MXPA99011774A - New compounds of spyroimidazole - Google Patents

Abstract

The invention relates to a compound of formula (I) (See Formula) in which: - A represents an optionally substituted benzene ring, - B represents an imidazoline ring, of formula (Ia) or (Ib) :( See Formula) and medicinal products that contain the same as are useful to treat or prevent depression, obesity, panic attacks, anxiety, obsessive-compulsive disorders, cognitive disorders, phobias, impulsive disorders associated with drug abuse and suppression, dysfunctions Sex and Parkinson's disease

Description

NEW COMPOUNDS OF SPYRIMIMIDAZOLINE FIELD OF THE INVENTION The present invention relates to novel spiroimidazoline compounds and their use as 2-adrenergic antagonists and monoamine reuptake blockers.

DESCRIPTION OF THE PREVIOUS TECHNIQUE AND BACKGROUND OF THE INVENTION The adrenergic nervous system plays an important role at many levels, for example, at the arterial, venous, cardiac and renal levels, and at the level of the central and peripheral autonomic nervous systems. Compounds capable of interacting with adrenergic receptors in this manner induce a large number of physiological responses such as vasoconstriction, vasodilation, an increase or decrease in heart rate, variation in the contraction force of the heart muscle and variation in metabolic activities. Various adrenergic compounds have been used in the past to modify these and other physiological responses. Sepiroimidazoline compounds for use as al- or a2-adrenergic agonists or partial agonists are found in the prior art (EP 635 495, EP 635 496, EP 635 497). In addition to the fact that the compounds described in the present invention are novel, they have an a2-adrenergic antagonist and monoamine reuptake blocker profile, which makes them suitable for use in the treatment of depression (Drug News &Perspectives, 4 (4), 1991). The main problem posed by antidepressants is that they require a prolonged time to be effective, associated with their particular mode of action. Studies have shown that the association of an α2-adrenergic antagonist with a monoamine reuptake inhibitor (serotonin and / or noradrenaline) makes it possible to reduce the length of time (Commun. Psychopharmacol, 4, pp. 95-100, 1980) . The combination of these effects in a single compound can lead to a new generation of much more effective antidepressants. Among these compounds, napamezole (US 5 017 584) is described and has an α2-adrenergic antagonist activity as well as a monoamine reuptake blocking activity.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention, which have a novel structure, have a selective o 2 -adrenergic antagonist profile and at the same time have the ability to inhibit monoamine reuptake.

The present invention relates more especially to compounds of formula (I): wherein: A represents a benzene ring unsubstituted or substituted by 1 to 4 identical or different groups which are selected from linear or branched Cg alkyl, linear or branched Ci-Cg alkoxy, hydroxy, polyhaloalkyl of which alkyl portion is linear or branched, cyano, nitro, amino, alkylamino, dialkylamino, thioalkyl, sulfonylalkyl, sulfinylalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, formyl, carbamoyl, carboxamide, phenyl, benzyl and halogen atoms. B represents an imidazoline ring as represented in formulas (la) and (Ib): (the) (Ib) wherein R represents a hydrogen atom, an alkyl group of Ci-Cg linear or branched or a benzyl group, it is understood that "alkyl" means an alkyl group of Cx-Cg linear or branched, its tautomers, enantiomers and diastereoisomers, in addition to the salts thereof with a pharmaceutically acceptable acid or base. Among pharmaceutically acceptable acids, mention may be made, by way of nonlimiting example, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc.

Among pharmaceutically acceptable doses may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, terbutylamine, etc. Preferred compounds of the invention are those in which R represents a hydrogen atom. Advantageously, the invention relates to compounds of formula (I) wherein B represents a ring of formula (la). Preferably, the invention relates to compounds of formula (I) wherein A is unsubstituted. When the ring A is substituted by 1 to 4 identical or different groups, the preferred substituents are linear or branched Ci-Cg alkyl, or straight or branched C-C6 alkoxy, hydroxy, polyhaloalkyl of C-C6 in the which alkyl portion is linear or branched, and halogen atoms. Very advantageously, the invention relates to compounds of formula (I) having a trans-ring linkage. Even more especially, the invention relates to spiro [(1,3-diazacyclopent-1-ene) -5: 2'- (trans-1 ', 2', 3 ', 4', 4 'a, 9 ', 9'a, 10'-octahydroanthracene)] and, preferably, with the mixture composed of spiro [(1, 3-diaz ac i cl opent-1-ene) -5: 2' (S) - (t s -1 ', 2', 3 ', 4', 4 'a (R), 9', 9 'a (S), 10' -octahydroanthracene)] and its enantiomer, with the mixture composed of spiro [(1 , 3 -diazac i cl opent-l-ene) - 5: 2 '(S) - (t ra s -l', 2 ', 3', 4 ', 4' a (S), 9 ', 9' a (R), 10 * -octahydroanthracene)] and its enantiomer. Tautomers, enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention. The invention also relates to a process for the preparation of compounds of formula (I) characterized in that a compound of formula (II) is used as starting material: wherein A is as defined in the foregoing, which is condensed with 1,4-cyclohexanedione monoethylene acetal enolate in order to obtain a compound of formula (III): wherein A is as defined in the foregoing, which is subjected to the action of methyl (triphenyl) phosphonium iodide to provide a compound of formula (IV): wherein A is as defined in the foregoing, which is cyclized in the presence of tributyltin hydride and AIBN to provide a compound of formula (V): wherein A is as defined in the foregoing, which is subjected, in succession, to the action of an acid medium followed by Strecker reaction to obtain a compound of formula (VI): wherein a is defined in the foregoing, which is subjected to the action of the reducing agent, such as LiAlH4 for example, to provide a compound of formula (VII): wherein A is as defined above, which is reacted with formaldehyde acetate and to obtain a compound of formula (I / a), a particular case of the compounds of formula (I): wherein A is as defined in the above and B 'represents an unsubstituted imidazoline ring as represented in the formulas (Ia / a) and (Ib / a): (ia / a) (Ib / a) which can be subjected, in the presence of a base, to the action of a compound of formula (VIII): R '-J (VIII) wherein R 'represents a linear or branched alkyl group or a benzyl group and J represents a leaving group, such as a halogen atom or a tosyl group, to provide a compound of formula (I / b), a particular case of the compounds of formula (I): wherein A is as defined in the above and B "represents a substituted imidazoline ring represented in the formulas (Ia / b) and (Ib / b): (Ia / b) (Ib / b) wherein R 'is as defined above, compounds of formula (I / a) and (I / b) which constitute the totality of the compounds of formula (I) and can be purified according to a separation technique and are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and separated, where appropriate, into their isomers according to a conventional separation technique. The compounds of the invention and the pharmaceutical compositions containing them have proven to be useful in the treatment of depression. In fact, the compounds of the present invention are specific a2-adrenergic antagonists and are also powerful inhibitors of serotonin and / or norepinephrine reuptake. As such, they can be used therapeutically in the treatment of depression, obesity, panic attack, anxiety, oppressive-compulsive disorders, cognitive disorders, phobias, impulsive disorders associated with drug abuse and suspension, sexual dysfunctions and disease. of Parkinson. The present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral, nasal, percutaneous or transcutaneous, rectal, perlingual, ocular or respiratory administration, and especially tablets or lozenges, sublingual tablets, sachets, packets, capsules can be especially mentioned. of gelatin, dragees with enteric layer, pieces, suppositories, creams, ointments, dermal gelee and ingestible or injectable ampoules. The dosage varies with the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatment, and varies from 1 to 1000 mg per 24 hours in 1 or more administrations. The following examples illustrate the invention, but do not limit it in any way.

EXAMPLE 1: Spiro Fumarate [(1,3-diazacyclopent-l-ene) -5: 2'IS -ffcrans-l ', 2', 3 ', 4', 4 'a (R), 9 •, 9 'a (S), 10' - octahydroanthracene)] and Spiro Fumarate [(1,3-diazacyclopent-1-ene) -5: 2 '(S) - (trans-1', 2 ', 3', 4 ', 4 • a (R), 9', 9 'a (S), 10 • - octahydroanthracene)] Stage 1: 7- (2- (bromobenzyl) -1,4-di-oxaepiro [4.5] decan-8 -one A solution of 1,4-cyclohexadione monoethylene acetal (20 g, 28 mmol) in THF (360 ml) is added dropwise to a solution, cooled to -78 ° C of lithium diisopropylamide IN in THF (150 mmoles, 150 ml), and then allow the mixture to return to room temperature. After stirring for 1 hour, the mixture is cooled to -78 ° C and 35.2 g (141 mmoles) of 2-bromobenzyl bromide are added dropwise. After stirring for 30 minutes at -78 ° C, the temperature of the mixture returns to 0 ° C. The mixture is stirred for 3 hours at 0 ° C and then hydrolyzed and extracted with ether. The organic phase is washed with a saturated solution of NaCl, dried over MgSO 4 and concentrated in vacuo. The title compound is purified by flash chromatography on a column. Melting point: 123 ° C Stage 2: 7 - (2 - b r o m or b e n c i l) - 8 - m e t i 1 e n - 1, 4 - dioxaspiro [4. 5] Dean A solution of sodium ter-pentoxide (70 ml of an IM solution), prepared for immediate use, is added to a suspension of methyl (triphenyl) phosphonium iodide (25 g, 61.8 mmol) and 50 ml of toluene, and the The mixture is stirred at room temperature under nitrogen for 20 minutes. The compound obtained in step 1 (6.70 g, 20.6 mmol) is dissolved in 50 ml of toluene which is added dropwise and the reaction mixture is refluxed for 3 hours. After cooling, the reaction mixture is hydrolyzed with a saturated solution of NH 4 Cl and extracted with ether. The organic phase is washed with a saturated solution of NaCl, H20, dried over MgSO4 and concentrated in vacuo. The title product is purified by flash chromatography on a column (SiO2, toluene / cyclohexane: 60/40). Melting point: 68 ° C Step 3: 2 - dioxolan-trans -1,2,3,4,4a, 9, 9a, 10 - octahydroanthracene A solution containing the compound obtained in step 2 (5 g, 15.5 mmol), 510 mg (0.02 mmol) of AIBN and 6. 75 g of Bu3SnH (23.2 mmoles) in 750 ml of toluene is refluxed for 5 hours under nitrogen. The solvent is removed by evaporation under reduced pressure and the resulting residue is stirred vigorously for 3 hours with a mixture of ether (120 ml) and a saturated solution of potassium fluoride (120 ml).

After filtration, extraction with ether, dried over MgSO4 and concentration under reduced pressure, the title product is purified by flash chromatography on a column (SiO2, cyclohexane / ether: 80/20). Melting point: 71 ° C Step 4: Trans -1, 2, 3, 4, 4a, 9, 9a, 10 -octahydro-2-anthracenone A solution of 6 g (24.6 mmoles) of acetal obtained in step 3 in 100 ml of acetone and 25 ml of water and 1.85 g (7.4 mmol) of pyridinium tosylate is refluxed for 4 hours. The excess solvent is removed by evaporation in vacuo and then 500 ml of ether are added and the reaction mixture is washed with a saturated solution of Na 2 CO 3 and a saturated solution of NaCl. The organic phase is dried over MgSO 4 and the solvent is removed by evaporation under reduced pressure. The title compound is obtained after purification by flash chromatography on a column (SiO2, cyclohexane / ethyl acetate: 80/20). Melting point: 99 ° C Step 5: 2 -amino -trans -1, 2, 3, 4, 4a, 9, 9a, 10-octahydro-2-an tra cen carboni tri 1 or 410 mg of KCN (6.3 mmol) and 340 mg of NH4C1 (6.3 mmol) are successively added to a vigorously stirred solution which is kept under nitrogen containing 1.25 g (6.2 mmol) of the compound obtained in step 4 in 30 g. ml of MeOH and 15 ml of water. After stirring for 12 hours at 20 ° C, the solution is diluted with CH2C12 and extracted with CH2C12. The organic phase is washed with a saturated solution of NaCl, dried over MgSO 4 and evaporated. The residue is treated with 25 ml of a methanolic solution of ammonia (7N) and stirred in a closed system for 12 hours at 20 ° C. Evaporation under reduced pressure gives the title compound in pure form. Melting point: 128 ° C Elemental microanalysis: C% H% N% Theoretical: 79. .61 8.02 12, .38 Found: 79. .88 8.18 12. .60 Step 6: 2 -aminome thi-trans-1, 2, 3, 4, 4 a, 9, 9 a, 1 0 - octahydro-2-anthracenamine A solution of 1.39 g (6.1 mmol) of nitrile obtained in step 5 in 35 ml of THF is added dropwise to a suspension of LiAlH4 (350 mg, 9.2 mmol) in 35 ml of anhydrous THF at -20 ° C under nitrogen . The mixture is stirred for 1 hour before being hydrolyzed with 2.3 ml of H20, 4.6 ml of a 35% sodium hydroxide solution and 4.9 ml of water. The resulting suspension is stirred and the filtrate is evaporated to provide an oil which is subjected to flash chromatography on a column; the title compound is isolated in the form of a mixture of two diastereoisomers which are separable by CLAP (Kromasil 100, 10 C18-210 mm-CH3CN / H20 / CF3C00H = 170/830/5). ((2S) -2-aminomethyl-trans-1, 2, 3, 4,4a (R), 9, 9a (S), 10-octahydro-2-anthracenamine and (2R) -2-aminomethyl-trans-1 , 2, 3,4, 4a (S), 9,9a (J?), 10-octahydro-2-anthracenamine) Melting point: 123 ° C ((2S) -2-aminomethyl-trans-1, 2, 3, 4, 4a (S), 9, 9a (-), 10-octahydro-2-anthracenamine and (2R) -2-aminomethyl-trans-1 , 2, 3, 4,4a (R), 9, 9a (S), l0-octahydro-2-anthracenamine) Melting point: 183 ° C Step 7: Spiro fumarate [(1,3-diazacyclopent-l-ene) -5: 2 '(S) -trans -1', 2 •, 3 ', 4', 4 'to (R), 9' , 9 'to (S), 10' - octahydroanthracene)] and Spiro Fumarate [(1,3-diazacyclopent-l-ene) -5: 2 '(R) - (trans -1', 2 •, 3 ', 4', 4 'to (S), 9', 9 'to (R), 10' - octahydroanthracene)] A mixture of 495 mg (2.2 mmol) of. { . { 2S) -2-aminomethyl-trans-1, 2,3,4,4a (S), 9,9a (J?), 10-oc ahydro-2-anthracenaminay (2R) -2-aminomethyl-trans-1, 2, 3.4, 4a (S), 9, 9a (J?), 10-octahydro-2-antracenamine obtained in step 6 and 258 mg (2.5 mmol) of formamidine acetate in 10 ml of EtOH is stirred at 20 ° C under nitrogen for 12 hours. The solvent is removed by evaporation and the residue is taken up in IN HCl. The acid phase is washed with ether, made basic with 35% NaOH and then extracted with CH2C12. The organic phase is washed with a saturated solution of NaCl, dried over MgSO 4 and evaporated. The residue is dissolved in 10 ml of EtOH and treated with a solution of fumaric acid (225 mg, 1.9 mmol) in 10 ml of EtOH. Evaporation and recrystallization from EtOH gives the title compound as a white powder. Melting point: 233-237 ° C EXAMPLE 2: Spiro fumarate [(1,3-diazacyclopent-l-ene) -5: 2 '(S) -trans-1' ^ '^' ^ '^' aíSJ ^ '^' aíRj ^ O'- octahidroantraceno )] and Spiro Fumarate [(1,3-diazacyclopent-l-ene) -5: 2- (R) - (trans-1 ', 2', 3 ', 4', 4 'to (R), 9', 9 'to (S), 10' - octahydroanthracene)] The procedure is the same as that used for step 7 of Example 1, starting from (25) -2-aminomethyl-trans-1, 2, 3, 4, 4a (5), 9, 9a (R), -octahydro-2-anthracenamine and its enantiomers. Melting point: 215 ° C Pharmacological studies: EXAMPLE A: Determination of affinity for a2-adrenergic receptors in the rat The affinity is determined by competition experiments with [3H] -RX 821,002. The membranes are prepared from rat cerebral cortex and incubated in triplicate with 0.4 nM [3 H] -RX 821.002 and the product to be tested in a final volume of 1.0 ml, for 60 minutes at 22 ° C. The incubation buffer contains 50 nM TRIS-HC1 (pH 7.5), 1 mM EDTA and 100 μM GppNHp. The non-specific binding is determined using 10 μM pentolamin.

Data analysis At the end of the incubation, the incubation medium is filtered through WHATMAN GF / B filters impregnated with 0.1% polyethylenimine and washed three times with 5 ml of cooled buffer. The preferred radioactivity in the filters is determined by liquid scintillation counting. The binding isotherms are analyzed by non-linear regression.

Result The compounds of the invention show a specific a2-adrenergic receptor antagonistic activity with the compound of Example 1, for example, which has a pKi of 8.0.

EXAMPLE B: Determination of affinity for norepinephrine reuptake sites in the rat Affinity was determined by competition experiments with [3H] -nisoxetine. The membranes are prepared from the frontal cortex of the rat and incubated in triplicate with 2 nM [3H] -nisoxetine and the product to be tested in a final volume of 0.05 ml, for 4 hours at 4 ° C. The incubation buffer contains TRIS-HC150 mM (pH 7.4), 120 mM NaCl and 5 mM KCl. The non-specific binding is determined using 10 μM desiperamine.

Data analysis At the end of the incubation, the incubation medium is filtered through WHATMAN GF / B filters impregnated with 0.1% polyethylenimine and washed three times with 5 ml of cooled buffer. The radioactivity retained in the filters is determined by liquid scintillation counting. The isotherms of union are analyzed by non-linear regression.

Results The compounds of the present invention show very good affinity for the noradrenaline reuptake sites. By way of example, the pKi of the compound of Example 1 is 6.7.

EXAMPLE C: Determination of affinity for serotonin reuptake sites in the rat The affinity was determined by competition experiments with [3H] -paroxetine. The membranes are prepared from the frontal cortex of the rat and incubated in triplicate with 0.25 nM [3 H] -paroxetine and the cold ligand in a final volume of 0.4 ml, for 2 hours at 25 ° C. The incubation buffer contains 50 M TRIS-HC1 (pH 7.4), 120 mM NaCl and 5 mM KCl. The non-specific binding is determined using 10 μM citalopran.

Data analysis At the end of the incubation, the incubation medium is filtered through WHATMAN GF / B filters impregnated with 0.1% polyethylenimine, and washed three times with 5 ml of cooled buffer. The radioactivity retained in the filters is determined by liquid scintillation counting. The binding isotherms are analyzed by non-linear regression.

Result The compounds of the present invention exhibit a very good affinity for the eitonin reuptake sites. By way of example, the pKi of the compote of Example 1 ee of 7.8.

EXAMPLE D: Pharmaceutical composition: Tablets 1000 tablets are prepared, each containing 5 mg Compound of Example 1 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

Claims (11)

1. A compoteto of formula (I¡ wherein: A represents a benzene ring unsubstituted or substituted by 1 to 4 identical or different groups selected from linear or branched Ci-Cg alkyl, linear or branched CL-Cg alkoxy, hydroxy, polyhaloalkyl of C-- C6 in which the linear or branched alkyl portion, cyano, nitro, amino, alkylamino, dialkylamino, thioalkyl, sulfonylalkyl, sulfinylalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, formyl, carbamoyl, carboxamide, phenyl, benzyl and halogen atoms. B represents an imidazoline ring as represented in formulas (la) and (Ib): (the) (Ib) wherein R represents hydrogen, straight or branched C.sub.Cg alkyl or benzyl, it is understood that "alkyl" means linear or branched alkyl, its tautomeric, enantiomeric and diastereomeric, in addition to the eelae thereof with an acid or base pharmaceutically acceptable.
2. 2. A compound of formula (I) as described in claim 1, wherein R represents hydrogen, eut tautomer, enantiomers and diastereoisomers, and addition salt thereof, with a pharmaceutically acceptable acid or base.
3. 3. A compound of formula (I) as recited in claim 1, wherein B represents a ring of formula (Ia), tautomers, enantiomer and diaeteroisomer, and addition thereof with a pharmaceutically acceptable acid or baee.
4. 4. A compound of formula (I) as recited in claim 1, wherein ring A is unsubstituted, tautomeric, enantiomeric and diaetereoyomeric, and addition thereof with a pharmaceutically acceptable acid or baee.
5. 5. A compound of formula (I) as recited in claim 1, wherein the ring A is substituted by 1 to 4 identical or different substituents which are selected from linear or branched Ci-Cg alkyl, hydroxy, linear alkoxy or branched, polyhaloalkyl of Cx-Cg in which the linear or branched alkyl portion ee, and halogen atom, tautomeric, enantiomeric, and diastereomeric, and additioner thereof, with a pharmaceutically acceptable acid or base.
6. 6. A compound of formula (I) as recited in claim 1, having a trans-ring linkage, eut tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
7. 7. A compound of formula (I) as described in claim 1, which is spiro [(1,3-diazacyclopent-1-ene) -5: 2 '- (trans-1', 2 ', 3', 4 ', 4' a, 9 ', 9' a, 10 '-octahydroanthracene), their tautomers, enantiomers and diaetereoieomers, and addition salts thereof with a pharmaceutically acceptable acid or baee.
8. 8. A compound of formula (I) as recited in claim 1, composed of the mixture of spiro [(1,3-diazacyclopent-1-ene) -5: 2"(5) - (trans-11, 2 ', 3 •, 4 ', 4' a, 9 ', 9' a, 10 '-octahydroanthracene), and spiro [(1,3-diazacyclopent-l-ene) -5: 2' - (R) - (trans) -1 ', 2', 3 ', 4', 4 'a (S), 9', 9 'a (R), 10' -octahydroanthracene), tautomeric, enantiomer and diastereomeric, and ealee of addition of the mole , with a pharmaceutically acceptable acid or baee.
9. 9. A compound of formula (I) as described in claim 1, composed of the mixture of spiro [(1,3-d i a z a c i c l op e n t-1-e n o) - 5: 2 '(5) -. { t ran s -1-, 2 ', 3', 4 ', 4'a (5), 9', 9 'a (R), 10"-octahydroanthracene), and eepiro [(1, 3-diazacyclopenthe- l-ene) -5: 2 '- (R) - (rans -l', 2 ', 3 •, 4', 4'a (RJ, 9 ', 9' to (5), 10 '-octahydroanthracene) ], tautomeric, enantiomers and diastereoisomers, and amino acid addition, with a pharmaceutically acceptable acid or bae.
10. 10. A method to treat a living body afflicted with depression, obesity, panic attack, anemia, obsexual-compulsive disorders, cognitive disorders, phobiae, deeordenee impuleivoe associated with the drug abuse and sleep of the legs, diefuncionee eexualee and Parkineon's disease , comprising the step of administering to the living body an amount of a compound of claims 9, which is effective for the relief of such a condition.
11. 11. A pharmaceutical composition useful to treat depreeion, obesity, panic attack, anemia, traumatic obese-compuleive, cognitive traetornoe, phobiae, impulsive disorders associated with drug abuse and euspeneion of laee, sexualee diefuncionee and Parkinson's disease, which comprises, as an active ingredient, an effective amount of a compound as described in claim 11, together with one or more pharmaceutically acceptable excipients or vehicles. SUMMARY OF THE INVENTION The invention relates to a formula compote (I! wherein: A represents an optionally substituted benzene ring, B represents an imidazoline ring, of formula (la) or (Ib): (la) (Ib) and medicinal products that contain the same that are useful to treat or prevent depression, obesity, panic attacks, anemia, disorder obeeeivoe-compuleivoe, traetornoe cognoecitivoe, phobias, trapporn associated with the drug and the euphereión of lae miemae, sexual diefuncionee and Parkinson's disease.