WO2014001348A1

WO2014001348A1 - Alkaloid derivatives of cytisine used in the treatment of diseases of the central nervous system

Info

Publication number: WO2014001348A1
Application number: PCT/EP2013/063305
Authority: WO
Inventors: Isabelle POUNY; Georges Massiot
Original assignee: Pierre Fabre Medicament; Centre National De La Recherche Scientifique (Cnrs)
Priority date: 2012-06-25
Filing date: 2013-06-25
Publication date: 2014-01-03
Also published as: FR2992315A1; FR2992315B1

Abstract

The present invention concerns a compound of the following formula (I): (I) or a pharmaceutically acceptable salt of same, and the method of preparing same, the pharmaceutical compositions comprising same and the use thereof as a drug, in particular intended for the treatment of a disease of the central nervous system, in particular tobacco withdrawal symptoms, for the improvement of cognitive functions, for the treatment of anxiety, for the treatment of depression, and for the treatment of pain, or as a neuroprotective agent.

Description

ALKALOIDS DERIVED FROM CYTISINE USEFUL IN THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM

The present invention relates to molecules extracted from a legume and its analogs, a method of extraction and semisynthesis and the use of these compounds as a medicament, especially for the treatment of diseases of the central nervous system.

For a long time, plants have been the subject of studies to isolate new active substances potentially useful in the pharmaceutical field, in particular of the alkaloid type.

The inventors have thus been able to isolate a new family of molecules from the plant Ormosia (Leguminosae), native to the tropics and more specifically from East Asia, which has activity on the nicotinic receptor.

Thus, the present invention relates to a compound of formula (I) below

or a pharmaceutically acceptable salt thereof,

in which :

R 1 represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, aryl, (C ₁ -C ₆ ) alkyl-aryl or aryl group; - (C ₁ -C ₆ ) alkyl,

R ₂ represents a hydrogen atom or a group -R ₅ or -C (O) R ₅ ,

- R ₃ represents a hydrogen atom or -OH, -OR _O, -OC (0) R _O, -OC (0) ORO, -OC (0) NR ₇ R _8, -C (0) R ₇ , -C (O) OR ₇ , or -C (O) NR ₇ R ₈ ,

R4 represents a hydrogen atom or an -OH group, - R ₅ and Re represent, independently of each other, a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, aryl, (Ci-C) group; ₆ ) alkyl-aryl or aryl- (C 1 -C ₆ ) alkyl, and

- R ₇ and R ₈ represent, independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl group, aryl, (C ₁ -C ₆ ) alkyl-aryl or aryl- (C ₁ -C ₆ ) alkyl.

In the present invention, the term "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither bio-logical nor otherwise undesirable and which is acceptable for veterinary use as well. than human pharmaceutical.

The term "pharmaceutically acceptable salts" of a compound means salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include:

(1) hydrates and solvates,

(2) pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, acid mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like, or

(3) pharmaceutically acceptable base addition salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or a aluminum; is coordinated with an organic or inorganic base pharmaceutically acceptable. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

By "(C ₁ -C ₆ ) alkyl" group is meant, in the sense of the present invention, a saturated hydrocarbon chain, linear or branched, having 1 to 6, preferably 1 to 4, carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups.

By "(C ₂ -C ₆ ) alkenyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one double bond and having 2 to 6 carbon atoms. By way of example, mention may be made of ethenyl or allyl groups.

By "(C ₂ -C ₆ ) alkynyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one triple bond and having 2 to 6 carbon atoms. By way of example, mention may be made of ethynyl or propynyl groups.

For the purposes of the present invention, the term "aryl" means an aromatic hydrocarbon group, preferably comprising from 6 to 10 carbon atoms, and comprising one or more contiguous rings, for example a phenyl or naphthyl group. Advantageously, it is phenyl.

By "aryl- (Ci-C ₆₎ alkyl" is understood within the meaning of the present invention, an aryl group, as defined above, bonded to the molecule via a chain (Ci-C ₆ ) alkyl, as defined above. By way of example, mention may be made of the benzyl group.

For the purposes of the present invention, the term "(Ci-C ₆ ) alkyl-aryl" means a (C ₁ -C ₆ ) alkyl chain, as defined above, linked to the molecule via an aryl group, as defined above. By way of example, mention may be made of the tolyl group. According to a particular embodiment of the invention, R 1 represents a hydrogen atom or a (C 1 -C 6) alkyl group, in particular a hydrogen atom or a methyl group.

According to another particular embodiment of the invention, R ₂ represents a hydrogen atom.

According to another particular embodiment of the invention, R ₃ represents a hydrogen atom or a group -OH, -OR, -OC (O) R 6, -OC (O) OR ₆ or -OC (O) NR ₇ R 8, especially a hydrogen atom or a -OH group.

According to yet another particular embodiment of the invention, R 4 represents a hydrogen atom or an -OH group, and in particular represents a hydrogen atom. act in particular of one of the following

4

The subject of the present invention is also a compound of formula (I) as defined above for its use as a medicament, in particular intended for the treatment of a disease of the central nervous system, in particular weaning. smoking, improvement of cognitive function, treatment of anxiety, treatment of depression, and treatment of pain, or as a neuroprotective agent.

The present invention also relates to the use of a compound of formula (I) as described above for the preparation of a medicament, intended in particular for the treatment of a disease of the central nervous system, in particular smoking cessation, the improvement of cognitive functions, treatment of anxiety, treatment of depression, and treatment of pain, or as a neuroprotective agent.

The invention also relates to a method of treating a disease of the central nervous system, in particular a method of smoking cessation, improvement of cognitive functions, treatment of anxiety, treatment of depression, treatment of pain, or neuroprotection, comprising administering to a person in need of an effective dose of a compound of formula (I) as defined above.

The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above and a pharmaceutically acceptable excipient.

The pharmaceutical compositions according to the invention can be formulated for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration intended for mammals, including man. The dosage varies according to the treatment and the condition in question.

The compounds of the invention as active ingredients can be used at doses of between 0.01 mg and 1000 mg per day, for example in a single dose administered once a day.

In a particular embodiment of the invention, the pharmaceutical composition is used as a medicament, for example for the treatment of a disease of the central nervous system, in particular for smoking cessation, improvement of cognitive functions, treatment of anxiety, treatment of depression, treatment of pain, or as a neuro-protective agent. The subject of the present invention is also a process for obtaining a compound as defined above, comprising the following successive stages:

(i) extracting a plant of the species Ormosia, and in particular roots or stems, to obtain a compound of formula (I) for which R 1 = CH ₃ and R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₄ = H and R ₃ = OH; or R 1 = R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₃ = H, and R ₄ = OH, and in particular to obtain a compound of formula (I) for which R 1 = CH ₃ and R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₄ = H and R ₃ = OH; or R 1 = R ₂ = R ₃ = R ₄ = H,

(ii) optionally substituting positions 12, 10 and / or 16 of the compound of formula (I) obtained in step (i) above, and

(iii) optionally salifcation of the compound of formula (I) obtained in step (i) or (ii) above.

Step (i):

Step (i) may include the following successive steps:

(he) maceration of an Ormosia mash, and in particular a mash of Ormosia roots and / or stems, in methanol, followed by filtration and evaporation to dry to give an extract dry methanol

(i-2) partition of the extract obtained in the preceding step (II) between an aqueous solution of hydrochloric acid (in particular at 1 to 5%, advantageously at about 2%) and ethyl acetate and separation of the resulting acidic aqueous phase and the organic phase,

(I-3) alkanization of the acidic aqueous phase obtained in the preceding step (i-2) (preferably to a pH of between 10 and 12, in particular of about 1 1, in particular by addition of a base such as Na ₂ CO ₃ ), adding dichloromethane and separating the resulting new aqueous and organic phases, and

(i-4) isolating the compound of formula (I) for which R 1 = CH ₃ and R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₄ = H and R ₃ = OH; or R 1 = R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₃ = H, and R ₄ = OH, in particular the compound of formula (I) for which R 1 = CH ₃ and R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₄ = H and R ₃ = OH; or R 1 = R ₂ = R ₃ = R ₄ = H, from the organic phase obtained in the preceding step (i-3). The last step (i-4) of isolation of the compound according to the invention may be carried out in particular by dry evaporation of the organic phase, followed by chromatography on silica gel. The product obtained can then be purified by techniques well known to those skilled in the art, and in particular by high performance liquid chromatography (HPLC).

Step (ii):

Before carrying out this or these substitution step (s), it may be necessary in advance to protect by a protecting group certain functionalities present on the molecule that could be reactive or sensitive to the substitution reaction conditions. These may include OH functions that can be protected by an O-protecting group.

For the purposes of the present invention, the term "protecting group" or "protecting group" is intended to denote a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can be selectively carried out at the level of another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.

For the purposes of the present invention, the term "O-protecting group" is intended to mean any substituent which protects the hydroxyl or carboxyl group, that is to say a reactive oxygen atom, against undesirable reactions such as cleavage groups. O-protecting described in Greene, "protective Groups in Organic synthesis," (John Wiley & Sons, New York (2006) - ^4th edition) and Harrison et al. "Compendium of Synthetic Organic Methods", Vols.1 to 8 (J. Wiley & Sons, 1971 to 1996) O-protecting groups include methyl or substituted or unsubstituted alkyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, benzyl ethers (substituted or unsubstituted), tetrahydropyranyl ethers, allyl ethers, substituted ethyl ethers, for example, 2.2 , 2-trichloroethyl, silyl ethers or alkylsilyl ethers, for example, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS or TBS) and t-butyldiphenylsilyl, hetero ring ethers and esters prepared by reaction of the hydroxyl group with a carboxylic acid for example, tert-butyl esters, benzyl or methyl, carbonates in particular benzyl or haloalkyl carbonate, acetate, propionate, benzoate and the like.

Once the substitution reaction has been performed, the previously protected functions may be deprotected in a so-called deprotection step.

By "deprotection" is meant, in the sense of the present invention, the process by which a protecting group is removed once the selective reaction is complete. Some protecting groups may be preferred over others because of their convenience or relative ease of disposal.

Those skilled in the art will be able to determine which functions need to be protected before this or these substitution reactions. It will also determine the conditions to be implemented to protect and unprotect these functions.

Case of position 12:

If starting from a compound of formula (I) for which R 1 = H, the substitution reaction of the secondary amine can be carried out by techniques well known to those skilled in the art. In particular, it can be carried out in the presence of a base and a compound of formula Ri-Ai with Ri ≠ H and Ai representing a leaving group.

For the purposes of the present invention, the term "leaving group" is intended to mean a chemical group which can be easily displaced by a nucleophile during a nucleophilic substitution reaction, the nucleophile being more particularly an amine, and in particular a secondary amine in this case. Such a leaving group may be more particularly a halogen atom such as a chlorine or bromine atom, a mesylate (-OS (O ₂ ) -CH ₃ ), a triflate (-OS (O) ₂ -CF ₃ or a tosylate (-OS (O) ₂ - (p-Me-C ₆ H ₄ )).

If starting from a compound of formula (I) for which R 1 = CH ₃ , it is necessary to carry out a demethylation step (leading to a compound for which R 1 = H), before carrying out the nucleophilic substitution reaction mentioned. above. This demethylation can be carried out in particular by a Polonovski or von Braun reaction, followed by hydrolysis of the adduct formed.

Case of position 10:

The position of a compound of formula (I), located in alpha of an amide function, can be deprotonated in a strongly basic medium, such as in the presence of LDA. (lithium diisopropylamide). The thus deprotonated molecule can then react with a compound of formula R ₂ -A ₂ with R ₂ ≠H and A ₂ representing a leaving group.

An analogous reaction is described in Hullier N. et al., Regio and diastereoselective functionalization of (-) - cytisine, Tetrahedron, 2006, 62, 50, 1 1679-11686.

Case of position 16:

This reaction can be carried out starting from a compound of formula (I) for which R ₃ = OH by techniques well known to those skilled in the art, in particular by oxidation reaction and / or nucleophilic substitution, this latter reaction being able to more particularly be carried out in a basic medium.

Step (iii):

This step may be carried out by techniques well known to those skilled in the art, and in particular by mixing the compound of formula (I) with a pharmaceutically acceptable acid or base.

The compound thus obtained may be separated from the reaction medium by methods well known to those skilled in the art, such as, for example, by extraction, evaporation of the solvent or by precipitation and filtration.

The compound may also be purified if necessary by techniques well known to those skilled in the art, such as by recrystallization if the compound is crystalline, by distillation, by column chromatography on silica gel or by high performance liquid chromatography (HPLC). ). The invention is more particularly described in a nonlimiting manner in the examples which follow.

EXAMPLES

Obtaining compounds according to the invention The roots and / or stems of the Ormosia species, dried and crushed, are macerated in methanol (1 g of roots / stems per 10 ml of methanol) at room temperature overnight. The mixture is then filtered on filter paper and brought to dryness under reduced pressure using a rotary evaporator. The dry methanolic extract obtained is dissolved in a solution of 2% HCl (prepared from a pure solution of 37% HCl) and partitioned by liquid / liquid extraction with ethyl acetate (2%). times). The acidic aqueous phase is then alkalinized with Na ₂ CO ₃ up to pH = 11, and partitioned by liquid / liquid with dichloromethane (twice). The organic fraction obtained is washed with water and then concentrated to dryness to become the alkaloid totum (TA). The TA is monitored by analytical high performance liquid chromatography (HPLC) on an XBridge RP18 column (100 x 4.6 mm, 5μιη). A mixture of water + 0.02% TEA and acetonitrile + 0.02% TEA is used as eluent phase with a linear gradient of 80/20 to 100% acetonitrile + 0.02% TEA, at a flow rate of 1 ml / min and detection at λ = 230 nm.

The TA is first purified by Medium Pressure Liquid Chromatography (MPLC) on a pre-packaged Silica column (gradient CH ₂ C1 ₂ / MeOH 1: 0 -

0: 1). After analysis of the fractions obtained by thin layer chromatography (TLC) (eluent dichloromethane / methanol 95/5), 5 fractions are formed. These different fractions are purified by semi-preparative reverse phase HPLC C18 (water gradient + 0.02% TEA / acetonitrile + 0.02% TEA). The compounds are then obtained

1 (5% in MT, 200 mg / kg of dry roots), 2 (1% in MT, 30 mg / kg of dry roots), 3 (0.2% in MT, 6 mg / kg of stems dry) and 4 (0.04% in MT, 1 m / Kg of dry stems) following.

4 4 4

4

Compound 1

Chemical formula: C15H20N2O

Exact Mass: 244.16

Molecular weight: 244.33

HRESIMS: m / z = 245.1650 [M + H] ⁺ (calcd. For C ₅ H ₂ iN ₂ O 245.1648)

UV (MeOH): _max (box) = 206, 234, 308

IR: v _max (film) = 1645 and 1543 (-CO-CH = CH-)

[?] _D ²⁰ : -130 ° (c 0.001, MeOH)

1H NMR (500 MHz, CD ₃ OD) δ = 7.46 (1H, dd, J = 9Hz, J = 7Hz, H-4), 6.43 (1H, dd, J = 9Hz, J = 1.3Hz, H -3), 6.25 (1H, dd, J = 7Hz, J = 1.3Hz, H-5), 4.06 (2H, m, H-10), 3.12 (1H, t, J = 5Hz, H1) , 2.81 (1H, tt, J = 4.2Hz, J = 2Hz, H-7), 2.63 (1H, dd, J = 11.6Hz, J = 4.2Hz, H-13 '), 2.53 (1H, m, H-9), 2.48 (1H, brd, J = 11.6 Hz, H-13 "), 2.23 (1H, dd, J = 14.2 Hz, J = 8.8 Hz, H-14 '), 2.12 (1H, m, H-15), 2.09 (3H, s, H-17), 1.87 (1H, t, J = 4.5Hz, H-8), 1.11 (3H, d, J = 7Hz, H-16), 1.09 ( 1H, dt, J = 14.2 Hz, J = 5 Hz, H-14 ").

¹³ C NMR (125 MHz, CD ₃ OD) δ = 165.7 (C-2), 154.3 (C-6), 141.7 (C-4), 116.8 (C-3), 107.8 (C-5), 68.8 ( C-11), 56.3 (C-13), 45.9 (C-10), 43.2 (C-17), 41.5 (C-7), 40.5 (C-8), 37.6 (C-9), 36.2 (C -15), 31.1 (C-14), 22.7 (C-16).

Compound 2

Chemical formula: C15H20N2O2

Exact Mass: 260.15

Molecular weight: 260.33

HRESIMS: m / z = 261.1594 [M + H] ⁺ (calculated for Η ₂ ιΝ ₂ 0 ₂ 261.1598) UV (MeOH): _max (box) = 206, 234, 308

IR: v _max (film) = 3396 (OH), 1646 and 1547 (-CO-CH = CH-)

[α] _D ²⁰ : + 65 ° (c 0.00075, MeOH)

1H NMR (500 MHz, CD ₃ OD) δ = 7.47 (1H, dd, J = 9Hz, J = 7Hz, H-4), 6.44 (1H, dd, J = 9Hz, J = 1.4Hz, H -3), 6.26 (1H, dd, J = 7 Hz, J = 1.4 Hz, H-5), 4.05 (2H, m, H-10), 3.51 (1H, dd, J = 10.6 Hz, J = 6 Hz, H-16 '), 3.45 (1H, dd, J = 10.6 Hz, J = 8.2 Hz, H-16 "), 3.11 (1H, t, J = 4.9 Hz, H1 1), 2.80 (1H, tt, J = 4 Hz, J = 1.8 Hz, H-7), 2.65 (1H, dd, J = 11.8 Hz, J = 4.2 Hz, H-13 '), 2.51 (1H, brd, J = 11.6 Hz, H-13 "), 2.45 (1H, m, H-9), 2.18 (1H, t, J = 4.4 Hz, H-15), 2.14 (1H, m, H-8), 2.11 (3H, s, H-17), 2.09 (1H, m, H-14 '), 1.16 (1H, dt, J = 13.9 Hz, J = 4.9 Hz, H-14 ").

¹³ C NMR (125 MHz, CD ₃ OD) δ = 165.7 (C-2), 154.1 (C-6), 141.7 (C-4), 116.9 (C-3), 107.8 (C-5), 67.9 ( C-11), 66.2 (C-16), 56.3 (C-13), 45.7 (C-10), 44.5 (C-8), 43.3 (C-17), 41.4 (C-7), 37.9 (C -9), 35.5 (C-15), 25.4 (C-14). Compound 3

Chemical formula: C14H18N2O

Exact Mass: 230.14

Molecular weight: 230.31

HRESIMS: m / z = 231.1496 [M + H] ⁺ (calculated for Ci ₄ Hi ₉ N ₂ 0 231.1492)

UV (MeOH): _max (box) = 210, 232, 308

IR: v _max (film) = 1644 and 1543 (-CO-CH = CH-)

[?] _D ²⁰ : -32 ° (c 0.0009, MeOH)

1H NMR (500 MHz, CD ₃ OD) δ = 7.48 (1H, dd, J = 9Hz, J = 7Hz, H-4), 6.45 (1H, dd, J = 9Hz, J = 1.3, H- 3), 6.25 (1H, dd, J = 7Hz, J = 1.3, H-5), 4.16 (1H, d, J = 16.2Hz, H-10), 4.11 (1H, dd, J = 16.2Hz, J = 7.7 Hz, H-10), 3.38 (1H, m, H1 1), 3.34 (1H, m, H-13 '), 2.80 (1H, t, J = 4.2Hz, H-7), 2.60 ( 1H, d, J = 13Hz, H-13 "), 2.49 (1H, m, H-9), 2.33 (1H, m, H-15), 2.12 (1H, dd, J = 14Hz, J = 8.7 Hz, H-14 '), 1.93 (3H, t, J = 4.6 Hz, H-8), 1.52 (1H, dt, J = 14Hz, J = 5.4Hz, H-14 "), 1.11 (3H). , d, J = 7 Hz, H-16).

1 ³ C NMR (125 MHz, CD ₃ OD) δ = 165.9 (C-2), 153.9 (C-6), 141.7 (C-4), 116.8 (C-3), 107.9 (C-5), 61.3 (C-11), 47.6 (C-13), 45.6 (C-10), 41.8 (C-7), 41.1 (C-8), 39.3 (C-14), 37.0 (C-9), 36.0 ( C-15), 22.8 (C-16). Compound 4

Chemical formula: C15H20N2O2

Exact Mass: 260.15

Molecular weight: 260.33

HRESIMS: m / z = 261.1594 [M + H] ⁺ (calc. For C ₅ H ₂ iN ₂ O ₂ 261.1598)

1H NMR (500 MHz, CD ₃ OD) δ = 7.47 (1H, dd, J = 9Hz, J = 7Hz, H-4), 6.42 (1H, dd, J = 9Hz, J = 1.3, H- 3), 6.26 (1H, dd, J = 7Hz, J = 1.3, H-5), 4.22 (1H, d, J = 15.5Hz, H-10), 3.82 (1H, d, J = 15.5Hz, H-10), 2.97 (1H, dd, J = 5.5 Hz, J = 1.3, H1 1), 2.94 (1H, dt, J = 4.5 Hz, H-7), 2.55 (1H, dd, J = 12 Hz , J = 4.5, H-13 '), 2.40 (1H, d, J = 12Hz, H-13 "), 2.12 (1H, m, H-15), 2.09 (1H, d, J = 12Hz, H-14 '), 2.05 (1H, m, H-15), 1.88 (1H, dd, J = 4.6 Hz, H-8), 1.48 (1H, dt, J = 13.2 Hz, J = 5.2 Hz, H -14 '), 1.26 (3H, d, J = 7Hz, H-16).

¹³ C NMR (125 MHz, CD ₃ OD) δ = 165.2 (C-2), 153.3 (C-6), 141.9 (C-4), 116.8 (C-3), 107.1 (C-5), 78.8 ( C-9), 74.2 (Cl 1), 55.1 (C-13), 53.8 (C-10), 46.0 (C-8), 44.6 (C-7), 43.1 (C-17), 37.4 (C-9), 15), 29.5 (C-14), 24.0 (C-16).

Pharmacology:

Compounds 1, 2 and 3 were evaluated on the radioligand α4β2 agonist test according to the method described by Gopalakrishnan M. et al. J. Pharmacol.Exp.Ther., 276: 289-297, 1996.

The displacement studies of the [ ³ H] cytisine radio-membrane ligand on human SH-SY5Y cell membranes were carried out with a concentration of [ ³ H] cytisine of 0.6 nM in the absence or presence of increasing concentrations of compound 1, 2 or 3 (from 0.03 nM to 100 nM triplicate) for 120 minutes at 4 ° C. Non-specific residual binding was measured using a concentration of 10 μΜ of nicotine (α4β2 reference ligand). After filtering and rinsing the membranes incubated on a fiberglass filter, the detection of the radioactivity is ensured by liquid scintillation. Receptor specific binding is defined as the difference between total and nonspecific binding (determined in the presence of an excess of unlabeled ligand, nicotine). The ICso values of compounds 1, 2 and 3 were calculated by nonlinear regression method of competition curves generated from mean values using software Hill software. The inhibition constant Ki was calculated from the Cheng Prusoff equation. The following values were obtained:

Ki of compound 1 = 0.32 Nm

Ki of compound 2 = 1.3 nM

Ki of compound 3 = 1.6 nM

The compounds 1, 2 and 3 according to the invention therefore have an equivalent or even better activity than those of the reference molecules (cytisine, nicotine) on the α4β2 nicotinic receptor assay (nicotine Ki = 1.6 nM, reference used in the test), thus demonstrating their activity on the nicotinic receptor.

Cytotoxicity:

In order to demonstrate a possible cytotoxic activity of compound 1, an inhibition test for cell proliferation was performed. The human line of acute myeloid leukemia KG-1 was chosen. These cells in suspension are seeded at 30,000 cells per well in a 96-well plate and then contacted with the compound at different doses for 72 hours. The measurement of cell proliferation is then performed by intracellular ΓΑΤΡ assay. Since ATP is present in metabolically active cells, its amount is directly proportional to cell viability.

Compound 1 showed no inhibition of proliferation of the KG-1 line after 72 hours of treatment and up to 20 μΜ, thus showing its absence of cytotoxicity.

Abbreviations:

ATP adenosine triphosphate

HPLC high pressure liquid chromatography

CLMP Medium Pressure Liquid Chromatography

HRESIMS Electrospray mass spectrum at high resolution

IR Infrared

NMR Nuclear Magnetic Resonance

TEA Triethylamine

Ultra-violet UV

Claims

or a pharmaceutically acceptable salt thereof,

in which :

R 1 represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, aryl, (C ₁ -C ₆ ) alkyl-aryl or aryl- ( Ci-C ₆ ) alkyl,

R ₂ represents a hydrogen atom or a group -R ₅ or -C (O) R ₅ ,

- R ₃ represents a hydrogen atom or -OH, -OR5, -OC (0) R _O,

-OC (O) ORÔ, -OC (O) NR ₇ R ₈ , -C (O) R ₇ , -C (O) OR ₇ , or -C (O) NR ₇ R ₈ ,

R4 represents a hydrogen atom or an -OH group,

- R ₅ and 5 represent, independently of one another, a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, aryl, (C ₁ -C ₆ ) ₆ ) alkyl-aryl or aryl- (C 1 -C ₆ ) alkyl, and

2. Compound according to claim 1, characterized in that R1 represents a hydrogen atom or a (C1-C6) alkyl group, especially a hydrogen atom or a methyl group.

3. Compound according to claim 1 or 2, characterized in that R ₂ represents a hydrogen atom.

4. Compound according to any one of claims 1 to 3, characterized in that R ₃ represents a hydrogen atom or a group -OH, -OR ₅ , -OC (O) R ₅ , -OC (O) OR ₅ or -OC (0) NRÔR7, in particular a hydrogen atom or an -OH group.

5. Compound according to any one of claims 1 to 4, characterized in that it is chosen from the following compounds:

4

6. A compound according to any one of claims 1 to 5 for use as a medicament.

A compound according to any one of claims 1 to 5 for use as a medicament for the treatment of central nervous system disease, particularly smoking cessation, cognitive enhancement, anxiety, treatment of depression, and treatment of pain, or as a neuro-protective agent.

8. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient.

9. Process for obtaining a compound according to any one of claims 1 to 5, comprising the following successive steps:

(i) extracting a plant of the species Ormosia, and in particular roots or stems, to obtain a compound of formula (I) for which R 1 = CH ₃ and R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₄ = H and R ₃ = OH; or R 1 = R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₃ = H and R ₄ = OH,

10. Method according to claim 9, characterized in that step (i) comprises the following successive steps:

(i-1) maceration of an Ormosia crushed material, and in particular a crushed root and / or stalk of Ormosia, in methanol, followed by filtration and evaporation to dryness to give a dry methanolic extract,

(i-2) partition of the extract obtained in step (i-1) above between an aqueous solution of hydrochloric acid (especially 1 to 5%, preferably about 2%) and acetate of ethyl and separation of the resulting aqueous acid phase and organic phase,

(I-3) alkanization of the acidic aqueous phase obtained in the preceding step (i-2) (preferably to a pH of between 10 and 12, and in particular of about 1 1, in particular by adding a base such as Na ₂ CO ₃ ), addition of dichloromethane and separation of the new aqueous and organic phases resulting, and

(i-4) isolating the compound of formula (I) for which R 1 = CH ₃ and R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₄ = H and R ₃ = OH; or R 1 = R ₂ = R ₃ = R ₄ = H; or R 1 = CH ₃ , R ₂ = R ₃ = H and R ₄ = OH from the organic phase obtained in the preceding step (i-3).