Substituted 3-amino-2,3,4,5-tetrahydro-1-aryloxy-3-benzazepines, a process for their preparation and their use as modulators of neurotransmitter function

Abstract: There are disclosed various compounds of the formula below, where n is 1 or 2; m is 1 or 2; each X is independently hydrogen or loweralkoxy; Y is hydrogen, halogen or trifluoromethyl; R₁ is hydrogen, loweralkyl, arylloweralkyl, heteroarylloweralkyl, pyridinyl, loweralkylcarbonyl, arylloweralkylcarbonyl, heteroarylloweralkylcarbonyl, trifluoromethylcarbonyl or arylcarbonyl; and R₂ is hydrogen, loweralkyl, loweralkoxycarbonyl, aminoloweralkylcarbonyl, loweralkylaminoloweralkylcarbonyl or diloweralkylaminoloweralkylcarbonyl; which are useful as modulators of neurotransmitter function such as serotonergic and adrenergic, and as such are useful as antidepressants and for the treatment of personality disorders such as obsessive compulsive disorders.

Description: The present invention relates to compounds of the formula I, where n is 1 or 2; m is 1 or 2; each X is independently hydrogen or C₁-C₆-alkoxy; Y is hydrogen, halogen or trifluoromethyl; R₁ is hydrogen, C₁-C₆-alkyl, imidazolyl-C₁-C₆-alkyl, thienyl-C₁-C₆-alkyl, pyridinyl-C₁-C₆-alkyl, pyrrolyl-C₁-C₆-alkyl, pyridinyl, C₁-C₆-alkylcarbonyl, imidazolyl-C₁-C₆-alkylcarbonyl, thienyl-C₁-C₆-alkylcarbonyl, pyridinyl-C₁-C₆-alkylcarbonyl, pyrrolyl-C₁-C₆-alkylcarbonyl, trifluoromethylcarbonyl, or phenyl-C₁-C₆-alkyl, phenylcarbonyl or phenyl-C₁-C₆-alkylcarbonyl, wherein the phenyl is substituted with 0, 1 or 2 substituents each of which being independetly C₁-C₆-alkyl, C₁-C₆-alkoxy, R₂ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl, amino-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl or di-C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl; which are useful as modulators of neurotransmitter function such as serotonergic and adrenergic, and as such are useful as antidepressants and for the treatment of personality disorders such as obsessive compulsive disorders. EP-A-0 096 838 relates to 1-aryloxy-2,3,4,5- tetrahydro-3-benzazepines, which have antidepressant, antihypertensive and/or analgesic activities. Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and the appended claims. The term C₁-C₆-alkyl shall mean a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said C₁-C₆-alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. The term halogen shall mean fluorine, chlorine, bromine or iodine. Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo, optical and tautomeric isomers where such isomers exist. The compounds of this invention are prepared by utilizing one or more of the synthetic steps described below. Throughout the description of the synthetic steps, the notations n, m, X, Y, R₁ and R₂ shall have the respective meanings given above unless otherwise stated or indicated. STEP A : A compound of Formula II where R₃ is is reduced in a routine manner known to the art (for instance, with the aid of sodium borohydride) to afford a compound of Formula III. STEP B : Compound III is detosylated or demesylated in a routine manner known to the art (for instance, with the aid of sodium metal in liquid ammonia or sodium bis(2-methoxyethoxy)aluminum hydride in toluene) to afford a compound of Formula IV. For details of STEPS A and B, the reader is referred to Effland et al., United States Patent 4,794,181. STEP C : Compound IV is allowed to react with a fluoro, chloro or bromo compound of the formula where Hal is fluorine, chlorine or bromine in a routine manner known to the art, for instance with the aid of NaH in a suitable medium such as dimethylformamide or benzene, to afford a compound of Formula V (Williamson ether synthesis). STEP D : Compound V is subjected to a nitrosation reaction conducted in a routine manner known to the art, for instance with the aid of sodium nitrite and hydrochloric acid, to afford a compound of Formula VI. STEP E: Compound VI is reduced with the aid of zinc dust and a suitable acid such as acetic acid in a routine manner known to the art to afford a compound of Formula VII. STEP F: Compound VII is allowed to react with a C₁-C₆-alkyl halide of the formula R₄-Hal where R₄ is C₁-C₆-alkyl and Hal is chlorine or bromine, or with a di-C₁-C₆-alkyl sulfate of the formula (R₄)₂SO₄ in a routine manner known to the art to afford a compound of Formula VIII. STEP G: Compound VII is allowed to react with a C₁-C₆-alkyl chloroformate of the formula Cl-CO-OR₅ where R₅ is C₁-C₆-alkyl to afford a compound of Formula IX. This reaction is typically conducted in a suitable solvent such as dichloromethane in the presence of a suitable base such as sodium bicarbonate or triethylamine at a temperature of about 20-60°C. STEP H As a special case where a compound of formula VIII in which the group R₄ is methyl is desired, the following method may be employed as an alternative to STEP F. Thus, a compound of formula IXa obtained from STEP G is allowed to react with LiAlH₄ in a suitable medium such as tetrahydrofuran at a temperature of about 25-100°C to afford a compound of formula VIIIa. STEP I Compound VII is allowed to react with an acid compound of formula X (in which the amino group is protected) where the group -R₆- represents a C₁-C₆-alkylene group and R₇ is hydrogen or C₁-C₆-alkyl in the presence of dicyclohexylcarbodiimide to afford a corresponding ester of formula XI and thereafter the latter is hydrolyzed in a routine manner known to the art or catalytically reduced with hydrogen to afford a compound of formula XII. In this reaction scheme, the same purpose can be accomplished where the benzyloxy moiety in formula X is tertiarybutyloxy. STEP J Compount VII is allowed to react with an acid compound of formula XIII where R₈ is C₁-C₆-alkyl and R₉ is also C₁-C₆-alkyl in the presence of dicyclohexylcarbodiimide in a routine manner known to the art to afford a compound of formula XIV. STEP K : A compound of Formula XV obtained from one of the foregoing STEPS is allowed to react with a halide compound of the formula R₁₀-Hal where R₁₀ is C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, wherein the phenyl group may be substituted as indicated above, or heteroaryl-C₁-C₆-alkyl, wherein the term heteroaryl means imidazolyl, thienyl, pyridinyl or pyrrolyl, or with a di-C₁-C₆-alkyl sulfate compound of the formula (R₁₀)₂SO₄ in substantially the same manner as in STEP F to afford a compound of Formula XVI. STEP L: Compound XV is allowed to react with an acid halide of the formula R₁₁-CO-Hal where R₁₁ is C₁-C₆-alkyl, phenyl or phenyl-C₁-C₆-alkyl, wherein the phenyl may be substituted as indicated above, heteroaryl-C₁-C₆-alkyl, wherein the term heteroaryl means imidazolyl, thienyl, pyridinyl or pyrrolyl, or trifluoromethyl in a routine manner known to the art to afford a compound of formula XVII. STEP M As a special case where a compound of formula XVII in which the group R₁₁ is trifluoromethyl is desired, the following method may be employed as an alternative to STEP L. Thus, compound XV is allowed to react with methyl trifluoroacetate in the presence of a suitable base such as triethylamine to afford a compound of formula XVIIa. This reaction is typically conducted in a suitable solvent such as anhydrous methanol at a temperature of about 25-70°C. STEP N Compound XV is allowed to react with a fluoro or chloropyridine of formula XVIII where Hal' is fluorine or chlorine to afford a compound of formula XIX. This reaction is typically conducted in a suitable ethereal solvent such as bis(2-methoxyethyl)ether or dioxane, or a polar aprotic solvent such as dimethylformamide. The compounds of Formula I of the present invention are useful as modulators of neurotransmitter function such as serotonergic and adrenergic, and as such are useful as antidepressants and for the treatment of personality disorders such as obsessive compulsive disorders. This utility is manifested in the ³H-Serotonin Uptake in Rat Whole Brain Test described below. ³H-Serotonin Uptake in Rat Whole Brain and Hypothalamic Synaptosomes Purpose: This assay is used as a biochemical screen for potential antidepressants which block serotonin (5HT) uptake. Introduction: Asberg and coworkers have suggested that subjects with serotonergic hypofunction comprise a biochemical subgroup of depressed patients (1), while others (2) claim that altered serotonergic function determines the mood changes associated with affective disorders. Although the role of 5HT in the etiology of depression is not clear; it is true that a number of antidepressant drugs block the 5HT reuptake mechanism. In vitro receptor binding assays have shown that [³H]-imipramine labels 5HT uptake sites (10). Trazodone and zimelidine are clinically effective antidepressants (3) with fairly selective effects on 5HT uptake (4,5). More recently, fluoxetine has been shown to be both a selective and potent 5HT uptake inhibitor. [³H]-5HT transport has been characterized in CNS tissue (6,7) and found to be saturable, sodium-and temperature-dependent, inhibited by ouabain, metabolic inhibitors, tryptamine analogs (8) and tricyclic antidepressants (tertiary amines >> secondary amines)(9). The latter findings differentiate 5HT uptake from catecholamine uptake. [³H]-5HT uptake can also be used as a marker for serotonin nerve terminals. Procedure: A. Animals: Male CR Wistar rats (100-125 g). B. Reagents - 1. Krebs-Henseleit Bicarbonate Buffer, pH 7.4 (KHBB): Make a 1 liter batch, containing the following salts. g/L mM NaCl 6.92 118.4 KCl 0.35 4.7 MgSO₄·7H₂O 0.29 1.2 KH₂PO₄ 0.16 2.2 NaHCO₃ 2.10 24.9 CaCl₂ 0.14 1.3 Prior to use add: Dextrose 2 mg/ml 11.1 Iproniazid phosphate 0.30 mg/ml 0.1 Aerate for 60 min. with 95% O₂/5% CO₂, check pH (7.4±0.1) 2. 0.32 M Sucrose: 21.9 g of sucrose, Q.S. to 200 ml. 3. Serotonin creatinine SO₄ is obtained from Sigma Chemical Co. A 0.1 mM stock solution is made up in 0.01 N HCl. This is used to dilute the specific activity of radiolabeled 5HT. 4. 5-[1,2-³H(N)]-Hydroxytryptamine creatinine sulfate (Serotonin), specific activity 20-30 Ci/mmol is obtained from New England Nuclear. The final desired concentration of ³H-5HT in the assay is 50 nM. The dilution factor is 0.8. Therefore, the KHBB is made up to contain 62.5 nM [³H]-5HT. Add to 100 ml of KHBB. A) 56.1 µl of 0.1 mM 5HT = 56.1 nM B) 0.64 nmole of ³H-5HT = 6.4 nM 62.5 nM 5. For most assays, a 1 mM solution of the test compound is made up in a suitable solvent and serially diluted such that the final concentration in the assay ranges from 2 x 10⁻⁸ to 2 x 10⁻⁵M. Seven concentrations are used for each assay. Higher or lower concentrations may be used depending on the potency of the compound. C. Tissue Preparation Male Wistar rats are decapitated and the brain rapidly removed. Either whole brain minus cerebella or hypothalamus is weighed and homogenized in 9 volumes of ice-cold 0.32 M sucrose using a Potter-Elvejhem homogenizer. Homogenization should be done with 4-5 up and down strokes at medium speeds to minimize synaptosome lysis. The homogenate is centrifuged at 1000 g for 10 min. at 0-4°C. The supernatant (S₁) is decanted and is used for uptake experiments. D. Assay - 800 µl KHBB + [³H]-5HT 20 µl Vehicle or appropriate drug concentration 200 µl Tissue suspension Tubes are incubated at 37°C under a 95% O₂/5% CO₂ atmosphere for 5 minutes. For each assay, 3 tubes are incubated with 20 µl of vehicle at 0°C in an ice bath. After incubation all tubes are immediately centrifuged at 4000 g for 10 minutes. The supernatant fluid is aspirated and the pellets dissolved by adding 1 ml of solubilizer (Triton X-100 + 50% EtOH, 1:4 v/v). The tubes are vigorously vortexed, decanted into scintillation vials, and counted in 10 ml of Liquiscint scientillation counting cocktail. Active uptake is the difference between cpm at 37°C and 0°C. The percent inhibition at each drug concentration is the mean of three determinations. IC₅₀ values are derived from log-probit analysis. References : 1. Asberg, M., Thoren, P., Traskman, L., Bertilsson, L., and Ringberger, V. "Serotonin depression: - A biochemical subgroup within the affective disorders. Science 191 : 478-480 (1975). 2. DeMontigy, C. Enhancement of 5HT neurotransmission by antidepressant treatments. J. Physiol. (Paris) 77 : 455-461 (1980). 3. Feighner, J.P. Clinical efficacy of the newer antidepressants. J. Clin. Psychopharmacol. 1 : 235-265 (1981). 4. Ogren, S.O., Ross, S.B., Hall, H., Holm, A.C. and Renyi, A.L. The pharmacology of zimelidine: A 5HT selective reuptake inhibitor. Acta Psychiat. Scand. 290 : 127-151 (1981). 5. Clements-Jewry, S., Robson, P.A. and Chidley, L.J. Biochemical investigations into the mode of action of trazodone. Neuropharmacol. 19 : 1165-1173 (1980). 6. Ross, S.B. Neuronal transport of 5-hydroxytryptamine. Pharmacol. 21 : 123-131 (1980). 7. Shaskan, E.G. and Snyder, S.H. Kinetics of serotonin accumulation into slices from rat brain: Relationship to catecholamine uptake. J. Pharmacol. Exp. Ther. 175 : 404-418 (1970). 8. Horn, S.A. Structure activity relations for the inhibition of 5HT uptake into rat hypothalamic homogenates by serotonin and tryptamine analogues. J. Neurochem. 21 : 883-888 (1973). 9. Horn, A.S. and Trace, R.C.A.M. Structure-activity relations for the inhibition of 5-hydroxytryptamine uptake by tricyclic antidepressant into synaptosomes from serotonergic neurones in rat brain homogenates. Brit. J. Pharmacol. 51 : 399-403 (1974). 10. Langer, S.Z., Moret, C., Raisman, R., Dubocovich, M.L. and Briley M. High affinity [³H]imipramine binding in rat hypothalamus: Association with uptake of serotonin but not norepinephrine. Science 210 : 1133-1135 (1980). Results of the above test are presented in Table 1 for representative compounds of this invention. Compound Inhibition of ³H-serotonin Uptake IC₅₀(µM) 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine maleate 2.13 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine maleate 9.36 (Reference Compound) Fluoxetine 0.25 Effective quantities of the compounds of the invention may be administered to a patient by any of the various methods, for example, orally as in capsule or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, increased solubility and the like. Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids. The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compounds, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0 - 300 milligrams of active compound. The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweeting agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, coloring and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied between 0.5 and about 30% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present inventions are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in disposable syringes or multiple dose vials made of glass or plastic. Examples of the compounds of this invention include: 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine; 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine; 3,5-dichloro-N-(7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)benzamide; N-[2,3,4,5-Tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepin-3-yl]carbamic acid ethyl ester; N-Methyl-N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepin-3-yl]carbamic acid ethyl ester; 3-Propylamino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine; N-[2,3,4,5-Tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepin-3-yl]acetamide; 3-Phenylethylamino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine; 3-Amino-7,8-dimethoxy-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine; 7,8-Dimethoxy-3-methylamino-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine; 3-Amino-1-(3-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine; 1-(3-chlorophenoxy)-3-methylamino-2,3,4,5-tetrahydro-3-benzazepine; 3-Imidazolethyl-2,3,4,5-tetrahydro-1-(4-(trifluoromethylphenoxy)-3-benzazepine; and N-[2,3,4,5-Tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepin-3-yl]imidazolacetamide. The following examples are presented in order to illustrate the present invention. EXAMPLE 1 3-Amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine maleate A solution of sodium nitrite (3 g) in 25 ml water was slowly added to a solution of 2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine (free base, 10 g) in 100 ml of 10% aqueous hydrochloric acid. After one hour, the reaction mixture was extracted with dichloromethane. The organic extract was dried (anhydrous magnesium sulfate), filtered and concentrated to a brown oil. This oil was eluted through silica with 30% hexane in dichloromethane via flash column chromatography to yield 9 g of pale yellow oil. Zinc dust (12 g) was added to a solution of 3-nitroso-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine (9 g) in 150 ml of 2:1 acetic acid/water mixture. After stirring at ambient temperature for three hours, the reaction mixture was filtered, stirred with ice and basified with ammonium hydroxide. The oil which had separated was extracted with dichloromethane. The dried (anhydrous magnesium sulfate) organic extract was filtered and concentrated. The residue was eluted through silica with 3% methanol in dichloromethane via high performance liquid chromatography to yield 6.3 g of white solid, mp 98-100°. A three gram portion was converted to the maleate salt in 5% methanol/ether to yield 2.7 g of white solid, mp 129-131°. ANALYSIS: Calculated for C₂₁H₂₁F₃N₂O₅: 57.53%C 4.83%H 6.39%N Found: 57.52%C 4.87%H 6.36%N EXAMPLE 2 3-Amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine maleate A solution of sodium nitrite (2.1 g) in 10 ml water was slowly added to a solution of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (free base, 7 g) in 100 ml of 10% aqueous hydrochloric acid. After one hour, the reaction mixture was extracted with dichloromethane. The organic extract was dried (anhydrous magnesium sulfate), filtered and concentrated to 6 g oil. This oil was eluted through silica with dichloromethane via flash column chromatography to yield 4 g of glassy solid. This was combined with 7.1 g product obtained from two previous batches of nitrosation. Zinc dust (9 g) was added to a solution of 7,8-dimethoxy-3-nitroso-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (10 g) in 150 ml of 2:1 acetic acid/water. After stirring at ambient temperate for three hours, the reaction mixture was filtered, stirred with ice and basified with ammonium hydroxide. The oil which had separated was extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, and thereafter dried (anhydrous magnesium sulfate), filtered and concentrated to 10 g brown oil. This was eluted through silica with ethyl acetate via high performance liquid chromatography to yield 8.6 g white solid, mp 98-100°. This solid was again eluted through silica with 5% methanol in dichloromethane via high performance liquid chromatography to yield 6 g white solid, mp 107-109°. A three gram portion was converted to the maleate salt in 10% methanol/ether to yield 3.3 g white solid, mp 132-134°. ANALYSIS: Calculated for C₂₂H₂₆N₂O₇: 61.38%C 6.09%H 6.51%N Found: 61.36%C 5.98%H 6.47%N EXAMPLE 3 3,5-Dichloro-N-(7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)benzamide 3,5-Dichlorobenzoyl chloride (1.7 g) was added to a solution of 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (2.1 g) in 100 ml dichloromethane containing sodium bicarbonate (3 g). After one hour, the mixture was filtered and concentrated. The solid residue was eluted through silica with 10% ethyl acetate in dichloromethane to yield 2.4 g of light tan solid, mp 182-184°. This solid was recrystallized from acetonitrile to yield 2 g of white crystals, mp 184-185°. ANALYSIS: Calculated for C₂₅H₂₄Cl₂N₂O₄: 61.61%C 4.96%H 5.75%N Found: 61.41%C 4.84%H 5.72%N EXAMPLE 4 N-[2,3,4,5-Tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepin-3-yl]carbamic acid ethyl ester A solution of ethyl chloroformate (3.6 g) in 25 ml dichloromethane was slowly added to a solution of 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine (9 g) in 100 ml dichloromethane containing sodium bicarbonate (7 g). After one hour, the reaction mixture was filtered and concentrated to 11 g solid. A 3 g sample was recrystallized from ether to yield 2.2 g white crystals, mp 156-157°. ANALYSIS: Calculated for C₂₀H₂₁F₃N₂O₃: 60.90%C 5.37%H 7.10%N Found: 61.04%C 5.46%H 7.11%N EXAMPLE 5 N-Methyl-N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepin-3-yl]carbamic acid ethyl ester Potassium- t -butoxide (3 g) was added as a powder to an ice-cooled solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)3-benzazepin-3-yl]carbamic acid ethyl ester (8 g) in 100 ml tetrahydrofuran. After thirty minutes, a solution of dimethyl sulfate (3.1 g) in 25 ml tetrahydrofuran was slowly added. After one hour, the reaction mixture was stirred with water and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated. The residue was triturated with ether to yield 6 g solid, mp 204-205°. A 2 gram sample was recrystallized from acetonitrile to yield 1.6 g white crystals, mp 218-219°. ANALYSIS: Calculated for C₂₁H₂₃F₃N₂O₃: 61.75%C 5.68%H 6.86%N Found: 61.92%C 5.86%H 6.88%N EXAMPLE 6 N-[2,3,4,5-Tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3-benzazepin-3-yl]trifluoroacetamide Methyl trifluoracetate (4.2 g) was added to a solution of 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H- 3-benzazepine (8.4 g) in 100 mL anhydrous methanol and triethylamine (3.3 g). The solution was allowed to stand overnight at ambient temperature and thereafter concentrated. The residue was triturated with ether and the resultant product was collected and dried to yield 8.5 g white solid, mp 192-195°. ANALYSIS: Calculated for C₁₉H₁₆F₆N₂O₂: 54.55%C 3.86%H 6.70%N Found: 54.49%C 3.94%H 6.72%N EXAMPLE 7 N-Methyl-N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3-benzazepin-3-yl] trifluoroacetamide Potassium- t -butoxide (1.4 g) was added as a powder to an ice-cooled solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3benzazepin-3-yl]-trifluoroacet amide (4 g) in 100 mL tetrahydrofuran. After thirty minutes, dimethyl sulfate (1.5 g) was added. After warming to ambient temperature, the reaction mixture was stirred with water and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated to 4.1 g solid, mp 210-212°. A 2.5 g portion was recrystallized from acetonitrile to yield 1.6 g white crystals, mp 216-218°. ANALYSIS: Calculated for C₂₀H₁₈F₆N₂O₂: 55.55%C 4.20%H 6.48%N Found: 55.62%C 4.16%H 6.47%N EXAMPLE 8 3-Methylamino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3-benzazepine maleate Lithium aluminum hydride (1 M in tetrahydrofuran, 105 mL) was added slowly to a solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3-benzazepin-3-yl] carbamic acid ethyl ester (8 g) in 160 mL tetrahydrofuran. The reaction mixture was stirred twenty hours at 70-75° and thereafter cooled and quenched by slow addition of a saturated ammonium chloride solution. The mixture was filtered and the organic filtrate was washed successively with water and a saturated sodium chloride soltuion and thereafter dried (anhydrous magnesium sulfate), filtered and concentrated to 7 g oil. This was eluted through silica 50% ethyl acetate in dichloromethane via flash column chromatography to yield 2.6 g pale yellow oil. This was combined with 0.6 g product obtained from a previous reaction and converted to the maleate salt in 5% methanol in ether to yield 1.6 g white crystals, mp 138-140°. ANALSIS: Calculated for C₂₂H₂₃F₃N₂O₅: 58.40%C 5.12%H 6.19%N Found: 58.56%C 4.79%H 6.15%N

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, PT, SE A compound of the formula where n is 1 or 2; m is 1 or 2; each X is independently hydrogen or C₁-C₆-alkoxy; Y is hydrogen, halogen or trifluoromethyl; R₁ is hydrogen, C₁-C₆-alkyl, imidazolyl-C₁-C₆-alkyl, thienyl-C₁-C₆-alkyl, pyridinyl-C₁-C₆-alkyl, pyrrolyl-C₁-C₆-alkyl, pyridinyl, C₁-C₆-alkylcarbonyl, imidazolyl-C₁-C₆-alkylcarbonyl, thienyl-C₁-C₆-alkylcarbonyl, pyridinyl-C₁-C₆-alkylcarbonyl, pyrrolyl-C₁-C₆-alkylcarbonyl, trifluoromethylcarbonyl, or phenyl-C₁-C₆-alkyl, phenylcarbonyl or phenyl-C₁-C₆-alkylcarbonyl, wherein the phenyl is substituted with 0, 1 or 2 substituents each of which being independetly C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or trifluoromethyl, R₂ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl, amino-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl or di-C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl; or a pharmaceutically acceptable acid addition salt thereof. A compound as defined in claim 1, wherein R₁ is hydrogen, C₁-C₆-alkyl, trifluoromethylcarbonyl or phenylcarbonyl, wherein the phenyl group may be substituted as defined in claim 1 and R₂ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy carbonyl. A compound as defined in claim 2, wherein Y is hydrogen or trifluoromethyl and n is 1. A compound as defined in claim 3, wherein R₁ and R₂ are both hydrogen. The compound as defined in claim 1, which is 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine or a pharmaceutically acceptable acid addition salt thereof. The compound as defined in claim 1, which is 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition, which comprises a compound of the formula I as defined in claim 1 as the active ingredient and a suitable carrier therefor. Use of a compound for the preparation of a medicament being effective for the treatment of depression and personality disorders. A process for the preparation of a compound of the formula I as defined in claim 1, which comprises a) reducing a compound of the formula VI wherein X, Y, m and n are as defined, with the aid of zinc dust and a suitable acid to form a compound of the formula I, wherein X, Y, m and n are as defined and R₁ and R₂ are both hydrogen, b) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a C₁-C₆-alkyl halide of the formula R₄Hal is chlorine or bromine, or with a di-C₁-C₆-alkylsulfate of the formula (R₄)₂SO₄, where R₄ is C₁-C₆-alkyl, to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is C₁-C₆-alkyl, c) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a C₁-C₆-alkyl chloroformate of the formula Cl-COOR₅ wherein R₅ is C₁-C₆-alkyl, to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is C₁-C₆-alkyloxycarbonyl, d) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is ethoxycarbonyl, with LiAlH₄ to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is methyl, e) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a compound of the formula X where R₆ is a C₁-C₆-alkylene group and R₇ is hydrogen or C₁-C₆-alkyl, in the presence of dicyclohexylcarbodiimide to form a compound of the formula XI, and hydrolyzing or catalytically reducing the compound of the formula XI with hydrogen, to form a compound of the formula I wherein R₁ is hydrogen ad R₂ is amino-C₁-C₆-alkylcarbonyl or C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl f) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a compound of the formula XIII wherein R₆ is a C₁-C₆-alkylene group and R₈ and R₉ are both C₁-C₆-alkyl, in the presence of dicyclohexylcarbodiimide, to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is di-C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl, g) optionally reacting a compound of the formula I wherein R₁ is hydrogen and R₂ is as defined in claim 1, but is not hydrogen, with a compound of the formula R₁₀Hal or of the formula (R₁₀)₂SO₄, where R₁₀ is C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, wherein the phenyl group may be substituted as defined in claim 1, or heteroaryl-C₁-C₆-alkyl, wherein the term heteroaryl has the meaning given in claim 1, to form a compound of the formula I, wherein R₁ is C₁-C₆-alkyl, optionally substituted phenyl-C₁-C₆-alkyl or heteroaryl-C₁-C₆-alkyl and R₂ is as defined in claim 1 but is not hydrogen, h) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is as defined in claim 1, but is not hydrogen, with an acid halide of the formula R₁₁COHal, where R₁₁ is C₁-C₆-alkyl, phenyl or phenyl-C₁-C₆-alkyl, wherein the phenyl group may be substituted as defined in claim 1, heteroaryl-C₁-C₆-alkyl, wherein the term heteroaryl has the meaning given in claim 1 or trifluoromethyl to form a compound of the formula I, wherein R₁ is C₁-C₆-alkylcarbonyl, optionally substituted phenylcarbonyl or phenyl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-carbonyl or trifluormethylcarbonyl and R₂ is as defined in claim 1 but is not hydrogen, i) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is as defined in claim 1, but is not hydrogen, with methyl trifluoroacetate to form a compound of the formula I, wherein R₁ is trifluoromethylcarbonyl and R₂ is as defined in claim 1, but is not hydrogen, j) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is as defined in claim 1, but is not hydrogen, with fluoro- or chloropyridine to form a compound of the formula I, wherein R₁ is pyridinyl and R₂ is as defined in claim 1 but is not hydrogen. Claims for the following Contracting States : ES, GR A process for the preparation of a compound of the formula I where n is 1 or 2; m is 1 or 2; each X is independently hydrogen or C₁-C₆-alkoxy; Y is hydrogen, halogen or trifluoromethyl; R₁ is hydrogen, C₁-C₆-alkyl, imidazolyl-C₁-C₆-alkyl, thienyl-C₁-C₆-alkyl, pyridinyl-C₁-C₆-alkyl, pyrrolyl-C₁-C₆-alkyl, pyridinyl, C₁-C₆-alkylcarbonyl, imidazolyl-C₁-C₆-alkylcarbonyl, thienyl-C₁-C₆-alkylcarbonyl, pyridinyl-C₁-C₆-alkylcarbonyl, pyrrolyl-C₁-C₆-alkylcarbonyl, trifluoromethylcarbonyl, or phenyl-C₁-C₆-alkyl, phenylcarbonyl or phenyl-C₁-C₆-alkylcarbonyl, wherein the phenyl is substituted with 0, 1 or 2 substituents each of which being independetly C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or trifluoromethyl, R₂ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl, amino-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl or di-C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl; or a pharmaceutically acceptable acid addition salt thereof, which comprises a) reducing a compound of the formula VI wherein X, Y, m and n are as defined, with the aid of zinc dust and a suitable acid to form a compound of the formula I, wherein X, Y, m and n are as defined and R₁ and R₂ are both hydrogen, b) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a C₁-C₆-alkyl halide of the formula R₄Hal is chlorine or bromine, or with a di-C₁-C₆-alkylsulfate of the formula (R₄)₂SO₄, where R₄ is C₁-C₆-alkyl, to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is C₁-C₆-alkyl, c) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a C₁-C₆-alkyl chloroformate of the formula Cl-COOR₅ wherein R₅ is C₁-C₆-alkyl, to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is C₁-C₆-alkyloxycarbonyl, d) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is ethoxycarbonyl, with LiAlH₄ to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is methyl, e) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a compound of the formula X where R₆ is a C₁-C₆-alkylene group and R₇ is hydrogen or C₁-C₆-alkyl, in the presence of dicyclohexylcarbodiimide to form a compound of the formula XI, and hydrolyzing or catalytically reducing the compound of the formula XI with hydrogen, to form a compound of the formula I wherein R₁ is hydrogen and R₂ is amino-C₁-C₆-alkylcarbonyl or C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl f) optionally reacting a compound of the formula I, wherein R₁ and R₂ are both hydrogen, with a compound of the formula XIII wherein R₆ is a C₁-C₆-alkylene group and R₈ and R₉ are both C₁-C₆-alkyl, in the presence of dicyclohexylcarbodiimide, to form a compound of the formula I, wherein R₁ is hydrogen and R₂ is di-C₁-C₆-alkylamino-C₁-C₆-alkylcarbonyl, g) optionally reacting a compound of the formula I wherein R₁ is hydrogen and R₂ is as defined above, but is not hydrogen, with a compound of the formula R₁₀ Hal or of the formula (R₁₀)₂SO₄, where R₁₀ is C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, wherein the phenyl group may be substituted as defined above or heteroaryl-C₁-C₆-alkyl, wherein the term heteroaryl has the meaning given above, to form a compound of the formula I, wherein R₁ is C₁-C₆-alkyl, optionally substituted phenyl-C₁-C₆-alkyl or heteroaryl-C₁-C₆-alkyl and R₂ is as defined above but is not hydrogen, h) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is as defined above, but is not hydrogen, with an acid halide of the formula R₁₁COHal, where R₁₁ is C₁-C₆-alkyl, phenyl or phenyl-C₁-C₆-alkyl, wherein the phenyl may be substituted as defined above, heteroaryl-C₁-C₆-alkyl, wherein the term heteroaryl has the meaning given above or trifluoromethyl to form a compound of the formula I, wherein R₁ is C₁-C₆-alkylcarbonyl, optionally substituted phenylcarbonyl or phenyl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl or trifluormethylcarbonyl and R₂ is as defined above but is not hydrogen, i) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is as defined above, but is not hydrogen, with methyl trifluoroacetate to form a compound of the formula I, wherein R₁ is trifluoromethylcarbonyl and R₂ is as defined above, but is not hydrogen, j) optionally reacting a compound of the formula I, wherein R₁ is hydrogen and R₂ is as defined above, but is not hydrogen, with fluoro- or chloropyridine to form a compound of the formula I, wherein R₁ is pyridinyl and R₂ is as defined above but is not hydrogen. A process as defined in claim 1, wherein R₁ is hydrogen, C₁-C₆-alkyl, trifluoromethylcarbonyl or phenylcarbonyl, wherein the phenyl may be substituted as defined in claim 1 and R₂ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy carbonyl. A process as defined in claim 2, wherein Y is hydrogen or trifluoromethyl and n is 1. A process as defined in claim 3, wherein R₁ and R₂ are both hydrogen. The process as defined in claim 1, wherein 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine or a pharmaceutically acceptable acid addition salt thereof is prepared. The process as defined in claim 1, wherein 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine or a pharmaceutically acceptable acid addition salt thereof is prepared. Use of a compound for the preparation of a medicament being effective for the treatment of depression and personality disorder.

Inventors: EFFLAND RICHARD CHARLES, KLEIN JOSEPH THOMAS, EFFLAND, RICHARD CHARLES, KLEIN, JOSEPH THOMAS
Applicants: HOECHST ROUSSEL PHARMA, HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1992
Main classification: C07D223
IPC codes: C07D401, C07D223, A61K31, A61P25, C07D409, C07D403