Pharmaceutical Compositions Containing Mesembrine And

Europäisches Patentamt *EP000910372B1* (19) European Patent Office

Office européen des brevets (11) EP 0 910 372 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 31/40, C07D 209/32, of the grant of the patent: C07D 209/08 03.09.2003 Bulletin 2003/36 // A61K35/78, A61P25/22, (21) Application number: 97924158.5 A61P25/24

(22) Date of filing: 03.06.1997 (86) International application number: PCT/GB97/01493

(87) International publication number: WO 97/046234 (11.12.1997 Gazette 1997/53)

(54) PHARMACEUTICAL COMPOSITIONS CONTAINING MESEMBRINE AND RELATED COMPOUNDS MESEMBRIN UND VERWANDTE VERBINDUNGEN ENTHALTENDE PHARMAZEUTISCHE ZUSAMMENSETZUNGEN COMPOSITIONS PHARMACEUTIQUES CONTENANT DE LA MESEMBRINE ET DES COMPOSES APPARENTES

(84) Designated Contracting States: • JEFFS: "Total synthesis of (+-) mesembrine, AT BE CH DE ES FR GB GR IE IT LI NL (+-)-joubertinamine, and (+-)-N-demethylmesembrenone"J.ORG.CHEM., (30) Priority: 04.06.1996 ZA 9604595 vol. 48, no. 21, 1983, pages 3861-3863, XP002040520 (43) Date of publication of application: • JEFFS: "Sceletium alkaloids. VI. Minor alkaloids 28.04.1999 Bulletin 1999/17 of S. namaquense and S.strictum" J. ORG. CHEM., vol. 39, no. 18, 1974, pages 2703-2710, (73) Proprietor: Pharma Natura (Proprietary) Limited XP002040521 Sandton (ZA) • LANGLOIS: "Recherches dans la série des aryl-3-pyrrolidines-II. Synthèse de produits (72) Inventors: appentés à la mesembrine et à la crinine" • GERICKE, Nigel, Peter TETRAHEDRON, vol. 27, no. 22, 1971, pages Cape Town 7985 (ZA) 5641-5652, XP002040522 • VAN WYK, Ben-Erik • TAGUCHI: "Synthesis of octahydroindole Johannesburg 2092 (ZA) derivatives" TETRAHEDRON LETT., vol. 55, 1968, pages 5763-5766, XP002040523 (74) Representative: Curtis, Philip Anthony et al • KRUGER: "Minor alkaloids from Sceletium A.A. Thornton & Co., strictum L. Bol. The structure of 235 High Holborn N-demethylmesembrenol and London WC1V 7LE (GB) N-demethylmesembranol" J. S. AFR. CHEM. INST., vol. 24, no. 9, 1971, pages 235-237, (56) References cited: XP002040524 DE-A- 3 604 112 • CAPPS: "Sceletium alkaloids. Part 7. Structure and absolute stereochemistry of (-) mesembrane • TAGUCHI: "Synthesis of octahydroindole and 3’-methoxy-4’-O-methyljoubertiamine, two derivatives" CHEM. PHARM. BULL., vol. 18, no. minor bases from S. Nmamaquense L.Bolus : 5, 1970, pages 1008-1014, XP002040519 X-ray analysis of (-)-mesembrane hydrochloride monohydrate" J. CHEM. SOC., PERKINS TRANS. 2, vol. 8, 1977, pages 1098-1104, XP002040525

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 910 372 B1

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• PFAEFFLI: "Demethylierungen am Mesembrin" • DATABASE CHEMABS CHEMICAL ABSTRACTS HELVET. CHIM. ACTA, vol. 56, no. 1, 1973, pages SERVICE, COLUMBUS, OHIO, US AN: 76:59442, 347-355, XP002040526 XP002040529 & JP 46 043 538 B (TANABE • HOSHINO: "Synthesis of Sceletium and SEIYAKU CO LTD) 23 December 1971 Amaryllidaceae alkaloids, (+-)-mesembrine and • DATABASE WPI Week 7201 Derwent (+-)-dihydromaritidine, Publications Ltd., London, GB; AN 72-01352T (+-)-epidihydromaritidine, (+-)-elwesine and XP002041042 cited in the application & JP 46 043 (+-)-epielwesine" CHEM. PHARM. BULL., vol. 35, 539 B (TANABE SEIYAKU CO) 23 December 1971 no. 7, 1987, pages 2734-2743, XP002040527 • SMITH : "Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae : a review" J. ETHNOPHARMACOL., vol. 50, no. 3, March 1996, pages 119-130, XP002040528 cited in the application

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Description

BACKGROUND OF THE INVENTION

5 [0001] This invention relates to the use of mesembrine and related compounds as serotonin-uptake inhibitors, to pharmaceutical compositions comprising as an active ingredient dry material or an extract of a plant of the family Mesembryanthemaceae, standardised as to its active content, and to new compounds. [0002] It is known that the naturally occurring alkaloid mesembrine is useful as a medicament having CNS-stimulating action (see JP71043539 to Tanabe Seiyaku Company Limited). 10 [0003] It is also known that a plant and plant products known colloquially as "kougoed", "channa" or "kanna" in the Cape of South Africa, are used traditionally by some communities as inebriants, sedatives and to elevate mood. The plants called "kougoed", "channa" or "kanna" are all members of the family Mesembryanthemaceae, and contains varying amounts of (-)-mesembrine and related alkaloids. [0004] An article entitled Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemace- 15 ae: a review, by Smith et al, in Journal of Ethnopharmacology, 50 (1996), Pages 119 to 130, reviews the historical data recorded over a 300 year period of the use of Sceletium plants in psychoactive preparations, describes techniques for the preparation and use of "kougoed" from plants of Sceletium and documents the subjective experiences of a number of contemporary users. The alkaloid distribution in Sceletium and other members of the family Mesembryanthemaceae are also considered. Chemical studies have indicated as many as nine alkaloids in Sceletium, which fall into three 20 distinct structural categories.

SUMMARY OF THE INVENTION

[0005] According to a first aspect of the invention there is provided the use of a compound having the formula I 25

wherein the ring A is selected from:

R1 and R2 are independently selected from H, OH, OCH3 and O(CH2)nCH3; R3 is selected from H, CH3 and (CH2)nCH3; n is an integer from 1 to 6; and Q1 and Q2 are independently selected from CH2, C=O and CHOH; 55 in the manufacture of a medicament for the treatment of diseases that respond to treatment with a serotonin-uptake inhibitor. [0006] In their role as serotonin-uptake inhibitors, these compounds may be used in the treatment of mild to moderate depression, psychological and psychiatric disorders where anxiety is present, major depressive episodes, ie single

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episode and recurrent depression with associated anxiety, in alcohol and drug dependence, in the treatment of bulimia nervosa, and in the treatment of obsessive-compulsive disorders. [0007] According to a second aspect of the invention there is provided a pharmaceutical composition for the treatment of diseases that respond to treatment with a serotonin - uptake inhibitor, in unit dosage form comprising a serotonin- 5 uptake inhibitor having the formula I as set out above, in a dose of from 20 micrograms to 2 milligrams inclusive, preferably in a dose of from 50 micrograms to 500 micrograms inclusive, more preferably in a dose of from 100 micrograms to 300 micrograms inclusive. [0008] According to a fourth aspect of the invention there is provided a pharmaceutical composition for the treatment of diseases that respond to treatment with a serotonin uptake inhibitor, comprising as an active ingredient plant material 10 or an extract of a plant of the family Mesembryanthemaceae, containing in each unit dose an amount of from 20 micrograms to 2 milligrams inclusive, preferably from 50 micrograms to 500 micrograms inclusive, more preferably from 100 micrograms to 300 micrograms inclusive, of a compound selected from the group consisting of mesembrine, mesembranol and mesembranone, or a mixture of two or more thereof. [0009] The plant of the family Mesembryanthemaceae is preferably a plant of the genus Sceletium, more preferably 15 a plant of the species Sceletium tortuosum(L.) N.E. Br. [0010] The pharmaceutical composition of the invention is also useful in the treatment of mild to moderate depression, psychological and psychiatric disorders where anxiety is present, major depressive episodes, ie single episode and recurrent depression with associated anxiety, in alcohol and drug dependence, in the treatment of bulimia nervosa, and in the treatment of obsessive-compulsive disorders. 20 [0011] According to a fifth aspect of the invention there is provided a compound having the formula I

wherein the ring A is selected from :

R1 and R2 are independently selected from H, OH, OCH3 and O(CH2)nCH3; R3 is selected from H, CH3 and (CH2)nCH3; n is an integer from 1 to 6; 50 and Q1 and Q2 are independently selected from CH2, C=O and CHOH; with the provisos that:

(1) when the ring A is

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R1 and R2 are OCH3, R3 is CH3, and Q1 is CH2, then Q2 is not C=O or CHOH; (2) when the ring A is 10

R1 and R2 are OCH3 or R1 is OH and R2 is H, R3 is CH3, and Q1 is CH2, then Q2 is not C=O; and 20 (3) when the ring A is

R1 and R2 are OCH3, R3 is CH3, and Q1 is C=O, then Q2 is not C=O.

30 BRIEF DESCRIPTION OF THE DRAWINGS

[0012]

Figure 1 is a graph for a serotonin-uptake assay comparing (-)-mesembrine, identified by the code number 18532, 35 as compared with the known serotonin-uptake inhibitor imipramine HCl; Figure 2 is a graph for a serotonin-uptake assay of a whole plant extract of a plant from the family Mesembryan- themaceae, identified by the code number 18639, as well as some comparisons with the known serotonin- uptake inhibitor imipramine HCl; Figure 3 is a graph for a serotonin-uptake assay for mesembranol, identified by the code number 18623, as well 40 as some comparisons with the known serotonin-uptake inhibitor imipramine HCl; and Figure 4 is a graph for a serotonin-uptake assay for mesembranone, identified by the code number 18622, as well as some comparisons with the known serotonin-uptake inhibitor imipramine HCl.

DESCRIPTION OF EMBODIMENTS 45 [0013] The first aspect of the invention is the use of compounds of the formula I as serotonin-uptake inhibitors. [0014] The compounds of the formula I may be utilised in either of their isomeric forms i.e as the (-)isomer or as the (+)isomer, or as the racemic mixture of the two isomers. The preferred form is the (-)isomer. [0015] The compounds of the formula I may be divided into three sub groups: 50

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[0016] In the compounds of the formula I, preferably R1 and R2 are both OCH3,R3is CH3,Q1is CH2 and Q2 is 20 selected from C=O and CHOH. [0017] The preferred compound of formula I.1, is that in which R1 and R2 are OCH3,R3is CH3,Q1is CH2 and Q2 is C=O. [0018] This is the compound known as mesembrine. [0019] The structure of mesembrine, also known as 3a-(3,4-dimethoxyphenyl)-octahydro-1-methyl-6H-indol-6-one, 25 has been reported by Popelak et al., Naturwiss.47,156 (1960), and the configuration by P W Jeffs et al., J.Am.Chem. Soc.91,3831 (1969). [0020] Mesembrine is preferably used as its (-)-isomer i.e (-)-mesembrine. [0021] Another preferred compound of the formula I.1 is that in which R1 and R2 are OCH3,R3is CH3,Q1is CH2 and Q2 is CHOH, i.e the compound known as mesembranol. 30 [0022] Preferred compounds of the formula I.2 are those in which R1 is selected from OH and OCH3,R2is selected from H and OCH3, R3 is CH3, Q1 is CH2 and Q2 is C=O. [0023] A particularly preferred compound of the formula I.2 is that in which R1 and R2 are OCH3,R3is CH3,Q1is CH2 and Q2 is C=O, i.e the compound known as mesembranone. [0024] The preferred compounds of the formula I.3 are those in which R1 and R2 are OCH3,R3is CH3, and Q1 and 35 Q2 are C=O. [0025] As stated above, it has been known that mesembrine is useful as a medicament having CNS stimulating action. However, it has now been discovered that the compounds of the invention have a totally different mode of action as serotonin-uptake inhibitors, and in specified doses act as antidepressants, minor tranquilizers and anxiolytics. [0026] Thus, the compounds of the formula I are useful in the treatment of diseases selected from the group consisting 40 of mild to moderate depression, psychological and psychiatric disorders where anxiety is present, major depressive episodes, alcohol and drug dependence, bulimia nervosa, and obsessive-compulsive disorders. [0027] The second aspect of the invention is a pharmaceutical composition in unit dosage form comprising a serotonin-uptake inhibitor having the formula I as set out above, in a unit dose of from 20 micrograms to 2 milligrams in a unit dose of from 20 micrograms to 2 milligrams inclusive, preferably from 50 micrograms to 500 micrograms inclusive, 45 more preferably from 100 micrograms to 300 micrograms inclusive, preferably as a once-a-day administration. [0028] The compounds of the formula I may be formulated in any suitable form for pharmaceutical administration, such as for example aqueous-ethanolic tinctures, tablets, capsules, nasal sprays and skin-patches. The formulations may be designed to be taken orally sublingually, intra-nasally and transdermally. [0029] The preferred compound for the pharmaceutical composition described above as (-) mesembrine, with 50 mesembranol and mesembranone also being preferred. [0030] The fourth aspect of the invention is a pharmaceutical composition for the treatment of diseases that respond to treatment with a serotonin-uptake inhibitor comprising as an active ingredient plant material or an extract of the family Mesembryanthemaceae, more preferably a plant of the genus Sceletium, most preferably a plant of the species Sceletium tortuosum(L.) N.E. Br., containing in each unit dose an amount of 20 micrograms to 2 milligrams inclusive , 55 preferably from 50 micrograms to 500 micrograms inclusive, more preferably from 100 micrograms to 300 micrograms inclusive, of a compound selected from the group consisting of mesembrine, mesembranol and mesembranone, or a mixture of two or more thereof [0031] In other words, this pharmaceutical composition, while derived from a natural plant material, must contain a

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known and specified content of the active component or components. [0032] The pharmaceutical composition of the invention may comprise fresh or dry portions of the plant, ground to a pulp or powder, or an aqueous or alcoholic extract of the plant, all containing amounts of mesembrine, mesembranol or mesembranone. 5 [0033] Again, the pharmaceutical composition may be formulated for example as an aqueous-ethanolic tincture, tablet, capsule, nasal spray or skin-patch for oral, sublingual, intra-nasal and transdermal application. [0034] Methods for the extraction of (-)-mesembrine from a plant material containing the product, and methods of analysis thereof are set out below.

10 1 EXTRACTION METHODS

Dry material:

[0035] Material (or alcoholic extracts) are air-dried at maximum 40°C before analysis. Yield figures for mesembrine 15 are variable but are typically between 15 and 35 mg per gram dry leaves (mean value around 15 mg per gram dry weight). Finely ground material (pestle and mortar) is mixed with 15 ml 0,05 M H2SO4 and left standing at room temperature for 20 minutes. After filtration, the remaining solids are re-extracted with 5 ml 0,05 M H2SO4. The aqueous phases are combined, applied to glass columns with a coarse grade celite (24 g), alkalinized with ammonia (4 ml) and extracted (1X) with 100 ml CH2Cl2. The CH2Cl2 extracts are dried with anhydrous Na2SO4 and the solvent evaporated 20 under reduced pressure to leave the alkaloid as a pale brown oil. The alkaloids can also be extracted with hot or cold water instead of H2SO4, or with methanol, ethanol, acetonitrile, chloroform or dichloromethane.

Fresh material:

25 [0036] The leaf sap of fresh leaves (or alcoholic extracts) can be studied directly, or the alkaloids may be directly extracted in hot or cold water, ethanol, ethanol/acetonitrile, chloroform or dichloromethane or any other suitable solvent. For HPLC or GC, the sample has to be filtered (eg 0,45 µm filter) in order to protect the columns from impurities. Yield figures for mesembrine are variable, but are typically between 0,8 and 6,5 mg per ml leaf sap (mean value around 3,3 mg per ml). 30 2 METHODS OF ANALYSIS

2.1 Thin-layer Chromatography

35 [0037] This method can be used only for rough screening purposes, as there is a poor separation between mesembrine alkaloids with a 4,5 double bond (such as mesembrenone) and those without (such as mesembrine). For routine screening, the following system is suitable (Rf of mesembrine = 0,6): Merck 60 F254 silica gel plates (0,25 mm layer thickness) developed in CHCl3:cyclohexane:Et2NH (4:5:1). The plates are dried at 100°C for 3 minutes, studied under UV254 and UV365 and then sprayed with iodoplatinate or dragendorff spray reagents. 40 2.2 Gas Chromatography (GC)

[0038] Extracts are dissolved in minimum MeOH and studied by comparative GC and GC-MS. Authentic mesembrine should be used as external standard to quantify the alkaloid content. 45 A Routine analyses for large numbers of samples (fast system): DB-1 fused silica capillary column (30 m x 0,25 mm internal diameter; He as carrier gas at 4 ml min-1; column temperature 200°C to 300°C at 100 min-1,15 minute isotherm; injector 230°C; FID (Flame Ionization Detector) detection 300°C; split ratio 30:1; injection volume 1 µl). 50 B High resolution analyses (selected samples, slow): DB-1 fused silica capillary column (30 m x 0,25 mm internal diameter; He as carrier gas at 4 ml min-1; column temperature 150° to 320°Cat60min-1 15 minute isotherm; injector 230°C; PND (Phosphorus-Nitrogen Detector) detection 300°C; split ratio 30:1; injection volume 1µl). C For GC-MS: Typical system such as DB-1 fused silica capillary column (30 m x 0,32 mm internal diameter; He as carrier gas; column temperature 150° to 300°C at 60 min-1, split ratio 20:1; injection volume 1 µl). 55 2.3 High Performance Liquid Chromatography (HPLC)

[0039] A phenomenex IB-Sil column is used (C18 reverse phase, 5 µm particle size, 250 mm x 4,6 mm internal

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diameter, flow rate 1 ml per minute, 20 µl sample loop). An isocratic solvent system comprising 30% A in B (A = 1% triethylamine in water; B= 60% acetonitrile). Total run time is 10 minutes. Detection by diode array detector, using two channels (A set at 280 ± 30 nm, B set at 292 ± 10 nm). Results expressed in mg mesembrine per ml leaf sap (calculated from detector response, mean value of channels A and B). For concentrations below 0,05 mg per ml, channel A is 5 more accurate (lower detection limit of ca. 0,01 mg per ml leaf sap). The method depends on a calibration curve which was calculated using five different concentration levels of pure mesembrine, using the System Gold (Beckman) software package. For yield figures see 'fresh material extraction'.

3 IDENTIFICATION OF MESEMBRINE BY MASS SPECTROMETRY AND 1H NMR SPECTROSCOPY 10 [0040] In the two populations of Sceletium tortuosum studied, mesembrine occurs in leaves as virtually the only compound (small but negligible amounts of mesembrenone and mesembrenol may sometimes be present). The alkaloid was isolated from the leaves using the methods described above and fully identified by mass spectrometry (relative structure) and 1H NMR spectroscopy (absolute configuration). The optical rotation was measured, which confirmed 15 that the natural product is the (-)-form. [0041] Mesembranol and mesembranone may be extracted from suitable plant material, analysed and identified as set out above for mesembrine. [0042] Derivatives of mesembrine, mesembranol and mesembranone, within the group of compounds of formula I, may be prepared from these starting compounds by methods known in the art. 20 [0043] Higher order alkyl ethers of mesembrine, mesembranone or mesembranol may be prepared by acidolytic cleavage of the methoxy methyl groups (for example using anhydrous hydrogen fluoride) which gives the corresponding hydroxyl compound (R1.2=OH) followed by alkylation using the appropriate alkyl halide (for example CH3(CH2)nBr). [0044] The hydroxyl compounds above may be reduced to the corresponding benzyl compound (R1.2=H) by catalytic hydrogenation (for example over palladium). 25 [0045] Mesembranol may be prepared from mesembrine by catalytic hydrogenation (for example over palladium). [0046] Compounds of formula I.3 may be prepared from the appropriate mesembrine derivatives described above by dehydrogenation with mecuric acetate. [0047] Compounds of formulas I.2 and I.3 may be prepared from mesembrine by oxidation using selenium dioxide (SeO2) in tertiary butanol with subsequent purification of the desired positional isomer. 30 [0048] The isolated pure compound (-)-mesembrine was screened for biological activity by the National Institute of Mental Health in the United States of America, through a contract with Novascreen, a division of Oceanix Biosciences Corporation. As illustrated in Figure 1, in comparison to the tricyclic anti-depressant imipramine HCl, (-)-mesembrine was found to be a highly potent serotonin-uptake inhibitor with an IC50 in nano-molar concentrations. [0049] This testing of (-)-mesembrine also gave the following results set out in Table 1, and below. 35 Table 1 Receptor Percent Inhibition (Average:N=2) Concentration 5,0E1

40 GABA B -0,6% Serotonin-uptake 96,5 %

[0050] The inhibitory constant (Ki) of (-)-mesembrine, with reference to imipramine HCl was found to be Ki = 3,6E-8. [0051] In addition, the whole plant extract of Sceletium N.E.Br., mesembranol and mesembranone were screened 45 for biological activity by the National Institute of Mental Health in the United States of America through the contract with Novascreen. The results of these assays are illustrated in Figures 2 to 4. These assays show that the whole plant extract, as well as mesembranol and mesembranone are highly potent serotonin-uptake inhibitors. [0052] Various in vitro studies of the effects of the compounds of the invention were carried out in adult volunteers as follows: 50 Study 1. N=3 Healthy adult volunteers, all health professionals 13 September 1996.

[0053] A single dose of standardised preparation of dried whole plant, standardised to contain 400 micrograms of mesembrine was taken sublingually. 55 [0054] Rapid onset of action (10-15 minutes) noted by all. Anxiolytic effect noted by all. Sustained elevation of mood noted by all. Duration of anxiolytic action ranged from five hours to eight hours.

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Study 2. N=2 Healthy adult volunteers, all health professionals 21 September 1996.

[0055] A single 200 microgram dose of pure (-)-mesembrine dissolved in 1ml of 60% ethanol was taken sublingually. [0056] Rapid onset of action (7 and 12 minutes, respectively) noted by both. Anxiolytic effect noted by both. 5 Sustained elevation of mood noted by both (for approximately eight hours and eleven hours respectively). Duration of anxiolytic action ranged from five hours to eight hours.

Study 3. N=2 Adult volunteers, both self-confessed alcoholics and polysubstance abusers 21 September 1996. 10 [0057] A single 5ml dose of a whole-plant aqueous-ethanolic extract containing 100 micrograms of mesembrine per ml of extract (60% ethanol) was administered orally (total dose of mesembrine 500 micrograms). [0058] Rapid onset of action (15-20 minutes) noted by both. Anxiolytic effect noted by both. 15 Neither volunteer imbibed alcohol or used any illicit or other drug for a twenty-four hour period following the administration of the single dose. [0059] Examples of pharmaceutical compositions of the invention will now be given.

Example 1 20 [0060] A liquid composition comprises a 60% ethanol/water solvent containing about 200 µg/ml of (-)-mesembrine. [0061] A typical dose of the liquid composition is from 1 ml to 5 ml inclusive daily.

Example 2 25 [0062] A sublingual tablet contains a spray-dried 30% aqueous-ethanolic extract of Sceletium tortuosum, containing 200 micrograms of (-)-mesembrine, and conventional pharmaceutical excipients.

Example 3 30 [0063] An oral tablet contains 200 micrograms of pure (-)-mesembrine, and conventional pharmaceutical excipients.

Claims 35 1. The use of a compound having the formula I.

wherein the ring A is selected from :

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R1 and R2 are independently selected from H, OH, OCH3 and O(CH2)nCH3; R3 is selected from H, CH3 and (CH2)nCH3; 10 n is an integer from 1 to 6; and Q1 and Q2 are independently selected from CH2, C=O and CHOH; in the manufacture of a medicament for the treatment of diseases that respond to treatment with a serotonin-uptake inhibitor.

15 2. The use according to claim 1 wherein R1 and R2 are OCH3,R3is CH3,Q1is CH2 and Q2 is selected from C=O and CHOH.

3. The use according to claim 1 wherein the ring A is

R1 and R2 are OCH3, R3 is CH3, Q1 is CH2 and Q2 is C=O.

4. The use according to claim 1 wherein the compound of formula I is (-)-mesembrine. 30 5. The use according to claim 1 wherein the ring A is

R1 and R2 are OCH3, R3 is CH3, Q1 is CH2 and Q2 is CHOH.

6. The use according to claim 1 wherein the ring A is

R1 is selected from OH and OCH3, R2 is selected from H and OCH3, R3 is CH3, Q1 is CH2 and Q2 is C=O.

55 7. The use according to claim 1 wherein the ring A is

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R1 and R2 are OCH3, R3 is CH3, Q1 is CH2, and Q2 is C=O. 10 8. The use according to claim 1 wherein the ring A is

20 R1 and R2 are OCH3, R3 is CH3, and Q1 and Q2 are C=O.

9. The use according to any one of claims 1 to 8 wherein the disease is selected from the group consisting of mild to moderate depression, psychological and psychiatric disorders where anxiety is present, major depressive episodes, bulimia nervosa, and obsessive-compulsive disorders. 25 10. A pharmaceutical composition for the treatment of diseases that respond to treatment with a serotonin-uptake inhibitor, in unit dosage form comprising a serotonin-uptake inhibitor having the formula I

wherein the ring A is selected from : 45

R1 and R2 are independently selected from H, OH, OCH3 and OCCH2)nCH3; R3 is selected from H, CH3 and (CH2)nCH3; 55 n is an integer from 1 to 6; and Q1 and Q2 are independently selected from CH2, C=O and CHOH; in a dose of from 20 micrograms to 2 milligrams inclusive.

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11. A pharmaceutical composition according to claim 10 comprising the serotonin-uptake inhibitor in a does of from 50 micrograms to 500 micrograms inclusive.

12. A pharmaceutical composition according to claim 10 or 11 wherein the serotonin-uptake inhibitor is (-)-mesembrine. 5 13. A pharmaceutical composition for the treatment of diseases that respond to treatment with a serotonin-uptake inhibiton comprising as an active ingredient plant material or an extract of a plant of the family Mesembryanthemeae containing in each unit dose an amount of from 20 micrograms to 2 milligrams inclusive of a compound selected from the group consisting of mesembrine, mesembranol and mesembranone, or a mixture of two or more thereof. 10 14. A pharmaceutical composition according to claim 13 for use in the treatment of a disease which is selected from the group consisting of mild to moderate depression, psychological and psychiatric disorders where anxiety is present, major depressive episodes, alcohol and drug dependence, bulimia nervosa, and obsessive-compulsive disorders. 15 15. A pharmaceutical composition according to claim 13 or claim 14 wherein each unit dose contains an amount of from 50 micrograms to 500 micrograms inclusive of the compound.

16. A pharmaceutical composition according to any one of claims 13 to 15 in the form of an aqueous-ethanolic tincture, 20 a tablet, a capsule, a nasal or a skin patch.

17. A compound having the formula I

wherein the ring A is selected from: 40

R1 and R2 are independently selected from H, OH, OCH3 and O(CH2)nCH3; R3 is selected from H, CH3 and (CH2)nCH3; 50 n is an integer from 1 to 6; and Q1 and Q2 are independently selected from CH2, C=O and CHOH; with the provisos that:

(1) when the ring A is 55

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R1 and R2 are OCH3, R3 is CH3, and Q1 is CH2, then Q2 is not C=O or CHOH; (2) when the ring A is

R1 and R2 are OCH3 or R1 is OH and R2 is H, R3 is CH3, and Q1 is CH2 then Q2 is not C=O; and (3) when the ring A is

R1 and R2 are OCH3, R3 is CH3, and Q1 is C=O, then Q2 is not is not C=O.

Patentansprüche 30 1. Die Verwendung einer Verbindung mit der Formel I.

wobei der Ring A aus einer der folgenden Möglichkeiten gewählt wird:

R1 und R2 unabhängig voneinander aus H, OH, OCH3 und O(CH2)nCH3 gewählt werden, R3 aus H, CH3 und (CH2)nCH3 gewählt wird,

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n eine ganze Zahl von 1 bis 6 ist, und Q1 und Q2 unabhängig voneinander aus CH2, C=O und CHOH gewählt werden, für die Herstellung eines Medi- kaments für die Behandlung von Krankheiten die auf Behandlung mit einem Serotonin-Aumahme-Inhibitor reagieren. 5

2. Die Verwendung nach Anspruch 1, wobei R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist, Q1 gleich CH2 ist und Q2 aus C=O und CHOH gewählt wird.

3. Die Verwendung nach Anspruch 1, wobei der Ring A 10

ist, R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist, Q1 gleich CH2 ist und Q2 gleich C=O ist.

20 4. Die Verwendung nach Anspruch 1, wobei die Verbindung von Formel I gleich (-)-Mesembrin ist.

5. Die Verwendung nach Anspruch 1, wobei der Ring A

30 ist, R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist, Q1 gleich CH2 ist und Q2 gleich CHOH ist.

6. Die Verwendung nach Anspruch 1, wobei der Ring A

40 ist, R1 aus OH und OCH3 gewählt wird, R2 aus H und OCH3 gewählt wird, R3 gleich CH3 ist, Q1 gleich CH2 ist und Q2 gleich C=O ist.

7. Die Verwendung nach Anspruch 1, wobei der Ring A

ist, R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist, Q1 gleich CH2 ist und Q2 gleich C=O ist.

8. Die Verwendung nach Anspruch 1, wobei der Ring A 55

14 EP 0 910 372 B1

ist, R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist, und Q1 und Q2 gleich C=O sind.

10 9. Die Verwendung nach einem der Ansprüche 1 bis 8, wobei die Krankheit aus einer Gruppe gewählt wird die leichte bis mittelschwere Depression, psychologische und psychiatrische Erkrankungen mit Angstzuständen, schwere depressive Vorfälle, Bulimia nervosa und Zwangsvorstellungen einschließt.

10. Eine pharmazeutische Mischung für die Behandlung von Krankheiten die auf Behandlung mit einem Serotonin- 15 Aufnahme-Inhibitor reagieren, in Dosierungseinheiten die einen Serotonin-Aufnahme-Inhibitor mit der Formel I enthalten

wobei der Ring A aus einer der folgenden Möglichkeiten gewählt wird:

R1 und R2 unabhängig voneinander aus H, OH, OCH3 und O(CH2)nCH3 gewählt werden, R3 aus H, CH3 und (CH2)nCH3 gewählt wird, n eine ganze Zahl von 1 bis 6 ist, und Q1 und Q2 unabhängig voneinander aus CH2, C=O und CHOH gewählt werden, in Dosierungen von insgesamt 45 20 Mikrogramm bis 2 Milligramm.

11. Eine pharmazeutische Mischung nach Anspruch 10, welche den Serotonin-Aufhahme-Inhibitor in Dosierungen von insgesamt 50 Mikrogramm bis 500 Mikrogramm enthält.

50 12. Eine pharmazeutische Mischung nach Anspruch 10 oder 11, wobei der Serotonin-Aufnahme-Inhibitor (-)-Mesem- brin ist.

13. Eine pharmazeutische Mischung für die Behandlung von Krankheiten die auf Behandlung mit einem Serotonin- Aufnahme-Inhibitor reagieren, die als aktive Komponente Pflanzenmaterial oder ein Extrakt einer Pflanze aus der 55 Familie Mesembryanthemeae enthält, wobei jede Dosierungseinheit eine Gesamtmenge von 20 Mikrogramm bis zu 2 Milligramm enthält, welche eine Verbindung einschließt, die aus der Gruppe von Mesembrin, Mesembranol und Mesembranone gewählt wird, oder aus einer Mischung aus zwei oder mehreren Komponenten in dieser Grup- pe besteht.

15 EP 0 910 372 B1

14. Eine pharmazeutische Mischung nach Anspruch 13 für die Anwendung bei der Behandlung von Krankheiten die aus einer Gruppe gewählt wird die leichte bis mittelschwere Depression, psychologische und psychiatrische Er- krankungen mit Angstzuständen, schwere depressive Vorfälle, Bulimia nervosa und Zwangsvorstellungen ein- schließt. 5 15. Eine pharmazeutische Mischung nach Anspruch 13 oder 14, wobei jede Dosierungseinheit eine Gesamtmenge von 50 Mikrogramm bis 500 Mikrogramm einschließlich der Verbindung enthält.

16. Eine pharmazeutische Mischung nach einem der Ansprüche 13 bis 15 in der Form einer Wasser-Alkohol-Tinktur, 10 einer Tablette, einer Kapsel, eines Nasensprays oder eines Hautpflasters.

17. Eine Verbindung mit der Formel I

wobei der Ring A aus einer der folgenden Möglichkeiten gewählt wird: 30

R1 und R2 unabhängig voneinander aus H, OH, OCH3 und O(CH2)nCH3 gewählt werden, R3 aus H, CH3 und (CH2)nCH3 gewählt wird, 40 n eine ganze Zahl von 1 bis 6 ist, und Q1 und Q2 unabhängig voneinander aus CH2, C=O und CHOH gewählt werden, mit den folgenden Einschränkun- gen:

(1) wenn der Ring A 45

ist, R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist und Q1 gleich CH2 ist, dann ist Q2 nicht gleich C=O oder CHOH;

55 (2) wenn der Ring A

16 EP 0 910 372 B1

ist, R1 und R2 gleich OCH3 sind oder R1 gleich OH und R2 gleich H ist, R3 gleich CH3 ist und Q1 gleich CH2 ist, dann ist Q2 nicht gleich C=O; und 10 (3) wenn der Ring A

20 ist, R1 und R2 gleich OCH3 sind, R3 gleich CH3 ist und Q1 gleich C=O ist, dann ist Q2 nicht gleich C=O.

Revendications

25 1. L'utilisation d'un composé ayant la formule I.

40 dans lequel l'anneau A est sélectionné à partir de

R1 et R2 sont choisis indépendamment de H, OH, OCH3 et O (CH2) n CH3 ; 50 R3 est choisi à partir de H, CH3 et (CH2) n CH3 ; n est un nombre entier entre 1 et 6 ; et Q1 et Q2 sont choisis indépendamment de CH2 C = O et CHOH ; dans la fabrication d'un médicament pour le traitement de maladies qui répondent à un traitement grâce à un inhibiteur d'apport de sérotonine. 55

2. L'utilisation d'après la revendication 1 où R1 et R2 sont OCH3,R3est CH3, Q1 est CH2 et Q2 est choisit à partir de C = O et CHOH.

17 EP 0 910 372 B1

3. L'utilisation d'après la revendication I dans laquelle l'anneau A est

10 R1 et R2 sont OCH3, R3 est CH3, Q1 est CH2 et Q2 est C = O.

4. L'utilisation d'après la revendication I dans laquelle le composé de la formule I est la (-)mesembrine.

5. L'utilisation d'après la revendication I dans laquelle l'anneau A est 15

R1 et R2 sont OCH3, R3 est CH3, Q1 est CH2 et Q2 est CHOH

6. L'utilisation d'après la revendication I dans laquelle l'anneau A est 25

R1 est choisi à partir de OH et OCH3,R2est choisi à partir de H et OCH3,R3est CH3,Q1est CH2 et Q2 est C = O.

7. L'utilisation d'après la revendication I dans laquelle l'anneau A est 35

R1 et R2 sont OCH3, R3 est CH3, Q1 est CH2 et Q2 est C = O.

8. L'utilisation d'après la revendication I dans laquelle l'anneau A est 45

R1 et R2 sont OCH3, R3 est CH3, et Q1 et Q2 sont C = O.

55 9. L'utilisation d'après n'importe quelle revendication de I à 8 dans laquelle la maladie est choisie à partir du groupe consistant en une dépression bénigne ou modérée, des perturbations psychologiques et psychiatriques où l'an- xiété est présente, des épisodes de dépression grave, boulimie nerveuse et des troubles de névroses obsessionnelles.

18 EP 0 910 372 B1

10. Une composition pharmaceutique pour le traitement de maladies qui répondent à un traitement avec un inhibiteur d'apport de sérotonine ayant la formule I

dans lequel l'anneau A est choisi à partir de 20

R1 et R2 sont choisis indépendamment de H, OH, OCH3 et O (CH2)n CH3 ; R3 est choisi à partir de H, CH3 et (CH2) n CH3 ; 30 n est un nombre entier entre 1 et 6 ; et Q1 et Q2 sont choisis indépendamment de CH2 C = O et CHOH ; D'une dose allant de 20 microgrammes à 2 milligrammes inclus.

11. Une composition pharmaceutique d'après la revendication 10 comprenant un inhibiteur d'apport de sérotonine 35 dans une dose allant de 50 microgrammes à 500 microgrammes inclus.

12. Une composition pharmaceutique d'après la revendication 10 ou 11 dans laquelle l'inhibiteur de sérotonine est la (-)mesembrine.

40 13. Une composition pharmaceutique pour le traitement de maladies qui répondent au traitement avec une inhibition d'apport de sérotonine comprenant comme principe actif une substance végétale ou un extrait d'une plante de la famille des Mesembryanthema-cées contenant dans chaque dose une quantité allant de 20 microgrammes à 2 milligrammes incluant un composé choisi à partir du groupe qui se compose de mesembrine, mesembranol et mesembranonem ou d'un mélange de deux ou plus de cela. 45 14. Une composition pharmaceutique d'après la revendication 13 pour l'utilisation dans un traitement d'une maladie qui est choisie à partir du groupe consistant en une dépression bénigne ou modérée, des troubles psychologiques et psychiatriques où l'anxiété est présente, des épisodes de dépression grave, une dépendance à l'alcool et aux drogues, une boulimie nerveuse et des troubles de névroses obsessionnelles. 50 15. Une composition pharmaceutique d'après la revendication 13 ou la revendication 14 où chaque dose contient une quantité allant de 50 microgrammes à 500 microgrammes incluant le composé.

16. Une composition pharmaceutique d'après n'importe quelle revendication 13 à 15 sous la forme de teinture étha- 55 nolique aqueuse, un cachet, une gélule, un patch nasal ou de peau.

17. Un composé ayant la formule I

19 EP 0 910 372 B1

15 Où l'anneau A est sélectionné à partir de

25 R1 et R2 sont choisis indépendamment de H, OH, OCH3 et O (CH2) n CH3 ; R3 est choisi à partir de H, CH3 et (CH2) n CH3 ; n est un nombre entier entre 1 et 6; et Q1 et Q2 sont choisis indépendamment de CH2 C = O et CHOH ; A condition que : 30 (1) quand l'anneau A est

R1 et R2 et sont OCH3, R3 est CH3 et Q1 est CH2, alors Q2 n'est pas C = O ou CHOH. 40 (2) quand l'anneau A est

50 R1 et R2 et sont OCH3 R1 est OH et R2 est H, R3 est CH3 et Q1 est CH2 alors Q2 n'est pas C = O ; et

(3) quand l'anneau A est

20 EP 0 910 372 B1

R1 et R2 et sont OCH3, R3 est CH3 et Q1 est C = O, alors Q2 n'est pas C = O .

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