FR2992315A1 - DERIVATIVES USEFUL IN THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM - Google Patents
DERIVATIVES USEFUL IN THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM Download PDFInfo
- Publication number
- FR2992315A1 FR2992315A1 FR1256010A FR1256010A FR2992315A1 FR 2992315 A1 FR2992315 A1 FR 2992315A1 FR 1256010 A FR1256010 A FR 1256010A FR 1256010 A FR1256010 A FR 1256010A FR 2992315 A1 FR2992315 A1 FR 2992315A1
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- compound
- hydrogen atom
- aryl
- alkyl
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- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005945 von Braun degradation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un composé de formule (I) suivante : ou un sel pharmaceutiquement acceptable de celui-ci, ainsi que son procédé de préparation, les compositions pharmaceutiques le comprenant et son utilisation en tant que médicament, notamment destiné au traitement d'une maladie du système nerveux central, en particulier au sevrage tabagique, à l'amélioration des fonctions cognitives, au traitement de l'anxiété, au traitement de la dépression, et au traitement de la douleur, ou en tant qu'agent neuro-protecteur.The present invention relates to a compound of formula (I) below: or a pharmaceutically acceptable salt thereof, as well as its process of preparation, the pharmaceutical compositions comprising it and its use as a medicament, in particular for the treatment of a central nervous system disease, particularly smoking cessation, improvement of cognitive function, treatment of anxiety, treatment of depression, and treatment of pain, or as a neuroprotective agent.
Description
La présente invention concerne des molécules extraites d'une légumineuse et ses analogues, un procédé d'extraction et d'hémi-synthèse et l'utilisation de ces composés en tant que médicament, notamment pour le traitement de maladies du système nerveux central. De longue date, les plantes sont le sujet d'études en vue d'isoler de nouvelles substances actives potentiellement utiles dans le domaine pharmaceutique, en particulier de type alcaloïde. Les inventeurs ont ainsi pu isoler une nouvelle famille de molécules à partir de la plante Ormosia (Leguminosae), originaire des régions tropicales et plus spécifiquement d'Asie de l'Est, qui présente une activité sur le récepteur nicotinique.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.
Ainsi, la présente invention a pour objet un composé de formule (I) suivante : 16 R3 (I) ou un sel pharmaceutiquement acceptable de celui-ci, dans laquelle : R1 représente un atome d'hydrogène ou un groupe (Ci-C6)alkyle, (C2- C6)alcényle, (C2-C6)alcynyle, aryle, (Ci-C6)alkyl-aryle ou ary1-(Ci-C6)alkyle, R2 représente un atome d'hydrogène ou un groupe -R4 ou R3 représente un atome d'hydrogène ou un groupe -OH, -0R5, -0C(0)R5, -0C(0)0R5, -0C(0)NR6R7, -C(0)R6, -C(0)0R6, ou -C(0)NR6R7, R4 et R5 représentent, indépendamment l'un de l'autre, un groupe (Ci-C6)alkyle, (C2-C6)alcényle, (C2-C6)alcynyle, aryle, (Ci-C6)alkyl-aryle ou ary1-(CiC6)alkyle, et R6 et R7 représentent, indépendamment l'un de l'autre, un atome d'hydrogène ou un groupe (Ci-C6)alkyle, (C2-C6)alcényle, (C2-C6)alcynyle, aryle, (Ci-C6)alkyl- aryle ou ary1-(Ci-C6)alkyle. Dans la présente invention, on entend désigner par « pharmaceutiquement acceptable » ce qui est utile dans la préparation d'une composition pharmaceutique qui est généralement sûre, non toxique et ni biologiquement ni autrement non souhaitable et qui est acceptable pour une utilisation vétérinaire de même que pharmaceutique humaine. On entend désigner par « sels pharmaceutiquement acceptables » d'un composé, des sels qui sont pharmaceutiquement acceptables, comme défini ici, et qui possèdent l'activité pharmacologique souhaitée du composé parent. De tels sels comprennent : (1) les hydrates et les solvates, (2) les sels d'addition d'acide pharmaceutiquement acceptable formés avec des acides inorganiques pharmaceutiquement acceptables tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique, l'acide nitrique, l'acide phosphorique et similaires ; ou formés avec des acides organiques pharmaceutiquement acceptables tels que l'acide acétique, l'acide benzènesulfonique, l'acide benzoïque, l'acide camphresulfonique, l'acide citrique, l'acide éthane-sulfonique, l'acide fumarique, l'acide glucoheptonique, l'acide gluconique, l'acide glutamique, l'acide glycolique, l'acide hydroxynaphtoïque, l'acide 2-hydroxyéthanesulfonique, l'acide lactique, l'acide maléique, l'acide malique, l'acide mandélique, l'acide méthanesulfonique, l'acide muconique, l'acide 2-naphtalènesulfonique, l'acide propionique, l'acide salicylique, l'acide succinique, l'acide dibenzoyl-L-tartrique, l'acide tartrique, l'acide ptoluènesulfonique, l'acide triméthylacétique, l'acide trifluoroacétique et similaires, ou (3) les sels d'addition de base pharmaceutiquement acceptable formés lorsqu'un proton acide présent dans le composé parent est soit remplacé par un ion métallique, par exemple un ion de métal alcalin, un ion de métal alcalino-terreux ou un ion d'aluminium ; soit coordonné avec une base organique ou inorganique pharmaceutiquement acceptable. Les bases organiques acceptables comprennent la diéthanolamine, l'éthanolamine, N-méthylglucamine, la triéthanolamine, la trométhamine et similaires. Les bases inorganiques acceptables comprennent l'hydroxyde d'aluminium, l'hydroxyde de calcium, l'hydroxyde de potassium, le carbonate de sodium et l'hydroxyde de sodium. Par groupement « (Ci-C6)alkyle », on entend, au sens de la présente invention, une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comportant 1 à 6, de préférence 1 à 4, atomes de carbone. A titre d'exemple, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, sec-butyle, tert-butyle, pentyle ou encore hexyle.Thus, the subject of the present invention is a compound of the following formula (I): R3 (I) or a pharmaceutically acceptable salt thereof, wherein: R1 represents a hydrogen atom or a (C1-C6) group alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl, (C1-C6) alkyl-aryl or aryl (C1-C6) alkyl, R2 represents a hydrogen atom or a group -R4 or R3 represents a hydrogen atom or a group -OH, -OR5, -OC (O) R5, -OC (O) OR5, -OC (O) NR6R7, -C (O) R6, -C (O) OR6, or -C (O) NR6R7, R4 and R5 represent, independently of each other, a (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl, (C1- C6) alkyl-aryl or aryl (C1-C6) alkyl, and R6 and R7 represent, independently of one another, a hydrogen atom or a (C1-C6) alkyl, (C2-C6) alkenyl group, (C2-C6) alkynyl, aryl, (C1-C6) alkyl-aryl or aryl- (C1-C6) 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 biologically nor otherwise undesirable and which is acceptable for veterinary use as well as 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, acid glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, ptoluenesulphonic 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 a metal ion. alkaline, an alkaline earth metal ion or an aluminum ion; is coordinated with a pharmaceutically acceptable organic or inorganic base. 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.
Par groupement « (C2-C6)alcényle », on entend, au sens de la présente invention, une chaîne hydrocarbonée, linéaire ou ramifiée, comportant au moins une double liaison et comportant 2 à 6 atomes de carbone. A titre d'exemple, on peut citer les groupes éthényle ou allyle. Par groupement « (C2-C6)alcynyle », on entend, au sens de la présente invention, une chaîne hydrocarbonée, linéaire ou ramifiée, comportant au moins une triple liaison et comportant 2 à 6 atomes de carbone. A titre d'exemple, on peut citer les groupes éthynyle ou propynyle. Par « aryle », on entend, au sens de la présente invention, un groupement hydrocarboné aromatique, comportant de préférence de 6 à 10 atomes de carbone, et 20 comprenant un ou plusieurs cycles accolés, comme par exemple un groupement phényle ou naphtyle. Avantageusement, il s'agit du phényle. Par « ary1-(Ci-C6)alkyle », on entend, au sens de la présente invention, un groupe aryle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'une chaîne (Ci-C6)alkyle, telle que définie ci-dessus. A titre d'exemple, on peut citer le groupe 25 benzyle. Par « (Ci-C6)alkyl-aryle », on entend, au sens de la présente invention, une chaîne (Ci-C6)alkyle, telle que définie ci-dessus, liée à la molécule par l'intermédiaire d'un groupe aryle, tel que défini ci-dessus. A titre d'exemple, on peut citer le groupe tolyle. 30 Selon un mode de réalisation particulier de l'invention, R1 représente un atome d'hydrogène ou un groupe (Ci-C6)alkyle, notamment un atome d'hydrogène ou un groupe méthyle. Selon un autre mode de réalisation particulier de l'invention, R2 représente un atome d'hydrogène. Selon encore un autre mode de réalisation particulier de l'invention, R3 représente un atome d'hydrogène ou un groupe -OH, -0R5, -0C(0)R5, -0C(0)0R5 ou -0C(0)NR6R7, notamment un atome d'hydrogène ou un groupe -OH.By "(C2-C6) 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 "(C2-C6) 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. For the purposes of the present invention, the term "aryl (C 1 -C 6) alkyl" means an aryl group, as defined above, linked to the molecule via a (C 1 -C 6) chain. alkyl, as defined above. By way of example, mention may be made of the benzyl group. By "(C 1 -C 6) alkyl-aryl" is meant, within the meaning of the present invention, a (C 1 -C 6) alkyl chain, as defined above, linked to the molecule through a group aryl, as defined above. By way of example, mention may be made of the tolyl group. According to one particular embodiment of the invention, R 1 represents a hydrogen atom or a (C 1 -C 6) alkyl group, especially a hydrogen atom or a methyl group. According to another particular embodiment of the invention, R2 represents a hydrogen atom. According to yet another particular embodiment of the invention, R3 represents a hydrogen atom or a group -OH, -OR5, -OC (O) R5, -OC (O) OR5 or -OC (O) NR6R7, especially a hydrogen atom or a -OH group.
Il pourra s'agir en particulier de l'un des composés suivants : OH , et 1 2 3 La présente invention a également pour objet un composé de formule (I) tel que défini ci-dessus pour son utilisation en tant que médicament, notamment destiné au traitement d'une maladie du système nerveux central, en particulier au sevrage tabagique, à l'amélioration des fonctions cognitives, au traitement de l'anxiété, au traitement de la dépression, et au traitement de la douleur, ou en tant qu'agent neuro- protecteur. La présente invention concerne également l'utilisation d'un composé de formule (I) tel que décrit précédemment pour la préparation d'un médicament, destiné notamment au traitement d'une maladie du système nerveux central, en particulier au sevrage tabagique, à l'amélioration des fonctions cognitives, au traitement de l'anxiété, au traitement de la dépression, et au traitement de la douleur, ou en tant qu'agent neuro- protecteur.It may be in particular one of the following compounds: OH, and 1 2 3 The subject of the present invention is also a compound of formula (I) as defined above for its use as a medicament, in particular for the treatment of central nervous system disease, particularly smoking cessation, cognitive enhancement, anxiety therapy, depression treatment, and pain management, or as a treatment for 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.
L'invention concerne aussi une méthode de traitement d'une maladie du système nerveux central, en particulier une méthode de sevrage tabagique, d'amélioration des fonctions cognitives, de traitement de l'anxiété, de traitement de la dépression, de traitement de la douleur, ou de neuroprotection, comprenant l'administration à une personne en ayant besoin d'une dose efficace d'un composé de formule (I) tel que défini ci-dessus. La présente invention a également pour objet une composition pharmaceutique comprenant au moins un composé de formule (I) tel que défini ci-dessus et un excipient pharmaceutiquement acceptable. Les compositions pharmaceutiques selon l'invention peuvent être formulées pour une administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, transdermique, locale ou rectale, destinée aux mammifères, y compris l'homme. La posologie varie selon le traitement et selon l'affection en cause.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.
Les composés de l'invention en tant que principes actifs peuvent être utilisés à des doses comprises entre 0,01 mg et 1000 mg par jour, par exemple en une seule dose administrée une fois par jour. Dans un mode de réalisation particulier de l'invention, la composition pharmaceutique est utilisée en tant que médicament, par exemple pour le traitement d'une maladie du système nerveux central, en particulier pour le sevrage tabagique, l'amélioration des fonctions cognitives, le traitement de l'anxiété, le traitement de la dépression, le traitement de la douleur, ou en tant qu'agent neuro-protecteur. La présente invention a également pour objet un procédé d'obtention d'un composé tel que défini précédemment, comprenant les étapes successives suivantes : (i) extraction d'une plante de l'espèce Ormosia, et en particulier des racines ou des tiges, pour obtenir un composé de formule (I) pour lequel R1 = CH3 et R2 = R3 = H; ouR1 = CH3, R2 = H, et R3 = OH ; ou = R2 = R3 =H, (ii) éventuellement substitution des positions 12, 10 et/ou 16 du composé de formule (I) obtenu à l'étape (i) précédente, et (iii) éventuellement salification du composé de formule (I) obtenu à l'étape (i) ou (ii) précédente.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 neuroprotective agent. The subject of the present invention is also a process for obtaining a compound as defined above, comprising the following successive stages: (i) extraction of a plant of the Ormosia species, and in particular roots or stems, to obtain a compound of formula (I) for which R1 = CH3 and R2 = R3 = H; orR1 = CH3, R2 = H, and R3 = OH; or = R 2 = R 3 = H, (ii) optionally substitution of the 12, 10 and / or 16 positions of the compound of formula (I) obtained in the preceding step (i), and (iii) optionally salification of the compound of formula ( I) obtained in step (i) or (ii) above.
Etape (i) : L'étape (i) pourra notamment comprendre les étapes successives suivantes : (i-1) macération d'un broyat d' Ormosia, et en particulier d'un broyat de racines et/ou de tiges d' Ormosia, dans du méthanol, suivie d'une filtration et d'une évaporation à sec pour donner un extrait méthanolique sec, (i-2) partition de l'extrait obtenu à l'étape (i-1) précédente entre une solution aqueuse d'acide chlorhydrique (notamment à 1 à 5 %, avantageusement à environ 2 %) et de l'acétate d'éthyle et séparation de la phase aqueuse acide et de la phase organique résultantes, (i-3) alcanisation de la phase aqueuse acide obtenue à l'étape (i-2) précédente (de préférence jusqu'à un pH compris entre 10 et 12, notamment d'environ 11, notamment par ajout d'une base telle que Na2CO3), ajout de dichlorométhane et séparation des nouvelles phases aqueuse et organique résultantes, et (i-4) isolement du composé de formule (I) pour lequel R1 = CH3 et R2 = R3 = H; ou R1 = CH3, R2 = H, et R3 = OH; ou R1 = R2 = R3 = H à partir de la phase organique obtenue à l'étape (i-3) précédente. La dernière étape (i-4) d'isolement du composé selon l'invention pourra être réalisée notamment par évaporation à sec de la phase organique, suivie d'une chromatographie sur gel de silice. Le produit obtenu pourra alors être purifié par des techniques bien connues de l'homme du métier, et notamment par chromatographie liquide haute performance (CLHP). Etape (ii) : Cas de la position 12: Si l'on part d'un composé de formule (I) pour lequel R1 = H, la réaction de substitution de l'amine secondaire peut être réalisée par des techniques bien connues de l'homme du métier. En particulier, elle peut être réalisée en présence d'une base et d'un composé de formule R1-A1 avec R1 H et A1 représentant un groupe partant. Par « groupe partant », on entend, au sens de la présente invention, un groupement chimique qui peut être facilement déplacé par un nucléophile lors d'une réaction de substitution nucléophile, le nucléophile étant plus particulièrement une amine, et notamment une amine secondaire dans le cas présent. Un tel groupe partant peut être plus particulièrement un atome d'halogène tel qu'un atome de chlore ou de brome, un mésylate (-0S(02)-CH3), un triflate (-0S(0)2-CF3) ou encore un tosylate (-0S(0)2-(p-Me-C6H4)). Si l'on part d'un composé de formule (I) pour lequel R1 = CH3, il convient de réaliser une étape de déméthylation (conduisant à un composé pour lequel R1 = H), avant de réaliser la réaction de substitution nucléophile mentionnée ci-dessus. Cette déméthylation peut être réalisée notamment par une réaction de Polonovski ou de von Braun, suivie d'une hydrolyse de l'adduit formé. Cas de la position 10: La position 10 d'un composé de formule (I), située en alpha d'une fonction amide, peut être déprotonée en milieu fortement basique, tel qu'en présence de LDA (diisopropylamidure de lithium). La molécule ainsi déprotonée peut alors réagir avec un composé de formule R2-A2 avec R2 H et A2 représentant un groupe partant. Une réaction analogue est notamment décrite dans HOULLIER N. et coll., Regio- and diastereoselective functionalization of (-)-cytisine, Tetrahedron, 2006, 62, 50, 11679-11686. Cas de la position 16: Cette réaction peut être réalisée à partir d'un composé de formule (I) pour lequel R3 = OH par des techniques bien connues de l'homme du métier, notamment par réaction d'oxydation et/ou substitution nucléophile, cette dernière réaction pouvant plus particulièrement être réalisée en milieu basique. Etape (iii) : Cette étape pourra être réalisée par des techniques bien connues de l'homme du métier, et en particulier par mélange du composé de formule (I) avec un acide ou une base pharmaceutiquement acceptable. Le composé ainsi obtenu pourra être séparé du milieu réactionnel par des méthodes bien connues de l'homme du métier, comme par exemple par extraction, évaporation du solvant ou encore par précipitation et filtration. Le composé pourra par ailleurs être purifié si nécessaire par des techniques bien connues de l'homme du métier, comme par recristallisation si le composé est cristallin, par distillation, par chromatographie sur colonne sur gel de silice ou encore par chromatographie liquide haute performance (CLHP). L'invention est plus particulièrement décrite de manière non limitative dans les exemples qui suivent. EXEMPLES: Obtention des composés selon l'invention : Les racines et/ou tiges de l'espèce Ormosia, séchées et broyées, sont mises à macérer dans du méthanol (1g de racines/tiges pour 10 mL de méthanol) à température ambiante pendant une nuit. Le mélange est ensuite filtré sur papier filtre et amené à sec sous pression réduite à l'aide d'un évaporateur rotatif L'extrait méthanolique sec obtenu est dissout dans une solution d'HC1 2 % (préparée à partir d'une solution pure d'HC1 à 37 °A), puis partitionné par extraction liquide/liquide avec de l'acétate d'éthyle (2 fois). La phase aqueuse acide est ensuite alcalinisée avec Na2CO3 jusqu'à pH = 11, et partitionnée par liquide/liquide avec du dichlorométhane (2 fois). La fraction organique obtenue est lavée à l'eau, puis concentrée à sec pour devenir le totum alcaloïdique (TA).Step (i): Step (i) may in particular comprise the following successive steps: (i-1) maceration of a crushed Ormosia, and in particular a crushed root and / or stems of Ormosia in methanol, followed by filtration and dry evaporation to give a dry methanol extract, (i-2) partition of the extract obtained in the preceding step (i-1) between an aqueous solution of hydrochloric acid (in particular at 1 to 5%, advantageously at approximately 2%) and ethyl acetate and separation of the resulting acidic aqueous 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, in particular of approximately 11, in particular by addition of a base such as Na 2 CO 3), addition of dichloromethane and separation of the new resulting aqueous and organic phases, and (i-4) isolating the compound of formula (I) wherein R1 = CH3 and R2 = R3 = H; or R1 = CH3, R2 = H, and R3 = OH; or R1 = R2 = R3 = 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): Case of the 12-position: 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 which are well known in the art. skilled person. In particular, it can be carried out in the presence of a base and a compound of formula R1-A1 with R1 H and A1 representing a leaving group. By "leaving group" is meant, in the sense of the present invention, a chemical group that can be easily moved 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 (-SO (O 2) -CH 3), a triflate (-SO (O) 2-CF 3) or a tosylate (-SO (O) 2- (p-Me-C6H4)). 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. -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 the 10-position: The position of a compound of formula (I), situated 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 R2-A2 with R2 H and A2 representing a leaving group. A similar reaction is described in Hullier N. et al., Regio and diastereoselective functionalization of (-) - cytisine, Tetrahedron, 2006, 62, 50, 11679-11686. Case of position 16: This reaction may 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 can 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 the 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 ambient temperature for a period of night. 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 dichloromethane). HC1 at 37 ° A), then partitioned by liquid / liquid extraction with ethyl acetate (2 times). The acidic aqueous phase is then basified with Na2CO3 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).
Le TA est contrôlé par Chromatographie Liquide Haute Performance (CLHP) analytique sur une colonne XBridge RP18 (100 x 4.6 mm, 51.1m). Un mélange Eau + 0,02 % TEA et acétonitrile + 0,02 % TEA est utilisé comme phase éluante avec un gradient linéaire de 80/20 à 100 % d'acétonitrile + 0,02 % TEA, à un débit de 1 ml/mn et une détection à X=230 nm.The TA is monitored by analytical high performance liquid chromatography (HPLC) on an XBridge RP18 column (100 x 4.6 mm, 51.1m). 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 X = 230 nm.
Le TA est purifié dans un premier temps par Chromatographie Liquide Moyenne Pression (CLMP) sur colonne pré-packée de Silice (gradient CH2C12 / Me0H 1 : 0 - 0 : 1). Après analyse des fractions obtenues par Chromatographie sur Couche Mince (CCM) (éluant dichlorométhane /méthanol 95/5), 5 fractions sont constituées. Ces différentes fractions sont purifiées par CLHP semi-préparative sur phase inverse C18 (gradient eau + 0,02 % TEA/ acétonitrile + 0,02 % TEA). On obtient alors les composés 1 (5 % dans le TA, 200 mg/Kg de racines sèches), 2 (1 % dans le TA, 30 mg/Kg de racines sèches) et 3 (0,2 % dans le TA, 6 mg/Kg de tiges sèches) suivants.The TA is first purified by Medium Pressure Liquid Chromatography (HPLC) on a pre-packaged silica column (gradient CH2C12 / 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). Compounds 1 (5% in TA, 200 mg / kg of dry roots), 2 (1% in TA, 30 mg / kg of dry roots) and 3 (0.2% in TA, 6 are then obtained. mg / kg of dry stems) following.
Composé 1 Formule chimique : Ci5H20N20 Masse exacte : 244.16 Poids moléculaire : 244.33 HRESIMS :m/z = 245.1650 [M+H] (calculé pour Ci5H2iN20 245.1648) 10 UV (Me0H) (loge)= 206, 234, 308 IR :v',a' (film) = 1645 et 1543 (-CO-CH=CH-) [OE]D2° _13- u0 ,c ( 0.001, Me0H) 1H RMN (500 MHz, CD30D) Ô= 7.46 (1H, dd, J = 9 Hz, J = 7 Hz, H-4), 6.43 (1H, dd, J = 9 Hz, J = 1.3 Hz, H-3), 6.25 (1H, dd, J = 7 Hz, J = 1.3 Hz, H-5), 4.06 (2H, m, H-10), 15 3.12 (1H, t, J = 5 Hz, H-11), 2.81 (1H, tt, J = 4.2 Hz, J = 2 Hz, H-7), 2.63 (1H, dd, J= 11.6 Hz, J = 4.2 Hz, 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 = 4.5 Hz, H-8), 1.11 (3H, d, J = 7 Hz, H-16), 1.09 (1H, dt, J = 14.2 Hz, J = 5 Hz, H-14"). 20 13C RMN (125 MHz, CD30D) Ô= 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). Composé 2 25 Formule chimique : Ci5H20N202 Masse exacte : 260.15 4 1 4 2 4 3 14 16 9 Poids moléculaire : 260.33 HRESIMS :m/z = 261.1594 [M+H] (calculé pour Ci5H21N202 261.1598) UV (Me0H) (loge)= 206, 234, 308 IR :v',a' (film) = 3396 (OH), 1646 et 1547 (-CO-CH=CH-) [0]D2o +650 (c 0.00075, Me0H) 1H RMN (500 MHz, CD30D) Ô= 7.47 (1H, dd, J = 9 Hz, J = 7 Hz, H-4), 6.44 (1H, dd, J = 9 Hz, J = 1.4 Hz, 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, H16"), 3.11 (1H, t, J = 4.9 Hz, H-11), 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"). 13C RMN (125 MHz, CD30D) Ô= 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). Composé 3 Formule chimique : Ci4Hi8N20 Masse exacte : 230.14 Poids moléculaire : 230.31 HRESIMS :m/z = 231.1496 [M+H] (calculé pour Ci4Hi9N20 231.1492) UV (Me0H) (loge)= 210, 232, 308 IR :v',a' (film) = 1644 et 1543 (-CO-CH=CH-) [OE]D2° _320 ,c t 0.0009, Me0H) 1H RMN (500 MHz, CD30D) Ô= 7.48 (1H, dd, J = 9 Hz, J = 7 Hz, H-4), 6.45 (1H, dd, J = 9 Hz, J= 1.3, H-3), 6.25 (1H, dd, J = 7 Hz, J= 1.3, H-5), 4.16 (1H, d, J = 16.2 Hz, H- 10), 4.11 (1H, dd, J = 16.2 Hz, J = 7.7 Hz, H-10), 3.38 (1H, m, H-11), 3.34 (1H, m, H13'), 2.80 (1H, t, J = 4.2 Hz, H-7), 2.60 (1H, d, J = 13 Hz, H-13"), 2.49 (1H, m, H-9), 2.33 (1H, m, H-15), 2.12 (1H, dd, J = 14 Hz, J = 8.7 Hz, H-14'), 1.93 (3H, t, J = 4.6 Hz, H-8), 1.52 (1H, dt, J = 14 Hz, J = 5.4 Hz, H-14"), 1.11 (3H, d, J = 7 Hz, H-16). 13C RMN (125 MHz, CD30D) Ô= 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 1 Chemical formula: C15H20N2O Exact mass: 244.16 Molecular weight: 244.33 HRESIMS: m / z = 245.1650 [M + H] (calcd for C15H21N2O: 245.1648) UV (MeOH) (lodge) = 206, 234, 308 IR: v ' , a '(film) = 1645 and 1543 (-CO-CH = CH-) [EO] D2 ° _13- u0, c (0.001, MeOH) 1H NMR (500 MHz, CD30D) δ = 7.46 (1H, dd, J = 9 Hz, J = 7 Hz, H-4), 6.43 (1H, dd, J = 9 Hz, J = 1.3 Hz, H-3), 6.25 (1H, dd, J = 7 Hz, J = 1.3 Hz, H-5), 4.06 (2H, m, H-10), 3.12 (1H, t, J = 5Hz, H-11), 2.81 (1H, tt, J = 4.2Hz, J = 2Hz). , H-7), 2.63 (1H, dd, J = 11.6 Hz, J = 4.2 Hz, 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 = 4.5 Hz, H-8), 1.11 (3H, d, J = 7 Hz, H-16), 1.09 (1H, dt, J = 14.2 Hz, J = 5 Hz, H 14 "). 13C NMR (125 MHz, CD30D) δ = 165.7 (C-2), 154.3 (C-6), 141.7 (C-4), 116.8 (C-3), 107.8 (C-5), 68.8 (C-1), 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: C12H20N2O2 Exact mass: 260.15 4 1 4 2 4 3 14 16 9 Molecular weight: 260.33 HRESIMS: m / z = 261.1594 [M + H] (calcd for C15H21N2O2 261.1598) UV (MeOH) (box) = 206, 234, 308 IR: v ', a' (film) = 3396 (OH), 1646 and 1547 (-CO-CH = CH-) [O] D20 +650 (c 0.00075, MeOH) 1H NMR (500 MHz , CD30D) 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, H16 "), 3.11 (1H, t, J = 4.9 Hz, H-11), 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 ") 13C NMR (125 MHz, CD30D)? = 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] (calcd for C14H19N2O 231.1492) UV (MeOH) (Lane) = 210, 232, 308 IR: v ', a '(film) = 1644 and 1543 (-CO-CH = CH-) [OE] D2 ° _320, and 0.0009, MeOH) 1H NMR (500 MHz, CD30D) δ = 7.48 (1H, dd, J = 9 Hz , J = 7 Hz, H-4), 6.45 (1H, dd, J = 9 Hz, J = 1.3, H-3), 6.25 (1H, dd, J = 7Hz, J = 1.3, H-5) , 4.16 (1H, d, J = 16.2 Hz, H-10), 4.11 (1H, dd, J = 16.2 Hz, J = 7.7 Hz, H-10), 3.38 (1H, m, H-11), 3.34 (1H, m, H13 '), 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 = 8.7Hz, H-14 '), 1.93 (3H, t, J = 4.6Hz, H-8). 1.52 (1H, dt, J = 14Hz, J = 5.4Hz, H-14 "), 1.11 (3H, d, J = 7Hz, H-16). 13C NMR (125 MHz, CD30D) 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).
Pharmacologie : Les composés 1, 2 et 3 ont été évalués sur le test radioligand agoniste a4132 selon la méthode décrite par Gopalakrishnan M et al. J.Pharmacol.Exp.Ther., 276:289-297, 1996.Pharmacology: Compounds 1, 2 and 3 were evaluated on the radioligand agonist test a4132 according to the method described by Gopalakrishnan M et al. J. Pharmacol.Exp.Ther., 276: 289-297, 1996.
Les études de déplacement du radio ligand [3H]cytisine sur membrane de cellules humaines SH-SY5Y ont été réalisées avec une concentration de [3H]cytisine de 0,6 nM en absence ou présence de concentrations croissantes de composé 1, 2 ou 3 (de 0,03 nM à 100 nM en triplicate) pendant 120 minutes à 4°C. La liaison résiduelle non spécifique a été mesurée en utilisant une concentration de 101.1M de nicotine (ligand de référence a4132). Après filtration et rinçage des membranes incubées sur filtre en fibre de verre, la détection de la radioactivité est assurée par scintillation liquide. La liaison spécifique au récepteur est définie comme la différence entre la liaison totale et non spécifique (déterminée en présence d'un excès de ligand non marqué, la nicotine). Les valeurs d'IC50 des composés 1, 2 et 3 ont été calculées par méthode de régression non linéaire des courbes de compétitions générées à partir des valeurs moyennes à l'aide du logiciel Hill software. La constante d'inhibition Ki a été calculée à partir de l'équation de Cheng Prusoff Les valeurs suivantes ont été obtenues : Ki du composé! = 0,32 Nm Ki du composé 2 = 1,3 nM Ki du composé 3 = 1,6 nM Les composés 1, 2 et 3 selon l'invention présentent donc une activité équivalente, voire meilleure, que celles des molécules de référence (cytisine, nicotine) sur le test récepteur nicotinique a4132 (Ki de la nicotine = 1,6 nM, référence utilisée dans le test), démontrant ainsi leur activité sur le récepteur nicotinique.The SH-SY5Y human cell membrane [3 H] cytisine radioactivity displacement studies were performed 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 ( 0.03 nM to 100 nM triplicate) for 120 minutes at 4 ° C. Non-specific residual binding was measured using a 101.1M concentration of nicotine (a4132 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 IC50 values of compounds 1, 2 and 3 were calculated by nonlinear regression method of the competition curves generated from the mean values using the software Hill software. The inhibition constant Ki was calculated from the Cheng Prusoff equation. The following values were obtained: Ki of the compound! = 0.32 Nm Ki of the compound 2 = 1.3 nM Ki of the compound 3 = 1.6 nM The compounds 1, 2 and 3 according to the invention thus have an equivalent or even better activity than those of the reference molecules ( cytisine, nicotine) on the nicotinic receptor a4132 test (nicotine Ki = 1.6 nM, reference used in the test), thus demonstrating their activity on the nicotinic receptor.
Cytotoxicité : Afin de mettre en évidence une éventuelle activité cytotoxique du composé 1, un test d'inhibition de la prolifération cellulaire a été réalisé. La lignée humaine de leucémie aigüe myéloïde KG-1 a été choisie. Ces cellules en suspension sont ensemencées à 30 000 cellules par puits dans une plaque 96 puits puis mises en contact avec le composé à différentes doses pendant 72 heures. La mesure de la prolifération cellulaire est alors réalisée par dosage de l'ATP intracellulaire. L'ATP étant présent dans les cellules métaboliquement actives, sa quantité est directement proportionnelle à la viabilité cellulaire. Le composé 1 n'a montré aucune inhibition de prolifération de la lignée KG-1 après 72 heures de traitement et ce jusqu'à 201.1M, montrant ainsi son absence de cytoxicité. Abréviations : ATP Adénosine triphosphate CLHP Chromatographie liquide haute pression CLMP Chromatographie liquide moyenne pression HRESIMS Spectre de masse en électrospray à haute résolution IR Infrarouge RMN Résonance magnétique nucléaire TEA Triéthylamine UV Ultra-violet15Cytotoxicity: In order to demonstrate a possible cytotoxic activity of compound 1, a cell proliferation inhibition test was performed. The human acute myeloid leukemia line 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 assaying the intracellular ATP. Since ATP is present in metabolically active cells, its amount is directly proportional to cell viability. Compound 1 showed no inhibition of proliferation of KG-1 line after 72 hours of treatment and up to 201.1M, thus showing its absence of cytotoxicity. Abbreviations: ATP Adenosine Triphosphate HPLC High Pressure Liquid Chromatography CLMP Medium Pressure Liquid Chromatography HRESIMS High Resolution Electrospray Mass Spectrum IR Infrared NMR Nuclear Magnetic Resonance TEA Triethylamine UV Ultra Violet 15
Claims (10)
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| FR1256010A FR2992315B1 (en) | 2012-06-25 | 2012-06-25 | DERIVATIVES USEFUL IN THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM |
| PCT/EP2013/063305 WO2014001348A1 (en) | 2012-06-25 | 2013-06-25 | Alkaloid derivatives of cytisine used in the treatment of diseases of the central nervous system |
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| FR1256010A FR2992315B1 (en) | 2012-06-25 | 2012-06-25 | DERIVATIVES USEFUL IN THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM |
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| FR2992315A1 true FR2992315A1 (en) | 2013-12-27 |
| FR2992315B1 FR2992315B1 (en) | 2014-08-08 |
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| FR (1) | FR2992315B1 (en) |
| WO (1) | WO2014001348A1 (en) |
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| GB201602145D0 (en) | 2016-02-05 | 2016-03-23 | Achieve Pharma Uk Ltd | Salt |
| EP3454904B1 (en) * | 2016-05-13 | 2022-12-14 | Institut Pasteur | Inhibition of beta-2 nicotinic acetylcholine receptors to treat alzheimer's disease pathology |
| JP7178538B2 (en) | 2016-08-19 | 2022-11-28 | ザ ユニバーシティ オブ ブリストル | Compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0581457A1 (en) * | 1992-07-07 | 1994-02-02 | R.J. Reynolds Tobacco Company | Use of cytisine compounds for the manufacture of a medicament for the treatment of neurodegenerative diseases |
| WO1998018798A1 (en) * | 1996-10-30 | 1998-05-07 | Pfizer Inc. | Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy |
-
2012
- 2012-06-25 FR FR1256010A patent/FR2992315B1/en not_active Expired - Fee Related
-
2013
- 2013-06-25 WO PCT/EP2013/063305 patent/WO2014001348A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0581457A1 (en) * | 1992-07-07 | 1994-02-02 | R.J. Reynolds Tobacco Company | Use of cytisine compounds for the manufacture of a medicament for the treatment of neurodegenerative diseases |
| WO1998018798A1 (en) * | 1996-10-30 | 1998-05-07 | Pfizer Inc. | Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy |
Non-Patent Citations (2)
| Title |
|---|
| CHELLAPPAN SHEELA K ET AL: "SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NOVEL 9- AND 10-SUBSTITUTED CYTISINE DERIVATIVES. NICOTINIC LIGANDS OF ENHANCED SUBTYPE SELECTIVITY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 49, no. 9, 6 April 2006 (2006-04-06), pages 2673 - 2676, XP009082275, ISSN: 0022-2623, DOI: 10.1021/JM051196M * |
| KINGHORN ET AL: "Alkaloid distribution in seeds of Ormosia, Pericopsis and Haplormosia", PHYTOCHEMISTRY, PERGAMON PRESS, GB, vol. 27, no. 2, 1 January 1988 (1988-01-01), pages 439 - 444, XP022478154, ISSN: 0031-9422, DOI: 10.1016/0031-9422(88)83116-9 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014001348A1 (en) | 2014-01-03 |
| FR2992315B1 (en) | 2014-08-08 |
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