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(21)Application Number:KE/P/2004/ 000367       
 
(72) Inventors:DARGAZANLI, Gihad of 47, boulevard de Ia Vanne F-

(22) Filing Date: 94230 Cachan, France; MAGAT, Pascale of 34, avenue 15/10/2004 Mazarin, F-91380 Chilly-Mazarin, France; ROGER,Pierre of6, rue Paul Valery, F-78180 Montigny le

(30) Priority data:        Bretonneux, France; ESTENNE-BOUHTOU, Genevieve 03/12,165  17110/2003    FR    of 18, rue des Jardins, F-94550 Chevilly-Larue,  France and MARABOUT, Benoit of 45 bis, rue de Versailles,

(86) PCT data F-91300 Massy, France PCT/FR04/00264315/1012004     wo 2005/037783    28/04/2005    (74) Agent/address for correspondence: Kaplan & Stratton Advocates, P.O. Box40111-00100,

Nairobi

(54) Title: DERIVATIVES OF N-HETEROCYCLYLMETHYLBENZAMIDES, PREPARATION METHOD THEREOF AND APPUCATION OF SAME IN THERAPEUTICS

(57) Abstract: The invention relates to a compound having general fonnula (1), wherein; R represents a hydrogen atom

or a vinyl group; n represents 0, I or 2; X represents a groups having formula CH or a nitrogen atom; R1 represents a phenyl or naphthyl group, or a cyclohexyl group, or It a heteroaryl group; R2 represents a hydrogen atom, or one or more substituents selected from among the halogen atoms and the

trifluoromethyl, alkyl, alkoxy, thienyl, phenyloxy, hydroxyl, mercapto, thioalkyl, cyano groups or a group having general fonnula -NR, NRs, SO,NR,Rs. -S02,-alkyl, -S02-phenyl, -CONR,Rs.-COOR7, -CO-alkyl, -CO-phenyl, -NHCO,,-NHSO,.alkyl, -NHSO,-phenyl and -NHSO,NR,Ns or a divalent group having formula -OCF20-; and ~ and Rs, each represent a hydrogen atom or an alkyl group~ and

Rs, together with the nitrogen atom bearing same, form a pyrrolidine, piperidine or morpho line ring. The invention also relates to the use of such compound in therapeutics.
 


Derivatives of N-Heterocyclylmethylbenzamides, prepara-tion method thereof and application of same in therapeutics

5    The subject of the present invention is N-heterocyclyl-methylbenzamide derivatives, their preparation and their therapeutic application.

The compounds of the invention correspond to general 10 formula (I)


in  which

R  represents  a  hydrogen  atom  or  a  vinyl  group;

n    represents   0  or  1  or  2  when  R  represents  a   hydrogen

15    atom and n represents 1 when R represents a vinyl group;

X represents a group of formula CH or a nitrogen atom when R represents a hydrogen atom and X represents a group of formula CH when R represents a vinyl group;
20 R1 represents either a phenyl or naphthyl group optionally substituted with one or more substituents chosen from halogen atoms, linear or branched {C1 -

Co) alkyl, hydroxyl and (C, -C6 ) alkoxy groups, the tri fluoromethyl group r or a cyclohexyl group, or a

25    heteroaryl group chosen from the thienyl, pyridinyl, oxazolyl, furanyl, thiazolyl, quinolinyl, and
 


-    2   -

isoquinolinyl  groups;

R 2 represents either a hydrogen atom, or one or more substi tuents chosen from halogen atoms and the trifluoromethyl, (C1 -C6 ) alkyl, (CJ. -C6 ) alkoxy, thienyl, phenyloxy, hydroxyl, mercapto, thio (C1 -C6 ) alkyl and cyano groups or a group of general formula -NR.:.R5 ,

S02NR 4R5 ,    -802 -  (Cl-C6)alkyl,   -802 -phenyl,   -CO~R5 ,  -COOR7 ,
-CO- (C,-C6 ) alkyl,    -CO-phenyl,    -NHCOR8 ,    -NHSO,- (C,-C,)-

alkyl,    -NHS02 -phenyl    and   -NHS02 NR4R5     or   a    group   of

10 formula -OCF20 attached at the 2- and 3-positions of the phenyl group;

the groups (c,-c,)alkyl, (C,-C,)alkoxy, -so,- (c,-c,)alkyl, -co- (C1 -C6 ) alkyl and -NHS02 - (C1 -C6 ) alkyl being optionally substituted with one or more groups R3 ;

15 the groups phenyl, -802 -phenyl, -CO-phenyl and -NHS02 - phenyl being optionally substituted with a group R6 ;

R3 represents a halogen atom, or a phenyl, (CJ.-C6) alkoxy or -~Rs group;

R4     and   Rs   represent,    independently   of   each   other,    a

20    hydrogen atom or a (C1 -C6)alkyl group or R; and R5 form with the nitrogen atom bearing them a pyrrolidine ring, a piperidine ring or a morpho line ring;

R6 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group,

25    a mercapto group, a (C1 -C6)alkyl or (C1 -C6)alkoxy group; R7 represents a hydrogen atom or a (C1 -C6) alkyl group optionally substituted with one or more groups R3 , or a phenyl group optionally substituted with a group R6;

Ra    represents    a    (C1 -C6) alkyl    group    optionally

30    substituted with one or more groups R3 , or a (C1 - CG) alkoxy group, or a phenyl group optionally substituted with a group R6.

Among  the  compounds  of  general  formula   (I),   a  number  of

35    subgroups  of  preferred•compounds  can  be  distinguished:

group 1: compounds of three configuration and of general formula (I) in which n represents 0 or 1;
 


group    2 :    compounds   of   group   1   in   whose   formula   X

represents  a  group  of  formula  CHi

group 3 : compounds of group in whose formula R represents a hydrogen atom;

group    4:    compounds   of   group    in   whose   formula   n

represents  1;

10 group 5: compounds according to group 4 in whose formula R1 represents an optionally substituted phenyl group.

The    compounds    of    formula    (I)    may    contain    several

15    asymmetric centers. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof,

including    the    racemic    mixtures,    form    part    of    the

invention.

20    More particularly, the compounds of formula (I), for which R = H, can exist in the form of three ( (lS 1 2S) and (lR, 2R)) or erythro ((18, 2R) and (lR, 28)) diastereoisomers or of pure enantiomers or as a mixture of such isomers.

25

The compounds of formula (I) can exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.

These    salts    are    advantageously    prepared    with

30    pharmaceutically acceptable acids, but the salts of other acids useful, for example, for the purification or isolation of the compounds of formula (I) also form part of the invention. The compounds of formula (I) can

also    exist  in  the  form  of  hydrates  or  solvates,   namely

35    in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.

The   compounds   of   the   invention   exhibit   a   particular

activity    as    specific    inhibitors    of    the    glycine

transporters  glytl  and/or  glyt2.

The  compounds  of  general  formula   (I)   may  be  prepared  by

a  method  illustrated  by  scheme  1  which  follows.

Scheme
3~- (III)
I    R,

.0

(I)



10    According   to   scheme   1,   a   diamine   of   general   formula

(II),   in  which  n,  X,  Rand  R1    are  as  defined  above,   is

coupled with an activated acid or an acid chloride of general formula (III) in which Y represents a leaving group, such as a halogen atom, and R2 is as defined

15    above, using methods known to persons skilled in the art.

The diamines of general formula (II) , in which R = H and n, X and R1 are as defined above, may be prepared by

20    a  method  illustrated by  scheme  2  which  follows.

Scheme  2
R,0YH,ln - (II)

N,
OCH2C6H5

(IV)    {VJ

25    The ketone of general formula (IV), in which n, X and R~ are as defined above, is reacted with benzyloxy-


hydroxylamine    hydrochloride,   at   the   reflux  temperature

of    pyridine,   in  order   to   obtain   the  oxime  of   general

formula    (V) .  The  two  forms  Z  and  E  of  the  oxime  may  be

separated  according  to  methods  known  to  persons  skilled

in    the   art   such   as   chromatography   on   a   silica   gel

column.

The  oxime   (V),   preferably  in  the  Z  hydrochloride  form,

is    then    reduced    at    the    reflux    temperature    of

10    tetrahydrofuran with lithium aluminum hydride to give the predominantly threo-diamine of general formula

(II)    .

By  reducing  the  E  form  of  the  oxime  of  general  formula

(V),    a  diamine   (II}   mixture  is  obtained  in  the  form  of

15    the  two  diastereoisomers  (threo/erythro).

The erythro- and threo-diastereoisomers may be separated according to methods known to persons skilled in the art such as chromatography on a silica gel column.

20

Another variant preparation of the diamines of general formula (II), in which Rand R1 are as defined above, n is equal to 1 and X is a CH, is illustrated by the scheme 3 which follows.

25

Scheme  3

    ~R        _ L..Vi~.   
'  L..VCH2)n    -       
R,Y    •v        R,y    NV  .   
OH    (VI)        NH    (II)   
            2       

The    alcohols  of  general   formula   (VI}   are   converted  to

30    amines by a Mitsunobu reaction according to the method described in Bull. Soc. Chim. Belg. (106), 1997, 77-84 and in Tetrahedron: Asymmetry, (6), 1995, 1699-1702.


Moreover,    the  chiral  compounds  of  general   formula   (I),

corresponding    to  the  enantiomers   (1R,2R)   or   (1S,2S)   of

the    threo-diastereoisomer    and    to    the    enantiomers

(1S,2R)    or   (1R,2S)   of  the  erythro-diastereoisomer,   may

also    be   obtained   either   by   separating   the   racemic

compounds    by   high   performance   liquid   chromatography

(HPLC)    on   a   chiral   column,   or   from   the   chiral   amine

obtained    either   by   resolving   the   racemic   amine   of

general  formula  (II),  by  the  use  of  a  chiral  acid,  such

10    as tartaric acid, camphorsulfonic acid, dibenzoyl-tartaric acid, N-acetylleucine, by fractional and

preferential    recrystallization   of   a   diastereoisomeric

salt    from   a   solvent   of   the   alcohol    type,    or   by

enantioselective    synthesis   from   an   erythro-   or   threo-

15    chiral alcohol using a method similar to that described in scheme 3. The chiral alcohols may be obtained by a method similar to that described in Tetrahedron, (55},

1999, 2795-2810. In the case where R represents a vinyl group and R1 represents a quinolinyl group, the diamine

20    of general formula (II} may be prepared according to scheme 3 using the corresponding commercially available chiral alcohols.

The   racemic   ketone   of   general   formula    (IV)    may   be 25    prepared    either    by    deprotonation    of    an    activated complex  of  the  bridged  cyclic  amines  and  reaction  with an  electrophile,   such  as  an  ester  or  a   Weinreb  amide, according   to   a   method   similar   to   that   described   in

Chem.   Cammun.,   1999,   1927-1928,   or  by  reaction   of   an 30    organometallic     compound    on     the     ethyl     ester    of 2-quinuclidinic  acid,   according  to  a  method  similar  to that  described  in  J.   Med.   Chern.,   1980,   180-184,   or  by oxidation   of    the   corresponding   alcohol   obtained   by various  methods   similar  to  those  described  in   J.   Org.

35    Chem., 50, 1985, 29-31 and Chem. Comm., 1999, 1927-1929 with oxidizing agents known to persons skilled in the art such as manganese dioxide or the oxalyl chloride-dimethyl sulfoxide system.


The    alcohols    of   general    formula    (VI)    may   also   be

obtained    by   reducing    the    corresponding   ketones   of

general    formula   (IV)   under  conditions  known  to  persons

skilled  in  the  art.

The    acids  and  acid  chlorides  of  general   formula   (III}

are    commercially  available  or  are  prepared  by  analogy

with  methods  known  to  persons  skilled  in  the  art.

10    For example, 4-amino-3-chloro-5-trifluoromethylbenzoic acid may be prepared by chlorination of 4-amino-5-trifluoromethylbenzoic acid with sulfuryl chloride in a chlorinated solvent such as chloroform, according to a

method    similar  to   that   described   in  Arzneim.   Forsch.,

15    34,   lla,   (1984),   1668-1679.

2,6-Dichloro-3-trifluoromethylbenzoic acid may be prepared by methods similar to those described in us 3,8231134.

20

The benzoic acids derived from sulfonamides may be prepared according to methods similar to those described in patents DE-2436263 1 BE-620741 1 DE-1158957 1

US-3112337 I      GB-915259 I     US-3203987 I      DE-642758 I      EP-68700 I

25    FR-2396757,    DE-2734270,    and   in   J.    Phann.    Phannacol.

(1962) 1 14, 679-685. The meta-chlorosulfonylated acids may be obtained according to a method similar to those described in J. Chem. Soc. (C), (1968), 13 1 and in patents US-2273444, DE-19929076 1 EP-0556674.

30

Chlorosulfonylation at the ortho or para position may be carried out starting with a diazonium salt according to a method similar to that described in patent US-3663615 with 4-amino-3-chlorobenzoic acid.

35

The sulfonamides are obtained by the reaction of the chlorosulfonylated derivatives in the presence of an excess of amine in a solvent such as tetrahydrofuran 1 at room temperature or under reflux.

The    secondary  sulfonamides  may  be  methylated  according

to    a    method   similar   to   that   described   in   patent

BE-620741.  The  primary  sulfonamides  may  be  reacted  with

an  isocyanate,  in  a  solvent  such  as  tetrahydrofuran,   in

the    presence   of   a   base   such   as   potassium   carbonate.

Some    sulfoxide    derivatives    of    benzoic    acids    are

described    in    patents    DE-2056912,    DE-2901170    and

US-3953476   or   may   be   obtained   by   methods   similar   to

10    those   described   in   patent   BE-872585   and   in   J.    Org.

Chern.   (1991),   56 (1),   4976-4977.

The benzoic acid derivatives of general formula (III), in which R2 represents a branched alkyl group, may be

15    prepared according to methods similar to that described in patent US-4879426 and in Syn. Lett. (1996), 473-474 and J. Med. Chern. (2001), 44, 1085-1098.

The  benzoic   acid  derivatives  of   the   biphenyl   type   may 2 o   be   prepared   according    to   methods   known   to   persons skilled  in   the   art.   Finally,   the   carbonylated  benzoic acids   may   be   synthesized  according   to  methods   similar

to    those  described  in  patents  US-3725417  and  GB-913100

and  in  Chern.   Pharm.   Bull.,   (1988),   36 (9),   3462-3467  and

25    J.   Labelled  Compd.  Radiophann.,   (1997),   39 (6),   501-508.

The esters or amides may be introduced by direct carbonylation with a strong base at the para position of the acid, under the conditions described in

30    Tetrahedron  Lett.,   (2000),   41,   3157-3160.

Finally 1       the   cyano   derivatives   of   benzoic   acids   are

obtained  by  heating  a  halogenated  benzoic  acid  or  ester

in  the  presence  of  potassium  cyanide,  a  catalyst  of  the

35    tetrakistriphenylphosphinepalladium type, in a solvent of the tetrahydrofuran type, according to a method similar to that described in J. Org. Chern. (1967) 62,

25,   8634-8639.

Other  acids  and  acid  chlorides  of  general  formula   (III)

may    be   obtained  according   to  methods   similar  to   those

described    in  patents   EP-0556672,   US-3801636   and   in   J.

Chern.    Soc.,    (1927),    25,    Chern.   Pharm.   Bull.,    (1992),

1789-1792,    Aust.    J.    Chern.,    (1984),    1938-1950    and

J.D. C.,   1980),   527.

The  examples  which  follow  illustrate  the  preparation  of

a    few    compounds   of    the    invention.    The    elemental

10    microanalyses, and the IR and NMR spectra, and the HPLC on a chiral column confirm the structures and the enantiomeric purities of the compounds obtained.

The    numbers   indicated   in   brackets   in   the   headings   of

15    the examples correspond to those of the 1 a~ column of the table given later.

In the names of the compounds, the dash 11 - 11 forms part of the word, and the dash n_n only serves for splitting

20    at the end of a line; it is deleted in the absence of splitting, and should not be replaced either by a normal dash or by a gap.


25    Example  1   (compound  No.  3)

threo-2-Chloro-N- [ (1-azabicyclo [2 .2 .2] oct-2-yl) phenyl-methyl]-3-trifluoromethylbenzamide hydrochloride 1:1

30    1.1.   (Z) -1-Azabicyclo [2 .2 .2] oct-2-yl (phenyl) methanone

0-benzyloxime  hydrochloride

2.2 g (9.35 mmol) of 1-azabicyclo [2. 2. 2] oct-2-yl(phenyl)methanone (Chern. Commun., 1999, 1927-1928)

35 and 3 g (18. 69 mmol) of benzyloxyhydroxylamine hydrochloride in 50 ml of pyridine are introduced into a 100 ml round-bottomed flask equipped with magnetic stirring, and the mixture is heated under reflux for

20  h.

After    evaporation    of    the    solvents    under    reduced

pressure,    the    residue    is    diluted   with   water   and

chloroform,   the   aqueous   phase   is   separated,   and  it   is 5    extracted  with   chloroform.   After   washing   the   combined organic    phases,     drying    over    sodium    sulfate    and evaporation  of  the  solvent  under  reduced  pressure,   the residue   is  purified  by  chromatography  on  a   silica  gel column,    eluting    with    a    mixture    of    chloroform   and

10    methanol.

There  are  obtained  0. 5  g  of  a  fraction  corresponding  to

(E) -1-azabicyclo [2. 2. 2 .] oct-2-yl (phenyl)methanone

O-benzyloxime    and    2.25gofanotherfraction
15corresponding    to    (Z)-l-azabicyclo[2.2.    2.]oct-2-
yl (phenyl} methanone  0-benzyloxime  hydrochloride   
m.p.  195-197°C.           

1. 2. threo- [1-Azabicyclo [2 .2 .2 .] oct-2-yl (phenyl)-20 methyl] amine

1.3 g (34.32 mmol) of lithium aluminum hydride in suspension in 10 ml of tetrahydrofuran are placed in a 250 ml three-necked flask equipped with magnetic

25 stirring under a nitrogen atmosphere, 2.2 g (6.16 mmol) of (Z) -1-azabicyclo [2 .2 .2 .] oct-2-yl (phenyl) methanone O-benzyloxime hydrochloride are added in portions and the mixture is heated under reflux for 2 h.

30    After cooling, the solution is hydrolyzed at 0°C with successively 1. 3 ml of water and then 1. 3 ml of aqueous

sodium hydroxide at 15% and 3. 9 ml of water. The heterogeneous mixture is filtered on Celite®, the filtrate is concentrated under reduced pressure and

35    then the residue is diluted with 1N hydrochloric acid and chloroform. The organic phase is separated and the aqueous phase is basified with aqueous ammonia. It is extracted twice with chloroform. After washing the combined organic phases, drying over sodium sulfate and

evaporating  the  solvent  under  reduced  pressure,   1.25  g

of    three- [1-azabicyclo [2 .2 .2 .] oct-2-yl (phenyl) methyl]-

amine    are    obtained    in    the    form   of    an   oil    which

crystallizes    and  which   is   used  as   it   is   in   the   next

step.

Melting  point:  120-140°C.

1.3.  threo-2-Chloro-N- [ (1-azabicyclo [2 .2 .2] oct-2-yl)-

10    phenylmethyl]-3-trifluoromethylbenzamide hydrochloride 1:1

0.51  g   (2.12  mmol)   of  2-chloro-3-trifluoromethylbenzoic

acid    chloride   in   solution   in   5   ml   of   chloroform   is

15    placed in a 100 ml round-bottomed flask equipped with magnetic stirring, in the presence of 0. 29 g

(2.12 mmol) of potassium carbonate at 0°C, and a solution of 0.42 g (1.93 mmol) of threo-[1-azabicyclo-

[2. 2. 2.] oct-2 -yl (phenyl) methyl] amine    in    solution    in

20    5 ml of chloroform is poured in and the mixture is stirred at room temperature for h.

After hydrolyzing with water and diluting with chloroform, the aqueous phase is separated and it is

25    extracted with chloroform. After washing the combined organic phases, drying over sodium sulfate and

evaporating the solvent under reduced pressure, the residue is purified by chromatography on a silica gel column, eluting with a mixture of chloroform and

30    methanol.  0.18  g  of  an  oily  product  is  obtained.

The latter is dissolved in a few ml of propan-2-ol, 6 ml of a 0 .1N hydrochloric acid solution in propan-2-ol are added and the mixture is concentrated under

35    reduced pressure in order to reduce the volume of the solvent. After trituration, 0.15 g of hydrochloride is finally isolated in the form of a solid.

Melting  point:  257-262°C.

Example  2  (compound  No.  4)

threo-2, 6-Dichloro-N- [ (1-azabicyclo [2. 2. 2] oct-2-

yl)phenylmethyl] -3-trifluoromethylbenzamide

5    hydrochloride  1: 1

0.36   g   (1.38   mmol)   of   2,6-dichloro-3-trifluoromethyl-

benzoic    acid,    0.187   g    (1.38   mmol)    of   hydroxybenzo-

triazole,    0.264   g   (1.38  mmol)   of   1- [3- (dimethylamino)-

10    propyl] -3-ethylcarbodiimide hydrochloride in solution in 7 ml of chloroform are introduced into a 100 ml round-bottomed flask equipped with magnetic stirring, and the mixture is stirred at room temperature for

30  min.

15

0. 3   g   (1. 38   mmol)   of   three- [1-azabicyclo [2. 2. 2 .] oct-2-

yl (phenyl) methyl] amine    in    solution    in    5    ml    of

chloroform  is  added  and  the  mixture  is  stirred  at  room

temperature  overnight.

20

After hydrolyzing with water and diluting with chloroform, the aqueous phase is separated and it is extracted with chloroform. After washing the combined organic phases, drying over sodium sulfate and

25    evaporating the solvent under reduced pressure, the residue is purified by chromatography on a silica gel

column, eluting with a mixture of chloroform and methanol. 0.37 g of an oily product is obtained.

30    The latter is dissolved in a few ml of propan-2-ol, 20 ml of a O.lN hydrochloric acid solution in propan-2-ol are added and the mixture is concentrated under reduced pressure in order to reduce the val ume of the

solvent.  After  trituration,   0.35  g  of  hydrochloride  is

35    finally isolated in the form of a solid. Melting point: 270-273°C.

Example  3   (compound  No.  14)

2-Chloro-N-(Sa,9S)cinchonan-9-yl)-3-trifluoromethyl-benzamide hydrochloride 2:1

3.1.  Ba-95-Cinchonan-9-amine

5

0.74  g    (2.5  mmol)    of    8a,9R-cinchonan-9-ol

(cinchonidine)    and    0. 79  g    (3  mmol)    of    triphenyl-

phosphine  in  suspension  in  15  ml  of  tetrahydrofuran  are

introduced    into   a   100   ml   three-necked   flask   equipped

10    with magnetic stirring, under a nitrogen atmosphere, and 3. 5 ml of a 0. 9 M solution of hydra zoic acid in benzene (3 mmol) are added. A solution of 0. 55 ml (2. 75 mmol) of diisopropylcarbodiimide in 1.5 ml of

tetrahydrofuran is added to this solution dropwise and 15 the mixture is heated at 40°C for 16 h.

0. 65 g (2. 5 mmol) of triphenylphosphine is added and the mixture is stirred for 30 min, 0. 5 ml of water is added and the stirring is resumed for 6 h.

20

The mixture is hydrolyzed with lN hydrochloric acid and diluted with chloroform. The aqueous phase is basified with aqueous ammonia and it is extracted several times with chloroform. After washing the combined organic

25    phases, drying over sodium sulfate and evaporating the solvent under reduced pressure, 0.97 g of an orange-colored oil is obtained containing Sa, 95-cinchonan-9-amine which is used crude in the next step.

30 3.2. 2-Chloro-N-(8a,95-cinchonan-9-yl)-3-trifluorometh-ylbenzamide hydrochloride 2:1

According to the method described in Example 1. 3, starting with 0. 97 g (3. 3 mmol) of Sa, 95-cinchonan-9-

35    amine, 0.84 g (3.4 mmol) of 2-chloro-3-trifluoromethyl-benzoic acid chloride and 0.5 g (3.63 mmol) of potassium carbonate, 0. 360 g of oil is obtained which is dissolved in 30 ml of lN hydrochloric acid. The aqueous phase is extracted with chloroform and then the

solvent  is  evaporated  under  reduced  pressure.   0.26  g  of

hydrochloride    is  thus  obtained  in  the  form  of  a  white

solid.

Melting  pointo  l85-205°C;   [ctlo"  =  -5.4   (c=0.986,  MeOH).

Example  4   (compound  No.  17)

2, 6-Dichloro-N- [ (18)- [ (28) (l-azabicyclo [2 .2 .2] oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamide hydro-

1 o    chloride  1' l

4.1    (18)- [ (28) -1-Azabicyclo [2 .2 .2.] oct-2-yl (phenyl)-

methyl] amine  D-tartrate

15    9.4 g (43.45 mmol) of three- [1-azabicyclo[2 .2 .2 .]oct-2-yl (phenyl) methyl] amine are dissolved in 150 ml of ethanol. A solution of 6.52 g (43.45 mmol) of

D-tartaric acid in solution in 200 ml of ethanol is poured in. After evaporating the solvent under reduced
20    pressure, the residue is placed in 500 ml of a solution of ethanol and of water (9/1) and then heated until dissolution is obtained. After 3 successive recrystallizations, 5.39 g of (1S)-[(2S)-l-azabicyclo-

[2. 2.2.] oct-2-yl (phenyl) methyl] amine D-tartrate are

2 5    obtained.

Melting  point:  125-135°C.

[ale"  =  -46.1   (c=0.616;  MeOH).

4.2.  2,6-Dichloro-N- [(18)- [(28) (1-azabicyclo[2.2.2]oct-

30    2-yl)phenylmethyl]-3-(trifluoromethyl)benzamide hydrochloride 1o1

3.33    g    (12.02    mmol)    of    2,6-dichloro-3-(trifluoro-

methyl)benzoic    acid   chloride   in   solution   in   30   ml   of

35    chloroform are placed in a 100 ml round-bottomed flask equipped with magnetic stirring in the presence of
1.82  g   (13.22  mmol}   of  potassium  carbonate  at   0°C,   and

a    solution   of   2. 6   g    (12. 02   mmol)    of    (18)- [ (28) -1-

azabicyclo [2 .2 .2.] oct-2-yl (phenyl) methyl] amine

(obtained  by  basification  of  the  salt  described  in  4.1,

followed    by   extraction)    in   solution   in   40   ml    of

chloroform    is  poured  in  and  the  mixture   is  stirred  at

room  temperature  for  6  h.

After    hydrolyzing    with    water    and    diluting    with

chloroform,    the   aqueous   phase   is   separated   and   it   is

extracted    with   chloroform.   After   washing   the   combined

organic    phases,    drying    over    sodium    sulfate    and

10    evaporating the solvent under reduced pressure, the residue is purified by chromatography on a silica gel

column,    eluting   with   a   mixture   of   chloroform   and

methanol.

5.4  g  of  an  oily  product  are  obtained.

15

The    latter   is   dissolved   in   a   few   ml   of   chloroform,

600  ml    of    a    solution    of    ether    saturated    with

hydrochloric    acid   are    added,    and    the    mixture    is

concentrated    under   reduced   pressure.    The   residue   is

20    recrystallized from e~hyl acetate. 4. 7 g of 2, 6-dichloro-N- [ (1S)- [ (2S) (1-azabicyclo [2. 2 .2] oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamide

hydrochloride are thus obtained. Melting point: 264-268°C.
25    [a] 0 25   =  +61.1 °   (c=O. 32;  MeOH)

Example  5   (compound  No.   26)

threo-N- [1-Azabicyclo [2. 2 .2] oct-2-yl (4-fluorophenyl)-

methyl] -2, 6-dichloro-3- (trifluoromethyl)benzamide 3 0 hydrochloride 1: 1

5.1    1-Azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)-

methanol

35    1.11 g (10 mmol) of quinuclidine in 40 ml of dry tetrahydrofuran at 0°C are placed in a 100 ml three-necked flask under argon. 1.33 ml (10.5 mmol) of ether-boron trifluoride complex are added dropwise and the mixture is stirred for 30 min at 0°C (solution A). In

parallel,    2.47   g    (22   mmol)    of   dry   potassium   tert -

butoxide    in  60  ml  of  dry  tetrahydrofuran  are  placed  in

a  250  ml  three-necked  flask  under  argon.  The  mixture  is

cooled    to   -70°C   and   22   ml   of   a   1M   solution   of   sec-

butyllithium    in    the    cyclohexane/hexane    mixture

(22  mmol)   are  poured  in  dropwise  while  the  temperature

is    kept   below   -60°C   (solution   B).   At   the   end   of   the

addition,    the  solution  A  is  delivered  by  a  cannula-like

tube    into  the  solution  B  while  the  temperature  is  kept

10    at  around  -70°C.  The  mixture  is  kept  stirring  for  2  h.

2.36  mol   (22  mmol)   of  distilled  4-fluorobenzaldehyde  in

solution in 20 ml of tetrahydrofuran at -70°C are placed in a 50 ml three-necked flask under argon. The

15    solution B is delivered by a cannula-like tube while the temperature is kept at around -70°C. The resulting solution is left for 30 min at -70°C and allowed to rise to -20°C. The mixture is then hydrolyzed with a 10% hydrochloric acid solution. The mixture is

20    extracted with ether and then the aqueous phase is taken up and basified with aqueous ammonia. The mixture is extracted with chloroform and then the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on a silica gel

25 column, eluting with a mixture of chloroform and methanol. 0 . 53 g of l-azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)methanol is thus obtained in the form of a yellowish solid.

Melting  point:  69-70°C.

30

5.2 l-Azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)meth-a none

1.3    ml    of    dimethyl    sulfoxide    in    40    ml    of

35    tetrahydrofuran at -70°C are placed in a 250 ml three-necked flask under nitrogen, and 0. 9 ml of oxalyl chloride {11 mmol) is added dropwise and the mixture is kept stirring for 30 min at this temperature. A solution of 1 g {4.6 mmol) of 1-azabicyclo[2.2.2]oct-2-

yl (4-fluorophenyl)methanol   in  40   ml   of   tetrahydrofuran

is added dropwise. After 30 min, 4 ml (27. 6 mmol) of triethylamine are added at -70°C. The reaction mixture is then stirred for 30 min at -70°C, for 30 min at 0°C

5    and  then  for  1  h  at  room  temperature.

The mixture is poured into an aqueous ammonia solution and then extracted several times with chloroform. The organic phases are dried over sodium sulfate and

10 evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column, eluting with a mixture of chloroform and methanol. 1 g of 1-azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)methanone is thus obtained.

15    Melting  point:   68-69°C.

5.3 (Z) -1-Azabicyclo [2. 2 .2] octyl (4-fluorophenyl) meth-anone 0-benzyloxime hydrochloride

20    According to the procedure described in Example 1.1, starting with 1.17 g (5 mmol) of ketone, 1. 4 g of (Z)-

1-azabicyclo [2. 2 .2] cetyl (4-fluorophenyl) methanone    0-
benzyloxime    hydrochloride    are    obtained    after

trituration,    in   ether,   of   the   residue   obtained   after

25    the treatment of the reaction. Melting point: 202-203°C.

5.4    threo-1-Azabicyclo[2.2.2]octyl(4-fluorophenyl)-

methanamine

30

According    to   the   procedure   described   in  1. 2,   starting

with    1.47  g   (4.54   mmol)   of   (Z)-1-azabicyclo[2.2.2]oct-

yl (4-fluorophenyl) methanone    0-benzyloxime    hydro-

chloride,    1    g    of    threo-1-azabicyclo [2. 2. 2] cetyl (4-

3 5    fl uorophenyl) methanamine    ( diastereoisomeric    excess,

de=90%).

5. 5   N- [ (S)- (2S) -1-Azabicyclo [2. 2 .2] oct-2-yl (4-fluoro-

phenyl)methyl]-2,6-dichloro-3-

( trifl uoromethyl) benz amide  hydrochloride  1: 1

According    to   the   procedure  described  in   1. 3,   starting

with    0.39    g    (1.66    mmol)    of    threo-1-azabicyclo-

[2 . 2 . 2] octyl ( 4- fl uorophenyl) methanamine,    0 . 5  g

(1. 83 mmol) of 2, 6-dichloro-3-trifluoromethylbenzoic acid chloride, 0. 25 g (1. 83 mmol) of potassium carbonate, 0. 79 g of threo-N- [1-azabicyclo [2. 2. 2] oct-2-

yl(4-fluorophenyl)methyl]-2,6-dichloro-3-(trifluoro-

10    methyl)benzamide is obtained, after purification by chromatography, in the form of an oil which is salified with a solution of gaseous hydrochloric acid in ethyl ether.

Melting  point:  290-291°C.

15

The other compounds are obtained according to the methods described in Examples 1, 2 and 5 from other

functionalized  aldehydes.

20 The following Table 1 illustrates the chemical structures of a few compounds of the invention.

In  the  11 R 11   column,   -CH=CH2   denotes  a  vinyl  group,   in  the

11 R1 11     column,    C6H5     denotes   a   phenyl   group   and   4-C9H6N

25    denotes a quinolin-4-yl group. In the 11 Salt 11 column, - denotes a compound in the base state, 11 HC1 11 denotes a hydrochloride and 11 tfan denotes a trifluoroacetate.

The   compounds   14,   19  to   23,   24   of   the   table   exist   in

30    the hydrochloride or dihydrochloride form (see table) solvated with one or more water molecules.

The compounds 15 and 16 of the table form a pair of enantiomers which are separated by preparative HPLC

35    using a 20 J.lm CHIRACEL® AD column and, as solvent, a 95/5 isohexane/propan-2-ol mixture, likewise for the compounds 17 and 18.

Table   2   gives   the   physical   properties, the   melting


points    and  optical   rotations   of  the   compounds   of   the

table.    "{d} 11    indicates    a    melting    point    with

decomposition.
 



                            -   20    -                           
                                Table    1                           
                                R,0y-£,:.                           
                                0()NH        (I)                   
                            "<::                               
                                R,                               
                                                               
I  No.    R,    R    X    n                R,        Salt    Stereochemistry   
                                                           
1    C5Hs    H    CH    1        3-S02N (CH3) 2 1    4-Cl        -    three    ( lR, 2R; lS, 2S)   
                                                           
2    CGHs    H    CH    1        2-Cl,   5-CE'J        HCl    three    ( lR, 2R;.1S, 2S)   
                                                           
3    C5Hs    H    CH    1        2-Cl,  3-CFJ        HC1    three    ( lR, 2R; lS, 2S)   
                                                           
4    C6Hs    H    CH    1        2 1  6-(Cl)z 1    3-CI!'J        HC1    three    (lR, 2R; lS, 2S)   
                                                           
5    C5Hs    H    CH    1        2-Cl,    3-CHJ, 6-F        HC1    three    {lR, 2R; lS, 2S)   
                                                           
6    C5Hs    H    CH    1        2-Cl,   3-CHJ        HC1    three    ( lR, 2R; lS, 2S)   
                                                           
7    CsHs    H    CH    1        2,4,6-(Cl)J        HC1    threo    (lR, 2R; lS, 28),   
                                                           
B    C5Hs    c_______ll        CH    1        2-CHJ,   3-CFJ        HC1    three    (1R, 2R; 1S, 2S) I   
-    --                                                           
 



                                -    21  -                               
                                                                   
        No.I    "'    R    X    n            R,    Salt        Ste.reochemistry       
                        1        2, 6- (Clh    HCl        threo    (lR, 2R; lS, 2S)       
                    CcHs    H    CH                                   
                                                                       
10            Celis•    H    CH    1        2,5-(CE'Jh    HCl        threo    (lR, 2R; lS, 25)       
                                                                       
11            CGHs    H    Cll    1        2-F,  3-Cl,   6-CE'J    HC1        threo    (lR, 2R; lS, 2S)       
                                                                       
12            CGHs    II    CH    1        2-CHJ,  3-Cl    HCl        threo    (1R,2R;l5,2S)       
                                                                       
13            CcHs    H    CH    1        2,3-(Clh    HC1        threo    (lR1 2R;lS,2S)       
                                                                       
        l4            ol-C9HcN    CH.,CH:z    CH    1        2-Cl,   3-CFJ    2HC1            (15,25)       
                                                                       
15            CcHs    H    CH    1        2-Cl,   3-CFJ    tfa            (lli1 2R)       
                                                                       
16            CsHs    II    CH    l        2-Cl,  3-CFJ    tfa            (1S,2S)       
                                                                       
17            CcHs    II    Cll    1        2, 6- (Cl) ::1    3-CFJ    HC1            (1S1 2S)       
                                                                       
18            CsHs    II    Cll    1        2, 6- (Cl):z,    3-CFJ    HC1            (1R, 2R)       
                                                                       
        l9            CcHs    H    N    1        2-Cl,   3-CFJ    2HC1        threo    (lR, 2R; lS, 2S)       
                                                                       
20            CcHs    H    N    1        2,6-('Cll:z,   3-CFJ    2HC1        threo    UR, 2R; lS, 2SJ       
                                                                       
21            CsHs    H    N    l        2,6-(Clh    2HC1        threo    (lR, 2R; lS, 2S)       
                                                                       
22            CcHs    II    N    1        2-CHJ,  3-CFJ    2HC1        threo    (lll, 2R; lS, 2SJ       
                                                                       
23            CsHs    II    N    l        2-CHJ,   3-Cl    2HC1        threo    (lR, 2R; lS, 2S)       
                                                                       
24            CcHs    u    CH    l        3, 5   (Clh, t1-NH2    HCl        threo    (lR, 2R; 15, 2S)       
                                                       
                                                                       
 



                                                    -    22   -                                   
    Ho.        .,        R        X        "            .,            Salt        stereochemistry       
                                                                           
                                                                           
25                    4-E'-CGHt        H        CH        1            2-Cl,3-CFJ        HC1        three    (lR, 2R; 15, 25)       
                                                                                                   
26                    -1-E'-CsHt        H        CH        1            2, 6- (Cl):, 3-CFJ        HCl        three    (lR, 2R;lS, 25)       
                                                                                                   
27                    !-naphthyl        H        Cll        1            2, 6-(Cl)2, 3-CE'J        HCl        threo    (lR, 2R;ls, 25)       
                                                                                                   
    2B            !-naphthyl        H        CH            l        2-Cl,3-CF3        HCl        threo    (lR, 2R; 15, 25)       
                                                                                                   
29                    !-naphthyl        H        CH            l        2-CH,,3-Cl        HCl        threo    (lR, 2R; 15, 2S)       
                                                                                                   
30                    2-CH,  -C6Ht        H        CH            l        2-Cl 1 3-CF3        HCl        th:r:eo    (lR, 2R;lS, 25)       
                                                                                                   
    31                    2-CHJ  -CGHt        H        CH        1            2, 6- (Cl) 2, 3-CF,        HCl        th:r:eo    (lR, 2R; 15, 25)       
32                    Coli,        H        CH            l        6-CH,, 3-Cl, 2-NH:z        HCl        threo    (lR, 2ll;l5, 25)       
                                                                                                   
33                    Cd;ls        II        CH            l        3, 6- (Cl):,2-NH:z        HCl        threo    {lR,2R;lS,2S)       
                                                                                                   
    ..                    CGIIs        H        CH        1            2,6-{Cl)2,3-CHJ        HCl        three    {lll,2R;lS,2S)       
                                                                                               
35                    CGHs        H        CH        1            2-CH,,J-Cl        HCl            (15,25)       
                                                                                                   
36                    CGHs        H        CH        1            2-Cl,J-CFJ        HC1        erythro    (15, 2R; lR, 2SI       
                                                                                                   
37                    4-F-C6Hf        H        CH        1            2-CH,, 3-Cl        liCl        threo/erythro:    9/1       
                                                                                                   
    3B            3-F-C6Ht        H        CH        1            2, 6- (Cl)z, 3-CFJ        HCl        three    (lR, 2R;lS, 2S)       
    ,.                                                                                               
                        3-F-CGHt        H        CH            l        2, G- (Cl) :z1  3-CE'J        llCl        erythro    (15, 2R; lR, 25)       
    <10  4-E',3-CH3-C~H3        "                CH        1            2-CH3, 3-0CH3        HCl        threo/eryl:hro    1/1       
                                                                                                           
                                                                                                           
 



                    -    23   -                   
                                           
    Ho.    R,    R    X    n        R,    Salt    Stereochemistry   
                                           
    <ll    4:-F, 3-CH3-C6lb    "    CH    1        3,5-(0CHJ):z    HCl    threo/erythro  1/1   
42    'l-F,3-CHJ-CsHJ            1        2, 6- (Cl) oz, 3-CFJ    HCl    thrco    (lR, 2.R;1S,25)   
"        "    CH                               
    3-F-CsHt            1        2-CIJ,, 3-0CHJ    HCl    th:teo    (l.R,2R;lS,2S)   
        "    CH                               
                                           
    CsHs        CH    1        2-0CJb, 5-Cl    HCl        (1S,2S)   
.."        "                                   
    CsHs        CH    1        2-Br, 5-0Cih    JICl        {1S,2S)   
46        "                                   
    CsHs        CH    1        2,3- (OCF20l    HCl        (1S,2S)   
                                       
            "                                   
"    Cdls        CH    1        2,6-(0CHJ):z    HCl        (1S,2S)   
        "                                   
                                           
46    CsHs        CH    1        3,5-(0CHJh    HCl        (1S,2S)   
            "                                   
"    CGHs        CH    1        2,3-(0Cihh    HC1        (lS 1 2S)   
        H                                   
                1        2-NH2 1 3-Cih               
    so    CsHs    H    Cll                2HC1        (lS, 2S)   
                                               
51    CsHs    ll    CH    1        2-0CHJ, 3, 6- (Cl):z    HCl        (lS, 2S)   
                                               
52    CGfls    H    CH    l        3-(0-CsHs)    I!Cl        (15 1  2S)   
                                               
53    Cslls    H    CH    1        2,5-{0Cibl2    i-tcl        (ls, 2s1   
                                               
54    CGHs    H    CH    1        2-CH 3, 3-0CH3    HCl        (lS,2S)   
55    CsHs    II    CH    1        2-0CHJ 1  3 1 5(Cl):z    HCl        (15,25)   
                                               
56    C5Hs    u    CH    1        2-Cl, 6-CHJ    Bel        (lS,2S)   
                                               
 



                        -    24   -                               
                                                               
    No.    R,    R    X    n        R2    Salt        Stereochemistry       
                                                                   
57    CGHs    H    CH    1            2-NH2 ,  6-CHJ    2HC1            (15,25)       
                                                               
58    C&Hs    H    CH    1            2-NHz, 5-Br    2HC1            (15,25)       
                                                               
59    CGHs    fl    CH    1            2-NHz, 5-CH3    2HC1            (15,25)       
                                                               
    60    C&Hs    H    CH    1            2-0CHJ, 3-CHJ    f!C1            (15,25)       
                                    '                           
    61                                2-NH 21 5-0CH3                        (1S 1 2S)       
        CGHs    H    CH    1                2HC1                       
                                                               
62    CGHs    H    CH    1            2-NH2 ,  3-0CH3    2HC1            (15,25)       
                                                               
63    CGHs    H    CH    1            2-Cl, 5-CHJ    HGl            (15,25)       
64    CGHs    H    CH    1            2-0CHJ, 5-CHJ    HCl            (15,25)       
                                                               
65    CGHs    H    CH    1            2-CHJ 1 3-0H    HCl                (1S,2S)       
                                                               
66    CGHs    H    CH    1            2-CHJ, 5-Cl    HCl            {15,25)       
                                                               
67    4-0CHJ-CGH4    H    CH    1            2, 6- (Cl)2 1  3-CFJ    11Cl    three    (lR, 2R; lS, 2S)       
                                                               
68    4-0H-CGH4    H    CH    1            2, 6- (Cl) 2 ,3-CF3    -        three    (lR, 2R; 15, 25)       
                                                               
69    3-E'-CGH4    H    CH    1            2-CHJ 1 3-Cl    HCl    three    (lR, 2R; 15, 2S)       
                                                               
 


    -    25  -       
    Table    2       
                   
No.    m.p. ("C)    [a]~s    (")       
                   
1    233-235    -           
2    267-269    -           
3    257-262    -           
4    270-273    -           
5    315-316    -           
6    319-320    -           
7    >300    -           
                   
8    281-283    -           
9    359-361    -           
10    281-283    -           
11    347-349    -           
12    311-313    -           
13    316-318    -           
14    185-205  .    -5.4    (c=0.986    MeOH)   
15    196-197    -51.3   (c=l. 03  MeOH)   
16    214-215    +48. 2    (c=O. 618    MeOH)   
17    264-268"C    +61.1    (c=0.32    MeOH)   
18    265-268    -58.9   (c=0.3  MeOH).   
19    207-208    -           
20    214-215    -           
21    210-211    -           
22    215-217    -           
23    210-212    -           
24    336-339    -           
25    271-273    -           
26    290-291    -           
27    317-318    -           
                   
28    314-315    -           
29    315-316    -           
30    215-230    -           
31    210-220    -           
 


-    26  -

No.   m.p.  ('C)    [Cl]~5  (')

32    328-330 -

33    275-280 -
34    338-344 -

35    295-300 +55.2   (c=O. 3  MeOH)

36    281-291 -
37    >300    -
36    232-234    -
39    269-291 -
40    124-126 -

41    154-156    -    ..

42    254-256 -

43    280-282 -

44    162-164 +87. 4   (c=O. 32  ;  MeOH)

45    275-277 +43. B  (c=O. 32  ;  MeOH)

46    191-193 +42.4   (c=O, 32  ;  MeOH)

47    234-236 +53.2   (c=0.30  ;  MeOH)

48    297-299 +21.3   (c=O. 31  ;  MeO!I)

49    264-266 +66. 6   (c=O. 32  ;  MeOH)

50    244-246 +41.1  {c=O, 30  ;  MeOl!)

51    194-196 +73. 9   (c=O. 29  ;  MeOH)

52    105-106 +26. 7   (c=0.30  ;  MeOH)

53    169-171 +82.3   (c=0.30  ;  MeOH)

54    298-300 +46. 6   (c=O. 31  ;  MeOH)

55    213-215 +75.9   (c=O, 30  ;  MeOH)

56    331-333 +67. 9   (c=O, 31  ;  MeOH)

57    295-297 +79 .4   (c=O. 30  ;  MeOH)

56    244-246    +16. 1   (c=O. 30  ;  MeOH)

59    262-284 +26. 4  (c=O. 31  ;  MeOH)

60    235-237 +116. 6  (c=0.29  ;  MeOH)

61    278-280 +14.2   (c=O. 30  ;  MeOH)

62    264-266 +40. 5   (c=O. 30  ;  ~leOH)

No.    m.p.("C)    [a]~s  (")

63    128-130    +61. 9  (c=O. 32  ;  MoOH)

64    185-187 +81.9  (c=D.30  ;  MeO!l)

65    329-331 +45.9  (c=O. 29  ;  Me Of!)

66    242-244 +8.4   (c=O. 31  ;  MeOH)

67    284-286 -
68        -
69    291-293    -

The    compounds   of   the   invention   were   subjected   to   a

series    of   pharmacological   trials   which   demonstrated

their    importance    as    substances    with    therapeutic

activity.

Study    of   the   transport   of   glycine   in   SK-N-MC   cells

expressing  the  native  human  transporter  glytl.

The  capture  of   [14 C]glycine  is  studied  in  SK-N-MC  cells

{human    neuroepithelial   cells)    expressing   the   native

10 human transporter glytl by measuring the radioactivity incorporated in the presence or in the absence of the test compound. The cells are cultured in a monolayer for 48 h in plates pretreated with fibronectin at

0.02%.    On  the  day  of  the  experiment,  the  culture  medium

15    is removed and the cells are washed with a Krebs-HEPES ( [4- (2-hydroxyethyl) piperiazine]l-ethanesulfonic acid)

buffer    at   pH  7. 4.   After  a   preincubation  of   10   min  at

37°C  in  the  presence  either  of  buffer   (control  batch),

or  of  test  compound  at  various  concentrations,  or  of  10

20    mM glycine (determination of the nonspecific capture}, 10 JlM [14 C]glycine (specific activity 112 mCi/mmol) are then added. The incubation is continued for 10 min at 37cc, and the reaction is stopped by 2 washes with a Krebs-HEPES buffer at pH 7.4. The radioactivity

25    incorporated by the cells is then estimated after adding 100 .ul of liquid scintillant and stirring for
1  h.  The  counting  is  performed  on  a  Microbeta  'l'ri-lux~

counter. The efficacy of the compound is determined by the IC50 , the concentration of the compound which

30    reduces by 50% the specific capture of glycine, defined by the difference in radioactivity incorporated by the control batch and the batch which received the glycine at 10 roM.

35    The most active compounds of the invention, in this test, have an IC50 of the order of 0.001 to 10 JiM.

The individual results for some compounds are as follows (ICso in JLM) :
 


        -    29  -
Compound  No.        0. 017
Compound  No.        0. 004
Compound  No.    14    0    .07
Compound  No.    17    0    . 001
Compound  No.    26    0. 07

Study ex vivo of the inhibitory activity of a compound on the capture of [14 C] glycine in mouse cortical
10    homogenate

Increasing    doses   of   the   compound   to   be   studied   are

administered    by    the    oral    route    (preparation    by

trituration    of   the   test   molecule   in   a   mortar   in   a

15    solution of Tween/Methocel 1"' at a. 5% in distilled water) or by the intraperitoneal route (dissolution of the test molecule in physiological saline or preparation by trituration in a mortar in a solution of

Tween/Methocel 1M     at   0. 5%   in   water,    according   to   the

20    solubility  of   the   molecule)   to   20   to   25   g  Iffa  Cr€:do

OFl male mice on the day of the experiment. The control group is treated with the vehicle. The doses in mg/kg, the route of administration and the treatment time are determined according to the molecule to be studied.

25

After the animals have been humanely killed by decapitation at a given time after the administration, the cortex of each animal is rapidly removed on ice, weighed and stored at 4°C or frozen at -80°C (in both

30    cases, the samples are stored for a maximum of 1 day) . Each sample is homogenized in a Krebs-HEPES buffer at pH 7.4 at a rate of 10 ml/g of tissue. 20 JLl of each homogenate are incubated for 10 min at room temperature

in    the   presence   of   10  mM   L-alanine   and   buffer.    The

35    nonspecific capture is determined by adding 10 mM glycine to the control group. The reaction is stopped by filtration under vacuum and the retained radioactivity is estimated by solid scintillation by counting on a Microbeta Tri-luxm counter.
 


-    30  -

An inhibitor of the capture of [14C] glycine will reduce the quantity of radioligand incorporated into each homogenate. The activity of the compound is evaluated by its ED50 , the dose which inhibits by 50% the capture of [14 C] glycine compared with the control group.

The    most   potent   compounds   of   the   invention,    in   this

test,    have    an    ED50    of    0.1    to    mg/kg    by    the

10    intraperitoneal  route  or  by  the  oral  route.

Study of the transport of glycine in mouse spinal cord homogenate

15    The capture of [14 C] glycine by the transporter glyt2 is studied in mouse spinal cord homogenate by measuring the radioactivity incorporated in the presence or in the absence of the compound to be studied.

20 After the animals have been humanely killed (Iffa Credo OF1 male mice weighing 20 to 25 g on the day of the experiment), the spinal cord of each animal is rapidly removed, weighed and stored on ice. The samples are homogenized in a Krebs-HEPES ( [4- (2-

25    hydroxyethyl) piperazine] 1-ethanesulfonic acid) buffer, pH 7. 4, at a rate of 25 ml/g of tissue.

50  ILl  of  homogenate  are  preincubated  for  10  min  at  25°C

in  the   presence   of   Krebs-HEPES   buffer,   pH  7. 4   and  of 30    compound  to  be  studied  at  various  concentrations,   or  of 10   mM   glycine   in   order   to   determine   the   nonspecific capture.    The    [14 C] glycine    (specific   activity        112 mCi/mrnol)   is  then  added  for  10  min  at  25°C  at  the  final concentration   of   10  J.LM.    The   reaction   is   stopped   by 35    filtration    under    vacuum    and    the    radioactivity    is estimated   by   solid   scintillation   by   counting   on   a

Microbeta  Tri-lux~ counter.

The efficacy of the compound is determined by the concentration IC50 capable of reducing by 50% the
 


-    31  -

specific  capture  of  glycine,   defined  by  the  difference

in    radioactivity  incorporated  by  the  control  batch  and

the  batch  which  received  the  10  mM  glycine.

The  most  active  compounds  of  the  invention  in  this  test

have  an  IC50   of  the  order  of  o. 02  to  10  ~M.

The    IC50   of  the  compound  No.   17  is  0.69  p.M.

10    The results of the trials carried out on the compounds of the invention of general formula (I) show that they
are    inhibitors  of  the  glycine  transporters  glytl  which

are predominantly present in the brain, and of the glycine transporters glyt2, which are predominantly
lS    present  in  the  spinal  cord.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular of medicaments inhibiting the glycine

20    transporters  glytl  and/or  glyt2.

Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a

compound  of  formula   (I},   or  an  additional  salt  thereof

25    with a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of the formula (I).

The compounds of the invention may be used in particular for the treatment of behavioral disorders

30    associated with dementia 1 psychoses, in particular schizophrenia (deficient 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 35    disorders 1        for    the    treatment    of    various   forms    of depression,    including   psychotic   depression 1       for    the treatment   of   disorders   due   to   alcohol   abuse   or   to withdrawal    from   alcohol,    sexual   behavior   disorders, food    intake    disorders,    and    for    the    treatment    of


migraine.

Moreover,    the  compounds  of  the  invention  may  be  used

for  the  treatment  of  painful  muscular  contractures  in

5    rheumatology and in acute spinal pathology, for the treatment of spastic contractures of medullary or cerebral origin 1 for the symptomatic treatment of acute and subacute pain of mild to moderate intensity, for the treatment of intense and/or chronic pain, of

10    neurogenic pain and rebellious algia, for the treatment of Parkinson 1 s disease and of Parkinsonian symptoms of neurodegenerative origin or induced by neuroleptics, for the treatment of primary and secondary generalized epilepsy, partial epilepsy with a simple or complex

15    symptomatology, mixed forms and other epileptic syndromes as a supplement to another antiepileptic treatment, or in mono therapy, for the treatment of sleep apnea, and for neuroprotection.

20 The subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a pharmaceutically acceptable base or salt or solvate, and in the form of a mixture,

25 where appropriate, with one or more suitable excipients.

Said excipients are chosen according to the pharmaceutical dosage form and the desired mode of
30    administration.

The pharmaceutical compositions according to the invention may thus be intended for oral, sublingual,

subcutaneous,    intramuscular,    intravenous,    topical,

35    intratracheal, intranasal, transdermal, rectal or intraocular administration.

The unit forms for administration may be, for example, tablets, gelatin capsules, granules, powders, oral or


injectable solutions or suspensions, patches or suppositories. For topical administration, it is

possible  to  envisage  ointments,  lotions  and  collyria.

By  way  of  example,   a  unit  form  for  administration  of  a

compound according to the invention in tablet form may comprise the following components:

Compound  according  to  the  invention    50.0    mg
10Mannitol    223.75  mg
croscarmellose  sodium    6.0    mg
corn  starch    15.0    mg
Hydroxypropylmethylcellulose    2.25    mg
Magnesium  stearate    3.0    mg

15

Said  unit  forms  contain  doses  in  order  to  allow  a  daily

administration of 0. 01 to 20 mg of active ingredient per kg of body weight, according to the galenic form.

20    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 for each patient is determined by the doctor according to the mode of

25    administration, the weight and the response of said patient.

The present invention, according to its other aspects, also relates to a method for treating the pathologies

30    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 or the hydrates or solvates.
 


-    34  -

Claims

1.    A  compound  corresponding  to  general  formula   (I)


5
in  which

R represents  a  hydrogen  atom  or  a  vinyl  group;

n    represents   0   or  1   or  2   when  R  represents  a   hydrogen

atom    and   n   represents   1   when   R   represents   a   vinyl

10    group;

X represents a group of formula CH or a nitrogen atom when R represents a hydrogen atom and X represents a group of formula CH when R represents a vinyl group;

R:~.  represents    either    a    phenyl    or    naphthyl    group

15    optionally   substituted   with   one   or   more   substituents

chosen from halogen atoms, linear or branched (C:~.­ c6) alkyl, hydroxyl and (C,-C6) alkoxy groups, the trifluoromethyl group, or a cyclohexyl group, or a heteroaryl group chosen from the thienyl, pyridinyl,

20    oxazolyl,    furanyl,    thiazolyl,    quinolinyl,    and

isoquinolinyl  groups;

R2 represents either a hydrogen atom, or one or more substituents chosen from halogen atoms and the trifluoromethyl, (C1 -C6) alkyl, (C1 -C 6) alkoxy, thienyl,

25    phenyloxy, hydroxyl, mercapto, thio(C1 -C6)alkyl and cyano groups or a group of general formula -NR4R5 ,
S02~Rs,  -S02 -  (CJ,-C6)alkyl,   -SOz-phenyl,   -CONR4R5 ,    -COOR7 ,
-CO- (C,-C6 )alkyl,    -CO-phenyl,    -NHCOR,,    -NHS02 -  (C1 -C6 ) -
 


-    35  -

alkyl,    -NHS02-phenyl    and    -NHS02NR.;Rs    or    a    group    of

formula    -OCF2 0-   attached  at   the   2-   and  3-positions   of

the  phenyl  group;

the groups (C1-c,)alkyl, (C1-c,)alkoxy, -so,-(C1-C6 )alkyl, -CO- (C1-Col alkyl and -NHS02 - (C1-Co) alkyl being optionally
substituted  with  one  or  more  groups  R3 ;

the groups phenyl 1 -802 -phenyl, -CO-phenyl and -NHS02 - phenyl being optionally substituted with a group R6 ;
R3   represents  a  halogen  atom,   or  a  phenyl,   (C~-c6)alkoxy
10    or  -NR4R5   group;

R4     and   R5    represent,    independently   of   each   other,   a

hydrogen atom or a (CJ.-C6)alkyl group or R4 and Rs form with the nitrogen atom bearing them a pyrrolidine ring,

a  piperidine  ring  or  a  morpholine  ring;

15 R6 represents a hydrogen atom, a hi!ilogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, a mercapto group, a (CJ.-C6 )alkyl or {C1 -C6 )alkoxy group; R7 represents a hydrogen atom or a {C1 -C6 ) alkyl group optionally substituted with one or more groups R3 , or a

20    phenyl  group  optionally  substituted  with  a  group  R6 ;

R8 represents a {C1 -C6 ) alkyl group optionally substituted with one or more groups R3 , or a (C1 - C6) alkoxy group, or a phenyl group optionally

substituted  with  a  group  R6,

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

2. The compound as claimed in claim 1, characterized in that it is of the threo configuration.

30

3. The compound as claimed in either of claims 1 and 2, characterized in that n represents 0 or 1.

4.    The  compound  as  claimed  in  claim  3,   characterized

35    in  that  X  represents  a  group  of  formula  CH.

S. The compound as claimed in claim 4, characterized in that R represents a hydrogen atom.

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