slide 1

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(ll)PatentNumber: ICE 413   

(45)Dateofg..,,nt' 04/10/2010   

(ll) Appllea.don Number:KE'JP/20081000806               
               
(72) Inventor: ZHANG, Jidong of do SANOFI A VENTIS,  Departement des Brevets -Tri E2/l44 Avenue de France, F-75013 Paris.France;COMMERCON, Alain of do SANOFI A VENTIS, Depatement des    Brevets- Tri E2/144, 174 Avenue de France, F-75013 Paris.France    and HITilNGER, Augustin of do SANOFI A VENTIS,    Departementdes Brevets -Tri E2/144, 174Avenue de France, F-75013 Paris.France.   

(73)0wner:SANOFI-A VENTIS of  174 Avenue de France, F-75013 PARIS,France

(30) Priority data:06/03,209  11/0412006 FR  

(ll)FilingDate:    06/04/2007

(86)  PCTdata PCT!FR07/000585    06/0412007 WO  2007/116135    AI    18110/2007

(74) Agmt/address for correspondence:Kaplan & Stratton Advocates, P.O. Box40111-00100, Nairobi   
                       
(54)    Title:DIMERS OF ARTEMISININ DERJVATIVES, PREPARATION TiffiREOF AND THERAPEUTIC USE THEREOF.

(57)    Abstract: The present invention relates to novel dimers of specific artemisinin derivatives, to the preparntion thereof, to compositions containing them, and to their use as a medicament, in particular as anticancer agents. (I).
 
DIMERS    OF   ARTEMISININ  DERIVATIVES,   PREPARATION  THEREOF

AND  THERAPEUTIC  USE  THEREOF

The    present   invention  relates   to  dimers  of  artemisinin

derivatives,    their   preparation   and   their   therapeutic

application.

More particularly, the invention relates to dimers of artemisinin derivatives having an anticancer activity,

10    and    in   particular   a    cell    proliferation    inhibiting

activity.

Currently,    most    commercial    compounds    used    in

chemotheraphy    have   major  problems   of   side   effects,   of

15    tolerance by patients o:r of resistance. Thus, there is a great •need for novel classes of compounds capable of
acting  as  anticancer  agents.

Among natural products, artemisinin is a sesquiterpene 20 endoperoxide which was isolated in 1971 from the plant

Artemisia annua and has antimalarial properties. Some simple derivatives, such as dihydroartemisinin or artemether, have been prepared and also have antimalarial properties. In addition to this activity,

25    it has been shown that some artemisin derivatives and dimers have anticancer properties {J. Med. Chern. 2003,

46,   967-994;  patent  US  6,790,663).

The    problem   which   the   present   invention   proposes   to

30    solve is to obtain novel products in the form of artemisinin dimers having an anticancer activity.

The subject of    the    present invention   ~~~

corresponding  to  the  general  formula   (I)


in  which:

a)    A   is   a   divalent   group   chosen   from   -s-,   -so-,

-802 - ,    -NRa-,   -W (0~) Ra-,   -CONRa-,   -NRaS02 - ,    -CO-,

-COO-,    -NRaCONRb-,    -NR8 S02NRb-,    -OP (O)  {ORal 0-,

-OCONRa-,    -ocoo-,    -o-,    -c (=N-ORa)-,    or    an

epoxide,    (C1 -C6 )alkylene,    (C1 -C6 )alkenylene,

(C1 -C6 ) alkynylene, (C3 -C8 ) cycloalkylene, (C4-C8 ) - cycloalkenylene, arylene, heteroarylene or
heterocyclyl  group,  it  being  possible  for  these

last    nine   groups   to   be   optionally   substituted

with  one  or  more  substituents  Ra  or  Rb;

b)    X1 and X2 are identical or different, and are chosen from N, 0, S;

c)    B, and    B, are identical    or    different and

represent a - (CF2)p-Rc in which Rc is independently F, (C1 -C,)alkyl, (C1 -C,) alkenyl, (C1 -C,) alkynyl, (C3 -C8 ) cycloalkyl, (C.-C8 ) cyclo-alkenyl, aryl, heteroaryl, heterocyclyl, -COR1,

-COOR1, -CONR1R2, -ORl or -SRl, it being possible for these groups to be optionally substituted with one or more substituents R, or R;, which are identical or different, and p has the value

1,   2  or  3;

d)    n, and n, are identical or different and have the value 0, 1' 2' 3 or 4;


e)    Ra and Rb are identical or different and are independently chosen from: H, halogen, - {C1 -C 6 ) -

alkyl, - (C1 -C6 )alkyl-COO-R1 , - (C1 -C6 )alkyl-NR1 R,, - (C1 -C6 ) alkyl aryl, - (C1 -C6 ) alkenyl, - (C1 -C6 ) - alkynyl, aryl, heteroaryl, (C3 -C8 ) cycloalkyl,
( C4 -  C8 )  cycloalkenyl,   heterocyclyl,   -OR1 ,     -OCOR1 ,

-COR1,   -COOR1,   -CONR1R2,   -NR1R2,   -NR1COR2,   -SR1,   -

S02R1,    -CN;

10    f) R, and R, are identical or different and are independently chosen from H, (C,-C,)alkyl,
(C1 -C6 ) alkenyl, ( c,- c,) alkynyl, (C3 -C8 ) cyclo-alkyl, (CrC 8 ) cycloalkenyl, aryl, heteroaryl, heterocyclyl;

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

None    of   these   dimers  of   the   prior  art   (J.   Med.   Chern.

2003,    46,   987-994;   patent  US   6,790,863)   is   substituted

20    with a B1 or B:~ group as described above according to the present invention.

Among  the  products  of  general  formula   (I)  which  are  the

subject of the invention, there may be mentioned in 25 particular the products for which B1 and B2 are
identical  and  are  CF3 •

Among the products of general formula (I) which are the subject of the invention, there may also be mentioned

30    the products of general formula (I) for which X1 and X2 are identical and are 0.

Among these products, preferred products are those for which A is -s-, -so- or -802 - .

35

Other products of general formula (I) are those for which A is -N{CH3)-.

According    to   the   present    invention,    n 1     and   n 2     are


preferably  identical  and  have  the  value  2,   3  or  4.

Other    products   of   general   formula    (I)    are   those   for

which  A  is   chosen   from  -NH-,   -N (CH2 -C (O) 0-CHrCH3 ) -    or

-N (CH2 -COOH)-, and optionally characterized in that n 1 and n 2 are identical and have the value 2.

Other    products   of   general   formula   {I)   are   those   for

which  A  is  chosen  from   (C1 -C6 )alkenylene  or  epoxide,   and

10    optionally characterized in that n 1 and n 2 are identical and have the value 1.

Other    products   of   general   formula   {I)   are   those   for

which  A  is   chosen   from   -NHCO-   or   -1,2,3-triazole,   and

15    optionally characterized in that n1 and n 2 are different and independently have the value 1 or 2.

The    products   of   formula   (I)   may   contain   one   or   more

asymmetric    carbon   atoms.   They   can   therefore   exist   in

20    the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof,

including the racemic mixtures, form part of the invention.

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

These    salts    may   be    prepared    with    pharmaceutically

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

35    The products of formula (I) can also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.

In  the  context  of  the  present  invention:

a    halogen    atom    is    understood    to    mean:    a

fluorine,    a  chlorine,  a  bromine  or  an  iodine;

an    alkyl    group    is    understood    to    mean    a

saturated  linear  or  branched  aliphatic  group.  By  way  of

examples,    there   may   be   mentioned   the   methyl,    ethyl,

10    propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups, and the like;

a   cycloalkyl   group   is   understood   to   mean:    a cyclic   alkyl   group.   By  way   of   examples,   there   may  be 15     mentioned       the        cyclopropyl,        methylcyclopropyl, cyclobutyl,   cyclopentyl   and  cyclohexyl   groups,   and  the

like;

a    fluoroalkyl   group   is   understood   to   mean:   an

20    alkyl group in which one or more hydrogen atoms have been substituted with a fluorine atom;

an  alkenyl  group  is  understood  to  mean:   a  mono-or  polyunsaturated,   linear  or  branched,   aliphatic  group 25    comprising,     for     example,     one     or     two     ethylenic

unsaturations;

an  alkynyl  group  is  understood  to  mean:  a  mono-or  polyunsaturated,   linear  or  branched,   aliphatic  group 30    comprising,     for     example,     one    or    two    acetylenic

unsaturations;

an alkoxy group is understood to mean: an -0-alkyl radical where the alkyl group is as defined

35    above;

an aryl group is understood to mean: a cyclic aromatic group comprising from 5 to 14 carbon atoms. The phenyl, naphth-1-yl; naphth-2-yl, anthracen-9-yl,


1, 2, 3, 4-tetrahydronaphth-5-yl and 1, 2, 3, 4-tetrahydro-naphth-6-yl substi tuents are examples of aryl
substituents;

a heteroaryl group is understood to mean: a cyclic aromatic group comprising from 1 to 13 carbon atoms and from 1 to 4 heteroatoms. The pyrrol-1-yl, pyrrol-2-yl, pyrrol-3 -yl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothia:zolyl, 1, 2, 4-

10 triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, 1, 3, 5-triazinyl,

indolyl,    benzo[b]furyl,    benzo[b)thienyl,    indazolyl,

benz imidazolyl, azaindolyl, quinolyl, isoquinolyl, carbazolyl and acridyl substituents are examples of

15    heteroaryl substituent. The term ,.heteroatom" refers here to an at least divalent atom different from carbon. N, o, S and Se are examples of heteroatom.

a    cycloalkyl   group   is   understood   to   mean:   a

20    saturated or partially unsaturated cyclic hydrocarbon substituent having from 3 to 12 carbon atoms. The cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,

cycloheptyl,    bicyclo[2.2.1)heptyl,    cyclooctyl,

25    bicycle [2 .2 .2] cetyl, adamantyl and perhydronaphthyl substituents are examples of cycloalkyl substituent.

a   heterocyclyl   group   is  understood   to   mean:   a saturated   or   partially   unsaturated   cyclic   hydrocarbon 30    substituent  having  from  1  to  13  carbon  atoms  and  from  1 to          heteroatoms.     Preferably,     the     saturated    or partially   unsaturated   cyclic   hydrocarbon   substituent will  be  monocyclic  and  will  contain  4  or  5  carbon  atoms

and  1  to  3  heteroatoms.

35

It is understood that the divalent group A is capable of being bonded in the two possible directions. For example, when the divalent group A is -NHSOr, the product of general formula (I) may be:


In    accordance  with  the  present   invention,   the  products

of    general   formula    (I)   may   be   prepared   according   to

conventional    methods   of   organic  chemistry.   Examples   of

sythesis are illustrated in schemes 1 to 4 below, in which the starting materials and reagents, when their mode of preparation is not described, are commercially

available    or  are  described  in  the  literature  or  may  be

10 prepared according to methods which are described therein or which are known to persons skilled in the

art.

i    a.-f"i;-..            0           
        0        0        ''"   
                ..ElOH,.  4B;••::''"       
        ~•            ~•   
H----        H    0    ''Cf• C    :   0  ~HO .,,,   
a.-   CF1        0    CIF1    ~    0'}-t;:'i-1':.0   
        [4,-.        .,    .,   
                IIICPU 1 .1eq       
                ..... ~       
;-.    ..:~        ~--•. ..~-   
4a. ~n~)/•...            .~D.~••••   
    0~                rt<   

The    subject   of   the   present   invention   relates   to   a

process  for  preparing  a  product  of  general  formula   (I),

characterized    in   that   the   product   of   the   following

general  formula   (III):
~(Ill)
:~...
10
in  which  B  represents  a  substituent  B1  or  B2   as  defined

above, undergoes a substitution of the bromine atom with the aid of a nucleophile such as a bromoalcohol, to give a product of the following general formula


in  which  X  represents  a  substituent  X1   or  X2 ,    as  defined

above,    n   represents  n 1    or  n 2 ,     as  defined  above,   and  in

which    either   G  represents   a   leaving   group   such   as   a

bromine    atom,   and  then  this  product  of  general   formula

(II)    undergoes  a   nucleophilic  substitution  in  order  to

form a dimer of general formula (I) or a precursor of a product of general formula {I), or G represents a chemical functional group Fl, which may be optionally

activated    by   a   reduction   or   oxidation   reaction,   and

10    then this product of general formula (II) reacts with another product of formula (II) where G represents a
leaving    group   such   as   a   bromine   atom   or   a   chemical

functional    group   F2   capable   of   reacting   with   Fl,    in

order    to   form   a   dimer   of   general   formula    (I)    or   a

15    precursor  of  a  product  of  general  formula   (I) .

The   subject   of    the   present   invention   relates   more

particularly  to  the  products  of  general  formula   (II)   in

which  X  is  an  oxygen  atom,   n  has  the  value  0,   1,   2,   3

20    or 4, B is a trifluoromethyl group and G represents a bromine atom or an -N3, -NH2, alkenyl, alkynyl or -COOH group. These compounds are useful as intermediate products for the synthesis of the products of general formula (I).

25

The expression leaving group is understood to mean a group which can be easily cleaved from the molecule by breaking a heterolytic bond, with departure of an electron pair. This group may thus be easily replaced

30    by another group during a substitution reaction for example. Such leaving groups are, for example, halogens or an activated hydroxyl group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate,

triflate,    acetate   and   the   like.   Examples   of   leaving

35    groups and references for their preparation are given in "Advances in Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, p. 310-316.

The  following  examples  describe  the  preparation  of  some


products    in    accordance    with    the    invention.    These

examples    are   not   limiting   and   only   illustrate   the

present  invention.

Abbreviations:

°C    degrees   Celsius;   TLC   thin   layer   chromatography;

0  chemical   shift;   d   doublet;   dd   doublet   of   doublets;

DMSO•d6    deuterated   dimethyl   sulfoxide;   dt   doublet   of

10    triplets;    eq.    equivalent;    ES+/-    electrospray

(positive/negative    modes);   g   gram;   h   hour;   Hz   hertz;

IC50 inhibition constant at SO% of activity; J coupling constant; m multiplet; mg milligram; MHz megahertz;
ml  milliliter;    !J.l    microliter;    mm    millimeter;    IJ.m

15    micrometer; mmol millimole; ppm. parts per million; q quadruplet; Rf retardation factor; 1H NMR proton nuclear magnetic resonance; s singlet; bs broad singlet; t triplet; U. V. ultraviolet

20    BX1: {3S, SaS,6R, BaS, 9R,lOR,12R,12aR,3' s, s 'aS,6'R, a~ as,-9'R,lO'R,12'R,12 1aR)-10 110'-(thiobis{2,1-ethanediyl-oxy)] bis (decahydro-3, 6 1 9-trimethyl-10- {trifluoro-methyl) -3 1 12-epoxy-12H-pyrano [4 1 3 -j] -1 1 2-benzodioxepine

~~

~•

25    EXI   
       

a) Step 1: Preparation of {3S,SaS,6R,BaS,9R,lOR,12R,-12aR1 3' S, 5' aS, 6'R, 8' aS, 9' R, 10' R,12 1 R, 12' aR) -10- {2-bromoethoxy)decahydro-3,6,9-trimethyl-10-{tri-fluoromethyl) -3, 12-epoxy-12H-pyrano [4, 3 -j] -1, 2-

3 0    benzodioxepine  ~
 

1.2  ml  of  hexafluoropropanol   (5  eq.)   and  then  1.6  ml  of

2-bromoethanol   (10   eq.)   are   successively  added  at   room

temperature    to   a   solution   of   942   mg    (2.27   mmol)    of

(3S, SaS, 6R, BaS, 9R, lOS,l2R,12aR) -10- (bromo) decahydro-

3, 6, 9-trimethyl-10- {trifluoromethyl) -3, 12-epoxy-12H-

pyrano[4,3-j] -1,2-benzodioxepine   ,!  (prepared   according

to    Org.   Lett.   2002,   4,   757-759),   in  20  ml   of  dichloro-

10    methane. The reaction mixture is then stirred at room temperature for 2 hours 15 minutes, and then 10 ml of a saturated sodium bicarbonate solution are added. The

organic    phase   is   dried   over   magnesium   sulfate   and

evaporated  to  dryness  under  reduced  pressure.   The  oily

15    residue    obtained   is    chromatographed   on   silica   gel

conditioned  beforehand  in  heptane  and  then  eluted  with

a    linear   gradient   from   0   to   100%   of   the   mixture   B

[(Heptane/Ethyl    acetate),    (90/10),    (V/V)]    in    A

(Heptane) .   217  mg   (21%)   of   the  expected  product  .3,  are

20    obtained  in  the  form  of  an  oil.

Rf    0.45    in    the    system    (Heptane/Ethyl    acetate) ,

(90/10)'    (V/V)

ES,    m/z=461   (MNa•)

25    'H NMR at 400 Mllz on a BROKER AVANCE DRX-400 spectrometer with the chemical shifts (li in ppm) - in the solvent chloroform-dl (CDC13-dl) referenced at 7.27

at    the   temperature   of   303K:   0. 92   (partially  masked  m,

1H);    0.96   (d,   J   =   6.5  Hz,   3H);   1.01   (broad  d,   J   =  7.5

30    Hz, 3H); from 1.21 to 1.58 (m, 4H); 1.42 (s, 3H); from 1.65 to 2.06 (m, 5H); 2.36 (m, 1H); 2.66 (m, 1H); from


3.45    to 3.57 (m, 2H); 4.02 (m, 1H); 4.17 (m, 1H); 5.57 (s, 1H).

b)    Step  2:  Preparation  of  EXl

,Aof&.-o~-,Ao~~:-~~~

EX1

18    mg   (0.234   mmol)   of   sodium  sulfate  are   added,   after

10  minutes,   to  a  solution  of  215  mg   (0.47  mmol)  of  ~ in

16 ml of anhydrous ethanol, under an inert atmosphere of argon at a temperature in the region of 20°C. The

10    stirring is maintained at this temperature for about 190 hours. 20 ml of saturated sodium chloride solution are then added. The mixture is extracted with 3 X 20 ml of ethyl acetate. The organic phases are combined, washed with 20 ml of a saturated NaCl solution, dried

15 over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue obtained is
chromatographed  on  silica  gel  conditioned  beforehand  in

heptane,    and  then  eluted  with  a   linear  gradient   from  0

to    100%   of   the   mixture   B    [(Heptane/Ethyl   acetate),

20    (85/15), (V/V)] in A (Heptane). 60 mg (33%) of the expected product EXl are obtained in the form of a

foam.

Rf    0.20    in    the    system    (Heptane/Ethyl    acetate),

(90/10),    (V/V)

25    ES,  m/z=835  (M  + HCOOH-H).

1 H NMR at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced

at  2.50  ppm  at  the  temperature  of  303K:   0.86   (partially

30    masked  m,   2H);   0.90   (d,   J   =  6.5  Hz,   6H);   0.93   {broad  d,

J = 7.5 Hz, 6H); 1.22 (m, 2H); from 1.27 to 1.60 (m, 8H); 1.31 (s, 6H); 1.66 (m, 2H); from 1.75 to 1.89 (m, 4H); 2.04 (m, 2H); 2.21 (m, 2H); 2.67 (m, 2H); from

2.71    to  2.87   (m,   4H);  3.64   (m,   2H);  3.94   (m,   2H);  5.58


(s,    2H)

EX2:    (3S, SaS, 6R, BaS, 9R,lOR,12R, 12aR, 3 1 S, 5' aS, 6'R, 8 1 aS,-

9'R,lO'R,12'R,l2'aR)-10,10'-[sulfinylbis(2,1-ethane-

diyloxy) J bis [decahydro-3, 6, 9 -trimethyl-10- (trifluoro-

methyl) -3, 12-epoxy-12H-pyrano [4, 3-j] -1, 2-benzodioxepine

and    EX3:    {3S,SaS,6R,8aS,9R,lOR,12R,12aR,3'S,S'aS,6 1 R,-

8'aS,9'R,lO'R,l2'R,l2'aR)-10,10'-[sulfonylbis(2,1-

ethanediyloxy)] bis [decahydro-3, 6, 9-trimethyl-10-tri-

10    fluoromethyl)- 3, 12-epoxy-12H-pyrano [ 4, 3 -j] -1, 2 -benzo-dioxepine


16.4  mg   ( 0. 066  mmol)   of  meta-chloroperbenzoic  acid  are

15    slowly added to a solution of 35 mg (0.044 mmol) of EXl in 3 ml of dichloromethane at a temperature in the region of 20°C. The stirring is maintained at this temperature for about 3 hours and then 3 ml of a saturated sodium bicarbonate solution are added. The

20    mixture   is  extracted  with  3  x   10  ml   of   ethyl   acetate.

The  organic  phases  are  combined,   washed  with  2  x  10  ml of  a   saturated  aqueous  sodium  chloride  solution,   dried over   magnesium   sulfate,    filtered   and   evaporated   to dryness    under    reduced    pressure.    The    oily    residue 25    obtained   is   chromatographed  on   silica   gel   conditioned beforehand   in  heptane,   and   then   eluted   with   a   linear gradient   from   0   to   100%   of   ethyl   acetate   in   heptane.

14.5 mg {40%) of the product EX3 are obtained in the form of a white solid:

30    Rf    0.60    in    the    system    (Heptane/Ethyl    acetate),

(50/50),    (V/V)


ES,    m/z=667   (M  +  HCOOH-H)-

1H    NMR    at    500    MHz    on    a    BROKER    AVANCE    DRX-500

spectrometer with the chemical shifts (8 in ppm) - in the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced at 2.50 ppm at a temperature of 298K: 0.85 (partially masked m, 2H); 0.89 (d, J = 6.5 Hz, 6H); 0.92 (broad d,

J    =   7.5   Hz,   6H);   1.16   (m,   2H);   1.32   (s,   6H);   1.36   (m,

2H);    from  1.47  to  1.58   (m,   6H);   1.62   (m,  2H);   1.71   (m,

2H);    1.64   (m,   2H);   2.04   (m,   2H);   2.21   (m,   2H);   2.66   (m,

10    2H); 3. 46 (m, 2H); 3. 59 (m, 2H); 3. 63 (m, 2H); 4.19 (m, 2H); 5.63 (e, 2H).

and  12.4  mg   (35%)   of   the  product  EX2   in  the   form  of   a

white  foam:

15    Rf    0.22    in    the    system    {Heptane/Ethyl    acetate),

(SO/SO),    (V/V)

ES'    m/z=651   (M  + HCOOH-H)-

1 H    NMR    at    500    MHz    on    a    BROKER   AVANCE    DRX-500

spectrometer    with   the   chemical   shifts   (8  in  ppm)   -   in

20    the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced at 2.50 ppm at a temperature of 298K (a 50%-sot mixture

of    isomers) :    0. 85    (partially   masked   m,    2H);   o. 88   {d,
J    =  6.5  Hz,    3H);   0.90   (d,   J   =  6.5  Hz,   3H);   0.93   (broad
d,    J   =   7.5    Hz,   6H);   from  1.14   to   1. 69    (m,   16H);   1. 31

25    (e, 3H); 1.32 (e, 3H); 2.03 (m, 2H); 2. 20 (m, 2H); 2. 67 (m, 2H); 2.96 (m, 2H); 3.12 (m, 2H); 3.79 (m, 1H); 3.67 (m, 1H); from 4.11 to 4. 20 (m, 2H); 5.56 (e, 1H); 5.61 (s, 1H).


30    EX4: {3S,5aS,6R,BaS,9R,lOR,l2R,l2aR,3'S,5'aS,6'R,B'aS,-

9'R,lO'R,l2'R,l2'aR)-l0,10'-[thiobis(3,1-propanediyl-oxy)] bis [decahydro-3, 6, 9-trimethyl-10- (trifluorometh-yl) -3, 12-epoxy-12H-pyrano [4, 3-j] -1, 2-benzodioxepine
f)P .. _,
"''"    "'H


a)    Step 1: Preparation of (3S, SaB,6R, BaS, 9R,lOR,l2R,-12aR,3 'S,S 'aS, 6'R, B 'aB,9'R, 10 'R,l2'R,l2 'aR) -10 {3-bromo-

propoxy)decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-

3,12-epoxy-12H-pyrano [4, 3-j] -1, 2-benzodioxepine  ~


0.607  ml  of  hexafluoropropanol   (5  eq.)   and  then  1.03  ml

of    3-bromopropanol   (10   eq.)   are   successively  added   at

10    room  temperature  to  a  solution  of  471  mg   (1.14  mmol)   of

.!  in   7   ml   of   dichloromethane.   The   reaction  mixture   is

then    stirred    at    room    temperature    for    hours

30  minutes,    and   then    ml    of   a    saturated   sodium

bicarbonate    solution   are   added,   the   organic   phase   is

15    dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oily residue
    obtained   is   chromatographed   on   silica   gel   conditioned
    beforehand   in   heptane   and   then   eluted   with   a   linear
    gradient    from    to    100%    of    the    mixture    B
20    [(Heptane/Ethyl    acetate),    (90/10),    (V/V)]    in    A

{Heptane) . .2.29 mg {43%) of the expected product ,! are obtained in the form of an oil.

Rf 0. 38 in the system (Heptane/Ethyl acetate), (90/10)' (V/V)

25    CI' m/z=490 (MNH,)•; m/z=354 (m/z=490 - BrCH2CH2CH20H + 2H)•

'H NMR at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts {0 in ppm) - in the solvent chloroform-d1 {CDC13-d1) referenced at 7 . .27

30    ppm at the temperature of 303K: 0. 90 {partially masked m, 1H); 0.97 (d, J = 6.5 Hz, 3H); 1.00 (broad d, J = 7.5 Hz, 3H); from 1..2.2 to 1.54 {m, 4H); 1.44 {s, 3H); from 1. 60 to 1. 73 {m, .2H) ; 1. 8.2 (m, 1H) ; 1. 91 (m, 1H) ;
 


- 17  -

from 2.00 to 2. 20 (m, 3H); 2.39 (m, 1H); 2.87 (m, 1H); from 3. 45 to 3. 55 (m, 2H); 3.80 (m, 1H); 3. 94 (m, 1H); 5.41 (s, 1H).

o>  ""'        ~of:~4.....    ~•••   
    -  "oj<o~    0    ..~....,H   
        o       
    '}£"=           
    '--Z_Br    0~•~   
    !        El4   

18.2  mg   (0.23  mmol)   of   sodium  sulfide  are  added,   after

10    minutes,   to  a   solution  of  220  mg   (0.46  mmol)   of  the

product  3  in  16  ml  of  anhydrous  ethanol,  under  an  inert

10    atmosphere of argon at a temperature in the region of 20°C, the stirring is maintained at this temperature for about 80 hours and then 20 ml of a saturated sodium chloride solution are added. The mixture is extracted with 3 X 20 ml of ethyl acetate. The organic phases are

15    combined, washed with 20 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oily residue obtained is chromatographed on silica gel conditioned beforehand in heptane and

20    then eluted with a linear gradient from 0 to 100% of the mixture B [(Heptane/Ethyl acetate), (85/15), (V/V)] in A (Heptane) . 103 mg {54%) of the expected product EX4 are obtained in the form of a white solid.

Rf    0.20    in    the    system    (Heptane/Ethyl    acetate),

25    (90/10),   (V/V)

ES:    m/z=841  MNa+

1 H NMR. at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts {0 in ppm) - in the solvent chloroform-d1 (CDC13-d1) referenced at 7.27

30    at   the   temperature   of   303K:   0. 93   {partially  masked  m,

2H); 0.97 (d, J = 6.5 Hz, 6H); 1.00 (broad d, J = 7.5 Hz, 6H); from 1.22 to 1.38 (m, 4H); 1.43 (s, 6H); from 1.44 to 1.55 (m, 4H); from 1.63 to 1.74 (m, 12H); 2.04 (m, 2H); 2.38 (m, 2H); from 2.51 to 2.66 (m, 4H);


2.85   (m,   2H);   3.71   (m,   2H);   3.91   (m,   2H);   5.37   (s,   2H).

EXS:    (38, 5aS, 6R, Bas, 9R, lOR,l2R,12aR,3 • s, 5'aS,6'R, B 'aS,-

9'R,l0'R,l2'R,l2'aR)-10,10'-[sulfinylbis(3,1-propane-

diyloxy)] bis (decahydro-3, 6, 9-trimethyl-10- {trifluoro-

methyl) -3, 12-epoxy-12H-pyrano [4, 3-j] -1, 2-benzodioxepine

and    EX6:    (3S,SaS,6R, BaS, 9R, lOR,l2R,l2aR,3 'S,S'aS, 6'R,-

8'aS,9'R,lO'R,l2'R,l2'aR)-10,10'-[sulfonylbis(3,1-

propanediyloxy))bis[decahydro-3,6,9-trimethyl-10-

10    (trifluoromethyl I -3, 12-epoxy-12H-pyrano [4, 3 -j] -1, 2-

benzodioxepine

9.1  mg   (0.036   mmol)   of   meta-chloroperbenzoic   acid  are

slowly  added  to  a   solution  of  21.4   mg   (0.026  mmol)   of

15    EX4 in 2 ml of dichloromethane at a temperature in the region of 20°C. The stirring is maintained at this temperature for about 3 hours and then 3 ml of a saturated sodium bicarbonate solution are added. The mixture is extracted with 3 X 10 ml of ethyl acetate.

20    The organic phases are combined, washed with 2 X 10 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oily residue obtained is chromatographed on silica gel conditioned

25    beforehand in heptane and then eluted with a linear gradient from 0 to 100% of ethyl acetate in heptane. 7. 7 mg {34%) of the product EX6 are obtained in the

form  of  a  white  solid.

Rf    0.68    in   the    system    {Heptane/Ethyl    acetate),

30    (50/50),   (V/V)

ES:  m/z=873  MNa+


1H    NMR    at    400    MHz    on    a    BRUKER   AVANCE    DRX-400

spectrometer    with  the   chemical   shifts   (0  in  ppm)   -   in

the  solvent  chloroform-dl   (CDC13-dl)   referenced  at  7.27

at the temperature of 303K: 0.92 (partially masked m, 2H); 0.97 (d, J . 6. 5 Hz, 6H); 1. 00 (broad d, J . 7.5 Hz, 6H); from 1.23 to 1. 38 (m, 4H); 1. 43 (s, 6H); from

1.44 to 1.72 (m, 8H); 1. 83 (m, 2H); 1. 92 (m, 2H); 2.05 (m, 2H); 2.12 (m, 4H); 2 .38 (m, 2H); 2. 87 (m, 2H); 3.00 (m, 2H); 3.13 (m, 2H); 3. 75 (m, 2H); 3.97 (m, 2H); 5.34

10    Is,  2H).

and    8. 5   mg   (39%)   of   the   product   EXS   in  the   form  of   a

white  foam.

Rf    0.20    in   the    system    (Heptane/Ethyl    acetate),

(50/50),    (V/V)

15    ES:  m/z=B57  MNa+

1H NMR at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in

the  solvent  chloroform-dl   (CDC13-dl)   referenced  at  7.27

at    the    temperature    of    303K    (50%-SO%    mixture    of

20    isomers) :   0. 90   (partially  masked  m,   2H) ;   0. 97   (d,   J   =

6.5 Hz, 6H); 1.00 (broad d, J = 7.5 Hz, 6H); from 1.24 to 1.36 (m, 4H); 1.43 (s, 6H); from 1.45 to 1. 72 (m, BH); 1.82 (m, 2H); 1.92 (m, 2H); from 2.00 to 2.11 (m, 6H), 2.38 (m, 2H); from 2.68 to 2.82 (m, 4H); 2.86 (m,

25    2H); 3.77 (m, 2H); 3.96 (m, 2H); 5.33 (s, 1H); 5.35 (s, 1H).

EX7: (3S,SaS,6R, 8aS,9R, lOR,12R,12aR,3 'S,S 'aS,6 'R, 8 'aS,-

9 'R, 10 1 RI12 'RI12 'aR) -10 I 10 r - [thiobis (4, 1-butanediyl-3 o oxy)] bis [decahydro-3, 6 1 9-trimethyl-10- (trifluoro-



a)    Step    1:    Preparation    of    3S, SaS, 6R, SaS, 9R, lOR,-

12R,l2aR,3'S,S'aS,6'R,B'aS,9'R,lO'R,l2'R,l2'aR)-10-(4-

bromobutoxy)decahydro-3,6,9-trimethyl-lO-(trifluoro-

methyl) -3, 12 -epoxy-12H-pyrano [4, 3 -j] -1, 2-benzo-dioxepine, !




1.36 ml of hexafluoropropanol (5 eq.) and then 2.5 g of 4-bromobutanol (6.3 eq.) are successively added at room temperature to a solution of 1.07 g (2.58 mmol) of ! in

10    15  ml  of  dichloromethane.   The  reaction  mixture  is  then

stirred  at   room  temperature  for   3  hours  and  then  6  ml

of  a   saturated  sodium  bicarbonate  solution.   The  organic

phase    is   dried   over   magnesium   sulfate,   filtered   and

evaporated    to  dryness  under  reduced  pressure.   The  oily

15    residue    obtained    is    chromatographed    on    silica    gel

conditioned  beforehand  in  heptane  and  then  eluted  with

a    linear   gradient   from   0   to   100%   of   the   mixture   B

[(Heptane/Ethyl    acetate),    (90/10),    (V/V)]    in    A

(Heptane).   90   mg   (7%)   of   the   expected   product   .!  are

20    obtained  in  the  form  of  an  oil.

Rf  = 0.40   in  the  system   (Heptane/Ethyl  acetate),   (9/1),

(V/V)

CI:    m/z=504  ~+

1 H    NMR    at    400    MHz    on    a    BRUKER    AVANCE    DRX.-400

25    spectrometer with the chemical shifts (S in ppm) - in the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced at 2.50 ppm at the temperature of 29BK: 0.92 (partially

masked  m,   lH);   0.97   (d,   J   =  6.0  Hz,   3H);   1.00   (broad  d,

J    =  7.5  Hz,   3H);  from  1.05  to  1.62   (partially  masked  m,

30    6H); 1.43 (s, 3H); from 1.65 to 2.10 (m, 7H); from 2.33 to 2. 45 (m, 1H) ; 2. 94 (m, 1H) ; from 3. 4 0 to 3. 51 (m, 2H), 3.63 (m, lH); 3.BB (m, lH); 5.32 (s, lH).

b)    Step  2:  preparation  of  BX7
 
s. 7 mg (0. 073 mmol) of sodium sulfide are added after 10 minutes to a solution of 90 mg (0.19 mmol) of i in

s  ml  of  anhydrous  ethanol,  under  an  inert  atmosphere  of

argon at a temperature in the region of 20°C. The stirring is maintained at this temperature for about 42 hours and then 5 ml of a saturated sodium chloride solution are added. The mixture is extracted with 3 x

5  ml  of  ethyl  acetate.  The  organic  phases  are  combined,

10    washed with 5 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oily residue obtained is chromatographed on silica gel

conditioned  beforehand  in  heptane  and  then  eluted  with

15    a linear gradient from 0 to 20% of ethyl acetate in heptane. 33 mg (SO%) of the expected product BX7 are obtained in the form of a foam.

Rf  =  0.20  in  the  system   (Heptane/Ethyl  acetate),   (9/1),

(V/V)

20    ES:   m/z=B91   (M  +  HCOOH-H).

1 H NMR at 400 MHz on a BROKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in

the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced at 2.50 ppm at the temperature of 29BK: 0.93 (partially

25    masked m, 2H); 0. 97 (d, J = 6. 0 Hz, 6H); 1. 00 (broad d, J = 7.5 Hz, 6H); from 1.22 to 1.37 (m, 4H); 1.43 (s,

6H) ; 1. 50 (m, 4H) ; from 1. 62 to 1. 86 (m, 14H) ; 1. 91 (m, 2H); 2.04 (m, 2H); 2.38 (m, 2H); 2.54 (m, 4H); 2.84 (m, 2H); 3.62 (m, 2H); 3.85 (m, 2H); 5.33 (s, 2H).

30

EX8:    2- [ [ (3R, SaS,6R, BaS, 9R,10R, 12R 1 12aR) -decahydro-

3, 6, 9-trimethyl-10- (trifluoromethyl) -3,12-epoxy-12H-

pyrano [ 4, 3 -j] -1, 2-benzodioxepin-10-yl] oxy] -N- [2-

[ [ (3R, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -decahydro-3, 6, 9-


trimethyl-10- (trifluoromethyl) -3, 12-epoxy-12H-pyrano [ 4, 3 -j] -1,2 -benzodioxepin-10-yl] oxy] ethyl] -N-


EX8

33    mg    (0.218   mmol)    of    sodium   iodide   and   0.545   ml

(1.09  mmol)    of   a    2M   methylamine   solution   in   tetra-

hydrofuran  are  successively  added  to  a  solution  of  100

mg    (0.218  mmol)   of  compound~ in  0.6  ml  of  tetrahydro-

furan  under  an  inert  argon  atmosphere  at  a  temperature

10    in  the   region   of   20°C.   The   stirring   is  maintained  at

40°C  for  about  20  hours.   The  reaction  mixture  is  taken

up   in   3  ml   of   a   saturated   aqueous   sodium  bicarbonate sol uti on    and    then    extracted    with         x         ml    of dichloromethane.   The   organic   phases   are   combined   and 15    then    dried    over    magnesium    sulfate,     filtered    and

evaporated  to  dryness  under  reduced  pressure.   The  oily

residue    obtained    is    chromatographed    on    silica    gel

conditioned beforehand in heptane and then eluted with a gradient from 0 to 30% of ethyl acetate in heptane.

20    15 mg (18%) of the expected product BXB are obtained in the form of a white solid.

Rf    =  0.25  in  the  system   (Heptane/Ethyl  acetate),   (7/3),

(V/V)

ES,    m/z=788  Mll'

25 1 H NMR at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in the solvent chloroform-d1 (CDC13-d1) referenced at 7.27 at the temperature of 303K after addition of a drop of acetic acid-d4 (CD30D-d4) : 0. 91 (partially masked m,

30    2H);   0.95    (d,   J    =   6.5   Hz,    6H);    0.98    (broad   d,    J    =

7.0  Hz,   6H);   1.28   (m,   2H);   from  1.33  to  1.63   (m,   SH);

1.39 (s, 6H); 1.69 (m, 2H); 1.78 (m, 2H); 1.89 (m, 2H); 2.02 (partially masked m, 2H); 2.36 (m, 2H); 2.86
 

(partially masked m, 2H); 2.89 (s, 3H); 3.38 (m, 4H); 4.19 (m, 4H); 5.38 (s, 2H).

EX    9:    2-{ [ (38, Sa8, 6R, 8a8, 9R, lOR, 12R, 12aR) -3,6, 9-

trimethyl-10-(trifluoromethyl)decahydro-3,12-

epoxy [1, 2] dioxepino [4, 3-i] isochromen-10-yl] oxy} -N- (2-{ [ ( 38, Sa8, 6R, 8a8, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10-
(trifluoromethyl)decahydro-3,12-epoxy[l,2]dioxepino-

[4,3-i] isochromen-10-yl] oxy}ethyl) ethanamine

~~~0;f0
10    ...

a)    step  1:  preparation  of

(3R, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -10- {2-azidoethoxy)-

3, 6, 9-trimethyl-10- (trifluoromethyl) decahydro-3, 12-

15    epoxy[l,2]dioxepino[4,3-i]isochromene  ~


162.5 mg (2. 5 mmol) of sodium azide are added to a solution of 574 mg {1.25 mmol) of compound ! in 20 ml

20    of dimethylformamide under an inert atmosphere of argon at a temperature in the region of 20°C. The stirring is

maintained at a temperature in the region of 20°C for 3 hours. The reaction mixture is taken up in 60 ml of distilled water and then extracted with 2 x 100 ml of

25    ethyl acetate. The organic phase is washed with 2 x 80 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. 527 mg (quantitative yield) of the expected product 5 are obtained in the


form  of  a  yellow  oil.

Rf  = 0.43  in  the  system  (Heptane/Ethyl  acetate),   {8/2),

(V/V)

1 H NMR (CDC1 3 , 400 Mllz) Oppm' 5.48 (s, 1H); 3.97 (m, 1H); 3.78 (m, 1H); 3.48 (m, 2H); 2.88 (qu, 1H); 2.39 (td,

1H); 2.05 (dt, 1H); 1.97-1.88 (m, 1H); 1.87-1.77 (m, 2H); 1.76-1.68 (m, 1H); 1.53 (m, 1H); 1.50 (m, 1H); 1.43 (s, 3H); 1.39-1.25 (m, 2H); 1.03 (d, 3H); 1.01-0.89 (m, 1H); 0.98 (d, 3H).

10

b)    step  2:  preparation  of

2- { [ (3R, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9 -trimethyl-10-

(trifluoromethyl)decahydro-3,12-epoxy[l,2]dioxepino-

[4, 3-i] isochromen-10-yl] oxy) ethanamine,  !
4i4l
o...........,...,    I    ~ ....
15

328  mg   (1.25  mmol)   of  triphenylphosphine  are  added  to  a

solution  of  527  mg   {1. 25  mmol)   of  compound  2, in  7  ml  of

tetrahydrofuran  under  an  inert  atmosphere  of  argon  at  a

20    temperature in the region of 20°C. The stirring is maintained at a temperature in the region of 20°C for

about    24   hours.   The   reaction   mixture   is   taken   up   in

1  ml   of   distilled   water   and   then   the   stirring   is

continued    for   about   24   hours   at   the   same   temperature.

25    The reaction mixture is concentrated under vacuum and the residue thus obtained is taken up in 5 ml of dichloromethane, washed with 2 ml of a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to dryness

30    under reduced pressure. The oily residue obtained is chromatographed on silica gel conditioned beforehand in dichloromethane and then eluted with a linear gradient

from    to    100%    of    the    mixture    B

[ {Dichloromethane/Methanol) ,    (90/10).    (V/V)]    in    A


(Dichloromethane) .  344  mg   (70%)   of  the  expected  product

!  are  obtained  in  the  form  of  a  white  powder.

MS:    Es•:   [M+H] •  =  3 9 6 .

1 H  NMR  spectrum  at   400  MHz  on  a  BRUKER  AVANCE  DRX-400

spectrometer    with  the   chemical   shifts   (li  in  ppm)   -   in

the  solvent  chloroform-dl   (CDC13-dl)   referenced  at  7.27

at    the   temperature   of   303K:   0. 94   (partially  masked  m,

1H);    0.97    (d,    J   =  6.5   Hz,    3H);   1.03    (broad   d,    J   =

7.0Hz,   3H);   1.30   (m,   2H);   from   1.40   to  1.56   (m,   2H); 10     1.42   (s,   3H);   from  1.63  to  1.95   (m,   4H);   2.04   (m,   1H); 2.38   (m,   1H);   2.45   (m   spread,   2H);   2.87   (m,   1H);   2.94
(m,    2H);   3.75   (m,   1H);  3.85   (m,   lH);   5.42   (s,   1H).

c)    step  3:  preparation  of  BX9
~~        o'   
    •.~....0•.•   
    ...,CF,CF    !    l-H-.,   
~    0~~0    ex.   
I    a       
15           

98    mg    (0.593    mmol)    of    potassium    iodide,    164    mg

(1.19  mmol)    of    potassium    carbonate    and    232    mg

(0.587  mmol)   of  compound  ,!  are   successively  added  to  a

20    solution of 282 mg {0.534 mmol) of compound.,! in 7 ml of dimethylformamide under an inert atmosphere of argon at a temperature in the region of 20°C. The stirring is

maintained at 70°C for about 7 hours. The reaction mixture is concentrated to dryness under reduced

25    pressure. The residue obtained is taken up in 10 ml of dichloromethane and then washed with 6 ml of distilled water, the aqueous phase is again extracted with 10 ml of dichloromethane. The combined organic phases are

washed    with    ml    of    a    saturated    aqueous    sodium

30    bicarbonate solution and then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue obtained is chromatographed on silica gel conditioned befor~hand in the mixture (Heptane/Ethyl acetate), (9/1), (V/V) and


then    eluted   with   a   gradient   from   10   to   60%   of   ethyl

acetate    in   heptane.    116   mg    (28%)    of   the   expected

product    EX9   are  obtained  in  the   form  of   a   pale  yellow

solid.
Rf    = 0.16   in  the  system   (Heptane/Ethyl  acetate),    (8/2),

(V/V)

MS:    ES':   [M+H]•  =  774.

ES.:    [M+HCOOH+H] • = 818 .

10    1 H  NMR  spectrum  at   400  MHz  on  a  BRUKER  AVANCE  DRX-400

spectrometer with the chemical shifts {5 in ppm) - in the solvent chloroform-dl (CDC13-dl) referenced at 7.27 at the temperature of 303K: 0.92 {partially masked m,
2H);    0.98    (d,    J    =  6.5   Hz,    6H);   1.00    (broad   d,    J    =

15    7.0 Hz, 6H); from 1.20 to 1.39 (m, 4H); 1.42 (s, 6H); from 1.40 to 1.83 (m, llH); 1.90 (m, 2H); 2.03 (m, 2H); 2.38 (m, 2H); from 2.73 to 2.91 (m, 6H); 3.75 (m, 2H); 3.91 (m, 2H); 5.47 (s, 2H).

20    EX    10:    ethyl    N, N-bis (2- { [ (3S, 5aS, 6R, BaS, 9R, lOR,-

12R, 12aR) -3,6, 9-trimethyl-10- (trifluoromethyl) deca-

hydro-3, 12-epoxy [1,2] dioxepino [4, 3-i] isochromen-10-
yl]oxy:f;.~glyc~    JJ-.  ~•-~
~"V...
''"'
25

15 J!l ( 0 .133 mmol) of the ethyl ester of bromoacetic acid, a mg (0.047 mmol) of potassium iodide and 10 mg (0. 071 mmol) of potassium carbonate are successively added to a solution of 37 mg (0.047 mmol) of the

30    compound !.!! in 1 ml of dimethylformamide under an inert atmosphere of argon at a temperature in the region of 20°C. The stirring is maintained at 50°C for 1 hour. •The reaction mixture is concentrated to dryness under reduced pressure. The residue obtained is taken
 


-    27  -

up    in  5  ml   of   ethyl  acetate  and  then  washed  with  3  ml

of    distilled   water   and   the   aqueous   phase   is   again

extracted  with  2  X  5  ml  of  ethyl  acetate.   The  combined

organic  phases  are  washed  with  2  X  5  ml  of  a   saturated

aqueous sodium chloride solution and then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue obtained is chromatographed on silica gel conditioned beforehand

and  then  eluted  in  the  mixture   (Heptane/Ethyl  acetate),

10    (80/20),    (V/V).    30   mg    (74%)    of   the   expected   product

BXlO  are  obtained  in  the  form  of  a  colorless  paste.

TLC    Rf   ==   0. 49   in   the   system   {Heptane/Ethyl   acetate) 1

(7/3),    (V/V)

MS:    ES':   [M+H] •  :   860.

15    ES.:   [M+HCOOH+H] •  :   904

1 H  NMR  spectrum  at   400  MHz  on  a  BRUKER  AVANCE  DRX-400

spectrometer with the chemical shifts (5 in ppm) - in the solvent chloroform-d1 (CDC13-d1) referenced at 7.27 at the temperature of 303K: from 0.80 to 1.00 (m, 14H);

20    from   1.19   to   1. 38   (partially  masked   m,   4H);   1. 28   (t,

J:    7.0   Hz, 3H);    1.40 (s, 6H); from   1.44   to   1.58

(partially    masked  m,   4H) ;   from   1. 61   to   1. 82   (m,   6H);

1.89 (m, 2H); 2.02 (m, 2H); 2.36 (m, 2H); from 2.70 to 2.90 (m, 4H); 3.02 (m, 2H); 3.40 (d, J: 17.5 Hz, 1H);

25    3.61 (m, 2H); 3.67 (d, J: 17.5 Hz, 1H); 3.98 (m, 2H); from 4.06 to 4.22 (m, 2H); 5.40 (s, 2H).

EX 11: N,N-bis(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-

3, 6, 9-trimethyl-10- (trifluoromethyl) decahydro- 3, 12-

30    epoxy [1, 2] dioxepino [4, 3-il isochromen-10-yl] oxy}ethyl)-glycine
x.& ~-~•• -~
•~~    ~~~ ~~~
''"' -../    .., y

59    J.ll    (0.059   mmol)   of   a   1N   aqueous   sodium   hydroxide


solution  are  added  to  a   solution  of  10  mg   {0.011  mmol)

of    the    compound   !!!Q.  in   a. 5   ml   of   methanol    at    a

temperature    in   the   region   of   20°C.    The   stirring   is

maintained  at  the  same  temperature  for  about  6.5  hours.

The reaction mixture is concentrated to dryness under reduced pressure. The residue obtained is taken up in

3  ml   of   ethyl   acetate  and  then  washed  with  1   ml   of   a

saturated  aqueous  sodium  chloride  solution.  The  aqueous

phase    is   again  extracted  with   3   ml   of   ethyl   acetate.

10    The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under
reduced    pressure.    The    residue    obtained    is

chromatographed    on   silica   gel   conditioned   beforehand

and    then    eluted    in    the    mixture

15    (Dichloromethane/Methanol),    (95/05),    (V/V).    mg   (81%)

of    the   expected  product  EXll   are  obtained  in  the   form

of  a  colorless  solid.

MS:    ES':   [M+H]'  = 832

ES•:    [M-H]"  =  830.

20    1H  NMR  spectrum  at   300  MHz  on  a   BRUKER  AVANCE  DRX-400

spectrometer    with  the   chemical   shifts   {0  in  ppm)   -   in

the    solvent  chloroform-dl   (CDC13-dl)   referenced  at  7.27

at    the   temperature   of   303K:   0. 92   {partially  masked  m,

2H);    0.97    (d,    J    =  6.5   Hz,    6H);   1.01    (broad   d,    J    =

25    7.0  Hz,    6H);   from   1.20   to   1.38    (partially   masked   m,

4H);   1.42   (s,   6H);   from  1.44  to  1.75   (m,   BH);   from  1.80

to 2.10 (m, 6H); 2.39 (m, 2H); from 2.80 to 3.02 (m, 6H); 3.38 (d, J = 17.5 Hz, lH); 3.55 (d, J = 17.5 Hz, lH); from 3.77 to 3.98 (m, 4H); 5.32 (s, 2H).

30

EX    12:    2- { [ (38, 5aS, 6R, BaS, 9R, lOR, 12R, 12aR) -3,6, 9-

trimethyl-10- {trifluoromethyl) decahydro-3,12-

epoxy [1, 2] dioxepino [4, 3-i] isochromen-10-yl] oxy }-N- (2-{ [ ( 38, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10-

35    (trifluoromethyl) decahydro-3, 12-epoxy [1, 2] dioxepino-[4, 3-i] isochromen-10-yl] oxy}ethyl) acetamide
 


a)    step    1, preparation    of { [(3R,5aS,6R,8aS,9R,10R,-

12R, 12aR) -3, 6, 9-trimethyl-10- (trifluoromethyl) deca-

hydro-3, 12-epoxy [1,2] dioxepino [4, 3-i) isochromen-10-

"'-l••ey»•~' ~



117    mg   {0.742  mmol)   of  potassium  permanganate  and  then

10    11  mg    (0.127  mmol)    of    sodium    bicarbonate    are

successively  added  at  room  temperature  to  a   solution  of
100    mg    (0.255   mmol)    of   2   (prepared   according    to

W02003035651),    in  2  ml  of  acetone.   The  reaction  mixture

is    then   stirred   at   room   temperature   for   3   hours   and

15    then 1 eq. of a lN aqueous hydrochloric acid solution are added. The stirring is continued at room temperature for about 18 hours. The reaction medium is

filtered    and   then   evaporated  to  dryness   under   reduced

pressure.   The  residue  obtained  is  taken  up  in  10  ml  of

20    ethyl acetate. The organic phase is washed with 3 ml of distilled water, the aqueous phase is acidified with 2 ml of a 1N aqueous hydrochloric acid solution and then extracted with 10 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and

25    then evaporated to dryness under reduced pressure. 27 mg (26%) of the expected product ! are obtained in

the  form  of  a  white  solid.
1 H NMR (CDC1 3 , 300 MHz) s_, 5.47 (s, 1H); 4. 67 (d, 1H); 4.26 (d, 1H); 2.91 (qu, 1H); 2.38 (td, 1H); 2.19 (dq,

30    1H); 2.04 (dt, 1H); 1.90 (m, 1H); 1.77 (m, 2H); 1.70 (m, 1H); 1.59-1.48 (m, 1H); 1.48-1.45 (m, 1H); 1.42 (s,
 


3H);    1.40-1.24   (m,   2H);   1.05   (d,   3H);   0.98-0.87   (m,

1H);    0. 96  (d,   3H) .

b)    step  2:  preparation  of  EX12
~-•    n~EX1Z   
Io       

36    mg   (0.27   mmol)    of   hydroxybenzotriazole   and   52  mg

(0. 27   mmol)   of   1- (3-dimethylaminopropyl) -3-ethylcarbo-

diimide    hydrochloride    are    successively   added   to    a

10    solution of 37 mg (0.09 mmol) of the compound! in 3 ml of dichloromethane under an inert atmosphere of argon at a temperature in the region of 20°C. The stirring is maintained at a temperature in the region of 20°C for

about    30   minutes   and   then   39   mg   (0. 099   mmol)   of   the

15    compound ! are added. The stirring is continued at this temperature for 1 hour. The reaction mixture is taken up in 5 ml of distilled water and then extracted with

3 x 20 ml of ethyl acetate. The organic phase is washed with 2 X 10 ml of a saturated aqueous sodium chloride

20    solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The

residue    obtained    is    chromatographed   on    silica    gel

conditioned    beforehand   in   the   mixture    (Heptane/Ethyl

acetate),    (90/10),    (V/V)    and    then   eluted   with    a

25    gradient from 10 to 20%: of ethyl acetate in heptane. 40 mg (56%) of the expected product EX12 are obtained

in  the  form  of  a  viscous  gum.

MS:  ES+:   [M+H]+  =  788;   [M+Na]+  =  810

ES.:    [M-H]"  =  786;   [M+HCOOH+H] + =  832.

30 1 H NMR spectrum at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in the solvent chloroform-d1 (CDC13-d1) referenced at 7.27 at the temperature of 303K: from 0.87 to 1.03 (m, 11H);

1.8    (broad  d,  3H);  from  1.21  to  1.40  (m,  4H);  1.43   (s,
 



-    31  -

6H) ; from 1. 45 to 1. 65 (partially masked m, 6H) ; 1. 69 (m, 2H); from 1. 78 to 1. 97 (m, 4H) ; 2. 05 (m, 2H) ; from 2. 32 to 2.43 (partially masked m, 2H); from 2.82 to 2. 98 (m, 2H); 3.37 (m, 1H); from 3.65 to 3.81 (m, 2H); 3.95 (m, 1H); 4.14 (d, J = 16.0 Hz, 1H); 4. 43 (d, J =

16.0  Hz,   1H);   5. 33   (s,   1H);   5. 36   (s,   1H);   6. 52   (m,   1H).

EX    13:    (38, SaS,6R, BaS, 9R, 10R,12R, 12aR, 3 '8,5' aS,6 'R,-

B'aS, 9'R,10 'R,12 'R, 12'aR) -10,10'- [ (2E) -but-2-ene-1,4-

10    diylbis (oxy) ] bis [3, 6, 9 -trimethyl-10- (trifluoromethyl) - decahydro-3, 12-epoxy [1, 2] dioxepino [4, 3-i] isochromene] and EX14: {38, sas, 6R, BaS, 9R, 10R,12R, 12aR, 3 • s, s 'as, 6 • R, ~

8'aS,9'R,lO'R,12'R,l2'aR)-10,10'-[(2Z)-but-2-ene-1,4-

diylbis (oxy)] bis [3, 6, 9-trimethyl-10- (trifluoromethyl)-



A    suspension  of   200   mg   (0.51   mmol}   of   the   compound  2

and  43  mg   (0.051  mmol)   of  benzylidenebis(tricyclohexyl-

20    phosphine)dichlororuthenium in 1.3 ml of dichloro-methane is stirred for about 7 hours at a temperature in the region of 20°C. A solution containing 633 mg (5 .10 mmol) of trishydroxymethylphosphine and 1.43 ml (10.2 mmol) of triethylamine in 3 ml of dichloromethane

25 is added. Vigorous stirring is maintained at a temperature in the region of 20°C for about 10 minutes and then 6 ml of water are added, the stirring is continued for 1 hour. The organic phase is washed with 3 ml of distilled water, dried over magnesium sulfate,

30 filtered and evaporated to dryness under reduced pressure. The oily residue obtained is chromatographed on silica gel conditioned beforehand and then eluted in

the    mixture    (Heptane/Ethyl    acetate),    (95/5),    (V/V).
 


57.5  mg   (38%)   of  the  E  isomer  BX13  are  obtained  in  the

form    of   white   crystals.   20   mg   (10%)   of   the   Z  isomer

EX14  are  obtained  in  the  form  of  white  crystals.

EX13:

Rf    =  0.41  in  the  system   (Heptane/Ethyl  acetate),   (8/2),

(V/V)

IR:    983  cm- 1    (characteristic  trans  CH=CH  band) .

MS:    ES+:   [M+Na] +  =  779.

10    ES.:   [M+HCOOH+H] •  = 801.

'H NMR (CDCl,, 300 MHz) /i,pm: 5. 79 (t, 2H) ; 5. 32 (s, 2H) ; 4.37 (dd, 2H); 4.19 (dd, 2H); 2.87 (qu, 2H); 2.39 (td, 2H); 2.04 (dt, 2H); 1.97-1.87 (m, 2H); 1.85-1.75 (m, 2H); 1. 75-1.62 (m, 4H); 1.57-1.49 (m, 2H); 1. 47 (m,

15    2H); 1.43 (s, 6H); 1. 37-1.20 (m, 4H); 1. 02 (d, 6H); 1.00-0.84 (m, 2H); 0. 97 (d, 6H).

EX14:

Rf  = 0.47  in  the  system   {Heptane/Ethyl  acetate),   (8/2),

20    (V/V)

MS:    Es•:   [M+NII,]•  = 774.

'H  NMR  (CDC1 3 ,    300  Mllz)  /i,pm:   5.67   (t,   2H);   5.31   (s,  2H);

4.42 (dd, 2H); 4.25 (dd, 2H); 2.85 (qu, 2H); 2.38 (td, 2H); 2.04 (dt, 2H); 1.96-1.84 (m, 2H); 1.84-1.74 (m,

25    2H); 1.74-1.61 (m, 4H); 1.57-1.49 (m, 2H); 1.47 (m, 2H); 1.43 (s, 6H); 1.37-1.20 (m, 4H); 1.01 (d, 6H); 1.00-0.87 (m, 2H); 0.97 (d, 6H).

{3S,SaS,6R,8aS,9R,lOR,12R,l2aR,3'S,S'aS,6'R,-

30    a 'aS,9'R, 10 'R,12'R,l2' aR) -10,10'- [ (2R, 3R) -oxirane-2, 3-

diylbis (methyleneoxy)] his [3, 6, 9-trimethyl-10-

(trifluoromethyl) decahydro-3, 12-epoxy [1,2] dioxepino-

[4, 3-i] isochromene]
~
....
'''"
35


103    mg   (0.417   mmol)   of   meta-chloroperbenzoic   acid  are

added    to   a   solution   of   158   mg    (0.209   mmol)    of   the

compound !!!,! in 2. 75 ml of dichloromethane at a temperature in the region of 20°C. The stirring is maintained at this temperature for about 8 hours. The reaction mixture is successively washed with 3 x 5 ml

of    a   saturated  aqueous  sodium  bicarbonate   solution  and

13    ml  of   a   saturated  aqueous   sodium  chloride  solution.

The   organic   phase    is   dried   over   magnesium   sulfate, 10    filtered    and    evaporated    to    dryness    under    reduced pressure.   The  oily  residue  obtained  is  chromatographed

on  silica  gel  conditioned  beforehand  and  then  eluted  in

the    mixture    (Heptane/Ethyl    acetate),    (95/5),    (V/V).

70  mg   {43%)   of   one   of   the   two   trans   isomers   BXlS   are

15    obtained in the form of white crystals. MS: ES+: [M+Na] + = 795.

1 H NMR spectrum at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in the solvent chloroform-d1 (CDC13-d1) referenced at 7.27

20    at the temperature of 303K: from 0. 86 to 0. 98 (m, 14H); from 1.20 to 1.39 (m, 4H); 1.42 (s, 6H); from 1.44 to

1. 55 (m, 4H); from 1. 62 to 1. 77 (m, 6H); 1. B9 (m, 2H); 2. 04 (m, 2H); 2. 37 (m, 2H); 2. B5 (m, 2H); 3 .11 (broad s, 2H); 3.69 (broad d, J = 12.5 Hz, 2H); 4.31 (d, J =

25    12.5Hz,   2H);   5.39   (s,   2H).

EX 16: (1-(2-{ [(3S,5aS,6R,BaS,9R,lOR,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-

epoxy [1, 2] dioxepino [4, 3-i] isochromen-10-yl] oxy}ethyl)-

30    4- I { [ (3S, 5aS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-

10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino-

[4, 3 - i] isochromen-10 -yl] oxy }methyl) -1H-1, 2, 3 -triazole

and    EX17:    (1-(2-{  [(3S,5aS,6R,BaS,9R,lOR,12R,12aR)-

3, 6, 9-trimethyl-10- (trifl uoromethyl) decahydro-3, 12-

35    epoxy [1, 2] dioxepino [4, 3-i] isochromen-10-yl] oxy}ethyl)-

5- I { [ (3S, 5aS, 6R, BaS, 9R, 10R,12R, 12aR) -3, 6, 9-trimethyl-

10- (trifluoromethyl) decahydro-3, 12-epoxy [1, 2] dioxepino-[4, 3 -i] isochromen-10 -yl] oxy} ethyl) -1H-1, 2, 3-triazole

EX11

a) step 1: preparation of (3R, SaS, 6R,SaS, 9R, 10R,12R,-12aR) -3,6, 9-trimethyl-10- (prop-2-yn-1-yloxy) -10-
{trifluoromethyl)decahydro-3,12-epoxy[l,2]dioxepino-

[4,3-i] isoch:E .. 2 .

..X.o¥.-f..,

0.266    ml    of    hexafluoropropanol    (5    eq.)    and    then

10    0.289 ml of propargyl alcohol (10 eq.) are successively added at room temperature to a solution of 0. 206 g

(0. 5  mmol)    of    (3S, 5aS, 6R, BaS, 9R, lOS, 12R, 12aR) -10-

(bromo)decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-

3, 12 -epoxy-12H-pyrano [4, 3 -j] -1, 2-benzodioxepine  .!

15    (prepared  according  to  Org.   Lett.   2002,   4,   757-759)   in

5 ml of dichloromethane. The reaction mixture is then stirred at room temperature for 1 hour 15 minutes and then 5 ml of a saturated sodium bicarbonate solution are added. The organic phase is dried over magnesium

20 sulfate and evaporated to dryness under reduced pressure. The oily residue obtained is chromatographed on silica gel conditioned beforehand in heptane and then eluted with a linear gradient from 0 to sot of ethyl acetate in heptane. 0.064 g (34%) of the expected

25    product  !  are  obtained  in  the  form  of  an  oil.

Rf    0. 40    in   the    system    {Heptane/Ethyl    acetate),

(85/15),    (V/V)

ES    m/z=391    MH-+

m/z=335    MH-+-C3 H4 0

30

1 H NMR spectrum at 400 MHz on a BRUKER AVANCE DRX-400 spectrometer with the chemical shifts (0 in ppm) - in
 



-    35  -

the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced at 2.50 ppm at the temperature of 303K: 0.88 {partially masked m, lH); 0.91 (d, J = 6.5 Hz, 3H); 0.95 (broad d,

J = 7.5 Hz, 3H); 1.23 (m, lH); from 1.28 to 1.43 (m, 2H); 1.32 (s, 3H); from 1.50 to 1.63 (m, 2H); from 1.73 to 1.90 (m, 3H); 2.03 (m, 1H); 2.21 (m, 1H); 2.68 (m, 1H); 3.52 (t, J = 2.5 Hz, 1H); 4.30 (dd, J = 2.5 and 16.0 Hz, 1H); 4.51 (dd, J = 2.5 and 16.0 Hz, 1H); 5.57

(s,    1H).

10

b)    step  2:   preparation  of  EX16  and  EX17

~    +         ..._........r.kL41.


~~~
EXU    EJ:17    \=N

257   mg   (0.610   mmol)    of   compound   5   are   added   to   a 15     solution   of   119   mg   (0.305   mmol)   of   the   compound  2.  in 2. 5  ml   of   ethanol   at   a   temperature   in   the   region   of 20°C.   The  stirring  is  maintained  under  reflux  for  about 48  hours.   The  reaction  mixture  is  evaporated  to  dryness in   a    rotavapor   and   the   oily   residue    obtained   is

20 chromatographed on silica gel conditioned beforehand in dichloromethane and then eluted with a linear gradient from 0 to 100% of the mixture B ( (Dichloromethane/Ethyl acetate), (96/4), (V/V)] in A (Dichloromethane). 43 mg

(18%)    of  the  expected  product  EX16  are  obtained  in  the

25    form of a white solid and 17 mg (7%) of the expected product EX17 are obtained in the form of a white solid.

BX16:

Rf    0. 26    in    the    system    (Dichloromethane/Ethyl

acetate),    (96/4),   (V/V).

30    ES    m/z=B34    MNa•

m/z=Bl2    MH+
 

1H  NMR  spectrum  at   400  MHz  on  a  BRUKER  AVANCE  DRX-400

spectrometer  with  the  chemical   shifts   (S  in  ppm)   -   in

the  solvent  chloroform-dl   {CDC13-dl)   referenced  at  7.27

at    the    temperature    of    303K:    from    0. 75    to    1. 70

(partially masked m, 16H); 0. 92 (broad d, J : 7. 0 Hz, 9H); 0.98 (broad d, J: 7.0 Hz, 3H); 1.41 (s, 3H); 1.43

(s,   3H);   1.89   (m,   2H);   2.03   (m,   2H);   2.37   (m,   2H);   2.84 (m,   2H);   4.11   (m,   1H);   4.32   (m,   1H);   from  4.40   to  4.60 10     (m,    2H);    4.71    (d,    J    :    12.5   Hz,    1H);    5.04    (d,    J    :

12.5Hz,   1H);   5.20   (s,   1H);   5.70   (s,   1H);   7.53   (s,   1H).

EX17:

TLC    Rf   =  0.32   in   the   system   (dichloromethane/ethyl

15    acetate), (96/4), (V/V) ES m/z:834 MNa•

m/z=812 MH+

1 H  NMR  spectrum  at   500  MHz  on  a  BRUKER  AVANCE  DR.X-500

spectrometer  with  the  chemical  shifts   (0  in  ppm)   -   in

20    the  solvent  chloroform-dl   (CDC13-dl)   referenced  at  7.27

at the temperature of 303K: from 0. 55 to 1. 70 (partially masked m, 16H); 0. 90 (broad d, J = 7. 0 Hz,

9H); 1.01 (broad d, J: 7.0 Hz, 3H); 1.39 (s, 3H); 1.44 (s, 3H); from 2. 30 to 2.43 (m, 2H); from 1.97 to 2.09

25    (m, 2H); from 2.28 to 2. 42 (m, 2H); 2.80 (m, 1H); 2.90 (m, 1H); 4.11 (m, 1H); from 4.42 to 4.63 (m, 3H); 4.40

(d, J : 13.0 Hz, 1H); 5.04 (d, J : 13.0 Hz, 1H); 5.11 (s, 1H); 5. 24 (s, 1H); 7. 61 (s, 1H).

30    Antiproliferative  activity  of  the  products  prepared:

The products according to the invention have been the subject of pharmacological trials which make it possible to determine their antiproliferative activity.

35 It was determined by measuring the inhibition of cell proliferation of HCT116 cells. The cells are inoculated in a cell culture medium at a concentration of 10 000 cells per well, in 0.17 ml of medium, and 20 ~1 of test product, at various concentrations, and 10 ~1
 



-    37

of    Thymidine    [methyl-14C]    (100    J.!Ci/ml    specific

activity    47.90   mCi/mmol;    NEN   Technologies   reference

NEC568    batch   3550-001)   are   added,   and   then   the   cells

are  incubated  at  37°C  and  5%  C02 •

Medium    used   for   the   culture   of   HCT116    cells:    DMEM

medium mM L-glutamine, 200 IU/ml penicillin, 200 )lg/ml streptomycin and 10% (V/V) fetal calf serum

(Life  Technologies) .

10

After 96 hours, the incorporation of 14 C-thymidine is counted in a liquid scintillation counter 1450

Microbeta  Wallac  Trilux.  The  results  R  are  expressed  in

cpm    (counts  per  minute)   and  converted  to  percentage  of

15    growth inhibition GI% by first subtracting the mean of the number of cpm of the wells without cells B and then by dividing by the number of cpm of the wells of the untreated cells C comprising 20 ~1 of medium for

dilution    of    the    product    containing    1%    of    ethanol

20    (GI%  =   (R-B)  X  100/C%).

The IC50 values are calculated with the aid of the equation 205 of the XLFit software (IDBS company, UK) by nonlinear regression analysis using the Marquardt

25    algorithm (Donald W. MARQUARDT, J. Soc. industry appl., vel. 11, No. 2, June, 1963).

The products have an IC50 on the HCT116 cells generally of less than 10 ~ and preferably of less than 100 nM.

30

Examples    ICSO   (nM) /HCT116
EX1    47
EX2    23
EX3    21
EXB    30

The products according to the invention may therefore be used for the preparation of medicaments.
 



-    38  -

Thus,    according  to  another  of   its  aspects,   the  subject

of  the  invention  is  medicaments  comprising  a  product  of

formula (I) or an addition salt of the latter with a pharmaceutically acceptable acid, or a hydrate or a solvate.

These    medicaments   find   use   in   therapy,   especially   in

the  treatment  of  cancer.

10    The present invention therefore relates to the use of a product of formula (I) for the manufacture of a

medicament  useful   for  treating  a  pathological  condition

and more particularly the use of a product of formula {I) for the manufacture of a medicament useful for

15    treating  cancer.

The present invention also relates to the use of a product of formula (I) for the manufacture of a

medicament    useful   for   treating   pathologies   where   new

20    vascularization or angiogenesis occurs inappropriately, that is to say in cancers in general but also in specific cancers such as Kaposi's sarcoma or infantile hemoangioma, and also in rheumatoid arthritis,

osteoarthritis     and/or     its     associated    pains,     and 25    inflammatory    bowel     diseases     such     as     hemorrhagic rectocolitis   or   Crohn' s   disease,   eye   diseases   such  as age-related         macular         degeneration,          diabetic

retinopathies,    chronic  inflammation  and  psoriasis.

30 Angiogenesis is a process of generation of new capillary vessels from preexisting vessels. Tumor angiogenesis (formation of blood neovessels), essential for tumor growth, is also one of the main factors in metastatic dissemination (Oncogene. 2003 May 19 ;22 (20):

35    3172-9;  Nat  Med.   1995  Jan;  1(1):   27-31).

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a product according
 



-    39   -

to    the   invention.    These   pharmaceutical   compositions

contain    an   effective   dose   of   at   least   one   product

according    to    the    invention    or    a    pharmaceutically

acceptable    salt,   a   hydrate   or   a   solvate   of   the   said

product,    and   at   least   one   pharmaceutically   acceptable

excipient.

The    said   excipients   are   chosen   according   to   their

pharmaceutical    dosage   form   and   the   desired   mode   of

10    administration from the usual excipients which are known to persons skilled in the art.

In    the    pharmaceutical composi tiona    of the    present

invention    for    oral,    sublingual,    subcutaneous,

15    intramuscular,    intravenous,    topical,    local,    intra-

tracheal,    intranasal,    transdermal    or    rectal

administration, the active ingredient of formula (I) above, or its salt, solvate or hydrate, may be administered in unit form, as a mixture with

20    conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or treatment of the above disorders or diseases.

The    appropriate  unit   forms   for  administration  comprise

25    the forms for administration by the oral route such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, the forms

for   sublingual,   buccal,   intratracheal,   intraocular   or intranasal  administration,   the  forms  for  administration 30    by   inhalation,    the    forms    for    topical,    transdermal, subcutaneous,          intramuscular         or         intravenous administration,   the  forms   for   rectal   administration  or implants.     For     topical     application,     the     products according  to  the  invention  may  be  used  in  creams,  gels,

35    ointments  or  lotions.

By way of example, a unit form for administration of a product according to the invention in tablet form may comprise the following components:
 



-   40  -       
Product  according  to  the  invention    so. 0    mg
Mannitol    223.75    mg
Croscarmellose  sodium    6.0    mg
Corn  starch    15.0    mg
Hydroxypropylmethylcellulose    2. 25    mg
Magnesium  stearate    3.0    mg

There    may   be   particular   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   doctor   according   to   the   mode   of

administration,    the  weight  and  the  response  of  the  said

patient.

10

The present invention, according to another of its aspects, also relates to a method of treating the pathologies indicated above which comprises the

administration,    to  a  patient,   of  an  effective  dose  of  a

15    product according to the invention or one of its pharmaceutically acceptable salts or its hydrates or solvates.

The    products     of     the     present     invention    may     be 20    administered    alone    or    as    a     mixture    with    other anticancer   agents.    Among    the   possible   combinations,

there  may  be  mentioned:

•    alkylating    agents,    and    in    particular

25    cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine

•    platinum  derivatives  such  as  in  particular  cisplatin,

30    carboplatin  or  oxaliplatin
 



-    41

•    antibiotic   agents   such   as   in   particular   bleomycin,

mitomycin,    dactinomycin

•    antimicrotubule    agents    such    as    in    particular

vinblastine,    vincristine,    vindesine,    vinorelbine,

taxoids    (paclitaxel  and  docetaxel)

•    anthracyclines   such   as    in   particular   doxorubicin,

daunorubicin,    idarubicin,    epirubicin,    mitoxantrone,

losoxantrone

•    groups   I    and   II   topoisomerases   such   as   etoposide,

10    teniposide,    amsacrine,    irinotecan,    topotecan    and

tomudex

•    fluoropyrimidines    such    as    5-fluorouracil,    UFT,

floxuridine

•    cytidine  analogues  such  as  5-azacytidine,  cytarabine,

15    gemcitabine,   6-mercaptopurine,   6-thioguanine

•    adenosine   analogues   such   as   pentostatin,   cytarabine

or  fludarabine  phosphate

•    methotrexate  and  folinic  acid

•    various  enzymes  and  compounds  such  as  L-asparaginase, 20     hydroxyurea,   trans-retinoic  acid,   suramin,   dexrazoxane, amifostine,     herceptin    as    well    as    oestrogenic    and

androgenic  hormones

•    antivascular agents such as combretastatin derivatives, for example CA4P, chalcones or colchicine,

25    for  example  ZD6126,   and  their  prodrugs

•    kinase  inhibitors  such  as  ertonilib  or  imatinib

•    biotherapeutic agents such as antibodies such as rituximab, bevacizumab, cetuximab, trastuzumab or alemtuzumab
 



-    42   -

•    proteasome  inhibitors  such  as  bortezomib.

It is also possible to combine the compounds of the present invention with a radiation treatment. These treatments may be administered simultaneously,

separately    or    sequentially.    The    treatment    will    be

adapted  by  the  practitioner  according  to  the  disease  to

be  treated.
 



1.    A  product  corresponding  to  formula(!):


in  which:

a)    A  is  a   divalent  group  chosen  from  -s-,  -so-,  -S0 2 - ,    -

NH-, -N(CH3 ) - , -N(CH,-C(O)O-CH,CH3)-, -N(CH,-COOH)-, epoxide, (C 1-C6) alkenylen, -NHCO-, 1, 2, 3-triazole,

NHSO,-;

b)    x1 and X2 are identical or different, and are chosen from N, 0, S;

c)    B1   and  B2  are  identical  and  represent  -CF3 ;

d)    n 1 and n2 are identical or different and have the value 1, 2, 3 or 4;

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

2. The product of formula (I) as claimed in claim 1, characterized in that X1 and X2 are identical and are 0.

3. The product of formula {I) as claimed in claims 1 or 2, characterized in that n 1 and n2 are identical and have the value 2, 3 or 4.

4.    The  product   of  formula   (I)   as   claimed  in  claims   1   or  2,
characterized    in  that  A  is  -NH-,   -N (CH 2 C (0) OCH2CH3)-  or  -
N (CH2COOH)-   and    n 1   and   n2   are   identical   and   have   the

value  2.

s. The product of formula (I) as claimed in claims 1 or 2, characterized in that A is epoxide and n 1 and n 2 are
 



identical  and  have  the  value  1.

6. The product of formula (I) as claimed in claims 1 or 2, characterized in that A is -NHCO- or 1,2,3-triazole and n 1 and n 2 are different and independently have the value 1 or

2.

7.    A  product  chosen  in  the  following  list  :

(3S,5aS,6R,BaS,9R,10R,l2R,l2aR,3'S,5'aS,6'R,B'aS,-9' R, 1 0' R, 12' R, 12 1 aR) -10, 10'- [thiobis ( 2, 1-ethanediyl-oxy) ]bis [decahydro-3, 6, 9-trimethyl-10- (trifluoro-methyl) -3, 12-epoxy-12H-pyrano [ 4, 3-j] -1, 2-

benzodiox.epine;

-    ( 3S, 5aS 1  6R, BaS, 9R, lOR, 12R, 12aR, 3' S, 5' aS, 6 1  R, B 1  aS,-

9 1 R1  10' R, 12 1 R,l2 'aR) -10,10 1 -   [sulfinylbis (2, 1-ethane-

diyloxy) )bis [decahydro-3, 6, 9-trimethyl-10- (trif1uoro-methy1 I -3, 12-epoxy-12H-pyrano I 4, 3-j I -1, 2-

benzodiox.epine;

-    ( 3S, SaS, 6R, BaS, 9R, lOR, 12R, 12aR 1 3 1 s, 5 1 aS, 6 1 R, B 1 as,-9' R, 10 'R, 12' R,l2' aR) -10, 10'- [sulfonylbis (2 1 1-

ethanediyloxy) ] bis [decahydro-3, 6 1 9-trimethyl-10-tri-fluoromethyl) -31 12-epoxy-12H-pyrano [ 4, 3-j] -1, 2 -benzo-dioxepine;

-    (3S, 5aS, 6R, BaS, 9R, lOR, 12R, 12aR, 3' S, 5 1 aS, 6 1 R, B 'aS,-

9 • R1 10 'R, 12 'R, 12 1 aR) -10, 10 ' - [thiobis (3, 1-propanediyl-oxy) ] bis [ decahydro-3, 6, 9-trimethyl-10- (trifluorometh-yl) -3, 12-epox.y-12H-pyrano [ 4, 3-j] -1, 2-benzodioxepine;

-    ( 3S, 5aS, 6R, BaS, 9R, lOR, 12R, 12aR, 3' S, 5' aS, 6 1 R, B 1 aS,-9'R,10'R,12'R,l2 1 aR)-10,10'-[sulfinylbis(3,1-propane-diyloxy} ] bis [decahydro-3, 6, 9-trimethyl-10- (trifluoro-methyl I -3, 12-epoxy-12H-pyrano I 4, 3-j I -1, 2-benzodioxepine;

-    {3S, SaS, 6R, BaS, 9R, lOR, 12R, 12aR, 3 1 S, 5' aS, 6 1 R, B 1 aS,-
 



9 r R, 10 r R, 12 I R, 12 I aR) -10,10 I - [sulfonylbis {3, 1-propane-diyloxy)]bis[decahydro-3,6,9-trirnethyl-10-(trifluoro-methyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

-    (3S,5aS,6R,BaS,9R,l0R,l2R,12aR,3 1S,5 1aS,6 1 R,B 1 aS,-

91 R, 10 'R, 12 1 R, 12 1aR) -10,10 ' - [thiobis (4, 1-butanediyl-oxy) 1bis ( decahydro-3, 6, 9-trimethyl-10- {trifluoro-methyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

-    2-[[(3R,5aS,6R,BaS,9R,10R,12R,12aR)-decahydro-3,6,9-trimethyl-10- (trifluoromethyl) -3, 12-epoxy-12H-pyrano[4,3-j)-1,2-benzodioxepin-10-yl)oxy1-N-[2-[[{3R,5aS,6R,BaS,9R,10R,l2R,12aR)-decahydro-3,6,9-

trimethyl-10- {trifluoromethyl) -3, 12-epoxy-12H-pyrano [ 4, 3-j J -1, 2-benzodioxepin-10-yl] oxy] ethyl] -N-methylethanamine;

-    2-{[(3S,SaS,6R,BaS,9R,10R,12R,l2aR)-3,6,9-trirnethyl-lO-( triflU0TQffi€thyl) decahydro-3 1 12-epOXy [ 1 r 2] diOXepinO-

[ 4, 3-i] isochromen-10-yl J oxy} -N- (2-

{ [ (3S, 5aS, 6R, BaS, 9R, 10R,12R, 12aR) -3,6 1  9-trimethyl-10-

( trifluoromethyl) decahydro-3 1  12-epoxy [ 1, 2] dioxepino-

[ 4 1  3-i 1isochrornen-10-yl J oxy} ethyl) ethanamine;

-    ethyl    N, N-bis 12- I [ 13S, SaS, 6R, BaS, 9R, lOR, l2R, 12aR)-

3 r 6, 9-trimethyl-10- (trifluoromethyl) decahydro-3, 12-

epoxy [ 1, 2] dioxepino [ 4, 3-i] isochromen-10-yl] oxy) ethyl) glycinate;

-    N, N-bis 12- I [ 13S, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trirnethyl-10- (trifluoromethyl) decahydro-3,12-
epoxy [ 1 1 21 dioxepino [ 4, 3-i] isochromen-10-yl) oxy} ethyl)-glycine;


-    2-[ [ (3S, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10-{trifluorornethyl) decahydro-3, 12-
 



epoxy [ 1, 2] dioxepino [ 4, 3-i] isochromen-10-yl] oxy} -N- ( 2-{ ( (3S, 5aS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10-( trifluoromethyl) decahydro-3, 12-epoxy ( 1, 2] dioxepino-[ 4, 3-i] isochromen-10-yl] oxy}ethyl) acetamide;

- (3S,5aS,6R,8aS,9R,lOR,12R,l2aR,3'S,5'aS,6'R,8'aS,-9'R, 10'R, 12 'R, 12'aR)-10, 10 ' - [ (2E) -but-2-ene-1, 4-diylbis (oxy)] bis [3, 6, 9-trimethyl-10- (trifluoromethyl)-decahydro-3, 12-epoxy [ 1, 2] dioxepino [ 4, 3-i] isochromene] ;

-    (3S,5aS,6R,BaS,9R,10R,12R,12aR,3'S,5'aS,6'R,8'aS,-9 'R, 10' R, 12 'R, 12' aR) -10,10'- [ (2Z) -but-2-ene-1, 4-

diylbis (oxy)] bis (3, 6, 9-trimethyl-10- (trifluoromethyl)-decahydro-3 r 12-epoxy [ 1, 2 J dioxepino [ 4' 3-i] isochromene] ;

-    (3S,5aS,6R,8aS,9R,10R,l2R,l2aR,3'S,5'aS,6'R,8'aS,-9'R, lO'R, 12' R, 12' aR) -10,10'- [ (2R, 3R) -oxirane-2, 3-diylbis (methyleneoxy) ] bis [ 3, 6, 9-trimethyl-10-(trifluoromethy1) decahydro-3, 12-epoxy [ 1, 2] dioxepino-[4, 3-i] isochromene];

(1- (2- ( [ (3S, SaS, 6R, 8aS, 9R, lOR, 12R, 12aR) -3, 6, 9-

trimethyl-10- (trifluoromethyl) decahydro-3, 12-

epoxy [ 1, 2] dioxepino [ 4, 3- i] isochromen-10-yl] oxy} ethyl)-4- ( { [ (35, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10- (trifluoromethyl) decahydro-3, 12-epoxy [ 1, 2] dioxepino-[ 4, 3- i] isochromen-10-yl] oxy }methyl) -lH-1, 2, 3-triazole;

-    1- (2-{ [ (3S, SaS, 6R, BaS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10- (trifluoromethyl) decahydro-3, 12-

epoxy [ 1, 2] dioxepino [ 4, 3-i] isochromen-10-yl] oxy} ethyl)-5- ( ( [ (3S, SaS, 6R, 8aS, 9R, lOR, 12R, 12aR) -3, 6, 9-trimethyl-10- (trifluoromethyl) decahydro-3, 12-epoxy [ 1, 2] dioxepino-[ 4, 3-i] isochromen-10-yl] oxy} ethyl) -1H-1, 2, 3-triazole.

8.    The  product   of   general   formula   as   claimed  in   any   one   of

claims  1  to  7,   characterized  in  that  it  is
 



1)    in  nonchiral  form,   or

2)    in  racemic  form,   or

3)    in  a  form  enriched  in  one  stereoisomer,   or

4)    in  a  form  enriched  in  one  enantiomer;

and  in  that  it  is  optionally  salified.

9.    A medicament, characterized in that it comprises product of formula (I) as claimed in any one of claims to 8, or an addition salt of this product with pharmaceutically acceptable acid, or hydrate or solvate of the product of formula (I).


10.    Pharmaceutical composition, cha:tacterized in that it

comprises    a   product   of   formula   (I)   according   to   any   one

of claims 1 to 8, or a pharmaceutically acceptable salt, a hydrate or a solvate of this product, and at least one pharmaceutically acceptable excipient.

11. A process for preparing a product according to any one of claims 1 to 8, characterized in that the product of the following general formula (I I I) :
~""...

in which B represents -CF3 , undergoes a substitution of the bromine atom with the aid of a nucleophile such as a bromoalcohol, to give a product of the following general formula I II) :

in  which  X  represents  a  substituent  X1   or  X2,   n  represents

n 1 or n 2 and in which either G represents a leaving group such as a bromine atom, and then the product of general formula (II) undergoes a nucleophilic substitution in order to form a dimer of general formula (I) or a precursor of a product of general formula (I), or G represents a chemical functional group Fl, which may be optionally activated by reduction or oxidation reaction, and then this product of general formula (II) reacts with another product of formula (II) where G represents a leaving group such as a bromine atom or a chemical functional group F2 capable of reacting with Fl, in order to form a dimer of general formula (I) or a precursor of a product of general formula (I).
12.    The  use  of  a  product  as  claimed  in  any  one  of  claims  1  to

8, for the manufacture of medicament useful for treating a pathological condition.

13.    The use as claimed in claim 12, characterized in that the pathological condition is cancer.

14. The use of a product as claimed in any one of claims 1 to 8, for the manufacture of medicament useful for treating pathologies where new vascularization or angiogenesis occurs inappropriately, that is to say in cancers in general but also in specific cancers such as Kaposi's sarcoma or infantile hemoangioma, and also in rheumatoid arthritis, osteoarthritis and/or its associated pains, and inflammatory bowel diseases such as hemorrhagic rectocolitis or Crohn' s disease, eye diseases such as age-related macular degeneration, diabetic retinopathies, chronic inflammation and psoriasis.

15.    As   intermediate   products,    products   of   general    formula

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