MXPA01008749A - New diazole derivatives as serotonergic agents - Google Patents

Abstract

The present invention provides compounds of general formula (1) wherein:two atoms of X, Y, or Z are nitrogen and the third atom is sulfur or oxygen;R is H, halogen, OH, SH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, phenoxy, thiophenoxy, phenyl or substituted phenyl;A is C, CH, or N;R1 is aryl, heteroaryl, or cycloalkyl groups, optionally substituted by from 1 to 3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy;CF3, Cl, Br, F, CN, or CO2CH3;R2 is H or alkyl;R3 is C1-C6 alkyl, optionally substituted aryl, optionally substituted 5- or 6-membered heteroaryl, C3 to C8 cycloalkyl optionally substituted by C1-C6 alkyl, or a 3 to 8-membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods of treating central nervous system disorders using these compounds.

Description

NEW DIAZOL DERIVATIVES AS SEROTONERGIC AGENTS Field of Invention. This invention relates to a series of novel derivatives of diazolpiperazine, diazolpiperidine, and diazoldihydropiperidine, and to processes for their preparation, to pharmaceutical compositions containing them, and to their use in therapies concerning disorders of the central nervous system. These compounds are useful for the treatment of conditions related to, or affected by, the subtype receptor 5-h? Droxitriptamine-1-A (5-HT? A) in the CNS (abbreviations in English of the Central Nervous System), including withdrawal of the alcohol and drugs, sexual dysfunction, and Alzheimer's disease. The utility of these compounds lies in their ability to bind as agonists and antagonists to 5-HT? A receptors. The compounds of the present invention are also useful in the treatment of depression and CNS-related disorders (e.g., OCD, anxiety and panic) when combined with the use of serotonin reuptake inhibitors, such as Prozac® (fluoxetine hydrochloride). Background of the Invention Depression is a psychiatric condition that is associated with reduced serotonin release.

Ref: 132413 Most antidepressant agents potentiate the effects of serotonin by blocking the termination of its activity with re-absorption at the nerve terminals. U.S. Patent 3,655,663 (B- K. Wasson, April 11, 1972) covers the 4- (3-amino-2-hydroxypropoxy secondary) -1,2,5-thiadiazoles which exhibit useful beta-adrenergic blocking properties for the treatment of angina. The compounds of the present invention are structurally different from this prior art and are useful for the treatment of CNS disorders. WO 96/38431 (Eli Lilly, 31 May 1996) covers methods for making 1, 2, 5-thiadiazoles containing azacyclic ether or thioether substituents or azabicyclics for use as cholinergic muscarinic agonists. These compounds are useful as stimulants of the cerebellum and hypothalamus for the treatment of Alzheimer's disease. The compounds of this invention are structurally different from these compounds and are agonists and antagonists of the 5HT1A receptor, not muscarinic agonists. Brief description of the invention. The compounds of the present invention are represented by the general formula (1): (1) wherein: the dotted line represents an optional bond; two atoms of X, Y, or Z are nitrogen and the third atom is sulfur or oxygen; R is H, halogen, OH, SH, C? -C6 alkyl, C? C6, C?-C6 thioalkyl, phenoxy, thiophenoxy, or phenyl, the phenyl ring being optionally substituted by from one to three substituents selected from alkyl C? -C6; C6-C6 alkoxy; CF3; Cl; Br; F; CN; or C02CH3; A is C, CH, or N; Ri is an aryl, heteroaryl, or cycloalkyl group, the aryl, heteroaryl or cycloalkyl group being optionally substituted by from 1 to 3 substituents selected from Ci-Ce alkyl, C 1 alkoxy; C6; CF3, Cl, Br, CN, or C02CH3; R2 is H or C? -C6 alkyl; R3 is Ci-Ce alkyl, aryl, 5- or 6-membered heteroaryl, C3 to C8 cycloalkyl, the cycloalkyl group being optionally substituted by C?-C6 alkyl, or a 3- to 8-membered heterocyclic ring containing one or more selected heteroatoms of 0, S or N, the 5 or 6 membered aryl and heteroaryl groups being optionally substituted by from one to three substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, CF 3, Cl, Br, F, CN, or C02CH3; or a pharmaceutically acceptable salt thereof. Heteroaryl groups have one to three heteroatoms selected from oxygen, nitrogen and sulfur. As used herein, the term "alkyl" refers to straight or branched chain C? -C6, and wherein the term "cycloalkyl" refers to a C3 ring to Cs, preferably a C3 ring to Ce, or a ring substituted by I rent. The term "aryl" is phenyl or substituted phenyl, biphenyl, 1- or 2-naphthyl and "heteroaryl" refers to 5- or 6-membered heterocycles or heterocycles, including, but not limited to, thiazole, thiophene, 2-, 3-, or 4-pyridyl, benzothiophene, or indole. The aryl or heteroaryl groups herein can optionally be substituted with one to three substituents selected from the group consisting of C? -C6 alkyl; C6-C6 alkoxy; CF3; Cl; Br; F; CN; C02CH3. Among the preferred compounds of this invention are those of the formula (2): (2) wherein R, Ri, R2, and R3, are as defined above, or a pharmaceutically acceptable salt thereof. Further preferred are those compounds of the formula (1) or the formula (2) wherein: R is H, halogen, OH, SH, Ci-Cß alkyl, Ci-C6 alkoxy,; and / or Ri is an aryl, heteroaryl or cycloalkyl group, optionally substituted by from 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy; CF3, Cl, Br, F, CN or C02CH3; and / or R2 is H or C? -C6 alkyl; and / or R 3 is C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heteroaryl, C 3 to C 8 cycloalkyl optionally substituted by Ci-Cβ alkyl, or a 3 to 8 membered heterocyclic ring containing one or more heteroatoms selected from 0, S or N; or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic acid. . The compounds of formula I may possess at least one asymmetric center and accordingly the compounds may exist and be isolated in a number of optically active stereoisomeric forms. The invention encompasses the compounds of the formula I in any optically active form or mixtures thereof, for example, racemates. Standard separation techniques can be used to isolate particular enantiomeric or diastereomeric forms. For example, a racemic mixture can be converted to a mixture of optically active diastereomers by reaction with a simple enantiomer of a "resolving agent" (for example, by diastereomeric salt formation or formation of a covalent bond). The resulting mixture of optically active diastereoisomers can be separated by standard techniques (eg, crystallization or chromatography) and individual optically active diastereomers are then treated to remove the "resolving agent" whereby the single enantiomer of the compound of the invention is released. Chiral chromatography (using a chiral support, eluent or ion-pairing agent) can also be used to directly separate enantiomeric mixtures. Detailed description of the invention. The compounds of this invention possess a high affinity for the serotonin 5-HT1A receptor and, consequently, are useful as anti-depressant and anxiolytic agents for the treatment in a mammal of a variety of central nervous system (CNS) disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and / or ***e addiction, and related problems. The compounds of this invention can also be used to induce the increase of cognition in a mammal, preferably in humans. In addition, the compounds of this invention show a marked selectivity for 5-HTxA receptors, as opposed to al receptors. In view of their receptor linkage, these compounds can be characterized as anxiolytic agents and / or antidepressants useful in the treatment of depression and in relieving anxiety. As such, the compounds can be administered pure or with a pharmaceutical carrier or excipient to a patient in need thereof. The pharmaceutical carrier can be solid or liquid. It will be understood that the therapeutically effective dose to be used in the treatment of a specific psychosis should be determined subjectively by the attending physician. The variables involved include psychoses or specific states of anxiety and the patient's size, age and response pattern. The novel methods of the invention for the treatment, prevention or alleviation of the conditions described above, or to induce the increase of cognition, comprise administering to mammals in need thereof, including humans, an effective amount of one or more compounds of this invention or a pharmaceutically acceptable, non-toxic addition salt thereof. The compounds can be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose depends on the specific compound, treatment method and condition treated. An effective dose of 0.01-1000 mg / Kg can be used for oral application, preferably 0.5-500 mg / Kg, and an effective amount of 0.1-100 mg / Kg can be used for parenteral application, preferably 0.5-500 mg / Kg. . It will be understood that in combination with other serotonin receptor (5-HT? A) agonists or antagonists, such as those listed above, the effective dose of the present compounds can be reduced relative to the effective amount of the combined active ingredients. The present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Carriers or Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or disintegrating agents tablet or an encapsulating material. In the powders, the carrier is a finely divided solid that is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in appropriate proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins . Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, eg cellulose derivatives, preferably carboxymethyl cellulose solution, sodium), alcohols (including monohydric alcohols and polyhydric alcohols, eg glycols) and its derivatives, and oils (for example, fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The oral administration can be in the form of liquid or solid composition. Preferably the pharmaceutical compositions and the combination compositions of this invention are in unit dosage form, for example, as tablets or capsules. In such form, the composition is sub-divided into a unit dose containing the appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example, packaged powders, small vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or it may be the appropriate number of any of the compositions in packaged form.

This invention also provides a process for preparing compounds of the formula (1), which process comprises: a) acylating a compound of the formula (3) (3) wherein the dotted line R, R1 f R2, X, Y, Z and A are as defined above, with a compound of the formula: R3COOH (4) or a reactive derivative thereof (eg, acid halide) such as chloride or a mixed anhydride) wherein R3 is as defined above; or b) converting a basic compound of the formula (1) to a pharmaceutically acceptable acid addition salt thereof. The compounds of the present invention can be prepared by those skilled in the art of organic synthesis employing conventional methods using reagents and readily available starting materials.

The methods for preparing compounds of this invention will be understood from the reaction schemes herein. With reference to Reaction Scheme 1, the required dichlorodiazole is allowed to react with tert-butyl carboxy piperazine (BOC) -prepared in an organic solvent, such as dimethylformamide (DMF) at an elevated temperature under a nitrogen atmosphere to give the corresponding diazolpiperazines I BOC-protected. The treatment of the protected piperazines I with an acid, such as hydrochloric acid, in an inert solvent, such as dioxane, under an inert atmosphere, gives the deprotected piperazines II. The reaction of diazolepiperazines II with nitrogen-protected amino acids, such as N-BOC-protected amino acids, in an organic solvent, such as methylene chloride, at room temperature under an inert atmosphere in the presence of an organic base, such as triethylamine ( TEA), and a coupling reagent such as cyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT), forms the amides III. Agitation of the amides III with an acid, such as hydrochloric acid, in an organic solvent, such as dioxane, at room temperature under an inert atmosphere, gives the amino amides IV. Reduction of the amides with diborane in an organic solvent, such as tetrahydrofuran (THF) gives the corresponding amines V. Acylation of the terminal amine with an acylating agent, such as an acyl halide or coupling the amine with a carboxylic acid, gives the products of this invention VI.

Reaction Scheme 1 With reference to Reaction Scheme 2, the required chlorodiazole piperazine II, is allowed to react with a metal, such as sodium, in a polar solvent, such as methanol, at elevated temperatures under an inert atmosphere to give diazolpiperazine derivatives VII. By allowing these piperazines VII to react with a protected N-BOC-amino acid and a coupling reagent, such as DCC in the presence of HOBT and a base, such as TEA, in an organic solvent, such as methylene chloride, gives the amides VIII . Agitating the amides VIII with an acid, such as hydrochloric acid, in an organic solvent, such as dioxane, gives the amino amides IX. Reduction of amino amides IX with diborane in an organic solvent, such as THF, under an inert atmosphere, at elevated temperature, gives the amines X. Acylation of the terminal amine with an acylating agent, such as an acyl halide, or coupling the amines with a carboxylic acid, gives the products of this invention XI.

Reaction Scheme 2 With reference to Reaction Scheme 3, the required chlorodiazolepiperazine amide III is allowed to react with a metal, such as sodium, in a polar solvent, such as methanol, at elevated temperatures under an inert atmosphere to give diazolpiperazine VIII derivatives. Agitation of the amides VIII with an acid, such as hydrochloric acid, in an organic solvent, such as dioxane, gives the amino amides IX. Reduction of amino amides IX with diborane in an organic solvent, such as THF, under an inert atmosphere, at elevated temperatures, gives the amines X. Acylation of the terminal amine with an acylating agent, such as an acyl halide, or coupling the amines with a carboxylic acid, gives the products of this invention XI.

Reaction Scheme 3 With reference to Reaction Scheme 4, the N-protected 4-acylpiperidine or N-protected 4-acyldihydropiperidine is added to the carbethoxyhydrazine in a polar solvent, such as methanol, at a low temperature, such as 0-5 ° C, and then it is heated under reflux to give the hydrazones XII. The hydrazones XII are heated from 30-100 ° C in the presence of thionyl chloride to give the derivatives of 1,2,3-thiadiazole XIII. Deprotection of XIII gives the secondary amines XIV. Reaction of XIV with the N-protected amino alcohols containing a starting group, such as tosylate, in a polar solvent, such as dimethylsulfoxide, at elevated temperatures, such as 30-100 ° C, gives the amine intermediates N -protected XV. The removal of the protecting group gives the XVI and the reaction of the XVI with an acylating agent or with a carboxylic acid and a coupling reagent such as DCC gives the compounds of this invention XVII.

Reaction Scheme 4 With reference to Reaction Scheme 5, the 4-substituted pyridines XVIII which can be prepared by known methods [Per Sauerberg, et al., J. Med. Chem,. 1992 35, 2274-2283] are protected in nitrogen by a removable group, such as the N-carbethoxy group, to give XIX. The XIX is reduced to the 20th using a reducing agent, such as NaBH4. The protecting group is removed [for the BOC group, an acid such as hydrogen chloride can be used] to give the XXI which is allowed to react with an N-protected amino acid, such as a BOC-protected amino acid, to give the amides XXII . Removal of the protecting group, such as treatment of the BOC group with an acid such as hydrogen chloride, gives the XXIII. The reduction of the amides XXIII with a reducing agent such as diborane in an organic solvent such as tetrahydrofuran, gives XXIV. Acylation of XXIV with acylating agents or reaction of XXIV with carboxylic acids * and a coupling agent such as DCC gives the compounds of this invention XXV.

Linkage Test of the 5-HT Receptor? A. The high affinity for the serotonin 5-HT? A receptor is established by testing the ability of the claimed compounds to displace the [3 H] 8-OH-DPAT linkage in CHO cells stably transfected with the human 5-HT? A receptor. . Stably transfected CHO cells grow in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are completely scraped off the plate, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 minutes, 4 ° C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -80 ° C. On the day of the test, the cells are thawed on ice and resuspended in buffer. The binding assay is performed in a 96-well microtiter plate in a total volume of 250 mL. The non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. After 30 minutes of incubation at room temperature, the reaction is terminated by the addition of ice-cold buffer and rapid filtration through a pre-wet GF / B filter for 30 minutes in 0.5% PEI. The compounds are initially tested in a single-point assay to determine the percent inhibition at 0.1, and 0.01 mM, and Ki values are determined for the active compounds.

Intrinsic Activity Assay of the 5-HTiA Receptor. The intrinsic activity of the compounds of the present invention is established by testing the ability of the claimed compounds to reverse the stimulation of cyclic adenosine monophosphate (cAMP) in CHO cells transfected with the human 5-HT? A receptor. Stably transfected CHO cells grow in DMEM containing heat-inactivated FBS and non-essential amino acids. Cells are seeded at a density of x106 cells per well in a 24-well plate and incubated for 2 days in a C02 incubator. On the second day, the medium is replaced with 0.5 mL of treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 M pargyline) and incubated for 10 minutes at 37 ° C. The wells are treated with forskolin (final concentration lmM) followed immediately by the test compound (0.1 and 1 mM for separation by initial exclusion) and incubated for an additional 10 minutes at 37 ° C. The reaction is terminated by stirring the medium and adding 0.5 mL of ice-cold assay buffer (supplied in the RIA kit). The plates are stored at -20 ° C before evaluating the formation of cAMP by RIA. The EC50 values are determined by the active test compounds. Compounds that do not show to have agonist activities (Emax = 0%) are further analyzed for their ability to reverse the activity induced by the agonist. In separate experiments, 6 concentrations of antagonists are preincubated for 20 minutes before the addition of agonist and forskolin. The cells were harvested as described above. The cAMP kit is supplied by Amersham and the RIA is carried out according to the instructions of the kit, and IC50 calculations were performed by GraphPad Prism. Compound 5-HT link A CAMP Ki (nM) Emax Compound 4 0.84 93.00 (EC50 = 4.61 nM Compound 5 425.20 Compound 6 47% @ 1_M Compound 7 4.55 0.00 (IC50 = 49.26 nM) Compound 8 1.55 0.00 (IC50 = 72.74 nM) Compound 9 9.87 Compound 11 3.04 0.000 (IC50 = 113.00 nM) The following specific non-limiting examples are included to illustrate the synthetic procedures used to prepare the compounds of formula 1. In these examples, all chemicals and intermediates whether commercially available or can be prepared by standard procedures found in the literature or are known by those skilled in the art of organic synthesis. Several preferred non-limiting embodiments are described to illustrate the invention. Example 1. 1- (4-Chloro- [1,2,5] thiadiazol-3-yl) piperazine hydrochloride. The tert-butyl ester of 1-carboxylic acid (10 g, 0.054 m) was dissolved in anhydrous dimethylformamide (DMF, 50 mL) under nitrogen in a single neck round bottom flask. The clear solution was placed in a previously heated oil bath (50 ° C - 60 ° C). 4, 5-Dichloro- [1,2,5] thiadiazole (5.0 mL, 0.054 m) was added and the reaction mixture was allowed to stir for 24 hours. A yellow solution containing a white solid was observed. After cooling to room temperature, the mixture was diluted with an equal volume of anhydrous ethyl ether for 5 minutes. The solid was removed by filtration and the yellow filtrate was concentrated under a vacuum aspirator to remove the ether and then evaporated under an oil pump vacuum to remove the DMF. The yellow residue was dried under vacuum of the oil pump overnight to give 9.91 g of 4- (4-chloro- [1,2,5] thiadiazol-3-yl) piperazine-1-tert-butyl ester. -carboxylic Two recrystallizations of the crude product from hexane gave white crystals: mp 83-86 ° C. Analysis calculated for CuH? 7ClN402S. 0.075 mol of hexane: Theory:% C, 44.18; % H, 5.85; % N, 18.00 Found:% C, 44.44; % H, 5.84; % N, 17.80. The tert-butyl ester I (400 mg, 1.3 mmol) was treated with 4N HCl (5.0 L) in dioxane under a nitrogen atmosphere. The ester dissolved and a white precipitate formed gradually. The mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with heptane and filtered to collect a crystalline solid which was rinsed with heptane and dried to give 285 mg of the title compound as a pale yellow solid, mp: 205 ° C (dec). Analysis calculated for C6H9C1N4S. HCl. 0.15 H20 Theory:% C, 29.56; % N, 4.26; % N, 22.98 Found:% C, 44.44; % N, 4.40; % N, 22.34. Example 2. 4-Piperazin-1-yl- [1, 2, 5] thiadiazol-3-ol hydrochloride. The title compound of Example 1 (1.25 g, 5.18 mmol) was combined with 2.5 N NaOH (10 mL) and dimethylsulfoxide (DMSO, 1.0 mL) and heated under reflux with stirring for 2.5 hours. The heat was removed and the cloudy mixture was allowed to cool and stirred overnight. The pale yellow solution was refrigerated in an ice bath and acidified to a pH of 0 with concentrated HCl. The mixture was cooled in an ice bath for several hours and filtered to collect a white crystalline solid which was dried under reduced pressure on Drierite to give 0.469 g of the title compound, mp: 230 ° C (dec). Analysis calculated for C6H? 0N4S. HCl. 0.25 H20 Theory:% C, 31.69; % H, 5.06; % N, 24.65 Found:% C, 31.54; % H, 4.66; % N, 24.21. Example 3. 1- (4-Methoxy- [1,2- 5] thiadiazol-3-yl) piperazine hydrochloride. The title compound of Example 1 (0.95 g, 3.9 mmol) was suspended in anhydrous methanol (10 mL) under a nitrogen atmosphere. Sodium metal pellets (0.733 g, 32 g atoms) were slowly added with stirring. An exotherm occurred until reflux. Heating under reflux was continued for 2 hours in a previously heated oil bath. The reaction mixture was then cooled to room temperature and allowed to stir overnight. The volatiles were removed under reduced pressure and the mustard-colored residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3X). The organic phases were combined, dried (MgSO4) and evaporated to give 0.268 g of a yellow oil. The oil was dissolved in methanol and treated with ether HCl in ether (2.0 L) to give a brown solid which was recrystallized from isopropanol: isopropyl ether to give 89 mg of the title compound as mustard yellow crystals. , mp: 190 ° C (dec). Analysis calculated for C7H? 2N4OS. HCl. 0.1 isopropanol Theory:% C, 36.12; % H, 5.73; % N, 23.08 Found:% C, 36.21; % H, 5.68; % N, 23.37. 4. Use 4. Fumarate. { (SS) -l-benzyl-2- (4- (4-chloro [l, 2,5] thiadiazol-3-yl)? Iperazin-1-yl] ethyl} - cyclohexanecarboxylic acid amide. BOC-L-phenylalanine (6 g, 22.6 mmol) in methylene chloride (240 mL) under nitrogen atmosphere To this was added the compound of Example 1 (5.0 g, 20.7 mmol) followed by triethylamine (TEA, 2.1 g). ), HOBT (3.65 G), and cyclohexylcarbodiimide (DCC, 4.7 g) The reaction mixture was allowed to stir at room temperature overnight The reaction mixture was filtered to remove the insolubles, and the volatiles were removed from the filtrate under The residue was taken up in methylene chloride, cooled in a freezer, and filtered to remove a white solid.The filtrate was purified by chromatography on silica gel eluting with 0.4% MeOH -0.6% in methylene chloride to give Intermediate I (tert-butyl ester of acid. {l-benzyl-2- [4- (4-chloro [1,2, 5] thiadiazol-3-yl) piperazin-1-yl] -2- oxo-ethyl.}. car bamic) as an amorphous solid, mp: 45-51 ° C. Analysis calculated for C2oH26ClN503S Theory:% C, 53.15; % H, 5.80; % N, 15.49 Found:% C, 53.02; % H, 5.64; % N, 15.27. Intermediary I (2.0 g) was dissolved in dioxane (5 mL) and treated with 4M HCl in dioxane under a nitrogen atmosphere overnight. A mass of white solid was observed. The reaction mixture was diluted with dioxane and filtered to collect the solid. After drying under reduced pressure, 1.57 g of (2S) -2-amino-l- [4 (4-chloro- [1,2,5] thiadiazol-3-yl) piperazin-1-] - hydrochloride were obtained. 3-phenylpropan-l-one [Intermediate II]: mp 201-205 ° C. Analysis calculated for Ci5H? 8ClN5OS. HCl 0.45 dioxane Theory:% C, 47.15; % H, 5.32; % N, 16.36 Found:% C, 47.03; % H, 5.35; % N, 15.88. Intermediate II (0.92 g, 2.6 mmol) was dissolved in anhydrous THF (30 mL) under a nitrogen atmosphere. BH3MI in THF (8.2 mL, 3 equivalents) (foam) was added and the reaction mixture was heated under reflux for 1 hour. After cooling to room temperature, IN HCl (10 mL) was carefully added and stirring continued overnight at room temperature. After extracting with ether, the aqueous phase was cooled in an ice bath and adjusted to a pH of 14 with solid NaOH. A separate yellow oil which was extracted into ethyl acetate, dried (MgSO4), filtered, and evaporated to give a thick yellow oil which was dried under reduced pressure to give 376 mg of Intermediate III. Intermediary III (357 mg, 1.06 mmol) was dissolved in anhydrous methylene chloride (20 mL) under a nitrogen atmosphere, followed by triethylamine (0.3 mL, 2 equivalents). Cyclohexylcarbonyl chloride was diluted (160 mg, 1 equivalent) with methylene chloride (10 mL) and added dropwise at 0-5 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched with saturated NaHCO3 (10 mL) and saturated NaCl (10 mL). The organic phase was separated, washed with water (2X), and dried (MgSO4). The solution was filtered and the volatiles were removed under reduced pressure to give a viscous yellow oil purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexane to give 185 mg of the free base of the title compound . The compound was converted to the fumarate salt by treatment with fumaric acid in ethanol to give the title compound: mp, 138-140 ° C. Analysis calculated for C22H30N5ClOS. C4H404 Theory:% C, 55.6; % H, 6.08; % N, 12.41 Found:% C, 55.08; % H, 5.96; % N, 12.14. Example 5. N-. { (SS) -benzyl-2- [4 [(4-chloro- [1,2,5] thiadiazol-3-yl) piperazin-1-yl) ethyl) isonicotinamide. Intermediate III (120 mg, 0.35 mmol) was dissolved in methylene chloride (15 mL) under nitrogen. Isonicotinic acid (50 mg, 0.41 mmol) was added followed by triethylamine (0.08 mL), 1-hydroxybenzotriazole hydrate, HOBT, (55 mg), and dicyclohexylcarbodiimide, DCC, (85 mg). The reaction mixture was stirred at room temperature overnight. After filtration to remove the solids, the volatiles were removed from the filtrate under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with methylene chloride for 2% methanol in methylene chloride to give the title compound, 100 mg, as a white solid. The free base was converted to the fumarate salt using fumaric acid in ethanol and isopropyl ether. An amorphous solid is obtained, mp: 99-125 ° C.

Analysis calculated for C2? H23N6ClOS. 1 . 5C4H404. 0 75 H20 Theory:% C, 51. 38; % H, 4 97; % N, 13 05 Found:% C, 51.63; % H, 4.77; % N, 12.43. Example 6. { (SS) -l-benzyl-2, 3- [4 (4-chlorp [1, 2, 5] thiadiazol-3-yl) piperazin-1-yl] ethyl} pyridine-2-carboxylic acid amide. Example 6 was prepared using Intermediate III and pyridine-2-carboxylic acid according to the method of Example 5. The fumaric acid salt was a granular solid: mp 60-70 ° C. Analysis calculated for C2? H23N6C10S. C4H 04 1H20. 0 2 diisopropyl ether Theory:% C, 52.67; % H, 5.36; % N, 14.07 Found:% C, 52.89; % H, 5.05; % N, 13.59. Example 7. { (2R) -l-benzyl-2- [4- (4-chloro [1,2,5] thiadiazol-3-ylpiperazin-1-yl] ethyl]} - methylamide of cyclohexanecarboxylic acid The compound of Example 1 and N -methyl-D-phenylalanine protected with BOC, they were allowed to react according to the method of Example 4 to give the Intermediate IV, tert-butyl ether of acid. { (IR) -l-Benzyl-2- [4- (4-chloro [1,2,5] thiadiazol-3-yl) piperazin-1-yl] -2-oxo-ethyl} methylcarbamic: mp 109-111 ° C.

Intermediate IV was allowed to react with 4N HCl in dioxane according to the method of Example 4 to give Intermediate V, (2R-l- [4- (4-chloro [1, 2, 5] thiadiazol-3-yl. ) piperazin-1-yl) -2-methylamino-3-phenylpropan-l-one: mp 230-232 ° C. chloride (0.08 mL) in methylene chloride (1 mL) at room temperature. After stirring for 5 minutes, 2.5 N NaOH (5 mL) and brine (12 mL) were added. The organic phase was separated and the aqueous phase was extracted with brine (2X). The combined organic phases were dried (MgSO4), evaporated and the residue was purified on silica gel eluting with 1% methanol in methylene chloride to give 185 mg of the title compound as an oil (89%). The free base was converted to the fumaric acid salt: mp 51-59 ° C. Analysis calculated for C23H32N50SC1 + 1.0 CH40 + 1.0 H20 Theory:% C, 54.88; % H, 6.65; % N, 11.40 Found:% C, 54.88; % H, 6.65; % N, 11.40. Example 8. { (1 R) -l-benzyl-2- [4- (4-methoxy- [1, 2, 5] thiadiazol-3-yl) -piperazin-1-yl] ethyl} methyl amide of cyclohexanecarboxylic acid.

Intermediate IV of Example 7 (2.20 g, 4.9 mmol) was dissolved in warm methanol (50 mL) with stirring. The sodium spheres were added in portions taking care of the reaction mixture at reflux and following the reaction by mass spectrometry. When the reaction was complete, the volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, extracted with ethyl acetate and the organic phases were combined, dried (MgSO 4), filtered and evaporated to give an oily residue. The residue was purified by chromatography on silica gel eluting with 0.5% methanol to 0.75% in methylene chloride to give Intermediate VI as a viscous foam. The foam was dissolved in anhydrous dioxane (20 mL), treated with 4N HCl in dioxane (10 mL) and stirred at room temperature for 5 hours. Ethyl ether (15 mL) was added and Intermediate VII was collected by filtration (800 mg, 40%) as a white solid, mp: 237-239 ° C (dec). Intermediate VII (726 mg, 1.82 mmol) was reduced with BH3 IN in THF (7 mL) containing TEA (0.3 mL) as described in Example 7. The crude product was purified by chromatography on silica gel eluting with methanol 3.5% to 6% in methylene chloride to give 398 mg (63%) of Intermediary VIII.

A solution of Intermediate VIII (298 mg, 0.86 mmol) in methylene chloride containing TEA (0.17 mL) was treated with a solution of cyclohexylcarbonyl chloride (0.17 L) in methylene chloride (2 L). After stirring for 15 minutes, the reaction was quenched by the addition of brine (25 mL). The layers were separated and the aqueous phase was extracted twice with methylene chloride. The organic layers were combined, dried (MgSO), filtered, and evaporated to give a residue which was purified by chromatography on silica gel eluting with 0.5% methanol in methylene chloride to give the title compound (252 mg , 64%) as an oil. The oil was dissolved in ether, treated with volatile HCl to give the HCl salt of the title compound as a white solid, mp: 190-193 ° C. Analysis calculated for C24H35N502S + 1.00 HCl + 0.4 H20 Theory:% C, 57.50; % H, 7.40; % N, 13.97 Found:% C, 57.78; % H, 7.12; % N, 13.49. Example 9. N-. { l-Benzyl-2- [4- (4-methoxy- [1,2,5] thiadiazol-3-yl) piperazin-1-yl] ethyl} -N-methylbenzamide. A solution of Intermediate VIII (100 mg, 0.29 mmol) in methylene chloride containing TEA (0.12 mL) was treated with a solution of benzoyl chloride (0.05 L) in methylene chloride (1 mL). After stirring for 4 hours, the reaction was quenched by the addition of brine (10 mL). The layers were separated and the aqueous phase was extracted twice with methylene chloride. The organic layers were combined, dried (MgSO 4), filtered, and evaporated to give a residue which was purified by chromatography on silica gel eluting with 0.3-0.5% methanol in methylene chloride to give the title compound ( 90 mg, 69%) as an oil. The oil was dissolved in ether, treated with volatile HCl to give the HCl salt of the title compound as a white solid, mp: 311-315 ° C. Analysis calculated for C24H29N502S + HCl Theory:% C, 59.06; % H, 6.2; % N, 14.35 Found:% C, 58.69; % H, 6.18; % N, 14.16. Example 10. { L-benzyl-2- [4- (4-methoxy [1,2,5] thiadiazol-3-yl) piperazin-1-yl] ethyl} methylamide of morpholin-4-carboxylic acid. A solution of Intermediate VIII (100 mg, 0.29 mmol) in methylene chloride containing TEA (0.12 L) was treated with a solution of morpholine carbonyl chloride (0.05 mL) in methylene chloride (1 mL). After stirring for 4 hours, the reaction was quenched by the addition of brine (10 mL). The layers were separated and the aqueous phase was extracted twice with methylene chloride. The organic layers were combined, dried (MgSO), filtered, and evaporated to give a residue which was purified by chromatography on silica gel eluting with 0.3-0.5% methanol in methylene chloride to give the title compound ( 100 mg, 75%) as a waxy solid. The solid was dissolved in ether, treated with volatile HCl to give the 2 HCl salt of the title compound as an amorphous white solid, mp 68-97 ° C. Analysis calculated for C2H32N603S + 2 HCl Theory:% C, 49.53; % H, 6.42; % N, 15.75 Found:% C, 49.74; % H, 6.66; % N, 15.64. Example 11. { (IR) -2-. { 4- (4-methoxy- [1,2,5] thiadiazol-3-yl) piperazin-1-yl] -l-pyridin-3-ylmethyl ethyl} 1-methylcyclohexanecarboxylic acid amide. The compound of Example 1 was allowed to react with BOC-D-3-pyridylalanine according to the method of Example 1 to give Intermediate X, tert-butyl ester of the acid. { (2R) -2- [4- (4-Chloro- [1,2,5] thiadiazol-3-yl) piperazin-1-yl] -2-oxopyridin-3-ylmethylethyl] carbamic acid as an amorphous solid. Analysis calculated for Ci9H25ClN603S Theory:% C, 50.38; % H, 5.56; % N, 18.55 Found:% C, 51.25; % H, 5.65% N, 18.18.

The method of Example 4 was used to convert Intermediate X to Compound 11, with the exception that methylcyclohexylcarbonyl chloride was used in place of cyclohexanecarbonyl chloride. Analysis calculated for C23H3N602S + 2 HCl + 0.33 H20 Theory:% C, 51.40; % 'H, 6.87; % N, 15.64 Found:% C, 51.38; % H, 6.90; % N, 15.21. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of the formula (1): (i) characterized in that the dotted line represents an optional link; two atoms of X, Y, or Z are nitrogen and the third atom is sulfur or oxygen; R is H, halogen, OH, SH, Ci-Ce alkyl, Ci-C alkoxy, C?-C6 thioalkyl, phenoxy, thiophenoxy, or phenyl, the phenyl ring being optionally substituted by from one to three substituents selected from C-alkyl ? -C6; C6-C6 alkoxy; CF3; Cl; Br; F; CN; or C02CH3; A is C, CH, or N; Ri is an aryl, heteroaryl, or cycloalkyl group, the aryl, heteroaryl or cycloalkyl group being optionally substituted by from 1 to 3 substituents selected from Ci-Ce alkyl, Ci-C6 alkoxy; CF3, Cl, Br, CN, or C02CH3; R2 is H or C? -C6 alkyl; R3 is Ci-Cß alkyl, aryl, 5- or 6-membered heteroaryl, C3 cycloalkyl to Cs, the cycloalkyl group being optionally substituted by C?-C6 alkyl, or a 3- to 8-membered heterocyclic ring containing one or more selected heteroatoms of O, S or N, the 5 or 6 membered aryl and heteroaryl groups being optionally substituted by from one to three substituents selected from C 1 -C 6 alkyl, Ci-C 6 alkoxy, CF 3, Cl, Br, F, CN, or C02CH3; or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, characterized in that it has the formula (2): (2) wherein R, Ri, R2, and R3, are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
3. 3. The compound according to claim 1 or claim 2, characterized in that: R is selected from H, halogen, OH, SH, Ci-C6 alkyl, C?-C6 alkoxy, or Ci-Cβ thioalkyl, "R1 is selects from aryl, heteroaryl, or cycloalkyl groups, optionally substituted by from 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, CF 3, Cl, Br, CN, or C 2 CH 3; R 2 is H or C 1 -C 6 alkyl; Ce, R 3 is C 1 -C 6 alkyl, optionally substituted aryl, 5 or 6 membered heteroaryl optionally substituted by Ci-Cß alkyl, or a 3- to 8-membered heterocyclic ring containing one or more heteroatoms selected from O, S or N, or a pharmaceutically acceptable salt thereof
4. 4. The compound according to claim 1, characterized in that it is { (1S) -1-benzyl-2- [4- (4-chloro [1,2, 5] thiadiazol-3-y1) piperazin-1-yl] ethyl.}. Cyclohexanecarboxylic acid amide or a pharmaceutically acceptable salt thereof.
5. 5. The compound according to claim 1, characterized in that it is N-. { (1S) -1-benzyl-2- [4- (4-chloro [1, 2, 5] thiadiazol-3-yl) piperazin-1-yl] ethyl} isonicotinamide or a pharmaceutically acceptable salt thereof.
6. 6. The compound according to claim 1, characterized in that it is. { (SS) -1-benzyl-2- [4- (4-chloro [1,2,5] thiadiazol-3-yl) piperazin-1-yl] ethyl} pyridine-2-carboxylic acid amide, or a pharmaceutically acceptable salt thereof.
7. 7. The compound according to claim 1, characterized in that it is. { (2R) -1-Benzyl-2- [4- (4-chloro [1,2,5] thiadiazol-3-yl) piperazin-1-yl] ethyl} cyclohexanecarboxylic acid methylamide, or a pharmaceutically acceptable salt thereof.
8. 8. The compound according to claim 1, characterized in that it is. { (IR) -1-Benzyl-2- [4- (4-methoxy [1,2,5] thiadiazol-3-y1) piperazin-1-yl] ethyl} cyclohexanecarboxylic acid methylamide, or a pharmaceutically acceptable salt thereof.
9. 9. The compound according to claim 1, characterized in that it is N-. { (l-Benzyl-2- [4- (4-methoxy [1,2,5] thiadiazol-3-yl) piperazin-1-yl] ethyl} N-methylbenzamide, or a pharmaceutically acceptable salt thereof.
10. 10. The compound according to claim 1, characterized in that it is. { l-Benzyl-2- [4- (4-methoxy [1,2,5] thiadiazol-3-yl) piperazin-1-yl] ethyl} morpholin-4-carboxylic acid methylamide, or a pharmaceutically acceptable salt thereof.
11. 11. The compound according to claim 1, characterized in that it is. { (IR) -2- [4- (4-methoxy- [1,2,5] thiadiazol-3-y1) piperazin-1-yl] -1-pyridin-3-ylmethyl ethyl lamide of 1-methylcyclohexanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
12. 12. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier or excipient and a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
13. 13. A method for the treatment of depression in a mammal, the method characterized in that it comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
14. 14. A method for the treatment of anxiety in a mammal, the method comprising administering to the mammal in need thereof, a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
15. 15. A process for preparing a compound of the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it comprises: a) acylating a compound of the formula (3) (3) wherein the dotted line R, Rlf R2, X, Y, Z and A are as defined above, with a compound of the formula: R3COOH (4) or a reactive derivative thereof (eg, acid halide) as the chloride or a mixed anhydride) wherein R3 is as defined above; or b) converting a basic compound of the formula (1) to a pharmaceutically acceptable acid addition salt thereof. Summary of the Invention The present invention provides compounds of the general formula (1) (1) wherein two atoms of X, Y, or Z are nitrogen and the third atom is sulfur or oxygen; R is H, halogen, OH, SH, C?-C6 alkyl, Ci-C alco alkoxy, Ci-Cß thioalkyl, phenoxy, thiophenoxy, or phenyl, the phenyl ring being optionally substituted by from one to three substituents selected from C-alkyl? -C6; C6-C6 alkoxy; CF3; Cl; Br; F; CN; or C02CH3; A is C, CH, or N; Ri is an aryl, heteroaryl, or cycloalkyl group, the aryl, heteroaryl or cycloalkyl group being optionally substituted by from 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy; CF3, Cl, Br, CN, or C02CH3; R2 is H or Ci-Cß alkyl, "R3 is Ci-Cß alkyl, optionally substituted aryl, optionally substituted 5 or 6-membered heteroaryl, C3 to C8 cycloalkyl, the cycloalkyl group being optionally substituted by Ci-Ce alkyl, or a ring 3 to 8 member heterocyclic containing one or more heteroatoms selected from 0, S or N, or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods for the treatment of disorders of the central nervous system using these compounds.