WO2003095459A2

WO2003095459A2 - Alkaloid-derived compounds and use thereof in cancer and malaria treatment

Info

Publication number: WO2003095459A2
Application number: PCT/FR2003/001358
Authority: WO
Inventors: Alfred François TRIGALO; Philippe Rasoanaivo; Suzanne Ratsimamanga; François Frappier
Original assignee: Centre National De La Recherche Scientifique; FRAPPIER, Jérôme, Jean-Claude; FRAPPIER, Marie-Pierre, Claudie
Priority date: 2002-05-07
Filing date: 2003-04-30
Publication date: 2003-11-20
Also published as: AU2003246880A8; FR2839513A1; AU2003246880A1; WO2003095459A3

Abstract

The invention relates to compounds having general formula (I) wherein, the dotted bond in the ring represents a simple or double bond and R, R' and R'' denote a hydrogen atom, a linear or cyclic, substituted or non-substituted alkyl group with between 1 and 7 carbon atoms, a benzyl group, an alkylene group with between 1 and 3 carbon atoms, an acyl group with between 1 and 5 carbon atoms.

Description

NOVEL COMPOUNDS DERIVED FROM ALKALOIDS, THEIR PREPARATION PROCESS, AND THEIR USE FOR THE PREPARATION OF MEDICINES

The present invention relates to new compounds derived from alkaloids, their process of preparation. It also relates to their use for the preparation of medicaments, in particular in the context of the treatment of malaria and cancer.

Malaria is a parasitic and endemic disease that affects 300 to 500 million people worldwide. Malaria is caused by protozoan parasites of the genus Plasmodium. From

4 responsible species, P. vivax and P. falciparum are the most widespread, the latter being the cause of the most serious and often fatal symptoms.

For forty years, chloroquine has been the main drug in the fight against malaria (prophylaxis and treatment). Today, chloroquine is no longer effective against P. falciparum, the main agent of human malaria, due to the increase in the phenomenon of resistance. The search for new strategies has therefore become a priority.

The raw alkaloid extract of Strychnos myrtoides, Logagniaceae, a plant used in traditional Malagasy medicine in the treatment of malaria as an adjuvant to chloroquine, has no significant antimalarial activity, either in vitro or in vivo. On the other hand, associated with chloroquine at doses lower than the IC ₅₀ , this extract has a potentiating effect in vitro on the strains of R. falciparum and in vivo on P. yoelii. From this raw extract were isolated strychnobrasiline, known indolic alkaloid and malagashanine, alkaloid of new structure which are 'responsible for the activity of the total extract observed in vitro, while in vivo only malagashanine, minority alkaloid turned out to be active. However, malagashanine is not easy to isolate from the plant in large quantities, unlike strychnobrasiline, which, moreover, is present in its natural state in a higher quantity than malagashanine.

Synthetic molecules such as verapamil, calcium channel blockers such as dihydropyridines or phenylalkylamines, make the resistance to chloroquine of P. falciparum in vitro and that of P. bergheii in mice reversible (Martin et al., 1987; Ginsburg, 1991; Salomone et al., 1990). Furthermore, such a reversion activity has been described for alkaloids of the bis-benzylisoquinoline type, the tetrandrine (international application WO 92/18191). However, the disadvantage of these molecules currently used lies in their toxicity.

The present invention aims to provide a new molecule providing an effective and economical alternative to the problem of the resistance of the parasite responsible for malaria vis-à-vis chloroquine.

The object of the present invention is the use of an adjuvant drug making it possible to raise the resistance of the parasite responsible for malaria, with respect to chloroquine.

The present invention relates to compounds corresponding to the following general formula (I):

in which :

- the dotted link in the cycle represents a single or double link,

- R represents a hydrogen atom, an alkyl group of 1 to 7 carbon atoms, substituted or not, linear or cyclic, a benzyl group, an alkylene group of 1 to 3 carbon atoms, an acyl group of 1 to 5 carbon atoms,

- R 'represents a hydrogen atom, an alkyl group of 1 to 7 carbon atoms, substituted or not, linear or cyclic, a benzyl group, an alkylene group of 1 to 3 carbon atoms, an acyl group of 1 to 5 carbon atoms,

- R "represents a hydrogen atom, an alkyl group of 1 to 7 carbon atoms, substituted or not, linear or cyclic, a benzyl group, an alkylene group of 1 to 3 carbon atoms, an acyl group of 1 to 5 carbon atoms.

The products according to the invention therefore correspond to one of the following formulas:

(II) (III) the substituents R, R 'and R''being as defined above. The present invention also relates to the compounds of formula (I), (II) or (III) defined above, characterized in that R represents an acetyl group -COCH ₃ .

The present invention also relates to the compounds of formula (I), (II) or (III) defined above, characterized in that R "is a methyl group or a hydrogen atom.

The present invention also relates to the compounds of formula (I), (II) or (III) defined above, characterized in that:

- Either R is a COCH ₃ group, R 'is a methyl, ethyl, propyl, butyl, allyl or benzyl group, and R''is a methyl group;

- Either R is a hydrogen atom, R 'is a methyl, ethyl, butyl, allyl or benzyl group, and R "is a methyl group;

- Either R and R 'are methyl, ethyl, butyl, allyl or benzyl groups, and R "is a methyl group;

- Either R is a hydrogen atom, R 'is a methyl, ethyl, butyl, allyl or benzyl group, and R "is a hydrogen atom.

Particularly advantageous compounds of the present invention correspond to one of the following formulas:

The compound (11) corresponds to the same formula as the compound (10) but it contains a benzene ring. The present invention also relates to compounds capable of being used as synthesis intermediates for the preparation of the compounds of formula (I), as defined above, and corresponding to one of the following formulas:

(4) (7)

Compounds (4) and (7) are new compounds.

The invention also relates to a process for preparing the compounds of formula (10) or (11) defined above, characterized in that it comprises:

a step for oxidizing the alcohol function of the compound (7) as defined above, in order to obtain the compound (8), of the following formula:

a step of deacetylation of the above-mentioned compound (8) in order to obtain the compound (9) of the following formula:

a step of reductive amination of the above-mentioned compound (9), in order to obtain, according to the conditions of reductive amination, the compound (10) or (11) as defined above.

The passage from compound (9) to compound (10) is carried out in particular in 0.1M acetic acid in the presence of platinum oxide (PtO ₂ ) and hydrogen gas, while the passage of compound (9) to compound (11) is in particular carried out in 1,2-dichloromethane in the presence of sodium triacetoxyborohydride.

The present invention also relates to a process for preparing the compound (7) as defined above, characterized in that it comprises:

a methylation step, in particular in the presence of diazomethane, of the compound (6) of the following formula:

The above-mentioned methylation step is specific for the compounds of formula (6). The conventional technique which consists first of all in acidifying the medium in order to release the acid function -COOH from the ammonium salt -COONH ₄ , then in adding diazomethane, leads mainly to lactone (4). In order to avoid this lactonization reaction, the ethereal solution of diazomethane is first added to the compound (6), then the acid function is released by adding small amounts of silica until the yellow solution discolours (this operation is repeated 4 to 5 times).

The present invention also relates to a process for preparing the compound (6) as defined above, characterized in that it comprises:

a step for opening the lactone function of the compound (4) as defined above, by treatment with a base, in particular KOH, in order to obtain the compound (5) of the following formula:

- A cation exchange step associated with the base used above, in the compound of formula (5) obtained in the previous step.

According to the present invention, it is necessary to go through the aforementioned step of cation exchange. Indeed, the conventional method of direct transformation of lactones into methyl alcohol-ester without passing through the acid salt, described in the literature (Pizey, 1975), gives no result with the compound (4) in because of its very strong thermodynamic stability. The transesterification reaction mentioned above is carried out in the prior art by boiling the lactone in methanol under reflux in the presence of an acid catalyst such as phosphoric acid or an acid resin.

The present invention also relates to a process for preparing the compound (4) as defined above, characterized in that it comprises: an acetylation step, in particular in the presence of acetic anhydride, of the compound (2) of the following formula:

in order to obtain the compound (3) of the following formula

- A step of oxidation of the alcohol function of the above-mentioned compound (3).

The present invention also relates to a process for preparing the compound (4) as defined above, characterized in that it comprises:

a step of treatment with LiAlH ₄ of the compound (1) of the following formula:

in order to obtain the compound (2) as defined above,

an acetylation step, in particular in the presence of acetic anhydride, of the compound (2) as defined above, in order to obtain the compound (3) as defined above, and

- A step of oxidation of the alcohol function of the above-mentioned compound (3). The first stage of treatment with LiAlH. leads to the opening of the 9-atom ring and the formation of the pyranose-hemiacetal ring, as well as to the reductive deacetylation of indolic nitrogen. (Trigalo et al., 1999)

The present invention also relates to a process for the preparation of the compounds of formula (10) and (11) defined above, characterized in that it comprises:

a step of treatment with LiAlH of the compound (1) as defined above, in order to obtain the compound (2) as defined above,

a step for oxidizing the alcohol function of the above-mentioned compound (3), in order to obtain the compound (4) as defined above,

a step for opening the lactone function of the compound (4) as defined above, by treatment with a base, in particular KOH, in order to obtain the compound (5) as defined above,

a step for exchanging the cation associated with the base used above, in the compound (5) obtained in the preceding step, in order to obtain the compound (6) as defined above,

a methylation step, in particular in the presence of diazomethane, of the above-mentioned compound (6), in order to obtain the compound (7) as defined above,

a step for oxidizing the alcohol function of the above-mentioned compound (7), in order to obtain the compound (8), as defined above,

a step of deacetylation of the above-mentioned compound (8) in order to obtain the compound (9) as defined above, a step of reductive amination of the above-mentioned compound (9), in order to obtain, according to the conditions d reductive amination, the compound (10) or (11) as defined above.

The compounds of the invention can be used to make reversible the resistance of an organism to a pharmaceutically active substance. The present invention relates to a pharmaceutical composition containing a compound as defined above, in combination with a pharmaceutically active substance, and a pharmacologically acceptable vehicle. The present invention also relates to a pharmaceutical composition as defined above, characterized in that the pharmaceutically active substance is chosen from aminoquinolines, aminoacridines or phenanthrene methanol.

The pharmaceutically active substance is in particular chosen from aminoquinolines such as chloroquine, aminoacridines such as quinacrine or pyronaridine, quinoline-methanols such as quinine or mefloquine or phenanthrene-methanols such as halofantrine.

The present invention relates to a pharmaceutical composition as defined above, characterized in that the pharmaceutically active substance is chloroquine.

The present invention also relates to a pharmaceutical composition as defined above, characterized in that the pharmaceutically active substance is an anti-malarial agent.

The present invention also relates to a pharmaceutical composition as defined above, characterized in that the pharmaceutically active substance is an anti-tumor agent.

The anti-tumor agent can in particular be chosen from the following compounds: daunorubicin, doxorubicin, vinblastine, vincristine, vinarelbine, etoposide, taxol, taxotere, tamoxifene or camptothecin. The present invention relates to a pharmaceutical composition as defined above, characterized in that it contains from 50 to 200 mg per unit dose, in particular from 80 to 160 mg per unit dose, of the compound as defined above.

The present invention relates to the use of the compound as defined above, for the preparation of a medicament intended to make reversible the resistance of an organism to a pharmaceutically active substance.

The compounds according to the present invention can be used in the context of the appearance of the phenomenon of resistance to chemotherapy, in particular in the context of the following infectious pathologies: microbial pathologies such as infections with Gram + or Gram- bacteria, pathologies viral such as AIDS, parasitic pathologies such as malaria, leishmaniasis or trypanosomiasis, mycoses such as candidiasis.

The present invention also relates to the use as defined above, characterized in that the pharmaceutically active substance is an antimalarial agent. The present invention also relates to the use as defined above, characterized in that the pharmaceutically active substance is an anti-tumor agent.

DESCRIPTION OF THE FIGURES

Figure 1 represents a diagram of isobologra me, in which:

the abscissa axis corresponds to the IC ₅₀ measured for chloroquine in the presence of the drug tested, and expressed as a fraction of the IC ₅₀ of chloroquine,

- the ordinate axis corresponds to the fraction of the IC ₅₀ of the drug tested.

The IC ₅₀ measured for a molecule corresponds to the concentration inhibiting at 50% the in vitro growth of Plasmodium falciparum.

Figure 2 shows the isobologram obtained for compounds (10) and (11). The curve with the black circles corresponds to the compound (10) and the curve with the black triangles to the compound (11).

FIG. 3 shows the isobologram of interaction between doxombicin on the one hand and compound (11), malagashanin and verapamil respectively on strains resistant to doxombicin. The curve with the white squares corresponds to malagashanine, the curve with the black diamonds to compound (11) and the curve with the black circles to verapamil. PROTOCOL FOR THE PREPARATION OF THE COMPOUNDS OF THE INVENTION

EXAMPLE 1 Process for the preparation of the compounds of formula (10) and (11)

1) First step:

C H N O C H N O

22 26 2 3 20 28 2 3

Exact mass: 366.1943 Exact mass: 344.2100

This first step is described in the publication by Trigalo, F.; Martin, M.T.; Blond A.; Brouard, J.P.; Rafatro, H.; Ramanitrahasimbola, D. and Frappier, F., Tetrahedron (1999) 55, 6139-6146.

To one millimole of strychnobrasiline (1) (367 mg) dissolved in 12 ml of anhydrous THF (tetrahydrofuran) are added 2 ml of LiAltL _t 1M in solution in THF. The mixture is stirred magnetically and kept under argon for one hour. An ether / H ₂ O (95/5) 50 ml mixture is added slowly and the precipitate formed is filtered and then washed with 5 ml of methanol. After evaporation under vacuum, the residue is chromatographed on a silica column. 250 mg of product (2) (yield 72%) are collected by elution with dichloromethane-methanol-ammonia 20% (85/15/2).

Melting Point:> 250 ° C (decomposition)

[OC] _D = -26 ° (solvent: MeOH, product concentration during measurement c = 0.35, which conventionally corresponds to 3.5 mg / ml)

SMHR (High resolution mass spectrometry) for C ₂ oH ₂₈ N ₂ O ₃ :

M +. ; calculated 344.2100; found 344.2111.

SMEI (Electron Impact mass spectrometry): m / z ≈ 344 (30), 285 (100), 286 (130), 269 (14), 268 (1), 144 (37), 143 (32).

SMIC (Chemical ionization mass spectrometry) (isobutane): m / z = 345 (100), 327 (18).

1H NMR: δ 1.27 (d, J = 6.5); 1.32 (m); 1.49 (m); 1.50 (m); 1.83 (m); 1.85 (m); 1.92 (m); 2.33 (s); 2.55 (m); 2.68 (m); 3.48 (m); 3.48 (d, J = 7.2); 3.56 (dd, J = 11.6; 2.2); 3.97 (d, J = 11.6); 4.36 (d, J = 3.4); 5.07 (d, J = 8.5); 6.65 (d, J = 7.9); 6.70 (dd, J = 7.7; 7.2); 6.95 (d, J = 7.7); 7.02 (dd, J = 7.9; 7.2).

¹³ C NMR: δ 20.6; 31.2; 32.6; 35.5; 36.9; 42.8; 46.7; 47.4; 52.2; 71, .8; 69.9; 72.3; 76.7; 92.5; 111.9; 119.5; 124.2; 129.2; 137.6; 150.8.

2) Second step:

Cao ^ N ^ C ₂₄ H ₃₂ N ₂ O ₅ Exact mass: 344.2100 Exact mass: 428.2311

One millimole of compound (2) (344 mg) is dissolved slightly hot and with magnetic stirring in 3 ml of acetic anhydride. Returning to room temperature, the compound (3) crystallizes after 10 to 15 minutes, it is filtered, washed with 10 to 20 ml of ethyl ether. After drying under vacuum, 385 mg (90% yield) of product are collected.

Melting Point:> 203 ° C

[α] _D = + 84.8 ° (CHC1 ₃ , c = 2.0)

SMHR for C ₂ H ₃₃ N ₂ θ ₅ : M + 1H 12.8% calculated: 429 89; found: 429.2395

C ₂ H ₃₁ N ₂ O ₄ : M + 1H-H ₂ O 100% calculated: 411.2284; found: 411.2281 3) Third step:

C ₂₄ H ₃₂ N ₂ O ₅ C ₂₄ H ₃₀ N ₂ O ₅ Exact mass: 428.2311 Exact mass: 426.2155

One millimole of compound (3) (i.e. 428 mg) is dissolved in 3 ml of dichloromethane, and 300 mg of pyridinium dichromate (PDC) are added. The suspension is left under magnetic stirring for 18 hours. It is then concentrated under vacuum, the residue is taken up 3 times with 25 ml of hot ethyl acetate, the organic solution is filtered and the residue obtained after evaporation is chromatographed on a silica column (dichloromethane, 98/2 methanol). 318 mg of lactone are obtained, a yield of 75%.

Melting Point: 126-128 ° C

[α] _D = 49 ⁰ (CHCl ₃ , c = 1.4)

SMHR for C ₂₄ H ₃ ιN ₂ O ₅ : M + 1H. 100%, calculated: 427.2233; found: 427.2238

4) Fourth step:

C ₂₄ H ₃₅ N ₃ O ₆ Exact mass: 461.2526

One millimole of the compound (4), or 426 mg, is dissolved in 4 ml of a methanol water mixture (v / v) and 560 mg of potassium hydroxide are added. After five hours of reaction, the solution is concentrated in vacuo and the residue is chromatographed on silica. After elution with dichloromethane, methanol, water, 90/10/1 then 75/25/5, 320 mg of the product (6) are collected, ie a yield of 70%.

Melting Point: 182-183 ° C,

[α] _D = -19.1 ° (MeOH, c = 1.0)

SMHR for C ₂₄ H ₃₃ N ₂ O ₆ : M + 1H (35.9%); calculated 445.2339; found 445.2326

C ₂₄ H ₃ iN ₂ O ₅ : M + 1H-H ₂ O (20.9%); calculated 427.2233; found 427.2222 5) Fifth step:

8

C ₂₅ H ₃₂ N ₂ O ₆ Exact mass: 456.2260

461 mg of the compound (6) (ie one millimole) are dissolved in 5 ml of methanol. After cooling to 0 ° C in ice, 2 ml of a solution of diazomethane in ether are added, with magnetic stirring, then very slowly and gradually very small amounts of silica until the yellow solution discolours. This operation is repeated 5 to 6 times, then the organic solution is evaporated under vacuum. The dry residue is dissolved in 3 to 4 ml of dichloromethane to which 300 mg of PDC are added. The heterogeneous solution is stirred for 17 hours. It is then concentrated in vacuo and the residue is taken up 3 times with 25 ml of hot ethyl acetate. The organic solution is filtered and the residue obtained after evaporation is chromatographed on a silica column. By elution with the dichloromethane / methanol mixture 97/3, 225 mg of the compound (8) are obtained in the form of a yellow oil, ie a yield of 49%.

SMHR for C ₂₅ H ₃₃ N ₂ O ₆ : M + 1H (100%) calculated 457.2339; found 457.2339

6) Sixth step

8

C ₂ ιH ₂₈ N ₂ O ₄

C ₂₅ H ₃₂ N ₂ O ₆ Exact mass: 372.2049 Exact mass: 456.2260

One millimole of compound (8) (456 mg) is dissolved in a mixture of 2 ml of acetic acid, 2 ml of fuming HCl and 2 ml of water. The solution is heated at reflux for 5 hours, then evaporated to dry vacuum. The residue is dried under vacuum in the presence of potassium hydroxide overnight, then chromatographed on a silica column. By elution with the dichloromethane, methanol, ammonia (90/10/1) mixture, 223 mg of a colorless oil are collected, ie a yield of 60%>.

7) Seventh step

10

C ₂₁ H ₂₈ N ₂ O ₄ C ₂₁ H ₃₄ N ₂ O ₃ Exact mass: 372.2049 Exact mass: 362.2569 93 mg (0.25 mmol) of compound (9) are dissolved in 4 ml of 0.1M acetic acid and allowed to hydrogenate, with magnetic stirring and hydrogen atmosphere, in the presence of 50 mg of platinum oxide. After one hour, the catalyst is filtered and the acetic solution is concentrated in vacuo. 80 mg of a colorless oil are collected, ie a yield of 88%).

1H NMR: δ 1.08 (m, C9H); 1.10 (m, C12H); 1.31 (d, J = 6.9 Hz; C18H ₃ ) 1.49 (m, C14H); 1.54 (m, C11H); 1.58 (m, C6H); 1.58 (m, C10H); 1.65 (m, C9H) 1.71 (m, C8H); 1.93 (m, C6H); 1.77 (m, C12H); 1.89 (m, Cl 0H); 1.98 (m, C14H) 2.41 (m, C15H); 2.45 (s, C22H ₃ ); 2.53 (dd, J = 5.7; 11.0 Hz; C3H); 2.56 (dd, J = 7.4 8.9 Hz; C5H); 2.76 (dd, J = 2.6; 8.9 Hz; C5H); 3.03 (dd, J = 5.2; 5.2 Hz; C20H) 3.36 (m, C2H); 3.44 (dd, J≈ 4.6; 11.7 Hz; C17H); 3.59 (s, OC23H ₃ ); 3.59 (m, C13) 3.75 (dd J = 11.7 Hz; 11.7 Hz; C17H); 4.35 (dq, J≈ 6.9; 5.2 Hz; C19H),

¹³ C NMR: δ 16.8 (Cl 8); 19.9 (Ci 1); 23.1 (C9); 24.1 (C14); 24.4 (Cl 2); 27.3 (C10); 29.3 (C6); 30.0 (Cl 5); 40.5 (C22); 41.1 (Cl 6); 46.3 (C8); 47.7 (C20); 51.4 (C23); 51.9 (C5); 56.1 (C13); 59.7 (C2); 59.2 (Cl 7); 69.0 (Cl 9); 68.8 (C3); 171.9 (C21).

SMHR for C ₂ ιH ₃₅ N ₂ O ₃ : M + 1H (100%); calculated 363.2648; found 363.2642

8) Eighth step

acetoxy borohydride

11

C ₂₁ H ₂₈ N ₂ O ₄ C ₂ ι ^H H2 ₂ 8 ₈ N ₂ O ₃ Exact mass: 372.2049 Exact mass: 356.2100

93 mg (0.25 mmol) of compound (9) are dissolved in 4 ml of 1-2 dichloroethane, to which is added, with magnetic stirring, 106 mg of sodium triacetoxy borohydride. After 24 hours, the heterogeneous solution is concentrated in vacuo. After passing through a silica column and eluting with a dichloromethane, methanol mixture, ammomaque (95/15 / 0.5), 50 mg of a colorless oil are collected, giving a yield of 56%.

1H NMR: δ 1.21 (d, J ≈ 6.6 Hz; C18H ₃ ); 1.43 (m, C16-H); 1.48 (m, C14H); 1.80 (dd, J ^≈ 2.3; 7.5 Hz; C6H); 1.94 (m, C14H); 2.12 (m, C6H); 2.25 (m, C15); 2.47 (s, C22H ₃ ); 2.62 (dd J ≈ 7.5; 9.2 Hz); 2.70 (dd, J ,8 3.8; 5.9 Hz; C20H); 2.75 (m, C3H); 2.94 (m, C5H); 3.46 (dd, J = 4.6; 12.4 Hz; C17H); 3.65 (s, C23H ₃ ); 3.71 (m, C19H); 4.07 (dd, J = 3.6; 12.4 Hz; Cl 7H); 4.09 (d, J≈ 9.7 Hz; C2H); 6.60 (m, C12H); 6.69 (dd, J ^≈ 1.2; 7.4 Hz, C10); 7.01 (dd, J≈ 1.2; 7.6 Hz, Ci 1); 7.03 (m, C9)

¹³ C NMR: δ 18.5 (C18); 28.3 (C14); 32.4 (C15); 35.8 (C16); 38.5 (C6); 40.3 (C22); 49.1 (C20); 51.2 (C23); 53.2 (C5); 55.8 (C7); 63.8 (C2); 66.0 (C17); 73.3 (C19); 68.8 (C3); 109.7 (C12); 118.4 (C10); 123.3 (C9); 127.7 (Ci 1); 137.2 (C8); 148.4 (C13); 172.5 (C21).

SMHR for C ₂ ιH ₂₉ N ₂ O ₃ : M + 1H, (100%) calculated 357.2178; found 357.2176

EXAMPLE 2 Process for the preparation of the compounds corresponding to one of the following general formulas:

EXAMPLE 2a: the group R represents a methyl, ethyl, butyl, benzyl or allyl group, and the groups R 'and R "represent a methyl group:

The compounds concerned then correspond to one of the following general formulas:

The above-mentioned compounds are obtained following protection of the indole nitrogen by an alkyl group. This protection is effected by heating at reflux of the above-mentioned compounds (10) and (11), in acetone in the presence of K ₂ CO ₃ and of RI as an alkylating agent.

The yields of such reactions easily exceed more than 70%.

EXAMPLE 2b: the group R represents a COCH ₃ group, and the groups R 'and R "represent a methyl group:

The compounds concerned therefore correspond to one of the general formulas

In order to obtain these compounds, the above-mentioned compounds (10) and (11) are treated with acetic anhydride in the presence of dry sodium acetate or pyridine.

More specifically, the compounds (10) and (11) are dissolved in acetic anhydride in the presence of dry sodium acetate and, after overnight at room temperature, the mixture thus obtained is poured onto crushed ice, placed with magnetic stirring for 3 to 4 hours and extracted with dichloromethane.

EXAMPLE 2c: R and R 'represent a methyl, ethyl, butyl, benzyl or allyl group; and R "represents a methyl group:

The compounds concerned therefore correspond to one of the following general formulas:

(10c) (lie) These compounds are obtained by transesterification by heating the compounds (10a) and (l ia), corresponding to the compounds (10) and (11) protected beforehand on indolic nitrogen, in the presence of the appropriate alcohol, chosen in particular from l 'methyl, ethyl, propyl, butyl, allylic or benzylic acid, and an acid catalyst.

The same reactions applied to compounds (10b) and (1 lb) make it possible to obtain the compounds (10c) and (l ie) in which R is an acetyl group. After deprotection of indolic acid in an acid medium, in particular hydrochloric acid N at 100 ° C. for 1 to 2 hours), the compounds are obtained (10c) and (l ie) in which R is a hydrogen atom .

EXAMPLE 2d: R represents a hydrogen atom, R 'represents a methyl group and R "represents a hydrogen atom:

The compounds concerned therefore correspond to one of the general formulas

These compounds are obtained from the above-mentioned compounds (10) and (11). Thus, the cleavage of the methyl group of the amine is carried out photochemically in the presence of electron acceptors such as 9,10-dicyanoantriracene.

EXAMPLE 3 Preparation of the amine salts, corresponding to one of the following general formulas:

(10th) (lie) In these formulas, the ion X ^" can represent a hydrochloride, phosphate, sulfate, tartrate or citrate ion.

In order to obtain the above-mentioned compounds (10e) and (l ie), the compounds (10), (11), (10a) or (l ia) are treated with two equivalents of the appropriate acid (hydrochloric acid, phosphoric acid, sulfuric, tartaric or citric), then the solvents are evaporated, crystallized or precipitated according to the salt.

The present invention also relates to monosalts corresponding to one of the following formulas:

(10f) (llf)

In these formulas, the ion X ^" can represent a hydrochloride, phosphate, sulfate, tartrate or citrate ion.

In order to obtain the above-mentioned compounds (10f) and (1f), the compounds (10b) or (11b) are treated with an equivalent of the appropriate acid (hydrochloric, phosphoric, sulfuric, tartaric or citric acid), then the solvents are evaporated, crystallized or precipitated depending on the salt.

EXAMPLE 4: ACTIVITIES OF COMPOUNDS 10 AND 11

A) The combinatorial effect on the in vitro growth of Plasmodium falciparum, with respect to chloroquine, was determined by the isobologram method.

For this purpose, one determines the CI ₅ 0 chloroquine in the presence of increasing amounts of the drug, the concentration thereof being less than its own IC ₅₀ determined beforehand. From the experimental data, risobologram is constructed by carrying (see Figure 1):

- the abscissa the IC ₅₀ measured for chloroquine in the presence of the tested drug, expressed as a fraction of CI ₅ 0 chloroquine, namely:

CI ₅₀ (chloroquine + drug tested) CI ₅₀ (chloroquine alone)

- on the ordinate, the IC ₅₀ fraction of the drug tested.

Depending on whether the curve obtained is concave (curve a) or convex (curve b), the drug has a synergistic or antagonistic action. If the curve is close to the diagonal (curve c), there is additivity of the effects.

To try to quantify the synergistic activity, an interaction factor (IF) is defined as the inverse of the fraction of IC ₅ 0 obtained on the experimental curve corresponding to half of the IC ₅ 0 of the drug tested ( FI = 1 / n). The action measured is additive when FI = 2, synergistic when FI> 2 and antagonistic when FI <2.

From FIG. 2, it appears that the compounds (10) and (11), although devoid of notable intrinsic antimalarial activity, exhibit, in vitro, a potentiating activity of chloroquine with respect to resistant strains of P falciparum (concave curves). Table I below indicates the values of the interaction factors (IF) calculated from the results presented in Figure 2. It therefore appears that the activities of compounds (10) and (11) are similar to that of malagashanine .

B) The potentiating properties of the compound (11) of the invention with respect to doxorubicin were also tested and determined by the isobologram method.

Doxombicin hydrochloride is an anti-cancer agent with the following formula:

The procedure is the same as for chloroquine, by determining the IC ₅₀ of doxorubicin in the presence of increasing amounts of this same compound, the concentration of the latter being lower than its own IC ₅₀ previously determined.

From Figure 3, it appears that the compound (11) has a potentiating activity of doxorubicin vis-à-vis the resistant strains P388 (LGC Promochem, Molsheim, France). REFERENCES

- Ginsburg H (1991) Enhancement of antimalarial effect of chloroquine on dmg resistant parasite strains: a critical examination of the reversai of multidrug resistance,

Experimental Parasitology, 73, 227-232,

- Martin SK, Oduola AM, Milhous WK (1987) Reversai of chloroquine resistance in Plasmodium falciparum by vérapamil, Science, 235, 899-901,

- Pizey, J.S. (1975) Synthetic Reagents, vol. 2, Wiley, New York, pages 65-142, - Salomone S, Goldfraind T (1990) D gs that reverse chloroquine resistance in malaria, TIPS, 475-476,

- Trigalo F., Martin M.T., Blond A., Brouard J.P., Rafatro H., Ramamtrahasimbola D., Frappier F. (1999) Tetrahedron, 55, 6139-6146,

Claims

Compounds corresponding to the following general formula (I):

in which :

- the dotted link in the cycle represents a single or double link,

2. Compounds according to claim 1, characterized in that R represents an acetyl group -COCH ₃ .

3. Compounds according to one of claims 1 or 2, characterized in that R "is a methyl group or a hydrogen atom.

4. Compounds according to one of claims 1 to 3, characterized in that:

- Either R is a COCH ₃ group, R 'is a methyl, ethyl, propyl, butyl, allyl or benzyl group, and R''is a methyl group; - Either R is a hydrogen atom, R 'is a methyl, ethyl, butyl, allyl or benzyl group, and R''is a methyl group;

5. Compounds according to one of claims 1 to 4, corresponding to one of the following formulas:

(H) (10)

6. Compounds capable of being used as synthesis intermediates for the preparation of the compounds of formula I, defined in one of claims 1 to 5, and corresponding to one of the following formulas:

(4) (7)

7. Process for the preparation of the compounds as defined in claim 5, characterized in that it comprises:

a step for oxidizing the alcohol function of the compound (7) as defined in claim 6, in order to obtain the compound (8), of the following formula:

a step of reductive amination of the above-mentioned compound (9), in order to obtain, according to the conditions of reductive amination, the compound (10) or (11) as defined in claim 5.

8. Process for preparing the compound (7) as defined in claim 6, characterized in that it comprises:

9. Process for preparing the compound (6) as defined in claim 8, characterized in that it comprises:

a step for opening the lactone function of the compound (4) as defined in claim 6, by treatment with a base, in particular KOH, in order to obtain the compound (5) of the following formula:

- A cation exchange step associated with the base used above, in the compound obtained in the previous step.

10. Process for the preparation of the compound (4) defined in claim 6, characterized in that it comprises:

an acetylation step, in particular in the presence of acetic anhydride, of the compound (2) of the following formula:

in order to obtain the compound (3) of the following formula

11. Process for the preparation of the compound (4) as defined in claim 6, characterized in that it comprises:

in order to obtain the compound (2) as defined in claim 10, an acetylation step, in particular in the presence of acetic anhydride, of the compound (2) as defined in claim 10, in order to obtain the compound (3) as defined in claim 10, and

12. Process for the preparation of the compounds as defined in one of claims 1 to 5, characterized in that it comprises:

- a step of treatment with LiAlF _t of the compound (1) as defined in claim 11, in order to obtain the compound (2) as defined in claim 10, - an acetylation step, in particular in the presence of acetic anhydride of the compound (2) as defined in claim 10, in order to obtain the compound (3) as defined in claim 10, and

- a step of oxidizing the alcohol function of the above-mentioned compound (3), in order to obtain the compound (4) as defined in claim 6, - a step of opening the lactone function of the compound (4) as as defined in claim 6, by treatment with a base, in particular KOH, in order to obtain the compound (5) as defined in claim 9,

a step for exchanging the cation associated with the base used above, in the compound (5) obtained in the preceding step, in order to obtain the compound (6) as defined in claim 8,

a methylation step, in particular in the presence of diazomethane, of the above-mentioned compound (6), in order to obtain the compound (7) as defined in claim 6,

a step for oxidizing the alcohol function of the above-mentioned compound (7), in order to obtain the compound (8), as defined in claim 7,

a step of deacetylation of the above-mentioned compound (8) in order to obtain the compound (9) as defined in claim 7,

13. Pharmaceutical composition containing a compound as defined in one of claims 1 to 5, in association with a pharmaceutically active substance, and a pharmacologically acceptable vehicle.

14. Pharmaceutical composition according to claim 13, characterized in that the pharmaceutically active substance is chosen from aminoquinolines, aminoacridines or phenanthrene methanol.

15. Pharmaceutical composition according to claim 13, characterized in that the pharmaceutically active substance is chloroquine.

16. Pharmaceutical composition according to claim 13, characterized in that the pharmaceutically active substance is an anti-tumor agent.

17. Pharmaceutical composition according to one of claims 13 to 16, characterized in that it contains from 50 to 200 mg per unit dose, in particular from 80 to 160 mg per unit dose, of the compound as defined in one of claims 1 to 5.

18. Use of the compound as defined in one of claims 1 to 5, for the preparation of a medicament intended to make the resistance of an organism to a pharmaceutically active substance reversible.

19. Use according to claim 18, characterized in that the pharmaceutically active substance is an anti-malarial agent.

20. Use according to claim 18, characterized in that the pharmaceutically active substance is an anti-tumor agent.