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(21) Application Number: KElP/ 2010/ 001050

(11) Patent Number: KE 484

(45) Date of grant: 05/01/2012
   
(51) Int.CI.S: A 61K 31/454, 31/496, A 61P 3/00, 3/04, 3!1 0, C 07D 209/08, 209/40, 211/26, 401112

(22) Filing Date: 14/08/2008

(30) Priority data: 0705858  16/08/2007  FR
 
(73) Owner: SANOFI-A VENTIS of 174, avenue de France, F-75013 Paris, France

(72) Inventor:BARONI, Marco  c/o Sanofi-Aventis, Departement Brevets, 174, avenue de France.

(7 4) Agent/address for correspondence: Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi
 
(86) PCT data PCT/FR08/001190 14/08/2008 wo 2009/056707 07/05/2009

(54) Title: INDOL-2-0NE DERIVATIVES DISUBSTITUTED IN THE 3-POSITION, PREPARATION THEREOF AND  THERAPEUTIC USE THEREOF.

(57) Abstract: The subject oftbe present invention is indol-2-one derivatives disubstituted in tbe 3-position, of general formula (1); in which -, Rl, R2, R3, R4, R5, Ar and n are as defmed in claim I, the method for preparing said compounds and the therapeutic use of said compounds.
 
INDOL-2-0NE DERIVATIVES DISUBSTITUTED IN THE 3-POSITION,

PREPARATION THEREOF AND THERAPEUTIC USE THEREOF


5    The present invention relates to 3-disubstituted indol-2-one derivatives, to their preparation and to their therapeutic application.

Ghrelin is a 28 amino-acid peptide hormone produced mainly in the stomach

by a post-translational process after cleavage of pre-pro-ghrelin (Kojima M.,

10    et al., Nature 1999; 402: 656-60). Ghrelin is an endogenous ligand of the growth hormone secretagogue pituitary receptor (GHSR1a).

GHS-R is encoded by two exons: exon 1 encodes the transmembrane domains (TMs) 1-5 and exon 2 encodes TM6 and 7 of the G-protein-coupled

15    receptor (GPCR).


The two transcripts have been identified in the pituitary gland and the brain: one encoding the full-length GPCR (GHS-R1a) and the other encoding a truncated receptor (GHS-R1 b) lacking TM6 and 7. Only the subtype GHS-

20    R1a is activated by ghrelin and ghrelin mimetics. GHS-R1b is present in the liver and other peripheral tissues, but its function is unknown (Smith R.G. et al., Trends in Endocrinology and Metabolism, 2005, 16, No. 9).

It is a receptor of rhodopsin type, with seven transmembrane domains of

25    family A coupled to Gq/phospholipase C. The ghrelin receptor may also be coupled to the Gs/protein kinase A pathways in certain tissues (Ueno, N. et al., Endocrinology, 2004, 145, 4176-4184; Kim, M.S. et al., Int. J. Obes. Relat. Metab. Disord., 2004, 28: 1264-1271). Interestingly, the ghrelin receptor has

the    relatively  uncommon  characteristic  of  having  significant  ligand-

3D    independent  constitutive  activity  (Barazzoni,  R.  et  al.,  Am.  J.  Physiol.

Endocrinol. Metab., 2004, 288: E228-E235).
 

Low levels of expression of ghrelin have been docume ~ ¥,anous tissues,, such as the intestines, the pancreas, the kidneys, the * ~1;)e.,..s~m~~
~. •. r 4. L  }i'  '.>•••"'
placenta, the testicles,  pituitary tissue and the hypothalamu ~ '•  •cc    •

2003; 59 (3): 109-17).

5

It has been demonstrated that ghrelin is involved in hunger at mealtimes, and in the initiation of meals. The circulating levels decreases with the intake of food and increase after meals, reaching concentrations that are sufficient to stimulate hunger and the intake of food. Ingestion of ghrelin stimulates food

10    intake rapidly and transiently, mainly by increasing the appetitive feeding behaviour and the number of meals. Ghrelin stimulates the. short-term taking of food more efficiently than any other molecule, with the exception of neuropeptide Y, with which it is approximately equipotent 0/Vren A.M. et al., J. Clin. Endocrinol. Metab., 2001; 86: 5992-5). However, ghrelin is unique in its

15    capacity to exert this effect, whether it is injected peripherally or centrally.


It is also the only mammalian substance that has demonstrated its capacity to

increase  the  appetite  and  the taking  of food  when  it  is  administered  to

humans (Druce M.R., et al., Int. J. Obes., 2005; 29: 1130-6; Wynne K., et al.,

20    J. Am. Soc. Nephrol., 2005; 16: 2111-8).


Beyond its role in the initiation of meals, ghrelin also satisfies the established

criteria of an adiposity-related hormone involved in regulating the long-term body mass. The levels of ghrelin circulate as a function of the energy

25    reserves and display compensatory changes in response to changes in body mass.

Ghrelin crosses the blood-brain barrier and stimulates the taking of food by acting on certain standard body mass-regulating centres, such as the

30    hypothalamus, the hindbrain and the mesolimbic compensatory system.
 
Chronic administration of ghrelin increases the body mass via diverse concerted actions on the taking of food, energy expenditure and the utilisation of resources. Congenital ablation of ghrelin or of the ghrelin receptor gene causes a resistance to feeding-induced obesity, and pharmacological

5    blocking of ghrelin reduces the intake of food and the body mass.


The existing evidence appears to favour the role of ghrelin both in the short-

term initiation of meals and long-term energy homeostasis, thus making it an

attractive  target  as  a  medicament  for  treating  obesity  and/or  slimming

10    disorders.


Ghrelin also exerts both physiological and pharmacological actions on the endocrine pancreas. Acylated bioactive ghrelin is produced in the s cells,
recently described in the pancreatic islets (Prado, C.L., et al., 2004, Proc. Nat/

15    A cad. Sci. USA, 101: 2924-2929), potentially providing a local source of ghrelin that acts on the p cells of the islets. Blockage of this function of endogenous ghrelin by means of an antagonist for its receptors substantially reduced the fasted glucose concentrations, attenuated the glycaemic

movement and increased the responses to insulin during glucose tolerance

20    tests, suggesting an inhibitory role of ghrelin in the control of insulin secretion (Dezaki, K., et al. 2004, Diabetes, 53: 3142-3151).

Ablation of ghrelin in mice (ghrelin -/- mice) increases the glucose-dependent

secretion of insulin by the p cells of the pancreas, by reducing the Ucp2

25    expression and increases the sensitivity to peripheral insulin (Sun Y. et al., 2006, Cell Metabolism, 3: 379-386).

Ghrelin receptor antagonists could thus regulate hunger, the taking of meals

and their frequency, and also, in the long-term, the weight, especially weight

30    gain following diets or therapeutic regimens. Furthermore, in the context of an antidiabetic treatment, ghrelin antagonists could be useful for maintaining the
 

equilibrium between insulin and glucose for controlling diabetic hyperphagia.

Ghrelin  antagonists  could  thus  be  used  as  anorexic  and/or  anti-obesity

agents, or alternatively in the treatment of diabetes and its effects.


5    Patent application WO 95/181 05 describes 5-chloro-3-(2-chlorophenyl)-1 ,3-dihydro-3-[2-( 4-methylpiperazin-1-yl)acetamido]indol-2-one and 5-chloro-3-(2-chloroacetamido)-3-(2-chlorophenyl)-1 ,3-dihydroindol-2-one compounds as synthetic intermediates for 1 ,3-dihydroindol-2-one derivatives 3-substituted with a nitrogenous group and having affinity for vasopressin and/or oxytocin.

10

One subject of the present invention is compounds corresponding to formula

(I):

r:-"-y-R5
H_(yjt-tl

Rti}4Ar  0n   
5    ~        3   
R3    "'    N    2  0   
e_,__,           
R2    7    1 \       
        R1   

(I)

in which:


15    represents a single or double bond,
-c~,
X represents -N<, -CH< or

Y represents >N- or >CH-, it being understood that at least one from among X andY represents N;
Ar represents an aryl or heteroaryl group optionally substituted with one or

20    more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, (C1-6)haloalkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy and aryl groups;
 

R1 represents a hydrogen atom or a (C1-6)alkyl, -C(=O)(C1-6)alkyl or -C(=O)aryl group;

R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen

5    atom, a halogen atom, CN, OH, a (C1-6)alkyl group optionally substituted with a halogen atom or an OH; perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylamino-carbonyl, aryl, aryloxy; heteroaryl; the aryl, aryloxy or heteroaryl group possibly being optionally substituted with a halogen atom, CN, OH or a (C1-

10    6)alkyl, perhalo(C1-3)alkyl or (C1-6)alkoxy group; it being understood that at least one from among R2, R3 and R4 is other than H and that the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6)alkoxy group;

R5 represents a (C1-6)alkyl or (C2-6)alkenyl group; and

15    n represents 1 or 2; with the exclusion of 5-chloro-3-(2-chlorophenyl)-1 ,3-d ihyd ro-3-[2 -( 4-methyl piperazin-1-yl)aceta m ido] indol-2-one.

The compounds of formula (I) comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers.

20    These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

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

25

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

30    In the context of the present invention, the following definitions apply: -a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
 
- an alkyl group: a linear or branched saturated aliphatic group. Examples that may be mentioned include a (C1-6)alkyl group containing from 1 to 6 carbon atoms, more particularly (C1-4)alkyl, which may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

5    -an alkenyl group: a linear or branched, monounsaturated or polyunsaturated aliphatic group comprising, for example, one or two unsaturations and containing from 2 to 6 carbon atoms;
- a haloalkyl group: an alkyl group in which one or more hydrogen atoms have been replaced with a halogen atom; for example a fluoroalkyl: an alkyl group

10    in which one or more hydrogen atoms have been replaced with a fluorine atom;

- a perhaloalkyl group: an alkyl group in which all the hydrogen atoms have been replaced with a halogen atom; for example, a perfluoroalkyl: an alkyl group in which all the hydrogen atoms have been replaced with a fluorine

15    atom;

-    an alkoxy group: a radical -0-alkyl in which the alkyl group is as defined above;

-    a perhaloalkoxy group: a radical -0-perhaloalkyl in which the perhaloalkyl

group  is  as  defined  above;  mention  may  be  made,  for  example,  of

20    trifluoromethoxy;

-an aryl group: a cyclic aromatic group containing between 6 and 10 carbon atoms. Examples of aryl groups that may be mentioned include phenyl and naphthyl;

-    a heteroaryl group: a cyclic aromatic group containing between 2 and 10

25    carbon atoms and comprising between 1 and 3 heteroatoms, such as nitrogen, oxygen or sulfur. Examples of heteroaryl groups that may be

mentioned include fury!, pyrrolyl, imidazolyl, pyrazolyl, thienyl, oxadiazolyl, oxazolyl, isoxazolyl, furazanyl, thiadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl groups, and also the corresponding

30    groups resulting from fusion with a phenyl group, for instance benzothiophene, benzofuran, benzothiazole, etc.
 

Ar represents an aryl or heteroaryl group optionally substituted with one or

5    more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy and aryl groups;

R1 represents a hydrogen atom or a (C1-6)alkyl, -C(=O)(C1-6)alkyl or -C(=O)aryl group;

R2,  R3 and R4, which may be identical or different, located on any of the

10    available positions of the phenyl nucleus, independently represent a hydrogen atom,'a-- halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C 1-3)alkoxy, aminocarbonyl, (C 1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy or heteroaryl group, it being

understood that at least one from among R2, R3 and R4 is other than H;

15    R5 represents a (C1-6)alkyl group.


Among the compounds of formula (I) that are subjects of the invention, one group of compounds is constituted by the compounds for which:
=    represents a single or double bond; and/or
-::;::::;
-......C_,
20    X represents -N<, -CH< or    ; and/or

Y represents >N-or >CH-, and/or

it being understood that at least one from among X and Y represents N; and/or

Ar  represents  an  aryl  group  optionally  substituted  with  one  or  more

25    substituents chosen from halogen atoms, preferentially chlorine or bromine, and (C1-6)alkoxy, (C1-6)alkyl, aryl, trifluoromethyl and trifluoromethoxy groups; and/or

R1 represents a hydrogen atom or a -C(=O)(C1-6)alkyl, -C(=O)aryl or (C1-6)alkyl group; and/or
 
R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, preferentially chlorine or bromine, or a (C1-6)alkyl or trifluoromethyl group, it being understood that at least one from among R2,

5    R3 and R4 is other than H; and/or

R5 represents a (C1-6)alkyl group; and/or n represents 1 or 2;

in the form of the base or of an acid-addition salt.

10    Among  the  compounds  of formula  (I) that are  subjects  of the  invention,
-    ~

another group of compdunds•is constituted by the compounds for which:

-    represents a single or double bond; and/or

C       
.......       
--- =    ; and/or   
X represents -N<, -CH< or       
Y represents >N- or >CH-, and/or       

15    it being understood that at least one from among X and Y represents N; and/or

Ar represents a phenyl or naphthyl group optionally substituted with one or

more  substituents  chosen  from  halogen  atoms,  preferentially  chlorine  or

bromine,    and  methoxy,  methyl,  tert-butyl,  phenyl,  trifluoromethyl  and

20    trifluoromethoxy groups; and/or

R1 represents a hydrogen atom or a -C(=O)methyl, -C(=O)phenyl or methyl group; and/or

R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen

25 atom, a halogen atom, preferentially chlorine or bromine, or a methyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H; and/or
R5 represents a methyl, ethyl or 2-propyl group; and/or n represents 1 or 2;

30    in the form of the base or of an acid-addition salt.

Among the compounds of formula (I) that are subjects of the invention, another group of compounds is constituted by the compounds for which:
Ar  represents  a  heteroaryl  group  optionally  substituted  with  one  or  more

5    substituents, which may be identical or different, chosen from halogen atoms and (C 1-6)alkyl, perhalo(C 1-3)alkyl, (C 1-6)alkoxy and aryl groups.

Among  the  compounds  of formula  (I)  that  are  subjects  of the  invention,

mention may be made especially of the following compounds:

10    (+)-N-[5,6-dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(4-
•'
methylpiperazin-1-yl)acetamide

( + )-N-[4, 6-d ich loro-3-( 4-trifluoromethylphenyl)-2 -oxo-2, 3-d ihyd ro-1 H-i ndol-3-yl]-2 -( 1-ethylpiperid-4-yl)acetamide N-[4,6-dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(4-
15    methylpiperazin-1-yl)acetamide

N-[4-trifluoromethyl-6-cyano-3-(4-ch lorophenyl)-2-oxo-2, 3-d ihyd ro-1 H-i ndol-3-yl]-2-( 4-ethylpiperazin-1-yl)acetamide
( + )- N -[ 1-benzoyl-5,6-d ich loro-3-(4-ch lorophenyl)-2-oxo-2, 3-d ihyd ro-1 H-ind ol-3-yl]-2-( 4-methylpiperazin-1-yl)acetamide

20    3-( 4-chlorophenyl)-3-[2-( 4-ethylpiperazin-1-yl)acetylam ino]-2-oxo-4-trifluoromethyl-2, 3-dihyd ro-1 H-indole-6-carboxamide N-[6-chloro-3-( 4-chlorophenyl)-1 ,5-dimethyl-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-( 4-methylpiperazin-1-yl)acetamide

( + )-N-[ 4, 6-d ich loro-3-( 4-trifluoromethylphenyl)-2 -oxo-2, 3-d ihyd ro-1 H-indol-3-

25    yl]-2-( 1-ethyl-1, 2,3, 6-tetrahydropyrid-4-yl)acetamide N-[4,6-dichloro-3-(3,4-dichlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(4-ethy lpiperazin-1-yl)acetamide N-[4,6-dichloro-3-(3-fluoro-4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide

30    N-[4 ,6-d ich loro-3-(3-trifl uoromethyl-4-chlorophenyl)-2 -oxo-2, 3-d ihydro-1 H-indol-3-yl]-2 -( 4-ethylpiperazin-1-yl) acetamide

N-[4, 6-dich loro-1-ethyl-3-(2-methylbenzo[b ]thiop hen-5-yl)-2-oxo-2, 3-dih yd ro-1H-indol-3-yl]-2-( 1-ethylpiperid-4-yl)acetamide

N-[4, 6-d ich loro-1-ethyl-3-(2-methyl-5-benzofuryl)-2 -oxo-2, 3-d ihyd ro-1 H-ind ol-3-yl]-2-( 4-ethylpiperazin-1-yl)acetamide

5    N-[4, 6-d ichloro-3-( 4-trifluoromethoxyphenyl)-2 -oxo-2, 3-d ihyd ro-1 H-ind ol-3-yl]-2-( 4-ethylpiperazin-1-yl)acetamide

in the form of the base or of an acid-addition salt.


In the text hereinbelow, the term "protecting group Pg" means a group that

10    makes it possible firstly to protect a reactive function such as a hydroxyl or an amine during a synthesis, and, secondly, to regenerate t~e-lntact reactive

function at the end of the synthesis. Examples of protecting groups and of

protection  and  deprotection  methods  are  given  in  Protective  Groups  in

Organic Synthesis, Greene et al., 2nd edition (John Wiley & Sons, Inc., New

15    York).


In the text hereinbelow, the term "leaving group" means a group that may be readily cleaved from a molecule by breaking a heterolytic bond, with loss of

an electron pair. This group may thus be readily replaced with another group

20    during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc.

group. Examples of leaving groups and references for their preparation are

given  in  Advances  in  Organic  Chemistry,  J.  March,  3rd  edition,  Wiley

25    lnterscience, pp. 310-316.


In accordance with the invention, the compounds of general formula (I) may be prepared according to the process that follows:
 

Scheme 1:

The compound offormula (1), in which R1 is other than H and  .:.:..::  , R2, R3,

5    R4, R5, Ar, X, Y and n are as defined in the general formula (1),  may be
 

prepared by reacting a compound of formula (I) i~\~cm. R1 , = .H with a compound of formula (II):

R1-Hal (II)

in which R1, which is other than H, is defined as in the general formula (I) and

5    Hal represents a halogen atom, for example chlorine, according to methods

known to those skilled in the art, for example in the presence of a base such as K2C03, NaH or t-Buo-K+, in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane or dimethyl sulfoxide (DMSO).

10    The compound of general formula (I) in which R1 = H may be prepared according to one or other of the following variants:

When X= -N<, the compound of general formula (I) in which R1 = H, i.e. the compound of general formula (II), may be prepared by reacting a compound of general formula (Ill):

H~Hal

R~ 0
R3~ro

R2    ~ ~
H
(Ill)
15

with a compound of general formula (IV):

in which Y, R2, R3, R4, R5, Ar and n are as defined in the general formula (1).

This reaction is generally performed using an organic or mineral base, such 20 as K2C03, Na2C03, pyridine or 4-dimethylaminopyridine, in the presence of
 
Nal or Kl, in an inert solvent such as DMF, dichloromethane, THF, dimethoxyethane or toluene.

The compound of general formula (Ill) may be prepared from a compound of 5 general formula (V):
Rti}:4ArH2

R3    O
.0    N
R2    \
H

(V)

and from a compound of general formula (VI):

Hal"
Hal'_(
0

(VI)

in which R2, R3, R4, R5 and Ar are as defined in the general formula (I) and

10    Hal'and Hal", which may be identical or different, independently represent a halogen atom, preferably chlorine.

This    reaction   is   generally   performed   using   pyridine    or   4-

dimethylaminopyridine    in   a  solvent  such   as  toluene,   benzene   or

15    dichloromethane, preferentially at a temperature of between room temperature and the reflux point of the solvent.

When X = -CH, -N< or -c<' , the compound of general formula (I) in which R1 =H may also be prepared from a compound of general formula 0./):
 
and from a compound of general formula (VII):

(VII)

in which  ::.::.:..:  , R2, R3, R4, R5, Ar, X, Y and n are as defined in the general

5    formula (1). This reaction is generally performed using a halogenating agent,

such as a chlorinating agent, for example phosphorus chlorides, especially PCI5, or alternatively PCh or POCh. The reaction is generally performed in the presence of pyridine or 4-dimethylaminopyridine, in a solvent such as dichloromethane or DMF.

10

The intermediates of general formula (V) are known and may be prepared

according to the processes illustrated by scheme that follows:
 


in which R2, R3, R4 and Ar are as defined in the general formula (I) and Hal represents a halogen atom, for example chlorine.

5

In step c of Scheme 2, the compound of formula (V) is prepared from a compound of formula (VIII) by sparging with ammonia gas according to the method described in patent application FR 2 714 378.

10    It is also possible to prepare the same compound via reduction of a compound of formula (X) according to methods known to those skilled in the art, for example by means of zinc in a solvent such as methanol. The preparation of a compound of formula (X) of the step is described in patent application FR 2 714 378.
 

15
 





16

An optically pure compound of formula M may be synthesized according to

steps  d  and  e  of  Scheme  3,  as  described  in  patent  application  WO

03/008 407.


5    The intermediates of general formula (VIII) may be prepared according to the processes described in patent application WO 03/008 407 and illustrated by Scheme 3:
 
The compounds of general formula (XIV) may arso oe preparea oy appllcatron or adaptation of the procedures described in the Journal of Heterocyclic Chemistry, 43(4), 1031-1035; 2006.

5

Thus, the compounds of general formula (XIV) may be prepared by reducing

a compound of formula (XV):
RC(Ar

~    COOAik

R3    h-
R2    N02

(XV}

in which R2, R3, R4 and Ar are as defined in the general formula (I) and Alk

10    represents an alkyl group, for example a methyl, ethyl or butyl group. This reaction is generally performed using iron, in acidic medium, for example using acetic acid.

The compound of general formula (XV) may be obtained by reacting a 15 compound of general formula (XVI):

R~F

R3~
R2    N02

(XVI)

in which R2, R3 and R4 are as defined in the general formula (I), with a compound offormula (XVII):

Ar

lCOOAik
 

(XVII)

in which Ar is as defined in the general formula (I) and Alk represents an alkyl group, for example a methyl, ethyl or butyl group, according to methods known to those skilled in the art and described in the Journal of Heterocyclic Chemistry, 43(4), 1031-1035; 2006, for example in the presence of a base

5    such as t-BuOK or NaH.


The compound of general formula (VII) may be prepared according to one or other of the following methods, illustrated by Scheme 4:

10   Scheme 4:                   
1)  X=-CH<                   
£(R5    (EIO),P(O)CH,CN    v0/R5    Mg    N~/R5   
                   
0        NC           
                   
(XVIlQ        (XIX)        (XX)   
                   
                   

HOOC~R5

(VII)


2)    X=-N<

aR5 Ha~COOA!k    r  RS  w    f  /F   
HN                HOOC'-./N~   
            A!kDOC'-./NJ           
                       
(XXI)        (XXIQ    (VII)   
               
                   
3)X=  -<                   
D~R5+        If\    If\   
0        CNCH2COOH    CN...........-C'---/•!\...!!;...    Hooc...........-c' --.IY-R5   
(XVIII)    (XXIII)    {XXIV)    (VII)   
                       
According to the first embodiment, when X =-CH<, th,.. potJ.•~d5oHW~
(VII) may be prepared by hydrolysis of a compound of    .  Ia p<X):
,_t."    .

(''(R5

NC~

(XX)

5    in which R5 and Yare defined as in the general formula (1), in acidic medium, for example using concentrated hydrochloric acid.

The compound of general formula• (XX) may be prep<jred by reducing a compound of formula (XIX):

('y'R5

NC~


(XIX)
10

in which R5 and Y are defined as in the general formula (1), for example using

magnesium.  This  reaction  is  generally  performed  in  a  solvent  such  as

methanol or ethanol.


15    The compound of general formula (XIX) may be prepared via a Wittig-Horner reaction starting with the compound of general formula (XVIII):


in which R5 and Y are defined as in the general formula (1). Generally, this

reaction is performed using a suitable phosphonate derivative, such as diethyl

(cyanomethyl)phosphonate. The process is advantageously performed in the

presence  of  a  base,  such  as  K2C03,  in  a  solvent  such  as  THF  or

5    dimethoxyethane.


According to the second embodiment, when X = -N<, the compound of formula (VII) may be. prepared from a compound of formula (XXII):






(XXII)

10    in which R5 and Y are defined as in the general formula (I), and Alk represents an alkyl group, for example a methyl, ethyl or butyl group. This reaction is generally performed in acidic medium, for example using concentrated hydrochloric acid.

15    The compound of general formula (XXII) may be prepared by condensation of a compound of general formula (XXI):


in which R5 and Y are defined as in the general formula {I), with a corresponding halo compound, such as Hai"'CH2C00Aik, in which Hal"'

20    represents a halogen atom  such as chlorine and Alk  represents an  alkyl
 
group, such as ethyl. This reaction is advantageously performed in a solvent such as toluene, benzene or dioxane.

-c"""'
According to the third embodiment, when X =    ""- , the compound of

5    formula  (VII)  may  be  prepared  by  hydrolysis  of a  compound  of formula

(XXIV):

1/\
CN--......rC\.._...}Y-R5

(XXIV)

in which R5 and Yare defined as in the general formula (1), in acidic medium, for example using concentrated hydrochloric acid.
10

The compound of general formula (XXIV) may be prepared by reaction starting with the compound of general formula (XVIII):





(XVIII)

in  which  R5  and  Y are  defined  as  in  the general formula  (1),  using  the

15    compound of general formula (XXIII):

NC-CH2COOH    (XXIII)


Generally, this reaction is performed in a solvent such as THF.


20    According to another embodiment, the compounds of general formula (I) in which R1 represents an alkyl group and R2, R3, R4, R5, Ar, X, Y and n are as defined in the general formula (I) may also be prepared according to Scheme 5 below:
 

Scheme 5:
ALK-Hal   R3~MHO
R2

ALK
(XXVl)
(XIIO

l

k    N,
-    R3b)=O


R2 ~ ~ ALK

(XXVIQ

Hal(VI)'-(/Har
ooc~F\

~Y-RS
 
~~~~
Y--r=
 

n    (IIIQ

O}_;;Q-ru

R4    M    0
 
ALK    -------        '-'::    0   
(XXIX)    -----.s3        ..-:;:;       
    y-RS    R2        ~   
Hr., . ,)            ALK   
    \'"/n   {IV)            (I)   


The compound of general formula (XXV) may be prepared by reacting a 5 compound of formula (XIII) with a compound of formula (XIV):

ALK-Hal    (XIV)

in which ALK represents a linear or branched saturated aliphatic group containing from 1 to 6 carbon atoms and Hal represents a halogen atom, for example chlorine, according to methods known to those skilled in the art, for

10    example in the presence of a base such as K2C03, NaH or t-Buo•K+ in a solvent such as DMF, THF, dimethoxyethane or DMSO.
 

The compounds of general formula (XXVIII) may be prepared according to methods analogous to those described previously.

The compounds of general formula (XXVIII) may also be prepared according

5    to Scheme 6 below: Scheme 6:


PG


(XXX)    (XXXI)



RA~H,
R3V-N>=O
R2    ~
ALK

(XXVIII): (+) or (-)

According to this scheme, a compound of formula (V) is reacted with a protecting group PG to give the compound of formula (XXX). Examples of

10    protecting groups PG for the amine that may be used include benzimine and t-butyl carbamate. These protecting groups are introduced according to

methods known to those skilled in the art, for example in the presence of a base such as K2C03, NaOH or triethylamine, in a solvent such as dioxane, THF or DMSO.

15

The compound of general formula (XXXI) may be prepared by reacting a compound of formula (XXX) with a compound of formula (XIV)

ALK-Hal    (XIV)

in  which  ALK  represents  a  linear or  branched  saturated  aliphatic  group

20    containing from 1 to 6 carbon atoms and Hal represents a halogen atom, for example chlorine.
 

methods, for example in acidic medium with HCI or trifluoroacet1c acid.


5    By then working by application of the methods described above for the compounds of general formulae (XIII), (XIV), (X), M. (Ill) and (I) of Schemes 1, 2 and 3, the compounds of general formulae (XXV), (XXVI), (XXVII), (XXVIII), (XXIX) and (I) are obtained.

10    Optionally, the compound of formula (I) is converted into an acid-addition salt thereof.

The process according to the invention may optionally include the step that consists in isolating the desired product of general formula (I).

15

In Schemes 1, 2, 3, 4, 5 and 6, the starting materials and the reagents, when their mode of preparation is not described, are commercially available or described in the literature, or else may be prepared according to methods that are described therein or that are known to those skilled in the art.

20

According to another of its aspects, a subject of the invention is also the compounds of formula (Ill); with the exclusion of 5-chloro-3-(2-chloro-acetamido)-3-(2-chlorophenyl)-1 ,3-dihydroindol-2-one. These compounds are useful as synthetic intermediates for the compounds of formula (I).

25

Among the compounds of formula (Ill) that are subjects of the invention, one group of compounds is constituted by the compounds for which:

Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms
30    and (C 1-6)alkyl, perhalo(C 1-3)alkyl, (C 1-6)alkoxy and aryl groups.
 
According to another of its aspects, a subject of the invention is also the

. compounds of formulae (XXVIII) and (XXIX). These compounds are useful as synthetic intermediates for the compounds of formula (I).

5    The examples that follow describe the preparation of certain compounds in accordance with the invention. These examples are not limiting, and serve

merely to illustrate the present invention. The numbers of the illustrated compounds refer to those given in the table hereinbelow, which illustrates the chemical structures and the physical properties of a few compounds
10    according to the invention.

I
The physicochemical measurements were performed in the following manner:


The melting points were measured using a Buchi B-540 machine.

15

The proton nuclear magnetic resonance CH NMR) spectra were recorded at 500 MHz on a BrOker machine equipped with an Avance Ill console. The chemical shifts are given in ppm relative to the frequency of TMS.

20    All the spectra were recorded at a temperature of 40°C.


The abbreviations used to characterized the signals are as follows:

s = singlet, bs = broad singlet, m = multiplet, d = doublet, t = triplet, q = quartet.
25    * = not integratable due to interference with a broad peak resulting from water.

**= not integratable due to interference with a peak resulting from the NMR solvent.
 


The  HPLC  was

equipped with  an

detector.


5    The analysis conditions by liquid chromatography coupled to mass spectrometry (LC/UV/MS) are as follows:

For the liquid chromatography part, three different chromatographic systems

are used:

10

-    chromatog~aphic system A

-    Eluent A= H20 + 0.005% TFA

-    Eluent B = CH3CN

-    gradient from 95% A to 90% B over 17 minutes, followed by elution with 15 . 90% B for 5 minutes

-flow rate 0.3 ml/minute

-    injection of 2 JJL of solution at 0.1 mg/ml in a 9/1 CH3CN/H20 mixture


-    chromatographic system B

20    - Eluent A= H2 0 + 0.01% TFA

-    Eluent B = CH3CN

-    gradient from 98% A to 95% B over 10 minutes, followed by elution with 95% B for 5 minutes

-flow rate 0.5 ml/minute; temperature 40°C

25    - injection of 2 JJL of solution at 0.1 mg/ml in a 9/1 CH3CN/H20 mixture

-    chromatographic system C

-    Eluent A= H20 + 0.005 M ammonium acetate pH 6.5

-    Eluent B = CH3CN

30    - gradient from 95% A to 90% B over 17 minutes, followed by elution with 90% B for 5 minutes
 


-flow rate 0.3 ml/minute

-    injection of 2 IJL of solution at 0.1 mg/ml in a 9/1 CH3CN/H20 mixture


The columns used are:

5    -Waters XTerra MS C18 2.1 x 50 mm 3.51-Jm column No. 186000400 -Waters XBridge C18 2.1 x 50 mm 2.51-Jm column No. 186003085
-    Phenomenex Gemini C18 2.1 x 100 mm 510 1Jm column No. OOD-4435-BO

-    Waters Sunfire C 18 2.1 x 100 mm 3.5 IJm column No. 186002534.


10    The products are detected by UV at 220 nm.


For the mass spectrometry part:

-ionization mode: positive electrospray (API-ES polarity+) -scanning from 100 to 1200 amu.

15

Thin layer chromatography was performed on silica gel TLC plates from Merck. The silica gel for the flash column chromatography is sold by Biotage.

All the solvents used are of "reagent grade" or "HPLC grade" purity.

20

The aD measurements were carried out on a Perkin Elmer model PE341 polarimeter using a cell with a 1 dm optical path.

In the examples and preparations:

25    AcOH and EtOAc represent, respectively, acetic acid and ethyl acetate. MeOH, EtOH and t-BuOH represent, respectively, methanol, ethanol and tert-butanol.
m.p. means melting point.
 

Preparation 1:

(1-Methylpiperid-4-yl)acetic acid

(i)    ( 1-Methylpiperid-4-ylidene)acetonitrile

9.36    g of K2C03 and 8.89 ml of diethyl (cyanomethyl)phosphonate are placed 5   in 12 ml of THF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen, and the mixture is left to react for 15 minutes at room temperature and then refluxed for 20 minutes. The resulting mixture is allowed to cool and 6.5 ml of 1-methyl-4-piperidone are added dropwise. This mixture is refluxed for 16 hours. The reaction mixture is then poured into

10    water and extracted with ethyl acetate. The organic phase is dried over Na2S04 , filtered and evaporated Linder vacuum. 6.8 go{ oif are obtained.

(ii) ( 1-Methylpiperid-4-yl)acetonitrile

1 g of the product obtained  in the preceding  step is placed  in 70  ml  of

15    methanol in a round-bottomed flask equipped with a magnetic stirrer. At 0°C, 7.2 g of magnesium are added portionwise. The mixture is stirred for 4 hours. It is filtered to remove the solid magnesium particles and the filtration and

liquors are evaporated. The residue is taken up in saturated NaCI solution and extracted with dichloromethane. The organic phase is dried over Na2S04 ,

20    filtered and evaporated under vacuum. 450 mg of oil are obtained. TLC: 9/1 EtOAc/MeOH, Rf =0.2

(iii)    (1-Methylpiperid-4-yl)acetic acid

3.65    g of the product obtained in step (ii) are placed in 47 ml of concentrated

25    hydrochloric acid in a round-bottomed flask equipped with a magnetic stirrer. The mixture is refluxed for 20 hours. The resulting mixture is diluted with water and extracted with dichloromethane to remove the impurities. The aqueous phase is brought to pH 5-6 and extracted with dichloromethane. The aqueous phase is evaporated under vacuum and a white solid is isolated.

30    This solid is taken up in ethanol to separate the product from the salts. The filtration liquors are evaporated to isolate 3.6 g of pale yellow solid.
 






29


TLC: 99/1 MeOH/NH40H, Rf = 0.2


Preparation 2:

(1-Ethylpiperid-4-yl)acetic acid

5    By working as described in Preparation 1, but using 1-ethyl-4-piperidone instead of 1-methyl-4-piperidone, the title compound is obtained.

TLC: 100% MeOH, Rf= 0.15.


Preparation 3:

10    (4-Ethylpiperazin-1-yl)acetic acid

(i) Ethyl (4-ethylpiperazin-1-yl)acetate

8.9 ml of ethylpiperazine are placed in 91.5 ml of toluene in a round-bottomed flask. A solution of 4.1 ml of ethyl bromoacetate in 11.6 ml of toluene is added dropwise. The mixture is refluxed at 11 ooc for one hour, concentrated to a

15    small volume and left in a refrigerator for 3 hours. A white precipitate forms, which is filtered off and washed with dichloromethane. The filtration liquors are evaporated; 7 g of expected product are obtained.

TLC: 1/1 EtOAc/MeOH, Rf = 0.45.


20    (ii) (4-Ethylpiperazin-1-yl)acetic acid

7 g of the product obtained in the preceding step are added to 190 ml of 6N HCI and the mixture is refluxed for 4 hours. It is evaporated to dryness and washed with a 1/1 EtOAc/EtOH mixture, and the white solid obtained is dried. 7 g of expected product are obtained.

25    TLC: 100% MeOH, Rf= 0.2.


Preparation 4:

(4-Methylpiperazin-1-yl)acetic acid

By  working  as  described  in  Preparation  3,  but  using  1-methylpiperazine

30    instead of 1-ethylpiperazine, the title compound is obtained. TLC: 100% MeOH, Rf= 0.25.
 

Preparation 5:

(+)-3-Amino-5,6-dichloro-1 ,3-dihydro-3-(4-chlorophen~

(i) 5,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

5    A) Methyl (4-chlorophenyl)(4,5-dichloro-2-nitrophenyl)acetate

A solution of 5 g of 1 ,2-dichloro-4-fluoro-5-nitrobenzene and 4.4 g of methyl 4-chlorophenylacetate in 70 ml of DMF is added, under a stream of nitrogen, to a suspension at -10°C of 2.85 g of 60% NaH in 45 ml of DMF, and the temperature is maintained at -5°C. The mixture is reacted for 2 hours, while

10    allowing the temperature to return to room temperature. The resulting mixture is poured onto ice, aqueous 10% NH4CI solution is added and the mixture is extracted with ethyl acetate. The organic phase is dried, filtered and concentrated. 30 g of a brown oil are obtained, and are purified on a column with hexane and then with a 95/5 hexane/EtOAc mixture to give 3.18 g of oil.

15

B)    5,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

4.6    g of the product from step A, 60 ml of methanol, 15 ml of AcOH and 2.7 g of iron are placed in a round-bottomed flask equipped with a mechanical stirrer, under a stream of nitrogen, and the mixture is refluxed for 1 hour 30

20    minutes. The resulting mixture is poured onto ice and 10% NaHC03 solution is added to basic pH. Ethyl acetate is added and the mixture is filtered. The organic phase is separated out and dried, filtered and concentrated. A solid is obtained, which is taken up in isopropyl ether and filtered. 2.75 g of a white solid are obtained.

25    m.p.: 214-215°C


(ii)    5,6-dichloro[[( 1R)-2-hydroxy-1-phenylethyl]amino ]-1 ,3-dihydro-3-(4-chloro-phenyl)indol-2-one isomer A and isomer B
A)    3-bromo-5,6-dichloro-1 ,3-dihydro-3-( 4-chlorophenyl)indol-2-one

30    2.75 g of the product from step B above are dissolved in 100 ml of dichloromethane under a stream of nitrogen. The solution is cooled in an ice
 

bath, and a solution of 3.93 g of PhMe3NBr3 in 100 ml of dichloromethane is added dropwise. The mixture is reacted for 3 hours, and the temperature is allowed to return gradually to room temperature. The resulting mixture is washed with 1M hydrochloric acid and water. This mixture is dried, filtered

5    and concentrated. 3.7 g of oil are obtained.


B)    5,6-dichloro[[(1 R)-2-hydroxy-1-phenylethyl]amino]-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one isomer A and isomer B

3.4    g of the compound from the preceding step are mixed with  50 ml of

10    chloroform and 2.9 g of R-phenylglycinol, under a stream of nitrogen. The mixture is reacted for 2 hours at room temperature, 1.6 ml of OJ PEA are then added and the resulting mixture is reacted at room temperature. The solid formed is filtered off, and the filtration liquors are evaporated to dryness and purified on a column, eluting with 7/3 hexane/EtOAc.

15

1.8 g of the less polar product, isomer A (m.p. =79.8-80SC) and 2.2 g of the more polar isomer B (m.p. =213.2°C) are obtained.

(iii) ( +)-3-Amino-5,6-dichloro-1, 3-dihydro-3-( 4-chlorophenyl)indol-2-one

20    1.8 g of the product obtained in the preceding step are reacted in a mixture of 28 ml of dichloromethane and 12 ml of methanol. 1.9 g of Pb(0Ac)4 are added and the mixture is reacted at room temperature for 3 hours. The resulting mixture is evaporated to dryness and the residue is taken up in ethyl

acetate and then  washed  with  saturated  aqueous  NaHC03 solution.  The

25    organic phase is dried, filtered and concentrated. The resulting product is taken up in a mixture of 36 ml of 3N hydrochloric acid and 3.7 ml of methanol,

and  is  stirred  overnight.  This  mixture  is concentrated  and  diluted  with  a

mixture of water and dichloromethane. The organic phase is washed with 1N

hydrochloric acid solution. The aqueous phases are combined,  brought to

30    basic pH with aqueous NH3 solution and extracted with dichloromethane. The
 


organic phase is dried, filtered and concentrated to~~ 540 'rhgof a white solid product.
m.p. =221oC; a 0  =+32.5°, c =0.5 wt% MeOH


5    Preparation 6:

(-}-3-Amino-5,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

By working as described in Preparation 5 (iii), but using the more polar isomer B obtained in Preparation 5 (ii) instead of isomer A of the same preparation, the title compound is obtained.
10    a 0  = -23.6°, c = 0.35 wt% MeOH.


Preparation 7:

3-Amino-4,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

(i) 4,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl}indol-2-one 15 a) 4-chloro-0-acylmandelic chloride

10 g of 4-chloro-dl-mandelic acid, 88 ml of dichloromethane and 4.2 ml of acetyl chloride are placed in a two-necked round-bottomed flask equipped with a magnetic stirrer. The mixture is reacted at sooc for 3 hours. 7.8 ml of thionyl chloride are then added. The mixture is reacted at reflux for 2 hours.

20    The resulting mixture is evaporated under vacuum to give 13.7 g of an opaque liquid.

b)    4-chloro-N-3,5-phenylmandelamide

4.4    g of 3,5-dichloroaniline and 50 ml of toluene are  placed  in a three-

25    necked round-bottomed flask equipped with a mechanical stirrer, and under a stream of nitrogen. The solution is cooled to 0°C. 9.6 g of potassium

carbonate are then added. 6.8 g of the product obtained in the preceding step diluted in 10 ml of toluene are added slowly. The mixture is reacted at room temperature for one hour,  and 4.15 ml of methanol are then  added.  The 30    mixture is reacted at 80oC for 2 hours, followed by addition of 1 N hydrochloric
 
acid solution, and the resulting mixture is extracted with ethyl acetate. The organic phase is evaporated under vacuum. 5. 7 g of solid are obtained.

c) 4,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

5    22 ml of 96% sulfuric acid and 5 ml of fuming sulfuric acid are placed in a round-bottomed flask equipped with a magnetic stirrer. The mixture is cooled in an ice bath, and 5.7 g of the product obtained in the preceding step are added portionwise. The mixture is then left to react at room temperature for 4 hours. The reaction is poured into a bath of ice and brought to basic pH with

10    NaHC03 solution and then with concentrated sodium hydroxide solution. The resulting mixture is extracted with dichloromethane, and the organic phase is separated out, dried over Na2S04, filtered and evaporated under vacuum to give 7.5 g of a solid, which is taken up in ethyl ether. This mixture is filtered to give 4.2 g of powder.

15

(ii)    3-Azido-4,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

A)    3-bromo-4,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one This product is obtained by working as described in point (ii) of Preparation 5, but using the compound obtained in the preceding step.

20

B) 3-azido-4,6-dichloro-1, 3-dihydro-3-( 4-chlorophenyl)indol-2-one

550 mg of the compound obtained in the preceding step, 17 ml of acetonitrile and 270 mg of NaN3 are placed in a three-necked round-bottomed flask equipped with a mechanical stirrer, and under a stream of nitrogen. The

25    mixture is refluxed for 2 hours and then taken up in ethyl acetate and washed with saturated sodium chloride solution. The organic phase is separated out, dried over Na2S04, filtered and evaporated under vacuum to give 320 mg of a resin, which is purified by flash chromatography, eluting with 85/15

cyclohexane/ethyl acetate. The phase containing the product is evaporated to

30    give 220 mg of a white solid.
 

(iii) 3-Amino-4,6-dichloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one

220 mg of the product obtained in the preceding step, 5 ml of THF, 10 ml of methanol, 170 mg of NH4CI and 80 mg of zinc are placed in a two-necked round-bottomed flask equipped with a mechanical stirrer. The mixture is

5    reacted at room temperature for 3 hours. The resulting mixture is filtered and the residue is evaporated under vacuum. The resulting residue is taken up in ethyl acetate and washed with saturated sodium chloride solution. The organic phase is separated out, dried over Na2S04, filtered and evaporated under vacuum. 200 mg of oil are obtained, which product is purified by flash

10    chromatography, eluting with 8/2 cyclohexane/ethyl acetate. 74 mg of eKpected product are obtained.

TLC: 6/4 cyclohexane/EtOAc, Rf = 0.3


Preparation 8:

15    (+)-3-Amino-4,6-dichloro-1 ,3-dihydro-3-(4-trifluoromethylphenyl)indol-2-one

(i) 3-Hydroxy-4, 6-d ich loro-1 ,3-d i hyd ro-3-( 4-trifluoromethylphenyl)i ndol-2 -one

1.8 g of Grignard magnesium are placed in 19 ml of anhydrous ethyl ether in

a round-bottomed  flask equipped with a mechanical stirrer,  and  under a

20    stream of nitrogen. A mixture of 8.9 ml of 4-bromotrifluoromethylbenzene in 46 ml of anhydrous ethyl ether is then added. The mixture is stirred for one hour, followed by addition of a solution of 5.7 g of 4,6-dichloro-1 H-indole-2,3-

dione in 100 ml of anhydrous THF. The mixture is stirred at room temperature for 4 hours 30 minutes. Water is added and the resulting mixture is extracted

25    with ethyl acetate. The organic phase is separated out and dried over Na2S04, filtered and evaporated under vacuum. The residue is taken up in ethyl acetate and washed with 1N sodium hydroxide solution. The organic phase is dried over Na2 S04, filtered and evaporated under vacuum. The solid is taken up in ethyl ether and filtered off. 4.7 g of expected product are

30    obtained.
 

(ii)    3, 5,6-trichloro-1 ,3-dihyd ro-3-(4-trifh..ioromethylphe~

1.2    g of the product from the preceding step are placed in 8 ml of dichloromethane in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. 0.47 rill of pyridine and a mixture of 0.34 ml

5    of SOCb in 4 ml of dichloromethane are added, at 0°C. The mixture is reacted at room temperature and then poured into saturated aqueous NH4CI solution. The organic phase is separated out and dried over Na2S04 , filtered and evaporated under vacuum.

TLC: 1/1 hexane/EtOAc, Rf = 0.85

10

(iii) 4,6-di~hloro[[(1 S)-2-hydroxy-1-phenylethyl]amino]-1 ,3-dihydro-3-(4-trifluoromethylphenyl)indol-2-one isomer A and isomer B

By working as described in step (ii) A and B of Preparation 5, but using the compound from the preceding step and (S)-phenylglycinol instead of (R)-

15    phenylglycinol, the title compounds are obtained.

TLC: 4/6 EtOAc/cyclohexane, Rf = 0.5 (isomer A), Rf = 0.2 (isomer B)


(iv)    (+)-3-Amino-5,6-dichloro-1 ,3-dihydro-3-(4-trifluoromethylphenyl)indol-2-

one

20    This  compound  is  obtained  by  working  as  described  in  step  (ii)  B  of

Preparation 5.

a0  =+60°, c =0.25 wt% in MeOH


Preparation 9:

25    3-Am ino-1 ,5-dimethyl-6-chloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one
(i)    6-Chloro-3-(4-chlorophenyl)-3-hydroxy-1 ,5-dimethyl-1 ,3-d ihydroindol-2-one This compound is prepared from 3-hydroxy-5-methyl-6-chloro-1 ,3-dihydro-3-(4-chlorophenyl)indol-2-one (compound obtained according to the process
30    described in point (i) of Preparation 8), and 1.2 g thereof are dissolved in 8 ml of DMF. 167 mg of 60% NaH are added at 0°C, under a stream of nitrogen.

260 !JI of CH3 1 are then added and the mixture is reacted for 30 minutes. The resulting mixture is poured into water and extracted with dichloromethane. The organic phase is dried, filtered and concentrated. The product is purified on a column, eluting with 9/1 hexane/EtOAc.

5    TLC: 1/1 EtOAc/hexane, Rf = 0.7


(ii) 6-Chloro-3-(4-chlorophenyl)-1,5-dimethyl-1,3-dihydroindol-2-one

1 g of the product obtained from the preceding step is mixed with 4 ml of TFA and 1.3 ml of HSiEh. and the mixture is reacted for one hour at 80°C. The

10    resulting mixture is poured into water and brought to basic pH with aqueous NH3 solution._This mixture is extracteg with ethyl acetate. The organic phase is dried, filtered and concentrated. The residue is taken up in ethyl ether and filtered. 688 mg of a white solid are obtained.

TLC: 4/6 EtOAc/hexane, Rf = 0.7

15

(iii) 3-Amino-1,5-dimethyl-6-chloro-1, 3-dihydro-3-( 4-chlorophenyl)indol-2-one by working as described in Preparation 7 in points (ii) and (iii}, but using the product from the preceding step instead of the product obtained in step (i} of Preparation 7, the title compound is obtained.

20    TLC: 1/1 EtOAc/hexane, Rf = 0.5


Preparation 10:

(1-Ethyl-1 ,2,3,6-tetrahydropyrid-4-yl)acetic acid

(i)    ( 1-ethyl-1, 2, 3,6-tetrahydropyrid-4-yl)acetonitrile

25    2.9 g of 1-ethyl-4-piperidone, 3.3 g of cyanoacetic acid and 36 ml of toluene are placed in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. The mixture is refluxed for 4 hours, while removing the water using Markusson apparatus. The solvent is evaporated off under vacuum. 4.2 g of oil are obtained.

30
 

(ii) (1-Ethyl-1 ,2,3,6-tetrahydropyrid-4-yl)acetic acid

By working as described in Preparation 1 (iii), but using the product from the preceding step instead of the product of Preparation 1 (ii), the title compound is obtained.
5    TLC: 99/1 MeOH/NH40H, Rf = 0.2

1 H NMR: 8 (ppm, DMSO-d6): 1.09 (t, J = 7.2 Hz, 3H), 2.18 (m, 2H), 2.62 (q, J = 7.2 Hz, 2H), 2.68-2.76 (m, 2H), 2.92 (s, 2H), 3.11 (bs, 2H), 5.49 (m, 1 H).

Preparation 53:

10    (+)-3-amino-1-isopropyl-4,6-dichloro-1 ,3-dihydro-3-(3,4-dichlorophenyl)-
indol-2-one    .   
       
(i) (+ )-3-am ino-4 ,6-d ich loro-1 ,3-d ihyd ro-3-(3 ,4-d ichlorophenyl)indol-2 -one

The compound is obtained by working as described in Preparation 5, but using in step (i) 3,4-dichlorobromobenzene instead of 4-bromotrifluoromethyl-

15    benzene.


(ii)    (+)-3-benzimino-4 ,6-dichloro-1 ,3-dihyd ro-3-(3 ,4-dichlorophenyl)indol-2-one 215 mg of the product obtained in the preceding step and 120 IJI of
benzaldehyde are placed in a round-bottomed flask. The mixture is heated at

20    100°C for 5 minutes in a microwave reactor. A solid is obtained, which is dried under vacuum to remove the benzaldehyde.

(iii)    (+) -3-benzimino-1-isopropyl-4, 6-d ich loro-1 ,3-d ihyd ro-3-(3 ,4-d ich loro-

phenyl)indol-2-one

25    144 mg of the product obtained in the preceding step are placed in DMF (BOO IJI) in the presence of K2C03 (49 mg) and isopropyl bromide (30 IJI) in a round-bottomed flask. The mixture is heated at 140°C for 5 minutes in a microwave reactor. The resulting mixture is filtered and the crude product is used for the following step.

30


(iv)    (+)-3-amino-1-isopropyl-4,6-dichloro-1,3-dihydr~

indol-2-one

The product obtained in the preceding step (157 mg) is dissolved in methanol

(550 iJI} and 2.7 ml of a 3N HCI solution are added. After 5 hours at room

5    temperature, the mixture is neutralized with aqueous ammonia and extracted with ethyl acetate. The extracts are dried and evaporated. A semisolid product (112 mg) is obtained.

The following intermediates of general formula (V) in which R1, R2, R3, R4

10    and Ar are as defined in Table 1 were also prepared via the methods used for Preparations 5, 6, 7, 8 and 9.

Table  1 that follows  illustrates  the  chemical  structures  and  the  physical

properties of a few preparations according to the invention. In this table:

15    - in the "isomer" column, "rae" represents a racemic mixture, and (+} or (-) represents one or other of the stereo isomers,

-    Me, Et, n-Pr, i-Pr, n-Bu and i-Bu represent, respectively, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl groups, and

-    Ph and Bn represent, respectively, phenyl and benzyl groups.
 


    Preparation    Ar    R2    R3    R4    Isomer    Analyses   
                               
    70    ~    6-CI    H    4CI    rae    (M+H) ::363   
        a-r.                           
    71    ~    6~CI    H    H    (+}    (M+H) =313   
        a-r.                           
                                   
                                   
    72    ~    ~cr    H    4Cl    (+)    (M+H)    = 361   
                                   
    73    -(}-a    5-Br    H    H    (+}    (M+Ht=337   
                                   
    74    ~    6-Br    H    H    (+)    (M-NH3} =356   
                               
                                   
        %                           
                                   
                                   
                                   
    75    -ro    6-CI    H    4Cl    (+)    7/3 dichloromethane/   
                            EtOAc, Rf=0.85   
    76    -ro    6-CI    H    4CI    (+)    a.D=+81",   
                            c=0.11 in MeOH   
    77    -<=0    ~CI    H    4C!-    (-)    a.D=-82",   
                            c=0.10 in MeOH   
    --                        -    --------   
 

1 Preparation            Ar    R2    R3    R4    Isomer        Analyses           
                                                                               
    78            -{\a    6-CI    H    4CI    (+)        a.D:+154•,           
    I                                c=0.25 in MeOH           
!                                               
                                                                           
        79            --0-a    6~CI    H    4CI    (-)        a.D=-216•,           
                                                               
                                            c=0.25 in MeOH           
                                                       
                                                                               
                                                                           
        80            -Q    6-CI    H    4Cl    (-)        a.D=-116°,           
                                                       
                                            c=0.1 0 in MaOH           
                    a    a                                           
                                                                           
        81            -ctt0\    6-CI    H    H    (+)        (M+H)  = 327           
                                                       
                                                       
                                                               
                                                               
        82            ~(F.3    6-Cl    H    H    (+)        (M-NH3) = 326           
                                                               
                                                               
                                                               
                                                                           
                                                                               
        83            ~(F.3    6-Br    H    H    (+)        (M+H) = 385   ff"           
                                            "-:\._ ''1           
                                                       
                                                    ~~•-\l   
                                                    Z'•'•   
                                                       
                                                                    •!':'/   
                                                                           
    84        ~    6-CI    H    H    rae        (M+Hr=274j    Iii? i  ,       
        --- --                            ---------            lli__   
                                                   




-1>-

(X)
 

Example 1:

(+)-N-[5,6-Dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-

(4-methylpiperazin-1-yl)acetamide

5    (i) 2-Chloro-N-[5,6-dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]acetamide:

1.3 g of the product obtained in Preparation 5, 47 ml of toluene, 0.32 ml of pyridine and 0.31 ml of chloroacetyl chloride are placed in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. The

10    mixture is left to react at 11 ooc for 4 hours, and the reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is dried over Na2S04, filtered and evaporated under vacuum. 900 mg of a beige solid

are obtained, which product is purified on a column by flash chromatography using an 8/2 cyclohexane/ethyl acetate mixture, to obtain 400 mg of the

15    expected product.

TLC: 1/1 hexane/EtOAc, Rf"'0.5


(ii) (+)-N-[5,6-Dichloro-3-(4-chlorophenyl)-2-oxo-2 ,3-dihydro-1 H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide:

20    0.4 g of the product from the preceding step, 0.11 ml of N-methylpiperazine (d 0.903), 0.14 g of potassium carbonate and 0.07 g of sodium iodide in 8 ml of DMF are placed in a round-bottomed flask equipped with a magnetic stirrer. The reaction mixture is left to react at 60°C for 4 hours, and is then poured into water and extracted with ethyl acetate. The organic phase is dried

25    over Na2S04, filtered and evaporated under vacuum. 240 mg of oil are obtained, which product is taken up in ethyl ether to give 140 mg of white solid. The filtration liquors are purified by flash chromatography, eluting with 9/1 ethyl acetate/methanol and then 7/3 ethyl acetate/methanol, so as to isolate 40 mg of white solid.

30    m.p. "'207.1-207.6°C;[a.o] = +141°C, c = 0.25 wt% MeOH; 1H NMR 8 (ppm, DMSO-d6): 2.37 (bs, 3H), 2.50-2.74 (m,**), 2.94-3.16 (m, 2H), 7.08 (s, 1H),
 





wo 2009/056707    50

7.31 (m, 2H), 7.48 (m, 2H), 7.52 (s, 1H), 8.71 (s, ~.(10.7Cl'j, ~F&, tt:!-MS (M+Ht = m/Z 467 amu

Example 2:

5    (+)-N-[4,6-Dichloro-3-(4-trifluoromethylphenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(1-ethylpiperid-4-yl)acetamide

1)    172.84 mg of PCis are added to 4.4 ml of anhydrous dichloromethane cooled in an ice bath, under a stream of nitrogen, followed by slow addition of

142.13    mg of the acid of Preparation 2. The reaction mixture is left to react at

10    ooc for 10 minutes and then at room temperature for 3 hours.

2)    Separately, 100 mg of the product of Preparation 8 are suspended, under a

stream of nitrogen, in 4.4 ml of dichloromethane, followed by addition of 0.1 ml of pyridine. This mixture is cooled in an ice bath. The solution prepared in 1) is added dropwise and stirred at room temperature for one hour.

15    The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with saturated NaHC03 solution, dried over Na2S04, filtered and evaporated under vacuum. 145 mg of an orange-coloured solid are obtained, which product is purified on a column by flash

chromatography, eluting with  1/1  ethyl acetate/methanol to give 85 mg of

20    product, which is taken up in isopropyl ether to give 75 mg of white/pink solid

product.

m.p. = 158-162°C; [a0 ]  = +194°, c = 0.125 wt% in MeOH; 1H NMR: 8 (ppm,

DMSO-d6): 0.97 (t, J = 7.1 Hz, 3H), 1.07-1.23 (m, 2H), 1.47-1.67 (m, 3H), 1.71-1.85 (m, 2H), 2.07-2.22 (m, 2H), 2.27 (q, J =7.1 Hz, 2H), 2.78 {m, 2H),

25    6.90 {bs, 1H), 7.18 (bs, 1H), 7.47 (m, 2H), 7.78 {m, 2H), 9.15 {s, 1H), 10.74 (bs, 1H); LCMS: (M+Ht = m/z 514 amu
 





51


Example 3:

N-[4,6-Dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydrcJt.\tM..J.ndol-3-vll-2-(4-

methylpiperazin-1-yl)acetamide

By  working  as  described  in  Example  2,  but  using  the  compound  of

5    Preparation 4 instead of the compound of Preparation 2, and the compound of Preparation 7 instead of the compound of Preparation 5, the title compound

is obtained.

m.p. =248-251°C; LC MS: (M+Ht =m/z 467 amu; 1H NMR: 8 (ppm, DMSO-

d6): 2.16 (s, 3H), 2.24-2.42 (m, 4H), 2.43-2.57 (m, **), 2.98~3.12 (m, 2H), 6.92

10    (d, J = 1.8 Hz, 1H), 7.18 (d, J =1.8 Hz, 1H), 7.26 (m, 2H), 7.50 (m, 2H), 8.70 (s, 1H), 10.78 (s, 1H).

Example 4:

N-[4-Trifluoromethyl-6-cyano-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-

15    indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide

By working as described in Example 1, but using the product of Preparation 28 instead of the product of Preparation 5, and N-ethylpiperazine instead of N-methylpiperazine, the title compound is obtained.

m.p. = 260-262°C; LCMS: (M+Ht = m/z 506 amu; 1H NMR: 8 (ppm, DMS0-

20    d6): 0.98 (t, J = 7.3 Hz, 3H), 2.23-2.42 {m, 6H), 2.42-2.61 (m, **), 2.87-3.17 (m, 2H), 7.14 (m, 2H), 7.47 (m, 2H), 7.59 (bs, 1H), 7.91 (bs, 1H), 8.91 {s, 1H), 11.12 (bs, 1H).

Example 5:

25    (+)-N-[1-Benzoyl-5,6-dich loro-3-( 4-ch lorophenyl)-2-oxo-2,3-dihyd ro-1 H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide

0.14 g of the compound of Example 1 is placed in 9 ml of DMF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. 0.01 g of 60% NaH is added, at 0°C. PhCOCI is then added

30    dropwise and the mixture is left to react at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The
 






52


organic phase is dried over NazS04, filtered and evaporated under vacuum. 120 mg of oil are obtained, which product is purified on a column by flash chromatography, eluting with 95/5 ethyl acetate/methanol, to isolate 20 mg of white solid.

5    m.p. =92-94•c; 1H NMR: 8 (ppm, DMSO-d6): 2.16 (s, 3H), 2,24-2.40 (m, 4H), 2.40-2.50 (m, **), 2.94-3.16 (m, 2H), 7.30 (m, 2H), 7.45 (m, 2H), 7.54 (m, 2H), 7.58-7.66 (m, 3H), 7.74 (s, 1H), 8.00 (s, 1H), 9.14 (s, 1H); LCMS: (M+Ht = m/z 571 amu.

10.    Example 6:

~- . 3-(4-Chlorophenyl)-3-[2-(4-ethylpiperazin-1-yl)acetylamino]-2-oxo-4-

trifluoromethyl-2,3-dihydro-1 H-indole-6-carboxamide

0.16 g of the product obtained in Example 4, 0.47 g of potassium hydroxide and 7 ml of t-BuOH are placed in a round-bottomed flask equipped with a

15    magnetic stirrer. The mixture is left to react at so•cfor 5 hours. The resulting mixture is filtered through Celite and washed with THF. The filtrate is

evaporated under vacuum and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over Na2S04, filtered and evaporated under vacuum. 100 mg of an oil are obtained, which oil is purified

20    by flash chromatography, eluting with 8/2 ethyl acetate/methanol. 10 mg of white solid are isolated.
1H NMR: 8 (ppm, DMSO-d6): 0.99 (t, J = 7.2 Hz, 3H), 2.25-2.42 (m, 6H), 2.42-

2.62    (m, **), 2.92-3.16 (m, 2H), 7.12 (m, 2H), 7.47 (m, 2H), 7.55 (bs, 1H),

7.64    (bs,  1H), 7.84 (bs,  1H), 8.24 (bs,  1H), 8.75 (s,  1H), 10.95 (bs,  1H);

25    LCMS: (M+Ht = m/z 571 amu.


Example7:

N-[6-Chloro-3-(4-chlorophenyl)-1 ,5-dimethyl-2-oxo-2,3-dihydro-1 H-indol-

3-yl]-2-(4-methylpiperazin-1-yl)acetamide

30    By working as described in Example 1, but using the product of Preparation 9 instead of the product of Preparation 5, the title compound is obtained.
 






53

m.p. =217-219"C; 1H NMR: 8 (ppm, DMSO-d6): 2.26-2.35 (m, 6H), 2.44-2.64 (m, **), 2.89-3.15 (m, 5H), 7.19 (s, 1H), 7.25-7.33 (m, 33H), 7.46 (m, 2H), 8. 71 (bs, 1H). LCMS: (M+Ht =m/z 461 amu.

5    Example 8: {+)-N-[4,6-Dichloro-3-{4-trifluoromethylphenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-{1-ethyl-1 ,2,3,6-tetrahydropyrid-4-yl)acetamide

By working as described in Example 2, but using the product of Preparation 10 instead of the product of Preparation 2, the title compound is obtained.
10    m.p. = 155-156"C; 1H NMR: 8 (ppm, DMSO-d6): 1.03 (t, J = 7.2 Hz, 3H), 2.06 (m, 2H), 2.~1.:2.65 (m, **), 2.80-3.05 (m, 4H), 5.46 (bs, 1H), 6.91 (d, J =

1.7    Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.49 (m, 2H), 7.79 (m, 2H), 9.3 (s, 1H),

10.8    (s, 1 H).

LCMS: (M+Ht = m/z 459 amu

15   
    Table 2 below illustrates the chemical structures and the physical properties
    of a few examples of compounds according to the invention. In this table:
    -in the "stereoisomer''column, "rae" represents a racemic mixture, and (+) or
    (-) represents one or other of the stereoisomers,
20    - in the "salt" column, "-" represents a compound in free base form, whereas
    "HCI"  represents  a  compound  in  hydrochloride  form  and  the  ratio  in
    parentheses is the (acid: base) ratio,
    - Me, Et, n-Pr, i-Pr, n-Bu and i-Bu represent,  respectively, methyl, ethyl, n-
    propyl, isopropyl, n-butyl and isobutyl groups, and
25    - Ph and Bn represents, respectively, phenyl and benzyl groups.
 


Example 53:

1H NMR: 8 (ppm, DMSO-d6): 0.86-1.15 (m; 3H); 2.52-2.78 (m; **); 3.02-3.19 (m; *); 6.93 (d; J= 1.5 Hz; 1H); 7.06 (dd; Ja= 8Hz; Jb= 2Hz; 1H); 7.21 (d; J= 1.5 Hz; 1 H); 7.56 (d; J= 2 Hz; 1H); 7.67 (d; J= 8Hz; 1 H); 8.96 (bs; 1 H); 10.88

5    (s; 1H).


Example 61:

1H NMR: 8 (ppm, DMSO-d6): 1.08-1.37 (m; 3H); 2.55-3.50 (m; **; *); 6.94 (d; J= 2 Hz; 1 H); 6.98 (dd; Ja= 8 Hz; Jb= 2 Hz; 1H); 7.21 (d; J= 2 Hz; 1 H); 7.33

10    (dd; Ja= 10 Hz; Jb= 2 Hz; 1H); 7.63 (m; 1H); 8.99 (s; 1H); 9.83 (bs; 1H); 10.88 (ey; 1H).

Example 65:

1H NMR: 8 (ppm, DMSO-d6): 1.14-1.28 (m; 3H}; 2.55-2.80 (m; 2H); 2.80-3.74

15    (m; *); 6.96 (d; J= 2 Hz; 1 H); 7.24 (d; J= 2 Hz; 1 H); 7.36 (dd; Ja= 8 Hz; Jb= 2 Hz; 1 H); 7.75 (d; J= 8 Hz; 1 H); 7.84 (d; J= 2 Hz; 1H); 9.27 (s; 1 H); 9.90 (bs; 1H); 10.96 (s; 1 H).

Example 72:

20 1H NMR: 8 (ppm, DMSO-d6): 0.96-1.14 (m; 6H}; 1.14-1.46 (m; 4H); 1.49-1.63 (m; 1 H); 1.63-1.83 (m; 2 H); 2.16 (dd; Ja= 13Hz; Jb= 7 Hz; 1 H); 2.23 (dd; Ja= 13Hz; Jb= 7Hz; 1 H); 2.55 (s; 3H); 2.81-3.12 (m; 2H); 3.65 (m-->q; J= 7 Hz; 2H); 7.08-7.19 (m; 2H); 7.22 (d; J= 1.8 Hz; 1H); 7.30 (d; J= 1.8 Hz; 1 H); 7.57 (d; J= 2 Hz; 1H); 7.86 (d; J= 9 Hz; 1H); 9.16 (s; 1H).

25

Example 75:

1H NMR: 8 (ppm, DMSO-d6): 0.98 (t; J= 7 Hz; 3H); 2.29 (m-->q; J= 7 Hz; 2H); 2.33-2.41 (m; 4H); 2.44 (s; 3H); 2.52-2.63 (m; **); 3.01 (d; J= 15Hz; 1H); 3.07 (d; J= 15 Hz; 1H); 6.61 (s; 1 H); 6.91 (d; J= 2 Hz; 1 H); 7.11 (dd; Ja= 8 Hz; Jb=

30    2Hz; 1H); 7.18 (d; J= 2Hz; 1H); 7.37 (d; J= 2Hz; 1H); 7.52 (d; J= 8Hz; 1H); 8.60 (s; 1H); 10.69 (bs; 1H).
 

Example 79:

1H NMR: 8 (ppm, DMSO-d6): 0.98 (t; J= 7 Hz; 3H); 2.30 (m-.q; J= 7 Hz; 2 H); 2.33-2.58 (m; **); 3.02 (d; J= 15 Hz; 1H); 3.08 (d; J= 15 Hz; 1 H); 6.92 (d; J=

5    1.6 Hz; 1H); 7.20 (d; J= 1.6 Hz; 1H); 7.33-7.41 (m; 2H); 7.41-7.47 (m; 2H); 8.78 (bs; 1H); 10.79 (bs; 1H).

Example 91:

1H NMR: 8 (ppm, DMSO-d6): 0.99 (t; J= 7 Hz; 3H); 1.07 (t; J= 7 Hz; 3H); 1.12-

10    1.29 (m; 2H); 1.47-1.57 (m; 1H); 1.57-1.72 (m; 2H); 1.81-1.98 (m; 2H); 2.12 (dd;-Ja= 13 Hz; Jb= 7 Hz;,1 rf);. 2.22 (dd; Ja= 13 Hz; Jb= 7 Hz; 1H); 2.26-2.40 (m; 2 H); 2.55 (s; 3H); 2.76-2.91 (m; 2H); 3.64 (m-.q; J= 7Hz; 2H); 7.07-7.18 (m; 2H); 7.22 (bs; 1H); 7.29 (bs; 1H); 7.57 (bs; 1H); 7.83 (d; J= 9 Hz; 1H); 9.13 (bs; 1H).

15

The compounds according to the invention underwent in vivo studies.


in vivo test

Male Crl CD BR rats (Charles River, Italy) weighing 150-175 g were housed

20    in a chamber at regulated temperature (22±1.C) and humidity (55±10%) and with a 12-hour lightness-darkness cycle, for at least 7 days before their use. Feed and water were available ad libitum. The feed was removed 18 hours before sacrificing the animals. The rats were sacrificed by cervical dislocation,

and the stomach was removed surgically, opened along the shorter curvature

25    and placed in a Krebs solution (of composition (mM): 118.4 NaCI; 4.7 KCI; 2.5 CaCb; 3.7 NaHzP04; 1.2 MgS04; 25 NaHC03; 5.6 glucose). The animals were cared for and sacrificed according to the Sanofi-Aventis international

code  of  ethics  and  the  international  principles  governing  the  care  and

treatment  of  laboratory  animals  (EEC  Directive  86/609,  DJL358,  1,

30    12 December 1987). Strips of approximately 1 em (5 mm wide) of gastric fundus were cut out along the longitudinal axis and suspended in 20 ml of
 





73


bath filled with the Krebs solution at 3JOC and aerated ~% <h5% C. 0. 2 gas mixture. The strips were maintained at a resting loa~~.J..:. ~ft~r.

washing, 10 !JM of choline (acetylcholine precursor) and 10 1-1M of indomethacin (prostaglandin synthetase inhibitor) were added to the medium,
5    to reduce the spontaneous phasic contractions (Depoortere et al., Eur. J. Pharmacal. 515, 1-3, 160-168, 2003; Dass et al., Neurosciences 120, 443-453, 2003). Isotonic contractions were initiated by stimulation with an electric field. Two platinum wire electrodes were placed at the surface and at the

bottom of the organ bath, and the electric-field stimulation was performed with

10    a Power Lab stimulator (AD Instruments Pty Ltd, Castle Hill, Australia) coupled to a multiplex-pulse propeller (Ugo Basile, Varese, Italy) (Fukuda et
(

al., Scand. J. Gastroenterol. 12, 1209-1214, 2004). The supramaximal stimulation was applied to create maximum contractions (20 Hz, pulse width: 2 milliseconds; 5 volts; batch trains every 2 minutes, 150 mA). Next, the

15    current was reduced to obtain a submaximal stimulation (50% reduction of the maximum contractile response). The contractions were recorded by computer with a data recording and analysis system (Power Lab, Chart 5) connected to isotonic transducers (Ugo Basile, Varese, Italy) via preamplifiers (Octal Bridge

Amp).  After  stabilization,  concentration-response  cumulative  curves  for

20    ghrelin (0.1 nM-1 !JM} were plotted, with and without incubation (contact time: 30 minutes) of the antagonist molecules. Supramaximal electric-field stimulation was used for each strip as reference (100%) to classify the

responses per test substance. The agonist concentration producing 50% of

the maximum effect (ECso) was calculated  using a four-parameter logistic

25    model according to Ratkovsky and Reedy (Biometrics, 42, 575-582, 1986), with adjustment by non-linear regression using the Levenberg-Marquard algorithm in the Everstat software. The pKb values for the antagonists were

calculated    according  to  the  Cheng-Prusoff  equation  (Kenakin  et  al.,

Competitive    Antagonism,   Pharmacologic   Analysis   of   Drug-Receptor

30    Interaction, 3rd edition, 331-373, Philadelphia, New York; Raven: Lippincott, 1997).
 





74



The compounds of formula (I) show antagonist activity towards the ghrelin receptor with IC5o values ranging from 10-6 to 10-11 M.

5    For example, compounds 1 and 2 have an IC5o value of 5x10-8 M and 1X 1o-9 M'respectively.

It is thus seen that the compounds according to the invention have antagonist activity towards the ghrelin receptor.

10

The  compounds  according  to  the  invention  may  thus  be  used  for  the
' . preparation of medicaments, in particular medicaments for preventing or

treating any pathology in which the ghrelin receptor is involved.


15    Thus, according to another of its aspects, a subject of the invention is medicaments comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.

Thus, the compounds according to the invention may be used, for man and

20    animals, in the treatment or prevention of various ghrelin-dependent complaints. Thus, the compounds according to the invention may be used as anorexic agents, for regulating the appetite, the taking of meals and their frequency, and also, in the long-term, the weight, especially weight gain following diets or therapeutic regimens. The compounds according to the

25    invention are thus particularly useful for preventing or treating obesity, appetite disorders, diabetes, excess weight and/or the effects thereof.

According  to  another  of  its  aspects,  the  present  invention  relates  to

pharmaceutical compositions  comprising,  as  active  principle,  a compound

30    according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a
 


pharmaceutically acceptable salt thereof, ~'it P.!§o at least ..®IJ pharmaceutically acceptable excipient.

The said excipients are chosen, according to the pharmaceutical form and the

5    desired mode of administration, from the usual excipients known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local,

1 0 intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or the salt thereof, may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to animals and human beings, for the prophylaxis or treatment of the above disorders or diseases.

15

The appropriate unit administration forms include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, topical,

20    transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to. the invention may be used in creams, gels, ointments or lotions.

25    By way for example, a unit administration form of a compound according to
    the invention in tablet form may comprise the following components:
    Compound according to the invention    50.0 mg
    Mannitol    223.75 mg
    Sodium crosscarmellose    6.0 mg
30    Corn starch    15.0 mg
    Hyd roxypropylmethylcell ulose    2.25 mg
 





wo 2009/056707    76    PCT/FR2008/001190
Magnesium stearate        3.0mg


Via the oral route, the dose of active principle administered per day may be from 0.1 to 100 mg/kg in one or more dosage intakes. Via the parenteral

5    route, it may be from 0.01 to 10 mg/kg/day


There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention.

According to the usual practice, the dosage that is appropriate to each patient

10    is determined by the practitioner according to the mode of administration, and the weight and response of the said patient.

Possible combinations

The  present  invention  also  relates  to  combinations  of  one  or  more

15    compound(s) according to the invention of general formula (I) with one or more active ingredient(s).

As active ingredient(s) that is (are) suitable for the said combinations, mention

may be made especially of anti-obesity and  antidiabetic agents,  and  also

20    rimonabant, metformin or sulfonylureas.


According to another of its aspects, the present invention also relates to a

method for treating the  pathologies indicated above, which  comprises the

administration to a patient of an effective dose of a compound according to

25    the invention, or of a pharmaceutically acceptable salt thereof.


According to another of its aspects, the present invention also relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, for treating the pathologies indicated above.
 





77


CLAIMS


1.    Compound corresponding to formula (1):

0y - R5
H_(x~
Rt0=4Ar 0 n
R3    O
././    N
R2    \
    R1

(I)

5    in which:

represents a single or double bond,

-;::::::-

X represents ...:N<, -CH< or-~ ;

Y represents >N- or >CH-, it being understood that at least one from among X andY represents N;

10    Ar represents an aryl or heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, (C1.:6)haloalkyl, perhalo(C 1-3)alkyl, (C 1-6)alkoxy, perhalo(C 1-3)alkoxy and aryl groups;

R1  represents  a  hydrogen  atom  or  a  (C1-6)alkyl,  -C(=O)(C1-6)alkyl  or

15    -C(=O)aryl group;

R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen

atom, a halogen atom, CN, OH, a (C1-6)alkyl group optionally substituted with a halogen  atom  or an  OH;  perhalo(C1-3)alkyl,  (C1-6)alkoxy,  perhalo(C1-20   3)alkoxy,       aminocarbonyl,       (C 1-6)alkylaminocarbonyl,       di(C 1-6)alkylaminocarbonyl, aryl, aryloxy; heteroaryl; the aryl, aryloxy or heteroaryl group possibly being optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl,  perhalo(C1-3)alkyl  or (C1-6)alkoxy group;  it being  understood
 





78


that at least one from among R2, R3 and R4 is other than Hand that the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6)alkoxy group;
R5 represents a (C1-6)alkyl or (C2-6)alkenyl group; and

5    n represents 1 or 2;

in the form of the base or of an acid-addition salt; with the exclusion of 5-ch loro-3-(2-chlorophenyl)-1 ,3-d ihyd ro-3-[2-( 4-methylpiperazin-1-yl)acet-amido]indol-2-one.

10    2.    Compound according to Claim 1, such that, in the general formula (I):

represents a single or double bond;

::;:::;
-c.....,_
X represents -CH<, -N< or

Y represents >N- or >CH-, it being understood that at least one from among X andY represents N;

15    Ar represents an aryl or heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy and aryl groups;

R1  represents a hydrogen atom or a -C(=O)(C1-6)alkyl,  -C(=O)aryl or (C1-

6)alkyl group;

20    R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen

atom, a halogen atom, a (C1-6)alkyl, perhalo(C1-3)alkyl, CN, aryl, heteroaryl, OH, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6) (C 1-6)alkylaminocarbonyl or di(C 1-6)alkylaminocarbonyl group, it being

25    understood that at least one from among R2, R3 and R4 is other than H; R5 represents a (C 1-6)alkyl group;

n represents 1 or 2;

in the form of the base or of an acid-addition salt.
 





79


3.    Compound according to Claim 1 or 2, suclf(~,!t, in t~lii!lle.ralfornitifci'tl

(I):

represents a single or double bond;

-c::;:::::::-
X represents -N<, -CH< or    ".'   
       
5    Y represents >N- or >CH-;

it being understood that at least one from among X andY represents N;

Ar  represents  an  aryl  group  optionally  substituted  with  one  or  more

substituents chosen from halogen atoms, preferentially chlorine or bromine,

and  (C 1-6)alkoxy,  (C 1-6)alkyl,  aryl,  trifluoromethyl  and  trifluoromethoxy

10    groups;

R1 represents a hydrogen atom or a -C(=O)(C1-6)alkyl, -C(=O)aryl or (C1-6)alkyl group;

R2, R3 and R4, which may be identical or different, located on any of the

available positions of the phenyl nucleus, independently represent a hydrogen

15    atom, a halogen atom, preferentially chlorine or bromine, or a (C1-6)alkyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H;

R5 represents a (C1-6)alkyl group; n represents 1 or 2;

20    in the form of the base or of an acid-addition salt.


4. Compound according to any one of the preceding claims, such that, in the general formula (1):

::..::..::..:  represents a single or double bond;
-c,:;::::::.
25    X represents -N<, -CH< or

Y represents >N-or >CH-; it being understood that at least one from among X andY represents N;
 





80


Ar represents a phenyl or naphthyl group optionally substituted with one or more substituents chosen from halogen atoms, preferentially chlorine or bromine, and methoxy, methyl, tert-butyl, phenyl, trifluoromethyl and trifluoromethoxy groups;

5    R1 represents a hydrogen atom or a -C(=O)methyl, -C(=O)phenyl or methyl group;
R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen

atom, a halogen atom or trifluoromethyl group, it being understood that at 10 least one from among R2, R3 and R4 is other than H;
R5 represents. a methyl, ethyl or 2-propyl group;
.

n represents 1 or 2;

in the form of the base or of an acid-addition salt.


15    5. Compound according to Claim 1 or 2, such that, in the general formula (I):

Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkoxy, aryl, perhalo(C1-3)alkyl and (C1-6)alkyl groups.

20

6.    Compound according to any one of the preceding claims, chosen from

the following compounds:

(+ )-N-[5,6-dich loro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-( 4-

methylpiperazin-1-yl)acetamide

25    (+)-N-[4,6-dichloro-3-(4-trifluoromethylphenyl)-2-oxo-2, 3-dihydro-1 H-indol-3-yl]-2-( 1-ethylpiperid-4-yl)acetamide

N-[4, 6-dich loro-3-( 4-ch lorophenyl)-2 -oxo-2, 3-d i hydro-1 H-indol-3-yl]-2-( 4-methylpiperazin-1-yl)acetamide

N-[ 4-trifluoromethyl-6-cyano-3-(4-ch lorophenyl)-2 -oxo-2, 3-d ihyd ro-1 H-ind ol-3-

30    yl]-2-( 4-ethylpiperazin-1-yl)acetamide
 





81

(+) -N-[ 1-benzoyl-5, 6-d ich loro-3-(4-ch lorophenyl)-2-oxo-216atfhyd r~t'\'&iil~ot-y •-3-yl]-2-( 4-methylpiperazin-1-yl)acetamide

3-( 4-ch lorop henyl)-3-[2-(4-ethylpiperazin-1-yl)acetylamino ]~n-4-trifluoromethyl-2,3-dihydro-1 H-indole-6-carboxamide
5    N-[6-chloro-3-(4-chlorophenyl)-1 ,5-dimethyl-2-oxo-2, 3-dihydro-1 H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide

(+) -N-[4 ,6-dichloro-3-(4-trifluoromethylphenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(1-ethyl-1 ,2,3,6-tetrahydropyrid-4-yl)acetamide
N-[4, 6-d ich loro-3-(3 ,4-d ichlorophenyl)-2 -oxo-2, 3-d ihyd ro-1 H-indol-3-yl]-2 -( 4-

10    ethylpiperazin-1-yl)acetamide

N:[4, 6-d ich loro-3-(3-fl uoro_-4-ch lorophenyl)-2 -oxo-2, 3-d ihyd ro-1 H-indol-3-yl]-2-

(4-ethylpiperazin-1-yl)a~etamide

N-[4, 6-dichloro-3-(3-trifluoromethyl-4-chlorophenyl)-2-oxo-2, 3-d ihyd ro-1 H-

indo 1-3-yl]-2-(4-ethylp iperazin-1-yl)acetamide

15    N-[4, 6-d ich loro-1-ethyl-3-(2-methylbenzo[b]th iophen-5-yl)-2 -oxo-2, 3-d ihyd ro-1H-indol-3-yl]-2-(1-ethylpiperid-4-yl)acetamide N-[4,6-dichloro-1-ethyl-3-(2-methyl-5-benzofuryl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide

N-[4, 6-d ich loro-3-(4-trifluoromethoxyphenyl)-2-oxo-2, 3-d ihyd ro-1 H-i ndo 1-3-yl]-

20    2-( 4-ethylpiperazin-1-yl)acetamide

in the form of the base or of an acid-addition salt


7.    Process for preparing a compound of formula (I) according to any one

of Claims 1 to 6,  characterized  in that it comprises a step that consists in

25    reacting a compound of general formula (V):

Rti}4ArH2

R3    O
R2  °    ~
H
 

(V)
 





82


in which R2, R3, R4 and Ar are as defined according to any one of Claims 1

to 6.



5    8. Process according to Claim 7, comprising the steps consisting in:

- reacting the said compound of general formula M with a compound of general formula (VI):

Hal"

Hal'_(
0

(VI)

in which Hal' and Hal", which may be identical or different,  independently

10    represent a halogen atom;

- and then in reacting the compound of general formula (Ill) obtained
~_( Hal"
0

R3    0


(Ill)

with a compound of general formula (IV):






(IV)
 





83


in which R2, R3, R4, R5, Y, Ar and n are defined as in the general formula (I) and Hal" represents a halogen atom;
- optionally followed by the step that consists in reacting the product of formula (I) obtained, in which X represents -N< and R1 is equal to H, with a

5    compound of formula (II):

R1-Hal (II)

in which R1, which is other than H, is defined as in the general formula (I) and Hal represents a halogen atom.

10    9. Process according to Claim 7, comprising the step that consists in reacting the said compound of gen~ral formula (V) with a compound of general formula (VIII):

Hooc"""C/-R5

\~

(VIII)

in which  ::..:.:...:: , X, Y, R5 and n are as defined according to any one of

15    Claims 1 to 6;

optionally followed by the step that consists in reacting the product of formula

(I)    obtained, in which R1 is equal to H, with a compound of formula (II):

R1-Hal (II)

in which R1, which is other than H, is defined as in the general formula (I) and

20    Hal represents a halogen atom.


10. Process for preparing a compound of formula (I) according to any one of Claims 1 to 6, characterized in that it comprises a step that consists in reacting a compound of general formula (XXVIII):
 





84





R3    0


(XXVIII)

in which R2, R3, R4 and Ar are defined according to any one of Claims 1 to 6

and ALK represents an alkyl group.


5    11. Process according to Claim 10, comprising the steps that consist in

-reacting the said compound of general formula (XXVIII} with a compound of, general formula (VI):

Hal"

Hal'-{"
0

(VI)

in which  Hal' and  Hal",  which  may be identical or different,  independently

10    represent a halogen atom;

- and then in reacting the compound of general formula (XXIX) obtained

~--fHal"

0

0
R3

R2

(XXIX)

with a compound of general formula (IV):
 





85


r-'v-R5

HN~

'n

(IV)

in which R2, R3, R4, R5, Y, Ar and n are as defined in the general formula (1),

and Hal" represents a halogen atom.


5    12. Process -according to Claim 10, comprising the step that consists in reacting the said compound of general formula (XXVIII) with a compound of general formula (VII):

HOOC/'-...ry-RS
M!

(VII)


in which  -    , X, Y, R5 and n are defined according to any one of Claims

10    1 to 6.


13.    Process according to any one of Claims 7 to 12, compnsmg the subsequent step that consists in separating out the desired compound of general formula (I).

15

14.    Compound of formula (Ill):

--    (Hal
R4CO=Ar~ 0

R3    .0    O   
R2        ~   
H
(Ill)
 


in which R2, R3, R4 and Ar are defined according to any one of Claims 1 to 6

and  Hal  represents  a halogen  atom,  with the exclusion  of 5-chloro-3-(2-

chloroacetamido)-3-(2-chlorophenyl)-1 ,3-dihydroindol-2-one.


5    15.    Compound of formula (Ill) according to Claim 14, in which:

Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkoxy, aryl, perhalo(C1-3)alkyl and (C1-6)alkyl groups.

10    16.    Compound of general formula (XXVII 1):




R3


(XXVIIO

in which R2, R3, R4 and Ar are defined according to any one of Claims 1 to 6 and ALK represents an alkyl group.

15    17.    Compound of general formula (XXIX):


(XXIX)
 

in which R2, R3, R4 and Ar are defined according to any one of Claims 1 to 6, ALK represents an alkyl group and Hal" represents a halogen atom.
 





87



18.    Medicament, characterized in that it comprises a compound of formula

(I)    according to any one of Claims 1 to 6, or an addition salt of this compound with a pharmaceutically acceptable acid.

5

19. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt.

10    20. Use of a compound according to any one of Claims 1 to 4 for the preparation of a medicament for preventing or treating obesity, diabetes, appetite disorders and excess weight.

21.    Compound according to any one of Claims 1 to 6, for preventing or

15    treating obesity, diabetes, appetite disorders and excess weight.


22.    Combination comprising one or more compounds according to any one of Claims 1 to 6 with one or more active ingredient(s).


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