SA06270023A - Anethole dithiolethione and other dithiolethiones for the treatment of conditions associated with dysfunction of monoamine neurotransmission - Google Patents

Abstract

The present invention relates to dithiolethion derivatives as monoamine oxidase amino inhibitors, specifically MAO-B inhibitors, and methods for the preparation of these compounds, and to new useful intermediate compounds to synthesize the derivatives of the first ethon mentioned. The invention also relates to the use of a compound disclosed that it is herein to manufacture a drug that gives a beneficial effect. In embodiments of the invention specific compounds disclosed in this patent are used to manufacture a drug that is useful in treating, mitigating, or preventing cases associated with monoamine neurotransmission deficiency. Compounds have the general formula (I) where symbols have the meanings given in the standard.

Description

oy - - anethole dithiolethone and other dithiolethone compounds for the treatment of conditions associated with insufficiency of monoamine neurotransmission Full Description BACKGROUND BACKGROUND The present invention relates to dithiolethone derivatives as GOD monoamine oxidase inhibitors; Specifically MAO-B inhibitors and methods for preparing these lS pall and new intermediates Bade for the synthesis of the aforementioned dithiolethone derivatives. The invention Lind relates to the use of a compound disclosed in this patent for the manufacture of a drug that gives a beneficial effect. of a beneficial effect herein or manifest to a person skilled in the art from the specification and general information in the art. The invention also relates to the use of a compound of the invention to manufacture a drug for the treatment or prevention of a disease or condition. More specifically, the invention relates to a new use for the treatment of a disease or condition disclosed in This patent or is indicated to a person skilled in the art from the specification and general information in the art.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 insufficiency. 4.3.4.4.3.4 sind-mono-oxidase inhibitors can cause an increase in the levels of norepinephrine, epinephrine, dopamine, tryptamine, and serotonin in the brain and other tissues, and thus can cause a wide variety of pharmacological effects caused by 1 their effectson these neurotransmitters. The currently available MAO inhibitors have Jie. Lazabemid Glas has a wide range of side effects including psychological (delirium; hallucinations; agitation); And hearty

Ag —_ _ vascular (orthostatic hypotension; hypertension); and neuroticism (extrovertedness; unusual movements). fl " ~ N mofegeline 1- 0 sis Cl = l " SN Nex ;8 0 lazapimid rasagiline 0 General description HAS The object of the invention Jad is to develop Gana inhibitors MAO is structurally unrelated to the available Ula and has minimal side effects. Application No. 27970/98 WO discloses the use of 1-7-dithiol compounds = F-thiones to treat dl damage or prevent cellular damage caused by oxygen-containing radicals. Requisition No. WO 0 01/091138 discloses dithiolthione compounds for the treatment of neurological disorders and memory impairment. These compounds have been shown to inhibit ©-amino acid oxidase (143.3 “(DAAO, EC). It is the enzyme that sterically deaminates 0- sud acids (AE), thus generating hydrogen peroxide” which is a reactive oxygen species. Dithiolthiones have never been shown to inhibit monoamine oxidase, which is an entirely different enzyme.

- surprisingly; It has now been found that dithiolthione compounds strongly inhibit MAO-B activity in cellular extracts derived from LOA-derived rat striated astrocyte microglia; While no significant effect on the activity of MAO-A was observed, the invention relates to the use of compounds of the general formula (1) S—S (1) flattened R, ° where: - Ry and Y are the same or different; It is hydrogen; alkyl; alkenyl; alkenyl; aryl; fluoro; chloro-bromo or hydroxy; alkyl-oxy; alkenyl-oxy; aryl-oxy; acyl-oxy-amino; alkyl-amino or di-alkyl 01 amino; or aryl amino or thio or alkylthio or arylthio; or cyano or nitro or acyl; or amido; or alkyl amido; or dialkylamido; or may form Ry and 82 together with the carbon atoms being attached led an aromatic or non-aromatic ring containing 0, 1, or Y heteroatom selected of nitrogen, oxygen, or sulfur; Ji rings furan; thiophene; doom or oxazole; thiazole or imidazole.” or ve pyrazole; or isoxazole; or isothiazole” or 1 7*- oxadiazole; or 1-SV triazole; or SA 1-thiadiazole” or pyridine; or pyridazine; or pyrimidine; or pyrazine; may Rpg Ry itself carries select additional substitution groups of hydrogen, alkyl, or alkenyl; or an alkynyl or an aryl; or fluoro; or chloro; or promo; or hydroxyl; or alkyl oxy; or

This is an alkyl oxy amino; or -;-yl-alkyl-alkyl-morpholine or -1-yl-alkyl-oxy piperidine; or to alkyloxy; or an aryloxy, acyloxyene, amino, alkylamine, dialkylamine, or arylamino; or thio, alkylthio, arylthio, cyano, or oxo; or nitro; or soothe; or amido or alkyl cad or dialkylamido; © and ligand compounds, stereoisomers and terminal nitrogen oxides as well as salts, hydrates and acceptable solutes Liana of the said compounds of formula (1) and their sterose compounds and their stereoisomers and nitrogen oxides; To prepare a pharmaceutical composition for the treatment, mitigation or prevention of conditions associated with monoamine neurotransmission insufficiency. The invention relates particularly to the use of compounds of general formula o(1) wherein Ros Ry is the same or different from 0; represents hydrogen; or (JST) or aryl; optionally substituted by one or more selected hydrogen atoms or groups; alkyl; aryl; fluoro; chloro; bromo; hydroxyl; alkyloxy; aryloxy; or esd Alkyl amino, or dialkyl amino, thio, oxo, or nitro, more specifically the invention relates to the use of ©-(©-methoxyphenyl)-117-0,7-dithiol-vo*-thion (anethole) glo thiol 0 —HY 5 (ADT ?-dithiol -*-thione” (D3T) f;-methyl 0 (?-pyrazenyl) -113- 0 7-dithiol T= thione (ultipraz): 73 is b one SAS liga CH,0 ultepraz anethole dithiolthione D3T

ut —__ and most preferably to use 0— —P) methoxyphenyl -”11- =X) dithiol-7-thione; Anethole dithiol-thione (ADT) is a call analog of the lipids with a substitution of “HY 7-dithiol-?-thione” (031; in use for decades as a bile diluent and saliva diluent with no major adverse reactions observed) (1995, 252, 323 (Christen, M-O., Methods Enzymol.,

° In another respect the invention relates to compounds of formula (1) S——S (1) > molybdenum R, where: Ry is an optionally substituted phenyl and represents —CHp-S (;-methyl-phenyl) or one of the following subgroup: CH, \/l “S-(-CHa) CH-N-CH, 0 =CH —N N— aryl Rs ( i) 0" 0 jag LC

0 where « has the value 1 or © or ; or © and Ry is hydrogen or (Cra)alkyl” or Ry - is ;- hydroxyphenyl and Ry is hydrogen; or

Ry - is a phenyl with an Rp substitution representing SH or subgroup: 5 5 5-5 - (iv) Ry - is a hydrogen Ros representing CH = CH- -; - (diethyl sudvinyl); or - CH = 1©- (7-quinolyl); or the subset: what (CH,),-N ml AN Rs 0 where ' has the same meaning as given before; Rss Ry independently represents (C13) an alkyl or forms together with the nitrogen atom to which they are attached a saturated ring of © or Cdn optionally containing one or more selected heteroatoms of NN or 0 or “S or Ry- is (Cra) an alkyl and Ry is (gh YY) -1-hydro-1-01 benzo-dioxin -*-yl) in feces -;- yell; or Ry - is cyano and Ry is the subgroup -2111(0)0-1111 phenyl; in which the subgroup is an optionally substituted vinyl group; or Ry - is and802011- 5 Ry Aminos; their enantiomers, stereoisomers, and nitrogen oxides; Lads are pharmaceutically acceptable salts, hydrates, and solutes of the said compounds of formula (1), and their enantiomers, stereoisomers, and nitrogen oxides.

. TAC

The invention relates to racemic compounds and mixtures of stereoisomers as well as to stereoisomers

Each separately for compounds having formula (1). In the description of substituent groups the abbreviation “alkyl” (JS Cp means “alkenyl”; © Alkenyl; “alkenyl”” means © alkyl; Jad! (Cra) means “alkyl carbonyl” or “aryl carbonyl” or (Cua) aryl alkyl carbonyl” meaning "aryl";

0 viorel; or thienyl; or pyrrolyl; or to oxazolil; or to a thiazolyl; or to an imidazole; or to pyrazolil; or to isoxazolyl; or to isothiazol; or Peredil; or to pyridazinil, pyrimidinil, or pyrazinil; or

1 - me triazinyl; or vinyl; or to indazolyl; or to indolyl; or to indolesinyl; or isoindolyl »

or benzo[5]furanyl; or benzo[0]thiophenyl; or (7; gh mY hydro = ;- benzodioxene (deme) or benzimidazolyl; or benzthiazolyl; or purenyl; or quinolinyl; or isoshenolyl; or

0 shiennoll; or to phthalazinyl; or to quinazolyl; or quinolsalienil, or 8-0-naphthyridinyl, or piperidinyl; or naphthyl; or to azolenyl; Preferably Jud or (7; gh = F hydro = ;-benzodioxin –o—

Yale). means Jose JST (Cra), Ji), or common propyl; or sof propyl; (Cra) (JSS) means methyl” or ethyl; or normal propyl or isopropyl; or normal butyl; or =Y butyl; or

Isobutyl or '-methyl-propyl propylene. "Has an optional substitution" means that the group may be

1 and may not have additional substitution by one or more selected alkyl groups; or to alkyl; or an alkynyl or an aryl; or fluoro; or chloro; or bromo-or hydroxychloroquine; or alkyl oxy; or Ju oxy; or aryl-oxy; or acyl oxy; or amino; alkyl aminos; OD Alkyl Aminos;

or aryl amino; or a thior or an alkylthio; or aryl thieu, cyano, or oxis, or nitrous, or acyl; or

ad, alkyl oad, dialkyl coud, or carboxylate; Or two substitution groups may form

© Optional together with carbon atoms to which they are attached an aromatic or non-aromatic ring of © or + atoms containing 0, 1, or Y selected heterocyclic atom of nitrogen, oxygen, or

And - sulfur. The same Optional Replacement Kits may carry additional Optional Replacement Kits. Preferred optional substitution combinations include JS Cry, for example; Methyl, Ethyl, Trifluoromethyl, Fluoro, Chloro, Bromo, Hydroxyl, Cras Alkyl Oxy; For example; methoxy, ethoxy and trifluoromethoxy; and amino.

0 The prodrugs of the previously referred compounds are within 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, ALE solubility, permeability, stability, pre-systemic metabolism, and targeting limitations.

Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.

D.) 01

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

sla) (prodrugs”, 1 Med.Chem., 47, 2393-2404, 2004

metabolized when administered to a human by any known route; It belongs to compounds of formula (1).

1 to the invention. Specifically, this Gla is in compounds with primary or secondary amino groups or

Hydroxy. Such compounds can be reacted with organic acids to produce compounds of formula (1)

where there is an extra group which is easily removed after administration; For example, not

Restrictive amidine, enamine, Mannach base, Gite hydroxyl-methylene, 0-(acyloxymethylenecarbamate) derivative, carbamate, ester, amide, or enamineone.

- N=

Law The formation of nitrogen oxides of the compounds referred to before is in the scope of the present invention. May convert to nitrogen oxides metabolites. The extent to which Lao tertiary amines undergo oxidation varies from quantitative to near quantitative conversion. Nitrogen oxides may be more active than their corresponding amines, or less effective. while the nitrogen oxides are easily reduced to their corresponding tertiary amines by chemical means; This happens in the human body to variable 0 degrees. Some nitrogen oxides undergo almost no quantitative reductive conversion to tertiary amines. The corresponding Jel; In other cases, the conversion is simple

M.H. Bickel: “The pharmacology and biochemistry of N-oxides”, Pharmaco-logical

Reviews, 21(4), 325 — 355, 1969 General Features of Synthesis 0 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 reactants used and the possibility of using protecting groups, catalysts and agents. Activation, conjugation and final structural profiles present in the final compound: which is being prepared. Pharmaceutical acceptable salts: vo Pharmacologically acceptable salts can be obtained using well-known standard procedures in hydrochloric acid; Or with an organic acid. Jie An example is an inorganic acid

- 11 -

Pharmaceutical Preparations: The compounds of the invention can be rendered into forms suitable for administration by normal processes using adjuvants such as a liquid or solid carrier. Pharmaceutical compositions may be administered enterally, orally, non-intestinal (intramuscularly or intravenously), rectally, or locally (topical), and may be administered in the form of solutions, powders, or al A or capsules (including microcapsules); or ointments (creams or gels) or suppositories. Suitable excipients for such formulations are commonly used liquid or solid pharmaceutical fillers, extenders, solvents, emulsifiers, lubricants, flavor enhancers, colorants and/or pH regulators. One of the most frequently used adjuvants

0. May be referred to are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, cellulose and derivatives, animal and building oils Jie cod liver oil, sunflower oil, peanut oil or sesame oil; polyethylene glycols and solvents; For example; Sterile water and mono- and polyhydric alcohols such as glycerol.

1 The compounds of the present invention are generally given on A pharmaceutical formulations which 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, but are not limited to, tablets 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

0 and general information in the field. in invention forms; A pharmaceutical package or kit is provided

1 Comprising one or more containers filled with one or more ingredients of the pharmaceutical composition of the invention. Associated with such container(s) can be various written materials such as 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 manufacturing, use, or sale for human and veterinary administration. 6 Pharmaceutical Methods

MAO Specify an activity

MAO-A as a source of both aly activity were used in rat striatal astrocyte glia cells that were cultured with MAO-B (Carlo et al, Brain Res 711, 175-183, 1996) and after a week in the star (Langeveld et al., Neurosci. Lett. 192, 13-16, 1995) as described in 0 air and at 37°C; Cells were treated with trypsin 745 [CO, 78 cultured in icy-cooled Tris-1101 pH-buffered Yo and ultrasound thereafter; 1 mM EDTA containing (Vif = (pH) and 4 M was centrifuged and equal parts of 00001 of the obtained degradation products were centrifuged for 0 minutes at

Ampbx Red model MAO using MAO evaluation kit supernatant fractions to determine vo activity based mainly on the described method Alls (Molecular Probes, Leiden, The Netherlands) 0. (4nal. Biochem. 253, 169-174, 1997) Panchuk, Voloshina 3 Zhou by Eld. Samples were incubated for eld measurements according to manufacturers' instructions. Briefly and prior to microaddition into a 976-well plate with drugs or solvent (total volume 00 µl). after that; © 1 unit/ml peroxidase Grjar contains Amplex Red sale reaction Retalorchem 00 add ¥. (MAO Bs MAO A mM substrate each of Y) HCl Tyramine = P (HRP)

Das - ‎V+) (Youdim and Finberg, Biochem.

Pharmacol, 41, 155-162, 1991 (mM) Cad.

Amplex Red these conditions; Via MAG-catalyzed oxidation of tyramine in a conjugate reaction with HRP, Amplex Red is converted to fluorescent resorufin. To measure MAO activity, the time-dependent increase in resorufin formation was determined at time intervals of 2 minutes for 71 min at room temperature in a fluorinated microplate reader (BMG Labtechnologies GmbH, (Germany) using excitation at 544 nm and emission at 090 nm. During this time limit, I find that the increase in fluorescence is linear. To calculate the results, the Data corrected for previous readings (i.e., in the absence of MAO precursor tyramine) and expressed as excess facultative fluorescence units/min. Protein content was determined according to the method of Bradford et al. o(4nal.

Biochem. 72, 248-254, 7970 (0) using BSA as standard. Statistical comparisons between groups were made using one-way analysis of variance (ANOVA) followed by Newman-Keuls post-hoc selection. 1.10 was considered Pad < Important The inhibitory activity of MAO-B compounds 26-81 was measured at CEREP (Paris - France), according to the method described by JL 192, 128, 1979.

Salach, Arch.

Biochem.

Biophys., ve anethole dithiolthione and related dithiolthione compounds are effective in doses in the range 0 to 100 mg/kg following oral administration; and its selective inhibition of monoamine oxidase-3 makes it particularly useful in the treatment of psychiatric and neurological disorders caused by or that can be remedied by dysregulation of the major monoaminergic systems; The disorders mentioned are selected from the group consisting of: mood disorders such as bipolar disorder]; bipolar TT and unipolar depressive disorders such as major depression and seasonal affective disorder; postpartum depression, blues and major depression; Ley's heart disorders include panic disorder (with or without agoraphobia) and awe

- 14

Social and obsessive-compulsive disorder (with or without chronic co-morbidities or

dissociative-type disorder), post-traumatic stress disorder and generalized anxiety disorder;

and substance-related disorders, including substance use disorders (eg, dependence,

use) and substance-induced disorders (eg withdrawal of .substance); and attention deficit

0 Disruptive Behavior Disorders Jie Attention Deficit Hyperactivity Disorder and Involuntary Sleepiness;

Jie, impulse control disorders, pathological gambling, and eating disorders, Jie, anorexia nervosa.

bulimia; and disturbances of the earth Jie Turte's disturbance; restless legs syndrome;

Disorders characterized by impairment of knowledge and/or memory Jie Alzheimer's disease, Parkinson's disease, and dementia

AIDS and / or psychological disorders associated with the disease and neurological rehabilitation (brain lesions after

0 injury); and other ONS disorders Jie epilepsy; Down syndrome, Huntington's chorea, and Tyre

Various types of pain including headache, atypical facial pain, pain disorder and pain syndrome

chronic amyotrophic lateral sclerosis and impotence; and disorders of the cerebrovascular system

oceanic; necessarily including; renal, pulmonary and ocular hypertension; and thrombosis

myocardial infarction and cerebral vascular apoplexy; nonvascular smooth muscle disorders; Le in

ve include airway obstruction, asthma and other breathing disorder and gastrointestinal motility disturbances;

hemorrhoids; sphincter; contraction of smooth muscle in the gastrointestinal tract; and bladder insufficiency. Bonus

Thus, MAO inhibitors may be contraindicated in preterm labor and relaxation of the birth canal during childbirth may be beneficial

In the relaxation of the urinary tract for the passage of kidney stones; It may be used to relieve muscle contractions and contractions.

0 preferably; The compounds of the invention are used to treat mood disorders; and secondary disorders

of bipolar and bipolar disorders oT and unipolar depressive disorders; And mild depression

seasonal affective disorder and postpartum depression; mental fatigue; major depression;

1- SRI disorders, panic disorder; social dread; obsessive-compulsive disorder, post-traumatic stress disorder, old anxiety disorder, substance-related disorders, gall-use disorders, substance-induced disorders, ala withdrawal, cola weakness, and substance-related disorders. disruptive behaviour, attention deficit hyperactivity disorder, somnolence, impulse control disorders, pathological psychosis, eating disorders, anorexia nervosa, bulimia nervosa, involuntary muscle contraction disorders, Tourette's disorder, restless legs syndrome, pain, headache, atypical facial pain; and pain disorder; chronic pain syndrome” and sexual impotence; obstruction of the tract; Ad sed and asthma; The potency of the compounds of the invention as MAO-B inhibitors is as described above. From the measured potency of a known compound of Formula (1), one can estimate the lowest theoretical effective dose. At a concentration of the compound equal to twice the measured inhibition constant, 70010 of the compounds will be inhibited enzyme approximately by 1 compound. Converting this concentration to mg of compound per kg of patient yields a lower theoretical effective dose; enforce dynamic availability; pharmacokinetics; optimal pharmacodynamics; Other considerations may change the dose actually administered to a higher or lower value. The appropriately administered dose is 00011 mae) mg/kg; Preferably 1.1 - 001 mg/kg of the patient's body weight. Treatment ov The term “treatment” as used herein refers to any treatment of a mammalian and preferably a human condition or disease that includes: (i) preventing the disease or condition from occurring in a person who may be predisposed to the disease but has not diagnosed after or affected by it; or (vii) inhibition of disease or

1 ht — _ state. i.e. stopping cosh or (©) alleviating a disease or condition; i.e. bring about a regression of the condition; or (£) alleviate the conditions caused by the patients i.e. stop the symptoms of the disease. Examples Example 1: Materials and Methods All reactions involving moisture-sensitive compounds were carried out in a dry nitrogen atmosphere. The reactions were followed using thin layer chromatography (TLC) on plastic slides coated with silica (Mark Silica gel 60 F254) with the filter material shown. The compounds were theoretically examined by ultraviolet light (YO£ (nm) or Lp) flash chromatography indicates 0 stochastic using sale The filter shown and silica gel (YO = 4,0 Ve) Acros 0, + mm). The NMR spectrum was determined in the shown solvent. The coupling constants are given in Hz. The shapes of the peaks in the NMR spectrum are indicated by the symbols “9” (quad); "dg" (quadruple binary); w" "dt" 1 DU) (binary pu 1 "l" (binary); sk) "dd" binary); "f" (singular); "bs" (singular wide even if" (multiple). 0 Example No. *: Synthesis of specific compounds means the specific compounds for which the synthesis is explained Led Following is the invention being further explained in more detail; Therefore, it does not appear to limit the scope of the invention in any way.

— \ l _ structural formulas of the specified compounds of the invention

S-8 (1)

R, Ns

R, pyr

Q

H A2

H A3 oe = e = b.

S(CHCHCHINI -1- Jia

SICH) CHCHINH -7- propenyl SCH) CHCHINH -7- propenyl A | bs | me

S(CHCHCHINCH) -1- Probiel ‎come | what na

18- Other embodiments of the invention will be clear to those skilled in the field from the consideration of practice and the practice of the invention disclosed in this patent. This means that the specification and examples may be considered as exemplary only” provided that the true scope and spirit of the invention is indicated by the claims.

Al the compound 5 5 ob Ya generation 0 m 0 .

Al diagram Al of diagram j step dimethylformamide) “N N) DMF (Je Yor) mol) sulfur to 1 g; FY) added

SA) and heat the resulting mixture to the point of reflux until [the sulfur has almost melted. (;- «-hexyl oxyphenyl)-propene was added dropwise. After completion of SY (mmol) 001 g 0 (TLC layer chromatography addition; stirring and heating were used for the reaction followed by den filtration: toluene) » after; hours The reaction mixture was made available at sale (Ald Hl) room temperature. Filtration and vacuum evaporation produced a residual reaction mixture which was subjected to filtrate: toluene. The combined product containing (SiO) was concentrated by column chromatography. of TAN (parts in vacuo; recrystallization of the remaining cyclohexane, yielding) 0 g; 1 melting point 120 °C Al of desired compound

1 5 — _ compound A2 m m a a d l tg 1 + 3 OH Cl 0 C 2 5 0 = 0 m 8 ? 0 N a ~~ ncr a z 2m 0 0 Diagram A2 Step: Diagram A-2

1 To a solution of absolute ethanol containing 7 eq. sodium ethoxide 078010 0 chloroethyl)morpholine was added. After TN-7) equivalent of 1 eq-hydroxyacetophenone together with complete addition, the reaction mixture was allowed to reflux for ¾ hours; then the heating was stopped and continued for 1 hour at room temperature. The solvent was removed in Vacuum and lift the remaining VY stirring for a period of approximately ! The last solution was washed with diethyl (Y) in aqueous hydrogen chloride

01 yr. All ag daly was neutralized with sodium hydroxide solution (approximately standard Af) ¢ after which extraction was performed with diethyl ether. The combined organic fractions were dried using +80 E1. Removal of drying agent by filtration and removal of solvent in hatcher atmosphere produced AY: phenolic in the form of orange-yellow oil produced by JAY

. - Y=

A-2 of diagram jj the step to the amount of cold absolute toluene containing 0 (Thuillier et al., Bull. Chim.Soc., (1959)1398 (according to an 'l equivalent of 1 over 7 eq. of +- Sodium Amylate (:0100)01:0:011:013 Added phenolic ether from step 6 and 1 eq. of dissolved carbon disulfide. When complete; dibromoY = 1 eq. of 1 The reaction mixture was stirred for 7 hours. After that, the reaction mixture was added by Jue solution 1 hour. VY Stirring was continued for 7.bas ethane and with water until the pH reached (Luis sodium hydroxide) ¥ N The organic part was dried using ,20:580. Removal of the drying agent by filtration produced di-thiolane in the form of orange crystals by producing FO and removing the solvent in vacuo the derivative

ATE

A-2 of the scheme ii 3 shal in (PaS10) by tetraphosphodeca sulfide ii dithiolane derivative was treated from step min. After cooling, it was washed with a Vo-xylene hydroxide solution in reflux for a titer time; Then chloroform was added; The resulting organic fraction was dried 1 aqueous sodium. Removal of the drying agent by filtration and removal of the solvent in vacuo produced NapSOg with 1 residue which was purified by column chromatography (8:02; filtrate: diethyl ether/ Desirable Jf grade in the form of orange crystals yielding A2 (toluene 1/1); Which yields compound M. 011 fusion: '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). Y.

Compound A3 was prepared similarly to the procedure described for compound 82. Red oil; (CDCls, 8 ppm): 1.49 (q, 2H), 1.67 ) 4H, 2.63 ) 4H), 2.97 (t, 2H), 4.24 ( 11-11 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 S 1 0 P i N the - mr 7 2 os 0 ra 0 0 0 ' 0 Scheme B-1 Step j of Scheme B- 1 thawed? of piperazine and 1 equivalent of 0--methyl Jalil-;-phenyl-IY OT-di0-thiol-?- (Grandin, A. et al., Bull.Soc.

Chim.

Fr., 11(1968)4555) Osh in absolute ethanol; Then the reaction mixture was brought to the reflux temperature. After 7 days the solvent was removed in an incubator and the residue was purified by chromatography (0:5 d; filtrate: Jel in toluene v/v). The combined product containing the fractions was concentrated in vacuum; recrystallization of the remaining acetone; Which produces orange crystals with a production of 717 from compound 31. The melting point: 174 C.

Y Y —_ — H-NMR (CDCl, & ppm): 2.97 (t, 4H), 3.44 (t, 4H), 4.23 (m, 4H), 6.42-6.76 (m, 3H), ( m, SH). 3.45 (t, 4H), 4.23 (m, 4H), 6.43- o H-NMR (CDCl, (m, 3H), 7.22-7.28 (m, 4H) 6.76 Compound 33 (crystals) was prepared red; melting point: VEA -150 °C with decomposition) similarly to the procedure described for compound 31. compound 1© 1 i ~ d ha sub + "= this oS ve 0 and s—S 0 diagram C-1 Step E of Scheme C-1 1 (g; mM TA) (Use of *-methyl = [YO]-dithiol-7-thione dissolved in ov mL absolute ethanol. Then (0.0 g (Y) (£) mmol) 4-(diethylamino)-ve benzaldehyde and (1 mL) pyridine were added; after that the reaction mixture was heated over Water bath for 2 hours The reaction mixture was concentrated under vacuum and the residue was placed in the freezer where crystals had formed

isolation and recrystallization of the crystals from isopropyl alcohol, yielding (1.0 g; 6.2 mMol 8?))_of the desired C1 compound” Melting point: a 11 see Lad Patent No. JP 1319477 Compound C2 (TLC) SiOz prepared Refining material: Toluene; RE = 776© in the presence of © starting materials); Similar to the procedure described for Cl

D1 Compound L E | | I lost 50 8-5 Me, NH,* or ! Ss” 5 PN Z —_ N ii Hcl 95-5 l | boc B _ N and as full as 8 ml and loose D1.HCI schematic D-1 step j of schematic D-1 0 dissolved (1,5) gram' 87.5 mmol) of -1bromo-?-phenylpropane in (Ja Foo) DMF after which (VED gram; 1 mmol) sulfur was added. The reaction mixture was allowed to reflux for one night after which the stirring was continued at room temperature for another night. The reaction mixture was concentrated under vacuum after which approximately (de 001) toluene was added; crystals formed and

Y $ — _ collected and dried in a vacuum. yield 1 9 grams; 8 mmol (L5) is a yellow solid containing the dimethylammonium salt of the compound ;-phenyl methyl mercapto-IY A]-dithiol-7-thione. Step ji of Scheme D-1 Cah ° dissolving (0,016 ol a Y, mmol) of iodide (for iodide synthesis ¢ see above) in ) 6

ml) methanol, after which it was done Add (©g; 01.4 mM) dimethylammonium salt (Use) from step 0 (I) and stir the reaction mixture overnight; then concentrate under vacuum; as subject the remainder to column chromatography ( D510; filtrate: heptane/ethyl acetate 1/7 yield product concentrate containing parts (700 mg; 1.6 mM; 110) red oil.

1-1 of the diagram jij step 0 in a little dichloromethane followed by ii mmol) step 1 product, 1 mg Yio) then dissolving N (in isopropanol); so that the final concentration was about ? M.

1 Compound D2 (melting point: 47 = 101 C; with decomposition) was prepared; Similar to the described procedure for DIS all, the iodide that was used to synthesize the iodide used to prepare DI (see below) can be prepared. Compound D3 (melting point: AY - AY m) was prepared; Similar to the procedure described for compound 1. The iodide used for the synthesis of the iodide used for the preparation of D1 can be prepared

Y o — _— Then prepare compound D4 (Melting point: 665 = No. 8 » Similar to the described procedure DIS all can be prepared iodide that was used to synthesize the iodide used to prepare D1 Compound 25 was prepared ( Melting point: 165 - YY m), in a manner similar to the described procedure for the compound (Sey DI preparation of iodide that was used to synthesize the iodide used to prepare D1 ee then prepare compound 16 (degree Yo - 14: Olea ") ¢ Similar to the described procedure for the preparation of compound (DT) starting from para-bromomethyltoluene as an alkylation agent. Synthesis of iodide used in the preparation of compound DI (Scheme (D-2 OH | | ; J 0 Ben | Je) HN OH HN PN boc ) iii boc J 0 I N OH mn SN I l 00 l scheme 1-2 0 step g for scheme 1-2 dissolved (1.4 g; YT mmol) ;-hydroxy-7-butane in You (ml) SY 1 dichloromethane; then 0.0 ca 80 mM (Use propargylamine) was added. The reaction mixture was stirred for 10 minutes after that, then oy to 0 m ya. Then add (1 gram « 0 mmol) NaBH(OAc); part of the mixture in a saturated aqueous NaHCO; solution. Produce extraction of the solution watery

the latter by 0014 gram of the desired product after concentration in vacuum. class has been made

aqueous alkaline by a solution of NaOH (777 aqueous) and saturated with NaCl (solid); done el a).

A second drawing by 20/6. The combined organic fractions were dried using 118:50 and after

removal of the drying agent by filtration and removal of the solvent by concentration under incubator; been obtained

0 on (TAY loa VT) of desired product Je (orange oil form). This was used in

Step 11 without further scrubbing. J-step for chart 1-2

V1) grams dissolved; 89.8 mM (Usa of the sudpropanol derivative (from step ) in Yoo)

| ml; About 65 mmol) triethylamine was added (4,Y) and then done! Addition of DCM (Je butyl oxycarbonyl). The mixture was stirred (+ = Boc) 0000 mmol) +5 cela VE) 0

The product was then concentrated overnight and the residue dissolved again in BtOAC.

the organic fraction by a solution of NaHCO; saturated aqueous, water and ale solution after which it was dried

using ,218:80. After removing the drying agent by filtration and removing the solvent by concentrating in

"vacuum atmosphere" (TY) isolated grams; (Thee brown oil contains sud propanol protected Vo by N-BOC

Step ZZZ for chart D-2

YY) grams dissolved; 177 mmol) triphenylphosphine in DMF (Je Tov) after which it was

add) 14 g; 7880 mmol) imidazole; The resulting mixture was brought to zero degrees C.

A solution of (70.0 g) was added; 0460 mM (Use iodine in DCM (de Yoo) (dichloro©_methane) dropwise into the reaction mixture; after stirring continued for 10 minutes. After lly was

vy - - add A) grams; YO mmol) aminopropanol protected by N-Boc (from step (ii) was dissolved in 00 DCM (Je) and stirring was continued at dia C for 10 minutes. At that time access was made available The reaction mixture was brought to room temperature and stirred for 17 h The mixture was filtered (Jeli) and the filtrate was washed with brine and concentrated under vacuum The residue was filtered over a short column of SiO (filter material: heptane/ = EtOAc and concentrate the filtrate under vacuum, yielding 1.5 (g 7) of the corresponding iodide as a light yellow oil. This iodide was used in the preparation of DI (see Scheme 0-1). The corresponding iodide required for the preparation of compounds D2, 03 and 14 5 D5 can be prepared according to the conditions described in the synthesis of iodide used in the preparation of 01 (scheme 0-2). They are unnecessary due to the methyl group “Basa sell” on the nitrogen atom Example No. “: Formulation of compound Al for oral administration (P.O) Desired amount (0.5 - © mg) of compound has been added Al solid in a glass tube; some glass beads and the solid were ground by Boas Spin 1 _ for 2 minutes. After adding (1Jo) of a solution of methylene cellulose 71 in water and 77 (vol/v) of ¢(Lutrol F68) Polaxamer 188 the complex was suspended by vortexing for 10 minutes. The pH was adjusted to 1 with a few drops of aqueous NaOH (0+N). The remaining particles were also suspended in the metal by using an ultrasonic bath. For administration into the peritoneal cavity (..0: to desired amount (4.0 - V0 mg) of solid Al 0 compound in a glass tube; and some glass beads and the solid was ground by vortexing for two minutes. After adding (do 1) of a solution of methylene cellulose 71 in water and 75 mannitol in

m - water; The compound was suspended by vortexing for 10 minutes. The pH was finally adjusted to . Example No.: Pharmaceutical test results 0 except MA .| Hala - Gna] gms Shatt d focus | ADT | Clor | D3T | ADT | L-dep | ADT | L-dep here now I would have been a shan would have been a would have been it would have been the lah that who would have been would have been the shan would have been the SS would have been the ET would have been the EY would have been fre ll ll ll Co If you don't like it IEEE EE yours it wouldn't have been a l NTE ON A RT I ANA AA WE D EY EEE EY EE I melody no it would have been EEE SE 0 I would have been

f - Effects of Diprinyl (L-dep) and Anethole Dithiolthione (ADT) on Blas monoamine oxidase g 'MAO) (Column ? (V5) and for HY 5 ADTs L-dep -1-=Y-dithiol-*-thione (D3T) has monoamine-3-oxidase activity (MAO-B) (columns 05 and 1); on the activity of monoamine-(MAO-A) oxidase (columns As 1) in 0 cell extracts obtained from WIA cultures of neonatal rat striatal glia. MAO activity and drug effects on it were determined as follows. is preferred by. Data are expressed as percentages for corresponding comparisons and averages are made for two to five independent experiments conducted three times. Total activity of MAO was determined in the presence of solvent only (¥, +7) (DMSO) and activity of MAO-B in the presence of 101 μm of MAO-A selective 0 inhibitor chlorgiline” and MAO-A activity in the presence of 1 μm of MAO-B bie selective Duprenyl. It is known that neuroglia cells Astrocytes express MAO-B (Histochem.

Cytochem, 35, 23-32, 1987 using a non-selective tyramine base and the MAO-B inhibitor diprenyl (41, 153-162, 1991) (Youdim and Finberg, Biochem.

Pharmacol, even IAs of MAO activity were found to be MAO-B and the remaining MAO activity (approximately 1 Yr) in the presence of a maximum effective concentration of Deprinyl was completely inhibited by the addition of an MAO-inhibitor A selective clorgiline Diprinil inhibited 1 Gall MAO activity of the stellate neurotransmitter in a concentration-dependent manner with an apparent 10 μm of approximately 104 µm ADT similarly inhibited a concentration-dependently induced total MAO activity with an apparent 1 ICs 0.5 μm; maximum effect was reached (7780 μmL) inhibition (Lyi) at a concentration of To. After selective and complete inactivation of MAO-A Yo by clorgiline, identical concentration-effect relationships were observed for both daprinyl and ADT ‏

Keep in comparison with those found to inhibit total MAO activity. This cag lll was done in the presence of chlorgiline; A concentration-dependent inhibition of MAO-B activity was observed for D3T with an apparent ICsp of approximately 0.1 μM and a maximum effective concentration of 00 μM. upon selective and complete inactivation of MAO-B by Duprenil; No statistically significant effect of ADT 0 on MAO-A activity was detected. The inhibitory activity of MAO-B for D6 - Al compounds measured at CEREP (France) cul; According to the method described by JL 192, 128, 1979.

Salach, Arch.

Biochem.

Biophys., << Inhibition 104/405 at “01 Fuller LT A

Claims (1)

A Claims_YY) Compound use of formula (1) 1 5s Y 0 where: ¢ - Ry and Y are the same or different; represents hydrogen; or an alkyl; or to alkyl; or 8 alkynyl or aryl; or fluoro; or chloro; or promo; or hydroxychloroquine; or alkyl i!oxy” or alkenyl-oxy; or aryl-oxy; or acyl oxy; or amino; or 0 alkyl aminos; OD Alkyl Aminos; or ariel od theo; or alkyl thioes or A Aryl Theo; or Sianua or Nitro or Aseel; or Amido; or to an alkylamide; or dai | Jesu gs 0 Ros Ry together with the carbon atoms to which they are attached may form a ring 1 aromatic or non-aromatic containing 0, 1, or Y heteroatomic wooo selected from nitrogen, oxygen, or sulfur; Like Jost loops VY thiophene; or pyrol; or to oxazole; or to a thiazole; or to an imidazole; or to pyrazole; 3" or isoxazole; or isothiazole" or 7-0*-oxadiazole; or 7-0 Yo *- triazole or a ;- thiadiazole; Or pyridine, or pyridazine, or 5 pyrimidines; or to pyrazine; Ava, Ry, and Y itself may carry select additional substitution groups of hydrogen; YA or alkyl; or to alkyl; or edad or ariel; or fluoro; or chloro; or promo; 4 or hydroxyl; or an alkyloxy or an alkyloxy amino; or morpholine - 0 ;- yl - alkoxy; or piperidine-1-yl-alkyl RPV alkenyl Als 71 Oxy; or aryl-oxy; or acyloxy or amino or alkyl esd or di vY alkyl amino” or aryl amino or thio or alkylthio; or Ariel Theo or Cyano; or YY oxo; or nitro; or soothe; or Amido; or to an alkylamide; eau dialkylamido; Ye and its steric compounds, stereoisomers and terminated nitrogen oxides as well as yo salts and pharmaceutically acceptable hydrates and solutes of the said compounds of formula (1) 71 and their steric compounds, their stereoisomers and their nitrous oxides; for the preparation of a pharmaceutical composition for the treatment, alleviation or prevention of mood disorders; YA disorders bipolar, bipolar IT disorders, unipolar 1 depressive disorders; minor depression, seasonal affective disorder, postpartum depression, mental exhaustion, major depression, anxiety disorders, panic disorder, social anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, olay-related vy disorders, cold use disorders, salall ve-induced disorders, substance withdrawal; weakness of the ell and disruptive behavior disorders; Yo and Attention Deficit Hyperactivity Disorder; sleepiness” and 4+ control disorders, pathological psychosis, eating disorders, anorexia nervosa; gluttony b nervous; pain disorder; chronic pain syndrome; impotence; YA, Agel tract obstruction, asthma, and gastrointestinal motility disorders; v4 and hemorrhoids; The contraction of the smooth muscles and sphincters of the gastrointestinal tract 2 and the dysfunction of the bladder. vy —_ — SY) a use according to claim (1); it is characterized by the fact that the compounds mentioned in the formula (1) are 0— (m-methoxyphenyl)- HY )“ ?- dithiol- ?- Y thione or 119- 1 7-dithiol-7-thione or ;-methyl-—Y) —o ¢ pyrazenyl)-10 HY ?- gla thiol- VY thione. -14 1 use pursuant to claim (1); it is characterized by that the compound of formula (1) \is©-(m-methoxyphenyl)-117-—Y 0 dithiol- = 15-thion Compound of general formula (1) hy 0 b mothballed Y 8 1 where: Ry 3 is a phenyl with an optionally substituted Rpg representing 0112-5-(4-methyl-°phenyl) or one of the following subgroup : CH, S-(-CH,") EH N-CH,-C=CH —N N— aryl 1 \ nebula 2 | 2/n Rs (i) 0 jag LC 7 5 -S 2A 0 A where L has the value 1 or * or ; or * and Ry is 1 hydrogen or (Cra)alkyl" or vg - - Ry - Ve is ;- hydroxyphenyl and Ry is hydrogen; OR 8 - 11 is a substituted vinyl and 80 stands for (SH or subgroup: SSS 5 1 now 07 ' VY - .18 is hydrogen and stands for CH = CH- -;- (diethylaminoVephenyl); or -1( —CH = CH-quinolyl); or subgroup: ا or ml \r 0 1 where “has the same meaning as given by” dd and Rss Ry represents: VY independently (Cr) an alkyl or together with the nitrogen atom to which YA is attached they form a ring saturated with © or + atoms; Optionally 14 contains one or more heteroatoms selected from 7 or ©0” or JS AE - 8. is (Cra) an alkyl and Ry is -1 (7; =F dihydro 1 = ;-benzodioxin =o yl)piperazine edit or Ry - YY is a cyano and Ry is the subgroup -©(0)-1111- NH- 1 vinyl; in which the subgroup is a phenyl group having an arbitrary Y¢ substitution; or Ry - Yo is 50011- and Y stands for amino; a, their nucleophilic compounds, their stereoisomers, and their nitrogen oxides; Lads are pharmaceutically acceptable salts, hydrates and solutes of the aforementioned compounds of formula YA (1) and their adenotropic compounds, their stereoisomers and their nitrogen oxides. Ag o — _ 1 “11-_ The compound of claim (£) has the general formula (1): 6 d) 1 NS R, SN Y b m where: BGR - ¢ ;- hexyl oxyphenyl Roy stands for hydrogen; oO 5 0 BGR, - ° hydrogen Ry represents Ma “Ha 9 y 0" i! - ,6 represents hydrogen and 12 Ji rbt' 7 a 0 7/ - yl say phil rel say OOF l (Oe - «oa 0 0 9 JGR; - 4-methylphenyl Ros is represented by ¢ Ry - 01 representing ¢— methylphenyl y representing ;-phenylpiperazinyl; 0 - 8 represents hydrogen y represents (;-diethylaminophenyl) CH- - 011-;l- .18 represents hydrogen y represents (7-quinolinyl) CH- = 0131-;b - Ry 82 represents phenyl and 82 represents propenyl -7- 011:(:011)013:(1117- VE - 5) 8 :phenyl and 82 represents propenyl -7- -S(CH;);CH(CH5)NH . Ry - ve stands for phenyl 5 Ry stands for propenyl -7- -S(CHy)sCH(CH;)NH Ry — 1 stands for phenyl and y stands for propenyl -7- -S(CHy,CH) CH3)N(CH;) ¢ WW - :8 for phenyl and 82 for propenyl -7- -S(CHR);CH(CH3)N(CH3) ¢ 0° - .8 for phenyl and w for . =f) methylphenyl) “S-CHy - 7 - A (SIV) a pharmaceutical composition that includes; plus at least one pharmaceutically acceptable carrier and/or adjuvant Y Liana containing a pharmacologically active amount of at least 1 compound of the claim (;); or his salt; as an active ingredient. SIA) a method for preparing pharmaceutical compositions according to claim (1); It is characterized by the preparation of a compound according to the protection element (£) in a form suitable for administration. 1 1 10-_compound of claim o£) or its salt; For use as a medicine.