EP1086107A1

EP1086107A1 - Artemisinin derivatives, method for the preparation thereof and pharmaceutical compositions containing the same

Info

Publication number: EP1086107A1
Application number: EP99923702A
Authority: EP
Inventors: Ying Li; Feng Shan; Jin Ming Wu; Guangshao Wu; Jian Ding; Jianxian Han; Ghanem Atassi; Pierre Renard
Original assignee: Shanghai Institute of Materia Medica of CAS; ADIR SARL
Current assignee: Shanghai Institute of Materia Medica of CAS; Laboratoires Servier SAS
Priority date: 1998-06-17
Filing date: 1999-06-09
Publication date: 2001-03-28
Also published as: NZ508388A; AU4047499A; HUP0102599A3; ZA200007070B; CA2342990A1; WO1999065914A1; NO20006257L; NO20006257D0; JP2002518398A; AU748798B2; BR9911274A; CN1111162C; US6307068B1; PL344984A1; CN1305482A; HK1036985A1; CN1239097A; HUP0102599A2; CN1084333C

Abstract

The invention relates to compounds of the general formula (I): R - O - A, wherein R represents the radical of formula (II) and A is as defined in the description. The invention also relates to the geometric and/or optic isomers thereof and to the pharmaceutically acceptable acid or basic addition salts thereof.

Description

ININE ARTEMIS DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new artemisinin derivatives, their preparation process and the pharmaceutical compositions containing them.

Artemisinin is an active ingredient isolated from Artemisia annual. L., well known for its activity against malaria.

Many artemisinin derivatives are described, for their properties against malaria (IN 173339), in the treatment of toxoplasmosis (US 5486535), or also for their anticancer activity such as for example the artemisinin dimers described in the WO application. 9701548.

The compounds of the present invention, by their original structure, are new, and have particularly advantageous pharmacological properties as anti-tumor agents

More specifically, the present invention relates to the compounds of formula (I):

R - O - A (I) in which

R represents the radical of formula (II)

A represents

CN a group of formula (III) -CR (m) R in which - R ¹ represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group,

- R ² represents a hydrogen atom, or a linear or branched alkyl group (Ci -Ce) substituted or not,

- or a group of formula (IV) - C ^~ YCZ— R ³ (IV)

It II 'OO in which - Y represents a linear or branched alkylene (C ₂ -Cι) group substituted or not, alkenylene (C ₂ -Cι ₄ ) linear or branched substituted or not, alkynvlene (C ₂ -Cι) linear or branched substituted or not, phenylene, substituted phenvlene, naphthylene, or substituted naphthylene, - Z represents an oxygen or sulfur atom, or a group NR ' ² or R' ² can take the same values as R ² ,

- R ^Λ represents a group of formula (III) as defined above,

Being heard that

- by aryl means a phenyle, naphthyl, phenanthryl, fluorenyl or anthryl group, - by heteroaryl, we mean any mono or bicyc group that aromatic containing from 5 to

10 atoms and may contain from 1 to 3 heteroatoms chosen from oxygen, nitrogen or sulfur,

- the term "substitute affecting the expressions" aryl "," heteroaryl "," phenylene "," naphthylene ", means that these groups are substituted by one or more radicals, identical or different, chosen from linear or branched (CC ₆ ) alkyl , hydroxy, linear or branched alkoxy (C _r C ₆ ), alkoxycarbonyl (d-Cβ), linear or branched polyhalogenoalkyl (Cι-C ₆ ), aryloxy (not substituted or substituted by one or more groups, identical or different, chosen from hydroxy, alkyl _(Cι-C6) linear or branched alkoxy _(Cι-C6) linear or branched, polyhaloalkyl _(Cι-C6) linear or branched, or halogen atoms), nitro, amino, alkylamino (-C Ce) linear or branched, dialkylamino (Cι-C ₆ ) linear or branched, alkylcarbonylamino cvano or halogen atoms (fluorine, chlorine, bromine or iodine), or two adiacent carbon atoms can be substituted by an alkylenedioxy group,

- The term "substitute" affecting the expressions "alkyl", "alkylene", "alkenylene", "alkynylene" means that these groups are substituted by one or more radicals, identical or different, chosen from hydroxy, alkoxy (Cι-C ₆ ) linear or branched, polyhalogenoalkyle, amino or halogen atoms (fluorine, chlorine, bromine or iodine), their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base

Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, bromide, sulphonic, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, succinic malonic, glutinic, fumaic, tartic, maleic, citric, ascorbic, oxalic, methane sulfonic acids. , camphoric, etc

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, tπethylamine, tertbutylamine, etc.

The preferred compounds of the invention are those for which - A represents a group of formula (III),

- A represents a group of formula (IV),

- Z represents an oxygen atom,

Z represents a group NR ' ² ,

- Y represents an alkylene or alkenylene chain (C ₂ -Cj), substituted or not, - Y represents a phenvlene or a naphthylene, substituted or not,

- R ^! represents an aryl or substituted aryl group

Advantageously, the invention relates to the compounds of formula (I) for which A represents a group of formula (III) or R ¹ represents a substituted or unsubstituted phenyl group and R ² represents a hydrogen atom or a methyl group, or a group of formula (IV) or Y represents a chain - (CH ₂ ) _n - or n is such that 2 <n <7, Z represents an oxygen atom or a group NR ' ² and R ³ represents a group of formula (III) where R ¹ represents a substituted or unsubstituted phenyl or naphthyl group and R ² represents a hydrogen atom or a methyl group

Even more specifically, the invention relates to the compounds of formula (I) which are

- 2- (4-bromophenvl -2-dehydroartemιsιnιnyl-acetonιtπle,

- 2-phenyl-2- dihydroartemisininyl-acetonitπle,

- 1 4-succinate of [(2-chlorophenyl) (cyano) methyl] and of dihydroartemisimnyle, - 4 - {[(4-bromophenyl) (cyano) methyl] (methyl) amino} -4-dihydro-artemisininyl oxobutanoate

The enantiomers, diastereoisomers and the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.

The invention also extends to the process for preparing the compounds of formula (I) characterized in that the compound of formula (V) is used as starting material:

R ^Λ Λ v OH (V) in which R is as defined above,

on which we condense

- under acid catalysis conditions, a compound of formula (VI):

CN R ¹ - C— OH (VI)

R ² in which R ¹ and R ^" are as defined above, to lead to the compound of formula (I / a), special case of the compounds of formula (I):

CN

R ^VW QC - R ² (I / a)

R ¹ in which R, R and R "are as defined above,

- or a compound of formula (VII)

HO— C— Y— COOH (Seen)

II o in which Y is defined as above, (or the corresponding acid chloride or anhydride), to lead to the compound of formula (VIII)

in which R and Y are defined as above, on which it is reacted under acid catalysis conditions, in the presence of a coupling agent, or after transformation into the corresponding acid chloride,

• a compound of formula (VI) to obtain the compound of formula (I / b), special case of the compounds of formula (I)

CN

R ^W ^ O -C -YCO -C -R ¹ (I / b)

He II

0 OR ² in which R, R ¹ . R ² and Y are as defined above,

• a compound of formula (IX)

CN

R ¹ - C-NHR ' ² (IX)

2

R in which R ¹ , R ^" and R ' ² are as defined above, to lead to the compound of formula (I / c), special case of the compounds of formula (I)

R ' ² CN

Rwvwo-CYCNCR ¹ (I / c)

He II L

OOR ² in which R, R ^! R ² , R ' ² and Y are as defined above,

• or a compound of formula (X)

CN

R ¹ - C-SH (X)

R ² in which R ¹ and R ^" are as defined above, to lead to the compound of formula (I / d), special case of the compounds of formula (I):

in which R, Y, R ¹ and R ² are defined as above,

the compounds (I / a) to (I / d) forming all of the compounds of formula (I) and which can be purified according to a conventional separation technique, which is converted, if desired, into their salts d addition to a pharmaceutically acceptable acid or base, and from which the optical or geometric isomers are optionally separated according to conventional purification techniques.

The compound of formula (V) is easily accessible to those skilled in the art by conventional reduction of artemisinin (commercial). The compounds of formula (VI) are obtained by conventional condensation of a cyanide salt on the ketone of formula (XI):

R 'R ²

¥ (xo

in which R ¹ and R ² are defined as above.

The compounds of formula (IX) are obtained by the action of an amine R ' ² NH in which R' has the same definition as above on the compound of formula (VI).

The compounds of formula (X) are obtained by the action of H ₂ S in the presence of a catalyst such as Al O ₃ for example on the compound of formula (VI).

Another advantageous process of the invention relates to the preparation of the compounds of formula (I) for which A represents a group of formula (IV), characterized in that a compound of formula (VII) is used as starting material :

HO— C-Y— COOH (VII)

II o in which Y is as defined above, (or the corresponding acid chloride or anhydride), on which we condense - in the presence of a coupling agent, a compound of formula (IX)

in which R ¹ , R ² and R ' ² are defined as above, to lead to the compound of formula (XII)

in which R ¹ , R ² , R ' ² and Y are as defined above, on which a compound of formula (V) is condensed to obtain the compound of formula (I / c), special case of the compounds of formula (I )

in which R, Y, R ¹ . R ² and R ' ² are as defined above,

a compound of formula (VI)

CN i

R - C— OH (VI)

2

R in which R ¹ and R ^" are defined as above, to lead to the compound of formula (XIII)

in which R ¹ , R ² and Y are defined as above, on which a compound of formula (V) is condensed to obtain the compound of formula (I / b), special case of the compounds of formula (I)

CN

R W WO-C -Y-C -0-C -R (I / b) n II L

OOR ² in which R, Y, R ¹ and R ² have the same definition as above,

- or a compound of formula (X)

CN

R ¹ - C-SH (X)

R ² in which R ¹ and R ^: are defined as above, to obtain the compound of formula (XIV)

in which R ¹ , R ^' and ^ are as defined above, on which a compound of formula (V) is condensed to obtain the compound of formula (I / d), special case of the compounds of formula (I)

in which R, Y, R ¹ and R ² are defined as above,

the compounds (I / b), (L c) and (I / d) which can be purified according to a conventional separation technique, which can be converted if desired, into their addition salts with an acid or a pharmaceutically acceptable base, and from which the optical or geometric isomers are optionally separated according to conventional purification techniques

The compounds of formula (I) have interesting pharmacological properties They have excellent cytotoxicity m vitro not only on leukemic lines but also on solid tumor lines, and also have an action on the cell cycle These properties allow their use in therapeutic as anti-tumor agents

The present invention also relates to pharmaceutical compositions containing the products of formula (I) their optical isomers or one of their addition salts with a base or a pharmaceutically acceptable acid, alone or in combination with one or more inert non-toxic excipients or vehicles

Among the pharmaceutical compositions according to the invention, particular mention will be made of those which are suitable for oral, parenteral, nasal, rectal, perhnal, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packets , capsules, glossettes, tablets, suppositories creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nasal drops

The useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and ranges from 0.1 to

400 g per day, in one or more administrations

The following Examples illustrate the invention and do not limit it in any way

In the Examples which follow, we will adopt as nomenclature convention (1R.4S, 5R, 9R 3S) -1 5 9-tπmethyl-l l, 14,15-tπoxatetracyclo [10 3 1 O ^{4 13} 0 ^{8 13} ] hexadec- 10-yle

= R = = dihydroartemisimnyl radical

EXAMPLE 1: (S) 2- (4-Bromophenyl) -2-dihydroartemisininyloxy-acetonitrile

Has a solution of (1.5 g, 5.3 mmol) in 20 ml of dry CH C1 ₂ , 1 7 g (8 mmol) of 2- (4-bromophenyl) -2-hydroxyacetonιtπle is added at -20 ° C. After addition of BF ^ / And ₂ 0 (0 1 ml 0 8 mmol), the solution is allowed to rise to room temperature

After a conventional treatment, the title compound is separated by chromatography on a silica column, then re-installed in petroleum ether Melting point 12 ^' -129 ° C Elementary microanalysis:

C H N

% Calculated 57, 75 5, 90 2.93

% Found 57.80 6.07 2.85

EXAMPLE 2 (R) 2- (4-Bromophenyl) -2-dihydroartemisininyloxy-acetonitrile

During the separation by chromatography described in Example 1, the title product is obtained.

Melting point: 144-145 ° C

Elementary microanalysis: C H N

% Calculated 57.75 5.90 2.93% Found 57.52 5.88 2.65

EXAMPLE 3: (R) 2- (4-Fluorophenyl) -2-dihydroartemisininyloxy-acetonitrile

The procedure is as in Example 1, replacing 2- (4-bromophenyl) -2-hydroxyacetonitrile with 2- (4-fluorophenyl) -2-hydroxyacetonitrile.

Melting point: 122-125 ° C Elementary microanalysis:

C H N

% Calculated 66, 17 6, 76 3.36% Found 66, 16 6, 74 3.33

Examples 4 to 16 are obtained according to the same process from the appropriate nitriles.

EXAMPLE 4: (S) 2-Phenyl-2-dihydroartemisininyloxy-acetonitrile

Starting materials: dihvdroartemisinin and 2-phenyl-2-hydroxyacetonitrile. Melting point: 135-137 ° C EXAMPLE 5 (R) 2-PhenyI-2-dihydroartemisininyloxy-acetonitrile

Dihydroartemisinin and 2-phenyl-2-hydroxyacetonitrile starting materials Melting point: 98-100 ° C

EXAMPLE 6: (S) 2- (3,4-Dimethoxyphenyl) -2-dihydroartemisininyIoxy-acetonitrile

Dihydroartemisinin and 2- (3,4-dimethoxyphenyl) -2-hydroxyacetonitrile starting materials

Oil

EXAMPLE 7 (R) 2- (3,4-Dimethoxyphenyl) -2-dihydroartemisininyloxy-acetonitrile

Dihydroartemisinin and 2- (3,4-dimethoxyphenyl) -2-hydroxyacetonitrile Oil

EXAMPLE 8 (R) 2- (2-Fluorophenyl) -2-dihydroartemisininyloxy-acetonitrile

Starting materials dihydroartemisinin and 2- (2-fluorophenyl) -2-hydroxyacetonitrile Melting point ^• 120-124 ° C

EXAMPLE 9 (R) 2- (3-Fluorophenyl) -2-dihydroartemisininyloxy-acetonitrile

Dihydroartemisinin and 2- (3-fluorophenyl) -2-hydroxyacetonitrile starting materials Melting point: 131-134 ° C

EXAMPLE 10 (R) 2- (2-Bromophenyl) -2-dihydroartemisininyloxy-acetonitrile

Starting materials dihydroartemisinin and 2- (2-bromophenyl) -2-hydroxyacetonitrile Melting point: 128-129 ° C

EXAMPLE 11: (R) 2- (3-Bromophenyl) -2-dihydroartemisininyloxy-acetonitrile

Dihydroartemisinin and 2- (3-bromophenyl) -2-hydroxyacetonitrile starting materials

Melting point: 145-146 ° C EXAMPLE 12 (R) 2- (4-Chlorophenyl) -2-dihydroartemisininyloxy-acetonitrile

Starting materials: dihydroartemisinin and 2- (4-chlorophenyl) -2-hydroxyacetonitrile. Melting point: 142-145 ° C

EXAMPLE 13: (R) 2- (2-Chlorophenyl) -2-dihydroartemisininyIoxy-acetonitrile

Starting materials: dihydroartemisinin and 2- (2-chlorophenyl) -2-hydroxyacetonitrile.

Melting point: 137-140 ° C

EXAMPLE 14: (R) 2- (3-Chlorophenyl) -2-dihydroartemisininyloxy-acetonitrile

Starting materials: dihydroartemisinin and 2- (3-chlorophenyl) -2-hydroxyacetonitrile. Melting point: 132-135

EXAMPLE 15 2- (4-Nitrophenyl) -2-dihydroartemisininyloxy-propanenitrile

Starting materials: dihydroartemisinin and 2- (4-nitrophenyl) -2-hydroxy-propanenitrile.

EXAMPLE 16 1,4-Succinate of [(2-bromophenyI) (cyano) methyl] and of dihydroartemisininyl

Stage A: 4-Dihydroartemisininyloxy-4-oxobutanoic acid

The title product is conventionally obtained by condensation of succinic acid or its anhydride on dihydroartemisinin.

Stage B: 1, 4-Succinate of [(2-kromophenyl) (cyano) methyl] and of dihydroartemisininyl

To a solution of the compound obtained in stage A (2.0 g; 5.2 mmol) in 20 ml of CH ₂ C1 ₂ are added 2- (2-bromophenyl) -2-hydroxyacetonitrile (1.7 g; 8, 0 mmol), DCC (1.7 g; 8.2 mmol) and DMAP (0.1 g; 0.8 mmol) at 0-5 ° C. The reaction is stirred for 4 hours then the white solid formed is filtered. The organic phase obtained is concentrated under reduced pressure and chromatographed on a silica column (eluent: ethyl acetate / petroleum ether). The title product is obtained in the form of a white solid. Elementary microanalysis:

C H N

% Calculated 56.06 5.58 2.42% Found 56.28 5.60 2.31

EXAMPLE 17 1,4-Succinate of [(2-chlorophenyl) (cyano) methyl] and of dihydroartemisininyl

The procedure is as in Example 16, replacing 2- (2-bromophenyl) -2-hydroxyacetonitrile in stage B with 2- (2-chlorophenyl) -2-hydroxyacetonitrile. Elementary microanalysis:

C H N% Calculated 60, 73 6, 04 2, 62

% Found 60.91 6.15 2.69

Examples 18 to 27 are obtained according to the same process by replacing in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile with the appropriate reagent.

EXAMPLE 18 1,4-Succinate of [(phenyl) (cyano) methyl] and of dihydroartemisininyl

Starting material: 2-Phenyl-2-hydroxyacetonitrile.

Melting point: 142-144 ° C

EXAMPLE 19 1.4-Succinate of [(4-chlorophenyl) (cyano) methyl] and of dihydroartemisininyl

Starting material: 2- (4-Chlorophenyl) -2-hydroxyacetonitrile EXAMPLE 20 1,4-Succinate of (1-cyano-1-phenylethyl) and of dihydroartemisininyl

2-Phenyl-2-hydroxypropanenitrile starting material

EXAMPLE 21 1.4-Succinate of [(3,4-dimethoxyphenyl) (cyano) methyl] and of dihydroartemisininyl

Starting material ^• 2- (3,4-Dimethoxyphenyl) -2-hydroxyacetonitrile.

EXAMPLE 22 1,4-Succinate of [(1,3-benzodioxol-5-yl) (cyano) methyl] and of dihydroartemisininyl

Starting material 2- (1.3-Benzodioxol-5-yl) -2-hydroxyacetonitrile

EXAMPLE 23 1,4- (2,4-dimethoxyphenyl) (cyano) methyl) and dihydroartemisininyl succinate

Starting material 2- (2,4-Dimethoxyphenyl) -2-hydroxyacetonitrile.

EXAMPLE 24 1,4-Succinate of [(4-nitrophenyl) (cyano) methyl] and of dihydroartemisininyl

Starting material 2- (4-Nitrophenyl) -2-hydroxyacetonitrile

EXAMPLE 25 1,4-Succinate of [(4-methoxyphenyl) (cyano) methyl] and of dihydroartemisininyl

Starting product. 2- (4-Methoxyphenyl) -2-hydroxyacetonitrile

EXAMPLE 26 1,4-Succinate of [(4-cyanophenyl) (cyano) methyl] and of dihydroartemisininyl

Starting material 2- (4-Cyanophenyl) -2-hydroxyacetonitrile EXAMPLE 27 {- (4-benzyIoxy-3-methoxy) phenyl] [cyano] methyl} 1,4-succinate and dihydroartemisininyl

Starting material 2 - [(4-Benzyloxy-3-methoxy) phenyl] -2-hydroxyacetonitrile

EXAMPLE 28 1,4-Succinate of [(4-bromophenyl) (cyano) methyl] and of dihydroartemisininyl

Starting material 2- (4-Bromophenyl) -2-hydroxyacetonitrile

EXAMPLE 29 1,9-Azelaate of [(2-bromophenyl) (cyano) methyl] and of dihydroartemisininyl

The procedure is as in Example 16, replacing in stage A succinic acid with azelaic acid

Elementary microanalysis:

C H N

% Calculate 59.27 6.68 2.16% Find 59.50 6.44 2.25

EXAMPLE 30 1,8-Cyano (phenyl) methyl and dihydroartemisininyl suberate

The procedure is as in Example 16, replacing in stage A succinic acid by subeπque acid and in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile by 2-phenvl-2-hydroxyacetomtrile

EXAMPLE 31 1,6-Hexanedioate of [(2-chlorophenyl) (cyano) methyl] and of dihydroartemisininyl

The procedure is as in Example 16, replacing in stage A succinic acid by hexanedioic acid and in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile with 2- (2-chlorophenyl) -2-hydroxyacetonitrile.

EXAMPLE 32 Cyanophenyl and dihydroartemisininyl 1,2-phthalate

The procedure is as in Example 16, replacing in stage A succinic acid with phthalic acid and in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile with

2-phenyl-2-hydroxyacetonitrile. Elementary microanalysis:

C H N

% Calculated 68.12 5.90 2.56% Found 68.36 6.06 2.68

EXAMPLE 33 Cyan (2-bromophenyl) methyl and dihydroartemisininyl 1,2-phthalate

The procedure is as in Example 16, replacing in stage A succinic acid with phthalic acid. Melting point: 153-155 ° C

EXAMPLE 34 1, 4- (E) -2-Butenedioate of [(2-chlorophenyl) (cyano) methyl] and of dihydroartemisininyl

The procedure is as in Example 16, replacing in stage A succinic acid by (E) -2-butenedioιque acid and in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile by 2- (2-chlorophenyl) -2-hydroxyacetonitrile.

EXAMPLE 35 1, 4- (2.3-Dichloro) succinate of | (2-chlorophenyl) (cyano) methyl] and dihydroartemisininyl

The procedure is as in Example 16, replacing in stage A succinic acid with 2,3-dichlorosuccinic acid and in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile with 2- (2 -chlorophenyl) -2-hydroxyacetonitrile. EXAMPLE 36 1,4,2.2-Dimethylsuccinate of [(2-chlorophenyl) (cyano) methyl] and of dihydroartemisininyl

The procedure is as in Example 35, replacing 2,3-dichlorosuccinic acid with 2,2-dimethylsuccinic acid

EXAMPLE 37 1,8 (4-Bromo-1,8-naphthalene dicarboxylate) of (phenyl) (cyano) methyl and of dihydroartemisininyl

The procedure is as in Example 16, replacing in stage A succinic acid with 4-bromo-1,8-naphthalenedicarboxylic acid and in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile with 2-phenyl-2-hydroxyacetonitrile.

EXAMPLE 38: 4 - {[Cyano (phenyl) methyl] amino} -4-dihydroartemisininyl oxobutanoate

The procedure is as in Example 18, replacing 2-phenyl-2-hydroxyacetonitrile with 2-phenyl-2-aminoacetonitrile.

EXAMPLE 39: 4 - {[Cyano (2-chlorophenyl) methyl] amino} -4-dihydroartemisininyl oxobutanoate

The procedure is as in Example 17, replacing 2- (2-chlorophenyl) -2-hydroxyacetonitrile with 2- (2-chlorophenyl) -2-aminoacetonitrile.

EXAMPLE 40: 4 - ({[Cyano] [(3-methoxy-4-benzyloxy) phenyl] methyl} amino) -4- dihydroartemisininyl oxobutanoate

The procedure is as in Example 27, replacing the 2 - [(3-methoxy-4-benzyloxy) phenyl] -2-

-hydroxyacetonitrile with 2 - {(3-methoxy-4-benzyloxy) phenyl] -2-aminoacetonitrile. EXAMPLE 41: 4 - {[1-Cyano-1-phenylethyl] amino} -4-dihydroartemisininyl oxobutanoate

The procedure is as in Example 20, replacing 2-phenyl-2-hydroxy-propanenιtπle with 2-phenyl-2-amιnopropanenιtπle

EXAMPLE 42: 4 - {[Cyano (phenyl) methyl] [methyl] amino} -4-dihydroartemisininyl oxobutanoate

Stage A 2- (Methylamιno) -2-phenylacetonιtrιle

In a solution of NaHS0 ₃ (12 mmol in 4 ml of water), the benzaldehyde (11 mmol) is added with stirring When a white precipitate has formed, 28 ml of a 25% aqueous solution of methylamine are added dropwise then 12 mmol of potassium cyanide are added at 0 ° C. The reaction is stirred at ambient temperature until the end of the reaction After a conventional treatment the title product is obtained pure

Stage B Acid 4 - {[c \ ano (phenyl) methyl] (methyl) amιno} -4-oxobutanoιque

A mixture of the compound obtained in stage A (9 mmol), succinic anhydride (7.5 mmol) and pyπdine (1 ml) in methylene chloride (30 ml) is stirred overnight After a conventional treatment the product of title is obtained pure

Stage C 4 - {[Cyano (phenyl) methyl] [methyl] amιno} -4-dihydtoai temisminyle oxobutanoate

A mixture of dihvdroartemisinin (4.6 ml), of the compound obtained in stage B (5.5 ml), of DCC (6.9 mmol) and of DMAP (0 2 mmol) is stirred at room temperature At the end of the reaction, a conventional treatment is carried out and the title product is purified by chromatography on a silica column Tuswn point 146-148 ° C. Here is elementary analysis

C H N% Calculate 65 61 7 08 5.50

65 ^' 2 ^~ 09 5.56 EXAMPLE 43 4 - {[Cyano (4-chlorophenyl) methyl] - [methyl] amino} -4-dihydroartemisininyl oxobutanoate

The procedure is as in Example 42, replacing the benzaldehyde with 4-chlorobenzaldehyde. Melting point: 142-145 ° C

Elementary microanalysis:

C H N

% Calculated 61, 48 6.45 5, 12% Found 61.55 6.49 4.90

EXAMPLE 44 4 - {[Cyano (4-fluorophenyl) methyl] - [methyl] amino} -4-dihydroartemisininyl oxobutanoate

The procedure is as in Example 42, replacing the benzaldehyde by 4-fluorobenzaldehyde. Melting point: 143-145 ° C Elementary microanalysis:

C H N

% Calculated 63, 38 6, 65 5.28% Found 63, 12 6.43 4.95

Examples 45 to 48 are obtained by proceeding as in Example 1, replacing 2- (4-bromophenyl) -2-hydroxy acetonitrile with the appropriate nitrile.

EXAMPLE 45: (S) 2- (2-Bromophenyl) -2-dihydroartemisininyloxy-acetonitrile

Starting materials: dihydroartemisinin and 2- (2-bromophenyl) -2-hydroxy acetonitrile Elemental microanalysis:

C H N% Calculated 55, 75 5.90 2.93

% Found 57.84 5.83 2.82 EXAMPLE 46: (S) 2- (3-Bromophenyl) -2-dihydroartemisininyloxy-acetonitrile

Starting materials: dihydroartemisinin and 2- (3-bromophenyl) -2-hydroxy acetonitrile Elemental microanalysis:

C H N% Calculated 57, 75 5.90 2.93

% Found 57.94 5.92 2.92

EXAMPLE 47: (S) 2- {3- [3- (Trifluoromethyl) phenoxy] phenyl} -2-dihydroartemi- sininyloxy-acetonitrile

Starting materials: dihydroartemisinin and 2- {3- [3- (trifluoromethyl) phenoxy] phenyl} -2- hydroxy-acetonitrile

Elementary microanalysis:

C H N

% Calculated 64.39 5.76 2.50% Found 64.54 5.81 2.38

EXAMPLE 48: (R) 2- {3- [3- (Trifluoromethyl) phenoxy] phenyl} -2-dihydroartemisininylyloxy-acetonitrile

Starting materials: dihydroartemisinin and 2- {3- [3- (trifluoromethyl) phenoxy] phenyl} -2- hydroxy-acetonitrile Elemental microanalysis: C H N

% Calculated 64.39 5.76 2.50% Found 64.82 5.97 2.44

Examples 49 to 56 are obtained by proceeding as in Example 42, replacing: - in stage .A benzaldehyde with the appropriate reagent, - in stage B. succinic anhydride with the appropriate reagent. EXAMPLE 49: 4 - {[(4-BromophenyI) (cyano) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate

Starting materials: Stage A: 4-Bromobenzaldehyde Stage B: Succinic anhydride Elemental microanalysis:

C H N

% Calculated 56.86 5.96 4.74% Found 56.98 6.17 4.53

EXAMPLE 50: 4 - {[(Cyano [phenyl] methyl) (methyl) amino] carbonyl} dihydroartemisininyl benzoate

Starting materials: Stage A: Benzaldehyde

Stage B: Phthalic anhydride Elementary microanalysis:

C H N% Calculated 68.56 6.47 5.00

% Found 68.37 6.68 5.23

EXAMPLE 51: 4 - {[Cyano (phenyl) methyl] (methyl) amino} -4-dihydroartemisininyl oxo-2-butenoate

Starting materials: Stage A: Benzaldehyde Stage B: 2-Butenedioic acid

Elementary microanalysis:

C H N

% Calculated 65.8 ^' 6, 71 5.49% Found 65.96 6.96 5.43 EXAMPLE 52: 4 - {[Cyano (2,4-dimethylphenyl) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate

Starting materials Stage A 2,4-dimethylbenzaldehyde

Stage B Succinic anhydride Elementary microanalysis:

C H N

% Calculate 66.65 7.46 5.18% Find 66.93 7.71 4.96

EXAMPLE 53 4 - {[Cyano (2-fluorophenyl) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate

Starting materials Stage A 2-Fluorobenzaldehyde

Stage B Succinic anhydride Elementary microanalysis:

C H N% Calculated 63.38 6.65 5.28

% Found 63.54 6.86 5.19

EXAMPLE 54: 4 - {[Cyano (3-fluorophenyl) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate

Starting materials Stage A 3-Fluorobenzaldehyde Stage B Succinic anhydride

Elementary microanalysis:

C H N

% Calculate 63.38 6.65 5.28% Find 63.39 6.87 5.08 EXAMPLE 55: 4 - {[Cyano (2-bromophenyI) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate

Starting materials: Stage A: 2- Bromobenzaldehyde Stage B: Succinic anhydride Elemental microanalysis:

C H N

% Calculated 56.86 5.96 4.74% Found 56.92 5.96 4.68

EXAMPLE 56: 4 - [(Cyano {3- [3- (trifluoromethyl) phenoxy] phenyl} methyl) (methyl) amino] -4-dihydroartemisininyl oxobutanoate

Starting materials: Stage A: [3- (Trifluoromethyl) phenoxy] benzaldehyde

Stage B: Succinic anhydride Elementary microanalysis:

C H N% Calculated 62.49 5.84 4.16

% Found 62, 75 6, 08 3.94

Examples 57 to 67 are obtained by proceeding as in Example 16, replacing in Step B 2- (2-bromophenyl) -2-hydroxyacetonitrile with the appropriate acetonitrile.

EXAMPLE 57 4 - {[(4-Bromophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (4-Bromophenyl) -2-aminoacetonitrile Melting point: 165-167 ° C Elemental microanalysis:

C H N% Calculated 56, 16 5, 76 4.85

% Found 56.29 5.81 5.14 EXAMPLE 58 4 - {[(4-Chorophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (4-Chlorophenyl) -2-aminoacetonitrile Melting point: 164-165 ° C Elemental microanalysis:

C H N

% Calculated 60.84 6.24 5.25% Found 60.86 6.24 5.43

EXAMPLE 59: 4 - {[(4-Fluorophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (4-Fluorophenyl) -2-aminoacetonitrile Melting point: 159-162 ° C Elemental microanalysis:

C H N% Calculated 62, 78 6.44 5.42

% Found 62.86 6.49 5.62

EXAMPLE 60 4 - {[(Phenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting material: 2-Phenyl-2-aminoacetonitrile Melting point: 153-154 ° C

Elementary microanalysis:

C H N

% Calculated 65.04 6.87 5.62% Found 65.20 6.88 5.69 EXAMPLE 61 4 - {[(2-Bromophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (2-Bromophenyl) -2-aminoacetonitrile Melting point: 156-159 ° C Elemental microanalysis:

C H N

% Calculated 56, 16 5, 76 4.85% Found 56.31 5, 78 5, 11

EXAMPLE 62: 4 - {[(3-Bromophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (3-Bromophenyl) -2-aminoacetonitrile Melting point: 153-156 ° C Elemental microanalysis:

C H N% Calculated 56, 16 5, 76 4.85

% Found 56, 17 5, 65 4, 71

EXAMPLE 63 4 - {[(3-Chorophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting material: 2- (3-Chlorophenyl) -2-aminoacetonitrile Melting point: 154-156 ° C

Elementary microanalysis:

C H N

% Calculated 60.84 6.24 5.25% Found 60, 95 6.02 5.24 EXAMPLE 64: 4 - {[(2-Fluorophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (2-Fluorophenyl) -2-aminoacetonitrile Melting point: 161-162 ° C Elemental microanalysis:

C H N

% Calculated 62, 78 6.44 5.42% Found 62.91 6, 11 5.31

EXAMPLE 65 4 - {[Cyano (2-naphthyl) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (2-Naphtyl) -2-aminoacetonitrile Melting point: 127-129 ° C Elemental microanalysis:

C H N% Calculated 67.87 6, 61 5, 11

% Found 67.88 6.71 4.96

EXAMPLE 66: 4 - ({Cyano [4- (dimethylamino) phenyl] methyl} amino) -4-dihydroartemisininyl oxobutanoate

Starting material: 2- [4- (Dimethylamino) phenyl] -2-aminoacetonitrile Melting point: 160-162 ° C

Elementary microanalysis:

C H N

% Calculated 64.31 ~, 26 7.76% Found 64.50 ^' , 27 7.49 EXAMPLE 67 4 - {[(3-Fluorophenyl) (cyano) methyl] amino} -4-dihydroartemisininyl oxobutanoate

Starting product: 2- (3-Fluorophenyl) -2-aminoacetonitrile Melting point: 146-148 ° C Elemental microanalysis:

C H N

% Calculated 62, 78 6.44 5.42% Found 62.91 6, 11 5.31

EXAMPLE 68: 4 - {[Cyano (2-chlorophenyl) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate

The procedure is as in Example 42, replacing in stage A the benzaldehyde with 2-Chlorobenzaldehyde.

PHARMACOLOGICAL STUDY

The following examples make it possible to demonstrate the cytotoxic properties of the compounds of the invention as well as their action on the cell cycle

EXAMPLE A Cytotoxicity of the Compounds

Three cell lines were used

- 2 muπne leukemias L1210, P388

- 1 human lung carcinoma, non small cell, A549

The cells are cultured in complete RPMI 1640 culture medium containing 10% of fetal calf serum 2 mM of glutam e, 50 units / ml of penicillin, 50 μg / ml of streptomycin and 10 mM of Hepes

The cells are distributed in microplates and exposed to cytotoxic compounds. They are then incubated for the time necessary for cell doubling. The number of viable cells is then quantified by a coloπmetπque test, the Minoculture Tetrazo um Assay (Carmichael J De Graff WG, Gazdar AF , Mmna JD and Mitchell JR, Evaluation of a tetrazo um-based semi-automated coloπmetπc assay assessment of chemosensitivity testing, Cancer Res, 47 936-942, 1987)

The results obtained show a good general cytotoxicity on the L1210 and P388 lines. Furthermore, cytotoxic properties with respect to solid tumors such as the A549 line have been demonstrated.

EXAMPLE B: Action on the cell cycle

The L1210 cells are incubated for 21 hours at 37 ° C. in the presence of different concentrations of test products. The cells are then fixed with 70% ethanol (V / V), washed twice in PBS and incubated for 30 minutes. 20 ° C in PBS containing 100 μg / ml of R Ase and 50 μg / ml of propidium iodide The percentage in phase G2 + M is calculated and the results are expressed according to a classification determined according to the percentage of cells accumulated in phase G2 + M after 21 hours compared to the control (control 20%) The compounds of the invention show an accumulation of more than 60% of the cells in G2-M phase after 21 hours for product concentrations ranging from 0.5 to

50 μM

Furthermore, the compounds of the invention show an induction of apoptosis at cytotoxic doses

EXAMPLE C:

Tablets containing 10 mg of (R) 2- (4-bromophenyl) -2-dihydroartemisininyl-acetonitrile

Preparation formula for 1000 tablets

(R) 2- (4-bromophen \ l) -2-dehydroartemιsιnιnyl-acetonιtπle 10 g

Wheat starch 15 g

Corn starch 15 g

Lactose 65 g

Mg stearate 2 g

Silica 1 g

Hydroxypropylcellulose 2 g

Claims

1- Compound of formula (I)

R - O - A (I) in which

R represents the radical of formula (II)

A represents

CN ι,

- a group of formula (m) -C-R (ni)

R in which - R ¹ represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group,

- R ² represents a hydrogen atom, or a linear or branched (Ci-Ce) alkyl group substituted or not,

- or a group of formula (IV) - C-Y ~ C— Z— R (IV)

It II '

OO in which - Y represents a linear or branched alkylene (C ₂ -C _H ) group substituted or not, alkenylene (C ₂ -Cι ₄ ) linear or branched substituted or not, alkynylene (C ₂ -Cι ₄ ) linear or branched substituted or not, phenylene, substituted phenylene, naphthylene, or substituted naphthylene,

- Z represents an oxygen or sulfur atom, or a group NR 'where R'^" can take the same values as R ² , - R ^' represents a group of formula (III) as defined above,

Being heard that

- by aryl means a phenyl, naphthyl, phenanthryl, fluorenyl or anthryl group, by heteroaryl is meant any mono or bicyclic aromatic group containing from 5 to 10 atoms and which may contain from 1 to 3 heteroatoms chosen from oxygen, nitrogen or sulfur,

- the term "substituted" affecting the expressions "aryl", "heteroaryl", "phenylene", "naphthylene", means that these groups are substituted by one or more radicals, identical or different, chosen from linear (Ci-Ce) alkyl or branched, hydroxy, alkoxy

(Cι-C ₆ ) linear or branched, alkoxycarbonyl (Ci-Ce), polyhalogenoalkyle (Cι-C ₆ ) linear or branched, aryloxy (unsubstituted or substituted by one or more groups, identical or different, chosen from hydroxy, alkyl ( Ci-Ce) linear or branched, alkoxy (Cι-C ₆ ) linear or branched, polyhalogenoalkyle (CpCβ) linear or branched, or halogen atoms), nitro, amino, alkylamino (Ci-Ce) linear or branched, dialkylamino ( Cι-C ₆ ) linear or branched, alkylcarbonylamino. cyano or halogen atoms (fluorine, chlorine, bromine or iodine), or two adjacent carbon atoms may be substituted by an alkylenedioxy group,

- The term "substituted" affecting the expressions "alkyl", "alkylene", "alkenylene", "alkynylene" means that these groups are substituted by one or more radicals, identical or different, chosen from hydroxy, alkoxy (Cι-C ₆ ) linear or branched, polyhalogenoalkyl, amino or halogen atoms (fluorine, chlorine, bromine or iodine),

their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

2- Compounds of formula (I) according to claim 1 for which A represents a group of formula (III), their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

3- Compounds of formula (I) according to claim 1 for which A represents a group of formula (IV), their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

4- Compounds of formula (I) according to claim 1 for which Z represents an oxygen atom, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base. 5- Compounds of formula (I) according to claim 1 for which Z represents an NR 'group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

6- Compounds of formula (I) according to claim 1 for which Y represents an alkylene (C ₂ -Cι ₄ ) or alkenylene (C -Cι) chain, substituted or not, their enantiomers and diastereoisomers, as well as their addition salts to a pharmaceutically acceptable acid or base.

7- Compounds of formula (I) according to claim 1 for which Y represents a phenylene or a naphthylene, substituted or not, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a pharmaceutically acceptable base.

8- Compounds of formula (I) according to claim 1 for which R ¹ represents an aryl or substituted aryl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

9- Compound of formula (I) according to claim 1 which is 2- (4-bromophenyl) -2- dihydroartemisininyl-acetonitrile, its enantiomers and diastereoisomers ((R) -2- (4-bromophenyl) -2-dihydroartemisininyl- acetonitrile and (S) -2- (4-bromophenyl) -2-dihydroarte- misininyl-acetonitrile). as well as its addition salts with a pharmaceutically acceptable acid or base.

10- Compound of formula (I) according to claim 1 which is 2-phenyl-2-dihydroartemisininyl-acetonitrile, its enantiomers and diastereoisomers ((R) -2-phenyl-2-dihydroartemisininyl-acetonitrile and (S) -2- phenyl-2-dihydroartemisininyl-acetonitrile), as well as its addition salts with a pharmaceutically acceptable acid or base.

11- Compound of formula (I) according to claim 1 which is 1,4-succinate

[(2-chlorophenyl) (cyano) methyl] and dihydroartemisininyl, its enantiomers and diastereoisomers ((R) -1,4-succinate of [(2-chlorophenyl) (cyano) methyl] and dihydroartemisininyl and (S) -l , [(2-chlorophenyl) (cyano) methyl] and 4-succinate dihydroartemisininyiej. as well as its addition salts with a pharmaceutically acceptable acid or base.

12- Compound of formula (I) according to claim 1 which is 4 - {[((4- Bromophenyl) (cyano) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate, its enantiomers and diastereoisomers ((R) - 4 - {[(4-Bromophenyl) (cyano) methyl] (methyl) amino} -

Dihydroartemisininyl 4-oxobutanoate and (S) -4 - {[(4-Bromophenyl) (cyano) methyl] (methyl) amino} -4-dihydroartemisininyl oxobutanoate), as well as its addition salts with an acid or a base pharmaceutically acceptable.

13- Process for preparing the compounds of formula (I) according to claim 1 characterized in that the compound of formula (V) is used as starting material:

R ^ΛΛΛW OH (V) in which R is as defined above,

on which we condense

- under acid catalysis conditions, a compound of formula (VI):

CN ι

R - C— OH (VI)

2

R in which R ¹ and R ^" are as defined above, to lead to the compound of formula (I / a), special case of the compounds of formula (I)

CN

Rv ^v v oC— R ² (i / a)

R ¹ in which R, R ¹ and R ² are as defined above,

- or a compound of formula (VII):

HO— C— Y— COOH (VU)

II

O in which Y is defined as above, (or the corresponding acid chloride or anhydride), to lead to the compound of formula (VIII)

R ^ O-C— Y— COOH (vm)

II

O in which R and Y are defined as above, on which one reacts under acid catalysis conditions, in the presence of a coupling agent, or after transformation into the corresponding acid chloride,

in which R, R ¹ , R ² and Y are as defined above,

• a compound of formula (IX)

CN

R ¹ - C-NHR ^{* 2} (IX)

R ² in which R ¹ . R ^" and R ' ² are as defined above, to lead to the compound of formula (I / c), special case of the compounds of formula (I)

in which R, R ¹ . R ² , R ' ² and Y are as defined above,

• or a compound of formula (X)

CN

R ¹ - C-SH (X)

R ² in which R ¹ and R ² are as defined above, to lead to the compound of formula (I / d), special case of the compounds of formula (I)

CN

I,

Rvw O-C-Y-C-S-C-R (I / d)

H II L

0 OR ² in which R, Y, R ¹ and R ² are defined as above,

the compounds (I / a) to (I d) forming the set of compounds of formula (I) and which can be purified according to a conventional separation technique, which is converted, if desired, into their salts addition to a pharmaceutically acceptable acid or base, from which the optical or geometric isomers are optionally separated according to conventional purification techniques

14- Process for the preparation of the compounds of formula (I) according to claim 1 for which A represents a group of formula (IV), characterized in that a compound of formula (VII) is used as starting material

HO— C-Y— COOH (VII)

I I O in which Y is as defined above, (or the corresponding acid chloride or anhydride), on which we condense

- in the presence of a coupling agent, a compound of formula (IX)

in which R ¹ , R ² . R ' ² and Y are as defined above, on which a compound of formula (V) is condensed to obtain the compound of formula (I / c), special case of the compounds of formula (I) (I / c) in which R, Y, R ¹ , R ² and R ' ² are as defined above,

- a compound of formula (VI):

CN i ι R - C— OH (VI)

2

R in which R ¹ and R ² are defined as above, to lead to the compound of formula (XIII):

in which R ¹ , R ² and Y are defined as above, on which a compound of formula (V) is condensed to obtain the compound of formula (I / b), special case of the compounds of formula (I):

in which R, Y, R ¹ and R ² have the same definition as above,

- or a compound of formula (X):

CN

R ¹ - C-SH (X)

R ² in which R ¹ and R ² are defined as above, to obtain the compound of formula (XIV):

in which R ¹ , R ² and Y are as defined above, on which a compound of formula (V) is condensed to obtain the compound of formula (I / d), special case of the compounds of formula (I):

CN

R ^W ^ OCYC- SCR ¹ (I / d)

OOR ² in which R, Y, R ¹ and R ² are defined as above,

the compounds (I / b), (I / c) and (I / d) can be purified according to a conventional separation technique, which is converted, if desired, into their addition salts with an acid or to a pharmaceutically acceptable base, from which the optical or geometric isomers are optionally separated according to conventional purification techniques.

15- Pharmaceutical compositions containing as active principle at least one compound according to any one of claims 1 to 12, alone or in combination with one or more excipients or inert, non-toxic, pharmaceutically acceptable vehicles.

16. Pharmaceutical compositions according to claim 15 containing at least one active principle, antitumor agent according to any one of claims 1 to 12, useful in the treatment of cancers.