MXPA01010678A - Tetrahydroisoquinolinyl-indole derivatives for the treatment of depression - Google Patents

Abstract

Compounds are provided which have formula (I) wherein:R 1, R 2, R 3, and R 4 are, independently, hydrogen, halogen, alkoxy, or carboxamide;R 5 is hydrogen, halogen, CF 3, CN, carbamide or alkoxy;and X is (CH 2) n or a 4-6 membered carbocyclic ring, wherein n is an integer of 2 to 4;or pharmaceutically acceptable salts thereof.

Description

DERIVATIVES OF TETRAHIDROISOQUINOLINIL-INDOL FOR THE TREATMENT OF DEPRES FIELD OF THE INVENTION This invention relates to compounds that are useful for the treatment of diseases affected by disorders of neurological systems affected by serotonin, such as depres and anxiety. More specifically, the present invention is directed to the dihydroisoquinolinyl indole derivatives useful in the treatment of such disorders.

BACKGROUND OF THE INVENTION Pharmaceutical compositions that enhance the neurotransmis of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depres and anxiety. The first generation of non-selective drugs that affect serotonin, operated through a variety of phyogical functions that caused them to have numerous unwanted side effects. The most recently prescribed drugs, the selective inhibitors of serotonin reuptake (SSRIs), act predominantly by inhibiting 5-HT, which is Ref. 133483 released at the synapse, is actively removed from the synaptic cleft via a serotonin transport carrier, presynaptic. Since SSRIs require several weeks before they exert their full therapeutic effect, this mechanism of 5-HT blockade can not fully explain its therapeutic activity. It is speculated that this induction of two weeks, which occurs before a complete antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors that suppress the firing activity of the 5-HT neurons, causing a damping of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, desensitization of 5-HT autoreceptors occurs allowing a complete antidepressant effect in most patients (see, for example, LePaul et al., Arch. Pharmacol., 352 : 141 (1995)). Therefore, it is believed that by canceling out this negative feedback through the use of 5HT1A antagonists, the clinical antidepressant response could potentially be increased and accelerated. Recent studies by Artigas et al., Trends Neurosci., 19: 378-383 (1996) suggested that a combination of 5HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve an antidepressant effect more robust and faster action.

The present invention relates to a new class of molecules that have the ability to act on the autoreceptors of 5-HT1A and concomitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depres as well as other serotonin disorders. U.S. Patent No. 5,468,767 describes a series of substituted characters of the following formula, useful for the treatment of disorders associated with dysfunction in serotonergic neurotransmis, including depres. wherein: Ri is hydrogen or alkyl of 1 to 4 carbon atoms; and R2 is alkyl of 1 to 4 carbon atoms or (CH2) pAr. WO 94/15928 describes the reports of a series of piperazine derivatives of the following formula for the treatment of disorders of the Central Nervous System, including depres. wherein: R is hydrogen or alkyl; Rx and R2 are each mono- or bicyclic aryl or heteroaryl radicals; R3 is hydrogen, alkyl, or a spirocycloalkyl group; and n is 1 or 2; and m is 1 or 3. WO 93/10092 describes a series of substituted cyclohexenes of the following formula for the treatment of dopaminergic disorders. wherein: R1 is aryl; 2-, 3- or 4-pyridinyl; 2-, 4- or 5-pyrimidinyl; 2-pyrazinyl; 2- or 3-thienyl; 2- or 3-furanyl; or 2-, 4- or 5-thiazolyl; m is zero or an integer from 1 to 2; R2 is / \ OH; And R1 n is zero or an integer from 1 to 4. According to the present invention there are provided the dihydroisoquinolinoindole derivatives represented by Formula I: wherein: R x, R 2, R 3 and R 4 are, independently, hydrogen, halogen, alkoxy, or carboxamide; R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; Y X is (CH2) n or a carbocyclic ring of 4 to 6 members, wherein n is an integer from 2 to 4; or the pharmaceutically acceptable salts thereof. Preferably, the compounds of the present invention are those of Formula I, wherein: Ri 2 3 and R 4 are, independently, hydrogen or alkoxy; R5 is halogen or CN; and X is (CH) n or a 6-membered carbocyclic ring, wherein n is an integer from 2 to 3; or the pharmaceutically acceptable salts thereof. More preferably, the compounds of the present invention are selected from: 3 - [(1,4-cis) -4- (7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) cyclohexyl] -lH- indole-5-carbonitrile; 3 [(1,4-trans) -4- (7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1,4-cis) -4- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- t (1,4-trans) -4- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1,4-cis) -4- (6-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1,4-trans) -4- (6-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1,4-cis) -4- (5-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1,4-trans) -4- (5-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile; 3- [(1,4-cis) -4- (3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-carbonitrile; 3- [(1,4-trans) -4- (3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-carbonitrile; 2- [3- (5-fluoro-lH-indol-3-yl) -propyl] -5-methoxy-1,2,3,4-tetrahydroisoquinoline; 2- [3- (5-fluoro-lH-indol-3-yl) -propyl] -6-methoxy-1,2,3,4-tetrahydroisoquinoline; and 2- [3- (5-fluoro-lH-indol-3-yl) -propyl] -1,2,3,4-tetrahydroisoquinoline. As used herein, the term "alkoxy" includes the linear and branched alkyl chains and preferably contains from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. More preferably it is methoxy. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "carbocyclic ring" means saturated or unsaturated carbon rings such as aryl or cycloalkyl. Examples are phenyl and cycloalkyl of 4 to 6 carbon atoms. Preferably, the carbocyclic ring is a cycloalkyl of 4 to 6 carbon atoms. More preferably, it is cyclohexyl. The most preferred value of n is 3.

The compounds of Formula I can also be used in the form of a pharmaceutically acceptable acid addition salt, which has the utility of the free base. Such salts, prepared by methods well known in the art, are formed with inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric acids , salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric. The compounds of the present invention can be prepared by any suitable method which will be recognized by those skilled in the art. However, the present compounds can be advantageously prepared according to the following Reaction Scheme I.

Reaction Scheme 1 (D (2) (5) (6) The processes according to the above Reaction Scheme form a further aspect of the invention. The specific exemplification of the preparation of the representative compounds of this invention is provided in the following procedures.

INTERMEDIARY N- (methoxycarbonyl) -2- (4-methoxyphenyl) ethylamine To a solution of 4-methoxy-phenethylamine (5.81 mL, 39.7 mmol) in 200 mL of anhydrous tetrahydrofuran was added Et3N (6.6 mL, 48 mmol). The solution was cooled to 0 ° C and methyl chloroformate (15.38 ml, 199 mmol) was added slowly via syringe. The reaction was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred overnight. To the reaction mixture was added 50 ml of water and the resulting solution was extracted into 1 portion of 100 ml of Et20 and then in 2 portions of 75 ml of EtOAc. The combined organic fractions were washed with 200 ml of brine and 200 ml of 1 M HCl, dried over sodium sulfate, filtered and concentrated in vacuo to afford 7.98 g (96%) of the title compound as a pale yellow solid. .

INTERMEDIARY Ib N- (methoxycarbonyl) -2- (3-methoxyphenyl) ethylamine This compound was prepared in the manner described for Intermediate Ia, replacing 4-methoxy-phenethylamine with 3-methoxy-phenethylamine (10 g, 66 mmol) yielding 13.6 g (98%) of the title compound as a color oil. gold.

INTERMEDIARY 2a 7-methoxy-3,4-dihydro-2H-isoquinolin-l-one To a stirred solution of 50 g of polyphosphoric acid at 145 ° C was added N- (methoxycarbonyl) -2- (4-methoxyphenyl) ethylamine (4.5 g, 21.5 mmol). The resulting brown solution was stirred at 140 ° C for 40 minutes. The hot reaction mixture was emptied on ice, and. it was extracted in 3 portions of 200 ml of methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. The crude oil was purified by column chromatography on 10% methanol / methylene chloride as the eluent, affording 1.11 g (30%) of the title compound as a pale yellow solid: mp 90-93 ° C. Elemental analysis for CoHxi? TC: Calculated: C, 67.78; H, 6.26; N, 7.90 Found: C, 67.88; H, 6.54; N, 7.90 INTERMEDIARY 2b 6-methoxy-3,4-dihydro-2H-isoquinolin-l-one This compound was prepared in the same manner as Intermediate 2a, replacing N- (methoxycarbonyl) -2- (4-methoxyphenyl) ethylamine with N- (methoxycarbonyl) -2- (3-methoxyphenyl) ethylamine (6 g, 28.7 mmol ) providing 2.42 g (48%) of the title compound as a white solid: mp 131-133 ° C. Elemental Analysis for C10H ?? NO2 Calculated: C, 67.78; H, 6.26; N, 7.90 Found: C, 67.55; H, 6.36; N. 7.86 INTERMEDIARY 2c 8-methoxy-3/4-dihydro-2H-isoquinolin-l-one This compound was isolated at the same time as Intermediary 2b, providing 0.67 g (13%) as a white solid: mp 140-142 ° C. Elemental Analysis for C? 0H11NO2 «0.1H20 Calculated: C, 67.10; H, 6.31; N, 7.82 Found: C, 66.92; H, 6.49; N, 7.70 INTERMEDIARY 3a 7-methoxy-1,2,3,4-tetrahydro-isoquinoline A solution of Intermediate 2a (1 g, 5.6 mmol) dissolved in 30 ml of anhydrous tetrahydrofuran was slowly turned into a solution of LJ? H (7.35 ml, 1 M in THF) at 0 ° C under a nitrogen atmosphere. The resulting solution was heated to reflux for 2 hours. The reaction mixture was cooled to 0 ° C and added dropwise to quench. The resulting solution was made basic with 100 ml of 1 M sodium hydroxide, filtered through a pad of celite, and extracted into 3 portions of 150 ml of ethyl acetate. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated to give 0.88 g (96%) of a pale yellow oil. The hydrochloride salt was worked up in ethyl acetate to give a white solid; mp 224-227 ° C. Elemental Analysis for C10H? 3N »Calculated HCl: C, 60.15; H, 7.07; N, 7.01 Found: C, 60.11; H, 7.12; N, 6.87 INTERMEDIARY 3b 6-methoxy-l, 2, 3, 4-tetrahydro-isoquinoline This compound was prepared in the same manner as Intermediary 3a by replacing Intermediate 2a with Intermediate 2b (Ig, 5.6 mmol) by providing 0.87 g (95%) of the title compound as a pale yellow oil. The hydrochloride salt was worked up in ethyl acetate to give a white solid: mp 236-238 ° C. Elemental Analysis for C 10 H 3N * HCl Calculated: C, 60.15; H, 7.07; N, 7.01 Found: C, 60.12; H, 6.99; N, 6.82 INTERMEDIARY 3c 8-methoxy-1,2,3,4-tetrahydro-isoquinoline This compound was prepared in the same way as Intermediary 3a by replacing Intermediary 2a with Intermediate 2c (0.600 g, 3.4 mmol) by providing 0.41 g (74%) of the title compound as a pale yellow oil. The hydrochloride salt was worked up in ethyl acetate to give a white solid: pf decomposes > 210 ° C. Elemental Analysis for C? 0H? 3N * HCl Calculated: C, 60.15; H, 7.07; N, 7.01 Found: C, 59.98; H, 6.97; N, 6.83 INTERMEDIARY 5 5-methoxy-isoguinoline To a three-necked flask, dried in the oven, 5-hydroxy-quinoline (5 g, 34.5 mmol), and triphenylphosphine were added. The solid materials were dissolved in 100 ml of tetrahydrofuran and slowly added DEAD (8.19 ml, 51.7 mmol). The brown reaction mixture was stirred at room temperature overnight and then was emptied into 100 ml of water and extracted into 3 portions of 150 ml of ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 20% ethyl acetate / hexanes as the eluent. The title compound was isolated as 3.5 g (64%) of a white solid.

INTERMEDIARY 6 5-methoxy -1,2,3,4-tetrahydroisoquinoline To a Parr hydrogenation flask was added 165 mg of Pt02 and the solid was purged with nitrogen for 10 minutes. 40 ml of a solution of 5-methoxy-isoquinoline in HOAc was added to the flask, and hydrogen was added at 2.81 g / cm2. (40 psi) all night. The resulting solution was filtered through celite, concentrated and made basic with 100 ml of 1 M sodium hydroxide and extracted into 3 portions of 150 ml of ethyl acetate. The organic fractions were combined, dried over sodium sulfate, filtered, concentrated and purified by column chromatography with 10% methanol / methylene chloride / ammonium hydroxide as the eluent. The title compound was obtained as 2.49 g (70%) of a white solid: mp 124-126, Mass Spectrum (MS) M / e 163 M +.

EXAMPLE 3- [(1,4-cis) -4- (7-methoxy-3 4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile To a solution of 7-methoxy-1,2,3,4-tetrahydro-isoquinoline (500 mg, 3.1 mmol), 4- (5-cyano-lH-3-indolyl) -cycothexanone (730 mg, 3.1 mmol), and sodium triacetoxyborohydride (975 mg, 4.6 mmol) in 50 ml of dichloroethane was added acetic acid (0.35 ml, 6.1 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with 100 mL of 1M sodium hydroxide and extracted into 3 portions of 100 mL of methylene chloride and 2 portions of 100 mL of ethyl acetate. The organic fractions were combined, dried over sodium sulfate, concentrated, filtered and subjected to chromatography (5% methanol / ethyl acetate) yielding 480 mg (40%) of the cis isomer as a gold-colored oil. The hydrochloride salt was generated from ethyl acetate yielding a pale yellow solid: pf decomposes > 145 ° C. Elemental Analysis for C25H27N3O * HCl * 0.25H20 Calculated: C, 70.41; H, 6.74; N, 9.85 Found: C, 69.91; H, 6.69; N, 9.75 EXAMPLE Ib 3- [(1,4-trans) -4- (7-methoxy-3 4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -1H-indole-5-carbonitrile The trans isomer was isolated at the same time as the Example a, providing 320 mg (27%) as a pale yellow solid: pf decomposes a > 140 ° C Elemental Analysis for C25H27N3O * 0.25H20 Calculated: C, 76.99; H, 7.11; N, 10.77 Found: C, 76.79; H, 7.09; N, 10.50 EXAMPLE 2a 3- t (1,4-cis) -4- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile This compound was prepared in the same manner as the Example by replacing 7-methoxy-1,2,3,4-tetrahydro-isoquinoline with 8-methoxy-1,2,3,4-iso-quinoline (300 mg, 1.85 mmol ) to provide 300 mg (44%) of the title compound as a yellow oil. The hydrochloride salt was prepared from ethyl acetate yielding a white solid: pf decomposes a > 155 ° C. Elemental Analysis for C25H27N3O »HCl» 0.50H2O Calculated: C, 69.67; H, 6.78; N, 9.75 Found: C, 69.91; H, 6.77; N, 9.89 EXAMPLE 2b 3- [(1,4-trans) -4- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer of Example 2a, giving 200 mg (28%) as a pale yellow solid. The hydrochloride salt was generated from ethyl acetate to provide a white solid: pf decomposes a > 250 ° C. Elemental Analysis for C25H27N3O "HCl" 0.25H20 Calculated: C, 70.41; H, 6.74; N, 9.85 Found: C, 70.48; H, 6.65; N, 9.69 EXAMPLE 3a 3 - [(1,4-cis) -4- (6-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile This compound was prepared in the same manner as Example la, replacing 7-methoxy-1,2,3,4-tetrahydro-isoquinoline with 6-methoxy-1,2,3,4-tetrahydro-isoquinoline. (500 mg, 3.1 mmol) to give 520 mg (44%) of the title compound as a yellow oil. The hydrochloride salt was prepared from ethyl acetate yielding a white solid: pf decomposes a > 180 ° C. Elemental Analysis for C25H27N3O »HCl» 0.25H20 Calculated: C, 70.41; H, 6.74; N, 9.85 Found: C, 70.21; H, 6.80; N, 9.63 EXAMPLE 3b 3- [(1,4-trans) -4- (6-methoxy-3,4-dihydro-lH-isoq inolin-2-yl) -cyclohexyl] -1H-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer of Example 3a, giving 250 mg (21%) as a pale yellow solid: pf decomposes > 200 ° C.

Elemental Analysis for C25H27N3O * 0 .25H20 Calculated: C, 76. 99; H, 7 eleven; N, 10 77 Found: C, 76. 81; H, 7 08; N, 10 56 EXAMPLE 4a 3- [(1,4-cis) -4- (5-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile This compound was prepared in the same manner as Example la, replacing 7-methoxy-1,2,3,4-tetrahydro-isoquinoline with 5-methoxy-1,2,3,4-tetrahydroisoquinoline (500 mg, 3.1 mmol). to provide 400 mg (34%) of the title compound as a pale yellow solid: mp 223-226 ° C. Elemental Analysis for C25H27N3O »0.85H20 Calculated: C, 74.91; H, 7.22; N, 10.48 Found: C, 75.30; H, 7.15; N, 10.08 EXAMPLE 4b 3- [(1,4-trans) -4- (5-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-5-carbonitrile The trans isomer was isolated at the same time as the cis isomer of Example 4a to provide 200 mg (17%) as a white solid. The hydrochloride salt was generated in ethyl acetate yielding a white solid: pf decomposes a > 181 ° C. Elemental Analysis for C25H27N30 «HC1» 1H20 Calculated: C, 68.25; H, 6.87; N, 9.55 Found: C, 68.23; H, 6.64; N, 9.33 EXAMPLE 5a 3- [(1,4-cis) -4- (3 # 4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-carbonitrile This compound was prepared in the same manner as the Example by replacing 7-methoxy-1,2,3,4-tetrahydro-isoquinoline with the 1, 2, 3, 4-tetrahydro-isoquinoline commercially available (250 mg, 2.1 mmol ) to provide 330 mg (44%) of the title compound as a yellow solid. The hydrochloride salt was generated from ethyl acetate to yield an off-white solid: mp 188-191 ° C. . Elemental Analysis for C24H25N3 «HC1 * 0.75H20 Calculated: C, 71.10; H, 6.84; N, 10.36 Found: C, 71.37; H, 6.82; N, 9.89 EXAMPLE 5b 3- [(1,4-trans) -4- (3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole-carbonitrile The trans isomer was isolated at the same time as the cis isomer of Example 5a to provide 250 mg (21%) as a pale yellow solid: mp 196-200 ° C. Elemental Analysis for C24H25N3 »0.25H20 Calculated: C, 80.08; H, 7.14; N, 11.67 Found: C, 80.01; H, 7.14; N, 11.37 EXAMPLE 6 2- [3- (5-Fluoro-lH-indol-3-yl) -propyl] -5-methoxy-1, 2, 3, 4-tetrahydroisoquinoline A solution of 5-methoxy-1,2,3,4-tetrahydro-isoquinoline (500 mg, 3.1 mmol), 3- (5-fluoro-indolyl) -propyl bromide (604 mg, 2.36 mmol) and Et3N (0.86 mL, 6.2 mmol) was dissolved in 20 ml of DMSO and heated at 100 ° C for 5 hours then at room temperature overnight. The reaction was poured into 150 ml of water and extracted in 2 portions of 100 ml of ethyl acetate. The organic fractions were combined and washed with 150 ml of sodium acid carbonate, dried over sodium sulfate, filtered, and concentrated. The resulting oil was purified by column chromatography using 5% methanol / ethyl acetate as the eluent yielding 570 mg (71%) of a gold-colored oil. The hydrochloride salt was generated from ethyl acetate to give a white solid: mp 183-186 ° C. Elemental Analysis for C21H23FN20 »Calculated HC1: C, 67.28; H, 6.45; N, 7.47 Found: C, 67.00; H, 6.52; N, 7.30 EXAMPLE 7 2- [3- (5-Fluoro-lH-indol-3-yl) -propyl] -6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline This compound was prepared in the same manner as Example 6, replacing 5-methoxy-1,2,3,4-tetrahydro-isoquinoline with 6-methoxy-1,2,3,4-tetrahydroisoquinoline (190 mg, 1.16 mmol) to give the title compound as a brown solid. The hydrochloride salt was generated from ethyl acetate yielding a hygroscopic burned solid: pf decomposes a > 90 ° C. Elemental Analysis for C2H23FN20 * HCl * H2? Calculated: C, 64.20; H, 6.67; N, 7.13 Found: C, 64.18; H, 6.51; N, 6.90 EXAMPLE 8 2- [3- (5-Fluoro-lH-indol-3-yl) -propyl] -1,2,3,4-tetrahydroisoquinoline This compound was prepared in the same manner as Example 6, replacing 5-methoxy-1,2,3,4-tetrahydro-isoquinoline with 1, 2, 3, 4-tetrahydro-isoquinoline (500 mg, 4.2 mmol) giving 730 mg as a waxy orange solid. The hydrochloride salt was generated from ethyl acetate yielding a pale yellow solid: mp 235-238 ° C. Elemental Analysis for C2oH2? FN2 * Calculated HCl: C, 69.66; H, 6.43; N, 8.12 Found: C, 69.55; H, 6.34; N, 7.84 The activity of the present compounds is demonstrated by the following pharmacological test procedures, standards. PCR cloning of the human 5-HTA receptor subtype from a human genomic library has been previously described by Chanda et al. , Mol. Pharmacol. , 43: 516 (1993). A stable Chinese hamster ovary cell line expressing the subtype of the human 5-HT1A receptor (5-HT1A-CHO cells) was used throughout this study. The cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin. The cells were developed to a confluence of 95-100% as a monolayer before the membranes were harvested for binding studies. The cells were gently scraped from the culture plates, 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 concentrates were diluted in aliquots and maintained at -80 ° C. On the day of the assay, the cells were thawed on ice, and resuspended in buffer. The studies were conducted using [3 H] 8-OH-DPAT as the radioligand. The binding assay was performed in 96-well microtiter plates in a final total volume of 250 μl buffer. The comparison experiments were performed by using 7 concentrations of the unlabeled drug and a final ligand concentration of 1.5 nM. The non-specific binding was determined in the presence of 10 μM 5HT. Saturation analysis was conducted by using [3H] 8-OH-DPAT at concentrations in the range of 0.3 to 30 nM. After a 30-minute incubation at room temperature, the reaction was terminated by the addition of ice-cooled buffer and rapid filtration using a M-96 Brandel Cell Harvester (Gaithersburg, MD) through a pre-wetted GF / B filter. 30 minutes in 0.5% polyethyleneimine. A protocol similar to that used by Cheetham et al., Neuropharmacol. , 32: 737 (1993) was used to determine the affinity of the compounds for the serotonin transporter. Briefly, frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3 H-paroxetine (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained either vehicle, test compound (one to eight concentrations), or saturation concentration of fluoxetine (10 μM) to define the specific link. All reactions were terminated by the addition of ice-cooled Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound 3H-paroxetine from free. The bound radioactivity was quantified using a Wallac 1205 Beta Píate® counter. The non-linear regression analysis was used to determine the IC50 values that were converted to Ki values using the method described in Cheng and Prusoff, Biochem. Pharmacol. , 22: 3099 (1973) (Ki = IC50 / ((Radioligand conc.) / (1 + KD)).

The [35S] -GTP? S binding assay was similar to that used by Lazareno and Birdsall, Br. J. Pharmacol. 109: 1120 (1993). Briefly, the membrane fragments of the cloned 5-HT1A receptor (as used for the 5-HT1A receptor binding assays) were stored at -70 ° C. When necessary, the membranes were rapidly thawed, centrifuged at 40,000 xg for 10 minutes and resuspended at 4 ° C for 10 minutes in a test buffer (25 mM HEPES, 3 mM magnesium chloride, 100 mM sodium chloride, EDTA 1 mM, 10 μM GDP, 500 mM DTT, pH 8.0). These membranes were then incubated for 30 minutes at 30 ° C with [35S] GTPgS (1 nM) in the presence of the vehicle, the test compound (one to eight concentrations), or 8-OH-DPAT in excess to define the maximum response of the agonist. All reactions were terminated by the addition of ice-cooled Tris buffer, followed by rapid filtration using a Tom Tech® filtration device to separate the bound [35S] GTPgS from the free. The agonists produced an increase in the amount of [35S] GTPgS bound, whereas the antagonists produced no increase in the bond. The bound radioactivity was counted and analyzed as described above. The following assays were performed by incubating the cells with DMEM containing 25 mM HEPES, 5 mM theophylline, and 10 μM pargyline for a period of 20 minutes at 37 ° C. Functional activity was evaluated by treating the cells with forskolin (final concentration of 1 μM) followed immediately by the test compound (6 concentrations) for an additional 10 minutes at 37 ° C. In separate experiments, 6 concentrations of the antagonist were preincubated for 20 minutes before the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removing the media and adding 0.5 ml of the ice-cooled assay buffer. Plates were stored at -20 ° C prior to the evaluation of cyclic AMP formation (cAMP) by a cAMP SPA assay (Amersham).

TABLE A Example 5-HT1A ST GTPgS ED50 No. [Ki, nM: (% inh to 1 uM)] (Ki, nM) (% EMax) the (26%) 0.8 Ib (48%) 12 2a (14%) 1.0 2b (46%) 7.5 3a ( 21%) 0.1 3b 300 8.0 (0%) 4a (7%) 0.61 (12.%) 4b (47%) 12.0 350 (33%) 5a (0%) 1.3 5b (10%) 10.0 6 243 1.9 1346 ( 2. 3%) 7 288 1.4 (100%) 8 (48%) 4.85 (13%) As demonstrated by the results described above, the compounds of the present invention are active towards 5HT1A receptors and generally elevate serotonin levels by inhibiting 5-HT transport. Accordingly, the present compounds should be useful in the treatment of disorders related to defects in serotonin concentration. The compounds of the formula I for use in the methods of treatment or therapy form additional aspects of the present invention. The compounds of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending, fillers, glidants, compression aids, binders or tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Any of the solid carriers known to those skilled in the art can be used with the compounds of this invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting point waxes and ion exchange resins. The liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention. The compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (containing particularly additives as described above, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example 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 compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for example by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compositions for oral administration can be either in the form of liquid or solid composition. Preferably, the pharmaceutical compositions containing the compounds of this invention are in the unit dosage form, for example, tablets or capsules. In such form, the compositions can be subdivided into unit doses containing appropriate amounts of the present compounds. The unit dosage forms can be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or sacks containing liquids. Alternatively, the unit dosage form may be, for example, a capsule or tablet itself, or it may be the appropriate number of any such compositions in package form. Pharmaceutical compositions comprising compounds of the formula I and a pharmaceutically acceptable carrier form a further aspect of the present invention. The therapeutically effective amount of the compounds of this invention is administered and the dosage regimen depends on a variety of factors, including the weight, age, sex, and medical condition of the subject, the severity of the disease, the route and the frequency of administration, and the specific compound employed, and can thus vary widely. However, it is believed that the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2,000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg. The projected daily doses of the active compound are from about 0.01 to about 100 mg / kg of body weight. The daily dose can be conveniently administered two to four times per day. The present invention may be exemplified in other specific forms, without departing from the spirit and essential attributes thereof, and accordingly, reference should be made to the appended claims, rather than to the above specification, as indicated by the scope of the invention. invention.

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 (22)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of the formula: characterized in that: R x, R, R 3 and R 4 are, independently, hydrogen, halogen, alkoxy, or carboxamide; R5 is hydrogen, halogen, CF3 / CN, carbamide, or alkoxy; Y

X is (CH) n or a carbocyclic ring of 4 to 6 members, wherein n is an integer from 2 to 4; or the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, characterized in that: i2 / R3 and 4 are, independently, hydrogen or alkoxy; R5 is halogen or CN; and X is (CH2) n or a 6-membered carbocyclic ring, wherein n is an integer from 2 to 3; or the pharmaceutically acceptable salts thereof.

3. A compound according to claim 1, characterized in that it is 3- [(1,4-cis) -4- (7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) cyclohexyl] -lH -indol-5-carbonitrile.

4. A compound according to claim 1, characterized in that it is 3- [(1,4-trans) -4- (7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - 1H-indole-5-carbonitrile.

5. A compound according to claim 1, characterized in that it is 3- [(1,4-cis) -4- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - 1H-indole-5-carbonitrile.

6. A compound according to claim 1, characterized in that it is 3- [(1, 4-trans) -4- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - 1H-indole-5-carbonitrile.

7. A compound according to claim 1, characterized in that it is 3- [(1,4-cis) -4- (6-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - 1H-indole-5-carbonitrile.

8. A compound according to claim 1, characterized in that it is 3- [(1,4-trans) -4- (6-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) cyclohexyl] -1H -indol-5-carbonitrile.

9. A compound according to claim 1, characterized in that it is 3- [(1,4-cis) -4- (5-methoxy-3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - 1H-indole-5-carbonitrile.

10. A compound according to claim 1, characterized in that it is 3- [(1, 4-trans) -4- (5-methoxy-3, 4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] - 1H-indole-5-carbonitrile.

11. A compound according to claim 1, characterized in that it is 3- [(1,4-cis) -4- (3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole carbonitrile.

12. A compound according to claim 1, characterized in that it is 3- [(1,4-trans) -4- (3,4-dihydro-lH-isoquinolin-2-yl) -cyclohexyl] -lH-indole carbonitrile.

13. A compound according to claim 1, characterized in that it is 2- [3- (5-fluoro-lH-indol-3-yl) -propyl] -5-methoxy-1,2,3,4-tetrahydroisoquinoline.

14. A compound according to claim 1, characterized in that it is 2- [3- (5-fluoro-lH-indol-3-yl) -propyl] -6-methoxy-1,2,3,4-tetrahydroisoquinoline.

15. A compound according to claim 1, characterized in that it is 2- [3- (5-fluoro-lH-indol-3-yl) -propyl] -1,2,3,4-tetrahydroisoquinoline.

16. A pharmaceutical composition, characterized in that it comprises a compound of the formula: wherein: i 2 R 3 and 4 are, independently, hydrogen, halogen, alkoxy, or carboxamide; R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; Y X is (CH2) n or a carbocyclic ring of 4 to 6 members, wherein n is an integer from 2 to 4; or the pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

17. A compound of the formula: characterized in that: Ri, R2, R3 and R4 are, independently, hydrogen, halogen, alkoxy, or carboxamide; R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; and X is (CH2) r. or a 4- to 6-membered carbocyclic ring, wherein n is an integer from 2 to 4, or pharmaceutically acceptable salts thereof; for use in therapy.

18. A compound according to claim 17, wherein the use is for the treatment of diseases affected by disorders of neurological systems affected by serotonin.

19. The use of a compound of the formula: wherein: Ri 2 R 3 and are, independently, hydrogen, halogen, alkoxy, or carboxamide; R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; and X is (CH2) n or a carbocyclic ring of 4 to 6 members, wherein n is an integer from 2 to 4; or the pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating depression in a patient in need thereof.

20. A process for the preparation of the compounds of the formula where R, R2, R3, R4 and R5 are as defined according to claims 1 to 15, and X is a carbocyclic ring of 4 to 6 members; characterized the process because it comprises the reaction of a tetrahydro-isoquinoline of the formula where Rx, R2, R3, and R4 are as previously defined, with a compound of the formula where X and R5 are as previously defined; and optionally forming a pharmaceutical salt thereof.

21. A process according to claim 20, characterized in that the tetrahydro-isoquinoline of the formula is prepared by the reaction of a compound of the formula with methyl chloroformate to form the compound of the formula and cyclizing to form the compound of the formula and then reducing in the presence of a reducing agent.

22. The process for the preparation of the compounds of the formula where Rx, R2 and R5 are as defined in accordance with claims 1 or 2, R3 and R4 are both hydrogen, and X is (CH2) n; characterized the process because it comprises the reaction of a compound of the formula wherein R and R2 are as defined above, with a compound of the formula