = 10 and 2 Hz, 1H), 2.99 (dxt, J = 5.6 and 1.5 Hz, 2H), 2.86 (s, 2H), 2.70 (t, J = 2.9 Hz, 1H), 1.99-1.85 (m, 4H). : 1.5. (2-Allvl-2-azabicyclof2.1.1lhex-1-yl}{(phenyhmethanone O-benzyloxime 0.8 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methanone (compound according to stage 1.4) (3.7 mmol) is placed in 12 ml of pyridine in a 50 m! round-bottomed flask and then 0.91 g of O-benzylhydroxylamine hydrochloride (7.4 mmol) is added. The reaction medium is heated at reflux overnight and then concentrated under reduced pressure. | oo
The: residue is taken up in water basified with aqueous ammonia and then extracted oo three times with dichloromethane. The organic phases are combined, washed with a saturated sodium chloride solution, dried over sodium sulphate, filiered and evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ammoniacal methanol. 12g of (2-allyl-2-azabicyclo[2.1.1]hex-1- yh(phenyl)methanone O-benzyloxime are thus obtained in the form of an oil. 'H NMR (400 MHz, de-DMSO} & ppm 7.49-7.45 (m, 2H), 7.42-7.26 (m, 8H), 5.76 (m, 1H), 5.17 (m, J = 17 Hz and 1.7 Hz, 1H), 5.09 (s, 1H), 5.03 (m, 1H), 3.06 (dxt, J =5.9
Hz and 1.4 Hz, 2H), 2.66 (broad s, 2H), 2.62 (broad t, J = 3 Hz, 2H), 1.79 (m, 2H), 1.63 (m, 2H). 1.6. {(2-Allyl-2-azabicyclo[2.1.1]hex-1-yl {phenyhmethyllamine | : 0.32 g of lithium aluminium hydride (8.4 mmol) is placed in 15 ml of ether in a 50 ml three-necked flask under nitrogen. A solution of 07g of (2-allyl-2- azabicyclo[2.1.1]hex-1-yl)(phenyl)methanone O-benzyloxime (compound according to stage 1.5) (2.1 mmol) in 3 ml of ether is subsequently added and then the mixture is heated at 40°C for 3 hours. After cooling, the reaction medium is hydrolysed at 0°C with 1.4 ml of a 0.1M aqueous potassium sodium tartrate solution overnight.
After filtering the reaction medium, the filtrate is concentrated under reduced pressure.
The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ammeoniacal methanol. 0.3 g of " [(2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyllamine is thus obtained in the form of an oil. 'H NMR (400 MHz, de-DMSO) § ppm 7.36-7.15 (m, 5H), 6.87 (m, 1H), 5.23 (m, 1H), 5.06 {m, 1H), 4.14 (s, 1H), 3.36 {m, J = 13.5 and 5.5 Hz, 1H), 3.06 (m, J = 13.5 and 6.4 Hz, 1H), 2.76 (broad d, J = 8 Hz, 1H), 2.43 (m, 2H), 1.78 (broad s, 2H), 1.39-1.21 (m, 3H), 1.08 (m, 1H). : 1.7. N-[(2-Allyl-2-azabicyclo[2.1. 1]hex-1-yl)(phenyl)methyl]-4, 5-dibromothrophene-2- carboxamide 175g of [(2-allyl-2-azabicyclo[2.1.1}hex-1-yl)(phenyl)methyllamine (compound ~~ according to stage 1.6) (7.66 mmol) are placed in 30 ml of dichloromethane at 0°C in - cl the presence of 2.1g of potassium carbonate (15.3 mmol) in a 250 ml round- bottomed flask. A solution of 2.89 of 4,5-dibromothiophene-2-carbonyl chloride” =~ : 35 {9.2mmol) in 20 ml of dichloromethane is added and the mixture is left stirring at ambient temperature overnight. The reaction medium is subsequently diluted with 100 ml of dichloromethane and then washed successively with water (50 ml), a 1N sodium hydroxide solution (50 ml) and a saturated sodium chloride solution (50 ml).
The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ammoniacal methanol. 3.2g of N-[(2-allyl-2-azabicyclof2.1.1]hex-1-yi)(pheny)methyl}-4,5- dibromothiophene-2-carboxamide are thus obtained. "H NMR (400 MHz, CDCL;) § ppm 7.40-7.08 (m, 7H), 5.79 (m, 1H), 5.18 (m, 1H), 5.06 (m, 1H), 4.98 (m, 1H), 3.36 (m, 1H), 3.07 (m, 1H), 2.87 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1H), 1.55-1.22 (m, 4H).
M.p. = 59-60°C
Example 2 (compound No. 2): N-[(2-Azabicyciof2.1.1]hex-i-yl)(phenyl)methyi]- 4,5-dibromothiophene-2-carboxamide 4.7 mg of palladiumtetrakis(triphenylphosphine) (0.004 mmol) and 0.19g of N,N- dimethylbarbituric acid (1.2 mmol) in solution in 2 ml of dichloromethane are placed in a 10 ml round-bottomed flask under argon provided with a reflux condenser. The reaction medium is heated to 40°C, then 0.2 g of N-[(2-allyl-2-azabicyclo[2.1.1]hex-1- yl)(phenyl)methyl]-4,5-dibromothiophene-2-carboxamide (compound 1) (0.4 mmol) in 2 ml of dichloromethane is added and then the mixture is heated at 40°C for a further 2 hours. After cooling, the mixture is diluted with 10 ml of dichloromethane and subsequently hydrolyzed with 5 ml of a sodium carbonate solution.
The organic phase is separated and washed twice with 5 mil of 1N hydrochloric acid.
The aqueous phases are combined, then basified with aqueous ammonia to pH 9 and subsequently extracted twice with 25 ml of dichloromethane. The organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ammoniacal methanol. 70 mg of N-(2-
E azabicyclo[2.1.1]hex-1-yi)(phenyl)methyl}-4,5-dibromothiophene-2-carboxamide are
Co “thus obtained in the form of a powder. oo oo - : 'H NMR (400 MHz, ds-DMSO) 6 ppm 8.69 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 5.29 (d, J =7.8 Hz, 1H), 2.79 (s, 2H), 2.63 (m, J = 2.8
Hz, 1H), 1.62 (m, 2H), 1.15 (m, 2H). :
M.p. = 189-190°C ~ Example 3 (compound No. 17): (+)-N-[(2-Allyl-2-azabicyclo[2.1.1]hex-1- = yl)}{phenyl)methyl]-4.5-dibromothiophene-2-carboxamide
This compound is obtained by separation by preparative HPLC of N-[(2-Allyl-2- azabicyclo[2.1.1]hex-1-yl){phenyl)methyl]-4.5-dibromothiophene-2-carboxamide (compound No. 1) using a CHIRALpak® AD 20 um, and, as solvent, an 80/20 acetonitrile/propan-2-ol mixture. 'H NMR (400 MHz, d;-DMSO) & ppm 8.65 (m, 1H), 8.15 (s, TH), 7.4-7.2 (m, 5H), 6.75 (m, 1H), 5.40 (m, 1H), 5.30 {m, 1H), 5.02 (m, 1H), 3.20 (m, 2H), 2.70 (m, 1H), 2.60- 2.50 (m, 2H), 1.58 (m, 1H), 1.4 (m, 3H). ee = 909.7% [aplarc MeOH = +39.2° ¢ = 0.475 g/100 ml
Example 4 (compound No. 4): (+)-N-[(2-azabicyclo[2.1.1]hex-1- yl)(phenyl)methyl}-4,5-dibromothiophene-2-carboxamide, hydrochloride (1:1) :
This compound is obtained according to the method described in Example 2 starting - from compound No. 17 described according to Example 3, after salification in the hydrochloride form by dissolution of the base in ether, addition of an excess of 1N hydrochloric acid in ether and then concentration under reduced pressure. oo © "TH NMR (400 MHz, d-DMSO) & ppm 9.77 (m, 1H), 9.55 (d, J = 8.9 Hz, 1H), 8.93 (m, 1H), 8.46 (s, 1H), 7.56-7.38 (m, 5H), 5.70 (d, J = 9.2 Hz, 1H), 3.30 (m, 2H), 2.84 (m, 1H), 2.10 (m, 1H), 1.87 (m, 1H}, 1.66 (m, 2H).
M.p. = 211-213°C : ee = 99.7% : [op)z0ec MeOH = +35.5° ¢ = 1.02 g/100 mi
C0 | oo . Example 5 | (compound No. 18): (-)-N-[(2-Allyl-2-azabicyclo[2.1.1]hex~1- . oo yl){phenyl)methyl}-4,5-dibromothiophene-2-carboxamide
The compound is obtained by separation by. preparative HPLC of N-[(2-allyl-2- azabicyclof2.1.1]hex-1-yl)phenyl)methyl}-4,5-dibromothiophene-2-carboxamide
(compound No. 1) using a CHIRALpak® AD 20 um column and, as solvent, an 80/20 acetonitrile/propan-2-ol mixture. 'H NMR (400 MHz, dg-DMSO) § ppm 8.65 (m, 1H), 8.15 (s, 1H), 7.4-7.2 (m, 5H), 5.75 ~~ (m, TH), 5.40 (m, 1H), 5.30 (m, 1H), 5.02 {(m, 1H), 3.20 (m, 2H), 2.70 (m, 1H), 2.60- 2.50 (m, 2H), 1.58 (m, 1H), 1.4 (m, 3H). Co ee = 100% [op}a0-c MeOH = -36.4° ¢ = 0.45 g/100 ml
Example 64%" (compound No. 5); (-}-N-[(2-Azabicyclo[2.1.1]hex-1- : 10 yl)(phenyl)methyl]-4,5-dibromothiophene-2-carboxamide, hydrochloride (1:1) - This compound is obtained according to the method described in Example 2 starting from compound No. 18 described according to Example 5, after salification in the hydrochloride form by dissolution of the base in ether, addition of an excess of 1N hydrochloric acid in ether and then concentrated under reduced pressure, 'H NMR (400 MHz, d-DMSO) § ppm 9.52 (d, J = 9.2 Hz, 1H), 8.42 (s, 1H), 7.50-7.34 (m, 8H), 5.66 (d, J = 8.9'Hz, 1H), 3.25 (m, 2H), 2.80 (m, 1H), 2.07 (m, 1H), 1.83 (m, 1H), 1.62 (m, 2H).
M.p. = 227-228°C ee=100% [oplogrc MeOH =-36.2° ¢ = 1.02 g/100 ml
Example 7 (compound No. 7): N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl}-2- {methylsulphanyl)nicotinamide 7.1 [(2-Benzyl-2-azabicyclo[2. 1. 1]hex-1-yt)(phenvlmethyllamine 3 g of 2-benzyl-2-azabicyclo[2.1.1]hexane-1-carbonitrile (XI) (15.1 mmol) are placed at -70°C in 100 ml of anhydrous tetrahydrofuran in a 500 mi three-necked flask under
Co argon. 37.8 ml of a 0.8M solution (cyclohexane/ether). of phenyliithium (30.2 mmol) are added dropwise. oo Co a The reaction mixture is left stirring at -70°C for two and a half hours and is then hydrolysed at -20°C with 30 ml of water. )
After extracting, the organic phase is concentrated and then the residue is taken up in 40 ml of methanol. 2.8¢g of sodium borohydride (75 mmol) are added thereto portionwise. The reaction medium is left stirring at ambient temperature overnight.
After evaporating under reduced pressure, the residue is taken up in 100 ml of ether and 100 ml of water.
The medium is acidified with a 1N hydrochloric acid solution and then the ethereal phase is exiracted.
The aqueous phase is basified with aqueous ammonia and then reextracted twice with 100 ml of dichloromethane. The organic phases are combined and then dried over sodium sulphate, filtered and evaporated under reduced pressure. 4.15 g of [(2- benzyl-2-azabicyclo[2.1.1]hex-1-yt)(phenyl)methylJamine (lib) are thus obtained in the form of an oil which crystallizes in the cold. : 10H NMR (200 MHz, CDCls) 3 ppm 7.6-7.3 (m, 5H), 4.4 (s, 1H), 4.2 (d, J = 16 Hz, 1H), 3.6 (d, J = 16 Hz, 1H), 3.0 (d, J = 9 Hz, 1H), 2.6 (m,1H), 2.4 (d, J = 9 Hz, 1H), 1.8 (broad s, 2H), 1.6-1.2 (m, 4H).
M.p. = 63.5-64°C.
An analytical sample is obtained in the form of the hydrochloride by dissolution of the base in ether, addition of an excess of 1N hydrochloric acid in ether and then concentration under reduced pressure.
M.p. = 140-142°C : 20 7.2 [(2-Azabicyclo[2.1. 1Thex-1-vI}(phenyi)methyllamine 0.43 g of [(2-benzyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyllamine (1.54 mmol) is placed in 20 ml of ethanol and 5 ml of IN hydrochloric acid, in the presence of a : spatula tip of 10% palladium-on-charcoal, in a Parr bottle under 4 atmospheres of hydrogen at 40°C for 3 hours.
After filtering of the catalyst and concentrating the filtrate under reduced pressure, the residue is taken up in 30 mi of dichloromethane and 30 ml of water basified with aqueous ammonia. After extracting, the organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. 0.24 g of [(2-azabicyclo[2.1.1Thex-1- oo -. yl){phenyl)methyiJamine is thus obtained in the form of a yellow oil which solidifies in © 30 the cold and which is used as is in the following stage. -
Co M.p. = 46.5-47°C
An analytical sample is obtained in the form of the hydrochioride by dissolution of the base in ether, addition of an excess of IN hydrochloric acid in ether and then concentration under reduced pressure.
'H NMR (400 MHz, ds-DMSO) § ppm 10.12-8.71 (m, 4H), 7.46-7.35 (m, 6M), 4.83 (m, 1H), 3.15 (m, 2H), 2.72 {m, 1H}, 2.10 (m, 1H), 1.89 (m, 1H), 1.57 (broad t, J = 9.3 Hz, 1H), 1.36 (broad t, J = 9.3 Hz, 1H). : M.p. = 220-223°C (decomp.) 7.3 N-[(2-azabicyclo[2.1.11hex-1-vi}{phenyhmethvl]-2~(methyisulphanyl)nicotinamide 0.22 g of 2-(methylsulfanyl)nicotinic acid (1.27. mmol), 0.17 g of hydroxybenzotriazole (1.27 mmol) and 025g of 1-[3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (1.27 mmol) are placed in solution in 2 ml of dichloromethane in a 25 mi round-bottomed flask and the mixture is stirred at ambient temperature for 15 minutes. - 0.2 g (1.0 mmol) of [(2-azabicyclo[2.1.1]hex-1-yI)(phenyl)methyllamine in solution in : 2 ml of dichloromethane is added and the mixture is stirred at ambient temperature overnight.
The reaction medium is subsequently diluted with 10 m| of dichloromethane and then successively washed with water (5 ml), with 1N sodium hydroxide solution (5 ml} and + with a saturated sodium chloride solution (5 ml).
The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ammoniacal methanol. 63 mg of N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl}-2- (methyisulphanyl)nicotinamide are thus obtained in the form of a powder.
M.p. = 141-143°C "H NMR (400 MHz, dg-DMSO) & ppm 8.79 (d, J =8.5 Hz, 1H), 8.55 (dxd, J = 5 Hz and 1.7 Hz, 1H), 7.76 (dxd, J = 7.5 Hz and 1.8 Hz, 1H), 7.43-7.18 (m, 6H), 5.30 (d, J = 8.6
Hz, 1H), 2.77 (m, 2H), 2.63 (m, 1H), 2.45 (s, 3H), 1.70 (m, 1H), 1.64 (m, 1H), 1.14 (m, 2H).
The other compounds described in Table 1 are obtained according to the methods described in Examples 1 to 7 starting from the appropriate amines of formula (lia), (ib) or (lic), from appropriate lithium compounds of formula (VHI) or from appropriate carboxylic acid derivatives of formula (lil). =
The chemical structures of some compounds of the invention are illustrated in the following Table 1. :
In the column: - “Salts™ “” denotes a compound in the form of the base, "HCI" denotes a hydrochloride and the figure in brackets indicates the (base:acid) ratio,
: - the compounds in the table are provided in the form of the hydrochloride solvated by one or more water molecules, in the R, Ry and R; columns: } - “CI” means chlorine, -"Br” means bromine, - “CH” means methyl, - “OCH;" means methoxy, - “Ph” means phenyl, - “CF3” means trifluoromethyl, -“Bn” means benzyl; - in the “Ry” column, the figure in front of the substituents indicates the position in the general formula (1).
The physical properties, meiting points and optical rotations of the compounds of
Table 1 are given in Table 2. Co in Table 2: - the [Oplaoe column gives the analytical result for the optical rotation of the compounds in the table at the wavelength of 589 nM and at the temperature of 20°C.
The solvent shown in brackets corresponds to the solvent employed in carrying out the measurement of the optical rotation in degrees and the letter “c” shows the concentration of the solvent in g/100 ml. “N.A.” means that the measurement of the _ optical rotation is not applicable, - the “m/z” column gives the molecular ion (M+H") or (M") observed by analysis of the products by mass spectrometry, either by LC-MS (Liquid Chromatography coupled to :
Mass Spectroscopy), carried out on a device of Agilent LC-MSD Trap type in positive
ESI mode, or by direct introduction by MS (Mass Spectroscopy) on an Autospec M ~ (EBE) device using the DCI-NH; technique or using the electron impact technique on a device of Waters GCT type. oo
TABLE 1 : 4 5 3 a :
N 1 - a 2 | N OO
R H
(He)y—r, 4,5-Bry-thiophen- 1 allyl Ph racemic 2-vi : 4 5-Br,-thiophen- 2 H Ph racemic : 2-yl 2,5-Cl,-thiophen- 3 H Ph racemic 3-yl 4,5-Bro-thiophen- HCH chiral 4 H Ph 2-y (1:1) dextrorotatory 4,5-Bro-thiophen- HCI . chiral
Ph 2-yl (1:1) laevorotatory : 3-Cl-4-CF;-
H 4-F-Ph CL racemic pyridin-2-yl 2-SCHs-pyridin-3- ne PT] eee yl 3-Cl-4-CF5-
Ph oo racemic pyridin-2-yi . lo : 3-Cl-4-CF;- HCI Lo
H naphth-2-yl racemic pyridin-2-yl (1:1) : 2-SCHa-pyridin-3- | HCI 1 11 H naphth-2-yl racemic : yl (1:1) 3-Cl-4-CFx- HCl 12 H 3-0OCHj3-Ph Co racemic pyridin-2-yl (1:1) 2-SCH3-pyridin-3- HCI } 13 H 3-OCH3-Ph racemic yi (1:1)
2-SCH;-pyridin-3- HCI 14 H 3-CHz-Ph racemic yl (1:1) 3-Cl-4-CF5- HCI
H 3-CF;-Ph racemic pyridin-2-yl (1:1) = Ce 3-Cl-4-CF5- HCI 16 H 3-CH;-Ph } : racemic pyridin-2-yl (1:1) : 4,5-Bry-thiophen- chiral 17 allyl Ph 2 dextrorotatory 4,5-Brs-thiophen- chiral 18 allyl Ph 2-yl laevorotatory 2-Cl-3-CF;- HCI
Ph Co racemic pyridin-2-yl (1:1) |. : } HCI }
Bn Ph 2,5-(Cl)o-thien-3-yl (1:1) racemic 3,6-(Cl)o-pyridin-2- | HCI 21 Ph (Clery racemic vi (1:1) 3-CI-5-CF3- HCI 22 H Ph ] racemic pyridin-2-yl (1:1) 6-Cl-3-CF3- HCI 23 H Ph Co racemic pyridin-2-yl (1:1)
TABLE 2
No | M.p. (°C) [aplz0c® LCMS
MH* 59-60 189-190 135-136 211-213 +35.5 (MeOH) ¢=1.02 g/100 ml 227-228 -36.2 (MeOH) c=1.02 g/100 mi 6 [ 183.5-1845 141-143 8 | 153-154 000 NA | "396 9 140-143 10 | 199-200 162-163 119.5-120.5 146-147 195-196 110-120 150.5-151.5 +39.2 (MeOH) c=0.475 9/100 ml -36.4 (MeOH) ¢=0.457 9/100 m 19 | 144-145 165-166 169.5-170.5 133-134
The compounds of the invention have been subjected fo a series of pharmacological trials which have demonstrated their advantage as substances possessing therapeutic activities.
Study of glycine transportation in SK-N-MC cells expressing the native human transporter GiyT1. :
The uptake of [“*Clglycine is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native human transporter GlyT1 by measuring the radioactivity "incorporated in the presence or absence of the test compound. The cells are cultured ‘as a monolayer for 48 hours in plates pretreated with 0.02% fibronectin. On the dayof the experiment, the culture medium is removed and the cells are washed with
Krebs-HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulphonic acid) buffer at pH 7.4.
After preincubation for 10 minutes at 37°C in the presence either of buffer (control batch) or of test compound at various concentrations or of 10 mM of glycine
(determination of the non-specific uptake), 10 uM of ["“Clglycine (specific activity 112 mCi/mmol) are subsequently added. Incubation is continued for 10 min at 37°C and the reaction is halted by washing twice with pH 7.4 Krebs-HEPES buffer. The radioactivity incorporated by the cells is then estimated after adding 100 pl of liquid scintillant and stirring for 1 h. Counting is carried out on a Microbeta Tri-Lux™ counter. : The effectiveness of the compound is determined by the ICs;, 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 batch which received the 10 mM glycine.
The compounds of the invention have, in this test, an ICs of the order of 0.01 to 10 uM.
Some examples of Cg results for compounds according to the invention are shown in
Table 3.
TABLE 3 ew ees
The results of the in vitro trials carried out on the chiral compounds of the invention and their racemates according to the general formula (I) show that they are inhibitors of the glycine transporter GlyT1 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 or dementia; for the treatment of psychoses, in particular schizophrenia (deficit form and productive form); or acute or chronic extrapyramidal symptoms induced by neurolepiics; for the treatment of various forms of anxiety, panic attacks, phobias or obsessive-compulsive disorders; for the treatment of various forms of depression, including pyschotic depression; for the treatment of bipolar disorders, manic disorders or mood disorders; or for the treatment of disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders, migraine, pain or sleep disorders.
The compounds according to the invention can thus be used in the preparation of medicaments, in particular of medicaments which are inhibitors of the glycine transporter GlyT1.
Thus, according to another of its aspects, a subject-matter of the invention is medicaments which comprise a compound of formula (I) or an addition salt of the [latter with a pharmaceutically acceptable acid.
Another subject-matter of the present invention is pharmaceutical compositions comprising an effective dose of at least one compound according to the invention, in the form of the base or a pharmaceutically acceptable salt, as a mixture, if appropriate, with suitable excipients. ~The said excipients are chosen according to the pharmaceutical form and the method of administration desired.
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. oo The unit administration forms can be, for example, tablets, gelatin capsules, granules, powders, solutions or suspensions to be taken orally or to be injected, patches or suppositories. Ointments, lotions and collyria can be envisaged for topical administration. :
The said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active principie per kg of body weight, according to the pharmaceutical dosage form.
To prepare tablets, a pharmaceutical vehicle, which can be composed of diluents, such as, for example, lactose, microcrystalline cellulose or starch, and formulation adjuvants, such as binders (polyvinylpyrrolidone, hydroxypropylmethylceliulose, and the like), flow agents, such as silica, or lubricants, such as magnesium stearate, stearic acid, glyceryl tribehenate or sodium stearylfumarate, is added to the micronized or unmicronized active principle. Wetting or surface-active agents, such as sodium lauryt sulphate, can also be added.
The preparation techniques can be direct tableting, dry granulation, wet granulation or hot melt.
The tablets can be bare, coated with sugar, for example with sucrose, or coated with various polymers or other appropriate materials. They can be designed to make possible rapid, delayed or sustained release of the active principle by virtue of polymer matrices or of specific polymers used in the coating.
To prepare gelatin capsules, the active principle is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melt) or liquid or semisolid pharmaceutical vehicles.
The gelatin capsules can be hard or soft and coated or uncoated with a thin film, so as to have a rapid, sustained or delayed activity (for example, for an enteric form).
A composition in the form of a syrup or an elixir or for administration in the form of drops can comprise the active principle in conjunction with a sweetener, preferably a calorie-free sweetener, methylparaben or propylparaben, as antiseptic, a flavour enhancer and a colorant.
The water-dispersible powders and granules can comprise the active principle as a mixture with dispersing agents or wetting agents, or dispersing agents, such as polyvinylpyrrolidone, as well as with sweeteners and flavour-correcting agents.
Recourse is had, for rectal administration, to suppositories prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
Use is made, for parental administration, of aqueous suspensions, isotonic saline solutions or injectable sterile solutions comprising pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle can aiso be formulated in the form of microcapsules, opftionaily with one or more vehicles or additives or else with a polymer matrix or with a cyclodextrin (patches or 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 the appearance of a cream or of a gel, of microemulsions or of aerosols or in the form of vesicular dispersions comprising ionic and/or nonionic lipids. These pharmaceutical dosage forms are prepared according to methods conventional in the fields under consideration.
By way of example, a unit administration form of a compound according to the : invention in the tablet form can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium : 6.0 mg
Maize starch 15.0 mg
Hydroxypropyimethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
Orally, the dose of active principle administered daily can reach from 0.1 to 20 mg/kg, taken once or on several occasions.
There may be specific cases where higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to the usual practice, the dosage appropriate fo each patient is determined by the physician according to the method of administration and the weight and the response of the said patient.
The present invention, according to another of its aspects, also relates to a method for the treatment of the pathologies indicated above which comprises the administration, to a patient, of an effective dose of a compound according to the invention or one of . its pharmaceutically acceptable salts.

Claims (24)

- CLAIMS
1. Compound of general formula (I): —— N 0) 0 R HN (Her, in which: - R represents a hydrogen atom or a group chosen from {C;-Cg)alkyl, (C:-C;)cyclo- alkyl, benzyl or allyl groups which is optionally substituted by one or more groups chosen, independently of one another, from halogen atoms or (Cs-C;)cycloalkyl, (C1-Cs)alkyl, (C4-Cg)alkoxy or hydroxyl groups; - Rq represents a phenyl or naphthyl group which is optionally substituted by one or more substituents chosen, independently of one another, from halogen atoms or (C1-Cglalkyl, (C-Cglalkoxy, halo(C4-Cglalkyl, hydroxyl, halo{C,-Cglalkoxy, (Ci- Ce)alkylthio, (C4-Cg)alkyl-SO or (C4-Cgalkyl-SO, groups; - Het represents a heteroaryl group; - R; represents one or more substituents chosen from the hydrogen atom, halogen atoms or halo(C,-Cg)alkyl, (C1-Cglalkyl, (Cs-Cr)cycloalkyl, (Cs-Cr)cycloalkyl(Cy-Cj)alkyl, (C4-Cg)alkoxy, benzyl, (Ci-Cg)alkylthio, (C4-Cg)alkyl-SO or (C4-Cg)alkyl-SO, groups; in the form of the base or of an addition salt with an acid.
2. Compound of general formula (I) according to Claim 1, characterized in that R represents a hydrogen atom, a benzyt group or an allyl group;
: . Ry, Het and R; being as defined in claim 1, in the form of the base or of an addition salt with an acid.
:
3. Compound of general formula (I) according to Claim 1, characterized in that R, represents a phenyl or naphthyl! group which is optionally substituted by one or “more groups chosen, independently of one another, from halogen atoms or (C:- Celalkyl, {C4-Cs)alcoxy or halo{C4-Cgalkyl groups; - R, Het and R; being as defined in Claim 1, in the form of the base or of an addition salt with an acid.
4. Compound of general formula {I} according to Claim 1, characterized in that Het represents an indole, thiophene or pyridine group; R, Ry and R; being as defined in Claim 1, oo in the form of the base or of an addition salt with an acid.
5. Compound of general formula (1) according to Claim 1, characterized in that
R. represents one or more substituents chosen from the hydrogen atom, halogen atoms or halo(C4-Cg)alkyl, benzyl or (C;-Cs)alkylthio groups; R, Ry and Het being as defined in Claim 1, in the form of the base or of an addition salt with an acid.
6. Compound of general formula (I) according to Claim 1, characterized in that - Represents a hydrogen atom, a benzyl group or an allyi group; - Ry represents a phenyl or naphthyl group which is optionally substituted by one or more substituents chosen, independently of one another, from halogen atoms or {C4-Cs)alkyl, (C4-Cs)alcoxy or halo(Cs-Cg)alkyl groups; } - Het represents an indole, thiophene or pyridine group; - Rg represents one or more substituents chosen from the hydrogen atom, halogen atoms or halo(C+-Cg)alkyl, benzyl or (C4-Cg)alkylthio groups; in the form of the base or of an addition salt with an acid.
7. Compound of general formula (I} according to Claim 1 or 6, characterized in that - Represents a hydrogen atom, a benzyl group or an allyl group; - Rq represents a phenyl or naphthyl group which is optionally substituted by one or more substituents chosen, independently of one another, from the fluorine atom or methyl, methoxy or trifluoromethyl groups; - Het represents an indole, thiophene or pyridine group; - Rg represents one or more substituents chosen from the hydrogen atom, bromine or chlorine atoms or trifluoromethyl, methyithio or benzyl groups; in the form of the base or of an addition salt with an acid.
8. Compound according to one of Claims 1 to 7, characterized in that it is chosen from: N-[(2-Allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl}-4,5-dibromothiophene-2- carboxamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-4,5-dibromothiophene-2-carboxamide: N-{(2-Azabicyclo[2.1.1]hex-1-yl)(phenylYmethyl]-2,5-dichlorothiophene-3-carboxamide; (+)-N-[(2-Azabicyclo[2.1.1jhex-1-yl)}phenyl)methyi]-4,5-dibromothiophene-2- carboxamide, and its hydrochloride; : oo (-)}-N-{(2-Azabicyclo[2.1.1]hex-1-yi)(phenyl)methyl}-4,5-dibromothiophene-2- carboxamide, and its hydrochloride; N-{(2-Azabicyclo[2.1.1]hex-1-yI)(4-fluoropheny)methyi]-3-chioro-4- (trifluoromethyl }pyridine-2-carboxamide; N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-(methyisulfanyl)nicotinamide; N-[(2-Azabicycio[2.1.1]hex-1-yl)(phenyl)methyl}-3-chloro-4-(trifluoromethyi)pyridine-2- carboxamide; N-[(2-Azabicycio[2.1 Alhex-1-yl)(phenyl)methyil-1-benzyi-1H-indole-4-carboxamide; - N-[{2-Azabicyclo[2.1.1]hex-1-yl)(naphth-2-yl)methyl}-3-chloro-4- (trifluoromethyi)pyridine-2-carboxamide, and its hydrochloride; N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(naphth-2-yl)methyl}-2-(methylsulfanyl)nicotinamide, and its hydrochloride; N-[(2-Azabicyclo[2.1. 1]hex-1-yl)(3-methoxyphenyl)methyl]-3-chloro-4- (triftuoromethyt)pyridine-2-carboxamide, and its hydrochioride; : N-{(2-Azabicyclo[2.1.1]hex-1 -y1)(3-methoxyphenyl)methyl]-2- ~ (methyisulfanyl)nicotinamide, and its hydrochloride; N-[(2-Azabicyclo]2.1. 1]hex-1-yl)(m-tolyl)methyl]-2-(methylsulfanyl)nicotinamide, and its hydrochloride; i N N-[(2-Azabicyclo{2.1.1]hex-1-ylI}(3-(trifluoromethyl phenyl Yymethyl}-3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide, and its hydrochloride; N-[(2-Azabicyclo[2.1.1]hex-1-yl)}(m-tolyl)methyl}-3-chloro-4-(trifluoromethyl)pyridine-2- carboxamide, and its hydrochloride; (+)-N-[(2-Allyl-2-azabicyclo]2.1.1jhex-1-yl)}{phenyl)methyl]-4,5-dibromothiophene-2- * carboxamide; (-)-N-{(2-Allyl-2-azabicyclo[2.1.1]hex-1-y)(phenyl)methyl]-4,5-dibromothiophene-2- carboxamide; N-[(2-Benzyl-2-azabicycio[2.1.1]hex-1-yl){ 3-{trifluoromethyi)phenyl )methyl}-3-chloro-4- ~ (trifluoromethyl)pyridine-2-carboxamide, and its hydrochloride; N-f(2-Benzyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2,5-dichlorothiophene-3- carboxamide, and its hydrochloride; N-{(2-Azabicyclo[2.1. 1]hex-1-yl)(phenyl)methyi]-3,6-dichloropyridine-2-carboxamide,
and its hydrochloride; : N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl}-3-chloro-5-(trifluoromethyl )pyridine-2- carboxamide; N-[(2-Azabicyclo[2.1.1]hex-1-yl} phenyl)methyl}-6-chioro-3-(triflucromethyl)pyridine-2- : carboxamide.
:
9. Process for preparation of a compound of general formula (I) according to Claim 1, : characterized in that a compound of general formula (1): a N 0) RNR, in which R and Ry are as defined according to Claim 1, reacts with a compound of general formula (HI): : y Y 0 @& in which Y represents a leaving group or a chlorine atom and Het and R, are defined according to Claim 1. :
10. Compound of formula (I) - N (in R NH, in which R and R; are defined according to Claim 1.
11. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 8 or an addition salt of this compound with a : pharmaceutically acceptable acid. :
12. Pharmaceutical composition, characterized in that it comprises a compound of formula (1) according to any one of Claims 1 to 8 or a pharmaceutically acceptable sait of this compound and also at ieast one pharmaceutically acceptable excipient.
13. Use of a compound of formula (I) according to any one of Claims 1 to 8 in the preparation of a medicament intended for the treatment of cognitive and/or behavioural disorders associated with neurodegenerative diseases or dementia.
14. Use of a compound of formula (I) according to any one of Claims 1 to 8 in the preparation of a medicament intended for the treatment of psychoses, schizophrenia (deficit form and productive form) or acute or chronic extrapyramidal symptoms induced by neuroleptics.
15. Use of a compound of formula (I) according to any one of Claims 1 to 8 in the preparation of a medicament intended for the treatment of various forms of anxiety, panic attacks, phobias or obsessive-compulsive disorders.
16. Use of a compound of formula (I) according to any one of Claims 1 to 8 in the preparation of a medicament iniended for the treatment of various forms of depression, including psychotic depression; in the treatment of bipolar disorders, manic disorders or mood disorders; or in the treatment of disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders or migraine.
17. Use of a compound of formula (1) according to any one of Claims 1 to 8 in the preparation of a medicament intended for the treatment of pain.
18. Use of a compound of formula (I) according to any one of Claims 1 to 8 in the preparation of a medicament intended for the treatment of sieep disorders.
19. Compound according to any one of Claims 1 to 8, for the treaiment of cognitive and/or behavioural disorders associated with neurodegenerative diseases or dementia.
20. Compound according to any one of Claims 1 to 8, for the treatment of psychoses, schizophrenia (deficit form and productive form) or acute or chronic extrapyramidal symptoms induced by neuroleptics. :
21. Compound according to any one of Claims 1 to 8, for the treatment of various forms of anxiety, panic attacks, phobias or obsessive-compulsive disorders.
22. Compound according to any one of Claims 1 to 8, for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders or mood disorders; or for the treatment of disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders or migraine.
23. Compound according to any one of Claims 1 to 8, for the treatment of pain.
24. Compound according to any one of Claims 1 to 8, for the treatment of sleep disorders. :
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