BRPI0609043A2 - use of a compound, compound, pharmaceutical composition, and method for the preparation of pharmaceutical compositions - Google Patents

Abstract

USE OF A COMPOUND, COMPOUND, PHARMACEUTICAL COMPOSITION, AND METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS. The invention relates to dithiolethione derivatives as monoamino oxidase inhibitors, especially MAO-b inhibitors, methods for the preparation of these compounds and novel intermediates useful for the synthesis of said dithiolethione derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament which produces a beneficial effect. In embodiments of the invention the specific compounds disclosed herein are used for the production of a medicament useful in the treatment, amelioration or prevention of conditions associated with monoamine neurotransmission dysfunction. The compounds have the general formula (1) where symbols have the meanings given in the descriptive report.

Description

"USE OF A COMPOUND, COMPOUND, PHARMACEUTICAL COMPOSITION, AND METHOD FOR PREPARING PHARMACEUTICAL DECOMPOSITIONS"

The present invention relates to dithioletase derivatives such as monoamino oxidase inhibitors, especially MAO-B inhibitors, methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said dithioletase derivatives. The invention also relates to the use of a compound disclosed herein for the production of a drug which produces a beneficial effect. A beneficial effect is presented here or is apparent to a person skilled in the art from the descriptive report and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition.

More particularly, the invention relates to a novel use for the treatment of a disease or condition presented herein or apparent to a person skilled in the art from the descriptive report and general technical knowledge. In embodiments of the invention the specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment, amelioration or prevention of conditions associated with monoamine transmission dysfunction.

Flavo-enzyme monoamine oxidase inhibitors (MAO; EC1.4.3.4) may cause an increase in norepenephrin, epinephrine, dopamine, tryptamine and serotonin levels in the brain and other tissues, and therefore may cause a wide variety of pharmacological effects mediated by their effects on those neurotransmitters.

Currently available MAO inhibitors such as L-deprenyl, mofegiline, rasagiline, lazabemide have a wide range of side effects, including psychiatric (delirium, hallucinations, agitation), cardiovascular (ortho-static hypotension, and hypertension) and neurological (sedation, movements abnormal).

<formula> formula see original document page 3 </formula>

The object of the present invention is to develop new MAO inhibitors not structurally related to those available today, with fewer side effects.

WO 98/27970 discloses the use of 1,2-dithiol-3-thionas for treating diseases or preventing cellular damage caused by oxygen containing oxygen. WO-01/09118 discloses dithioletion compounds for the treatment of neurological disorders and for the improvement of memory. These compounds are considered to be inhibitors of D-amino acid oxidase (DAAO, E.C. 1.4.3.3), the enzyme that stereoselectively deaminates D-amino acids, thereby generating hydrogen peroxide, a species of reactive oxygen. Dithioletion has never been shown to inhibit monoaminooxidase, a completely different enzyme.

Surprisingly, it has now been found that dithioletion potentially inhibits MAO-B activity in cell extracts derived from cultured striatal astroglial cells of rats whereas no significant effect on MAO-A activity has been observed. The invention relates to the use of compounds of the general formula (1).

<formula> formula see original document page 3 </formula> where:

- R 1 and R 2 are the same or different, and represent hydrogen, alkyl, alkenyl, alkynyl, aryl, fluorine, chlorine, bromine, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, starch, alkyl starch, dialkyl starch, or

- R1 and R2 may together with the carbon atoms in which they are attached form a five-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms chosen from nitrogen, oxygen or sulfur such as fiirane, thiophene, pyrrol, oxazole thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine rings,

R 1 and R 2 may themselves contain additional substituents chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, fluorine, chlorine, bromine, hydroxy, alkyloxy, aminoalkyloxy, morpholin-4-yl alkoxy, piperidin-1-yl-alkyloxy, alkenyloxy aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, starch, alkylamido or diakylamido,

and N-oxide tautomers, stereoisomers thereof, as well as pharmaceutically acceptable salts, hydrates and solvates of said compounds of formula (1) and their tautomers, stereoisomers and N-oxides, for the preparation of a pharmaceutical composition for the treatment, improvement or prevention conditions associated with monoamine daneurotransmission dysfunction.

The invention relates especially to the use of compounds of general formula (1) wherein R 1 and R 2 are the same or different, and represent hydrogen, alkyl or aryl, optionally substituted by one or more atoms or groups selected from hydrogen, alkyl, aryl, fluorine, chlorine. , bromine, hydroxy, alkyloxy, aryloxy, amino, alkylamino, dialkylamino, thio, oxo, ouniter. More especially, the invention relates to the use of 5- (p-methoxyphenyl) -3H-1,2, dithiol-3-thione (anethole dithioletiona, ADT), 3 H -1,2-dithiol-3-thione (D 3 T) and 4-methyl-5- (2-pyrazinyl) -3 H -1,2-dithiol-3-thione (oltipraz):

<formula> formula see original document page 5 </formula>

More preferred is the use of 5- (p-methoxyphenyl) -3H-1,2-dithiol-3-thione, anethole dithiolethione (ADT) a 3 H-1,2-dithiol-3-thione lipophilic substituted analog (D3T ), in clinical use for decades as an ousialogogue collagogue without noticing any major adverse reactions (Christen, MO., Methods Enzymol., 252, 316 - 323,1995).

In another aspect, the invention relates to compounds of formula (1):

<formula> formula see original document page 5 </formula>

Where:

- R1 is optionally substituted phenyl and R2 represents S-CH2- (4-methylphenyl) or one of the subgroups:

<formula> formula see original document page 5 </formula>

where n is 2, 3, 4 or 5 and R3 is hydrogen or (C1-3) alkyl, or- R1 is 4-hexyloxyphenyl and R2 is hydrogen, or

- R1 is substituted phenyl and R2 represents SH, or the subgroup:

<formula> formula see original document page 6 </formula>

- R1 is hydrogen and R2 represents -CH = CH-4 (diethylamino-phenyl), -CH = CH- (2-quinolyl) or the subgroup:

where n has the same meaning given above, and R 4 and R 5 independently represent (C 1-3) alkyl, or together with the nitrogen atom to which they are attached form a five-membered saturated ring optionally containing one or more heteroatoms chosen from N , O or S, or

- R1 is (C1-3) alkyl and R2 is 1- (2,3-dihydro-1,4-benzodioxin-5-yl) piperazin-4-yl, or

- R1 is cyano and R2 is a subgroup -NH-C (O) -NH-phenyl, in which subgroup the phenyl group is optionally substituted, or

- R1 is -SO2 CH3 and R2 represents amino

and tautomers, stereoisomers and N-oxides thereof, as well as the pharmaceutically acceptable salts, hydrates and solvates of said compounds of formula (1) and their tautomers, stereoisomers and N-oxides.

The invention relates to racemates, mixtures of diastereomers as well as individual stereoisomers of the compounds having formula (1). In the description of the substituents, the abbreviation "alkyl" means C1-3 alkyl, "alkenyl" means C1-3 alkenyl means alkynyl C1-3, "acyl" means (C1-3) alkylcarbonyl, arylcarbonyl or aryl (C1-3) carbonyl, and "aryl" means furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl , pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, (2,3-dihydro-1,4-benzidioxin-2-one 5-yl), benzimidazolyl, benzithiazolyl, pyrinyl, quinolinyl, isoquinolinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, naphthyl, or azulenyl, preferably phenyl or (2,3-dihydro-1, 4-benzodioxin-5-yl). "(C1-3) alkyl" means "methyl, ethyl, n-propyl, or isopropyl," (C1-3) alkyl "means" methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or -methyl-n-propyl "," Optionally substituted "means that a group may or may not be further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy , amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, starch, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a ring aromatic or non-aromatic five- or six-membered containing 0, 1 or 2 heteroatoms chosen from nitrogen, oxygen or sulfur Optional substituents may themselves contain additional optional substituents. Preferred optional substituents include C1-3 alkyl such as, for example, methyl. 1α, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxy, C1-3 alkyloxy such as, for example, methoxy, ethoxy and trifluoromethoxy, and amino.

Prodrugs of the compounds mentioned above are within the scope of the present invention. Prodrugs are therapeutic agents that are inactive on their own but are transformed into one or more active metabolites. Prodrugs are bio-reversible derivatives of drug molecules used to overcome some barriers to the use of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and target limitations ( Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed .: FD King, p. 215; J. Stella, (Prodrugs as therapeutics, "Expert Opin. Ther. Patents, 14 (3), 277- 280, 2004; P. Ettmayer et al., "Lessons learned from the marketed and investigational prodrugs", J. Med. Chem., 47, 2393-2404, 2004). The prodrugs, ie compounds which when administered aseres by any known route, are metabolized to the compounds of formula (1) pertaining to the invention Especially this refers to compounds with primary or secondary amino or hydroxyl groups Such compounds may be reacted with organic acids to produce compounds having formula (1) wherein a G Additional group is present which is easily removed after administration, for example, but not limited to amidine, enamine, a Mannich base, a hydroxyl methylene derivative, a 0- (acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.

The N-oxides of the above mentioned compounds are within the scope of the present invention. Tertiary amines may or may not generate N-oxide metabolites. The extent to which N-oxidation occurs varies from trace amounts to near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines or less active. Although N-oxides are easily reduced in their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo almost quantitative reductive conversion in the corresponding tertiary amines, in other cases conversion is merely a reaction or even completely absent. (M.H. Bickel: "The Pharmacology and Biochemistry of N-oxides", Pharmacological Reviews, 21 (4), 325 - 355, 1969).

GENERAL SUMMARY ASPECTS

The choice of specific synthetic procedures depends on factors known to those skilled in the art, such as the compatibility of functional groups with the reagents used, the ability to use protecting groups, catalysts, reactivation and coupling reagents, and the main structural characteristics present in the final compound being used. prepared.

PHARMACEUTICALLY ACCEPTABLE SALTS

Pharmaceutically acceptable salts may be obtained by using standard procedures well known in the art, for example, by mixing a compound of the present invention with a suitable acid, for example an inorganic acid such as hydrochloric acid or an organic acid.

PHARMACEUTICAL PREPARATIONS

The compounds of the invention may be used in forms suitable for administration by usual procedures using auxiliary substances such as a liquid or solid carrier material. The pharmaceutical compositions of the invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They may be administered in the form of solutions, powders, tablets, capsules (including microcapsules, ointments (creams or gel) or suppositories. Suitable excipients for such formulations are customary fillers and extenders, solvents, emulsifiers, lubricants, flavors, dyes and / or buffer substances Commonly used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars or alcohols, talc, protein lactate, gelatin, starch, cellulose and its derivatives, animal and vegetable oils. such as fish liver oil, sunflower oil, sesame or ground brown oil, polyethylene glycol and solvents such as, for example, sterile water, mono- and polyhydric alcohols such as glycerol.

The compounds of the present invention are generally administered as pharmaceutical compositions which are important and the novel embodiments of the invention because of the presence of compounds, more especially the specific compounds set forth herein. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types set forth herein or apparent to a person skilled in the art from the descriptive report and general knowledge in the art. technique. In embodiments of the invention, a pharmaceutical package or set comprising one or more receptacles filled with one or more of the ingredients of a pharmaceutical composition of the invention is provided.

Associated with such receptacles may be various written materials, such as instructions for use, or a notice as described by a government agency that controls the manufacture, use, or sale of pharmaceutical products, the notice of which reflects the agency's approval of the manufacture, use, or sale for human or veterinary administration.

PHARMACOLOGICAL METHODS

MAO ACTIVITY DETERMINATION

Striatal astroglial cells of newborn rats have been used as a source for both MAO-A and MAO-B activities (Cario et al., Brain Res 711,175 - 183,1996). Astroglial cells were cultured as described (Langeveld et al., Neurosci. Lett. 192, 13 - 16,1995). After one week in 5% CO 2/95% air culture at 37 ° C, cells were trypsinized and sonicated in 25 mM chilled ice solution Tris-HCl buffer (pH 7.4) containing 1 mM EDTA. Subsequently the obtained lysates were centrifuged for 5 minutes at 10,000 g and 40 ° C and portions of the supernatant fractions were removed for MAO activity determination using an Amplex Red MAO assay kit (Molecular Probes, Leiden, The Netherlands), which is based on the method described by Zhou and Panchuk-Voloshina (Anal. Biochem. 253,169-174,1997). The measurements were performed according to the manufacturers instructions. In summary, prior to substrate addition, the samples were incubated for 30 minutes in a 96-well plate with solvent or solvents (total volume 50 microliters). Subsequently, 50 microliters of Amplex Red reagent containing 2U / ml horseradischperoxidase (HRP), p-tyramine HCl (2mM, substrate for both MAO-A and MAO-B (Youdim and the Finberg5 Biochem. Pharmacol., 41, 155 - 162.1991) and Amplex Red 1000 (10 mM) In these circumstances, by MAO-catalyzed tyramine oxidation in a HRP-coupled reaction, Amplex Red is converted to fluorescent resorufin. time dependent on resorufin formation was determined at two minute time intervals for 30 minutes at room temperature in a fluorescent microplate reader (BMG Labtechnologies GmbH, Germany) using excitation at 544 nm and emission at 595 nm. the fluorescence increase was found to be linear.For the calculation of the results, the data were corrected for the basic reading (ie, in the absence of tyramine of MAO substrate), and expressed as the increase in units / minute of arbitrary fluorescence. Protein content was determined according to the method of Bradford et al. (Anal. Biochem. 72, 248 - 254.1976) using BSA as standard. Statistical comparisons between groups were made using a single analysis of variance (ANOVA) followed by a testepost-hoc Newman-Keuls. P values <0.01 were considered significant.

MAO-B inhibitory activity of compounds A1-D6 was measured at CEREP (Paris, France) according to the protocol described by J.L. Salach, Arch. Biochem. Biophys., 192,128,1979.

Anethole dithioletiona and related dithioleteas are active at doses in the range of 0.1 -100 mg / kg after oral administration, and their selective inhibition of monoamine oxidase-B makes them especially useful in the treatment of psychiatric and / or neurological disorders caused. by disorders of the main monoaminergic systems or which can be treated by manipulation of those systems, said disorders chosen from the group consisting of temperament disorders such as bipolar I disorders, bipolar II disorders and unipolar depressive disorders such as minor depression, seasonal affective disorders, postoperative depression. natal, dysthymia and major depression; anxiety disorders, including panic disorder (with or without agoraphobia), social phobias, obsessive-compulsive disorders (with or without co-morbid chronic tics or schizotypic disorder), posttraumatic stress disorder, and generalized anxiety disorders; substance-related disorders, including substance use disorders (such as dependence and abuse) and substance-induced disorders (such as substance withdrawal), attention deficit and disruptive behavior disorders, such as attention deficit hyperactivity disorder and narcolepsy; impulse control disorders such as pathological gambling; eating disorders such as anorexia nervosa and bulimia nervosa; tic disorders, such as Tourette's syndrome; restless leg syndrome; disorders characterized by impairment of cognition and / or memory, such as Alzheimer's disease, Parkinson's disease and dementia of AIDS and / or co-morbid psychiatric disorders and neuro-rehabilitation (posttraumatic brain injury), other CNS disorders such as epilepsy, Down syndrome, Huntington's disease, various forms of pain, including headache, atypical pain, pain disorders, and chronic pain syndrome; lateral myotropic sclerosis and sexual dysfunction; disorders of cerebral or peripheral vascularization, including essential, renovascular, pulmonary and ocular hypertension, thrombosis, myocardial infarction, and cerebrovascular effusion; non-vascular smooth muscle disorders, including airway obstruction, asthma or other respiratory disorders, and gastrointestinal motility disorders, hemorrhoids, sphincter and smooth muscle spasms in the gastrointestinal tract, bladder dysfunction. In addition MAO inhibitors that may impair premature labor and relaxation of the birth canal during childbirth are useful for urinary tract relaxation for the passage of kidney stones, and may be used to relieve contraction and spasms of smooth muscles.

Preferably, the compounds of the invention are used for the treatment of temperament disorders, bipolar disorders I, bipolar disorders II, unipolar depressive disorders, minor depressions, seasonal affective disorders, postnatal depression, dysthymia, major depression, anxiety disorders, panic, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, substance-related disorders, substance-abuse disorders, substance-induced disorders, withdrawal of substance, and attention-deficit and disruptive temperament disorders attention deficit, narcolepsy; impulse control disorders, pathological gambling, eating disorders, anorexia nervosa, bulimia nervosa, tic disorders, Tourette's disorder, restless hip syndrome, pain, headache, atypical facial pain, pain disorder, chronic pain syndrome, sexual dysfunction , airway obstruction, asthma, gastrointestinal motility disorders, hemorrhoids, sphincter spasms, and smooth muscles in the gastrointestinal tract and bladder dysfunction.

DOSE

The potency of the compounds of the invention as MAO-B inhibitors was determined as described above. From the potency measured for a given compound of formula (1), a person can estimate the lowest theoretical effective dose. At a concentration of the compound twice the measured inhibition constant, possibly 100% of the enzyme will be inhibited by the compound. Converting that concentration to mg decomposed per kilo of patient yields the lowest theoretical effective dose, assuming optimal bioavailability. Pharmacokinetic, pharmacodynamic and other considerations may alter the dose actually administered to a greater or lesser value. The dosage administered is usually 0.001-1000 mg / kg, preferably 0.1-1000 mg / kg patient body weight.

TREATMENT

The term "treatment" as used herein refers to any treatment of a mammal, preferably a human condition or disease, and includes: (1) the prevention of the disease or condition occurring in an individual who may be predisposed to the disease but still not been diagnosed as having it, (2) inhibition of the disease or condition, ie, stopping its development, (3) alleviating the disease or condition, ie causing regression of the condition, or (4) alleviating the conditions caused by the disease. disease, that is, stopping the symptoms of the disease.

EXAMPLES

EXAMPLE 1: MATERIALS AND METHODS

All reactions involving moisture sensitive compounds were performed under a dry nitrogen atmosphere. Reactions were monitored using thin layer chromatography (TLC) on silica coated plastic sparks (Merck silica gel 60 F254) with the eluent indicated. Compounds were visualized by UV light (254 nm) or I2. Expansion chromatography refers to purification using the eluent indicated and Across silica gel (0.030 - 0.075 mm). Nuclear magnetic resonance spectrum (1H NMR and 13C NMR, APT) were determined in the indicated solvent. Coupling constants J are given in Hz. Peak shapes in the NMR spectrum are indicated with the symbols "q" (quartet), "dq" (double quartet), "t" (triple), "dt" (double triple ), "d" (double), "dd" (double double), "s" (single), "bs" (wide single) and "m" (multiple).

EXAMPLE 2: SUMMARY OF SPECIFIC COMPOUNDS

Specific compounds of which the synthesis is described below are intended to further illustrate the invention in more detail, and are therefore not considered to restrict the scope of the invention in any way.

<table> table see original document page 15 </column> </row> <table>

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the disclosure and practical report presented herein. It is therefore intended that the specification and examples be considered as examples only, with the true scope and spirit of the invention being indicated by the claims.

Al Compound

<formula> formula see original document page 15 </formula>

Scheme A. 1 Scheme i Scheme A. 1.

32 g (1 mol) of sulfur was added to 150 ml of DMF (N, N-dimethylformamide) and the resulting mixture was heated to reflux until the sulfur was almost dissolved. 43.6 g (200 mmol) of 2- (4-n-hexyloxyphenyl) propene was added dropwise. After addition was complete, stirring and heating were continued for the reaction followed by TLC (thin layer chromatography, eluent: toluene), after 4h, the reaction was allowed to reach room temperature. Filtration and evaporation under vacuum of the reaction mixture yielded a residue which was subjected to column chromatography (SiO 2, eluent: toluene). The combined product containing fractions was vacuum concentrated, the residue was recrystallized from cyclohexane, yielding 5g (8.1% of the desired compound A1. Melting point: 121 ° C.

<formula> formula see original document page 16 </formula>

Step I Scheme A.2

In an absolute ethanolic solution containing 2 equivalents of sodium ethoxide (NaOEt) was added 1 equivalent of A-hydroxyacetophenone along with 1 equivalent of N- (2-chloroethyl) morpholine. After the addition was complete, the reaction mixture was refluxed for 5h, then heating was stopped and stirring was continued for 12h at room temperature. The solvent was removed under vacuum and the residue was taken up in aqueous hydrochloric acid (ca.2N), this solution was washed with diethyl ether. The aqueous layer was neutralized with sodium hydroxide solution (ca. 2N), after which extraction with diethyl ether was performed. The combined organic fractions were dried (Na 2 SO 4). Removal of the drying agent by filtration and vacuum solvent removal produced the phenolic ether as an orange yellow oil in 91% yield.

Step ii Scheme A.2 (according to Thuillier et al., Bull. Chim. Soc., (1959) 1398)

In an absolute cold amount of toluene containing two equivalent sodium tert-amylate (NaOC (CH3) 2CH2CH3) was added 1 equivalent of the phenolic ether of step i, and 1 equivalent of dissolved carbon disulfide. When the addition was complete, the mixed reaction was stirred for 6h. Subsequently, 1 equivalent of 1,2-dibromoethane was added after which stirring was continued for 12h. The reaction mixture was washed with aqueous sodium hydroxide solution (ca.2N) and water until the pH reached 7. The organic fraction was dried over Na2 SO4. Removal of the drying agent by filtration and vacuum solvent removal yielded the 1,3-di-thiolane derivative as orange crystals in 70% yield.

Step III Scheme A.2

The di-thiolane derivative of step ii was treated with tetraphosphododesulfide (P4 SiO) at reflux in xylene for 15 minutes. After cooling the suspension was washed with 1 N sodium hydroxide solution (aq.), After which chloroform was added, the resulting organic fraction was dried over Na 2 SO 4. Removal of the drying agent by filtration and removal of the solvent in vacuo gave a residue which was purified by column chromatography (SiO 2, eluent: diethyl ether / toluene 1/1) to yield the desired A2 compound as orange crystals and yield 4. % Melting Point: 62 ° C. 1H-NMR (CDCl3, δ ppm): 2.59 (t, 4H), 2.83 (t, 2H), 3.73 (t, 4H), 4.17 (t, 2H), 6.98 ( d, 2H), 7.60 (d, 2H), 7.36 (s, 1H).

Compound A3 (red oil, 1H-NMR (CDCl3, δ ppm): 1.49 (q, 2H), 1.67 (t, 4H), 2.63 (t, 4H), 2.97 (t, 2H ), 4.24 (t, 2H), 7.00 (d, 2H), 7.38 (s, 1H), 7.60 (d, 2H)) was done analogously to the procedure described for compound A2.

Bl compound

<formula> formula see original document page 18 </formula>

scheme B.l

Step i scheme B. 1.

2 equivalents of piperazine and 1 equivalent of 5-methylsulfanyl-4-phenyl- [1,2] dithiol-3-thione (Grandin, A. et al., Bull. Soc. Chim. Fr., 11 (1968 ) 4555) were dissolved in absolute ethanol, after which the darning mixture was brought to reflux temperature. After seven days, the solvent was removed under vacuum and the residue was purified by chromatography (SiO2, eluent: 2% ethanol in toluene v / v). The collected product containing fractions was concentrated in vacuo, the residue was recrystallized from acetone, yielding orange crystals in 12% yield: compound BL Melting point: 174 ° C.

1H-NMR (CDCl3, 6 ppm): 2.97 (t, 4H), 3.44 (t, 4H), 4.23 (m, 4H), 6.42 - 6.76 (m, 3H), 7.34 - 7.49 (m, 5H).

Compound B2 (yellow crystals, mp 108 ° C, 1H-NMR (CDCl3, 6 ppm): 2.37 (s, 3H), 2.98 (t, 4H), 3.45 (t, 4H), 4 .23 (m, 4H), 6.43 - 6.76 (m, 3H), 7.22 - 7.28 (m, 4H)) was produced analogously to the procedure described for compound B1.

Compound B3 (red crystals, melting point 148-150 ° C with decomposition) was made analogously to the procedure described for compound B1.

Cl compound

<formula> formula see original document page 19 </formula>

C.l scheme

Step i scheme C. 1.

1 g (6.8 mmol) of 5-methyl- [1,2] dithiol-3-thione was dissolved in 50 ml of absolute ethanol. Then 2.5 g (14.1 mmol) of 4- (diethylamino) benzaldehyde and 1 ml of piperidine were added, after which the darning mixture was heated in a water bath for 2h. The reaction mixture was concentrated in vacuo and the residue was placed in a freezer in which crystals were formed. The crystals were isolated and recrystallized from alcohol propyl alcohol yielding 1.5 g (4.9 mmol, 35%) of the desired compound Cl, melting point: 130 ° C. See also JP 1319477.

Compound C2 (TLC (SiO 2, eluent: toluene), Rf = 0.36, in the presence of starting materials) was produced analogously to the procedure described for compound Cl.

Compound Dl

<formula> formula see original document page 19 </formula>

Scheme D. 1Step Scheme D. 1.

17.5 g (87.9 mmol) of 1-bromo-2-phenylpropane was dissolved in 300 mL of DMF and 14.1 g (441 mmol) of sulfur was added. The reaction mixture was refluxed overnight after which stirring was continued at room temperature for another night. The reaction mixture was concentrated in vacuo after which ca.100 ml of toluene was added, crystals were formed, the latter being collected and vacuum dried. Yield: 13 g (45.3 mmol, 52%) of a yellow solid containing 4-phenyl-5-mercapto- [1,2] dithiol-3-thione dimethylammonium salt.

Step ii scheme D. 1.

3.5 g (10.4 mmol) of iodide (for iodide synthesis, verinfra) was dissolved in 40 ml of methanol after which 3 g (10.4 mmol) of the dimethylammonium salt (from step i) was added. The reaction mixture was stirred overnight, after which it was concentrated in vacuo, the residue subjected to column chromatography (SiO2, eluent: heptane / ethyl acetate 6/1). Concentration of the product containing fractions yielded 700 mg (1.6 mmol, 15%) of a red oil.

Step iii Scheme D. 1.

700 mg (1.6 mmol) of the product from step ii was dissolved in a little dichloromethane after which an amount of 7N HCl (in isopropanol) was added so that the final concentration was around 3 N. The reaction mixture was stirred overnight after which time it was concentrated in vacuo, yielding 265 mg of an orange solid containing 1 HCl. Melting point: 243 ° C.

Compound D2 (melting point: 96 - 61 ° C with decomposition) was produced analogously to the procedure described for compound D1. The iodide that was used can be prepared in the synthesis of the diode used for the preparation of D1 (see below). Compound D3 (melting point: 82 - 87 ° C) was produced analogously to the procedure described for compound D1. The iodide which has been used may be prepared in the synthesis of the iodide used for the preparation of D1.

Compound D4 (melting point: 65 - 70 ° C, with decomposition) was made analogously to the procedure described for compound D1. The iodide that has been used can be prepared in the synthesis of iodide used for the preparation of D1.

Compound D5 (melting point: 65 - 72 ° C) was made analogously to the procedure described for compound D1. The iodide that has been used can be prepared in the synthesis of the iodide used for the preparation of DI.

Compound D6 (melting point: 134 - 135 ° C) was made in a manner analogous to the procedure described for compound D1, starting with bromo methyltholuene as the alkylating agent.

Synthesis of iodide used in the preparation of compound D1 (scheme D.2).

<formula> formula see original document page 21 </formula>

scheme D.2

Step i scheme D.2.

6.4 g (72.6 mmol) of 4-hydroxy-2-butanone was dissolved in 250 mL of 1,2-dichloroethane, after which 5.5 mL (81 mmol) of propargylamine was added. The reaction mixture was stirred for 10 minutes, after which it was cooled to 0 ° C. 20 g (94 mmol) of NaBH (OAc) 3 were added portionwise to the reaction mixture, stirring was continued for 48h, after which time the mixture was poured into a saturated NaHCO3 (aq.) Solution. Extraction of this latter aqueous solution with DCM yielded 3 g of the desired product after concentration in vacuo. The aqueous layer was alkalized with NaOH solution (33%, aq.) And saturated with NaCl (solid), a second EtOAc extraction was performed. The combined organic fractions were dried (Na 2 SO 4) and after removal of the filter-drying agent and removal of the solvent by vacuum concentration, 7.6 g (82%) of the desired product (as an orange oil) were obtained. This was used in step ii without further purification. Step ii scheme D.2.

7.6 g (59.8 mmol) of the aminopropanol derivative (from step) was dissolved in 200 mL of DCM, after which 9.2 mL (approximately 65 mmol) of triethylamine and 14 g (65 mmol) of ( Boc) 20 (Boc = tert-butyloxycarbonyl). The resulting mixture was stirred overnight after which it was concentrated in vacuo and the residue was once again dissolved in EtOAc. The organic fraction was washed with NaHCO 3 (aq.) Solution, water and brine, after which it was dried over Na 2 SO 4. After removing the drying agent by filtration and removing the solvent by vacuum concentration, 13.7 g (100% of a brown oil containing N-Boc protected aminopropanol was isolated.

Step iii scheme D.2.

33 g (126 mmol) of triphenylphosphine was dissolved in 600 mL of DCM, after which 19 g (281 mmol) of imidazole was added, resulting mixture was brought to 0 ° C. A solution of 35.5 g of iodine (140 mmol) in 300 mL of DCM (dichloromethane) was added dropwise to the reaction mixture, after which stirring was continued for 10 minutes. Subsequently, 8 g (35 mmol) of N-Boc-protected aminopropanol (from step ii) dissolved in 50 ml DCM was added, stirring was continued at 0 ° C for 20 minutes. Then the mixed reaction was allowed to reach room temperature and was stirred for 16h. The reaction mixture was filtered, the filtrate was washed with brine and vacuum concentrated. The residue was "filtered" over a short SiO 2 column (eluent: heptane / EtOAc 6/1) and the eluate was concentrated in vacuo yielding 5.1 g (%) of the corresponding iodide as a pale yellow oil. This iodide was used in the preparation of compound D1 (see scheme D.I.).

Corresponding iodides required for the preparation of compounds D2, D3, D4 and D5 may be prepared according to the conditions described in the synthesis of the iodide used in the preparation of D1 (Scheme D.2.). For compounds D4 and D5, the protection and deprotection (N-Boc) steps are not necessary because of the methyl group present in the denitrogen atom.

EXAMPLE 3: FORMULATION OF COMPOUND Al

For oral administration (po): In the desired amount (0.5-5mg) of solid compound Al in a glass tube, a few glass beads were added and the solid was vortexed for two minutes. After the addition of 1 ml From a 1% solution of methylcellulose in water and 2% (v / v) Poloxamer 188 (Lutrol F68), the compound was vortexed for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). The remaining particles in the suspension were suspended using an ultrasonic bath.

For intraperitoneal (ip) administration: At the desired amount (0.5 - 15 mg of solid compound Al in a glass tube, a few glass beads were added and the solid was vortexed for two minutes.) After adding 1 ml of a solution At 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortex for 10 minutes Finally, the pH was adjusted to 7. EXAMPLE 4: PHARMACOLOGICAL TEST RESULTS

<table> table see original document page 24 </column> </row> <table>

The effects of deprenil (L-dep) on anethole dithioletiona (ADT) on total monoamine oxidase (£ MAO) activity (columns 2 and 3); of L-dep, ADT and 3H-1,2-dithiol-3-thione (D3T) on monoamine oxidase-B (MAO-B) activity (lanes 4, 5 and 6); of Clorgillin (Chlor) and ADT on monoamine oxidase A (MAO-A) activity (columns 7 and 8) in cell extracts obtained from striatal astroglial cell cultures of newborn rats. MAO activity and drug effects on them were determined as detailed above.

Data are expressed as percentages of the respective controls, and are averages of 2 to 5 independent experiments performed in triplicate. Total MAO activity was determined in the presence of only solvent and (0.03% DMSO), and MAO-B activity in the presence of 0.1 µM of the selective MAO-A clorgiline inhibitor, and MAO-A activity in the presence 1 æM MAO-B selective inhibitor deprenyl.

Astroglial cells are known as expressing mainly MAO-B (Thorpe et al., J. Histochem. Cytochem., 35, 23 - 32,1987). Using the non-selective tyramine substrate and the selective MAO-B inhibitor deprenyl (Youdim and Finberg, Biochem. Pharmacol., 41, 155 -162, 1991), up to 80% of the total astroglial activity MAO was found to consist of MAO-B . The remaining MAO activity (approximately 20%) in the presence of a maximum effective deprenyl concentration was completely inhibited by the addition of the selective MAO-A clorgiline inhibitor. Adeprenil inhibited the total astroglial MAO activity in a concentration-dependent manner with an apparent IC50 of approximately 0.04uM. Similarly, concentration-dependent ADT inhibited MAO activity with an apparent IC50 of approximately 0.5 µM, achieving a maximum effect (approximately 80% inhibition) at a concentration of 30 µM. Following selective and complete blockade of MAO-A pelaclorgillin activity, identical effect - concentration ratios were observed for both deprenyl and ADT compared to those found for inhibition of total MAO activity. Under these conditions, that is in the presence of declorgillin, a similar blockade dependent on MAO-B activity concentration for D3T was observed, with an apparent IC50 of approximately 20uM and a maximum effective concentration of 300uM. After selective and complete blockade of MAO-B activity with deprenyl, no statistically significant effect of ADT on MAO-A activity was detected.

MAO-B inhibitory activity of A1-D6 AS compounds was measured at CEREP (Paris, France) according to the protocol described by

<table> table see original document page 25 </column> </row> <table>

Claims (8)

1. Use of a compound of the general formula (1) wherein: - R1 and R2 are the same or different and represent hydrogen, alkyl, alkenyl, alkynyl, aryl, fluorine , chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, starch, alkylamido, dialkylamido, or -R1 and R2 together with the carbon atoms in which they are attached form a five- or six-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms chosen from nitrogen, oxygen or sulfur such as furan, thiophene, pyrrol, oxazole, thiazole, imidazole, pyrazole , isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine rings, - R 1 and R 2 may themselves contain additional substituents chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, fluorine, chlorine, bromine, hydr oxy, alkyloxy, amino alkyloxy, morpholin-4-yl-alkoxy, piperidin-1-yl-alkyloxy alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, starch, alkyl starch, or dialkyl starch, and tautomers, stereoisomers and N-oxides thereof, as well as pharmaceutically acceptable salts, hydrates and solvates of said compounds of formula (1) and their tautomers, and stereoisomers and N-oxides, characterized in that they are for the preparation of a pharmaceutical composition for the treatment, amelioration or prevention of temperament disorders, bipolar disorders I, bipolar disorders II, unipolar depressive disorders, minor depressions, seasonal affective disorders, postnatal depression, dysthymia, major depression, anxiety disorders, disorder panic disorder, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, substance-triggered disorders, substance use disorders, substance-induced disorders, withdrawal of a substance, disorders of attention-deficit and disruptive behavior, attention-deficit and hyperactivity disorder, narcolepsy; Impulse control disorders, pathological gambling, eating disorders, anorexia nervosa, bulimia nervosa, tic disorders, Tourette's disease, restless hip syndrome, pain, headache, atypical facial pain, pain disorder, chronic pain syndrome, sexual dysfunction , airway obstruction, asthma, gastrointestinal motility disorders, hemorrhoids, sphincter spasm, and smooth muscles in the gastrointestinal tract and bladder dysfunction. Use according to claim 1, characterized in that the phage of said compounds of general formula (1) are 5- (p-methoxyphenyl) -3H-1,3-dithiol-3-thione, 3H-1,2-dithiol -3-thione or 4-methyl-5- (2-pyrazinyl) -3H-1,2-dithiol-3-thione. Use according to claim 1, characterized in that the pellet of said compound of general formula (1) is 5- (p-methoxyphenyl) -3H-1,2-dithiol-3-thione. Compound, characterized in that it is of the general formula (1): wherein: - R 1 is optionally substituted phenyl and R 2 is S-H 2 - (4-methyl-2-methyl). phenyl) or one of the subgroups: <formula> formula see original document page 28 </formula> where n is 2, 3, 4 or 5 and R3 is hydrogen or (Cu3) alkyl, or -R1 is 4-hexyloxyphenyl and R2 is hydrogen, or- R1 is substituted phenyl and R2 represents SH, or the subgroup: <formula> formula see original document page 28 </formula> - R1 is hydrogen and R2 represents -CH = CH-4- (diethylamino- phenyl), -CH = CH- (2-quinolyl) or the subgroup: <formula> formula see original document page 28 </formula> where not have the same meaning given above, and R4 and R5 independently represent C1-3 alkyl, or together with the denitrogen atom to which they are attached forms a saturated five-membered ring optionally containing one or more heteroatoms chosen from N, O or S, or -R 1 is (C 1-3) alkyl and R 2 is 1- (2,3-dihydro-1,4-benzodioxin-5-yl) piperazin-4-yl, or R 1 is cyano and R 2 is the subgroup -NH-C (O) -NH-phenyl , in which subgroup the phenyl group is optionally substituted, or -R 1 is -SO 2 CH 3 and R 2 represents aminoututomers, stereoisomers and N-oxides thereof, as well as the pharmaceutically acceptable salts, hydrates and solvates of said compounds of formula (1) and their tautomers, stereoisomers and N-oxide. A compound according to claim 4, characterized in that it has the general formula (1): Where: - R1 represents 4-hexyloxyphenyl and R2 represents hydrogen, - R1 represents R 2 represents hydrogen and R 2 represents R 1 represents phenyl and R 2 represents R 1 represents 4-methylphenyl and R 2 represents 4-methylphenyl and R 2 represents 4-phenylpiperazinyl, R 1 represents hydrogen and R 2 represents - CH-CH- (4-diethylaminophenyl), -R1 represents hydrogen and R2 represents -CH = CH- (2-quinolinyl), -R1 represents phenyl and R2 represents -S (CH2) 2CH (CH3) NH-2-propynyl, - R1 represents phenyl and R2 represents S (CH2) 3 CH (CH3) NH-2-propynyl, - R1 represents phenyl and R2 represents S (CH2) 4CH (CH3) NH-2-propynyl, - R1 represents phenyl and R2 represents -S (CH2) 4CH (CH3) -N (CH3) -2-propynyl, R1 represents phenyl and R2 represents S (CH2) 3CH (CH3) N (CH3) -2-propynyl, -R1 represents phenyl and R2 represents -S -CH2- (4 me phenylphenyl), Pharmaceutical composition, characterized in that it comprises, in addition to a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable auxiliary substance, a pharmaceutically effective amount of at least one compound of claim 4, or a salt thereof, as an active ingredient. Method for the preparation of pharmaceutical compositions as defined in claim 6, characterized in that the compound as defined in claim 4 is placed in a form suitable for administration. A compound according to claim 4, or a salt thereof, characterized in that it is used as a medicament.