FR2743809A1 - CARPAINE MACROCYCLIC ETHERS - Google Patents

Abstract

Novel cytotoxically active ether-type carpaine derivatives having general formulae (<u>1</u>) and (<u>2</u>), and therapeutically acceptable salts thereof, are disclosed. The therapeutical use and the preparation of said derivatives are also disclosed.

Description

NEW CARPAINE-DERIVED MACROCYCLIC ETHERS
Carpain is the major alkaloid of the leaves of Carica papaya. Its pharmacological properties have been studied, but no major effects could be clearly revealed. Cytotoxic activity in vitro has however been described [L.

Oliveros-Belardo, Asian J: Pharm., 2, 26, (1972)], but this result has not been exploited.

As part of our research into new anticancer drugs of natural origin, we have therefore prepared a series of carpaine derivatives, which we have evaluated on pharmacological tests (patents FR 2702768 and FR 2704858). These new compounds, in particular the mono-amides represented below, show a cytotoxicity markedly superior to that of carpain [Proceedings of the 86th Annual
Meeting, American Association for Cancer Research, Toronto, Abstr. 2315, (1995)].

rnono-amlaes
Carpalne (patent FR 2702768)
On the other hand, we did not observe a good correlation between cytotoxic activities in vitro and antitumor activity in animals. We then assumed that the two lactone functions of the carpain skeleton can be hydrolyzed in vivo. This would lead to products of the “monomer” type which would be inactive, which we have demonstrated: the derivatives shown schematically below do not exert significant cytotoxicity.

"Monomeric" derivatives
In order to avoid this phenomenon, we have synthesized a new family of “ether” type derivatives by selectively reducing the lactone functions. The derivatives obtained have the general structure L and have the advantage of resisting these possible hydrolysis reactions.

The present invention, carried out at the Pierre Fabre Research Center, therefore relates to new compounds of general formula I, their preparation by hemisynthesis from carpaine and their application in therapy.

where R1 and R2 represent:
either a hydrogen atom (R1 = R2 = H),
let R1 be a hydrogen atom, and R2 an A-Aryl group, for which:
- Aryl represents a phenyl, naphthyl or benzothienyl ring,
substituted or not by one or more halogen, methyl,
methoxy, trifluoromethyl or trifluoromethoxy,
- A represents a methylene group (CH2) or a carbonyl group
(C = O),
either an Aryl group (R1 = R2 = A-Aryl) as defined herein
above.

as well as their therapeutically acceptable salts.

où R1 et R2 représentent:
- soit tous deux un atome d'hydrogène (R1 = R2 = H),
- soit tous deux un groupement CH2-Aryle, Aryle étant défini ci-dessus ainsi que leurs sels thérapeutiquement acceptables.The invention also relates to the intermediate compounds of formula 2, which can be isolated during the reduction reactions, in which a single lactone function has been reduced to an ether function:

where R1 and R2 represent:
- either a hydrogen atom (R1 = R2 = H),
- Either both a CH2-Aryl group, Aryl being defined above as well as their therapeutically acceptable salts.

The invention relates more particularly to the products of general formula 1 chosen from the following compounds -3,16-dideoxy-12,25-di (3,4,5-trimethoxybenzyl) -3,3,16,16-tetrahydrocarpaine, - 12,25-dibenzyl-3,1 6-dideoxy-3,3,16,1 6-tetrahydrocarpaine, -3,16-dideoxy-3,3,1 6,1 6-tetrahydrocarpaine, -12-benzoyl-3, 16-dideoxy-3,3,16,16-tetrahydrocarpaine, -12,25-dibenzoyl-3,16-dideoxy-3,3,16,16-tetrahydrocarpaine, -3,16-dideoxy-3,3,16, 16-tetrahydro-12- (3-trifluoromethylbenzoyl) carpain, -12- (4-chlorobenzoyl) -3,16-dideoxy-3,3,16,16-tetrahydrocarpaine, -12,25-di (4-chlorobenzoyl) - 3,16-dideoxy-3,3,16,16-tetrahydrocarpaine, -3, lo-dideoxy-12 - (4-methylbenzoyl) - 3,3,16,16 -tetrahydrocarpaine, -3,16-dideoxy-12, 25-di (4-methylbenzoyl) -3,3,16,16-tetrahydrocarpaine, -3, lo-dideoxy-1 2- (2-naphthoyl) -3,3,16,1 6-tetrahydrocarpaine, -3, lo -dideoxy-1 2,25-di (2-naphthoyl) -3, 3,16,1 6-tetrahydrocarpaine, - 1 2- (3-chloro-2-benzo [b] thenoyl) -3, 1 6-dideoxy -3, 3,16, l 6-tetrahydrocarpaine, - 1 2,25-di (3 -chloro-2-ben zo [b] thenoyl) -3,1 6-dideoxy-3,3,16,1 o-tetrahydrocarpaine, -3,16-dideoxy-12,25-di (2-trifluoromethoxybenzoyl) -3,3,16,16 -tetrahydrocarpain, as well as their salts with therapeutically acceptable mineral or organic acids, in particular the hydrochloride, tosylate and maleate, for compounds comprising a free amine function.

The invention also relates more particularly to the products of formula 2 chosen from the following compounds - 3-deoxy-1 -dibenzyl-3,3 -dihydrocarpaine, -3-deoxy-3,3 -dihydrocarpaine, as well as their salts with acids therapeutically acceptable minerals or organic s, in particular the hydrochloride and the tosylate.

We have observed that the reduction of the lactone functions into ether functions is only carried out satisfactorily if the two secondary amines of carpain are protected in the form of an amide. These protected compounds have the general structure 3 in which A represents a carbonyl function C = O, and Aryl an aromatic group as defined above. The preparation of these derivatives is described in patent FR 2704858. They can be obtained, for example, by reacting carpaine with an acid chloride of Aryl-CO-C1 type, in the presence of triethylamine in dichloromethane.

Reduction of lactone to ether is not a general reaction, and relatively few examples are listed in the literature. Only the conditions described by H.

C. Brown et al. [R Org. Chem, 47 3153, (1982)] using the borane dimethylsulfide complex allowed us to access the desired products with good yields.

In the presence of an excess of this reaction, all the carbonyl functions (lactone and amide) of the compounds of general formula 3 where A = C = O are reduced. This reaction is therefore carried out in an anhydrous medium and under an inert atmosphere by the action of an excess of the borane - dimethylsulfide complex [BH3: (CH3) 2S] in tetrahydrofuran, at a temperature between -20 "C and reflux of the solvent used. , preferably tetrahydrofuran. The products of formula d where A = C = O are therefore converted into compounds of formula 1 in which R1 = R2 = A-Aryl (A = CH2). This step is shown schematically below

<tb><SEP> H, C <SEP> O <SEP> Hz <SEP> BH <SEP> H3C
<tb><SEP> AN <SEP> kNA <SEP> b <SEP> 3 <SEP> o <SEP> CH,
<tb>ry'o / <SEP> 000H <SEP> R1NH3
<tb>
3: A = C = O 1: R1 = R2 = A-Aryl (A = CH2)
Monitoring the progress of the reaction makes it possible to highlight several intermediate compounds, which have been isolated and characterized. This is easily achieved if the reaction medium is neutralized before the complete disappearance of the starting product 3 in which A = C = O or if the reaction is carried out in the presence of a lack of reduction reagent. Chronologically, the amide functions react first, leading to derivatives of formula 3 in which A represents a methylene group
(A = CH2). The compounds of formula 2 in which R1 and R2 are then isolated
represent the A-Aryl group (A = CH2) defined above. This suite of
reactions is shown schematically below

<tb><SEP> H3C
<tb><SEP> plyle <SEP> ~~~~~~~~~ <SEP> 0o
<tb> Aryle <SEP>, A <YIê <SEP> t <SEP> CH,
<tb><SEP> AN <SEP> Aryle
<tb> Arylo
<tb><SEP> Aryle
<tb><SEP> H3
<tb><SEP> 3 <SEP>: A = C = O <SEP> 3: A = <SEP> CH2
<tb><SEP> | <SEP> [BH31
<tb><SEP> H3C <SEP> O <SEP> Hz <SEP>{<SEP> t <SEP> 1BH31 <SEP> H3C <SEP> O
<tb><SEP> R1-NN-R <SEP> R1-N0N-R
<tb><SEP> OCH3 <SEP> OCN3
<tb>
1: R1 = R2 = A-Aryl (A = CH2) 2: R1 = R2 = A-Aryl (A = CH2)
The transformation of compounds of formula 1 where R1 = R2 = A-Aryl (A
CH2) as a derivative where R1 = R2 = H is carried out in the presence of a catalyst such as palladium supported on carbon, either by the action of hydrogen, at a pressure between atmospheric pressure and 8 bars, or by the action of a hydrogen donor agent such as hydrazine or ammonium formate, in a polar solvent, of
preferably methanol or ethanol, and at a temperature between the temperature
ambient and reflux of the solvent. This step is shown schematically below

1: R1 = R2 = A-Aryl (A = CH2) 1: R1 = R2 = H
Under the same conditions, the derivatives of formula 2 in which R1 = R2 =
A-Aryl (A = CH2) are transformed into a derivative of formula 2 in which R1 = R2 = H, as shown schematically below

2: R1 = R2 = A-Aryl (A = CH2) 2: R1 = R2 = H
The compounds of formula 1 in which R1 represents a hydrogen atom (R1 = H) and R2 represents an A-Aryl group where A is a carbonyl function (A = C = O) are prepared from the compound of formula 1 in in which R1 and R2 represent a hydrogen atom (R1 = R2 = H). During the same reaction, the disubstituted compounds of formula 1 in which R1 = R2 = A-Aryl (A = C = O) are also isolated. This step is carried out by the action of an acid chloride of general formula AryIe-A-CI, for which A = C = O, in an inert solvent such as tetrahydrofuran
or dichloromethane in the presence of a base such as a tertiary amine, at a
temperature between 0 C and reflux of the solvent, according to the diagram below:

<tb><SEP> H, C <SEP> 0 <SEP><
<tb><SEP> -NU <SEP> AN%
<tb><SEP> 90 <SEP> CH,
<tb><SEP> 1 <SEP> R1 <SEP> R2 <SEP> = H
<tb><SEP> Aryle-A-CI
<tb> H, C <SEP> O <SEP> Hz <SEP>\;)<SEP> H, C <SEP> 0
<tb> RI <SEP> - <SEP> NN- <SEP> Ri <SEP> + <SEP> RI- <SEP> NN <SEP> -R2
<tb><SEP> OCH3 <SEP> O <SEP> CH3
<tb>
L: R1 = H, R2 A-Aryl (A = C = O) 1: R1 = R2 = A-Aryl (A = C = O)
Monosubstituted derivatives of general formula 1 (R1 = H, R2 = A-Aryl, A =
C = O) and di-substituted (R1 = R2 = Aryl, A = C = O) are then separated by chromatography.

The following examples illustrate the invention, without however limiting its scope.

The physicochemical and spectroscopic characteristics confirm the structure of
compounds obtained according to the invention.

EXAMPLES
Example 1:
Compound Ia: 3,16-dideoxy-12,25-di (3,4,5-trimethoxybenzyl) -3,3,16,16tetrahydrocarpaine
R1 = R2 = 3,4,5-trimethoxybenzyl
In a 10 ml flask topped with a condenser and placed under a stream of nitrogen, 250 mg (0.28 mmol) of 12,25-di (3,4,5 trimethoxybenzoyl) carpaine are dissolved in 2 ml of dry THF. , prepared according to the method described in patent FR 2704858. 1.4 ml (2.8 mmol) of a 2 M solution of complex [BH3: (CH3) 2S] in THF are then added. After about 5 hours of heating under reflux, the mixture is poured into 100 ml of a saturated solution of ammonium chloride, which is extracted with 3 times 20 ml of dichloromethane. The organic phase is separated, dried over
MgSO4, filtered and evaporated. The oily residue obtained is purified by chromatography on a silica column eluted with a C6 H14: Et2O: AcOEt (50: 47: 3) mixture. The 3,16-dideoxy-l 2,25-di (3,4,5-trimethoxybenzyl) -3,3,16,1 o-tetrahydrocarpaine la (140 mg; 61%) is thus recovered in the form of a colorless oil. .

C48H78N2O8: 811.15
Melting point: (oil) IR (KBr): 2932, 2855, 1591, 1504, 1460, 1419, 1329, 1232, 1128, 1012 cm-1.

1H NMR (200 MHz, CDCl3): 1.07 (d, J = 6.7Hz, 6H); 1.26 - 1.83 (solid, 36H); 2.52 (m, 2H); 2.95 (m, 2H); 3.31 - 3.39 (m, 6H); 3.74 - 3.84 (m, 4H); 3.84 (s, 12H); 3.86 (s, 6H); 6.61 (s, 4H).

13C NMR (50.3 MHz, CDCl3): 14.47 24.13 25.64 25.92 27.37 28.31 28.85 29.34 29.79 32.29 54.50 56.07 56.92 59.05 60.94 67.95 77.61 104.72 136.26 137.47 152.99.

Mass spectrum (Electronic Impact): m / e = 810 (M +), 697, 629, 449, 406,260, 181 (100%), 84.

Example 2:
Compound Ib: 12,25-dibenzyl-3,16-dideoxy-3,3,16,16-tetrahydrocarpaine
R1 = R2 = Aryl, A = CH2, Aryl = phenyl
This compound is prepared according to the operating conditions described in Example 1, using as starting product 12,25-dibenzoylcarpaine, prepared according to the method described in patent FR 2704858, in place of 12,25-di ( 3,4,5 trimethoxybenzoyl) carpain. Purification is carried out by chromatography on a silica column eluted with a C6H14: AcOEt: MeOH (4: 2 1) mixture. The 12,25-dibenzyl-3,16-dideoxy-3,3,16,16-tetrahydrocarpaine lb is thus recovered with a yield of 60%.

C42 H66 N2 O2: 630.99
Fusion point: (buile)
IR (KBr): 2932, 2855, 1452, 1371, 1344, 1101, 738 cm-1
1H NMR (200 MHz, CDCl3): 1.32 - 1.62 (solid, 39H); 2.31 (solid, 4H); 3.65 (s, 18H); 4.21 (m, 1H); 4.69 (m, 1H); 4.99 (solid, 3H); 6.54 (s, 4H).

13C NMR (50.3 MHz, CDCl3): 14.85 24.64 24.94 25.94 27.31 28.40 28.83 29.37 29.83 32.56 53.63 56.33 57, 30 59.63 68.12 77.53 126.41 128.14 128.35 141.60.

Mass spectrum (D / CI in NH3): 631 (MH +)
Example 3:
Compound 1c: 3,16-dideoxy-3,3,16,16-tetrahydrocarpaine
R1 = R2 = H
800 mg (1.26 mmol) of compound 1b prepared in Example 2 are dissolved in 30 ml of absolute methanol, to which 90 mg of 10% palladium on carbon are added. The mixture is then placed under a hydrogen atmosphere. After 24 hours of stirring, the reaction medium is filtered through Celite and the solvent is evaporated off. The oily residue obtained is purified by chromatography on a silica column eluted with a CHCl 3 mixture.
EtOH (90 10) then (85:15). The 3,16-dideoxy-3,3,16,16-tetrahydrocarpain kc thus collected (480 mg; 84%) can then be salified in the form of dihydrochloride hydrate, ditosylate or dimaleate.

# Dihydrochloride: C28H54N2O2.2HCl, 1 H2O: 541.67
Elemental analysis:
% Calc. C62.08 H 10.79 N 5.17
% Tr. C 62.27 H 10.57 N 5.18
Melting point:> 260 C
IR (KBr): 3439,2934,2856, 1560, 1458, 1381, 1340, 1095, 1006 cm-1.

Ditosylate: C28 H54 N2 O2. 2 (C7H8O3S): 795.14
Elemental analysis:
% Calc. C 63.44 H 8.87 N 3.52
% Tr. C 63.17 H 8.89 N 3.58
Melting point:> 260 C
IR (KBr): 2932, 2856, 1599, 1460, 1251, 1219, 1161, 1120, 1029, 1010 cm-1.

# Dimaleate: C28H54N2O2.2 (C4H4O4), 1 H2O: 700.89
Elemental analysis:
% Calc. C 61.69 H 9.20 N 3.99
% Tr. C61.60 H 9.14 N 4.06
Melting point: 160 C IR (KBr): 3427,3167,2937,2855, 1701, 1577, 1468, 1361, 1194, 1105, 1087, 1001 cm-1.

1H NMR (200 MHz, CDCl3) based on: 1.07 (d, J = 6.7Hz, 6H); 1.22 - 1.41 (solid, 36H); 2.06 (t, J = 3.1Hz, 1H); 2.11 (t, J = 3.1Hz, 1H); 2.54 (m, 2H); 2.69 (q, J = 6.34Hz, 2H); 3.07 (br s, 2H); 3.27 (m, 2
H); 3.44 (m, 2H).

13C NMR (50.3 MHz, CDCl3) based on: 18.67 25.52 26.98 27.25 29.31 29.49 29.92 30.07 37.16 54.96 55.97 67.94 74.16
Mass spectrum (FAB): 451 (MH +)
Example 4:
Compound 1c: 3,16-dideoxy-3,3,16,16-tetrahydrocarpaine
R1 = R2 = H
8.2 g (13 mmol) of compound 1b, prepared according to Example 2, are dissolved in 100 ml of absolute methanol containing 1 g of palladium on carbon (5%). 6.5 ml (130 mmoles) of hydrazine hydrate are added thereto, and the whole is brought to reflux for three hours. The mixture is then filtered through Celite, concentrated in vacuo and extracted with dichloromethane. The organic phase is dried over MgSO4 and evaporated. The residue is purified on a silica column under the conditions described in Example 3. The 3,16-dideoxy-3,3,16,1 o-tetrahydrocarpaine 1c collected has the same characteristics as described in Example 3, and is then salified in the form of the dihydrochloride (6.3 g; 94%).

Example 5:
Compound 1f: 3,16-dideoxy-3,3,16,16-tetrahydro-12- (3-trifluoromethylbenzoyl) carpain
R1 = H, R2 = A-Aryl, A = C = O, Aryl = 3-trifluoromethylphenyl
700 mg (1.55 mmol) of compound k (in the form of free base) dissolved in 15 ml of dichloromethane are introduced into a 50 ml round-bottomed flask. The flask is placed under stirring, in an ice bath and under a nitrogen atmosphere, and 0.22 ml (1.58 mmol) of triethylamine is added thereto, then a solution of 0.23 is added dropwise. ml (1.52 mmol) of 3-trifluoromethylbenzoic acid chloride in 3 ml of dichloromethane.

After stirring for one hour, the reaction medium is washed with 2 times 15 ml of 3% tartaric acid in water. The organic phase is separated, dried over MgSO4, filtered and evaporated. The oily residue obtained is purified by chromatography on a silica column eluted with an Et2O: AcOEt: MeOH mixture (4: 2: 0.5). 190 mg (19%) of 3,16-dideoxy-3,3,16,16-tetrahydro-12- (3-trifluoromethylbenzoyl) carpam 1f are thus collected, which is salified by adding one equivalent of acid. para-toluenesulfonic.

C36 H57 N2 O3 F3. C7H8O3S: 795.04
Elemental analysis:
% Calc. C 64.96 H 8.24 N 3.52
% Tr. C64.14 H 8.18 N 3.55
Melting point: 182 C
IR (KBr): 2936,2858, 1631, 1419, 1358, 1323, 1234, 1163, 1122, 1032, 1008 cm-l
1H NMR (200 MHz, CDCl3) based on: 1.22 - 1.69 (solid, 45H); 3.01 - 3.49 (solid, 8H); 7.54 - 7.66 (solid, 4H).

Example 6:
Compound 1k: 3,16-dideoxy-12- (2-naphthoyl) -3,3,16,16-tetrahydrocarpain
R1 = H, R2 = A-Aryl, A = C = O, Aryl = 2-naphthyl
700 mg (1.55 mmol) of compound Li (in the form of free base) dissolved in 15 ml of dichloromethane are introduced into a 50 ml round-bottomed flask. The flask is placed under stirring and under a nitrogen atmosphere, and 0.25 ml (1.86 mmol) of triethylamine is added thereto, followed by a solution of 237 mg (1.24 mmol) of d-chloride dropwise. 2-naphthoic acid in 3 ml of dichloromethane.

After three hours of stirring at room temperature, the reaction medium is washed with 2 times 15 ml of 3% tartaric acid in water. The organic phase is separated, dried over MgSO4, filtered and evaporated. The residue obtained is purified by chromatography on a silica column eluted with an Et2O: AcOEt: MeOH mixture (3 2 1). 240 mg (25%) of 3,16-dideoxy-12- (2-naphthoyl) -3,3,16,16-tetrahydrocarpaine 1k are thus collected, which is salified in the form of hydrochloride by addition of a solution. of HCl in ethanol. After precipitation with ethyl ether and filtration, the product is obtained in the form of a hygroscopic white powder.

C39 H60 N2 O3. HCl, 1.5 H2O: 668.40
Elemental analysis:
% Calc. C 70.08 H 9.65 N 4.19
% Tr. C70.21 H 9.31 N 4.30
Melting point: 181 C
IR (KBr): 3429, 2934, 2856, 1624, 1570, 1473, 1415, 1352, 1340, 1309, 1097, 1016 cm-1
1H NMR (200 MHz, CDCl3) based on: 1.19 - 1.78 (solid, 42H); 2.02 - 2.25 (solid, 3H); 3.12 - 3.50 (solid, 8H); 7.46 7.55 (solid, 3H); 7.83 - 7.86 (solid, 4H).

Example 7:
Compound lm m 12- (3-chloro-2-benzo [b] thenoyl) -3,16-dideoxy-3,3,16,16-tetrahydrocarpaine
R1 = H, R2 = A-Aryl, A = C = O, Aryl = 3-chloro-2-benzo [b] thienyl
700 mg (1.55 mmol) of compound Li (in the form of free base) dissolved in 15 ml of dichloromethane are introduced into a 50 ml round-bottomed flask. The flask is placed under stirring and under a nitrogen atmosphere, and 0.30 ml (2.15 mmol) of triethylamine is added thereto, then a solution of 300 mg (1.29 mmol) of d-chloride dropwise. 3-chloro-2-benzo [b] thiophene carboxylic acid in 3 ml of tetrahydrofuran.

After two hours of stirring at room temperature, the reaction medium is washed with 2 times 15 ml of 5% tartaric acid in water. The organic phase is separated, dried over MgSO4, filtered and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a C6H14: AcOEt: MeOH (3: 2 1) mixture. 165 mg (16%) of 12- (3-chloro-2-benzo [b] thenoyl) -3,16-dideoxy-3,3,16,16-tetrahydrocarpaine lm is thus collected, which is salified in the form of tosylate by adding a stoichiometric amount of para-toluenesulfonic acid.

C35H57ClN2O3S.C7H8O3S: 817.58
Elemental analysis:
% Calc. C64.63 H 8.01 N 3.42
% Tr. C 64.47 H 8.02 N 3.52
Melting point: 194 C
IR (KBr): 3433, 2930, 2855, 1647, 1458, 1414, 1340, 1226, 1172, 1124, 1033, 1016 cm-1
1H NMR (200 MHz, CDCl3) based on: 1.17 - 1.74 (solid, 45H); 2.86 - 3.07 (solid, 2H); 3.41 (solid, 6H); 7.41 - 7.49 (m, 2H); 7.78 (m, 2H).

Example 8:
Compound 1n: 12,25-di (3-chloro-2-benzo [b] thenoyl) -3,16-dideoxy-3,3,16,16
tetrahydrocarpain
R1 = R2 = A-Aryl, A = C = O, Aryl = 3-chloro-2-benzo [b] thienyl
During the separation by column chromatography of the reaction mixture obtained in Example 7, the disubstituted derivative 12,25di (3-chloro-2-benzo [b] thenoyl) -3,16-dideoxy-3 is recovered in the first fractions. , 3,16,16-tetrahydrocarpaine 1n as a glassy solid.

C46 H60 N2 O4 Cl2 S2: 840.02
Elemental analysis:
% Calc. C 65.77 H 7.20 N 3.33 Cl 8.44
% Tr. C 65.47 H 7.02 N 3.52Cl 8.51
Melting point: 106 C
IR (KBr): 3429,2930,2854,1635,1521, 1416, 1347, 1306, 1252, 1110 cm-1
1H NMR (200 MHz, CDCl3) based on: 1.16 - 1.37 (41H mass); 1.76 (solid 4H); 3.48 (solid 3H); 3.79 (m, 1H); 4.18 (m, 1H); 4.74 (m, 1H); 5.16 (m, 1H); 7.45 - 7.52 (m, 4H); 7.81 (m, 4H).

Example 9:
Compound 2a: 3-deoxy-12,25-dibenzyl-3,3, -dihydrocarpaine
R1 = R2 = A-Aryl, A = CH2, Aryl = phenyl
In a 250 ml flask topped with a condenser and placed under a stream of nitrogen, 26 g (38 mmol) of 12.25 dibenzoylcarpaine, prepared according to the method described in patent FR 2704858, are dissolved in 60 ml of dry THF. 100 ml (1 mol) of a 10 M solution of complex [BH3: (CH3) 2S] in THF are then added. After 5 hours of stirring at room temperature, the mixture is poured little by little into 700 ml of methanol cooled to 0 ° C. The mixture is then concentrated in vacuo, and diluted with 300 ml of saturated NH4Cl solution. After extraction with twice 150 ml of dichloromethane, the organic phase is separated, dried over MgSO4, filtered and evaporated. The oily residue obtained is purified by chromatography on a silica column eluted with a hexane: AcOEt: MeOH (4: 2 1) mixture. We first recover 3,1 6-dideoxy-12,25-dibenzyl-3,3,16,1 o-tetrahydrocarpaine 1a, then 3-deoxy-12,25-dibenzyl-3,3-dihydrocarparne 2a, which is obtained pure after a second passage through a silica column eluted with a CHCl3: EtOH mixture (99 l). Yield: 35%. This compound can be isolated in the form of hygroscopic dihydrochloride by adding 2 equivalents of HCl dissolved in absolute ethanol.

C42 H64 N2 O3. 2 HCl, 2.5 H2O: 762.94
Elemental analysis:
% Calc. C66.12 H 9.37 N 3.67
% Tr. C65.98 H 9.15 N 3.61 Melting point: (glue)
1H NMR (free base, 200 MHz, CDCl3): 1.07 (d, J = 6.3Hz, 3H); 1.13 (d, J = 6.3Hz, 3H); 1.27 - 1.69 (solid 35H); 1.84 (solid 2H); 2.35 (m, 2H); 2.53 (m, 2H); 2.88 (m, 1H); 3.30 (m, 1H); 3.39 (solid 2H); 3.73 - 3.95 (m, 2H); 4.88 (m, 1H); 7.17 - 7.39 (solid 10H).

Example 10:
Compound 2b: 3-deoxy-3,3-dihydrocarpaine
R1 = R2 = H
760 mg (1.18 mmol) of compound 2a, prepared according to Example 8, are dissolved in 20 ml of absolute methanol containing 250 mg of palladium on carbon (5%) and 300 mg (4.76 mmol) of formate d 'ammonium. The mixture is left stirring for 16 hours at room temperature. The mixture is then filtered through Celite, concentrated in vacuo and partitioned between 50 ml of 10% Na2CO3 and 100 ml of dichloromethane. The organic phase is dried over MgSO4 and evaporated. 530 mg (96%) of 3-deoxy3,3-dihydrocarpain 2b are collected in the form of an oil, which can be isolated in the form of hydrated ditosylate.

C28 H52 N2 O3. 2 (C7 H8 3S), 1 H2O: 827.16
Elemental analysis:
% Calc. C 60.98 H 8.52 N 3.38
% Tr. C 61.13 H 8.36 N 3.51
Melting point:> 260 C
IR (KBr): 3017,2934,2858,1734,1597,1460,1338,1250,1217,1155,1120,1030,1010 cm-1
1H NMR (free base, 200 MHz, CDCl3): 1.02 (d, J = 6.4Hz, 3H); 1.07 (d, J = 6.4Hz, 3H); 1.29 - 1.66 (solid, 34H); 1.95 2.10 (solid, 2H); 2.30 (m, 2H); 2.54 (m, 2H); 2.70 (m, 1H); 2.84 (m, 1H); 3.07 (m, 1H); 3.28 (m, 1H); 3.43 (m, 1H); 4.73 (m, 1H).

Table I summarizes the main products synthesized which illustrate the invention, without however limiting its scope.

<SEP> ron <SEP> R <SEP> R <SEP> point <SEP> of
<tb><SEP> n <SEP> 1 <SEP> 2 <SEP> R2 <SEP> A <SEP> Aryle <SEP> Sel <SEP> fusion <SEP> (C)
<tb><SEP> OMe
<tb> the <SEP> | <SEP> A-Aryle <SEP> A-Aryle <SEP> CH2 <SEP> OMe <SEP> OM <SEP> (oil)
<tb><SEP> OMe
<tb><SEP> lb <SEP> A-Aryle <SEP> A-Aryle <SEP> CH2 <SEP> \ t <SEP> (oil)
<tb><SEP> lc <SEP> H <SEP> H <SEP> - <SEP> dimaleate (b) <SEP> 160
<tb><SEP> ld <SEP> H <SEP> A-Aryle <SEP> C = O <SEP> hydrochloride (b) <SEP> 130
<tb><SEP> the <SEP> A-Aryle <SEP> A-Aryle <SEP> C = O <SEP> Hz <SEP> 70
<tb><SEP> 1f <SEP> H <SEP> A-Aryle <SEP> C = O <SEP> ÉÉ <SEP> CF <SEP> tosylate <SEP> 182
<tb><SEP> 1 <SEP> g <SEP> H <SEP> A-Aryle <SEP> C = O <SEP> \ Xs <SEP> o <SEP> tosylate (a) <SEP> 198
<tb><SEP> 1h <SEP> A-Aryle <SEP> A-Aryle <SEP> CO <SEP> \ [Ss <SEP> 76
<tb><SEP> li <SEP> H <SEP> A-Aryle <SEP> CO <SEP> 43 <SEP> tosylate <SEP> 185
<tb><SEP> lj <SEP> A-Aryle <SEP> A-Aryle <SEP> C = O <SEP> 70
<tb><SEP> 1k <SEP> H <SEP> A-Aryle <SEP> CO <SEP> Hz <SEP> hydrochloride (c) <SEP> 181
<tb><SEP> li <SEP> A-Aryle <SEP> A-Aryle <SEP> C = O <SEP><3<SEP> 82
<tb><SEP> CI
<tb><SEP> lm <SEP> H <SEP> A-Aryle <SEP> C = O <SEP> t3 <SEP> tosylate <SEP> 194
<tb><SEP> CI
<tb><SEP> ln <SEP> A-Aryle <SEP> A-Aryle <SEP> C = O <SEP><<SEP> 106
<tb><SEP> lo <SEP> A-Aryle <SEP> A-Aryle <SEP> C = O <SEP> TO <SEP> 68
<tb><SEP> 2a <SEP> A-Aryle <SEP> A-Aryl <SEP> CH <SEP> 2 <SEP> Hz <SEP> hydrochloride (d) <SEP> (glue)
<tb><SEP> 2b <SEP> | <SEP> H <SEP> H <SEP> - <SEP> ditosylate (b) <SEP>><SEP> 260
<tb> (a): 0.5 H2O (b): 1 H2O (c): 1.5 H2O (d): 2.5 H2O
The compounds of general formula 1 and of general formula 2, prepared according to the invention, were subjected to pharmacological tests at the Research Center
Pierre Fabre (Castres, France). In particular, the cytotoxic properties of these compounds were evaluated on an in vitro test which consists in measuring the inhibition of growth of murine L1210 leukemia cells in the presence of these derivatives. The results are expressed by an IC50, which corresponds to the concentration of product tested which inhibits the growth of these cells by 50%.

By way of example, Table II groups together the ICso values for certain derivatives of the invention:

<tb><SEP> Product <SEP> n <SEP> 1c <SEP> 1d <SEP> 1g <SEP> 1k <SEP> 2b <SEP> Carpaine
<tb> L1210 <SEP> IC <SEP> 50 (uM) <SEP> 0.7 <SEP> 3.5 <SEP> 4.0 <SEP> 4.0 <SEP> 4.8 <SEP> 13, 9
<tb>
Table II
Also, taking into account these pharmacological properties, the compounds of the invention can be used in human therapy, in particular in the

Claims (13)

above, as well as their salts with therapeutically acceptable mineral or organic acids. e is both an A-Aryl group (R1 = R2 = A-Aryl) as defined herein (C = O), - A represents a methylene group (CH2) or a carbonyl group methoxy, trifluoromethyl or trifluoromethoxy, substituted or not by one or more halogen, methyl, - Aryl represents a phenyl, naphthyl or benzothienyl ring, e is R1 a hydrogen atom, and R2 an A-Aryl group, for which: o either a hydrogen atom (R1 = R2 = H), in which R1 and R2 represent:

1) New cytotoxic derivatives, of the carpaine di-ethers type, corresponding to general formula 1: 2) Compounds of general formula 1 according to claim 1, characterized in that they are chosen from - 3,16-dideoxy- 12,25 -di (3, 4,5-trimethoxybenzyl) -3, 3,16, 1 6-tetrahydrocarpaine, 12,25-dibenzyl-3,1 6-dideoxy-3,3,16,1 6-tetrahydrocarpaine, -3,16-dideoxy-3,3,16,16-tetrahydrocarpaine, -12-benzoyl -3,16-dideoxy-3,3,16,16-tetrahydrocarpaine, -12,25-dibenzoyl-3,16-dideoxy-3,3,16,16-tetrahydrocarpaine, - 3,16-dideoxy-3,3 , 16,16-tetrahydro- 12- (3 -trifluoromethylbenzoyl) carpalne, - 12- (4-chlorobenzoyl) -3,1 6-dideoxy-3,3,16,1 6-tetrahydrocarpaine, -12,25-di ( 4-Chlorobenzoyl) -3,16-dideoxy-3,3,16,16-tetrahydrocarpain, -3,16-dideoxy-12- (4-methylbenzoyl) -3,3,16,16-tetrahydrocarpain, -3,16 -dideoxy-12,25-di (4-methylbenzoyl) -3,3,16,16-terahydrocarpain, -3,16-dideoxy-12- (2-naphthoyl) -3,3,16,16-tetrahydrocarpaine, - 3,16-dideoxy-12,25-di (2-naphthoyl) -3,3,16,16-tetrahydrocarpain, -12- (3 -chloro-2-benzo [b] thenoyl) -3,1 6-dideoxy -3,3,16,1 o-tetrahydrocarpaine, - 1 2,25-di (3-chloro-2-benzo [b] th enoyl) -3, 1 6-dideoxy-3, 3,16,1 6-tetrahydrocarpaine, -3,16-dideoxy-12,25-di (2-trifluoromethoxybenzoyl) -3,3,16,16-tetrahydrocarpaine. 3) New cytotoxic derivatives, of the mono-ethers of carpaine type, corresponding to general formula 2:

in which R1 and R2 represent: 'either a hydrogen atom (R1 = R2 = H), e is both a CH2-Aryl group, Aryl being defined above, as well as their salts with therapeutically acceptable inorganic or organic acids. 4) Compounds of general formula 2 according to claim 3, characterized in that they are chosen from - 3 -deoxy- 12,25 -dibenz: yl-3, 3 -dihydrocarpaine, - 3-deoxy-3, 3- dihydrocarpaine, as well as their salts with therapeutically acceptable mineral or organic acids. 5) Process for the preparation of compounds according to claims 1 and 2, characterized in that one reacts a carpaine di-amide of general formula 3 with the borane - dimethylsulfide complex [BH3: (CH3) 2S] in the tetrahydrofuran, at a temperature between - 20 C and reflux of the solvent, according to the diagram:

3: A = C = O 1: R1 = R2 = A-Aryl (A = CH2) where A, Aryl, R1 and R2 are defined as above. <tb> <tb> <SEP> 3 <SEP> OC <SEP> H3 <tb> Aryle <SEP> 0OCH <tb> <SEP> kr. <SEP> N-A / <SEP> 3 <SEP> Rj-NN <tb> <SEP> H3C <SEP> 00Aryle <SEP> [BH31 <SEP> O 6) Process for the preparation of compounds according to claims 3 and 4, characterized in that a carpaine di-amide of general formula 3 is reacted with the borane - dimethylsulfide complex [BH3: (CH3) 2S] in tetrahydrofuran , at a temperature between -20 C and room temperature, and that the intermediate compounds of general formula 2 are isolated according to the scheme:

2: R1 = R2 = CH2-Aryl where A, Aryl, R1 and R2 are defined as above. <tb> <tb> <SEP> R, <SEP> - <SEP> NC <SEP> j <SEP> çN <SEP> - <SEP> R, <tb> <SEP> H3C <SEP> O <SEP> / < <tb> <SEP> 3: <SEP> A <SEP> = <SEP> C = O <SEP> 1BHS <SEP> 3: A = CH2 <tb> <SEP> 3 <SEP> OCH <tb> <SEP> OCH <SEP> AiyIe <SEP> o <tb> ryle <SEP> 0N <tb> <SEP> Aryle <tb> <SEP> A-N <SEP> -A1 <SEP> lBH3l <SEP> 0N <SEP> I <tb> <SEP> H, CX <SEP> Ays <SEP> H3C <SEP> O <SEP> "X <SEP> Aryle 7) Process for the preparation of compounds according to claims 1 and 2, characterized in that a derivative of formula 1 is reacted, in which R1 and R2 represent an A-Aryl group (A = CH2), in the presence of a hydrogenation catalyst such as palladium supported on carbon and a hydrogen generating reagent, depending on the diagram:

1: R1 = R2 = A-Aryl (A = CH2) 1: R1 = R2 = H 8) Process for the preparation of compounds according to claims 3 and 4, characterized in that one reacts a derivative of formula 2 in which R1 and R2 represent a CH2-Aryl group, in the presence of a hydrogenation catalyst such as palladium supported on carbon and a hydrogen-generating reagent, according to the diagram

2: R1 = R2 = CH2-Aryl 2: R1 = R2 = H 9) Process for the preparation of compounds according to claims 7 and 8, characterized in that the hydrogen-generating reagent can be chosen from hydrogen itself, at a pressure between atmospheric pressure and 8 bars, hydrazine or ammonium formate, in solution in a polar solvent such as methanol or methanol, at a temperature between room temperature and reflux of the solvent. 10) Process for the preparation of compounds according to claims 1 and 2, characterized in that one reacts the derivative of formula 1 in which R1 and R2 represent a hydrogen atom with an acid chloride of general formula Aryle- A-C1, in an inert solvent such as dichloromethane or tetrahydrofuran at a temperature between 0 "C and reflux of the solvent, according to the scheme:

1: R1 = H, R2 = A-Aryl (A = C = O) 1: R1 = R2 = A-Aryl (A = C = O) 11) Process for the preparation of compounds according to claims 1 and 2, characterized in that the mono-substituted derivatives of formula 1 (R1 = H, R2 = A-Aryl, A = C = O) are separated from derivatives of formula 1 di-substituted (R1 = R2 = A-Aryl, A = C = O) by chromatography. <tb> <tb> <SEP> OCH3 <SEP> OCH3 <tb> RlH $ NONR2 <SEP> + <tb> <SEP> 1 <tb> <SEP> Aryle-A-CI <tb> <SEP> 1: <SEP> R1 <SEP> R2 <SEP> = <SEP> H <tb> <SEP> / <SEP> O <SEP> CH3 <SEP> HIC1r '' <SEP> 12) As new drugs useful in human therapy, in particular in the treatment of cancerous pathology, the compounds defined according to one of claims 1, 2, 3 and 4. 13) Pharmaceutical composition characterized in that it contains as active principle at least one of the compounds according to claims 1, 2, 3 and 4, associated with a pharmaceutically acceptable vehicle.