SA06270023B1 - Anethole Dithiolethione and Other Dithiolethiones for the Treatment of Conditions Associated with Dysfunction of Monoamine Neurotransmission - Google Patents

Abstract

Anethole Dithiolethione and Other Dithiolethiones for the Treatment of Conditions Associated with Dysfunction of Monoamine Neurotransmission For the preparation of these compounds, and new intermediate compounds useful for the synthesis of the aforementioned dithiolethiones derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a drug which gives a beneficial effect. In embodiments of the invention, specific compounds disclosed herein are used to manufacture a drug useful in the treatment, mitigation, or prevention of conditions associated with monoamine neurotransmission deficiency. Compounds have the general formula (1), where the symbols have the meanings given in the specification.

Description

1 - Jalil Dithiolethione and Other Dithiolethiones for the Treatment of Conditions Associated with Dysfunction of Monoamine Neurotransmission Full Description The present invention relates to dithiolethiones derivatives as monoamino oxidase inhibitors, specifically (MAO-B) inhibitors, and methods for the preparation of these compounds; and new intermediates useful for the synthesis of said dithiolethiones derivatives. The invention also relates to the use of a compound disclosed aie in this patent © To manufacture a drug that gives a beneficial effect. A beneficial effect is disclosed herein or is apparent to a person skilled in the art from a specification and general information in the art. The invention also relates to the use of a compound of the invention to manufacture a drug to treat or prevent a disease or condition. More specifically, the invention relates to a new use For the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from specification and general information in the art.In embodiments of the invention specific compounds disclosed herein are used to manufacture a drug useful in treating, mitigating or preventing conditions Associated with insufficiency of neurotransmission: -monoamine neurotransmission Monoamino oxidase inhibitors can cause mitochondria: (MAO; EC 1.4.3.4) increase in levels of norepinephrine, epinephrine, dopamine, tryptamine and serotonin in the brain and other tissues 10; Thus, they can cause a wide variety of pharmacological effects caused by their effects on these neurotransmitters. The currently available MAO inhibitors are: Brain 7

1a L-deprenyl, mofegiline, rasagiline, lazabemide has a wide range of side effects, including psychiatric (delirium; hallucinations ¢ agitation); cardiovascular (orthostatic hypotension » hypertension); and neuroticism (extrovertedness; unusual movements). yo N > 72 L-deprenyl mofegiline Cl 2 solution "on 1 and 0 rasagiline lazabemide General description of the invention The objective of the present invention is to develop Gans MAO inhibitors that are not structurally related to those currently available with minimal effects Side Order No. 797990/98 discloses the use of 1,2-dithiol-3-thiones to treat diseases or prevent cellular damage caused by oxygen-containing moieties. For the treatment of neurological disorders and for memory enhancement, it has been proven that these compounds inhibit: acid oxidase (DAAO, E.C. 1.4.3.3) - an enzyme that deaminates D-gu amino acids 0 in a selective steric manner, which generates hydrogen peroxide + which is a kind of oxygen

A interacting. Dithiolethione compounds have never been shown to inhibit monoamine oxidase.” This is a completely different enzyme. surprisingly; It has now been found that dithiolethione compounds strongly inhibit MAO-B activity in AA cell extracts from cultured rat striated astrocytes; While no significant effect was observed on the activity of MAO-A, the invention relates to the use of compounds of the general formula (D S—S (1) molar R, where: Ry 5 Ry is isotropic or different; , arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido Ry Ry together with the carbon atoms to which they are attached may form an aromatic or non-aromatic ring containing zero, 1, or Y heteroatoms selected from oxygen nitrogen or sulfur Jia » sulfur 0 : thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1, 3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine rings, brain

_ 0 _

The same additional substituent groups selected from Ry 9 Ry may bear hydrogen, alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, aminoalkyloxy, morpholin-4-yl-alkoxy, piperidin-1- yl-alkyloxy alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, 0X0, nitro, acyl, amido, alkylamido or dialkylamido, © terminators and also salts of N-oxides s stereoisomers and isomers Stereotautomers, compounds, and pharmaceutically acceptable solutes of the mentioned compounds of formula (1) and their compounds, hydrates s and 01065-10; to prepare a pharmaceutical composition for the treatment of stereoisomers and their stereoisomers monoamine tautomers | monoamine relieve or prevent conditions associated with insufficiency of neurotransmission

. neurotransmission 00 homologous Rys Ry The invention relates particularly to the use of compounds of general formula (1) wherein they are optionally substituted by (3) an aryl, “alkyl, or hydrogen” group, or different; The bromo or “chloro” or “fluoro i” aryl sf “alkyl” hydrogen consists of one or more selected dialkylamino or “alkylamino” or 6 amino or ¢ aryloxy or “alkyloxy” or “hydroxyl” or “. nitro or ¢ 0X0 or ¢ thio or “Vo”: more specifically the invention relates to the use of 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione (anethole ditiolethione, ADT), 3H-1,2- dithiole-3-thione (D3T) and 4-methyl-5-(2-pyrazinyl)- 3H-1,2-dithiole-3-thione (oltipraz) brain

S—S U 5 > Ga Hb 1 1 8 o> nN" 2 5 CH,0 D3T anethole dithiolethione oltipraz Most preferred is the use of: 5-(p-methoxyphenyl)-3H-1, 2-dithiole-3-thione, anethole dithiolethione (ADT) A lipophilic isotope with a substitution of ¢3H-1,2-dithiole-3-thione (D3T) has been in use for decades as purity thinners and saliva thinners with no observed Principal adverse reactions: (Christen, M-O., Methods Enzymol., 252, 316-323, 1 995) In another aspect the invention relates to compounds of formula (1): 5c (1) “R, 5 R 1 where: Ry 0 0 is a phenyl optionally substituted 9 Ry has S-CH,-(4-methyl-phenyl) or one of the following due il group: CH, 1 / -S-(-CH,-),-CH-N-CH,-C =CH —N N-— aryl u” and (ii) 0 ch

YY —- - ,S 5

5 5- (iii) where n is Y or ¥ or 4 or © and Ry is hydrogen or alkyl (Crs) + or R is 4-hexyloxyphenyl and Ry is hydrogen ; or Ry is a phenyl substituted 5 (SH Judi Ry or subgroup: SS S 5-5 - (iv) 5 3le Ry for Rss hydrogen is: —CH=CH-4-(diethylaminophenyl),-CH=CH-(2-quinolyl) or subgroup: Ma {Ho (CH,),-N 8 > (v) Y£AA ‏

blood where “has the same meaning as given by “Jd” and represents Ry and Y independently (br6) alkyl or together with the nitrogen atom to which they are attached forms a saturated ring of © or eh 1 optionally containing one or more heteroatoms selected from SIN ©0; or 5; or b[le from alkyl (Cra) and Ry is: ¢1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-4-yl, © 0 Ry is a cyano and Ry is the subgroup NH-C(O)-NH-phenyl » in which the subgroup is an optionally substituted phenyl group; Or R; is Rss -SO,CHj3 representing amino ¢ and its tautomers and its stereoisomers N-oxides_s stereoisomers “and also salts of hydrates 0 and pharmaceutically acceptable constants for the mentioned compounds of formula (1) and their compounds The tautomers and their stereoisomers, N-oxides 5 stereoisomers. The invention relates to racemates and mixtures of diastereomers as well as to the stereoisomers separately of compounds of formula (1). In describing substitution groups the abbreviation alkyl -© ' alkyl" ¢ means alkenyl' "¢ means p-alkenyl and 0 means alkynyl" 0 "¢ p-alkenyl « acyl' means t-alkyl(Cy. ;)carbonyl » that arylcarbonyl + or arylalkyl (Cy3)carbonyl ¢ meaning aryl' furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl, 1,3,5-triazynyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, (2,3- dihydro-1,4-benzodioxin-5- yl), benzimidazolyl, benzthiazolyl, purinyl, quinolynyl, isochinolyl, chinolyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, naphthyl or azulenyl, preferably phenyl or (2,3-dihydro-1,4-benzodioxin-5 - yl). 'Alkyl(C,.;)' means 'methyl, ethyl, n-propyl or isopropyl', 'alkyl(C,.4)' means © 'methyl, ethyl, n-propyl, isopropyl, n-butyl, 2- butyl, isobutyl or 2-methyl-n-propyl'. “Optionally substituted” means that the group may or may not be additionally substituted by: one or more selected groups of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, Ve cyano, oxo, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl or two facultative substitution groups together with the carbon atoms to which they are attached may form a ring or ?selected heterocyclic 1 aromatic or non-aromatic atom of © or 6 atoms containing 0 or sulfur or sulfur or oxygen of nitrogen The same selective substitution groups may carry additional selective substituent groups. 0 : eg alkyl cis Preferred optional substituent groups include methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, m-alkyloxy .methoxy, ethoxy and trifluoromethoxy, and amino eg;

Y£4A

01- The prodrugs for the previously referred compounds are in the scope of the present invention. Prodrugs are therapeutic agents that are inactive by themselves but are converted to one or more active metabolites. Prodrugs are bio-reversible derivatives of drug molecules used to overcome some barriers to the benefits of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism, and targeting limitations.

King, p. 215; J. Stella, “Prodrugs as Therapeutics”, Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P. Ettmayer et al., “Lessons learned from marketed and investigational prodrugs”, J.Med.Chem., 47, 2393-2404, 2004. (aga) Prodrugs; that is, compounds that are metabolized when administered to a human by any pathway 0 to compounds of formula (1) belonging to the invention. Specifically, this relates to compounds with groups. Such compounds can be reacted with organic acids, primary, secondary, or amino, to produce compounds of formula (1) in which there are Additional group which is easily removed after administration; hydroxyl- or Mannich base derivative or enamine 5 amidine including but not limited to amide, ester, carbamate or O-(acyloxymethylene carbamate) or methylene derivative 0 or enaminone They are nioxides of the compounds referred to before in the field of the present invention Lam may be tertiary amines and Lan may not be N-oxides metabolites The extent to which they occur varies The oxidation of nitrogen from quantities to near quantitative conversion.N-oxides may be more effective than their corresponding amines or 0 less effective.While N-oxides are easily reduced to their corresponding tertiary amines by means of

VY — Abas This occurs in the human body to varying degrees. Some Nioxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines; In other cases, conversion is just a minimal interaction or even completely absent. General Features of Synthesis © The choice of specific synthetic procedures depends on factors known to those skilled in the art, eg

The compatibility of the functional groups with the used reaction materials, the possibility of using protecting groups, catalysts, activation and coupling agents, and the final structural features present in the final compound being prepared. Pharmaceutically acceptable salts:

0 Pharmaceutical acceptable salts can be obtained using well known standard procedures eg inorganic acid Jie ¢ or with an organic acid. Pharmaceutical Preparations: The compounds of the invention can be made into forms suitable for administration by normal processes

Liquid or solid carrier liquid Intravenously or intramuscularly (intramuscularly) locally (topical). They may be administered as solutions, powders, tablets, capsules, ointments (creams or gels) or suppositories. AEA are excipients Including capsules Ly)

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101 - L -_ Suitable for such formulations are pharmacologically familiar liquid or solid fillers and/or extenders and/or solvents and/or emulsifiers and/or lubricants and/or thickeners Flavorings and/or colorings and/or pH-regulating materials. Of the frequently used auxiliaries that may be referred to are titanium dioxide s magnesium carbonate © and its group 5 mannitol and other sugars or gelatin lactoproteiny talc 3 sugar alcohols starch, cellulose and their derivatives, animal and building oils Jie oil aX whale, sunflower oil, peanut oil, or sesame oil; polyethylene glycol s and solvents; For example » ele sterile 5 mono- or polyhydric alcohols glycerol Jie . 01 The compounds of the present invention are generally given in the form of Ally pharmaceutical formulations that are important and new models of the invention because the presence of the compounds; More specifically, specific compounds disclosed herein. The types of pharmaceutical formulations that can be used include; including but not limited to ald and chewable tablets; capsules; solutions; enteric solutions; suppositories; and other types disclosed in this patent or apparent to a person skilled in the art from the specification and general information 0 in the art. in invention models; A pharmaceutical package or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical composition of the invention is supplied. Attached to this container(s) can be different materials Jie written instructions for use; or noted in the image prescribed by the Governance Regulatory Agency for Manufacturing; use or sell pharmaceutical products; Where the note reflects the agency's approval of the manufacture, use, or sale of 0 for human and veterinary administration. Y£4A

1“ - - Pharmacological methods Determination of MAO activity The astroglial cells of a neonatal rat striatum were used as a source of both MAO-A activity (Carlo ct al, Brain Res 711, 175-183, 1996) MAO- B 5 LDA neuroglia © astrocytes were cultured as described (192, 13-16, 1995 et al., Neurosci.

Lett. 1.80867610). After a week in culture at 75 CO;7455 air and at 27°C; WAY was treated by trypsinization and ultrasound in YO mM Tris-HCl pH on ice (pH = 7.4) containing 1 mM EDTA thereafter; The obtained degradation products were centrifuged for 0 min at 8 000081 0C and equal parts of 0 cannabinoid supernatants were taken to determine MAO activity using de sane Ampbx Red ls MAO Assessment ( Molecular Probes, Leiden, The Netherlands) based primarily on the method described by (Anal.

Biochem. 253, 169-174, 1997) Panchuk, Voloshinas Zhou Measurements were performed according to the manufacturers' instructions. briefly; and before adding the base material; Samples were incubated for 0 min in a 976-well plate with drugs or solvent (total volume 00 µL). after that; Vo added 00 μl sale Amplex Red reaction containing 7 units/mL horseradisch Y) peroxidase (HRP), p-tyramine HCI mM; A precursor for MAO Bs MAO A (Youdim and Finberg, Biochem.

Pharmacol., 41, 155-162, 1991) and (10 mM) Amplex Red under these conditions” and by oxidation catalyzed by MAG for tyramine in a reaction conjugated with (HRP). Amplex Red to fluorescent resorufin to measure the activity of MAO Ye. The time-dependent increase in resorufin formation was determined at intervals of 2 min for 1 min at room temperature in a fluorinated flour plate. BMG ) brain fluorescence

E1 —

090 (165p12016000010);_using (38) at 4464© nm and emission at nm GmbH, Germany. within this time limit; The increase in fluorescence was found to be linear. to calculate results; The data for the previous readings (i.e., in the absence of them) were corrected for the expression “MAO (the substrate for tyramine) in the form of an increase in fluorescence units/min. The protein content was determined according to the method

© Bradford et al. (1976, 248-254, 72) (Anal.

Biochem., using BSA as standard. Statistical comparisons between groups were made using one-way analysis of variance (ANOVA) followed by Newman-Keuls post-hoc selection. Pad > 1.01 was considered significant. MAO-B inhibitory activity of compounds 06-81 was measured at CEREP (Paris - France); According to the method explained by 192, 128, 1979 .J.L.

Salach, Arch.

Biochem.

Biophys.,

Ve dithiolethione and related dithiolethione compounds are effective in doses in the range of 0.01 to [ona 0 kg] after administration by cadll and their selective inhibition of monoamine oxidase-B makes them particularly useful in the treatment of Mental and neurological disorders caused by irregularities in the main monoamine-generating systems or that can be treated by treating these All and the disorders mentioned are selected from the group consisting of:

¢ bipolar I disorders, bipolar disorder, Jia mood disorders, mood disorders, Vo and disorders causing unipolar depression, bipolar 11 disorders, bipolar disorders, seasonal affective disorder, minor depression, simple depression (Jie unipolar depressive disorders) Postnatal depression and postpartum depression + “seasonal affective disorder, including anxiety disorders and heart disorders” dysthymia and major depression

: Ye (with or without agoraphobias3all) panic disorder

hurt

#1 -

social anxiety, obsessive compulsive disorder (gay) (with or without chronic co-morbidity or schizotypal disorder), posttraumatic stress disorder, generalized anxiety disorder, substance-related disorders Narcotic disorders including

© Substance Use Jie Dependence and abuse and substance-induced disorders (such as substance withdrawal ¢ (substance withdrawal), attention deficit oly! Disruptive behavioral disorder Attention deficit hyperactivity disorder Involuntary sleep Narcolepsy ¢ Jie impulse control disorders Pathological gambling anorexia bas a Anorexia Jis eating disorders Pathological gambling 0 Jie tic disorders and earth disorders bulimia nervosa 5 m and neurotic bulimia

Tourette's disorder; restless legs syndrome; Disorders characterized by impairment of knowledge and/or memory Jie Alzheimer's disease and Parkinson's disease sponsored by AIDS AIDS dementia and/or psychological disorders associated with the condition

05 Pathogenesis and Neurorehabilitation Co-morbid psychiatric disorders and neurorehabilitation Post-traumatic brain lesions and other CNS disorders Jie epilepsy ¢ Down's syndrome Huntington's chorea Huntington's disease Ly several forms of pain including headache and atypical facial pain

chronic pain, chronic pain syndrome, pain disorder, atypical facial pain, impotence, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis ¢ syndrome 0; cerebral and peripheral vascular system disorders; Necessarily including; sexual dysfunction and thrombosis ¢ pulmonary and ocular hypertension

brain

- 11 -

myocardial infarction and thrombosis; nonvascular smooth muscle disorders; including cerebrovascular stroke, gastrointestinal motility disorders (AT), respiratory distress, asthma, and sphincter; contraction of smooth muscle in the duct ¢ hemorroids and hemorrhoids + motility disorders ¢ sphincter and smooth muscle spasm in the gastrointestinal tract © and premature birth and MAO inhibitors may be antagonized. 51800©" Bladder dysfunction during childbirth is useful in relaxing the urinary tract for the passage of kidney stones; BLE may be relaxed

Use it to relieve muscle contraction and spasms. preferably The compounds of the invention are used to treat mood disorders «0 and bipolar disorders of bipolar IT disorders; unipolar depressive disorders ¢ and minor depression “seasonal affective disorder” and postnatal depression; mental fatigue, dysthymia, major depression, anxiety disorders, panic disorder, social phobia 8, and obsessive compulsive disorder; posttraumatic stress disorder, generalized anxiety disorder, “substance related disorders,” substance use disorders, and substance-induced disorders.  Substance withdrawal  Poor attention; 0 and behavior disorders Attention deficit and disruptive behavior disorders ¢ Attention deficit hyperactivity disorder ¢ Narco-lepsy ;

a

ZY -

And impulse control disorders » and pathological psychosis

gambling ¢ and eating disorders and anorexia nervosa » and bulimia

¢ tic disorders in the muscles (gah and contraction disorders + nervous bulimia nervosa)

Tourette's disorder, restless legs syndrome ¢©, pain + headache ¢, atypical facial pain,

pain disorder chronic pain syndrome; and sexual impotence

dysfunction » airway obstruction, asthma, and other disorders

gastrointestinal motility disorders ¢ and hemorrhoids; And shrank

The sphincter and smooth muscle spasm in the gastrointestinal tract. Bladder dysfunction.

the dose

The potency of the compounds of the invention as MAO-B inhibitors was determined as previously described. of force

measured for a known compound of formula (1); A person can estimate the lowest theoretical effective dose. when

A concentration of the compound equal to twice the measured inhibition constant; Approximately 710,000 enzyme Vo will be inactivated by the compound.

Converting this concentration to mg of compound per kg of patient yields a lower theoretical effective dose;

to enforce dynamic availability; pharmacokinetics; optimal pharmacodynamics; Gal considerations may change the dose

actually given to a higher or lower value.

The appropriately administered dose is 00001 - inn) mg/canal and preferably 001 = 0.1 6 mg/kg of the patient's body weight.

processing

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108. The term 'treatment' as used herein refers to any treatment of a mammal and preferably a human condition or disease and includes: (i) preventing the disease or condition from occurring in a person who may be predisposed to the disease but has not or (vii) inhibiting the disease or condition, i.e. halting its progression; or (vii) mitigating the disease or condition, i.e. bringing about the regression of the condition; or (£) mitigating the conditions caused by the patients, i.e. stopping the disease. Examples Example No. 1: Materials and Methods All reactions involving moisture-sensitive compounds were carried out in a dry nitrogen atmosphere. Plastic slides coated with (TLC) shown. eluent with filter material (Mark Silica gel 60 F254) dL nm) or YO £) UV light The theoretical examination of the compounds was carried out with an ultraviolet light

Acros silica gels shown by eluent flash chromatography to purify with filter material ra VO = ...20 ( YO mm). The NMR spectrum was determined in the shown solvent. The pairing constants 1 are given in hertz. The shapes of the peaks in the NMR spectrum are indicated by the symbols “q” ds (ele) (two-quadrant); wa (three); "2" As (I) (binary); and "9" (singular); and "5" (large singular); “mg (multiple). Example No. ?: Synthesis of specific compounds Y£AA

Yq - — the specific compounds for which the synthesis is explained hereinafter are intended to further describe the invention in detail “is” and therefore do not appear to limit the scope of the invention in any way. Reversal of the structural formulas of the specified compounds of the invention 6 s) 1 R, a Ry Tw Tee H 4-hexyloxyphenyl 0 i nm-A2 H nm A3 0 4-methylphenyl b. -S(CH,)4CH(CH3)N(CHs)-2-propynyl phenyl -S(CH,);CH(CH;)N(CHj3)-2-propynyl phenyl would be further embodiments of the invention clear to those skilled in the art to consider the practice and practice of the invention disclosed herein, by which it means that the specification and examples may be taken as exemplary only, provided that the real scope and spirit of the invention is indicated by the claims, etc.

01 - Compound Al 5 8 / A 0 0 schema Al step: for schema Al (©) added TY grams”; 1 mol) sulfur to (NN- DMF (de Yor) dimethylformamide) and heating the resulting mixture to the reflux point Ja (Ald) sulfur is approximately. (7.47 Gy 001 mmol) 2-(4-n-hexyloxyphenyl)-propene was added drop by drop. After completing the addition; Stirring and heating were used for the reaction followed by TLC (thin layer chromatography ¢ filter material (toluene : eluent Ve) after ; hours the reaction mixture was allowed to reach room temperature. Filtration and evaporation produced under atmosphere vacuo to the remaining reaction mixture which was subjected to column chromatography (5:02; filtrate, toluene: eluent. The combined product containing the shal was concentrated under vacuo; the remaining ssh was returned from cyclohexane; yielding ) 0 (FAY aha) of the desired compound, Al, the melting point is 071 M. Yo, the compound, A2, is

71 - mm PH to the exit and reflux —_— + OH Cl 0 3 0.0 Hala Jw »[Per L H Drawer 2 M 0 0 Chart A2

A-2 chart i step

to an absolute ethanol solution containing ? 1 equivalent of (NaOEt) sodium ethoxide © 1 equivalent of 4-hydroxyacetophenone was added together with 1 equivalent of N-(2-chloroethyl)morpholine after

complete addition; The reaction mixture was allowed to reflux for ½ hours; The heating was then stopped and continued

Stir for 1 hour at room temperature.

The solvent was removed under vacuum and the residue was raised in aqueous hydrogenchloride “(Louis le Y).

washing of the last solution with 0 diethylether; the aqueous layer was neutralized with a solution of (~sodium hydroxide (Y)); Then it was done

Extraction by .diethylether and then drying of the combined organic fractions using .Na,;S0O,

The removal of the drying agent was produced by filtration of the aly solvent in vacuo over phenolic ether

Ju (orange-yellow) produced by JA

Step ji of Diagram 8-2

‎Y£AA

A YY — (according to y 1959(1398) -(Thuillier et al., Bull.Chim.Soc.,) to the amount of absolute toluene Bb containing ? equivalent of (:11200)011:(: 011:011) sodium tert.-amylate was added to 1 eq. of phenolic ether from step A and 1 eq. of dissolved carbondisulfide. When the addition was complete, the reaction mixture was stirred for 1 h. Thereafter; Addition of 1 equivalent of 1,2-dibromoethane© Then the stirring was continued for VY hours The reaction mixture was jue by sodium Y hydroxide solution (approximately N) and by water until the pH reached 11 pm to no. The organic part was dried using 0.214:50. The removal of the drying agent by filtration and removal of the solvent in vacuo produced the 1,3-di-thiolane derivative because it was in the form of orange crystals by producing JV step fii of scheme A-2 Vo then treated the di-thio derivative Because from step ii by tetraphosphorusdecasulfide (PsSio) in xylene in reflux for 11 minutes. After cooling and then washing with sodium 1 (Ale hydroxide standard solution), then chloroform was added, and the resulting organic part was dried using (Na; SO). Purified by column chromatography (D5:0; filtrate, diethylether: eluent toluene 0 1/1), yielding the desired compound 82 in the form of orange crystals with a yield of 74. Melting point: 011 C “H-NMR (CDCl, & 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). Then, compound 3 was prepared similarly to the described procedure for compound 2. Red oil 'YL4A'

17 - For “H-NMR (CDCls, 8 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 made analogously to the procedure described for compound A2.

H P 5 7 0 5 p i N de = 4 0 aX.” : 0 0 5 5 0 Scheme 3-1 Step 1 of Scheme 3-1 Y equivalent of piperazine and 1 were dissolved Equivalent of: 5-methylsulfanyl-4-phenyl-[1,2]-dithiole-3-thione (Grandin, A. et al., Bull.Soc.Chim.Fr., 01(11)(1968) )4555 in absolute cthanol; Then the reaction mixture was delivered to the Bla reflux. After 7 days the solvent was removed under vacuum and the residue was purified by chromatography (Si0; eluent: ethanol in toluene v/v). The combined product containing the fractions was concentrated in vacuum; and recrystallization of the remaining acetone; Which 0 produces orange crystals with a yield of 777 from the Bl compound and the melting point: 17/4 C. M7

ppm): 2.97 (t, 4H), 3.44 (t, 4H), 4.23 (m, 4H), 6.42-6.76 (m, 3H), H-NMR (CDCl, (m, 5H) 7.34-7.49 Compound B2 (shiva crystals melting point: 018 P) was prepared similarly to the described procedure for Bl ppm: 2.37 (3H), 2.98 (t, 4H), 3.45 (t, 4H), 4.23 (m, 4H), 6.43-° E” H-NMR (CDCl, (m, 3H), 7.22-7.28 (m, 4H)) 6.76 Compound 83 ( red crystals; melting point: VEA - 100 2 with decomposition) similar to the procedure described for compound BI compound Cl i No de XX ¥ = 8,! 5 s—S 01 7 0 Scheme C-1 Step E of Scheme C-1 Dissolved (1 girl TA mmol) of S-methyl-[1,2]- dithiol-3-thion in © mL absolute ethanol. Then (0.¥ g) was added; .£1 mmol) 4-(diethylamino)-benzaldehyde and 1 (0 mL) piperidine; Then the reaction mixture was heated in a sad water bath for 2 hours. The reaction mixture was concentrated in fie atmosphere and the residue was placed in the freezer on which the crystals formed. M7 has been isolated and reinstated

Yo - — crystallization of isopropylalcohol yielding 1.0 aba (£9.9 mM) AYO (Use) of the desired CI compound; melting point: 71 °C. See also JP No. 144677 17 The compound (TLC) C2 (SiOz) was prepared leaching material (1771 = Rf ¢ toluene : eluent in the presence of starting materials); Similar to the procedure described for compound Cl© compound DI J Me,NH,* S—$§ IN ii boc ! J 8-5 N _ i. R W Hall . L S$ ~~ STS D1.HCI Scheme D-1 Step j of Scheme D-1 dissolved (5.for 1 7 g; 897.95 mmol) of 1-bromo-2-phenylpropane in (Ja)++¥ (Ja DMF | 0) after which V£.Y) g was added; (££ mmol) sulfur . The reaction mixture was allowed to reflux for one night after which the stirring was continued at room temperature for another night. The Lis reaction was concentrated under vacuum after which 100 (mL) LE toluene was added to form crystals, collected and dried under vacuum. Yield (aha VY) 45.7 mL (Use 757) Yellow Solid (YLAA)

: of the compound dimethylammonium containing -4-phenyl-5-mercapto-[1,2]-dithiol-3-thion

D-1 for chart ji step £4); see above) in iodide (for synthesis of iodine mmol) from 0014 g; Y.0) dissolved (from dimethylammonium mmol) salt 00.4 (aha ml) methanol after that Add (?© and the remaining che is subject to step 1). The reaction mixture was stirred overnight; Then it was concentrated in an atmosphere to produce 1/1 ethylacetate / heptane: eluent to column chromatography (0.5:0; filtration material. Red oil 0 101 mmol 0.1 mg Yao ) Concentration of the product containing fractions

Diagram D-1 step jij after which dichloromethane in a little ii mmol (step product 0.6 cane Vor) 0 was dissolved; So that the final concentration was about ? N isopropanol (in 1 HCI an amount of (mg) YO substance) N was added. The reaction mixture was stirred for one night and then concentrated in vacuo; resulting in M. VEY an orange solid containing 01-110©1; melting point: m; with decomposition); Similar to Procedure 000 - 47 (Melting Point: D2) the compound used for the preparation of the jodide that was used for the synthesis of the described jodide of Compound 01 was prepared. V0 (see below) can be prepared as DI M); Similar to the described procedure for compound AY - 87 compound 03 was prepared (melting point:

DI used for the preparation of jodine, which was used for the synthesis of iodine, can be prepared.

71- Compound D4 was prepared (melting point: 66 - Vo m); Similar to the procedure described for compound 1, 100106 can be prepared which is then used to synthesize the iodine used to prepare 1 [compound 05 was prepared (melting point: VY = 10 C); Similar to the procedure described for compound 1. The jodine that was used for the synthesis of jodine used for the preparation of 11 2 and then the compound D6 (melting point: Yo — Ve m ¢) can be prepared similarly to the described procedure for the preparation of compound “D1 Starting with para bromomethyl toluene as an alkylation agent Synthesis of iodine used in the preparation of compound DI (scheme D-2 I a | | OH 00 mP (for HN OH HN AN Scheme 17-2 0 Step 1 of Scheme 1-2 (6.4 g; 7.6 mmol) 4-hydroxy-2-butanone was dissolved in (Ja You) 1,2-dichloroethane ¢ then (0.©A+ ce mM) propargylamine was added The reaction mixture was stirred for 10 min after which it was cooled to 0.9 mM (cab \K 9 mmol) NaBH(OAc) was added; Part the mixture in a saturated aqueous NaHCO solution. The extraction of the solution produced in me seven. DCM 0 _ last aqueous by DCM 7 grams of desired product after concentration in hatcher atmosphere. m was made

YA — aqueous layer basicized by a solution of NaOH (777 aqueous) and saturated with NaCl (solid); A second extraction was performed with EtOAc. The incorporated organic fractions were dried with Na; SOs and after removal of the drying agent by filtration and removal of the solvent by concentration in atmosphere ie VT g was obtained; TAY of desired product (as orange oil). This was used in © step ji without additional A850. Step jj of diagram D-2 dissolved (76. aba 4.48© mmol) of the aminopropanol derivative (from step You) (i ml) DCM was then added (3.7 ml; Approximately 10 mmol) triethylamine was added (0 (g) 10 mM Boc) (BockO (Use = dilatation < Hanyan-.16). The resulting mixture 0 was stirred overnight and then concentrated under vacuum The residue was dissolved again in 51086. The organic part was washed with a saturated aqueous NaHCO solution, water and ale solution (117) after which it was dried with B80. Jie g; (7001 brown oil containing aminopropanol protected by N-BOC step ji of chart D-2 VO dissolved [YY] g” 1776 mmol) triphenylphosphine in (DMF (de e+) after which V9 was added (g) 7880 mmol) imidazole; The resulting mixture was dialyzed to SVZ m. A solution of (70.0 g 146 mmol) iodine in (700 mL) DCM (dichloromethane) was added dropwise to the reaction mixture; After the stirring was continued for 10 minutes. after cell A) grams is added; ¥0 mmol) aminopropanol protected by N-Boc (from step (ii Yo) was dissolved in (04) DCM (Ja) and the stirring was continued at Safzam degree for 78 minutes. At that time the

Yq _ - allow the reaction mixture to come to room temperature and stir for VT 1 hour. The reaction mixture was filtered; The filtrate was washed with a saline solution and concentrated in an incubator. The residue was filtered over a short column of SiO (filterate V1) EtOAc/heptane: eluent and the filtrate concentrated under vacuo, yielding (04 aba 4) of the corresponding jodine as a light yellow oil. This jodine© was used in the preparation of compound DI (see Scheme 0-1).The corresponding jodine required for the preparation of compounds D2, 03, 04 and 05 can be prepared according to the conditions described in the synthesis of jodine used in the preparation of 31 (combined 0-2).For D4 cof compounds, protection steps - AY protection are not necessary due to the methyl group on the nitrogen atom. 0 Example No.?: Formulating the compound Al For oral administration (0.07: desired amount) (20.0 + © = mg) of compound Al solid were added into a glass tube, some glass beads and the solid anesthetic was ground by vortexing for 2 min. After addition of (Jo V) of a solution of 71 methylcellulose in water and 77 (vol/v) of 188 ¢ (Lutrol F68) Polaxamer the complex was suspended by swirling 01 sad 0 min.pH was adjusted to 7 by a few drops of 0.01 (N) aqueous NaOH.The remaining particles were also suspended in the metal by using an ultrasonic bath. For administration into the peritoneal cavity (6.2: to desired amount (0+ = 10 mg) of solid AT in a glass tube; And some glass beads and solid anesthetics were ground by vortexing for two minutes. After adding (de 1) of a solution of ZY methylcellulose in cla and 5/cele 4 mannitol 0 the compound was suspended by vortexing for 10 minutes. The pH 4 was finally adjusted to 17. MA

060 EXAMPLE 4: PHARMACOLOGY TEST RESULTS TOTAL ACTIVITY OF MAO-B ACTIVITY MAO-A ACTIVITY JANIS (MAO 7) (INhibition 7) ANT Concentration (μmolar) TAMER LA GA ATA L CTT eT So Clee [a eT Te a De] cl fave] ow A A A A A A A A A A A A A A De hee aj Cee eee ee dere ee Effects of deprenyl (L-dep) and anethole dithiolethione (ADT) on monoamine “(Ys Y J sac) oxidase (Z MAO) activity of ADT L-dep and 3H-1,2-dithiole-3-thione (D3T) on monoamine oxidase-B (MAO-B) activity (columns ¢ 1505(« clorgyline (chlor) Js ADT; © on the activity of monoamine oxidase A (MAO-A) (columns (As 1) in cell extracts obtained from cultures of neonatal rat striatal microglia. MAO activity and drug effects on it were determined as preferred by Then expressing the data in the form of percentages for the corresponding comparisons, and the averages were made for up to two brains

YY — - five independent experiments Shae three times. The overall activity of MAO was determined in the presence of solvent only (Lay 0 ); MAO-B activity in the presence of (+ μmolar) of the selective MAO-A inhibitor clorgyline ¢ and MAO-A activity in the presence of 1 μmolar of the selective MAO-B inhibitor deprenyl . It is known that astroglial cells predominantly express (Thorpe et al, J.) MAO-B (Histochem.

Cytochem, 35, 23-32, 1987 8. using a non-selective tyramine substrate and an inhibitor” (Youdim and Finberg, Biochem.

Pharmacol. 41, 155-162, 1991) deprenyl MAO-B ang that up to 77860 MAO activity forms MAO-B. The remaining MAO activity (about XY) was inhibited in the presence of an effective concentration limit Total deprenyl was maximized by addition of the selective MAO-A inhibitor deprenyl Li. clorgyline reduced MAO activity of astrocyte glia in a concentration-dependent manner with apparent ICs of approximately 004 µm. ADT concentration-dependently showed total MAO activity with an apparent 1.15 micromolar; maximum inhibition (A) was reached at a concentration of To 1 micromolar. After selective and complete inactivation of MAO-A by clorgyline 0 identical concentration-effect relationships were observed for ADT deprenyl as compared to those for inhibition of total MAO activity. These conditions were fulfilled; That is, in the presence of clorgyline 0 concentration-dependent inhibition of MAO-B activity was observed for D3T with apparent ICs of ~ micromolar To and maximum effective concentration of Tov micromolar. When selective and complete blocking of MAO-B activity by deprenyl « no statistically significant effect of ADT on MAO-A activity was detected. The inhibitory activity of MAO-B of Al - 06 compounds measured at CEREP (Paris, France); According to the method described by 192, 128, 1979 .J.L.

Salach, Arch.

Biochem.

Biophys., Y. Brain

—- YY - A Te

brain

Claims (1)

- their secret _ claims 1 1 - use a compound of formula (1) 1 aerated R, Y 7 where: ; Ry and Y8 are the same or different; And full: hydrogen, alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, ° alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, 1 arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, L dialkylamido, A together with the carbon atoms to which they are attached to an aromatic ring or Rog Ry may form 4 nitrogen or ¥ hetero-atom selected from 1 non-aromatic containing 0 or 0 : Jie; 1,2,3- VY triazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine rings Ve A itself selected additional substituent groups of Ry 3 Ry may carry 1 hydrogen, alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, 1 alkyloxy, aminoalkyloxy, morpholin-4-yl-alkoxy, piperidin-1-yl-alkyloxy 1 alkenyloxy, aryloxy, acyloxy, amino, alkylamine, dialkylamino, arylamino, YA thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, alkylamido or 1 dialkylamido, Ye brain DOS — 71 and tautomers and stereoisomers lie N-oxides s stereoisomers Lady YY salts hydrates and pharmaceutically acceptable solutes of the mentioned compounds of YY formula (1) and their tautomers and their stereoisomers stereoisomers ;?* N-oxidesy; To prepare a pharmaceutical formula to treat, mitigate, or prevent mood disorders Yo; bipolar 1 disorders; and unipolar depressive disorders YV; And simple depression, minor depression + disorder, ise YA seasonal, seasonal affective disorder ¢ and postnatal depression 4 - and mental exhaustion, dysthymia ¢ and major depression, major depression and anxiety disorders 00 anxiety disorders ¢ panic disorder ¢ social phobia 1 ¢ obsessive compulsive disorder ¢ YY posttraumatic stress disorder YY generalized anxiety disorder ¢ and drug-related compulsions;? | substance related disorders » substance use disorders Yo and substance induced disorders substance induced disorders | substance withdrawal © olay 0 attention deficit and disruptive behavior disorders 4 + attention deficit hyperactivity disorder ¢ 4 narco-lepsy ¢ and control disorders Pulse “impulse control disorders 0 and pathological gambling ¢ and eating disorders (eating) and anorexia nervosa ¢ and tic “bulimia nervosa for disorders, Tourette's disorder, restless legs disorders syndrome , pain, headache, atypical facial pain, ey and pain disorder and chronic pain syndrome e — Yo _ chronic pain syndrome £¢ ¢, sexual dysfunction, airway obstruction, asthma, gastrointestinal motility disorders 6; and hemorrhoids + sphincter and smooth muscle spasm in the gastrointestinal tract ¢A and bladder dysfunction .bladder dysfunction £9 Ona 1 7 - Use according to claim (1); it is characterized by the fact that the compounds mentioned in the formula (l) are: 5-(p-methoxyphenyl)-3H-1 2-dithiole-3-thione, 3H-1,2-dithiole-3- thione or ¥ 4-methyl-5-(2-pyrazinyl)-3H-1,2-dithiole-3-thione. ¢ 01© - use pursuant to claim (1); characterized by the compound of formula (1) being 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione (1):) ) is a compound of the general formula - 1 4 S—S Mm >. ground 8 Y Ces Ble Ri 4 for phenyl has an optional substitution 5 Ry representing S-CH,-(4-methyl-phenyl) 0 or one of the following subgroup: Mach CH, S-(-CH,) EHAN-CH C=CH N -9-(- Jn” -N- -C= Cb N— ary 2 | 2 \ 0 R, 1 0 (ii) 07 oe - 5 Lbg (iii) (C1. or hydrogen is Ry where L is ? or ¥ 5; or © is A or ¢ alkyl 3) 1 or “ hydrogen is 4-hexyloxyphenyl is 8.00 substituted in and stands for 511; or subgroup: phenyl of be Ry 11 3 5 5 = VY —-8—S (iv) : Ry 5 hydrogen represents Ry \Y - —CH=CH-4-(diethylaminophenyl) , VE or subset: -CH=CH-(2-quinolyl) 0 mam Mr (CH), -N >” Rs 0 Yi independently Rss Ry where “ has the same meaning as is given by; The IY to which they are attached represents a nitrogen saturated ring or forms together with an alkyl (Cla) VA © atom or atoms; Optionally containing one or more heteroatoms 4, 5, “QO, or N” selected from AE : is Ry and the alkyl (Cig) is Ry 1a , 1-(2,3-dihydro-1 4-benzodioxin-5-yl)piperazin-4-yl, YY; or Rp YY is a cyano and Ry is the subgroup NH-C(O)-NH-— phenyl 4 » in which the subgroup is a phenyl group substituted (eis) Yo or 1 87 is -SO,CH; and then amino Ji « Lal and its tautomers and its stereoisomers N-oxides s stereoisomers YA also salts of hydrates s and acceptable solutes Pharmacologically, the aforementioned compounds of formula (1) ¥ 4 and their tautomers and their stereoisomers N-oxidess 0 . 1 * - The compound according to the claim (€) has the general formula (1): S—S )0 AN associates R, R; 1 where: R 5 4- hexyloxyphenyl Ja Ry ¢ represents hydrogen “ —~)o Ry 5 represents hydrogen wj bit represents Ry 1 represents Ry hydrogen represents Lm ' J of pO R, Ja Ris phenyl l' 4 J Eo Ry A Ry 5 4-methylphenyl b ' l Ry 4-methylphenyl and with 4-phenylpiperazinyl ¢ YLAA repair “-CH=CH-(4-diethylamino-phenyl), representing Ry 3 hydrogen representing Ry 01 “-CH=CH-(2-quinolinyl) Ji<witha hydrogen representing 87 WY ¢ -S(CHy),CH(CH3)NH-2-propynyl and is composed of phenyl representing Ry VY ' -S(CHy);CH(CH3)NH-2-propynyl represents Ry 5 phenyl represents Ry \Y ¢ -S(CH,)4CH(CH3)NH-2-propynyl Jici Ry s phenyl represents 85 0 4 ' -S(CH;)sCH(CH3)N(CHj)-2-propyny! And with phenyl it represents Ry Yo ' -S(CH,)sCH(CH3)N(CHj)-2-propyny!l represents phenyl Jud Ry 5 «-S-CH,-(4-methylphenyl) and represents phenyl represents Ry 0 1 + - pharmaceutical composition comprising; plus at least one pharmaceutically acceptable carrier and/or adjuvant 1; contains a pharmacologically effective amount of at least one Wh compound of the protectant (4); Or ale as an active ingredient in the brain