MXPA00007127A - Pharmaceutically active morpholinol - Google Patents

Abstract

Disclosed is the compound (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol and pharmaceutically acceptable salts and solvates thereof, pharmaceutical compositions comprising them;also disclosed is a method of treating depression, attention deficit hyperactivity disorder (ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, or addiction to cocaine or nicotine-containing (especially tobacco) products using such compound, salts, solvates or compositions.

Description

MORPHOLINOL PHARMACEUTICALLY ACTIVE FIELD OF THE INVENTION This invention relates to an optically pure morpholinol, salts and solvates thereof, to pharmaceutical formulations containing them and to processes for their preparation and use.

BACKGROUND OF THE INVENTION Bupropion hydrochloride, (+ _) -1- (3-chlorophenyl) -2- [(1,1-dimethylethyl) -amino] -1-propanone hydrochloride, is the active ingredient of Wellbutrin® which is sold in the States United for the treatment of depression. It is also the active ingredient in Zyban® which is sold in the United States as an adjuvant to stop smoking. Bupropion is a relatively weak inhibitor of the uptake or neuronal uptake of noradrenaline (NA), sero tonin and dopamine (DA), and does not inhibit monoamine oxidase. Although the mechanism of action of bupropion, as REF .: 121947 with other antidepressants, it is unknown, it is presumed that this action is mediated by strong ñoradr and / or dopaminergic mechanisms. The available evidence suggests that Wellbutrin® is a selective inhibitor of noradrenaline (NA) in predictable doses of antidepressant activity in animal models. See Ascher, J.A., et al., Bupropion: A Review of its Mechanism of An pre idepre s an t Activity. Journal of Clinical Psychiatry, 56: p. 395-401, 1995.

Bupropion HCl Bupropion is extensively metabolized in man as well as in laboratory animals. The urinary and plasma metabolites include bio trans formation products formed by hydroxylation of the tert-butyl group and / or reduction of the carbonyl group of bupropion.

Four basic metabolites have been identified. They are erythro- and threo-amino alcohols of bupropion, erythro-amino diol of bupropion, and metabolite of morpholinol. These metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion has not been fully characterized. Because the plasma concentrations of the metabolites are higher than those of bupropion, the same may be of clinical importance. The morpholinol metabolite of (+/-) - (2R *, 3R *) -2- (3-chlorofenyl) -3,5,5-trimethyl-2-morpholinol is thought to be formed from hydroxylac on of the tert-butyl group of bupropion.

Morpholinol Metabolite of Bupropion HCl in Biomed. Chromatogr. (1997), 11 (3), 174-179 (Suckow, R. F et al) describes the separation and quantification of the individual enantiomers of the racemic morpholinole metabolite (+/-) - (2RS, 3RS), as well as also the fact that the plasma samples contain the (-) -enantiomer to the extent of approximately 96% of the total of this metabolite. However, no information is given regarding the pharmacological characteristics of each enantiomer and the subsequent clinical relevance of these.

DESCRIPTION OF THE INVENTION Surprisingly it has been found that despite the (-) form of the metabolite of morpholinol which predominantly predominates in human plasma samples, it is the (+) enanti omero, (+) - (2S, 3S) -2- (3- chlorophenyl) -3,5,5-trimethyl-2-morpholinol in which the activity resides. Accordingly, the present invention provides, in one aspect, pharmaceutically acceptable salts and solvates of a compound of the formula (I), (+) - (2 S, 3 S) -2 - (3-chlorophenyl) -3,5, 5- trimethyl-2-morpholinol.

Such pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrobromic hydrochloric, sulfuric, nitric, phosphorus, co, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, maleic, formic, malonic, succinic, isethionic, lactobionic, naphonic alen-2-s, sulphamic, etansul phonyl, and benzene phonyl. Especially preferred is the hydrochloride salt of a compound of the formula (I). Another aspect of the invention is the pharmaceutical composition comprising a compound of the formula (I) or pharmaceutically acceptable salts and solvents thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. A further aspect of the present invention is the use of a compound of the formula (I) or pharmaceutically acceptable salt and solvates thereof in therapy. Yet another aspect of the invention provides methods of treating depression, hyperactivity disorder by inattention (ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, or addiction. to cocaine or products containing nicotine (especially tobacco) in a human or animal subject comprising administering to the subject an effective amount of a compound of the formula (I) or pharmaceutically acceptable salts and solvates thereof or pharmaceutical compositions of the same. Still another aspect of the present invention is the use of the compound of the formula (I) or pharmaceutically acceptable salts and solvates thereof or pharmaceutical compositions thereof in the preparation of a medicament for the treatment of depression, hyperactivity disorder by lack of attention (for its acronym in English, ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, cocaine addiction or products containing nicotine (especially tobacco).

DESCRIPTION OF THE DRAWINGS Figure 1. Effect of Compounds at 25 mg / Kg (ip) in Depression Induced by TBZ Figure 2. Response of the Dose of the Compound of Formula I Against Depression Induced by TBZ (Compounds administered 30 minutes prior to Mice CD-1, Male, TBZ, i.p-, n = 6) Figure 3. Response of the dose of Compound of Formula II Against Depression Induced by TBZ (Compounds administered 30 minutes prior to TBZ, Mice CD-1, Males, i.p., n = 6).

DETAILED DESCRIPTION OF THE INVENTION The compound of the formula (I) or pharmaceutically acceptable salts and solvates thereof can be prepared by first synthesizing the racemate of the morpholinol metabolite of bupropion and subsequently separating the (+) and (-) enantiomers of the racemate via HPLC. The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/-) - (2R *, 3R *) - 2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol hydrochloride) can be synthesized by the following process. To 3 '-cl oropr opi ofenone (10. Og, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2 h at room temperature and poured into a mixture of ice and water (500 ml). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3'-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300Mhz, CDCl 3); d 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, "3 H) To a solution of 2 -bromo-3'-chloropropiophenone (19.3 g, 0.08 mol) in MeOH (100 ml) was added dropwise a solution of 2-amino-2-methyl t-1-propanol (27.8 g, 0.31 mol) in methanol ( 200 ml) at room temperature The mixture was stirred for 18 hours and concentrated in vacuo The residue was partitioned between water and diethyl ether The combined organic phase was extracted with 10% aqueous hydrogen chloride Aqueous acid extracts The combined extracts were cooled in an ice bath and made basic with 40% aqueous sodium hydroxide.The mixture was extracted with diethyl ether, the combined diethyl ether extracts were washed with water and saturated sodium chloride solution, dried (K2C03) and concentrated in vacuo to give 15.0 g (75%) of (+/-) - (2R *, 3R *) -2- (3-chloro-enyl) -3,5,5-t-rimethyl-2-morpholinol as a whitish solid. The (+/-) - (2R *, 3R *) - 2- (3-chlorophenyl) -3, 5, 5-t rime ti 1 -2 -mor fol ino 1 can be converted to hydrochloride (+/- ) - (2R *, 3R *) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-orpholinol by the following process. A 6.0 g sample was dissolved in diethyl ether, cooled in an ice bath and ethereal hydrogen chloride was added until the mixture was acidic. The resulting solid was filtered and recrystallized from ethanol / ether mixtures with ethereal hydrogen chloride to give 4.93 g of (+/-) - (2R *, 3R *) -2- hydrochloride ( 3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol as a white solid: mp 202-203 ° C. NMR (80Mhz, DMSO-de); d 10.9 (br, 1H), 8.85 (br, 1H), 7.60-7.41 (m, 5H), 4.04 (d, 1H), 3.50 (d, 1H), 3.37 (br, s, 1H), 1.58 (s) , 3H), 1.34 (s, 3H), 1.03 (d, 3H). Analysis Calculated for C? 3H? 9C? 2N? 2: C, 53.43; H, '6.55; N, 4.79. Found: C, 53.5; H, 6.58; N, 4.75. The hydrochloride of (+ / -) - (2R *, 3R *) -2 - (3-chlorophenyl) -3,5,5-t rime ti 1 -2 -morpholinol can be converted back to its free base by the next process. A sample of 3.0 g of (+ / -) - hydrochloride. { 2R *, 3R *) -2- (3-chlorofenyl) -3,5,5-t-rimethyl-2-morphol was dissolved in water (100 ml) and diethyl ether (200 ml) was added. The mixture was cooled in an ice bath and the pH adjusted to > 10 with 1.0N aqueous sodium hydroxide. After stirring for 30 minutes, the phases were separated and the aqueous phase was extracted with diethyl ether. The combined diethyl ether extracts were dried (Na2SO4) and concentrated in vacuo to give 2.6 g of (+/-) - (2R *, 3 R *) -2- (3-chlorofenyl) - 3, 5, 5-t r ime t i 1 -2-mor fol inol as a white solid. This was used without further purification for the chiral chromatography described below. The (+) and (-) enantiomers of (+/-) - (2R *, 3R *) - 2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol can be separated by the following process . The (+/-) - (2R *, 3R *) -2 - (3-chloro-phenyl-1) -3,5,5-trimethyl-2-morpholinol (2.54 gms) was dissolved in 250 ml of 2: 8 Isopropyl alcohol: Hexane (both at HPLC grade). An OD Daicel Chiralcel column (2 x 25 cm) was equilibrated for one hour at 8 ml / min., In the elution solvent, 1: 9: 0.2 Isopropanol: Hexane: Diethylamine. The solution of (+/-) - (2R *, 3R *) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol was injected into 1 ml of aliquots by a Waters Prep LC pump 2000 automated, using a Waters 510 EF pump for injections. Each tour was 15 minutes in length, using the conditions listed above. The separated optical isomers were collected by the fraction collector (Waters) at a baseline threshold of 2% above or above, based on 2 units of full-scale absorbance at 240 nm (Waters 490E UV detector). Each optical isomeric solution was evaporated in a rotary evaporator at 40 degrees Centigrade and vacuum aspirator. After drying for 6 hours under high vacuum at room temperature, optical isomer 1 weighed 1.25 gm and optical isomer 2 weighed 1.26 g. The enantiomeric purity of each isomer can be tested by analytical chiral HPLC on Waters 860 HPLC with detector of the Array of 996 Photodiodes, using a Daicel Chiralcel OD-H column (4.6 x 250 m) eluted with 1: 9: 0.2 Alcohol Isopropyl: Hexane: Diethylamine at 1 ml / min. Optical isomer 1 was 100% pure (R.T. 6.117 min.). Optical isomer 2 was 99.19% pure (R.T. 6,800 min.), Which contains 0.81% of optical isomer 1 (R.T. 6.133 min.). The hydrochloride salts of the separated enantiomers were obtained by the following processes. 1.25 g (0.005 mol) of optical isomer 1 (retention time 6,117 min.) ((-) - (2R, 3R) -2- (3-chlorophenyl) -3,5, 5-1 r ime t il -2 -morpholinol) was dissolved in diethyl ether. The solution was filtered and the filtrate was cooled in an ice bath by adding ethereal hydrogen chloride until the solution was acidic. After remaining at room temperature for 24 h, the resulting solid was filtered, washed with diethyl ether and dried in a vacuum oven at 60 ° C for 18 h to give 1.32 g (90%) of (-) hydrochloride - (2R, 3R) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol as a white solid: mp 208-209 ° C. NMR (300Mhz, DMSO-de); d 9.72 (br, 1H), 8.76 (br, 1H), 7.54-7.41 (m, 5H), 3.98 (d, 1H), 3.52 (d, 1H), 3.37 (br s, 1H), 1.53 (s, 3H), 1.29 (s, 3H), 0.97 (d, 3H). Analysis Calculated for C 13 H 19 Cl 2 NO 2: C, 53.43; H, 6.55; N, 4.79. 20 ° C Found: C, 53.35; H, 6.57; N, 4.71. [] D -33.2 ° (0.67, 95% EtOH) 1.26 g (0.005 mol) of optical isomer 2 was dissolved (retention time 6,800 min) (+) - (2S, 3S) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol) in diethyl ether. The solution was filtered and the filtrate was cooled in an ice bath by adding ethereal hydrogen chloride until the solution was acidic. After keeping at room temperature for 24 h, the resulting solid was filtered, washed with diethyl ether and dried in a vacuum oven at 60 ° C for 18 h to give 1.36 g (93%) of hydrochloride (+) - (2S, 3S) -2- (3-chlorophenyl) -3,5,5,5-trimethyl-2-morpholinol as a white solid: m.p. 208-209 ° C. NMR (300Mhz, DMSO-de); d 9.87 (br, 1H), 8.76 (br, 1H), 7.54-7.41 (m, 5H), 3.99 (d, 1H), 3.51 (d, 1H) > 3.37 (br s, 1H), 1.54 (s, 3H), 1.30 (s, 3H), 0.98 (d, 3H). Analysis Calculated for C 13 H 19 Cl 2 NO 2: C, 53.43; H, 6.55; N, 4.79. Found: C, 53.51; H, 6.58; N, 4.73. [a] 2 ° ° = + 31.9 ° (0.64, 95% EtOH) D The absolute configuration of (+) - (2S, 3S) -2- (3-chlorophenyl) -3, 5, 5 -trimeti 1-2 -morpholinol was determined by the following x-ray crystallographic method. Crystal Data: Ci3Hi8Cl2N02, M = 291, Orthohombic, space group P2 2? 21, a = 8.7348 (6), b = 14.9824 (10), c = 23.1605 (15) A, V = 3031 (4) Á 3, Z = d, Dc = 1.276 Mgm "3, F (000) = 1226.95 From the 12224 reflections measured, 3764 was unique and 2318 which had I> 3.0s (I) were used in subsequent calculations.Data was collected in a Siemens SMART difmetrometer using omega scanning and monochrome MoKa radiation (? = 0.71073 Á) The positions of all the atoms without hydrogen were determined by the direct methods and were re-stained anispicalmente.The hydrogen positions were all located in different syntheses and are included in subsequent refinement cycles using an equitation model and a idealized link length of 0.96 A. The absolute configuration was determined by the refinement of the Roger parameter and was confirmed by an analysis of the Bijvoet intensity differences of 185 better than a 0.006 probability that the model was in error. refinement of squares or mo delo, minor, minimizes Sw (? F) with weights based on counting statistics The final agreement factors were Rf = 0.064 (0.108 for all data), Rw = 0.068 (0.081 for all data), and GoF = 1.93. References include E.J. Gabe, Y. Le Page, J.-P. Charland, F.L. Lee and P.S. White, Journal of Applied Crys t al 1 ogr aphy, 22, 384-387 (1989) and D. Rogers, Acta Crystallographica, A37, 734-741, 1981. The amount of the compound of the formula (I) requires to achieve the effect The desired therapeutic, of course, will depend on a number of factors, for example, the mode of administration, the recipient and the condition being treated. In general, the daily dose will be in the range of 0.02 to 5.0 mg / kg. The most particular ranges include 0.02 to 2.5 mg / kg, 0.02 to 1.0 mg / kg, 0.02 to 0.25 mg / kg, 0.02 to 0.15 mg / kg and 0.02 to 0.07 mg / kg. The compound of the formula (I) can be used in the treatment of depression, hyperactivity disorder due to lack of attention (for its acronym in English, ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease , addiction to cocaine or products containing nicotine (especially tobacco) as the compound p er se, but preferably it is presented with one or more pharmaceutically acceptable carriers, diluents or excipients in the form of a pharmaceutical formulation. The carriers, diluents and excipients should, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and should not be detrimental to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the agent as a single dose formulation, for example, a tablet. The formulations include those suitable for oral administration, rectal, topical, buccal (for example, sublingual) and parenteral (for example, subcutaneous, intramuscular, intradermal or intravenous). Formulations suitable for buccal (sublingual) administration include tablets comprising a compound of formula (I) in a flavored base, usually sucrose and acacia or tragacanth, and lozenges comprising the agent in an inert base such as gelatin and glycerin or sucrose and acacia. Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the formula (I), preferably isotonic with the blood of the proposed receptor. These preparations are preferably administered intravenously, although administration can also be performed by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can be conveniently prepared by mixing the agent with water and rendering the resulting solution sterile and isotonic with the blood. Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by mixing a compound of the formula (I) with one or more conventional solid carriers, for example, cocoa butter, and then the resulting mixture is formed. Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, transdermal patch, spray, or oil. Carriers which may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. It should be understood that in addition to the above-mentioned particularly mentioned ingredients, the formulations may include other agents conventional in the art that are of interest to the type of formulation in question. The biological activity of the compound of the formula (I) was demonstrated by in vitro absorption models and the depression model of the behavior induced by the trabene zine. The racemic morpholinole metabolite, (+/-) - (2R *, 3R *) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol, is referred to herein as "Racemate". The shape . { -) of the metabolite of morpholinol is (-) - (2R, 3R) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol or pharmaceutically acceptable salts and solvates thereof and is referred to herein as a compound of the formula (II): Synaptosomal Absorption Experiments In vi t ro. In vitro absorption was determined, as previously reported, using the synaptosomes prepared from the rat caudoputamen (for dopamine uptake) and hypothalamus (for the uptake of NA and serotonin) using [3H] -dopamine, [3H] -NA and [3H] - s ero tina as transport substrates, respectively. See Eckhardt, S.B., R.A. Maxwell, and R.M. Ferris, A S tructure -Acti vi ty Study of the Transport Sites for • the Hypothalamic and Striatal Ca t echolamine Uptake Systems. Similarities and differences. Mol e cu r a Ph a rma co l o g y, 21: p. 374-9, 1982. Synaptosomes for use in obtaining in vitro absorption data, were prepared from the hypothalamus or striatum by gently homogenizing the tissue in a sucrose buffer 0.3M / 25 M Tris, pH 7.4, which contain iproniazido phosphate to inhibit monoamine oxidase. The homogeneous product was centrifuged at 1100 x g at 4 ° C for 10 min and the supernatant was used for absorption studies. The supernatant (~ 1 mg of protein in the tissue) was incubated with concentrations of Km of [H] -noradrenaline, [H] -dopamine [3 H] serotonin at 37 ° C for 5 minutes in Modified Krebs-Henseleit buffer (118 mM NaCl, 5 mM KCl, 25 mM NaHCO3, 1.2 mM NaH2P04, 1.2 M MgSO4, 11 mM Dextrose, 2.5 mM CaCl2) in the absence and presence of drug. Under these conditions the absorption was linear with respect to both the substrate and the tissue (with <5% total of the transported substrate). Nonspecific absorption was defined as absorption at 0 ° C. [3 H] -subs tr a t o, which has been transported in synaptosomes, was separated from [3 H] -substrate free by filtration on GF / B filters and washed with cold Krebs-Henseleit buffer. The filters were counted from tritium in a liquid scintillation spectrometer. The data for synaptosomal absorption in vitro are presented in Table 1. Among the 2 enantiomers of the morpholinol metabolite of bupropion, the (+) enantiomer, the compound of the formula (I), inhibits the absorption of adrenal gland (NA ) with an IC50 of 2.2 μM. In contrast, the (-) enantiomer was not effective at a concentration of 30 μM. In the absorption of dopamine (DA), the compound of the formula (I) had an IC 50 of -10 μM while the enantiomer (-) was inactive at 30 μM. No compound inhibits the absorption of serotonin at 30 mM. For comparison, Wellbutrin® was equipped to inhibit DA and ñoradrenal ina uptake with IC 50 values of 1.9 and 2.2 μM, and not to inhibit serotonin uptake at 30 μM. The absorption of NA inhibited imipramine (a non-specific antidepressant) and the absorption of serotonin with IC50 values of 0.072 and 0.24 m of 0.072 and 0.24 μM, respectively. The compound of formula (I) was about twice as potent as Wellbutpn (R) as an NA inhibitor but, different from the latter, was approximately 10 times less potent as an inhibitor of dopamine uptake. These data are consistent with the observed nonradrenal actions of Wellbu rin (R) and the metabolite of racemic morpholinol of bupropion. The hydrochloride of (+/-) - (2R *, 3R *) - 2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol, (306U73) in vivo, in its doses of anti-TBZ respective (Cooper, BR, et al, Ne uropsych oph a rma col ogy, 11: p. 133-41,1994). The behavioral and the biological data suggest that the effects of Wellbutrin ("R" ") are mediated by a noradrenergic mechanism (ibid) Behavior Depression Experiments Tetrabenzine-Induced: Behavioral-induced behavioral depression (TBZ) was used as an in vivo measure of antidepressant activity. The test has been validated with a wide range of antidepressants, known to act through noradrenergic mechanisms (Cooper BR et al, "Animal models used in the prediction of antidepressant efects in man." J. Clin. Psychiatry 44: 63-66 , 1983). In addition, the test was also used to identify Wellbutrin (R) as an anti-depressant. Briefly, the animals were injected with the chosen agent (p.o. or i.p) 30 minutes before they received an i.p. of tetrabenazine (35 mg / kg, as the HCl salt - prepared fresh for each use). Valuations were made 30 minutes after this were included: locomotor activity (scale 1-4); ptosis (scale 1-4) and body temperature as previously described (Cooper, BR, JL Howard, and FE Soroko, Animal models used in prediction of antidepressant effects in man (Journal of Clinical Psychiatry, 44: p. -6, 1983) In all the studies, the scientist who performed the evaluations was imprecise in the treatments All the parameters were also loaded to give a "grouped" result (X) through the following algorithm: X (1 + result of ptosis) / (activity result * [Temp treated / Temp, control] The results of the aatpartara.QTtD depression model induced by tetrabenazine are as follows: Titrated in vivo at 25 mg / kg (ip) the compound of formula (I), the racemate, Wellbutrin (R) and, for comparison, amitriptyline abolished all the depression of catpcrtam.Qtto induced by tetrabenazine. In contrast, the (-) enantiomer showed only the baia activity (Figure 1). In the TBZ model of depression of the carbohydrate the activity was in the compound of formula (I). When analyzed in a dose effect study with TBZ, the activity showed an acute increase in activity between 3 mg / kg and 6 mg / kg (ip) (Figure 2). The compound of formula II, in comparison, does not have any activity related to the dose and, at 50 mg / kg, it seems to worsen the condition of the animals (Figure 3). In Figures 2 and 3, AMIT (5) refers to amitriptyline dosed at 5 mg / kg and SHAM refers to a control group of animals that have not received full medication. Since the TBZ test has predicted the performance of the anti-depressants through noradrenergic mechanisms and the compound of formula (I) is an inhibitor of the absorption of noradrenaline and Wellbutrin (R is metabolized to its morpholinol in vivo, the data suggest that the antidepressant activity of Wellbutrin (R 'is similar to the result of the effects of the compound of formula (I) (Welch, RM, A., Lai, and DH Schroeder, Pharmacological significance of the species, diffrences in bupropion metabolism, Xenobio ti ca, 17: p.287-98, 1987.) By extension, other activities of Wellbutrin! R) may be attributed to the compound of formula (I) .In particular, a noradrenergic mechanism is common for the agents used to treat ADHD (for example methylphenidate and amphetamine) .While the molecular mechanism for the effects of Willbutrin on the smoking suspension is less well understood, a catheclaminergic pathway is considered to participate in the props. Effects of behavioral nicotine reinforcement. The Wellbutrin < R) (and, by extension, the compound of formula (I)), to increase the NA release in the synapse of the brain, can mimic some of the actions of nicotine and thereby diminish the signs associated with the separation of the nicotine. Additionally, amphetamines have been used to treat obesity. The addictive properties of amphetamine also prevent its use for more obese patients. Willbutrin (R) causes weight loss and, similar to amphetamine, acts through a noradrenergic mechanism (Zarrindast, MR and T. Hsseini-Nia, Anorectic and behavioral effects of bupropion.) General Pha rma col ogy, 19 : pp. 201-4, 1988 and Harto-Truax, N., et al., Effects of Bupropion on Body Weight, Journal of Clinical Psychiatry, 44: 183-6, 1983). In addition, similarly to amphetamine, the Willbutrin! R > It is not addictive. (Lamb, RJ and RR Griffiths, Self-administration in Baboons and the Discriminative Stimulus Effects in Rats of Bupropion, Nomifensine, Diclofensine and Imipramine, Phsychopha rma col ogy, 102: pp. 183-90 1990; Bergman, J., efc al , Effects of Cocaine and Related Drugs in Nonhuman Primates, III, Self-administration by Squirrel Monkeys, Journal of Pharmacolgy &Experimen tal Therapeutice, 25: P. 150-5, 1989 and Johanson, CE .; and JE Barrett , The Discriminative Stimulus Effects of Cocaine in Pigeons, Journal of Phramacolgy, Experimen tal Therapeutics, 267: p.1-8, 1993). By extension, the compound of formula (I) may be expected to be effective in obesity and cocaine addiction. The treatment of addiction to cocaine-containing products include both partial and complete relief from addiction. Therefore, with respect to tobacco products, as well as the suspension of activity, for example smoking, will also include the reduction of the level or frequency of such activity, for example the reduction of the number of cigarettes smoked in a given period. With respect to other products containing nicotine, the treatment will also involve both the suspension of, and a reduction in the level of, the use of such products.

Safety and Toxicity. Studies that vary the additional doses were performed to determine the safe dose range for the isomers and racemates. The animals were observed for the presence of serious adverse events (for example, aplopetic attack and deaths) following the administration of the compounds of formula I, formula II or the racemate by the oral and intraperitoneal routes (ip). The data are presented in Table II. Administered orally, at 100 mg / kg po, the aplopetic attacks were observed with the compound of formula II and the racemate but not with the compound of formula I. The aplopetic attacks were observed in all the animals with all 3 compounds when they were dosed at 300 mg / kg. Additionally, the oral dose of 300 mg / kg resulted in 100 and 80% lethal for the compound of formula II and although the racemate did not kill were observed with the compound of formula I. Administered ip, all compounds produce aplopegic attacks at 100 mg / kg. No death was observed with the compound of formula I while the compound of formula II and the racemate resulted in a lethality of 100% and 20% respectively. At the oral dose of 300 mg / kg all lethality was observed for all compounds.

Table 1 Effects on absorption Vi Vi tro Absorption of [H] -dopamine Compound IC50 (mM) SEM Bupropion 1.9 0.15 Formula (I) 9.3 0.41 Formula (II) > 100 Absorption of [H] -Noradrenaline Compound IC50 (mM) SEM Bupropion 2.2 0.7 Formula (I) 1.1 0.07 Formula (II) > 30 Imipramine 0.072 0.020 Absorption of [H] -Serotonin Compound IC50 (mM) SEM Bupropion > 30 Formula (I) > Formula (II) > 100 Imipramine 0.24 0.03 Table 2 Adverse Events Associated with the Compounds of Formula I, Formula II and the Racemate N / a means that the effect was not observed and, therefore, no percentage was given.

It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (6)

1. Pharmaceutically acceptable salts and solvates of (+) - (2S, 3S) -2- (3-chlorofenyl) -3,5,5-trimethyl-2-morpholinol.

2. hydrochloride (+) - (2 S, 3 S) -2 - (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol.

3. Pharmaceutical compositions characterized in that they comprise (+) - (2 S, 3 S) -2 - (3-chloropenic) -3,5,5- 1 rime t il-2 -mor folinol or pharmaceutically acceptable salts and solvates thereof according to claim 1 or claim 2 together with one or more pharmaceutically acceptable carriers, diluents or excipients.

4. A compound (+) - (2 S, 3 S) -2- (3-chlorophenyl) -3,5,5-trimethyl-2-morpholinol or a pharmaceutically acceptable salt or solvate thereof in accordance with claim 2 for use in therapy.

5. The use of a compound (+) - (2 S, 3 S) -2 - (3-chlorophenyl) -3,5,5-1-rimethyl-2-olofol or a pharmaceutically acceptable salt or solvate of the same according to claim 1 or claim 2 or pharmaceutical compositions thereof according to claim 3 in the preparation of a medicament for the treatment of depression, hyperactivity disorder due to lack of attention (for its acronym in English, ADHD) , obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, or addiction to products that contain cocaine or nicotine (especially tobacco).

6. A method of treating depression, attention deficit hyperactivity disorder (ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, or addiction to cocaine-containing products or nicotine (especially tobacco) in a human or animal subject characterized in that it comprises the administration to said subject of an effective amount of (+) - (2 S, 3 S) -2 - (3-chlorophenyl) -3,5, 5- trimethyl-2-morpholinol or pharmaceutically acceptable salts and solvates thereof according to claim 1 or claim 2 or pharmaceutical compositions thereof according to claim 3.