MXPA00003111A - Process for preparing cyclic thioamides - Google Patents

Abstract

The present invention relates to a process for preparing a compound of the formula wherein b, Y and R3 are defined as above, useful for preparing novel aralkyl and aralkylidene heterocyclic lactams and imides which are selective agonists and antagonists of serotonin 1 (5-HT1) receptors.

Description

PROCEDURE FOR PREPARING CYCLIC THIOAMIDES BACKGROUND OF THE INVENTION The present invention relates to a process for preparing cyclic thioamides useful for preparing aralkyl- and aralkylidene-lactams and heterocyclicimides, which are selective agonist and antagonist of serotonin 1 (5-HT?) Receptors, specifically, one or both of the 5-HT and 5-HT1D receptors, useful for treating or preventing migraine, depression and other disorders for which a 5-HT-? agonist or antagonist is indicated. European Patent Publication 434,561, published June 26, 1991, refers to 1- (1-piperazinyl substituted in 4-position) -naphthalenes substituted with alkyl, alkoxy and hydroxy in position 7. The compounds refer to agonist and 5-HT antagonists? which are useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain. European Patent Publication 343,050, published on November 23, 1989, refers to 1- (1-piperazinyl substituted in 4-position) -naphthalenes unsubstituted, halogenated and substituted with methoxy in position 7 as therapeutic agents as ligands of HT1A PCT patent application publication WO 94/21619, published September 29, 1994, refers to naphthalene derivatives as agonist and anatagonist agents of 5-HT ?. PCT Patent Application Publication WO 96/00720, published January 11, 1996, refers to naphthyl ethers as useful 5-HT? Agonists and antagonists. European Patent Publication 701,819, published March 20, 1996, refers to the use of 5-HT? Agonist and antagonist agents. in combination with a 5-HT reuptake inhibitor. Glennon et al. Refer to 7-methoxy-1- (1-piperazinyl) -naphthalene as a useful 5-HT? in his article "5-HTI D Serotonin Receptors", Clinical Druq Res. Dev. 22, 25-36 (1991). Glennon's article "Serotonin Receptors: Clinical Implications", Neuroscience and Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including suppression of appetite. Thermal regulation, cardiovascular and hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease. World patent publication WO 95/31988, published November 30, 1995, refers to the use of a 5-HTID antagonist in combination with a 5-HT ?A antagonist to treat CNS disorders (nervous system central) such as depression, generalized anxiety, panic disorder, agoraphobia, social phobia, disorder, obsessive-compulsive, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, disorders endocrine diseases such as hyperprolactinemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract in which changes in motility and secretion are involved, as well as sexual dysfunction. G. Maura et al., J. Neurochem. 66 (1), 203-209 (1996), have indicated that the administration of selective agonist agents for 5-HT-? A receptors or for both 5-HT1A and 5-HT-ID receptors may represent a great improvement in the treatment of human cerebellar ataxias, which is a multifaceted syndrome for which no consecrated one is available. European Patent Publication 666,261, published on August 9, 1995, refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing a compound of the formula wherein b is 0, 1, 2 or 3; And it is oxygen, sulfur, NH or N-acetyl; and each R 3 is independently selected from the group consisting of halo, cyano, alkyl (C-i-Cß), alkoxy (CrC 6) and trifluoromethyl; which comprises reacting a compound of the formula with a dehydrating agent. The present invention also relates to a more preferred process for preparing a compound of formula I, wherein the dehydrating agent is acetic anhydride. The present invention also relates to a process for preparing a compound of the formula which comprises reacting a compound of the formula with a haloacetic acid in the presence of a base. The present invention also relates to a more preferred process for preparing the compound of formula II, wherein the haloacetic acid is bromoacetic acid. The present invention also relates to a more preferred process for preparing the compound of formula II, wherein the base is potassium hydroxide. The present invention also relates to a process for preparing a compound of the formula which comprises reacting a compound of the formula IV with an agent, and reacting the compound thus formed with hydrochloric acid. The present invention also relates to a more preferred process for preparing the compound of formula III, wherein the reducing agent is a complex of borane and tetrahydrofuran. The present invention also relates to a process for preparing a compound of the formula which comprises reacting a compound of the formula with hydroxy-acetic acid, mercapto-acetic acid or 2-amino-acetic acid. The present invention also relates to a more preferred process for preparing the compound of formula IV, wherein the compound of formula V is reacted with mercapto-acetic acid. The present invention relates to a process for preparing a compound of the formula wherein b is 0, 1, 2 or 3; And it is oxygen, sulfur, NH or N-acetyl; and each R 3 is independently selected from the group consisting of halo, cyano, alkyl (C Ce), alkoxy (C-i-Cß) and trifluoromethyl; which comprises (a) reacting a compound of the formula with hydroxy-acetic acid, mercapto-acetic acid or 2-amino-acetic acid; (b) reacting a compound of formula IV, thus formed with a reducing agent, and reacting the intermediate compound thus formed with hydrochloric acid; (c) reacting a compound of formula III thus formed YH with a haloacetic acid in the presence of a base; and (d) reacting a compound of formula II thus formed with a dehydrating agent. The present invention also relates to a more preferred process for preparing the compound of formula I, wherein the compound of formula V is reacted with mercapto-acetic acid; the reducing agent is a complex of borane and tetrahydrofuran; the base is potassium hydroxide; halo-acetic acid is bromoacetic acid; the dehydrating agent is acetic anhydride. The present invention also relates to a compound of the formula The present invention also relates to a compound of the formula The present invention also relates to a compound of the formula DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, b, Y and R3 in the Reaction Schemes and the discussion that follows as defined above.

SCHEME 1 YH 15 twenty SCHEME 2 In reaction 1 of scheme 1, the aniline compound of formula V is converted into the corresponding compound of formula IV, wherein Y is oxygen, sulfur, NH or N-acetyl, by reacting compound V with hydroxy-acetic acid , mercapto-acetic acid or 2-amino-acetic acid, in the presence of an aprotic solvent, such as toluene. The reaction mixture thus formed is heated to reflux for a period of time comprised between 16 hours and approximately 24 hours, preferably around 20 hours. In reaction 2 of scheme 1, the compound of formula IV is converted into the corresponding compound of formula III by reducing compound IV with a reducing agent, such as a complex of borane and tetrahydrofuran. The compound thus formed is then treated with anhydrous hydrochloric acid in the presence of a polar protic solvent, such as ethanol. The reaction is carried out at a temperature between about 10 ° C and about 20 ° C, preferably at about 15 ° C, for a period of 15 ° C, for a period of time comprised between about 2 hours and about 4 hours. hours, preferably about 3 hours. In reaction 3 of scheme 1, the compound of formula III is converted to the corresponding compound of formula II by first treating compound III with a base, such as potassium hydroxide, under an inert atmosphere, in the presence of a solvent polar protic, such as ethanol, at a temperature comprised between about 0 ° C and about 20 ° C, preferably about 10 ° C, for a period of time between about 0.5 hours and about 2 hours, preferably about 1 hour. The alkylation of the intermediate compound thus formed is carried out with the addition of bromoacetic acid. Then the reaction mixture is stirred for an additional period of time comprised between about 2 hours and about 4 hours, preferably about 3 hours. In relation 4 of scheme j, the compound of formula II is converted into the corresponding compound of formula I by reacting compound II with excess acetic anhydride. The reaction mixture thus formed is heated to reflux for a period of time between about 0.5 hours and about 2 hours, preferably about 1 hour. In reaction 1 of scheme 2, the compound of formula VIII, wherein Q is an appropriate leaving group, such as halo, preferably fluoro; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, alkyl (Ci-Cß), hydroxy, trifluoromethyl, alkoxy (Ci-Cß), -S? T-alkyl (C? -C6) in which t is zero, one or two, -CO2R8 or -CONR9R10; wherein R8, R9 and R10 are each independently selected from hydrogen, (C-? -C) alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chlorine, fluoro, bromo, iodo, alkyl (Ci-Cd), alkoxy (C- | -C6), trifluoromethyl, cyano and -Sok-alkyl (Cr Cß) in which k is zero, one or two; and R2 is hydrogen, (C? -C4) alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, alkyl (d-C6) , alkoxy (Ci-Cß), trifluoromethyl, cyano and -Sok-alkyl (C? -C6) in which k is zero, one or two; it becomes the corresponding compound of formula VII, in which R1 is a group of the formula G1, G2, G3, G4, G5 or G6 represented below, G G2, G¿, G4, G5, G6, a is from zero to four; p is 1, 2 or 3; R 4 is selected from the group consisting of hydrogen, (Ci-Cβ) alkyl optionally substituted by (C C 6) alkoxy optionally substituted by (C 1 -C 6) alkoxy or by one to three fluorine atoms, or [(C 1) alkyl; -C)] aryl in which the aryl moiety is phenyl, naphthyl, or hateroaryl- (CH2) q- wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzo-isoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo-iodo, alkyl (Ci-Cβ) ), alkoxy (Ci-Cß), trifluoromethyl, cyano and -SOg-alkyl (Ci-Cß), in which g is zero, one or two; R5 is selected from the group consisting of hydrogen, alkyl (CI-CT), [(C 1 -C 4) alkyl] aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl- (CH 2) r-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzo-isoxazolyl and benzisothiazolyl and r is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, alkyl (CrC6), alkoxy (C Ce), trifluoromethyl, -C (= O) -alkyl (C? -C6), cyano and - Soj-alkyl (Ci-Ce), wherein j is zero, one or two; or R4 and R5 taken together form a chain of 2 to 4 carbons; R6 is hydrogen or alkyl (C -? - C6); each R7 is, independently, (C -? - C4) alkyl or a methylene bridge (C?, - C) ranging from one of the ring carbons of the piperazine ring of G1 to the same or another ring carbon or a ring nitrogen of the piperazine ring of G1 having a site available for bonding, or up to a carbon of R4 having a site available to bind; and E, of formula G3, is oxygen, sulfur, SO or SO2; reacting the compound VIII with a compound of the formula R1H, wherein H refers to a hydrogen atom in the group E from G3 or nitrogen atoms from G1, G2, G4, G5 or G6 and R1 is defined as before, in the presence of a base. This reaction is generally carried out at a temperature of about 25 ° C to about 140 ° C, preferably at about the reflux temperature, in a polar aprotic solvent, such as dimethyl sulfoxide, N, N-dimethyl-formamide , N, N-dimethyl-acetamide or N-methyl-2-pyrrolidinone, preferably N-methyl-2-pyrrolidinone. Suitable bases include anhydrous sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, as well as amines such as pyrrolidine, triethylamine and pyridine. Anhydrous potassium carbonate is preferred. In reaction 2 of scheme 2, the compound of formula VII is converted into the corresponding compound of formula VI by subjecting compound VII to an Aldol-elimination condensation. In an Aldolic condensation, the compound of the formula VII is reacted with a compound of the formula I in the presence of a base, to form an intermediate Aldolic compound of formula IX which can be isolated or, preferably, directly converted in the same reaction operation into a compound of the formula VI by the loss of water. The degree of completion for the conversion of compounds of formula IX into the aldol product of formula VI can be determined using one or more analytical techniques, such as thin layer chromatography (tic) or high pressure liquid chromatography (hplc). ). In some cases, it may be possible or desirable to isolate the intermediate compound of formula IX. In such a case, the compound of formula IX can be converted to the VI compound by removing water using techniques that are familiar to those skilled in the art sector., for example, by heating at the reflux temperature a solution of the compound of formula IX in a solvent such as benzene, toluene or xylene, in the presence of a catalytic amount of benzene- or p-toluene sulfonic acid, providing for the elimination of the water generated. Such techniques for water removal may involve the use of molecular sieves or a Dean-Stark collector to isolate the water created as an azeotrope with the solvent. The Aldolic reaction is typically carried out in a solvent of the ether type such as methyl t-butyl ether, diisopropyl ether or tetrahydrofuran, at a temperature of about -78 ° C to about 25 ° C. Preferably, this reaction is carried out in tetrahydrofuran at about 25 ° C. Suitable bases for use in the forming operation of Aldol include sodium hydride, potassium tert-butoxide, lithium diisopropyl-amide, sodium bis (trimethylsilyl) amide and bis (trimethylsilyl) lithium amide. Sodium bis (trimethylsilyl) amide is preferred. Aldolic condensations are described in "Modern Synthetic Reactions", Herbert O. House, 2nd edition, W.A. Benjamin, Menlo Park, California, 629-682 (1972) and Tetrahedron, 38 (20), 3059 (1982). The compounds of formula VI which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula VI from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter back in the free base compound, by treatment with an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the compounds with the character of bases of formula VI are easily prepared by treating the compound as a base with a substantially equivalent amount of the chosen inorganic or organic acid in an alkaline solvent medium or in an appropriate organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained. The compounds of formula VI and their pharmaceutically acceptable salts (hereinafter also referred to as "the active compound") are useful psychotherapeutic agents and are potent agonists and / or antagonists of the serotonin 1A (5-HT? .A) and / or serotonin 1D (5-HTID). The active compound is useful in the treatment of hypertension, depression, generalized anxiety disorder, phobias (eg, agoraphobia, social phobia and simple phobias), post-traumatic stress syndrome, elusive personality disorder, sexual dysfunction (e.g. premature ejaculation) ), eating disorders (for example anorexia nervosa and bulimia nervosa), obesity, dependence on chemical products (for example addictions to alcohol, cocaine, heroin, phenolbarbital, nicotine and benzodiazepines), grouped headache, migraine, pain, Alzheimer's, obsessive-compulsive disorder, panic disorder, memory disorders (eg, dementia, amnestic disorders and age-related cognitive decline (ARCD), Parkinson's disease (eg, dementia in a disease) of Parkinson's disease, parkinsonism induced by neuroleptics and tardive dyskinesias), endocrine disorders (for example, hyperpro lactinemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania , kleptomania, male impotence, cancer (for example, small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders). The affinities of the compound of formula VI for the various serotonin-1 receptors can be determined using classical radioligand binding assays as described in the literature. The affinity for 5-HT-? A can be measured using the procedure of Hoyer et al. (Brain Res., 376, 85 (1986)). The affinity for 5-HT1D can be measured using the procedure of Heuring and Peroutka (J. Neurosci., 7, 894 (1987)). The in vitro activity of the compound of formula VI at the 5-HT-I D binding site can be determined according to the following procedure. A caudate bovine tissue is homogenized and suspended in 20 volumes of a buffer comprising TRIS "50 mM Tris [hydroxymethyl] aminomethane hydrochloride (hydrochloride) at a pH of 7.7. Then the homogenized material is centrifuged at 45,000 G (= x g) for 10 minutes. Then the supernatant is discarded and the resulting pellet is resuspended in approximately 20 volumes of a TRIS buffer 50 mM hydrochloride at a pH of 7.7. This suspension is then pre-incubated for 15 minutes at 37 ° C, after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant is discarded. The resulting sediment (approximately 1 gram) is resuspended in 150 ml of a TRIS »15 mM hydrochloride buffer containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 μM pargyline and calcium chloride ( CaCl2) 4mM. The suspension is kept on ice for at least 30 minutes before use. The inhibitor, control or vehicle is then incubated according to the following procedure. To 50 μl of a 20 percent solution of dimethylsulfoxide (DMSO) in 80 percent distilled water is added 200 μl of tritiated 5-hydroxy-triptamine (2nM) in a TRIS buffer »50 mM hydrochloride containing ascorbic acid 0.01 percent at a pH of 7.7 and also containing 10 μM of pargyline and 4 μM of calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylamino-tetralin) and 100 nM of mesulergine. To this mixture is added 750 μl of caudate bovine tissue, and the resulting suspension is subjected to vortex turbulence to ensure a homogeneous suspension. The suspension is then incubated in a shaking water bath for 30 minutes at 25 ° C. After the incubation is complete, the suspension is filtered using glass fiber filters (eg Whatman GF / B® filters). The pellet is then washed three times with 4 ml of a TRIS buffer «50 mM hydrochloride at a pH of 7.7. Then, the sediment is placed in a vial for scintillation with 5 ml of a scintillation fluid (Aquasol 2®) and allowed to settle overnight. Percent inhibition can be calculated for each dose of the compound. Then, a Cl50 value (inhibitory concentration of 50%) can be calculated from the percent inhibition values. The activity of the compound of formula VI for the binding capacity of 5-HT ?A can be determined according to the following procedure. A rat brain cortex tissue is homogenized and divided into 1 gram batch samples and diluted with 10 volumes of a 0.32 M sucrose solution. Then the suspension is centrifuged at 900 G for 10 minutes and the supernatant is separated and centrifuge again at 70,000 G for 15 minutes. The supernatant is discarded and the pellet is resuspended in 10 volumes of TRIS »15 mM hydrochloride at a pH of 7.5. The suspension is allowed to incubate for 15 minutes at 37 ° C. After the previous incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supernatant is discarded. The resulting tissue pellet is resuspended in a buffer of TRIS »50 mM hydrochloride at a pH of 7.7, containing 4 mM calcium chloride and 0.01 percent ascorbic acid. The tissue is stored at -78 ° C until ready for an experiment. The fabric can be thawed immediately before use, dilute with 10 μM pargyline and keep on ice. Then the tissue is incubated according to the following procedure. Fifty microliters of control, inhibitor or vehicle (final concentration of DMSO 1 percent) are prepared in various dosages. To this solution is added 200 μl of tritiated DPAT at a concentration of 1.5 nM in a buffer of TRIS »50 mM hydrochloride at a pH of 7.7 containing 4 mM of calcium chloride 4, 0.01 percent of ascorbic acid and pargyline. To this solution is then added 750 μl of a tissue and the resulting suspension is subjected to vortex turbulence to ensure homogeneity. Then the suspension is incubated in a shaking water bath for 30 minutes at 37 ° C. The solution is then filtered, washed twice with 4 ml of TRIS * 10 mM hydrochloride at a pH of 7.5 containing 154 mM of sodium chloride. Percent inhibition is calculated for each dose of the compound, control or vehicle. The IC 50 values are calculated from the percentage inhibition values.

The agonist and antagonist activities of the compound of formula VI in 5-HT ?A and 5-HTID receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT-? A receptors are excised from the hippocampus, whereas 5-HT? D receptors are obtained by slicing at 350 mM in a Mcllwain tissue chopper and excising the Substance black from the appropriate slices. The individual tissues are homogenized in 5 mM HEPES buffer, containing 1 mM EGTA (pH 7.5) using a portable glass-Teflon® homogenizer and centrifuged at 35,000 x g for 10 minutes at 4 ° C. The pellets are resuspended in a 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) at a final protein concentration of 20 mg (in the hippocampus) or 5 mg (in the substantia nigra) of protein per tube. The following agents are added in such a way that the reaction mixture in each tube contains 2.0 mM MgCl2, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg / ml creatine phosphokinase , 100 μM of GTP and 0.5-1 microcuries of [32 P] -ATP (30 Ci / mmol: NEG-003-New England Nuclear). Incubation is initiated by adding tissue to siliconized microcentrifuge tubes (in triplicate) at 30 ° C for 15 minutes. Each tube receives 20 μl of tissue, 10 μl of a drug or buffer (in a final concentration of 10X (10 times)), 10 μl of a 32 nM agonist or buffer (at a final concentration of 10x), 20 μl of forskolin (at a final concentration of 3 μM) and 40 μl of the above reaction mixture. Incubation is terminated by the addition of 100 μl of 2% SDS, 1.3 mM cAMP, a 45 mM ATP solution containing 40,000 dpm of [3 H] -cAMP (30 Ci / mmol: NET-275-New England Nuclear) to monitor the recovery of cAMP from the columns. The separation of [32 P] -ATP and [32 P] -cAMP is achieved using the method of Solomon et al., Analytical Biochemistry, 1974, 58, 541-548. The radioactivity is quantified by counting the scintillation in a liquid. Maximum inhibition is defined by 10 μM (R) -8-OH-DPAT for 5-HT ?A receptors and by 320 nM 5-HT for 5-HT-ID receptors- Percent inhibitions produced by test compounds they are then calculated in relation to the inhibitory effect of (R) -d-OH-DPAT for 5-HT1A or 5-HT receptors for 5-HTID receptors. The inversion of the inhibition induced by an agonist of the adenylate-glycine activity stimulated by forskolin is calculated in relation to the effect of the 32 nM agonist agent. The compound of formula VI can be tested for in vivo activity for the antagonism of hypothermia induced by the 5-HT ?D agonist in guinea pigs according to the following procedure. Hartley guinea pigs from Charles River, weighing 250-275 grams upon arrival and 300-600 grams when tested, serve as subjects in the experiment. The guinea pigs are housed in classical laboratory conditions in a lighting scheme from 7 in the morning until 7 in the evening for at least seven days before experimentation. Water and food are available ad libitum until the time of the test. The compound of formula VI can be administered as a solution in a volume of 1 ml / kg. The used vehicle is varied depending on the solubility of the compound. The test compounds are typically administered either for sixty minutes orally (po) or 0 minutes subcutaneously (sc) before a 5-HTID antagonist agent, such as [3- (1-methyl-pyrrolidin-2 -ylmethyl) -1H-indol-5-yl] - (3-nityr-pyridin-3-yl) -amine, which can be prepared as described in PCT publication WO 93/11106, published on June 10, 1993, which is administered in a dose of 5.6 mg / kg sc Before a first reading of the temperature is taken, each guinea pig is placed in a transparent plastic shoe box containing wood shavings and a metallic trellis floor and allowed to acclimate to the surroundings for 30 minutes. Then the animals are returned to the same shoe box after each reading of the temperature. Before each temperature measurement, each animal is held firmly with one hand for a period of 30 seconds. A digital thermometer with a small probe in the animal is used for temperature measurements. The probe is made of semi-flexible nylon with a tip of epoxy resin. The temperature probe is inserted 6 cm into the rectum and held there for 30 seconds or until a stable record is obtained. Then the temperatures are recorded.

In po screening experiments, a "pre-drug" baseline temperature reading is made at -90 minutes, the test compound is administered at -60 minutes and an additional reading is taken at -30 minutes. minutes Then the 5-HT? Agonist? it is administered at 0 minutes and the temperatures are taken 30, 60, 120 and 240 minutes later. In subcutaneous scrutiny experiments, a baseline temperature reading is done "prior to the drug" at -30 minutes. The test compound and the 5-HT 1D agonist agents are administered concurrently and temperatures are taken 30, 60, 120 and 240 minutes later. The data is analyzed wa two-way analysis of variants wrepeated measurements in Newman-Keuls post hoc analysis. The active compound of formula VI can be evaluated as anti-migraine agents by testing the degree to which they mimic sumatriptan to contract the vein strip saphenous vein isolated from a dog [P. P. A. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked by metiotepine, which is a known serotonin antagonist. It is known that sumatriptan is useful for the treatment of migraine and produces a selective increase in vascular resistance of the carotid in an anesthetized dog. The pharmacological basis for the efficacy of sumatriptan has already been discussed in the citation of W. Fenwick et al., Br. J. Pharmacol .. 96, 83 (1989).

The activity of the 5-HT-? Agonist agent Serotonin can be determined by in vitro receptor binding assays, as described for the 5-HT-? A receptor using the cortex of a rat as the source of receptors and [3H] -8-OH-DPAT as the radioligand [D. Hoyer et al. Eur. J. Pharm. 118, 13 (1985)] and as described for the 5-HT1D receptor using bovine caudate tissue as the. source of receptors and [3H] -serotonin as the radioligand [R. E. Heuring and S. J. Peroutka,? Neuroscience. 894 (1987)]. The compound of formula VI can be advantageously used in conjunction wone or more therapeutic agents of other types, for example, different antidepressant agents such as tricyclic antidepressants (eg, amitriptyline, dotiepin, doxepin, trimipramine, butryipine, clomipramine, desipramine , imipramine, iprindol, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (eg, isocarboxazide, phenelzine or tranylcycloparamine) or 5-HT reuptake inhibitors (eg, fluvoxamine, sertraline, fluoxetine or paroxetine), and / or wantiparkinsonic agents such as dopaminergic antiparkinsonic agents (for example, levodopa, preferably in combination wa peripheral decarboxylase inhibitor for example, benserazide or carbidopa, or wa dopamine agonist agent for example, bromocriptine, lisuride or pergolide). The compound of formula VI and its pharmaceutically acceptable salts, in combination wa 5-HT reuptake inhibitor (eg, fluvoxamine, sertraline, fluoxetine or paroxetine), preferably sertraline, or a pharmaceutically acceptable salt or a polymorph thereof (the combination of a compound of formula VI wa 5-HT reuptake inhibitor is cited in the present context as the "active combination"), are useful psychotherapeutic agents and can be used in the treatment or prevention of disorders, whose treatment or prevention is facilitated by intensified serotonergic neurotransmission (eg, hypertension, depression, generalized anxiety disorder, phobias, post-traumatic stress syndrome, elusive personality disorder, sexual dysfunction, eating disorders, obesity, dependencies of products Chemicals, grouped headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, t panic disorder, memory disorders (for example, dementia, amnestic disorders and memory impairment associated wage), Parkinson's diseases (for example, dementia in Parkinson's disease, parkinsonism induced by neuroleptic agents and tardive dyskinesias), endocrine disorders (for example hyperprolactinemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion) ), chronic paroxysmal hemicrania and headache (associated with vascular disorders). Serotonin reuptake inhibitors (5-HT), preferably sertraline, exhibit positive activity against depression; dependencies of chemical products; anxiety disorders including panic disorders, generalized anxiety disorders, agoraphobia, simple phobias, social phobia and post-traumatic stress disorders; obsessive-compulsive disorder; elusive personality disorder and premature ejaculation in mammals, including humans, due in part to their ability to block synaptosomal serotonin absorption. U.S. Patent 4,536,518 describes the synthesis, a pharmaceutical composition and the use of sertraline for depression and is therefore incorporated by reference in its entirety to the present. PCT publication WO 98/14433 relates to novel aralkyl- and aralkylidene-lactams and heterocyclic imides, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use, and is incorporated herein by reference in its entirety The activity of the active combination as antidepressant agents and with related pharmacological properties can be determined by the following methods (1) - (4), which are described in the citation of Koe, B. et al., Journal of Pharmacology and Experimental Therapeutics, 226, (3), 686-700 (1983). Specifically, the activity can be determined by studying (1) its ability to affect the efforts of mice to escape from a swimming pool ("behavioral mismatch" test of Porsolt mice), (2) its ability to potentiate the symptoms of behavior induced by 5-hydroxy-tryptophan in mice in vivo, (3) its ability to antagonize the serotonin depleting activity of p-chloro-amphetamine hydrochloride in the brain of a rat in vivo, and (4) its ability to block the absorption of serotonin, norepinephrine and dopamine by rat brain synaptosomal cells in vitro. The ability of the active combination to counteract the hypothermia caused by reserpine in mice in vivo can be determined according to the methods described in U.S. Pat. No. 4,029,731. The compositions of the compound of formula VI can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compound of formula VI can be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form, for example, of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, poly (vinyl pyrrolidone)). or hydroxypropyl methylcellulose), fillers and fillers (eg, lactose, microcrystalline cellulose or calcium phosphate), lubricating agents (eg, magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or humectants (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the field of technology. Liquid preparations for oral administration may take the form, for example, of solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be produced by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (for example, the methyl or propyl p-hydroxybenzoates or sorbic acid). For oral administration, the composition can take the form of rhombic tablets or pills formulated in a conventional manner. The active compound of formula VI can be formulated for parenteral administration by injection, including using conventional catheterization or infusion techniques. Formulations for injection may be presented in a unit dosage form, for example, in ampules or in multi-dose containers, with an added preservative agent. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder for reconstitution with an appropriate vehicle, eg, sterile, pyrogen-free water, before use. The active compound of formula VI can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration or administration by inhalation, the active compounds of formula VI are conveniently supplied in the form of a solution or suspension from a pump spray container, which is squeezed or pumped by the patient, or a presentation form for spraying an aerosol from a pressurized container or a nebulizer, with the use of an appropriate propellant agent, for example dichloro-difluoro-methane, trichloro-fluoro-methane, dichloro-tetrafluoro-ethane , carbon dioxide or other appropriate gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to supply a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (which are made, for example, of gelatin) can be formulated for use in an inhaler or insufflator, which contain a mixture of powders of a compound of formula VI and a base suitable for powders such as lactose or starch. A proposed dose of the active compound of formula VI for oral, parenteral or buccal administration to an average adult human being for the treatment of the aforementioned conditions (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit of dosage that could be administered, for example, from 1 to 4 times per day.

Aerosol formulations for the treatment of the aforementioned conditions (e.g., migraine) in an average adult human are preferably arranged such that each measured or "puff" dose of aerosol contains from 20 μg to 1,000 μg of the compound of Formula VI The overall daily dose with an aerosol will be within the range of 100 μg to 10 mg. The administration can be done several times per day, for example 2, 3, 4 or 8 times, delivering for example 1, 2 or 3 doses each time. In connection with the use of an active compound of formula VI with a 5-HT reuptake inhibitor, preferably sertraline, for the treatment of individuals possessing any of the aforementioned conditions, it should be noted that these compounds can be administered either alone or in combination with pharmaceutically acceptable carriers by any of the routes indicated above, and that said administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., that these can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, rhombic pills, troches, hard candies, powders , projections, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, said oral pharmaceutical formulations can be appropriately sweetened and / or savored by means of various agents of the type currently used for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, ie, in amounts that are sufficient to provide the desired dosage unit and a 5-HT reuptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, ie, in amounts that they are sufficient to provide the desired unit dosage. A proposed daily dose of an active compound of formula VI in the combination formulation (a formulation containing an active compound of formula VI and a 5-HT reuptake inhibitor) for administration orally, parenterally, rectally or buccally to an average adult human being for the treatment of the aforementioned conditions is from about 0.01 mg to about 2,000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose that could be administered, for example , from 1 to 4 times per day. A proposed daily dose for a reuptake inhibitor of -HT, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to an average adult human being for the treatment of the aforementioned conditions is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg for the 5-HT reuptake inhibitor per unit dose that could be administered, for example, 1 to 4 times per day. A preferred dose ratio of sertraline to an active compound of formula VI in the combination formulation for oral, parenteral or buccal administration to an average adult human being for treatment of the aforementioned conditions is from about 0.00005 to about 20,000, preferably around 0.25 to about 2,000. The aerosol combination formulations for the treatment of the aforementioned conditions in an average adult human being are preferably arranged such that each metered dose or "puff" of aerosol contains from about 0.01 μg to about 100 mg of the active compound of formula SAW, preferably from about 1 μg to about 10 mg of said compound. The administration can be done several times per day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. Aerosol formulations for the treatment of the aforementioned conditions in an average adult human being are preferably arranged in such a way that the measured or "puffed" dose of aerosol contains from about 0.01 mg to about 2000 mg of an inhibitor of resorption of 5-HT, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. The administration can be carried out several times per day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. As indicated above, a 5-HT reuptake inhibitor, preferably sertraline in combination with compounds of formula VI readily adapts to therapeutic use as antidepressant agents. In general, these antidepressant compositions containing a 5-HT reuptake inhibitor, preferably sertraline, and a compound of formula VI are usually administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT reuptake inhibiting agent, preferably sertraline, preferably from about 0.1 mg to about 10 mg per kg of body weight per day of sertraline; with an amount of from about 0.001 to about 100 mg per kg of body weight per day of a compound of formula VI, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula VI, although Variations will necessarily occur depending on the conditions of the individual being treated and the particular route of administration that has been chosen. The following examples illustrate the preparation of the compounds of the present invention. The melting points are uncorrected. The NMR data are presented in parts per million (d) and are referred to as the deuterium blocking signal from the sample solvent (deuterium-chloroform, unless otherwise specified). Commercial reagents were used without further purification.

PREPARATION A 2- (3,4-Dichloro-phenylamino) -ethanethiol Hydrochloride A 3-neck, 2-liter round bottom flask equipped with an overhead stirrer, a temperature probe and a Dean-Stark collector reflux condenser was charged with 100.0 grams (0.617 mol) of 3.4- dichloro-aniline and 500 ml of toluene. The resulting solution was then treated with 64.4 ml (0.927 mol, 1.5 equivalents) of mercapto-acetic acid. The solution was heated to reflux (at 130 ° C) while water was collected in the Dean-Stark trap for 20 hours, then cooled to room temperature. Ethyl acetate (250 ml) was then added followed by 123 ml of 1N hydrochloric acid. The layers were separated and the organic layer was washed with 250 ml of water and then with 500 ml of saturated aqueous sodium hydrogen carbonate and washed with water. concentrated under vacuum to a volume of approximately 200 ml. After the addition of 200 ml of toluene, the solution was again concentrated to approximately 200 ml, diluted with 1 l of tetrahydrofuran and filtered. The filtrate was added dropwise to a 5 liter, 3-neck, bottom-flush, nitrogen-purged flask containing 1.73 I (1.73 mol, 2.80 equivalents) of a 1 N complex of borane and tetrahydrofuran, while which was maintained at a temperature of 10-15 ° C. Some gas evolution was observed. The reaction mixture was warmed to room temperature and stirred overnight and then cooled to 10 ° C. A solution of 252 grams (6.91 mole, 11.2 equivalents) of anhydrous hydrogen chloride in 840 ml of ethanol was added at 10-15 ° C during which time a significant evolution of gases and solid materials precipitated. After being stirred for 1 hour at 5-10 ° C, the solid materials were collected by filtration, washed with tetrahydrofuran and dried under vacuum to provide 100.0 grams (62.6% yield) of the title compound as a white solid , pf 185-188 ° C. 1H NMR (DMF- 7) 7.20 (d, J = 8.7 Hz, 1 H), 7.01 (d, J = 2.7 Hz, 1 H), 6.78 (dd, J = 2.7, 8.7 Hz, 1 H), 3.18 (dd, J = 6.4, 7.7 Hz, 2H), 2.61 (broad s, 2H), 2.37 (broad s, 1H). 13C NMR (DMF-d7) d 146.02, 132.94, 134.90, 122.70, 118.09, 117.19, 50.05, 23.07. HRMS (FAB) calculated for C8H9CI2NS: 221.9911; found: 221.9893.

EXAMPLE 1 4- (3,4-Dichloro-phenyl) -thiomorpholin-3-one A 3-neck, 3-necked round bottom flask equipped with an overhead stirrer, temperature probe and nitrogen inlet was charged with 100 grams (0.387 mol) of 2- (3,4-dichlorohydrochloride. phenylamino) -ethanethiol and 1 I of 2B-ethanol. In the resulting suspension, 76 grams (1.35 mol, 3.5 equivalents) of potassium hydroxide were charged. The addition resulted in an increase in temperature to about 35 ° C. This suspension was stirred at room temperature for 15-20 minutes, then cooled to 5-10 ° C and treated with a solution of 59.1 grams (0.425 mol, 1.1 equivalents) of bromoacetic acid in 152 ml of 2B-ethanol. After being stirred at room temperature for about 3 hours, the reaction mixture was concentrated under vacuum to a volume of about 225 ml. To this suspension was added 864 ml (9.15 mol, 23.6 equivalents) of acetic anhydride without external cooling, which resulted in an increase in temperature to about 100 ° C. The flask was coupled with a condenser and a receiving flask, and heated to 105-110 ° C at which point a distillate material began to be collected. With continued heating, the internal temperature rose to 115 ° C, the reaction flask was reconnected with a reflux condenser and the reaction mixture was refluxed for 1 hour. After allowing to cool to room temperature, the reaction mixture was poured into a 3-neck, 5 I capacity round bottom flask containing 1,700 ml of water and 864 ml of methylene chloride and stirred for 10 hours. -20 minutes at 20-25 ° C. The layers were separated and the organic layer was washed with 1 l of water and then treated with 2 l of 10% aqueous sodium hydroxide., which brought the pH to 9-10. The layers were separated, the organic layer was dried over magnesium sulfate and concentrated atmospherically to a volume of about 200 ml. The displacement of methylene chloride by diisopropyl ether was achieved by continuing to charge the diisopropyl ether and concentrate until an internal temperature of 68 ° C was reached. Then the solution was cooled to room temperature. They began to precipitate solids at 45 ° C. The resulting suspension was stirred at room temperature for two hours. The solids were collected by filtration, washed with diisopropyl ether and dried in vacuo at 45-50 ° C to provide 57.5 grams (yield 56.7%) of the title compound as a white solid, m.p. 81-83 ° C. 1 H NMR (CDCl 3) 7.44 (d, J = 8.7 Hz, 1 H), 7.38 (d, J = 2.5 Hz, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 3.93 (t, J = 11.5 Hz, 2H), 3.43 (s, 2H), 3.01 (t, J = 11.5 Hz, 2H). 13C NMR (CDCI3) d 168.10, 143.04, 134.201, 132.25, 132.09, 129.42, 126.83, 53.32, 31.81, 27.86. HMRS (FAB) calculated for C10H9CI2NOS: 261.9860; found: 261.9839.

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing a compound of the formula wherein b is 0, 1, 2 or 3; And it is oxygen, sulfur, NH or N-acetyl; and each R3 is independently selected from the group consisting of halo, cyano, alkyl (Ci-Cß), alkoxy (C? -C6) and trifluoromethyl; which comprises reacting a compound of the formula with a dehydrator.

2. A process according to claim 1, wherein the dehydrating agent is acetic anhydride.

3. A process according to claim 1, further including the preparation of the compound of the formula which comprises reacting a compound of the formula with a haloacetic acid in the presence of a base.

4. A process according to claim 3, wherein the haloacetic acid is bromoacetic acid.

5. A process according to claim 3, wherein the base is potassium hydroxide.

6. A method according to claim 3, which further includes the preparation of the compound of the formula which comprises reacting a compound of the formula with a reducing agent and reacting the compound thus formed with hydrochloric acid.

7. - A process according to claim 6, wherein the reducing agent is a complex of borane and tetrahydrofuran.

8. A method according to claim 6, further including the preparation of the compound of the formula which comprises reacting a compound of the formula with hydroxy-acetic acid, mercapto-acetic acid or 2-amino-acetic acid.

9. A process according to claim 6, wherein the compound of formula V is reacted with mercapto-acetic acid.

10. A process for preparing a compound of the formula wherein b is 0, 1, 2 or 3; And it is oxygen, sulfur, NH or N-acetyl; and each R3 is independently selected from the group consisting of halo, cyano, (C-i-C) alkyl, alkoxy (CrC6) and trifluoromethyl; which comprises (a) reacting a compound of formula with hydroxy-acetic acid, mercapto-acetic acid or 2-amino-acetic acid; (b) reacting a compound of formula IV thus formed with a reducing agent and reacting the compound thus formed with hydrochloric acid; (c) reacting a compound of formula III thus formed with a haloacetic acid in the presence of a base; and (d) reacting a compound of formula II thus formed with a dehydrating agent.

11. A process according to claim 10, wherein the compound V is reacted with mercapto-acetic acid; the reducing agent is a complex of borane and tetrahydrofuran; the base is potassium hydroxide; halo-acetic acid is bromoacetic acid; and the dehydrating agent is acetic anhydride.

12.- A compound of the formula

13. - A compound of the formula

14. - A compound of the formula