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(11) Patent Number: KE 457

(45) Date of grant: 21/07/20 II   

(51) Int.CI.8:A 61K 31/437, C 07D 471104, 487/04
       
(51) Int.CI.8:A 61K 31/437, C 07D 471104, 487/04

(73) Owner: SANOFI-AVENTIS of 174 avenue de France, F-75013 Paris., France                           
               
(21)Application Number:    KElP/ 2009/ 000879   

(72) Inventors:    DARGAZANLI, Gihad of C/0 Sanofi-aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France; MEDAISKO, Florence ofC/0 Sanofi-aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France; RENONES, Maria, Carmen ofC/0 Sanofi-aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France and ESTENNE-BOUHTOU, Genevieve ofC/0 Sanofi-aventis,Departement Brevets, 174 avenue de France, F-75013 Paris, France.       

(22) Filing Date: 21/09/2007           
                                   
(30) Priority data:0608348  22/09/2006                       
                   
(86)  PCT data    PCT/FR07/001545    21/09/2007 wo 2008/037881    03/04/2008
                   
(74) Agent/address for correspondence:Kaplan & Stratton Advocates, P.O. Box 40111-00100,Nairobi   

(54)Title: DERIVATIVES OF PYRROLIZINE, INDOLIZINE AND QUINOLIZINE, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

(57) Abstract: Compound corresponding to the general formula in which m and n are each the number 1 or 2, Ar is a group chosen from phenyl, naphth-1-yl, naphth-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, thiazol-2-yl and oxazol-2-yl groups, it being possible for this group Ar to be optionally substituted; R is either a hydrogen atom, or one or more substituents, which may be identical to or different from one another, chosen from halogen atoms and mono- or polyfluoro(C1-C6)alkyl and mono- or polyfluoro(C1-C6)alkyloxy, linear (C1-C6)alkyl, branched or cyclic (C3-C7)alkyl, (C3-C7)cycloalkyl(C 1-C6)alkyl, (C 1-C6)alkoxy, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkyl(C1-C6)alkyloxy, (C1-C6)alkylthio, cyano, amino, phenyl, acetyl, benzoyl, (C1-C6)alkylsulphonyl, carboxyl, (C l-C6)alkoxycarbonyl and pentafluorosulphanyl groups. Therapeutic use.

DERIVATNES OF PYRROLIZINE, INDOLIZINE AND QUINOLIZINE, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

A subject-matter  of the  present  invention  is  pyrrolizine,  indolizine  and  quinolizine

5    derivatives, their preparation and their therapeutic application.


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

15    in which:

m and n each represent, independently of one another, the number 1 or 2,

Ar represents a group chosen from the phenyl, naphth-1-yl, naphth-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, thiazol-2-yl and

oxazol-2-yl groups, it being possible for this group Ar optionally to be substituted by one or

20    more substituents chosen from halogen atoms and (C 1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7 )cycloalkyl(Ct-C6)alkyl, (Ct-C6)alkoxy, (C3-C7)cycloalkyloxy, (CyC7)cyclo-alkyl(C1-C6)alkyloxy, (Ct-C6)alkylthio, (C3-C7 )cycloalkylthio, (C3-C7)cycloalkyl-(C1-C6)alkylthio, mono- or polyfluoro(C1-C6)alkyl and mono- or polyfluoro(Ct-C6)alkyloxy groups,

25    R represents either a hydrogen atom or one or more substituents, identical to or different

from one another, chosen from halogen atoms and mono- or polyfluoro(C 1-C 6)alkyl and mono- or polyfluoro(Ct-C6)alkyloxy, linear (C 1-C6)alkyl, branched or cyclic (C3-C7)alkyl,
(C3-C7)cycloalkyl(Ct-C6)alkyl,   (Ct-C6)alkoxy,   (C3-C7)cycloalkyloxy,   (C3-C7)cyclo-
alkyl(C1-C6)alkyloxy,   (C 1-C6)alkylthio,   cyano,   amino,   phenyl,   acetyl,   benzoyl,
30    (C 1-C6)alkylsulphonyl, carboxyl, (C1-C6)alkoxycarbonyl and pentafluorosulphanyl groups.


The compounds of general formula (I) have three asymmetric centres; they can exist in the form of enantiomers or of threo or erythro diastereoisomers with a cis or trans

-    Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, it being possible for this group Ar optionally to be substituted by one or more halogen atoms,

-    R represents either a hydrogen atom or one or more substituents, identical to or different from one another, chosen from chlorine and the methyl, trifluoromethyl, trifluoromethoxy

5    and pentafluorosulphanyl groups.


Among the compounds of the invention, a fifth group of compounds is composed of the following compounds:

trans-threo-2-Chloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-

10    benzamide hydrochloride I: 1.

trans-erythro-2-Chloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride 1:1.

trans-threo-2,6-Dichloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-

benzamide hydrochloride 1:1.

15    trans-erythro-2,6-Dichloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl]-3 -trifluoromethyl-benzamide hydrochloride 1: I.

trans-thrco- 2-Chloro-N-[ ( octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride I: 1. 2-Chloro-N-[(S)-(3S,8aR)-(octahydroindo!izin-3-yl)phenylmethyl]-3-trifluoromethyl-

20    benzamide hydrochloride 1:1.

trans-threo-2-Methyl-N-[ ( octahydroindolizin-3-yl)phenylmethyl]-3-trifl uorom ethyl-benzamide hydrochloride 1:1.

cis-erythro-2-Methyl-N-[ ( octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride I: 1.

25    2-Chloro-N-[(S)-(3S,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethyl-benzamide hydrochloride I: 1.

2-Chloro-N-[ (S)-(3 S,SaR)-(octahydroindolizin-3-yl)( thiophen-3-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride 1: 1.

cis-erythro-2-Chloro-N-[ ( octahydroindolizin-3-yl)phenylmethyl ]-3-trifluoromethyl-

30    benzamide hydrochloride 1:1.

2-Chloro-N-[ (S)-(3 R,SaR )-( octahydroindo lizin- 3-yl)(thiophen-3-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride 1: 1.

2-Chloro-N-[ (S)-(3R,8aR)-(octahydroindo lizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoro-

methylbenzamide hydrochloride 1: 1.

trans-threo-2-Chloro-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-

benzamide hydrochloride 1:1.

trans-erythro-2-Chloro-N- [( octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethy1-

5    benzamide hydrochloride 1:1.

transcthreo- 2,6-Dichloro-N- [( octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride 1:1.

trans-erythro-2,6-Dichloro-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3 -trifluoromethyl-

benzamide hydrochloride 1:1.

10    trans-erythro-2-Methyl-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride I: 1.

trans-threo-2,6-Dichloro-N-[ (4-fluorophenyl)( octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide hydrochloride 1:1.

trans-threo-2-Chloro-N-[ ( octahydroquinolizin-4-yl)(pyridin-3 -yl)methyl]-3 -trifluoromethyl-

15    benzamide hydrochloride 1:1.

trans-erythro-2-Chloro-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride 1: 1.

trans-threo-2-Chloro-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-5 -trifluoromethyl-

benzamide hydrochloride 1:1.

20    trans-threo-2-Methyl-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3 -trifluoromethyl-benzamide hydrochloride 1:1.

trans-erythro- 2-Chloro-N-[ ( octahydroquinolizin-4-yl)(thiophen-3-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride 1: I.

trans-threo-2-Chloro-3 -methyl-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]benzamide

25    hydrochloride 1: 1.

trans-threo-2-Chloro-N-[ ( 4-fluorophenyl)( octahydroquinolizin-4-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride 1: 1.

trans-erythro-2-Chloro-N-[ ( 4-fluorophenyl)( octahydroquinolizin-4-yl)methyl]-3-trifluoro-

methylbenzamide hydrochloride 1:1.

3 0    trans-threo-2-Chloro- 3-methoxy-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]benzamide

hydrochloride I: I.

trans-threo-N-[(Octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethoxybenzamide

hydrochloride 1: I.

erythro and trans-threo stereochemistry.
I  'I

The compounds of general formula (II) with n = 2 and m = 1 or n and m = 2 have a trans relative stereochemistry and they result in the compounds of general formula (I) of trans-

5    erythro and trans-threo stereochemistry.


Finally, the compound of general formula (II) with nand m = 1 has a trans and cis relative stereochemistry and it results in the compounds of general formula (I) in the form of a mixture of isomers which can be separated by liquid chromatography.

10

Furthermore, the chiral compounds of general formula (I) can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column or by resolution of the racemic amine of general formula (V) by use of a chiral acid, such as tartaric acid, camphorsulphonic acid, dibenzoyltartaric acid or N-acetylleucine, by

15    the fractional and preferential recrystallization of a diastereoisomeric salt in a solvent of alcohol type, or by enantiose1ective synthesis using a chiral nitrile of general formula (II).

The nitriles of general formula (II) are described in Synlett, (1995), 519-522, when nand m

represent 1 with a cis and trans stereochemistry, in J 0. C., 55, (1990), 4688-4693 and

20    JO.C., 56, (1991), 4868-4874, when n represents 2 and m represents 1 with a trans stereochemistry, and in Org. Letters, 2, (2000), 2085-2088, when n represents 1 and m represents 2 with a trans and cis stereochemistry, and, finally, they can be prepared according to methods analogous to those described above when nand m represent 2 with a

trans stereochemistry in the racemic or chiral series. The lithiated derivatives of general

25    formula (III) are available commercially or they can be prepared according to methods known to a person skilled in the art and analogous to those described inJO.C., 62, (1997), 5484-5496 and Tetrahedron Letters, 35, (1994), 3673-3674.

Certain acids and acid chlorides of general formula (VI) are available commercially or can

30    be obtained according to methods analogous to those described in Patents EP-0 556 672 and US-3 801 636 and in J Chern. Soc., (1927), 25, Chern. Pharrn. Bull., (1992), 1789-1792, Aust. J Chern., (1984), 1938-1950 and J 0. C., (1980), 527.

The invention, according to another of its aspects, also has as subject-matter the compounds of general formula (V):
in which

5    m and n each represent, independently of one another, the number 1 or 2,

Ar represents a group chosen from the phenyl, naphth-1-yl, naphth-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, thiazol-2-yl and

oxazol-2-yl groups, it being possible for this group Ar optionally to be substituted by one or more substituents chosen from halogen atoms and (C1-C6)alkyl, (C3-C7 )cycloalkyl,

10    (C3-C7)cycloalkyl(Cl-C6)alkyl, (CJ-C6)alkoxy, (C3-C7 )cycloalkyloxy, (C3-C7)cyclo-alkyl(C1-C6)alkyloxy, (C1-C6)alkylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkyl-(C1-C6)alkylthio, mono- or polyfluoro(C 1-C6)alkyl and mono- or polyfluoro(C1-C6)alkyloxy groups.


15    These compounds are of use as intermediates in the synthesis ofthe compounds of formula (I).

Among the compounds of general formula (V) which are a subject-matter of the invention, a

first group of compounds is composed of the compounds for which:

20    m and n each represent, independently of one another, the number 1 or 2,

Ar represents a group chosen from the phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-

2-yl and thien-3-yl groups, it being possible for this group Ar optionally to be substituted by one or more substituents chosen from halogen atoms and (C1-C6)alkyl, (C3-C7)cycloalkyl,
(C3-C7)cycloalkyl(CJ-C6)alkyl,   (Cr-C6)alkoxy,   (C3-C7 )cycloalkyloxy,   (C3-C7 )cyclo-

25    alkyl(C 1-C6)alkyloxy, (Cr-C6)alkylthio, (C3-C7)cycloalkylthio, (C3-C7)cyclo-alkyl(C1-C6)alkylthio, mono- or polyfluoro(CJ-C6)alkyl and mono- or polyfluoro-(C1-C6)alkyloxy groups.
 


Among the compounds of general formula (V) which are a subject-matter of the invention, a 30 second group of compounds is composed of the compounds for which:

Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, it being possible for this group Ar optionally to be substituted by one or more substituents chosen from halogen atoms,
m and n being as defined above.

5

Among the compounds of general formula (V) which are a subject-matter of the invention, a third group of compounds is composed of the compounds for which:

-    m and n each represent, independently of one another, the number 1 or 2,

-    Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, it being

10    possible for this group Ar optionally to be substituted by one or more halogen atoms.


Among the compounds of general formula (V), mention may in particular be made of the following compounds:

trans-threo/erythro-1-( octahydroindolizin-5-yl)-1-phenylmethanamine;

15    trans-threo-1-( octahydroindolizin-3-yl)-1-phenylmethanamine; cis-erythro-1-(octahydroindolizin-3-yl)-1-phenylmethanamine; trans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-1-phenylmethanamine; trans-threo/erythro-1-( octahydro-2H-quinolizin-4-yl)-1-( 4-fluorophenyl)methanamine; trans-threo-1-( octahydro-2H-quinolizin-4-yl)-1-(pyridin-3-yl)methanamine;

20    trans-threo/cis-erythro-1-( octahydro-2H-quinolizin-4-yl)-1-(thien-3-yl)methanamine.


The examples which will follow illustrate the preparation of a few compounds of the invention. The elemental microanalyses, theIR and NMR spectra and chiral column HPLC confirm the structures and the enantiomeric purities of the compounds obtained.

25

The numbers shown in brackets in the titles of the examples correspond to those in the 1st

column of the table given later.


Example 1 (Compounds No.1 and 2).

30    trans-threo-2-Chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride 1: 1 and

trans-erythro-2-chloro-N-[ ( octahydroindolizin-5-yl)pheny1methyl]-3-trifluoromethyl-benzamide hydrochloride 1: 1.
 
1.1    trans-threo/erytbro-1-(octahydroindolizin-5-yl)-1-phenylmethanamine.

0.62 g (4 mmol) of bromobenzene in solution in 5 ml of anhydrous tetrahydrofuran is introduced, under an argon atmosphere, into a 50 ml round-bottomed flask equipped with a magnetic stirrer and then the medium is cooled to -75°C. 1.6 ml (4 mmol) of a 2.5M

5    solution of butyllithiurn in tetrahydrofuran are added and the mixture is left stirring for 40 min. 0.3 g (2 mmol) of trans-octahydroindolizine-5-carbonitrile in solution of 5 ml of tetrahydrofuran is added at -75°C and the mixture is allowed to return to ambient temperature over 3 h. Water and ethyl acetate are added and the aqueous phase is separated
and extracted with ethyl acetate.  The combined organic phases are dried over sodium

10    sulphate and filtered, and the imine is concentrated under reduced pressure and taken up in a 50 ml round-bottomed flask with 10 ml of methanol. The mixture is cooled to -5°C and 0.38 g (10 mmol) of sodium borohydride is slowly added. Stirring is continued while allowing the temperature of the mixture to return to ambient temperature over 12 h. The

mixture is concentrated under reduced pressure and the residue is taken up in water and

15    ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic phases, drying over sodium sulphate, filtering and evaporating, 0.5 g of product is obtained in the fonn of a yellow oil which is used as is in the following stage.

20    1.2. trans- threo-2-Chloro-N-[( octahydroindolizin-5 -yl)phenylmethyl]-3-trifl uoro-methylbenzamide hydrochloride 1:1 and trans-erythro-2-chloro-N-[(octahydro-indolizin-5-yl)phenylmethyll-3-trifluoromethylbenzamide hydrochloride 1:1.

0.5 g (2.17 mmol) ofl-(octahydroindolizin-5-yl)-1-phenyhnethanamine, 0.36 m1 (2.6 mmol)

oftriethylamine and 0.63 g (2.6 mmol) of2-chloro-3-trifluoromethylbenzoic acid chloride

25    are successively introduced into 10 ml of dichloromethane in a 50 ml round-bottomed flask and the mixture is stirred at ambient temperature for 1 h.

The mixture is treated with water and extracted several times with dichloromethane. After

washing the organic phases with water and then with a IN aqueous sodium hydroxide

30    solution, drying over magnesium sulphate, filtering and evaporating the solvent 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 methanol.
 
0.06 g and 0.130 g of products corresponding to the trans-threo and trans-erymro 1somers are obtained in the form of a colourless oil.

These products are subsequently converted to hydrochlorides starting from a 0.1N solution

5    of hydrochloric acid in propan-2-ol.


Finally, 0.039 g corresponding to the trans-threo isomer is isolated, Melting point: 132-134 °C.
1H NMR(200 MHz, CDC13): 0.75-2.00 (m, 12H), 2.6-2.9 (m, 2H), 5.00 (d, lH), 7.1-7.5 (m,

10    7H), 7.8 (t, 2H).

and 0.017 g corresponding to the trans-erythro isomer is isolated,

Melting point: 132-134 °C.

1H NMR(200 MHz, CDCl3): 0.70-2.00 (m, 11H), 2.1-2.45 (m, 2H), 3.15-3.35 (m, 1H), 5.20 (s, lH), 6.9 (s, lH), 7.1-7.4 (m, 6H), 7.6-7.75 (m, 2H).

15

Example 2 (Compound No. 5)

trans-threo-2-Chloro-N-[ ( octahydroindolizin-3 -yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride 1.1

20    2.1. trans-threo-1-(0ctahydroindolizin-3-yl)-1-phenylmethanamine.

0.61 g (4.12 mmol) of trans-octahydroindolizine-3-carbonitrile, in solution in 25 ml of anhydrous tetrahydrofuran, is introduced, under an argon atmosphere, into a 100 ml round-bottomed flask equipped with a magnetic stirrer. The medium is cooled to -75°C, 6.22 ml (12.24 mmol) of a 2M solution of phenyllithium in dibutyl ether are added and the mixture

25    is allowed to return, with stirring to ambient temperature over 5 h. 3 ml of methanol are added, then water and ethyl acetate are added and the aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate

and filtered, and the imine is concentrated under reduced pressure and taken up in a 50 ml

round-bottomed flask with 25 ml of methanol. The mixture is cooled to -5°C and 0.78 g

30    (20.6 mmol) of sodium borohydride is slowly added. Stirring is continued while allowing the mixture to return to ambient temperature over 12 h. The mixture is concentrated under reduced pressure, the residue is taken up in water and ethyl acetate, the phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic

phases, drying over sodium sulphate, filtering and evaporating, 0.8 g of product is obtained in the form of a yellow oil which is used as is in the following stage.

2.2.    trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethylJ-3-trifluoromethyl-

5    benzamide hydrochloride 1:1

0.4 g (1. 77 rnmol) of trans-threo-1-( octahydroindolizin-3-yl)-1-phenylmethanamine, 0.3 ml (2.1 rnmol) of triethylamine and 0.57 g (2.35 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride are successively introduced into 15 ml of dichloromethane in a 50 ml round-bottomed flask and the mixture is stirred at ambient temperature for 12 h.

10

It is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with a 1N aqueous sodium hydroxide solution, drying over magnesium sulphate, filtering and evaporating the solvent under reduced pressure, the residue is purified by chromatography on a column of silica gel, elution being carried out
15    with a mixture of dichloromethane and methanol.


0.35 g of product corresponding to the trans-threo isomer is obtained in the form of a colourless oil.

20    It is converted to the hydrochloride from a 0.1N solution of hydrochloric acid m propan-2-ol.

Finally, 0.28 g is isolated in the form of a white solid.

Meltingpoint: 138-139°C

25 1H NMR (200 MHz, CDC13): 1.0-1.9 (m, lOR), 2.9 (t, 1H), 3.05-3.25 (m, 2H), 3.5-3.6 (m, lH), 5.20 ( d, lH), 7.3-7.5 (m, 6H), 7.8 (t, 2H).

Example 3 (Compound No. 11).

cis-erythro-2-Chloro-N-[ ( octahydroindolizin-3-yl )phenylmethyl]-3-trifluoromethyl-30 benzamide hydrochloride 1:1.

3. 1.    cis-erythro-1-(octahydroindolizin-3-yl)-1-phenylmethanamine.

According to the protocol described in Example 1.1, starting from 0.61 g (4 mmol) of cis-

octahydroindolizine-3-carbonitrile, 0.9 g of product is obtained in the form of a yellow oil which is used as is in the following stage.

1H NMR (200 MHz, CDCb): 1.00-2.00 (m, 12H), 2.35-2.50 (m, IH), 3.00-3.15 (m, IH),

5    4.15 (d, IH), 7.1-7.4 (m, 5H).


3.2. cis-ervthro-2-Chloro-N-[(octahydroindolizin-3-yl)phenylmethyll-3-trifluoromethyl-

benzamide hydrochloride I: I.

According to the protocol described in Example 2.2, starting from 0.47 g (2 mmol) of cis-

10    erythro-1-(octahydroindolizin-3-yl)-1-phenylmethanamine and 0.58 g (2.4 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride, 0.44 g is obtained in the form of a colourless oil corresponding to the cis-erythro isomer.

This product is  subsequently converted to the hydrochloride from  a O.lN solution of

15    hydrochloric acid in propan-2-ol.


Finally, 0.28 g is isolated in the form of a white solid.

Melting point: 138-139°C.

1H NMR(200 MHz, CDC13): 0.09-l.O(m, 1H), 1.1-1.35 (m, 5H), 1.4-1.55 (m, 2H), 1.65-1.9

20    (m, 3H), 2.00-2.15 (m, !H), 2.7-2.80 (m, IH), 3.20-3.30 (m, lH), 5.25 (t, lH), 7.3-7.6 (m, 6H), 7.8-7.9 (m, 2H).

Example 4 (Compounds No. 14 and 21).

trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-

25    benzamide hydrochloride 1:1 and

trans-erythro-2-chloro-N-[ ( octahydroquino lizin-4-yl)phenylmethyl]-3 -trifluoromethyl-benzamide hydrochloride 1:1.

4.1.    trans-threo/ ervthro-1-( octahydro-2H-guino lizin -4-yl)-1-phenylmethanamine.

30    0.29 g (1.77 mmol) of trans-octahydroquinolizine-4-carbonitrile, in solution in 10 ml of anhydrous tetrahydrofuran, is introduced, under an argon atmosphere, into a 50 ml round-
bottomed flask equipped with a magnetic stirrer. The medium is cooled to -75°C, 2 ml

( 4 mmol) of a 2M solution of phenyllithium in cyclohexane/ethyl ether (70/30) are added
and the mixture is allowed to return to -50°C with stirring over 3 h. 1 ml of methanol is added, then water and ethyl acetate are added at 25°C and the aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered, and the imine is concentrated under reduced pressure and taken up in a

5    50 ml round-bottomed flask with 10 ml of methanol. The mixture is cooled to -5°C and 0.33 g (8.85 mmol) of sodium borohydride is slowly added. Stirring is continued while allowing the mixture to return to ambient temperature over 12 h. The mixture is

concentrated under reduced pressure and the residue is taken up in water and ethyl acetate.

The phases are separated and the aqueous phase is extracted with ethyl acetate. After

10    washing the combined organic phases, drying over sodium sulphate, filtering and evaporating, 0.18 g of product is obtained in the form of a yellow oil which is used as is in the following stage.

4.2.    trans-threo-2-Chloro-N-[(octahydroguinolizin-4-yl)phenylmethyll-3-trifluoro-

15    methylbenzamide hydrochloride 1:1 and trans-erythro-2-chloro-N-[(octahydroguinolizin-4-yl)phenylmethyl]-3-trifluoromethylbenzamide hydrochloride 1: 1.

0.18 g (0.74 mmol) of trans-threo/erythro-1-(octahydro-2H-quinolizin-4-yl)-l-phenylmethanamine, 0.20 g (0.89 mmol) of2-chloro-3-trifluoromethylbenzoic acid, 0.17 g

20    (0.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 0.045 g (0.37 mmol) of dimethylaminopyridine are successively introduced into 10 ml of dichloromethane in a 50 ml round-bottomed flask and the mixture is stirred at ambient temperature for 12 h.

25    It is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with a IN aqueous sodium hydroxide solution, drying over magnesium sulphate, filtering and evaporating the solvent 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 methanol.

30

0.13 g of compound corresponding to the trans-threo isomer and 0.024 g of compound

corresponding to the trans-erythro isomer are obtained in the colourless oil form.
 
They are converted to hydrochlorides from a O.lN solution of hydrochloric acid in propan-2-ol.

Finally, 0.13 g is isolated in the form of a white solid formed of trans-threo isomer: Melting point: 161-163°C

5    1H NMR (200 MHz, C5D5N): 1.2-2.0 (m, 1OH), 2.15-2.35 (m, 2H), 3.2 (t, lH), 3.65-3.8 (m,

!H), 3.85-4.0 (m, 2H), 6.30 (d, !H), 7.3-7.6 (m, 6H), 7.8 (d, 2H)

and 0.014 g is isolated in the form of a white solid formed of trans-erythro isomer: Melting point: 245-247°C.

1H NMR (200 MHz, C5D5N): 1.0-2.1 (m, 12H), 2.3-2.6 (m, 2H), 3.00 ( d, lH), 4.0 ( d, !H),

10    6.30 (d, !H), 7.2-7.8 (m, 7H), 8.3 (d, lH).


Example 5 (Compounds No. 26 and 27)

trans-threo-2-Chloro-N-[ ( 4- fluorophenyl)( octahydroquino lizin-4-yl)methyl]-3-

trifluoromethylbenzamide hydrochloride 1: 1 and

15    trans-erythro-2-chloro-N-[ ( 4-fluorophenyl)( octahydroquinolizin-4-yl)methyl]-3-trifluoromethylbenzamide hydrochloride 1: 1.

5.1. trans-threo/ervthro-1-(octahydro-2H-guinolizin-4-yl)-1-(4-fluorophenyl)-

methanamine.

20    1.33 g (7.61 mmol) of 1-bromo-4-fluorobenzene, in solution in 10 ml of anhydrous ethyl ether, are introduced, under an argon atmosphere, into a 50 ml round-bottomed flask equipped with a magnetic stirrer and then the medium is cooled to -75°C. 3.35 ml (8.37 mmol) of a 2.5M solution ofbutyllithium in hexane are subsequently added and the mixture is allowed to return to -40°C with stirring over 90 min. 0.5 g (3 mmol) of trans-

25    octahydroquinolizine-4-carbonitrile, in solution in 10 ml of ethyl ether, is subsequently

added at -75°C and this temperature is maintained for 90 min. The mixture is allowed to return to ooc and 2 ml of methanol are added, then, at 25°C, water and ethyl acetate are

added and the aqueous phase is separated and extracted with ethyl acetate. The combined

organic phases are dried over sodium sulphate and filtered, and the imine is concentrated

30    under reduced pressure in order to be taken up in a 50 ml round-bottomed flask with 20 ml of methanol. The mixture is cooled to -5°C and 0.57 g (15.2 mmol) of sodium borohydride is slowly added. Stirring is continued while allowing the mixture to return to ambient temperature over 12 h. The mixture is concentrated under reduced pressure and the residue

is taken up in water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic phases, drying with sodium sulphate, filtering and evaporating, 0.97 g of product is obtained in the form of a yellow oil which is used as is in the following stage.

5

5 .2. trans-threo-2-chloro-N- [( 4-fluorophenyl)( octahydroquinolizin-4-yl)methyll- 3-tri-fluoromethylbenzamide hydrochloride 1:1 and trans-erythro-2-chloro-N-[( 4-fluoro-phenyl)( octahydroquinolizin-4-yl)methyll-3-trifluoromethylbenzamide hydrochloride 1:1. 0.4 g (1.52 mmol) of trans-threo/erythro-1-( octahydro-2H-quinolizin-4-yl)-1-( 4-fluoro-

10    phenyl)methanamine, 0.23 ml (1.8 mmol) of triethylamine and 0.4 g (1.67 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride are successively introduced into 10 ml of dichloromethane in a 50 ml round-bottomed flask and the mixture is stirred at ambient temperature for 12 h.

15    The mixture is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with a lN aqueous sodium hydroxide solution, drying over magnesium sulphate, filtering and evaporating the solvent 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 methanol.

20

0.11 g of compound corresponding to the trans-threo isomer and 0.15 g of compound corresponding to the trans-erythro isomer are obtained in the colourless oil form.

These products  are subsequently converted to hydrochlorides from a O.lN solution of

25    hydrochloric acid in propan-2-ol.


Finally, 0.082 g of trans-threo isomer is isolated in the form of a white solid: Melting point: 176-l78°C.

1H NMR (200 J\lliz, CDC13):  1.3-2.3 (m, 12H), 2.6-2.85 (m, lH), 3.2 (t, lH), 3.55-3.8 (m,

30    2H), 5.65 (t, lH), 7.15 (t, 2H), 7.35 (t, 2H), 7.5 (t, lH), 7.8 (d, lH), 8.05 (d, lH), 8.75 (d, lH,NH)

and 0.095 g of trans-erythro isomer is isolated in the form of a white solid: Meltingpoint: 188-189°C.
 
1H NMR(200 MHz, CDCl3): 1.1-2.6 (m, 12H), 2.7-3.2 (m, 3H), 3.95 (d, IH), 5.80 (t, IH), 7.15 (t, 2H), 7.35 (t, 2H), 7.5 (t, IH), 7.8 (d, IH), 7.95 (d, IH), 9.3 (d, IH, NH).

Example 6 (Compound No. 20).

5    trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-trifluoromethyl-benzamide hydrochloride 1:1.

6.1.    trans-threo-1-(0ctahydro-2H-quinolizin-4-yl)-1-(pyridin-3-yl)methanamine.

According to the protocol described in Example 5.1, starting from 0.8 g (5.32 mmol) of

10    3-bromopyridine and 0.35 g (2.13 mmol) of trans-octahydroquinolizine-4-carbonitrile, 0.57 g of product is obtained in the form of a brown oil which is used as is in the following stage.


6.2.    trans-threo-2-Chloro-N-[(octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3-tri-

15    fluoromethylbenzamide hydrochloride 1 : 1 .

According to the protocol described in Example 5.2, starting from 0.57 g (2.32 mmol) of trans-threo-1-( octahydro-2H-quinolizin-4-yl)-1-(pyridin-3-yl)methanamine and 0.62 g (2.55 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride, 0.21 g of compound corresponding to the trans-threo isomer is obtained.

20

This product is subsequently converted to the hydrochloride from a O.IN solution of hydrochloric acid in propan-2-ol.

Finally, 0.042 g of trans-threo isomer is isolated in the form of a white solid:

25    Melting point: 236-238°C.

1H NMR (200 MHz, CDCh): 1.3-2.4 (m, 12H), 2.6-2.9 (m, IH), 3.2 (t, IH), 3.65-3.90 (m, 2H), 5.75 (t, IH), 7.3-7.55 (m, 2H), 7.8 (t, 2H), 8.05 (d, IH), 8.65 (d, IH), 8.8 (s, IH), 9.1

(d, IH, NH).


30    Example 7 (Compounds No. 10 and 12). trans-threo-2-Chloro-N-[(octahydroindolizin-3-yl)(thien-3-yl)methyl]-3-trifluoromethyl-benzamide hydrochloride 1:1 and

cis-erythro-2-ch1oro-N-[ ( octahydroindolizin-3-yl )( thien-3-yl)methyl]-3 -trifluoro-methylbenzamide hydrochloride 1:1.

7.1.    trans-threo/cis-ervtbro-1-( octahydro-2H-quinolizin-4-yl}-1-(thien-3-yl)methanamine.

5    According to the protocol described in Example 5.1, starting from 1.1 g (6.9 rnmol) of 3-bromothiophene and 0.41 g (2.76 mmol) of a trans/cis chiral mixture of octahydro-indolizine-5-carbonitrile, 0.51 g of product is obtained in the form of a brown oil which is used as is in the following stage.

1 0 7 .2. trans-threo-2-Chloro-N-[( octahydroindolizin-3-yl)( thien-3-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride 1:1 and cis-ervtbro-2-chloro-N-[(octahydroindolizin-3-yl)(thien-3-yl)methyll-3-trifluoromethylbenzamide hydrochloride 1: I.

According to the protocol described in Example 5.2, starting from 0.51 g (2.15 mmol) of trans-tbreo/cis-erytbro-1-( octahydro-2H-quinolizin-4-yl)-1-(thien-3-yl)methanamine and

15    0.57 g (2.37 mmol) of2-chloro-3-trifluoromethylbenzoic acid chloride, 0.25 g of compound corresponding to the trans-threo isomer and 0.14 g of compound corresponding to the cis-erythro isomer are obtained.

These products are subsequently converted to hydrochlorides  from a 0.1N solution of

20    hydrochloric acid in propan-2-ol.


Finally, 0.22 g of trans-threo isomer is isolated in the form of a white solid (RSS stereochemistry):

Melting point: 159-161 °C.

25    [a]o=-55.2°(c=l.01,MeOH)

1H NMR(200 MHz, CDC13): 1.1-2.2 (m, 10H), 2.85 (t, 1H), 3.0-3.2 (m, 2H), 3.55-3.70 (m, lH), 5.4 (t, 1H), 7.1 (d, lH), 7.2-7.35 (m, 2H), 7.5 (t, 1H), 7.8 (t, 2H)

and  0.16 g  of  cis-erythro  isomer  is  isolated  in  the  form  of  a  white  solid  (RSS

stereochemistry):

30    Melting point: 170-172°C. [a]o= +46.8° (c = 1.02, MeOH)

1H NMR (200 MHz, CDCh): 1.1-1.9 (m, 10H), 2.0-2.2 (m, 2H), 2.75-2.9 (m, lH), 3.25 (d, lH), 5.4 (t, lH), 7.1 (d, lH), 7.2 (s, lH), 7.35 (d, lH), 7.5 (t, 1H), 7.8 (t, 2H).
 
The stereochemistry of the compounds is illustrated on the following page.


The chemical structures and the physical properties of a few compounds of the invention are

5    illustrated in the following table.


In the "Ar" column, C6Hs denotes a phenyl group, z-X-C6H4 denotes a phenyl group substituted by X in the z position, C5H4N-3 denotes a pyridin-3-yl group and C4H3S-3 denotes a thien-3-yl group.

10

In the "Salt" column "-" denotes  a compound in the base state and "HCl" denotes a

hydrochloride.


In the "M.p. (°C)" column, (d) denotes a melting point with decomposition.

15

In the "St." column, t-t denotes a trans-threo configuration, t-e denotes a trans-erythro configuration, c-e denotes a cis-erythro configuration and rae. denotes a racemate.

    HNfo
n=l  m=2    C H R
chAr64

HNfo

C6 H4 R

o~M
HNfo

C6 H4 R

n=2  m=2
cS?r;c



c~:•R

HNfo

C6H4 R

n=2  m=l
6~Ar

HNfo

C6 H4 R

c~Ar trans  threo

HNfo
,,..____    C6 H4 R

CN~Ar cis  erythro

HNfo

C6 H4 R

o~Ar trans  threo

HNyo

C6 H4 R

G~Ar trans  erythro

HNyo
c?:::•R
trans  threo

HNfo

C6 H4 R

G~Ar trans  erythro

HNyo

C6 H4 R

Table

        No.            m        n    Ar    R    Salt    M.p. (OC)    St.   
                                                       
    1            1        2    CJ!s    2-Cl, 3-CF3    HC1    132-134    t-t (rae.)   
                                                       
    2            1        2    C6Hs    2-Cl, 3-CF3    HC1    132-134    t-e (rae.)   
                                                       
    3            1        2    C6Hs    2,6-(Cl)z, 3-CF3    HCl    206-208    t-t (rae.)   
                                                       
    4            1        2    C6Hs    2,6-(Cl)z, 3-CF3    HCl    254-256    t-e (rae.)   
                                                       
    5            2        1    CJ!s    2-Cl, 3-CF3    HCI    138-139    t-t (rae.)   
                                                       
    6            2        1    CJ!s    2-Cl, 3-CF3    HC1    240 (d)    t-t (RSS)   
                                                       
    7            2        1    C6Hs    2-CH3, 3-CF3    HC1    140-141    t-t (rae.)   
                                                       
    8            2        1    C6Hs    2-CH3, 3-CF3    HCl    247-248    e-e (rae.)   
                                                       
    9            2        1    CsH4N-3    2-Cl, 3-CF3    HC1    145-147    t-t (RSS)   
                                               
                                                       
    10            2        1    C4H3S-3    2-Cl, 3-CF3    HCl    159-161    t-t (RSS)   
                                                       
    11            2        1    CJ!s    2-Cl, 3-CF3    HCl    138-139    e-e (rae.)   
                                                       
        12            2        1    C4H3S-3    2-Cl, 3-CF3    HCl    170-172    e-e (RRS)   
                                                       
                                                       
        13            2            1    CsH4N-3    2-Cl, 3-CF3    HC1    131-133    e-e (RRS)   
                                                       
        14            2            2    C6Hs    2-Cl, 3-CF3    HC1    161-163    t-t (rae.)   
                                                       
        15            2            2    C6Hs    2-Cl, 5-CF3    HCl    142-144    t-e (rae.)   
                                                       
        16            2            2    CJ!s    2,6-(Cl)z, 3-CF3    HCl    286-288    t-t (rae.)   
                                                       
        17            2            2    CJ!s    2,6-(Cl)z, 3-CF3    HC1    205(d)    t-e (rae.)   
                                                       
        18            2            2    CJ!s    2-CH3, 3-CF3    HCl    166-167    t-e (rae.)   
                                                       
                                               
        19            2    2    4-F-C6H4    2,6-(Cl)z, 3-CF3    HCl    289-291    t-t (rae.)   
                                                       
                                               
                                                       
        20            2    2    CsH4N-3    2-Cl, 3-CF3    HCl    236-238    t-t (rae.)   
                                               
                                               
                                               
                                                       
                                                       
        21            2            2    C6Hs    2-Cl, 3-CF3    HCl    245-247    t-e (rae.)   
                                                                                               
22    2    2        C6Hs    2-C1, 5-CF3    HC1    255-257    t-t (rae.)   
                                       
23    2    2        C~s    2-CH3, 3-CF3    HC1    141-143    t-t (rae.)   
                                   
24    2    2        C,JI3S-3    2-C1, 3-CF3    HC1    157-159    t-e (rae.)   
                                   
25    2    2        C6Hs    2-C1, 3-CH3    HC1    171-173    t-t (rae.)   
                                   
26    2    2        4-F-C6H4    2-C1, 3-CF3    HC1    176-178    t-t (rae.)   
                                   
27    2    2        4-F-C6H4    2-Cl, 3-CF3    HCI    188-189    t-e (rae.)   
                                   
                                       
28    2    2        C6Hs    2-CH3, 3-0CH3    HCI    224-226    t-t (rae.)   
                                       
29    2    2        C6Hs    3-0CF3    HCI    258-260    t-t (rae.)   
                                   
30    2    2        C~s    3-SFs    HCI    248-250    t-t (rae.)   
                                       
31    1    1        C6Hs    2-Cl, 3-CF3    -    MW=423    -   
                                   
The compounds of the invention have been subjected to 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

5    GlyTl.

The uptake of [14C]glycine is studied in SK-N-MC cells (human neuroepithelial cells)

expressing the native human transporter GlyTl 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 day of the experiment, the

10    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 ofbuffer (control batch) or oftest compound at various concentrations or of 10 mM of glycine (determination of the non-specific uptake),
10 f!M ofe 4CJglycine (specific activity 112 mCi/mmol) are subsequently added. Incubation

15    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 J.Ll of liquid scintillant and stirring for 1 h. Counting is carried out on a

Microbeta Tri-Lux™ counter. The effectiveness ofthe compound is determined by the IC 50, the concentration of the compound which reduces by 50% the specific uptake of glycine,
20    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 IC 50 of the order ofO.OOl to 0.20 {!M.


    Compound I    ICso    = 0.08 11M
           
    Compound2    ICso    =0.023 11M
           
    CompoundS    ICso    = 0.003 11M
           

25

As shown by these results, the compounds of the invention exhibit a specific activity as inhibitors of the glycine transporters GlyTl.

The compounds according to the invention can thus be used in the preparation of 30 medicaments, in particular of medicaments which are inhibitors of GlyTl glycine

transporters.

These results suggest that the compounds of the invention can be used for the treatment of behavioural disorders associated with dementia, psychoses, in particular schizophrenia (deficit form and productive form) and acute or chronic extrapyramidal symptoms induced

5    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 disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders, for the treatment of migraine or in the treatment of primary generalised epilepsy, secondary generalised epilepsy, partial epilepsy

10    with a simple or complex symptomatology, mixed forms and other epileptic syndromes, in complementing another anti epileptic treatment or in monotherapy.

This is why another subject-matter ofthe present invention is pharmaceutical compositions

comprising an effective dose of at least one compound according to the invention, in the

15    form of the base or a pharmaceutically acceptable salt or solvate, as a mixture, if appropriate, with suitable excipients.

The said excipients are chosen according to the pharmaceutical form and the method of administration desired.

20

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.

25    The unit administration forms can be, for example, tablets, gelatin capsules, granules, powders, solutions or suspensions to be taken orally or to be injected, transdermal 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 0.0 I to 20 mg of active

30    principle 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, hydroxypropylmethylcellulose, 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.
5    Wetting or surface-active agents, such as sodium lauryl sulphate, can also be added.


The preparation techniques can be direct tableting, dry granulation, wet granulation or hot melt.

10    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.

15    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

20    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.

25

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.


30    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 also be formulated in the form of microcapsules, optionally with one or more vehicles or additives or else with a polymer matrix or with a cyclodextrin

5    (transdermal 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

10    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.

Finally, the pharmaceutical compositions according to the invention can comprise, in IS addition to a compound of the general formula (I), other active principles which can be of
use in the treatment ofthe disorders and diseases indicated above.
1. Compound, in the form of a pure enantiomer or of an erythro or threo diastereoisomer or of a mixture of such isomers, corresponding to the general formula (I)

in which:

m and n each represent, independently of one another, the number 1 or 2,

15    Ar represents a group chosen from the phenyl, naphth-1-yl, naphth-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, thiazol-2-yl and oxazol-2-y1 groups, it being possible for this group Ar optionally to be substituted by one or
    more  substituents  chosen  from  halogen  atoms  and  (C1-C6)alkyl,  (C3-C7)cycloalkyl,   
    (C 3-C7)cycloalkyl(Cl-C6)alkyl,    (C 1-C6)alkoxy,   (C3-C7)cycloalkyloxy,    (C3-C7)cyclo-   
20    alkyl(C -C6)alkyloxy,(CJ-C6)alkylthio,(C3-C7)cycloalkylthio,(C -C )cycloalkyl-   
                1        3    7       
    (C    -C )alkylthio, mono- or polyfluoro(Ct-C6)alkyl and mono- or polyfluoro(C -C )alkyloxy   
        1    6            1    6   
    groups,                   
    R represents either a hydrogen atom or one or more substituents, identical to or different   
    from one another, chosen from halogen atoms and mono- or polyfluoro(C1-C6)alkyl and   
25    mono- or polyfluoro(Ct-C6)alkyloxy, linear (C1-C6)alkyl, branched or cyclic (C3-C7)alkyl,   
    (C3-C7)cycloalkyl(Ct-C6)alkyl,    (C 1-C6)alkoxy,    (C3-C7)cycloalkyloxy,   
    (C    3    -C )cycloalkyl(Ct-C6)alkyloxy, (C -C6)alkylthio, cyano, amino, phenyl, acetyl, benzoyl,   
                7    1               
    (C        -C )alkylsulphonyl, carboxyl, (Ct-C )alkoxycarbonyl and pentafluorosulphanyl groups,   
        1    6    6               
in the form of the base, an addition salt with an acid and/or a solvate or hydrate.

30

2. Compound according to Claim 1, characterized in that:

Ar represents a group chosen from the phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl and thien-3-yl groups, it being possible for this group Ar optionally to be substituted by

one or more substituents, which are identical to or different from one another, chosen from halogen atoms and (CI-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(CI-C6)alkyl, (C 1-C6)alkoxy, (C3-C7 )cycloalkyloxy, (C3-C7 )cycloalkyl(CI-C6)alkyloxy, (CI-C6)alkylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkyl(CI-C6)alkylthio, mono- or polyfluoro(C1-C6)alkyl

5    and mono- or polyfluoro(C 1-C6)alkyloxy groups,

in the form of the base, an addition salt with an acid and/or a solvate or hydrate.


3. Compound according to Claim 1 or 2, characterized in that:

Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, it being

10    possible for this group Ar optionally to be substituted by one or more substituents, identical to or different from one another, chosen from halogen atoms,

in the form of the base, an addition salt with an acid and/or a solvate or hydrate.


4. Compound according to any one of Claims 1 to 3, characterized in that:

15    R represents either a hydrogen atom or one or more substituents, which are identical to or

different from one another, chosen from halogen atoms and mono- or polyfluoro(C 1-C6)alkyl, mono- or polyfluoro(CI-C6)alkyloxy, linear (C1-C6)alkyl and pentafluorosulphanyl groups,

in the form of the base, an addition salt with an acid and/or a solvate or hydrate.

20

5. Compound according to any one of Claims 1 to 4, characterized in that:

-    m and n each represent, independently of one another, the number 1 or 2,

-    Ar represents a group chosen from the phenyl, pyridin-3-yl and thien-3-yl groups, it being possible for this group Ar optionally to be substituted by one or more halogen atoms,

25    - R represents either a hydrogen atom or one or more substituents, identical to or different from one another, chosen from chlorine and the methyl, trifluoromethyl, trifluoromethoxy and pentafluorosulphanyl groups,

in the form of the base, an addition salt with an acid and/or a solvate or hydrate.


30    6. Compound according to Claim 1, characterized in that it is chosen from the following compounds: trans-threo-2-Chloro-N-[(octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride.

trans-erythro-2-Chloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-

benzamide hydrochloride.

trans-threo-2,6-Dichloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl ]-3-trifluoromethyl-

benzamide hydrochloride.

5    trans-erythro-2, 6-Dichloro-N-[ ( octahydroindolizin-5-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride.

trans-threo- 2-Chloro-N-[ ( octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride.

2-Chloro-N-[ (S)-(3 S,8aR)-(octahydroindolizin-3 -yl)phenylmethyl]-3-trifluoromethyl-

10    benzamide hydrochloride.

trans-threo-2-Methyl-N-[ ( octahydroindolizin-3-yl)phenylmethyl] -3-trifluoromethyl-benzamide hydrochloride. cis-erythro-2-Methyl-N-[(octahydroindolizin-3-yl)phenylmethyl]-3-trifluoromethyl-

benzamide hydrochloride.

15    2-Chloro-N-[ (S)-(3S,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoromethyl-benzamide hydrochloride.

2-Chloro-N-[ (S)-(3 S ,8 aR)-( octahydroindo lizin-3-yl)( thiophen-3-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride.

cis-erythro-2-Chloro-N-[ ( octahydroindolizin-3-yl)phenylrnethyl]-3-trifluoromethyl-

20    benzamide hydrochloride.

2-Chloro-N-[ (S)-(3R, 8aR)-(octahydroindolizin- 3-yl)( thiophen-3-yl)methyl]-3 -trifluoro-methylbenzamide hydrochloride. 2-Chloro-N-[(S)-(3R,8aR)-(octahydroindolizin-3-yl)(pyridin-3-yl)methyl]-3-trifluoro-

methylbenzamide hydrochloride.

25    trans-threo-2-Chloro-N- [ ( octahydroquinolizin-4-yl)phenylmethyl ]-3 -trifluoromethyl-benzamide hydrochloride.

trans-erythro-2-Chloro-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-5-trifluoromethyl-benzamide hydrochloride. trans-threo-2,6-Dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-

30    benzamide hydrochloride. trans-erythro-2,6-Dichloro-N-[(octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-benzamide hydrochloride.

trans-erythro-2-Methyl-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethyl-

benzamide hydrochloride.

trans-threo-2,6-Dichloro-N-[ ( 4-fluorophenyl)( octahydroquino lizin-4-yl)methyl]-3-

trifluoromethylbenzamide hydrochloride.

trans-threo-2-Chloro-N-[ ( octahydroquinolizin-4-yl)(pyridin-3-yl)methyl]-3 -trifluoromethyl-

5    benzamide hydrochloride.

trans-erythro-2-Chloro-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3 -trifluoromethyl-benzamide hydrochloride.

trans-threo-2-Chloro-N-[( octahydroquinolizin-4-yl)phenylmethyl]-5 -trifluoromethyl-

benzamide hydrochloride.

10    trans-threo-2-Methyl-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]-3 -trifluoromethyl-benzamide hydrochloride.

trans-erythro-2-Chloro-N-[ ( octahydroquinolizin-4-yl)( thiophen-3-yl)methyl]-3 -trifluoro-methylbenzamide hydrochloride.

trans-threo-2-Chloro-3 -methyl-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]benzamide

15    hydrochloride.

trans-threo-2-Chloro-N-[ ( 4-fluorophenyl)( octahydroquinolizin-4-yl)methyl]-3-trifluoro-methylbenzamide hydrochloride.

trans-erythro-2-Chloro-N- [ ( 4-fluorophenyl)( octahydroquinolizin-4-yl)methyl]-3 -trifluoro-

methylbenzamide hydrochloride.

20    trans-threo-2-Chloro-3 -methoxy-N-[ ( octahydroquinolizin-4-yl)phenylmethyl]benzamide hydrochloride. trans-threo-N-[(Octahydroquinolizin-4-yl)phenylmethyl]-3-trifluoromethoxybenzamide hydrochloride. trans-threo-N-[(Octahydroquinolizin-4-yl)phenylmethyl]-3-(pentafluorosulphanyl)-

25    benzamide hydrochloride. 2-Chloro-N-[(hexahydropyrrolizin-3-yl)phenylmethyl]benzamide hydrochloride.

7. Process for the preparation of a compound according to Claim 1, characterized in that a

nitrile of general formula (II)

cis-erythro-1-( octahydroindolizin-3-yl)-1-phenylmethanamine;

trans-threo/ erythro-1-( octahydro-2H-quinolizin-4-yl)-1-phenylmethanamine; trans-threo/erythro-1-( octahydro-2H-quinolizin-4-yl)-1-(4-fluorophenyl)methanamine; trans-threo-1-( octahydro-2H-quinolizin-4-yl)-l-(pyridin-3-yl)methanamine;

5    trans-threo/cis-erythro-1-( octahydro-2H-quinolizin-4-yl)-l-(thien-3-yl)methanamine.


10.    Pharmaceutical composition, characterized in that it comprises a compound according to Claim 1 in combination with an excipient.

10    11. Use of a compound according to Claim 1 in the preparationofamedicamentwhichis an inhibitor of GlyTlglycine transporters.

12. Use of a compound according to Claim 1 in the preparation of a medicament for the

treatment of behavioural disorders  associated with dementia, psychoses,  in particular

15    schizophrenia (deficit form and productive form) and 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 disorders due to alcohol

abuse or withdrawal, disorders of sexual behaviour, eating disorders, for the treatment of

20    migraine or for the treatment of primary generalised epilepsy, secondary generalised epilepsy, partial epilepsy with a simple or complex symptomatology, mixed forms and other epileptic syndromes, in complementing another antiepileptic treatment or in mono therapy.

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