1-(Pyridinylalkyl)-1H-indoles, indolines and related analogs

Abstract: This invention relates to compounds of the formula wherein R₁ is hydrogen, loweralkyl, arylloweralkyl, loweralkenyl or loweralkynyl; R₂ is hydrogen, lowralkyl, loweralkenyl, formyl or cyano; X is hydrogen, halogen, nitro, amino, loweralkyl, loweralkoxy or hydroxy; Y is hydrogen, loweralkyl, loweralkoxy, arylloweralkoxy, hydroxy, halogen, nitro or amino; the pharmaceutically acceptable acid addition salts thereof, and, where applicable, the geometric and optical isomers and racemic mixtures thereof. The compounds of the invention are useful for the treatment of various memory dysfunctions characterized by a decreased cholinergic function, such as Alzheimer's disease.

Description: This invention relates to compounds of the formula wherein R₁ is hydrogen, C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl; R₂ is hydrogen; X is hydrogen, halogen, nitro, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy or hydroxy; Y is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl-C₁-C₆-alkoxy, hydroxy, halogen, nitro or amino; the dotted line in formula I signifies an optional bond; and wherein the phenyl group in each occurence may be mono- or disubstituted with C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or trifluoromethyl, and with the proviso, that at least one of the substituents R₁ and Y is not hydrogen; the pharmaceutically acceptable acid addition salts thereof, and, where applicable, the geometric and optical isomers and racemic mixtures thereof. The compounds of the invention are useful for the treatment of various memory dysfunctions characterized by a decreased cholinergic function, such as Alzheimer's disease. In C. A. 1969 70 : 19857b; J. Org. Chem. 1986 , 51 , 2289; Tetrahedron 1986, 42 , 637; C. A. 1988, 109 : 150001j; and J. Med. Chem. 1974 17 , 1298 there have been disclosed 1-(2,3, or 4-pyridylmethyl)-indoles and -indolines, respectively, which may also be substituted at the pyridine or the indoline moiety. The compounds, however, have not been disclosed to show any activity as inhibitors of the acetylcholinesterase enzyme. When the double bond in formula (I) is present, the compounds represented are indoles. Throughout the specification and appended claims, a given chemical formula or name shall encompass all geometrical and optical isomers and racemic mixtures where such isomers and mixtures exist. Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and the appended claims. The term "C₁-C₆-alkyl" refers to a straight or branched chain hydrocarbon having from 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, neopentyl, n-hexyl, etc. The term "alkoxy" refers to a monovalent substituent which consists of an alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen; e.g., methoxy, ethoxy, propoxy, butoxy, etc. The term "alkenyl" refers to acyclic hydrocarbons with one double bond of the general formula C n H 2n , e.g., ethylene, butylene, etc. The term "alkynyl" refers to acyclic hydrocarbons with one triple bond of the general formula C n H 2n-2 , e.g., acetylene, butyne, etc. The term "halogen" refers to a member of the halogen family consisting of fluorine, chlorine, bromine and iodine. The compounds of this invention are prepared in the following manner. The substituents R₁, X and Y are as defined above unless otherwise indicated. Compound II of the formula is reacted with a haloalkylpyridine hydrochloride of the formula where Hal is halogen, to afford Compound III of the formula This reaction typically takes place in the presence of a base such as potassium hydroxide and a suitable solvent such as dimethylsulfoxide (DMSO) or dimethylformamide at ambient temperature to 50°C for 1 to 20 hours. Compound III, where Y is phenylmethoxy, is hydrogenated in a routine manner, for instance, using a noble metal catalyst under a hydrogen atmosphere, to afford Compound IV of the formula The noble metal catalyst is selected from palladium or platinum on carbon. The reaction typically takes place at a temperature of about 20°C to 70°C for 1 to 20 hours. Compound III may be reacted with n-butyllithium and a halide of the formula R₁-Hal, where R₁ is as previously defined and Hal is chlorine or bromine, in a suitable solvent to afford compound IIIa of the formula Typically, this reaction takes place in tetrahydrofuran or ether at a temperature of about -80° to 0°C for 1 to 8 hours. Compound IIIa, where Y is phenylmethoxy, is subsequently hydrogenated in a manner similar to that described above to afford Compound IV, where R₁ ≠ hydrogen. The compounds of formula I of the present invention are useful in the treatment of various memory dysfunctions characterized by decreased cholinergic function, such as Alzheimer's disease. This utility is manifested by the ability of these compounds to inhibit the enzyme acetylcholinesterase and thereby increase acetylcholine levels in the brain. Cholinesterase Inhibition Assay Cholinesterases are found throughout the body, both in the brain and in serum. However, only brain acetylcholinesterase (AChE) distribution is correlated with central cholinergic innervation. This same innervation is suggested to be weakened in Alzheimer patients. We have determined in vitro inhibition of acetylcholinesterase activity in rat striatum according to the method described below. In Vitro Inhibition of Acetylcholinesterase Activity in Rat Striatum Acetylcholinesterase (AChE), which is sometimes called true or specific cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. AChE may be distinguished from other cholinesterases by substrate and inhibitor specificities and by regional distribution. Its distribution in the brain correlates with cholinergic innervation and subfractionation shows the highest level in nerve terminals. It is generally accepted that the physiological role of AChE is the rapid hydrolysis and inactivation of acetylcholine. Inhibitors of AChE show marked cholinominetic effects in cholinergically-innervated effector organs and have been used therapeutically in the treatment of glaucoma, myasthenia gravis and paralytic ileus. However, recent studies have suggested that AChE inhibitors may also be beneficial in the treatment of Alzheimer's dementia. The method described below was used in this invention for assaying anticholinesterase activity. This is a modification of the method of Ellman et al., Biochem. Pharmacol. 7 , 88 (1961). Procedure : A. Reagents - 1. 0.05 M Phosphate buffer, pH 7.2 (a) 6.85 g NaH₂PO₄·H₂O/100 ml distilled H₂O (b) 13.40 g Na₂HPO₄·7H₂O/100 ml distilled H₂O (c) add (a) to (b) until pH reaches 7.2 (d) Dilute 1:10 2. Substrate in buffer (a) 198 mg acetylthiocholine chloride (10 mM) (b) q.s. to 100 ml with 0.05 M phosphate buffer, pH 7.2 (reagent 1) 3. DTNB in buffer (a) 19.8 mg 5,5-dithiobisnitrobenzoic acid (DTNB) (0.5 mM) (b) q.s. to 100 ml with 0.05M phosphate buffer, pH 7.2 (reagent 1) 4. A 2mM stock solution of the test drug is made up in a suitable solvent and q.s. to volume with 0.5 mM DTNB (reagent 3). Drugs are serially diluted (1:10) such that the final concentration (in cuvette) is 10⁻⁴M and screened for activity. If active, IC₅₀ values are determined from the inhibitory activity of subsequent concentrations. B. Tissue Preparation - Male Wistar rats are decapitated, brains rapidly removed, corpora striata dissected free, weighed and homogenized in 19 volumes (approximately 7 mg protein/ml) of 0.05 M phosphate buffer, pH 7.2, using a Potter-Elvehjem homogenizer. A 25 microliter aliquot of the homogenate is added to 1 ml of vehicle or various concentrations of the test drug and preincubated for 10 minutes at 37°C. C. Assay Enzyme activity is measured with the Beckman DU-50 spectrophotometer. This method can be used for IC₅₀ determinations and for measuring kinetic constants. Instrument Settings Kinetics Soft-Pac Module #598273 (10) Program #6 Kindata: Source - Vis Wavelength - 412 nm Sipper - none Cuvettes - 2 ml cuvettes using auto 6-sampler Blank - 1 for each substrate concentration Interval time - 15 seconds (15 or 30 seconds for kinetics) Total time - 5 minutes (5 or 10 minutes for kinetics) Plot - yes Span - autoscale Slope - increasing Results - yes (gives slope) Factor - 1 Reagents are added to the blank and sample cuvettes as follows: Blank: 0.8 ml Phosphate Buffer/DTNB 0.8 ml Buffer/Substrate Control: 0.8 ml Phosphate Buffer/DTNB/Enzyme 0.8 ml Phosphate Buffer/Substrate Drug: 0.8 ml Phosphate Buffer/DTNB/Drug/Enzyme 0.8 ml Phosphate Buffer/Substrate Blank values are determined for each run to control non-enzymatic hydrolysis of substrate and these values are automatically substracted by the kindata program available on kinetics soft-pac module. This program also calculates the rate of absorbance change for each cuvette. For IC₅₀ Determinations : Substrate concentration is 10 mM diluted 1:2 in assay yielding final concentration of 5 mM. DTNB concentration is 0.5 mM yielding 0.25 mM final concentration Results of this assay for a representative compound of this invention and eseroline (reference) are presented in Table 1. Inhibition of Brain Acetylcholinesterase Activity Compound % Inhibition @ Dose 1-(4-pyridinylmethyl)-1H-indol-5-ol 24% @ 100 µM Eseroline (Reference Compound) 50% @ 6.4 µM This utility is further demonstrated by the ability of these compounds to restore cholinergically deficient memory in the Dark Avoidance Assay described below. Dark Avoidance Assay In this assay mice are tested for their ability to remember an unpleasant stimulus for a period of 24 hours. A mouse is placed in a chamber that contains a dark compartment; a strong incandescent light drives it to the dark compartment, where an electric shock is administered through metal plates on the floor. The animal is removed from the testing apparatus and tested again, 24 hours later, for the ability to remember the electric shock. If scopolamine, an anticholinergic that is known to cause memory impairment, is administered before an animal's initial exposure to the test chamber, the animal re-enters the dark compartment shortly after being placed in the test chamber 24 hours later. This effect of scopolamine is blocked by an active test compound, resulting in a greater interval before re-entry into the dark compartment. The results for an active compound are expressed as the percent of a group of animals in which the effect of scopolamine is blocked, as manifested by an increased interval between being placed in the test chamber and re-entering the dark compartment. Results of this assay for a representative compound of this invention and those for 1-(4-pyridinylmethyl)-1H-indole, tacrine and pilocarpine (reference compounds) are presented in Table 2. Compound Dose (mg/kg of body weight, s.c.) % of Animals with Scopolamine-Induced Memory Deficit Reversal 1-[1-(4-pyridinyl)-butyl]-1H-indole 0.3 20 1-(4-pyridinylmethyl)-1H-indole 0.3 33 1.0 20 Tacrine 0.63 13 Pilocarpine 5.0 13 Effective quantities of the compounds of the present invention may be administered to a subject by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The compounds of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and the like. Preferred pharmaceutically acceptable addition salts include salts of 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 administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 75% of the weight of the unit. The amount of compound present in such composition 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 mgs of active compound. The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel™, corn starch and the like; a lubricant such as magnesium stearate or Sterotex®; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as 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 and colorings 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 the aforesaid 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 invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 mgs 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 ampules, disposable syringes or multiple dose vials made of glass or plastic. Examples of the compounds of the invention are listed below: 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole; 1-(4-pyridinylmethyl)-1H-indol-5-ol; 1-[1-(4-pyridinyl)butyl]-1H-indole; 5-phenylmethoxy-1-[1-(4-pyridinyl)butyl]-1H-indole; 1-[1-(4-pyridinyl)butyl]-1H-indol-5-ol; 1-[1-(4-pyridinyl)butyl]-5-methoxy-1H-indole; 1-[1-(3-methoxy-4-pyridinyl)butyl]-1H-indole; 1-[1-(3-fluoro-4-pyridinyl)butyl]-1H-indole; 1-[1-(3-fluoro-4-pyridinyl)butyl]-5-phenylmethoxy-1H-indole; 5-chloro-1-(4-pyridinylmethyl)-1H-indole; 5-methyl-1-[1-(4-pyridinyl)butyl]-1H-indole; 2,3-dihydro-1-[1-(4-pyridinyl)butyl]-1H-indole; 2,3-dihydro-5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole; 2,3-dihydro-5-fluoro-1-[1-(4-pyridinyl)butyl]-1H-indole; and 2,3-dihydro-1-[1-(3-fluoro-4-pyridinyl)butyl]-5-methoxy-1H-indole. The following examples are for illustrative purposes and are not to be construed as limiting the invention disclosed herein. All temperatures are given in degrees centigrade (°C) unless indicated otherwise. Example 1 5-Phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole To a solution of 5-phenylmethoxy-1H-indole (22.6 g) in 130 ml dimethylsulfoxide, was added milled potassium hydroxide (18 g) and the mixture was stirred at ambient temperature for two hours. The mixture was cooled with an ice bath, then 4-chloromethylpyridine hydrochloride (16.4 g) was added portionwise over a period of fifteen minutes. After stirring at ambient temperature for four hours, the mixture was poured into two liters ice water and stirred for ten minutes. The resultant precipitate was collected, washed with water and dissolved in ethyl acetate. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solution was evaporated to afford a solid, (∼30 g) which was triturated with ether, collected and dried to give 27 g of a solid, m.p. 123-125°C. A sample of this material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via high pressure liquid chromatography (HPLC). The desired fractions were combined to yield 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole, as a solid, m.p. 124-5°C. Analysis: Calculated for C₂₁H₁₈N₂O: 80.23%C 5.77%H 8.91%N Found: 79.92%C 5.41%H 8.79%N Example 2 1-(4-Pyridinylmethyl)-1H-indol-5-ol To a suspension of 10% Pd/C (1.5 g) in 50 ml ethanol in a 500 ml Parr hydrogenation bottle, was added a suspension of 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole in 200 ml ethanol. The mixture was shaken at 50°C under 3.45 bar (50 psi) hydrogen for one hour, then cooled, filtered, and the filtrate evaporated to a solid, 10 g, dec. 178°C. A sample of this material was eluted on a silica gel column with 2% methanol/dichloromethane via HPLC. The desired fractions were combined and evaporated to yield 2.3 g of 1-(4-pyridinylmethyl)-1H-indol-5-ol, as a solid, m.p. 185-186°C. Analysis: Calculated for C₁₄H₁₂N₂O: 74.98%C 5.40%H 12.49%N Found: 74.76%C 5.46%H 12.34%N Preparation - Example 3 1-(4-Pyridinylmethyl)-1H-indole To KOH (34 g) in 200 ml of DMSO was added indole (20 g), portionwise, and this mixture was stirred for 90 minutes at room temperature. 4-Chloromethylpyridine hydrochloride (10 g) was added portionwise, and the mixture was stirred for four hours at room temperature. The mixture was then poured into water and extracted with ether four times. The organics were combined and washed with 2N HCl. The acidic aqueous phase was then basified with NH₄OH and extracted with ether three times. The organics were combined and washed with NaCl and dried (anhy. MgSO₄). After filtering, the solvent was evaporated to yield an oil (14.5 g), which was eluted with 50% ethyl acetate/dichloromethane on a silica gel column via HPLC. The desired fractions were evaporated to yield 10.5 g of 1-(4-pyridinylmethyl)-1H-indole, as a solid, m.p. 65-68°C. Analysis: Calculated for C₁₄H₁₂N₂: 80.74%C 5.81%H 13.45%N Found: 80.59%C 5.87%H 13.45%N Example 4 1-[1-(4-Pyridinyl)butyl]-1H-indole To a solution of 1-(4-pyridinylmethyl)-1H-indole (4.0 g) in 100 ml of THF cooled to -78°C was added n-butyllithium (7.6 ml) dropwise, and the mixture was stirred for 45 minutes. 1-Bromopropane (2.34 g) was added dropwise, and the mixture was stirred for 3.5 hours, allowing the temperature to rise to 0°C. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO₄). After filtering, the solvent was evaporated to yield an oil (3.8 g) which was eluted with 50% ethyl acetate/dichloromethane on a silica gel column via HPLC. The desired fractions were evaporated to yield 2.65 g of 1-[1-(4-pyridinyl)butyl]-1H-indole, as a solid, m.p. 91-94°C. Analysis: Calculated for C₁₇H₁₈N₂: 81.56%C 7.25%H 11.19%N Found: 81.66%C 7.32%H 11.22%N Example 5 5-Phenylmethoxy-1-[1-(4-pyridinyl)butyl]-1H-indole oxalate To a solution of 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole (11.4 g) in 120 ml tetrahydrofuran at -78°C, was added n-butyllithium (2.5 M solution in hexane, 14.4 ml) and the solution was stirred at -78°C for one hour. 1-Bromopropane (30 ml) was added to the solution and the mixture was allowed to warm to ambient temperature over a period of two hours. The mixture was poured into 300 ml water, stirred for five minutes and extracted twice with ethyl acetate. The organic layer was washed with water and dried (saturated NaCl solution, anhydrous MgSO₄). After filtering, the solvent was evaporated to an oil, (13.5 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined and evaporated to give 8.2 g of an oil. A 1.0 g aliquot of this oil was dissolved in 10 ml methanol, and a solution of oxalic acid (0.3 g) in 5 ml methanol was added. The solution was diluted with 150 ml ether and the resultant precipitate was collected and dried to give 1.2 g of 5-phenylmethoxy-1-[1-(4-pyridinyl)butyl]-1H-indole oxalate, m.p. 148-149°C. Analysis: Calculated for C₂₄H₂₄N₂O·C₂H₂O₄: 69.94%C 5.87%H 6.28%N Found: 70.09%C 5.83%H 6.22%N Example 6 1-[1-(4-Pyridinyl)butyl]-1H-indol-5-ol To a suspension of 1.0 g of 10% Pd/C in 50 ml ethanol, was added a solution of 5-phenylmethoxy-1-[1-(4-pyridinyl)butyl]-1H-indole (7.2 g) in 200 ml ethanol. After shaking under under 3.45 bar (50 psi) hydrogen at 50°C for one hour, the mixture was filtered, then evaporated to a solid, which was tritured with hexanes to give 5.0 g of 1-[1-(4-pyridinyl)butyl]-1H-indol-5-ol, m.p. 73-75°C. Analysis: Calculated for C₁₇H₁₈N₂O: 76.66%C 6.81%H 10.52%N Found: 76.23%C 6.86%H 10.13%N

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A compound of the formula I wherein R₁ is hydrogen, C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl; R₂ is hydrogen; X is hydrogen, halogen, nitro, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy or hydroxy; Y is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl-C₁-C₆-alkoxy, hydroxy, halogen, nitro or amino; the dotted line in formula I signifies an optional double bond; and wherein the phenyl group in each occurrence may be mono- or disubstituted with C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or trifluoromethyl, and with the proviso that at least one of the substituents R₁ and Y is not hydrogen; the pharmaceutically acceptable acid addition salts thereof, and, where applicable, the geometric and optical isomers and racemic mixtures thereof. The compound as defined in claim 1 wherein Y is phenyl-C₁-C₆-alkoxy, wherein the phenyl may he substituted as defined in claim 1. The compound as defined in claim 1 wherein Y is hydroxy. The compound as defined in claim 1 wherein Y is hydrogen. The compound as defined in claim 1 which is selected from the group consisting of 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole, 1-(4-pyridinylmethyl)-1H-indol-5-ol, 1-[1-(4-pyridinyl)butyl]-1H-indole, 5-phenylmethoxy-1-[1-(4-pyridinyl)butyl]-1H-indole and 1-[1-(4-pyridinyl)butyl]-1H-indol-5-ol. A method of synthesizing a compound as defined in claim 1 which comprises reacting a compound of the formula where Y is as defined in claim 1, with a haloalkylpyridine hydrochloride of the formula where Hal is halogen and X is as defined in claim 1, in the presence of a base and suitable solvent, and optionally reacting a compound of the formula I, wherein R₁ is hydrogen, with n-butyllithium and a halide of the formula R₁-Hal, where Hal is chlorine or bromine and R₁ is as defined in claim 1, but is not hydrogen. A pharmaceutical composition which comprises a compound as defined in claim 1 in an amount effective for alleviating a memory dysfunction characterized by a cholinergic deficit and a pharmaceutically acceptable carrier therefor. Use of a compound of the formula I as defined in claim 1 for the preparation of the medicament having memory dysfunction alleviating activity. Claims for the following Contracting States : ES, GR A method of synthesizing a compound of the formula I wherein R₁ is hydrogen, C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl; R₂ is hydrogen; X is hydrogen, halogen, nitro, amino, C₁-C₆-alkyl, C₁-C₆-alkoxy or hydroxy; Y is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl-C₁-C₆-alkoxy, hydroxy, halogen, nitro or amino; the dotted line in formula I signifies an optional double bond; and wherein the phenyl group in each occurrence may be mono- or disubstituted with C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen or trifluoromethyl, and with the proviso that at least one of the substituents R₁ and Y is not hydrogen; the pharmaceutically acceptable acid addition salts thereof, and, where applicable, the geometric and optical isomers and racemic mixtures thereof, which comprises reacting a compound of the formula where Y is as defined above, with a haloalkylpyridine hydrochloride of the formula where Hal is halogen and X is as defined above, in the presence of a base and suitable solvent, and optionally reacting a compound of the formula I, wherein R₁ is hydrogen, with n-butyllithium and a halide of the formula R₁-Hal, where Hal is chlorine or bromine and R₁ is as defined above, but is not hydrogen. The method of claim 1 where the base is potassium hydroxide. The method of claim 1 where the solvent is selected from dimethylsulfoxide and dimethylformamide. The method of claim 1 wherein Y is phenyl-C₁-C₆-alkoxy, wherein the phenyl may be substituted as defined in claim 1. The method of claim 1 wherein Y is hydroxy. The method of claim 1 wherein a compound is prepared which is selected from the group consisting of 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole, 1-(4-pyridinylmethyl)-1H-indol-5-ol, 1-[1-(4-pyridinyl)butyl]-1H-indole, 5-phenylmethoxy-1-[1-(4-pyridinyl)butyl]-1H-indole and 1-[1-(4-pyridinyl)butyl]-1H-indol-5-ol.

Inventors: DAVIS LARRY, EFFLAND RICHARD CHARLES, OLSEN GORDON E, DAVIS, LARRY, EFFLAND, RICHARD CHARLES, OLSEN, GORDON E.
Applicants: HOECHST ROUSSEL PHARMA, HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1991
Main classification: C07D401
IPC codes: A61K31, C07D401, A61P25