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(21)Application Number:    KErP/2007/ 000684       
       
(22) Filing Date: 29/06/2006       
       
(30) Priority data: 05/07,032  Oi/07/2005    FR   
       
(86)  PCT data    PCT/FR06/001518   29/06/2006 wo 2007/003765    11/0112007   

(73)0wner:SANOFI-AVENTIS of 174 Avenue de France, 75013Paris, France

(72) Inventors: CASELLAS, Pierre of  I 0 Rue Carl Von Linne, F-34090 Montpellier,  France; BOURRIE, Bernard of 678 Rue Colline, F-34980 Saint Gely Du Fesc, France; PERREAUT, Pierre of  I I 0 Allee Des Peupliers, F-34980 Saint Clement De Riviere, France; JEGHAM, Samir of 206 Rue Des Asphadetes, F-34980 Montperrier, France and MUNEAUX, Claude of Chemin Perayrols, F-34270 Les Matelles, France

(74) Agent/address for correspondence: Kaplan & Stratton Advocates,  P.O. Box 40111-00100, Nairobi

(54)Title: DERIVATIVES OF PYRID0[2,3-D] PYRIMIDINE, THE PREPARATION THEREOF, AND THE THERAPEUTIC APPLICATION OF THE SAME.

(57) Abstract: The invention relates to derivatives of pyrido[2,3-d]pyrimidine, to the preparation thereof, and to the therapeutic application of the same. Said compounds are potentially useful for treating cellular proliferation disorders.

DERIVATIVES    OF    PYRID0[2,3-d]PYRIMIDINE,    THE    PREPARATION

THEREOF, AND THE THERAPEUTIC APPL!CA T!ON OF THE SAME

The    present  invention  relates  to  pyrido[2,3-d]pyrimidine  derivatives,  to  the

preparation thereof and to the therapeutic use thereof.

Compounds derived from pyrido[2,3-d]pyrimidine are described in patent applications WO 01/55 147 and WO 03/000 011 and in patents EP-B-790 997 and US 5 733 913.

These compounds are potentially useful for treating cell proliferation conditions.

10    Thus, and according to a first aspect, a subject of the present invention is compounds corresponding to formula (I):
N:xx'<:::AI,
II    .-<:    .-<:    (I)
~        N    NH-C-NH-R1
I            II
AI1            0
in which:

- R1 is selected from a group comprising (Cl-C6)alkyl, (CJ-C6)alkyl(C3-l5 C7)cycloalkyl, CH2COR3, phenyl, or phenyl substituted with hydroxyl and/or

halogen and/or (CJ-C6)alkyl;

-    R3 is a hydroxyl, (CJ-C4)alkoxy, amino, (CJ-C4)alkylamino or di(CJ-C4)alkylamino group;
-    Aq is a radical selected from:
a)    £ti
    d)    £tx
20    ~R '
in which X is  0 or S, Y is CH2 or NH, and R2 is selected from the group comprising

H, (CJ-C6)alkyl or (CH2ln~5, and R', is (CH2)nl\'R.4R5;
-R1 and R5 are each, independently of one another, a substituent selected from H,

(CJ-C4)alkyl, (CJ-C6)al1:yl(C3-C7)cycloalkyl, (C3-C7)cycloalkyl, C(=NH)NIJ, and

25    SO,(CJ-C6)alkyl, R5 can also be a CO-(CJ-C4)alkyl, CO-(C3-C7 )cycloalkyl, CO-aryl, SOraryl, tert-butoxycarbonyl or benzyloxycarbonyl group;


- or R4 and R5, together with the nitrogen atom to which they are attached, constitute

an azctidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical, said radical

being  unsubstituted  or  substituted  one  or  more  times  with  a  (Ct-CG)alk-yl,  (C1-

C4)alkyl-OHor COO(Ct-CG)alkyl group;

- Ar2 is a phenyl group which is unsubstituted or substituted from 1 to 5 times with

similar or different substituents selected from a halogen atom, a (C1 -C4)alkyl group, a

trifluoromethyl group or a (Ct-C4)alkoxy group;

-nisl,2or3.

According to a preferred variant, the compounds of formula (I) have a substituent Aq

10    which is a radical selected from:
a)-Q;
in which R, is CH, or (CH2lnNR.!R5, and R', is CH2NR.!R5, in which R, and Rs

are independently selected from Hand (Ct-C6)alkyl andY is CH, or NH.

The products according to the invention advantageously have a substituent AI2 which
15is a radical:    -a:•7   
       
in which each  Rti, R1 is independently selected from the group comprising H, CH3,

OCH,, F, Cl, Br. R,; and R, are advantageously in the 2- and 6-position.

The  products  according  to  the  invention  advantageously  have  a substituent  Ar2

20    selected from phenyl, 2-methoxyphenyl, 2,6-dichlorophenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,6-dibromophenyl, 2-bromo-6-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dimethylphenyl and 2,6-difluorophenyl.

According to a preferred variant, the compounds of formula (I) have a substituent Aq which is a radical selected from


25

A compound that is more particularly preferred according to the invention is:
(N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1, 1-dimethylethyl)urea ).

The compounds of the examples which follow are a subject of the present invention. A compound in accordance with the invention can (i) be in a non-chiral form1 or a racemic form, or a form enriched in one stereoisomer1 or enriched in one enantiomer; (ii) be optionally salified, and (iii) be optionally hydrated or solvated.

10    The compounds of formula (I) can contain one or more asymmetrical carbon atoms. They can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers and also mixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) can exist in the form of bases or of addition salts with

15    acids. \Vhen compounds of formula (I) contain free acid functions, for example carboxylic, sui phonic or phosphonic, these acid functions can be salified using bases so as to form addition salts. Such addition salts are part of the invention.

The addition salts with acids or with bases are advantageously prepared with, respectively, pharmaceutically acceptable acids or bases, but the salts of other acids or

20    of bases that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part ofthe invention.

The compounds of formula (I) can also exist in the form ofhydrates or of solvates, i.e. in the form of associations or of combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

25    In the context of the present invention:

-the term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine or an iodine;

-   the term "an alkyl group"  is intended to  mean:  a linear or branched, saturated

aliphatic group. By way of example, mention may be made of methyl, ethyl, n-propyl,

30    n-butyl, n-pentyl, n-hexyl, n-heptyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,

1 ,2-din1cthylpropyl, 2,2-dimethylpropyl, 1-methylpcntyl, 2-mcthylpentyl, 3-mcthylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimcthylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylhexyl, 2-methylhcxyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpcntyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 4,4-dimethylpentyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 1,2,2-trimethylbutyl, 1,2,3-

10    trimcthylbutyl, 1,3,3-trimethylbutyl, 2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl, 1,1,2,2-tetramethylpropyl, 1-ethylpentyl, 2-ethylpenty1, 3-ethylpentyl, 1-ethyl-1-methylbutyl, 1-ethyl-2-methylbutyl, 1-ethy1-3-methylbutyl, 2-ethyl-1-methyl butyl, 2-ethyl-2-mcthy1butyl, 2-ethyl-3-methylbutyl, 1-propylbutyl, 1-(1-methy1ethyl)butyl

and 1-(1-methylethyl)-2-methylpropyl groups;

15    - the term 11 a cycloalkyl group11 is intended to mean: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty1, bicyclo[2.2.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[3.2.l]octyl, adamantyl.

The compounds of formula (I)  are prepared by reaction between  a compound  of

20    formula (II):

SOw: - C - NH - R    (II)
I    II    1   
           
CH3    0       

in which R1 and AI2 are as defined for(!), and an amine offormula Ar'1NH2 (lli) in

whichAr't is ArJ, as defined for (I) or a precursor of Aq; where appropriate, the Ar'l

group of the compound thus obtained is converted to an Art group.

25    fu accordance with the invention, the compounds of formula (I) can be prepared according to a process characterized in that the following are reacted:
(i) a compound of formula: NXX""'
)l..-:;  ..-:;  AI,      (llb)
R10    R11
in which Rto is  a leaving group  such as:  (a)  halogen, in particular Cl or Br, or

30    (b) alkyl-S(O)m- with m = 0, 1, or 2; Ru is NHC(O)-NH-R,; and
 

(ii) an amine offormula Ar'J NHz (III) in which Ar' 1 is ArJ as defined for(!) or a

precursor of Aq; where appropriate, the Ar'1 group of the compound thus obtained is

converted to an Aq group.

\\'hen Rto is halogen or alkyl-S(O)m-, with m = 2, the reaction is carried out in a

solvent, preferably a polar solvent:

(i) for example tetrahydrofuran, dimethyl sulphoxide or ethanol, optionally in the

presence of a trace of acid such as hydrochloric acid; or

(ii) in dimethyl sulphoxide in the presence of a strong base such as tBuOK;

at a temperature between ambient temperature and the reflux temperature of the

10    solvent.

\\'hen R10 is aU..')'l-S(O)m- with m = 0 or 1, the reaction can be carried out with

Ar't NHz (Ill) in the molten state, preferably at a temperature in the region of 200°C, without catalyst.

'Where appropriate, the amine functions present in the Ar'1 group of compound (III)

15    are salified or protected beforehand.

The compounds of formula (II) are prepared by following the procedure described in

European patent  790 997 and patent US 5 733 913, as described in scheme I below:

SCHEMEl

20

    COOEt            COOEt        N:XCH,OH   
N    NH OH    r;c~    LiAIH4    II  h   
II    ~    1               
Mes""'N    Cl    tl    MeSh    'H,    l!J.    Mes-""NJom,   
MnO,    N:XCHO    Ar2-CH2CNIK,C03 orNaH    N~Ar,   
~MeS~ NH   _______.<!. l        MeS)l~~NH   
        2                2   
            H20 2 or        Ar   
R1NCO!:IN~ Ar,        mCPBA    NN~ 2   
~ )lh    h    -    fl.    V.L.h   h   
tl   MeS        N    NH-C-l.\'HR1        MeS    NHCOI\'HR1   
            II        II    (II)   
25            0        0       
                           

mCPBA: mCta-chloroperbenzoic acid.


The mnines of formula (III) Ar' 1NH2 are known or prepared by known methods from

the corresponding nitrated derivatives Ar'1 N02  (IV), by reduction  either (i) in an

acidic medium in the presence of a metal such as powdered zinc or iron, or (ii) by

hydrogen in the presence of a catalyst such as Pd/C. Ar' is  AI or a precursor of AI.

The compounds of formula (IV) are known or prepared by known methods.

The compounds according to the invention are obtained in racemic form; the optically pure isomers can then be prepared using resolving methods known to those skilled in the art, such as crystallization by fonnation of salts Y.ri.th chiral agents. Compounds according to the invention in optically pure fonn can also be prepared using methods

10    of asymmetric or stereospecific synthesis, the use of chromatographic techniques using a chiral phase. Moreover, the products of the invention can be separated via the

formation of diastereoisomers, separation thereo~ and then the decomposition of the pharmaceutically useful diastereoisomer into its enantiomerically pure active product. Enzymatic techniques can also be used. Additional known separating techniques can
15    be used. They include those disclosed in: Enantiomers, Racemates, and Resolutions,

John Wiley and Sons, New York (1981).

The compounds according to the invention can also be prepared in a fonn enriched in

one stereoisomer as soon as there is preparation of the synthesis intem1ediates. Thus,

the resolving of the enantiomers  of the amines of formula  (III) or of the nitrated

20    precursors (IV) can be carried out by one ofthe abovementioned methods.

The following examples describe the preparation of certain intennediates and of compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention.

In the examples, the following abbreviations are used:

25    Boc: tert-butoxycarbonyl

BOP: benzotriazol-1-y1oxytr:is( dimethylamino)phosphonium hexafluorophosphate
THF: tetrahydrofuran

AT: ambient temperature

30    TFA: trifluoroacetic acid

DCM: dichloromethane DMSO: dimethyl su!phoxide DMF: dimethylformamide
MeOH: methanol

35    DCCI: dicyelohexylcarbodiimide Dll'EA: diisopropylethylamine
 
KHS04/ K2S04: 5% solution ofKHS04/ K2S04.

The  proton  nuclear  magnetic  resonance  (NMR)  spectra  are  recorded  at  200  or

250 MHz  in  DMSO-d6,  unless  otherwise  indicated.  The  DMSO•d6  signal  is  at

2.5 ppm and sen•es as a reference. For the interpretation of the spectra, the following

abbreviations  are  used:  s:  singlet,  d:  doublet,  t:  triplet,  m:  unresolved  peak,  mt:

multiplet, bs: broad singlet, dd: doublet of a doublet, qd: quadruplet, qt: quintuplet.

Mp:  melting  point  (in  degrees  Celsius)  as  measured  on  a  Bilchi  B545

apparatus with a temperature gradient of 1°C per minute.

MH+: Mass spectrum. The compounds are analyzed by HPLC -  UV -  MS I 0          (liquid chromatography -  UV detection -  mass spectrometry) coupling. The device used, sold by Agilent, is composed of an HPI!OO chromatograph equipped with an

Agilent diode array detector and an MSD Quad quadripolar mass spectrometer.

The analytical conditions are as follows:

Column: C 18 Symmetry (50 x 2.1 mm; 3.5J!m)

15    Eluent A: H,O + 0.005% TFA atpH3.15 EluentB: CH3CN + 0.005% TFA

    Gradient:   
    Time(min)    %B
    0   
20    10    90
    !5    90
    16    0
    20   
    Column temperature: 30°C   

25    Flow rate: 0.4 ml/ min

Detection: l=210nm

tr: retention time

v:    volume.

30    Preparation of a compound of formula (II)

Preparation I

N-(t-Buty!)-N'-[6-(2,6-dich!orophenyl)-2-(methylsu!phonyl)pyrido(2,3-

d]pyrimidin-7-yl]urea.

I .I  Ethyl4-amino-2-(melhylthio)pyrimidine-5-carboxylate

140  ml  of  a  20%  l'Hi40H solution  are  added,  in  20  minutes,  and  while

maintaining  the  temperature  at  around  20°C,  to  a suspension  of 50.7  g  of ethyl

4-chloro-2-(methylthio)pyrimidin-5-carboxylate in 400 ml of EtOH. After stirring at

ambient temperature for 20 hours, the reaction medium is concentrated under vacuum

almost to dryness, and the residue is then taken up in 350 ml of water, stirred for 20 minutes, filtered, washed with 3x60 ml of water, and then dried under vacuum in the presence ofP205. A white solid is obtained, Mp = 134-J35"C, m = 39.9 g.

1.2  [4-Amino-2-(methylthio)pyrimidin-5-yl]methanol

10    210 ml  of a  IM solution of LiAIH4 in THP are added, in  45  minutes,  while

maintaining the temperature below 30°C, to 39.68 g of ester obtained in the previous stage dissolved in 1 litre of THF. The mixture is stirred for a further hour and the

temperature  is  then  decreased  to  5°C  and  9 ml  of water,  6.5  ml  of 5N sodium

hydroxide and then 32 ml of water are successively added dropv.':ise. After stirring for

15    I 0 minutes, the solid is filtered off and then rinsed with THP. The filtrate is concentrated to dryness under vacuum and the residue is then redissolved in 600 ml of boiling toluene, the product is rapidly filtered under hot conditions in order to remove

some of the insoluble material and the filtrate is left to cool overnight. The white crystals obtained are filtered, washed with a small amount of toluene and then of ether
20    and dried, Mp = 124-127°C, m = 23.9 g.

1.3    4-Amino-2-(methylthio)pyrimidine-5-carbaldehyde

79.5    g of active MnOz are added, in 2 minutes, to a suspension of 23.8 g of the alcohol obtained in the previous stage in 1600 ml of chloroform, and the mixture is stirred at ambient temperature overnight; the solid is filtered off, and washed with
2S    3x7S ml ofCHCl3, and the filtrate is concentrated to dryness under vacuum; the white

solid residue is taken up in ether, filtered and dried, Mp = 184-186°C, m = 21.05 g.

1.4    6-(2,6-Dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-arnine

5.47 g of60% NaH are added, in 5 minutes, to 21 g of the aldehyde obtained in

the previous stage, dissolved in 240 ml of DMF and cooled to  S°C,  followed by

30    29.05 g of 2,6-dichlorophenylacetonitrile, in 20 minutes, in small fractions. The stirring is continued for 30 minutes at soc and then at ambient temperature overnight. The reaction medium is cooled to S°C and 6S ml of a saturated NH4Cl solution and then SOO ml of a water/ice mixture are added; a red precipitate forms, which is filtered

off, washed twice with water, filteHiried to a maximum, and washed with ether, with

3S    100 ml of chloroform and then with ether again; after drying, a beige solid is obtained,

Mp = 250-253"C, m = 29.92 g.
 
The ether and chloroform washing phases are concentrated to dryness: and the product is taken up in a small amount of chlorofonn, to which ether is added: a second cast of 3.15 g is obtained, total m = 33.07 g.

1.5    N-(t-Butyl)-N'-[6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl]urea

4.6    g of 60% NaH are added, in 10 minutes and while maintaining the temperature below 25°C, to 29.9 g of the amine obtained above in solution in 300 ml
ofDMF; the mixture is stirred for a further 20 minutes and then 12.2 ml of tert-butyl

isocyanate are added in 20 minutes and the mixture is stirred overnight. The reaction

10    medium is poured slowly onto 800 ml of a water/ice mixture +100 ml of6NHCI; the precipitate formed is filtered, washed with water, filter-dried, and then stirred for 1 hour in 300 m1 of ether, then filtered, washed with ether and dried. A beige solid is obtained, Mp = !95-196'C (decamp.), m = 26.5 g.

1.6    N-(t-Butyl)-N'-[6-(2,6-dichlorophenyl)-2-(methylsulphonyl)pyrido[2,3-

15    d]pyrimidin-7-yl]urea

27 g of meta-chloroperbenzoic acid (77%) are added, in 25 minutes and while

maintaining the temperature below 25°C, to 21.95 g of urea obtained above in solution in 300 ml of chloroform. A precipitate forms. After 2 hours, the reaction medium is
diluted with !litre ofdichloromethane and Na2S04 followed by 14 g ofCa(OH)2 are

20    added. After stirring for 30 minutes, the solid is filtered off and washed with dichloromethane and the filtrate is then concentrated to dryness. The residue is triturated in 80 ml of ether under hot conditions; the product is left to cool, and the white solid is then filtered off, washed with ether and dtjed, Mp = 138-140'C, m=20.5 g.

25

In the  same  marmer  as  for  the  compound  described in  preparation  1,  the

compounds of formula (11) below can be prepared:

            TABLE!
~    Ar2    RI    NMR
    2,6-dichlorophenyl    tert-    1.40: s: 9H; 3.50: s: 3H; 7.50-7,70:  m: 3H;
        butyl    8.55: s: 1H; 9.10: s: 1H; 9.60: s: 1H; 9.95: s:
            1H.
    2,6-dichlorophenyl    phenyl    3.50 ppm: s: 3H; 7.10 ppm: t: lH; 7.40 ppm: t:
            2H; 7.55-7.75 ppm: m: 5H; 8.60 ppm: s: lH;
            9.60 ppm: s: lH; 9.80 ppm: s: IH; 11.90 ppm:
            s: !H.
 

                10   
                   
                   
        3,5-dimethoxyphenyl    tert-    1.40 ppm: s: 9H; 3.50 ppm: s: 3H; 3.80 ppm:
            butyl    s:  6H; 6.65-6.80 ppm: rot:  3H; 7.75 ppm:  s:
                IH;  8.45 ppm: s: !H; 9.60 ppm:  s:  IH; 9.80
                ppm:s:!H.   
        2,6-dichlorophenyl    ethyl    1.20 ppm: t: 3H; 3.40 ppm: qd: 2H; 3.50 ppm:
                s: 3H; 7.50 ppm -7.75 ppm: m: 3H; 8.55 ppm:
                s: !H; 9.40 ppm: s: IH; 9.60 ppm: s: IH; 9.70
                ppm:s:IH.   
        3,4-dimethoxyphenyl    tert-    1.40 ppm: s: 9H; 3.45 ppm: s: 3H; 3.80 ppm:
            butyl    s: 3H; 3.90 ppm: s: 3H; 7.10 -7.20 ppm: m:
                3H; 7.75 ppm: s:  !H; 8.45 ppm: s:  IH; 9.55
                ppm: s: !H; 9.80 ppm: s: !H.   
        phenyl    tert-    1.40 ppm: s: 9H; 3.50 ppm: s: 3H; 7.60 ppm:
            butyl    bs: 6H; 8.45 ppm: s: !H; 9.40 ppm: s: IH; 9.80
                ppm:s:IH.   
7    2-methoxyphenyl    tert-    1.40 ppm: s: 9H; 3.50 ppm: s: 3H; 3.80 ppm:
            butyl    s: 3H; 7.10- 7.40 ppm: mt: 4H; 7.60 ppm: t:
                IH;  8.40 ppm: s:  !H; 9.60 ppm:  s:  IH; 9.80
                ppm: s: !H.   
        2,6-dibromophenyl    tert-    1.40 ppm: s: 9H; 3.50 ppm: s: 3H; 7.40 ppm: t:
            butyl    IH; 7.85 ppm: d: 2H; 8.50 ppm:  s:  IH; 9.00
                ppm: s:  IH; 9.60 ppm: s:  IH;  10.00 ppm: s:
                !H.   
        2-bromo-6-    tert-    1.40 ppm: s: 9H; 3.45 ppm: s: 3H;  7.50 ppm:
        ch!orophenyl    butyl    t: IH; 7.65 ppm: d: IH;
                7.80 ppm: d: IH; 8.50 ppm: s: IH; 9.00 ppm:
                s: IH; 9.50 ppm: s: !H; 9.90 ppm: s: !H.   
!0    2,6-dibromophenyl    ethyl    1.15 ppm: t: 3H; 3.30 ppm: qd: 2H (masked by
                DOH); 3.50 ppm: s: 3H; 7.40 ppm: t: IH; 7.85
                ppm: d: 2H; 8.50 ppm: s: IH; 9.25 ppm: s: !H;
                9.60 ppm: s: !H; 9.70 ppm: s: !H.   
11    2-bromo-6-    phenyl    (DMSO + TFA) 3.55 ppm: s: 3H; 7.10 ppm: t:
        ch!orophenyl        IH; 7.30-7.90 ppm: m: 7H; 8.60 ppm: s: !H;
                9.65 ppm: s: !H.
 

                11   
                   
12    2,6~dibromophcnyl    phenyl    3.55 ppm: s: 3H; 7,10 ppm: t: 1H; 7.35 ppm:   
                qd: 3H; 7.60 ppm:  d: 2H;  7.85  ppm:  d:  2H;   
                8.60 ppm: s: !H; 9.70 ppm: s: !H; 9.80 ppm:   
                s: !H; 12.00 ppm: s: !H.   
13    2,4-dichlorophenyl    tert-    1.35 ppm: s: 9H; 3.50 ppm: s: 3H; 7.45 -7.60   
            butyl    ppm: mt: 2H; 7.80 ppm: s:  1H; 8.40 ppm: s:   
                !H; 8.80 ppm: s:  !H; 9.55 ppm:  s:  1H; 9.80   
                ppm:s:!H.   
14    2,6-dimethylphenyl    tert-    1.40 ppm: s: 9H; 2.00 ppm: s: 6H; 3.50 ppm:   
            butyl    s: 3H; 7.10 ppm: s:  IH; 7.25-7.45: m: 3H;   
                8.45 ppm: s: !H; 9.60 ppm: s: 1H; 9.80 ppm:   
                s:!H.   
15    2,6-difluorophenyl    tert-    1.40 ppm: s: 9; 3.50 ppm: s: 3H; 7.25-7.40:   
            butyl    mt: 2H; 7.55-7.70 ppm: mt: !H; 8.65 ppm: s:   
                !H; 9.20 ppm: s: 1H; 9.60 ppm: s: !H; 9.75   
                ppm:s:!H.   
16    2,6-dichlorophenyl    iso-    1.20 ppm: d: 6H; 3.50 ppm:  s: 3H; 3.85-4.00   
            propyl    ppm:  rut:  1H;  7.50-7.70  ppm:  m:  3H;  8.50   
                ppm: s: 1H; 9.25 ppm: s: 1H; 9.65 ppm: s: 1H;   
                9.75 ppm: bs: !H.   
Preparation of the compounds of formula (III)

The preparation numbers used refer to the numbers of lhe compounds in Table 2

hereinafter.

Preparations 17 and 18

Commercial product.

Preparation 19

Prepared according to J. Hetero. Chen1. 1986, 23, 1645-1649 and isolated in hydrochloride form.
10    Preparation 20

Prepared according to J. Chem. Soc. 1928, 121.

. Preparation 21

21.1

o,N'():} -    COOEt    NaBH,    o,N'():} -    CH,OH   
1    ~            I    ~       
~    0        -    ...-::;    0       

2.27 g ofNaBii4 are added, in small portions over a period of 8 hours, to 1.12 g

15    of ethyl 5-nitrobenzo[b]furan-2-carboxylate in 50 m1 of THF, and the mixture is then stirred for 40 hours. 5 ml of methanol and then 5 ml of water are added. The reaction medium is extracted with EtOAc, and the organic phase is washed with water, with a

5% KHSOJ!C2S04 solution, with water, and then with a saturated NaCl solution. After drying and concentration under reduced pressure, 0.74 g of the expected product
20    are recovered in solid form.

21.2

o,N'():} -    o,N'():} -
1    ~ CH OH   CH,sop     I         ~ CH,OSO CH
Ao2 - Ao    23

730 mg of the product obtained in stage 21.1 are dissolved in 9 m1 ofDCM and maintained at s•c. I m1 of triethylamine is added at s•c, and then 536 mg of

methanesulphonyl chloride are added in 15 minutes. The temperature is maintained at

25    5°C for 15 minutes, and the reaction mediwn is then allowed to return to ambient temperature for 55 minutes. The reaction medium is then diluted with DCM and water. The organic phase is separated by settling out, washed with water and with a saturated NaCl solution, dried and evaporated under reduced pressure. 0.98 g of oil, comprising a mixture of mesylate (expected product) and of chloride (product from
 

13

substitution of the CH2 0H in the 2-position of benzo(b]furan with CH,Cl), is obtained.

21.3

O,Nl)) -    O,N~
-  I    ~    CH,OSO,CH,  ~ I    ~
.6    0    .6    0)'-Et
            Et

0.97    g of the product obtained in stage 21.2, in 10 ml ofD.MF, are treated \\~th

1.5    g of diethylamine for 18 hours. The reaction medium is extracted with EtOAc, the organic phase is washed with water and with a saturated NaCl solution and dried,
and the solvents  are then evaporated off under reduced pressure.  0.93  g  of oil is

obtained.

10    21.4

O,N~    Zn/AoOH    H,N~   
I    ~    -        I    ~   
    .6    0    )'-Et        . 6    0N-Et   
        m            1   
                    m   
4.48 g of powdered Zn are added to 1.!6 g of product obtained in stage 21.3 in

40 ml ofTIIF, followed, at -5°C, by 5 ml of acetic acid, over a period of25 minutes. After lh 15 of reaction, the residual solid is eliminated from the reaction medium by filtration, the solid is washed with a small amount ofTHF, and the organic phases are
15    combined,  diluted with EtOAc  and water,  and then brought to  pH = 9 with  ION

NaOH. After separation by settling out, the organic phase is isolated and washed with a 15% Na2C03 solution, with water and with a saturated NaC1 solution, dried and evaporated. 900 mg of oil are obtained.

Preparation 22

20    22.1

o,NnN
- I ~CH.,N ~cr - 3

1.26 g of sodium azide are added to 1.64 g of2-chloromethyl-5-nitrobenzoxazole (prepared according to Synt/z. Communications !989, 19, 2921-2924) in 25 ml of

DMF and the mixture is stirred at ambient temperature overnight. The reaction 25 medium is poured onto 150 ml of EtOAc and washed twice with ice-cold water and
 

14


then  with  a saturated NaCl solution. The  organic phase  is dried  and  concentrated

under reduced pressure. 1.42 g of black oil are recovered.


22.2


2.84 g of triphenylphosphine are added, in 10 minutes to 1.40 g of the product

obtained in stage 22.1 in 30 ml ofEtOAc, and then, after 10 minutes, 1.16 ml ofwater

are added in 2 minutes. After 24 hours with stirring at 60°C, and then cooling, the reaction medium is diluted with EtOAc, and the organic phase is washed with water

10    and then with a saturated NaCl solution. The organic phase is dried and concentrated under reduced pressure. The residue is taken up in EhO and is extracted twice with

IN HCI. The acid phases are combined, brought into contact with EtOAc, and brought to pH= 10 \\~th lON NaOH. After separation by settling out, the organic phase is

washed with water and then with a saturated NaCl solution. The organic phase is dried

15    and concentrated under reduced pressure, to give 468 mg of the expected product in the form of an oil.

22.3

o,NY,YN    BOC,O    O,NY,YN
~rCH,NH, _              ~rCH,NHBOC

The  product  obtained  in  stage  22.2  is  dissolved  in  10  ml  of DCM,  and  then

0.4 equivalent of triethylamine followed  by  1.1  equivalents of BOC,O  are added.

20    After 5 h, the reaction medium is diluted with CH2Ch and then washed successively with a 5% KHSOJK2S04 solution, water and a saturated NaCl solution. The crude is dried and evaporated under reduced pressure, so as to obtain 388 mg of the expected product.

22.4

O,N'CrN        H,N'CrN
I    ')-CH,NHBOC  Zn/AoOH    I    }--cH,NHBOC
0    0    -    0    0

25    The product obtained in stage 19.3 is reduced quantitatively with Zn/AcOH, so as

to obtain an oil, according to the method described in preparation 18.4.

Preparation 23

23.1
Prepared according toJ. Hetero. Chem. 1973,10,755.

23.2

Reduction of the producct obtained in stage 23.1 with SniHBr in water according to

Clzem.Abstr. 1950,4474.

Preparation 24

Prepared accoring to J. Hetero. Clzem. 1970, 7, 1019-1027.

Preparation 25

Prepared according to Boll. Sci. Fa c. Chim. Ind. Bologna 1964 vol.22 pages 33-37

Preparation 26

10    Prepared according to the procedure described in patent application W092/05164.

The compounds of formula (!ll) are characterized in Table 2 below:

                    TABLE2       
15            Preparations of the compounds of formula (III).   
                           
    Prep.    Arl            X= N02 (IV), HCl    X=NH2 (!ll)   
                    NMR    NMR   
    17                -    Commercial product   
        X    N           
                       
        -Of           
    18    ,.s,            Commercial product   
        N~    t        -       
                           
        x-{)               
    19    ~so,    -    Prepared according to J.   
                   
                   
        X    kr        Hetero. Chem. 1986, 23,   
                        1645-1649 and isolated in   
                        hydrochloride form   
        0        Me           
    20    x-Q-1(        -    Prepared according to   
                       
                    J. Chen1. Soc. 1928, 121   
                       
                       
 

16

21        X~    21.3        21.4   
            1.00 ppm: t: 6H; 2.50    1.00 ppm: t: 6H; 2.55 ppm:   
            ppm: qd: 4H; 3.75 ppm: s:    qd: 4H; 3.65 ppm: s: 2H;   
            'Et    2H; 7.00 ppm: s: 1H; 7.75    4.90 ppm: bs: 2H; 6.45   
            Ef",...N    ppm: d: IH; 8.15 ppm: d:    ppm: s: IH; 6.50 ppm: dd:   
                       
                IH; 8.50 ppm: d: !H.    IH; 6.65 ppm: d: IH; 7.15   
                    ppm:d: !H.   
22        x-Q    22.3        22.4   
            1.40 ppm: s: 9H; 4.45    1.35 ppm: s: 9H; 4.25   
                ppm: d: 2H; 7.65 ppm: t:    ppm: d: 21-1; 4.95: bs: 2H;   
            l\'HBOC    IH; 7.95 ppm: d: IH; 8.30    6.55 ppm: dd: IH; 6.75   
            A               
                ppm: dd: IH; 8.60 ppm: d:    ppm: d: IH; 7.25 ppm: d:   
                !H.    IH; 7.45 ppm: t: !H.   
23            x-dd    23.1        23.2   
                Prepared according to J.    Prepared according to   
                Hetero. Chem. 1973, 10,    Cllem. Abstr. 1950, 4474.   
                755           
24            x-61    -    Prepared according to J.   
                    Hetero. Chem. 1970,7,   
                       
                    1019-1027   
            N,?    -    Prepared    according   to   
25                           
            x-6N        Boll. Sci. Fac. Chim. Ind.   
                    Bologna    1964   vo1.22   
                    pages 33-37   
                       
26                -    Prepared according to the   
            ~'H        procedure described in   
                       
        X            patent application   
                       
    -6'~'        W092/05!64   

The numbers of the compounds exemplified refer to those given in Table 3 hereinafter, which illustrates the chemical structures and the physical properties of some compounds according to the invention. When they contain an asymmetrical carbon, these compounds are obtained in racemic form.
 

17


EXAMPLE 1: (Compound No. I) N-[2-(2,!,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1, 1-dimethylethyl)urea

3.21 g (28.6 mmol) oft-BuOK are added, in IS minutes, to 3.32 g (20 mmol) of the amine of preparation 17 in Table 2, in 45 ml of DMSO, and then 7.71 g (16.5 mmol) of the urea of preparation I in Table I are added in 20 minutes. I g of

t-BuOK is again added after 2 hours, and then 1 g of t-BuOK is again added after 2 hours. After reaction for 6 hours, the reaction medium is diluted with ice-cold water, and then extracted with EtOAc. The organic phase is washed twice with water and
10    once with a saturated NaCl solution, dried and concentrated under reduced pressure.

The crude is triturated in an EhOfueptane mixture, and the precipitate is filtered off

and then chromatographed on silica gel, d1e eluent being 88/12 (v/v) CHCI3/Et0Ac. 5 g of expected product are obtained. MW = 539.

EXAMPLE 2: (Compound No. 2) N-[2-(2,1,3-benzothiadiazol-4-ylamino)-6-(2,6-15 dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

Compound 2 is prepared in the same way as compound 1, starting with the amine

of preparation IS in Table 2.

EXAMPLE 3:  (Compound  No.  3)  N-[6-(2,6-dichlorophenyl)-2-[(1,3-dihydro-2,2-

dioxido-2, 1-benzisotl>iazol-5-yl)amino]pyrido[2,3-d]pyrimidin-7-yl]-N'-(1, 1-

20    dimethylethyl)urea

A mixture of 437 mg of the amine of preparation 19 in Table 2, in hydrochloride

fonn, and of750 mg of the urea of preparation I in Table I, are heated in 15 ml of

ethanol for 5 hours. The reaction medium is_evaporated to dryness and then taken up

in 50 ml of CHCI, and 20 ml of a saturated NaHCO, solution. The organic phase is

25    separated by settling out, and washed with water and then with a saturated NaCl solution. The organic phase is dried and saturated under reduced pressure. The residue
is purified by flash chromatography with a gradient of 0 to 20% (v/v) of EtOAc in chloroform. 275 mg of a yellow solid are obtained. MW: 572.

EXAMPLE 4: (Compound No. 4) N-[6-(2,6-dichlorophenyl)-2-[(2-methyl-6-30 benzoxazolyl)amino]pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

210 mg of the amine of preparation 20 in Table 2 and 562 mg of the urea of preparation I in Table l are heated for 8 hours at 45'C in 20 ml of ethanol containing

0.02 ml of concentrated HCI. After concentration under reduced pressure, the residue

is chromatographed on silica gel, the eluent being CHCI,!MeOH: 9812 (v/v). 300 mg 35 of product in the form of a yellow solid are isolated. MW: 536.

EXAMPLES:    (Compound No.5)    N-[6-(2,6-dich1orophcnyl)-2-[[2-

[( diethylamino )methyl]-5-benzofuranyl]amino ]pyrido[2,3-d]pyrimidin-7-yl]-N'-( 1,1-dimethylethyl)urea

Compound 5 is prepared in the same way as compound 4, starting from the amine

21.4 of preparation 21 in Table 2.

EXAMPLE 6:  (Compound No.6)  1,1-dimethylethyl  [[5-[[6-(2,6-dich1orophenyl)-7-

[[[(1,1-dimethylethyl)amino]carbonyl]amino]pyrido[2,3-d]pyrimidin-2-yl]amino]-2-

benzoxazolyl]methyl]carbamate

10    Compound 6 is prepared in the same way as compound 4, starting from the amine

22.4 of preparation 22 in Table 2.

EXAMPLE 7: (Compound No.7) N-[2-[[2-(aminomethyl)-5-benzoxazolyl]arnino]-6-

(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-( 1, 1-dimethylethyl)urea

190 mg of compound 6 are treated for 1 hour with 3 ml ofTFA in 2 m1 ofDCM.

15    After concentration under reduced pressure, the residue is taken up in a DCM/water mixture and the pH is then brought to 9 by adding a 15% Na2C03 solution. After separation by settling out, the organic phase is washed with water and then with a saturated NaCl solution, dried, and concentrated under reduced pressure. The crude is purified by flash chromatography on silica gel, the eluant being 0 to 10% (v/v) of
20    methanol in DCM. 100 mg of yellow solid are isolated. MH': 551.

EXAMPLE 8:    (Compound No.8)    N-[6-(2,6-dichlorophenyl)-2-(imidazo[1,2-

a]pyridin-6-ylarnino )pyrido[2,3-d]pyrimidin-7-yl]-N'-(l, 1-dimethylethy1)urea

Compound 8 is prepared in the same way as compound 4, starting from the amine

23.2 of preparation 23 in Table 2.

25    EXAMPLE 9: (Compound No. 9) N-[6-(2,6-dichlorophenyl)-2-([1,2,4]triazolo[1,5-a]pyridin-6-ylarnino)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethy1)urea

Compound 9 is prepared in the same way as compound 4, starting from the amine of preparation 24 in Table 2.

EXAMPLE 10: (Compound No. 10) N-[2-(2,1,3-benzoxadiazo1-5-ylarnino)-6-(2,6-30 dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1, 1-dimethylethyl)urea

0.168 g of tBuOK is added in 25 min, to a mixture of 0.468 g of the product of preparation 1 and 0.202 g of the amine (III) of preparation 25 in Table 2, in 6 m1 of DMSO, and then a further 0.168 g is added in 1 hour. After stirring for 2 hours, the

reaction medium is extracted with ethyl acetate which is washed successively with

35    water and a saturated NaCl solution. After drying over Na2S04 and evaporation of the ethyl acetate, the crude product is purified by flash chromatography on silica gel with

a gradient of 0 to 8% (v/v) of ethyl acetate in dichloromethanc. A beige powder is

obtained,  m= 0.22 g. MH+=523.

EXAMPLE 11:    (CompoundNo.ll)    N-[2-(1,3-dihydro-2,2-dioxido-2,1,3-

benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-

(l,l-dimethylethyl)urea

Compound 11 is prepared in the same way as compound 4, starting from  the

amine of preparation 26 in Table 2.

EXAMPLES 12-21: (CompoundsNo.l2-21)

10    Compounds 12-21 are prepared in the same way as compound 1, starting from the

amine (Ill) of preparation 17 in Table 2 and an appropriate urea selected from the products offormula (II) of the preparations in Table L

EXAMPLE 12:  (Compound  No.  12)  N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2-

bromo-6-chlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

15    EXAMPLE 13: (Compound No. 13) N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-ethylurea

EXAMPLE 14: (Compound No. 14) N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

EXAMPLE 15: (Compound No.  15) N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-

20    dibromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-ethylurea

EXAMPLE 16: (Compound No. 16) N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-phenylurea

EXAMPLE 17: (Compound No. 17) N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

25    EXAMPLE 18: (Compound No. 18) N-[2-(2,1,3-benzothiadiazol-5-y1arnino)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

EXAMPLE 19: (Compound No. 19) N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-dimethylphenyl)pyrido[2;3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

EXAMPLE 20:  (Compound No. 20)  N-[2-(2,1,3-benzothiadiazol-5-ylamino)-6-(2,6-

30    difluorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea

EXAMPLE 21: (Compound No. 21) N-[2-(2,1,3-benzothiadiazol-5-ylarnino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1-methylethyl)urea

Tables 3 and 4 below illustrate the chemical structures and the physical properties

35    of some examples according to the invention. In these tables, Me, Et, iPr and tBu are,
 

20


respectively, methyl, ethyl, isopropyle and ter/-butyl groups, and Boc (or BOC) is the tert-butoxycarbonyl group.

TABLE3



(I)
Cl
!I
0    N~
H

Compounds    NMR

characterization

1.50 ppm: s: 9H; 7.50-7.70 ppm: m: 3H; 7.95 ppm: dd: 2H; 8.15 ppm: s: IH; 8.35 ppm: s: JH; 9.20 ppm: s: JH; 9.35 pmm: s: JH; 10.65 ppm: s: IH; 10.75 ppm: s:
I H.

1.40 ppm: s: 9H; 7.45-7.80 ppm: m: 5H; 8.15 ppm: s: JH; 8.35 ppm: s: IH; 8.80 ppm: d: IH; 9.20 ppm: s: JH; 9.55 pmm: s: IH; 10.60 ppm: s: IH.

1.45 ppm: s: 9H; 4.45 ppm: s: 2H; 6.75 ppm: d: IH; 7.45-7.70 ppm: m: 3H; 7.80 ppm: de: IH; 8.05 ppm: s: IH; 8.15 ppm: bs: 2H; 9.05 ppm: s: IH; 10.10 ppm: s: IH; 10.20 - 10.30 ppm: bs: IH; 10.60
I ppm:.s: !H.

1.45 ppm: s: 9H; 2.60 ppm: s: 3H; 7.50-7.70 ppm: m: 5H; 8.10 ppm: s: IH; 8.30 ppm: bs: IH; 8.90 ppm: bs: IH; 9.15 ppm: s: IH; 10.45 ppm: s: IH; 10.75 ppm: s: !H.
 

21       
           
        1.00 ppm:  t:  6H;  1.45 ppm:  s:  9H; 2.50   
    Et    ppm: qd: 4H; 3.70 ppm: s: 2H; 6.55 ppm:   
    I       
    N    s: IH; 7.40-7.70 ppm: m: 5H; 8.10 ppm:   
    'Et    s: 2H; 8.55 ppm: bs: IH; 9.10 ppm: s: IH;   
           
        10.15 ppm: s: IH; 10.65 ppm: s: !H.   
    ___f\__    1.30 ppm:  s: 9H;  1.40 ppm:  s: 9H; 4.35   
           
    "==<~NHBOC    ppm: d: 2H; 7.45-7.60 ppm: m: 5H; 7.75   
        ppm: dd: IH; 8.05 ppm: s: IH; 8.10 ppm:   
        bs: IH; 8.65 ppm: s: IH; 9.10 ppm: s: IH;   
        10.30 ppm: s: IH; 10.60 ppm: s: !H.   
        1.45 ppm: s: 9H; 2.10 ppm: bs: 2H; 3.90   
        ppm: s: 2H; 7.45-7.70 ppm: m: 4H; 7.80   
        ppm: dd: IH; 8.05 ppm: s: IH; 8.15 ppm:   
        bs: IH; 8.65 ppm: s: IH; 9.10 ppm: s: IH;   
        10.25 ppm: s: IH; 10.70 ppm: s: !H.   
        1.50 ppm: s: 9H; 7.40 -  7. 70 ppm: m: 7H;   
        8.10 ppm:  s:  IH;  8.20 ppm: s:  IH; 9.10   
        ppm: s: IH; 9.65 ppm: s: IH;  I 0.30 ppm:   
        s: IH; 10.60 ppm: s: !H.   
        1.50 ppm: s: 9H; 7.45-7.70 ppm: m: 3H;   
        7.85  ppm:  s: 2H; 8.15 ppm: s:  IH; 8.25   
        ppm: d: IH; 8.40 ppm: s: IH; 9.15 ppm: s:   
        IH; 10.10 pmrn: s: IH; 10.55 ppm: s: !H;   
        10.6Qppm: s: !H.   
10        1.45 ppm: s: 9H;  7.50-7.70 ppm: mt:   
        3H;  7.75  ppm: d:  IH;  8.00  ppm: d:   
        IH; 8.20 ppm: s: IH; 8.40 ppm: s: IH;   
        9.15  ppm: s:  IH;  9.25  ppm: s:  IH;   
        10.65 ppm: s: IH; 10.90 ppm: s: !H.   
11        1.45 ppm: s: 9H; 6.65 ppm: d: IH;   
           
        7.40 ppm: s: IH; 7.45-7.70 ppm: m:   
        4H; 8.05 ppm: s: 2H   
        9.05 ppm: s: IH; 10.00 ppm: s: IH;   
        10.55 ppm: s: IH; 10.75 ppm: bs: 2H.   
 

22


TABLE4


    Compound        Rl    Ar2    NMR   
                       
                    characterization       
12        te.-t-butyl    2-brorno-6-    !.50 ppm: s: 9H; 7.45 ppm: t: IH; 7.65   
                chlorophenyl    ppm: d: IH; 7.80 ppm: d: IH; 8.00 ppm:   
                    dd: 2H; 8.15 ppm: s:  IH; 8.25 ppm: s:   
                    IH; 9.20 ppm: s: !H; 9.30 ppm: s: 1H;   
                    10.75 ppm: s: IH; !0.85 ppm: s: !H.       
13        ethyl    2,6-dichloropheny!    (DMSO + TFA deuterate d)   
                    1.15  ppm:  t:  3H;  3.35  ppm:  qd:  2H;   
                    7.50-7.70 ppm:  m:  3H;  8.00 ppm:  dd:   
                    2H; 8.45 ppm: s: IH; 9.00 ppm: s:  IH;   
                    9.30 ppm: s: !H.       
14        tert-buty!    2,6-dibn>mopheny!    1.50 ppm: s: 9H; 7.35 ppm: t: 1H; 7.80   
                    ppm:  d:  2H;  8.00 ppm:  dd:  2H;  8.15   
                       
                    ppm: s: 2H; 9.15 ppm: s: IH; 9.30 ppm:   
                    s: IH; 10.75 ppm: s: 1H; 10.85 ppm: s:   
                    !H.       
15        ethyl    2,6-dibromophenyl    1.30 ppm: t: 3H; 3.30 ppm: qd: 2H; 7.35   
                    ppm: t: IH; 7.80 ppm: d: 2H; 8.00 ppm:   
                    dd: 2H; 8.15 ppm: s: 1H; 8.50 ppm: s:   
                    1H; 9.15 ppm: s: IH; 9.20 ppm: s:  IH;   
                    10.20 ppm: s: IH; 10.70 ppm: s: !H.   
!6        phenyl    2,6-dichlorophenyl    7.15  ppm:  t:  IH;  7.50-7.70 ppm:  mt   
                    5H; 7.75-8.10 ppm: mt: 4H; 8.30 ppm:   
                    s:  IH;  9.25 ppm:  s:  1H;  9.35 ppm:  s:   
                    IH; 9.50 ppm: s: IH; 10.85 ppm: s: lH;   
                       
                    13.30 ppm: s: !H.   
 

23

17    ten-butyl    3,5-    1.50 ppm: s: 9H; 3. 70 ppm: s: 6H; 6.65
        dimethoxyphenyl    ppm: s: 3H; 7.30 ppm: s: JH; 8.00 ppm:
            dd: 2H; 8.20 ppm: s:  lH; 9.20 ppm: s:
            JH; 9.30 ppm: s: lH; 10.50 ppm: s: JH;
            10.70 ppm: s: !H.
18    tert-buty}    phenyl    1.50 ppm: s: 9H; 7.25 ppm: s: lH; 7.45-
            7.65  ppm:  m:  5H;  8.00 ppm:  dd:  2H;
            8.20 ppm: s: lH; 9.20 ppm: s: lH; 9.35
            ppm:  s:  lH;  10.50 ppm:  s:  lH;  10.75
            ppm: s: !H.
19    fert-butyl    2,6-dimethylphenyl    1.45 ppm: s: 9H; 2.00 ppm: s: 6H; 6.55
            ppm:  s:  JH;  7.20-7.40:  m:  3H;  7.95
            ppm:  dd:  2H;  8.10  ppm:  s:  JH;  9.15
            ppm:  s:  JH;  9.30  ppm:  s:  JH;  10.45
            ppm: s: JH; 10.65 ppm: s: !H.
           
20    fert-butyl    2,6-difluorophenyl    1.45  ppm:  s:  9H;  7.15-7.30:  mt:  2H;
            7.50-7.70 ppm:  mt:  JH;  7.95 ppm:  dd:
            2H; 8.25 ppm: s:  lH; 8.45 ppm: s:  JH;
            9.15 ppm: s: lH; 9.30 ppm: s: lH; 10.50
            ppm: s: lH; 10.70 ppm: s: !H.
21    isopropyl    2,6-dichlorophenyl    1.35 ppm:  d:  6H;  3.80-4.00  ppm:  mt:
            lH;  7.40-7.55 ppm:  mt:  lH;  7.60-7.65
            ppm:  mt:  2H; 7.95  ppm: dd:  2H;  8.15
            ppm: s: lH; 8.60 ppm: s: JH; 9.15 ppm:
            s:  lH; 9.25 ppm: s:  lH; 10.45 ppm: d:
            lH; 10.75 ppm: s: !H.

The compounds according to the invention were subjected to pharmacological assays for determining their anticancer activity.

The compounds of fonnula (I) according to the present invention were tested in vitro on a panel of tumour lines of human origin, originating:

-  from  breast  cancer:  MDA-MB231  (American  Type  culture  collection,

Rockville, Maryland, USA, ATCC-HTB26), MDA-Al or MDA-ADR (called multi-
 

24


drug resistant MDR line, and described by E.Collomb et al., in Cytometry, 12(1):15-25, 1991), and MCF7 (ATCC-HTB22),

-from prostate cancer: DU!45 (ATCC-HTB81) and PC3 (ATCC-CRL1435),

-from colon cancer: HCT116 (ATCC-CCL247) and HCT15 (ATCC-CCL225),

- from lung cancer: H460 (described by Carmichael in Cancer Research 47 (4):936-942, 1987 and provided by the National Cancer Institute, Frederick Cancer
Research and Development Center, Frederick, Maryland, USA),

-    from  glioblastoma:  SF268  (described  by  Westphal  in  Biochemical  &

Biophysical Research Communications 132 (!): 284-289, 1985 and provided by the

I 0    National  Cancer  Institute,  Frederick  Cancer  Research  and  Development  Center,

Fred erick, Maryland, USA),

- from leukaemia: CML Tl (described by Kuriyama et a!. in Blood, 74: 1989, 1381-1387, by Soda eta!. in British Journal ofHaematology, 59: 1985, 671-679 and by Drexler, in Leukemia Research, 18: 1994, 919-927 and provided by the company

15    DSMZ  (Deutsche  Sarnmlung  van  Mikroorganismen  und  Zellkulturen  GmbH)

Mascheroder Weg lb, 38124 Braunschweig, Germany), K-562 (described by Lozzio eta!., J Nat! Cancer Jnst 50: 535 (1973), by Loizio eta!., Blood 45: 321 (1975), and

provided by DSMZ No. ACC 10), KG-I a (described by Koeffler eta!., Blood 56: 265 (1980), and provided by DSMZ No. ACC 421), and Kasumi-1 (described by Asou et

20    a!., Blood 77:2031 (1991), and provided byDSMZNo. ACC 220).

The  cell  proliferation  and  viability  were  determined  in  a  test  using  3-(4,5-

dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-

tetrazolium (MTS) according to Fujishita T. eta!., Oncology, 2003, M (4), 399406.

In this test, the mitochondrial ability of the live cells to convert MTS to a coloured

25    compOund is measured after 72 hours of incubation of a compound of fonnula (I) according to the invention. The concentrations of compound according to the invention which result in a 50% loss of cell proliferation and cell ~•iability (ICso) are between 1 riM and 10 ~~depending on the tumor line and the compound tested. For

example, compound No. I has an IC50 of 40 nM on the K-562 line, an IC50 of 50 nM

30    on the KG-I a line and an IC50 of 40 nM on the Kasumi-1 line. On the K-562 line, compound No. 5 has an IC50 of 5 nM, compound No. 9 has an lCso of 19 nM, and compound No. 13 has an IC50 of 74 nM. On the SF268, compound No. 7 has an IC50
of43 nM.

Thus,  according  to  the  present invention,  it appears  that  the  compounds  of

35    formula (I) bring about a loss of proliferation and of viability of the tumour cells. It therefore appears that the compounds according to the invention have an anticancer
 

25


activity  and  an  activity  in  the  treatment  of other  proliferative  diseases  such  as

psoriasis, restenosis, atherosclerosis or AIDS, for example, and also in diseases caused

by vascular smooth muscle cell proliferation and in rheumatoid arthritis.

Thus, according to another of its aspects, a subject of the invention is medicaments which comprise a compound of formula (!), or an addition salt of the latter with a pharmaceutically acceptable acid or a hydrate or a solvate of the compound of fonnula (I).

These medicaments find their use in therapeutics, in particular in the treatment or

prevention of diseases caused or exacerbated by cell proliferation, and in particular

10    tumour cell proliferation. A product in accordance with the invention may be used for the manufacture of a medicament that is of use in the treatment of a pathological state, in particular a cancer.

As an inhibitor of tumour cell proliferation, these compounds are of use in the

prevention and treatment of leukaemias, both primary and metastatic solid tumours,

15    carcinomas and cancers, in particular: breast cancer; lung cancer; cancer of the small intestine, colon cancer and rectal cancer; cancer of the respiratory tracts, of the oropharynx and of the hypopharynx; cesophageal cancer; liver cancer, stomach cancer,
cancer of the bile ducts, gall bladder cancer, pancreatic cancer; cancer of the urinary

tracts, including kidney, urothelium and bladder; cancers of the female genital tract,

20    including uterine cancer, cen•ical cancer, ovarian cancer, chloriocarcinoma and trophoblastoma; cancers of the male genital tract, including prostate cancer, cancer of the seminal vesicles, testicular cancer, germinal cell tumours; cancers of the endocrine

glands, incuding cancer of the thyroid, of the pituitary gland, of the adrenal glands;

skin  cancers,  include  hemangiomas,  melanomas,  sarcomas,  including  Kaposi's

25    sarcoma; brain tumours, nerve tumours, eye twnours, meningeal tumours, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neurinomas, neuroblastomas, schwannomas, meningiomas; malignant hematopoietic twnours; leukaemias, (acute

lymphocytic leukaemia  (ALL),  acute  myeloid  leukaemia  (Al\1L),  chronic  myeloid

leukaemia    (CML),    chronic    lymphocytic    leukaemia    (CLL)),    chloromas,

30    plasmocytomas, T- orB-cell leukaemias, non-Hodgkin's lymphomas or Hodgkin's lymphomas, myelomas, various malignant hemopathies.

According to another of its aspects, the present invention relates to phannaceutical compositions comprising, as active ingredient, a compound according to the invention. These pham1aceutical compositions contain an effective dose of at

35    least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and also at least one pharmaceutically
 

26


acceptable  excipient.  A pharmaceutical  composition  can  also  contain,  in  addition,

another anticancer ingredient.

Said excipients are selected according to the pharmaceutical form and the method of administration desired, from the usual excipients which are knO\VIl to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual,

subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula en above, or its optional salt, solvate or hydrate, can be administered in unit administration form, as a

10    mixture with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or the treatment of the conditions or diseases above.

Appropriate unit administration forms include the oral administration forms such

as  tablets,  soft  or hard  gelatin  capsules,  powders,  granules  and  oral  solutions  or

suspensions,    sublingual,    buccal,    intratracheal,    intraocular    and    intranasal

15    administration forms, forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants, For topical application, the compounds according

    to the invention can be used in creams, gels, ointments or lotions.
    By way of example, a unit administration form of a compound according to the
20    invention in the form of a tablet can comprise the following components:
    Compound according to the invention    50.0 rng
    Mannitol    223.75 rng
    Sodium croscarmellose    6.0 mg
    Com starch    15.0 mg
25    Hydroxypropy!methylcellulose    2.25 mg
    Magnesium stearate    3.0 rng

The compounds of formula (I) above can be used at daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses ofO.l to 300 mglkg. In human beings, the dose can range preferably from 0.02

30    to 10 000 mg per day, more particularly from 1 to 3000 rng, depending on the age of the individual to be treated or the type of treatment: prophylactic or curative.
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  to  each  patient  is  determined  by  the  physician

35    according to the method of administration, and the weight and response of said patient.
 

27

According tO another of its aspects, the present invention also relates to a method of treatment of the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or one of its phannaceutically acceptable salts or hydrates or solvates.

According  to  the  present  invention,  the  compound(s)  of  formula  (I)  can  be

administered in combination with one (or more) anticancer active ingredient(s), in particular antitwnour compounds such as alkylating agents, for instance aU-..ylsulphonates (busulphan), dacarbazine, procarbazine, nitrogenous mustards (chlonnethine, melphalan,

chlorambucil),    cyclophosphamide,   ifosfamide;   nitrosoureas   such   as   carmustine,

10    lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel or taxotere; antineoplastic antibiotics such as actinomycin; intercalating agents, antineoplastic antimetabo1ites, folate antagonists,

methotrexate;  purine  synthesis  inhibitors;  purine  analogues  such  as  mercaptopurine,

6-thioguanine;  pyrimidine  synthesis  inhibitors,  aromatase  inhibitors,  capecitabine,

15    pyrimidine analogues such as fluorouracil, gemcitabine, cytarnbine and cytosine arabinoside; brequinar; topoisomerase inhibitors such as camptothecin or etoposide; anticancer honnone agonists and antagonists including tarnoxifen; kinase inhibitors,

imatinib; growth factor inhibitors; anti-inflarnmatories such as pentosane polysulphate,

corticosteroids,  prednisone,  dexamethasone;  antitopoisomerases  such . as  etoposide,

20    anthracyclines including doxorubicin, bleomycin, mitomycin and methramycin; anticancer metal complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin; interferon alpha, triphenylthiophosphoramide, altretamine; antiangiogenic agents;

thalidomide; immunotherapy adjuvants; vaccines.

According to the present invention, the compounds of formula  (I) can also be

25    administered in combination with one or more other active ingredients that are of use in one of the pathologies indicated above, for example an anti-emetic agent, pain-killer, anti-inflammatory, or anti-cachexia agent.

It is also possible to  combine with the compounds of the present invention a

radiation treatment. These treatments can be administered simultaneously, separately

30    or sequentially. 'fhe treatment will be adapted by the practitioner according to the disease to be treated.
 



35

NEW  SET  OF  CLAIMS

1.    Compound  corresponding  to  the  formula:





characterized in that Ar2 and R1 are respectively: 2, 6-dichlorophenyl and tert-butyl;

or 2-bromo-6-chlorophenyl and tert-butyl; or 2, 6-dichlorophenyl and ethyl;

or 2, 6-dibromophenyl and tert-butyl; or 2, 6-dibromophenyl and ethyl;
10    or 2, 6-dichlorophenyl  and  phenyl;

or 3, 5-dimethoxyphenyl and tert-butyl; or phenyl and tert-butyl;

or 2,6-dimethylphenyl and tert-butyl; or 2, 6-difluorophenyl and tert-butyl;

15    or    2, 6-dichlorophenyl  and  isopropyl.

2.    Compound  of  the  formula:







20    3.    Compound  according  to  Claim  1  or  2,   characterized

in  that  it  is  in:

a  non-chiral  or  racemic  form  or  a  form  enriched

in    one    stereoisomer    or    enriched    in    one

enantiomer;

25    in  that  it  is  optionally  salified;

and in that it is optionally hydrated or solvated.
 



-    36  -


4.    Pharmaceutical composition characterized in that it comprises a compound according to any one of

Claims to 3 and also at least one pharmaceutically acceptable excipient.

5.    Pharmaceutical   composition   according   to   Claim   4 1

characterized    in   that    it   further   comprises   at

least  one  other  anti-cancer  active  ingredient.

10

6.    Medicament   characterized   in   that   it   comprises   a

compound  according  to  any  one  of  Claims  1  to  3  or

an    addition   salt   of   such    a    compound    with   a

pharmaceutically    acceptable    acid,    or    else    a

15    hydrate  or  a  solvate  of  such  a  compound.

7.    Compound  according  to  any  one  of  Claims  1  to  3  as

an  anti -cancer  agent.

20    8.    Use  of  a  compound  according  to  any  one  of  Claims  1

to 3 for the preparation of a medicament intended for the treatment and for the prevention of diseases caused or exacerbated by cell proliferation.

25

9.    Use according to Claim 8 for the prevention and treatment of leukaemias, primary and metastatic solid tumours, carcinomas and cancers.

30 10. Method of preparation of a compound according to Claim 1, characterized in that a compound of formula:
 



-    37  -






in    which  R1  and  Ar2  are  as  defined  in  Claim  1  is

reacted  with  an  amine  of  formula
l~

'N~~

11.    Method  of  preparation  of  a   compound  according  to

Claim 1 1 characterized in that the following are reacted:

(i)    a  compound  of  formula:

(lib)


10

in  which:

- R1o is a leaving group such as (a) halogen, in particular Cl or Br, or (b) alkyl-S (O)m- in which m = 0, 1, or 2;

15    -  Ru  is  NHC (O) -NH-R1 ;

l~
(ii)    and  the  amine  of  formula    N~NH2

in  which:

(a)    when  R1o  is  halogen  or  alkyl-S (O)m-  with  m =

20    2, the reaction is carried out in a solvent, preferably a polar solvent, at a temperature between ambient temperature and the reflux temperature of the solvent;

25    (b)   when  R1o  is   alkyl-S (Olm-  with  m    0   or  1 1

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