N-ARALKYL PIPERIDINEMETHANOL DERIVATIVES

Abstract: This invention relates to a new class of compounds hav­ ing important biochemical and pharmacological properties. More particularly, this invention relates to N-aralkyl pipe­ ridinemethanol derivatives which are potent and selective in­ hibitors of the binding of serotonin at the 5HT₂ receptor site, and to the processes for their preparation and use.

Description: N-Aralkyl piperidinemethanol derivatives This invention relates to a new class of compounds having important biochemical and pharmacological properties. More particularly, this invention relates to N alkyl piperidinemethanol derivatives which are potent and selective inhibitors of the binding of serotonin at the 5BT2 receptor site, and to the processes for their preparation and use. The compounds of this invention are represented by the general formula I EMI1.1 including optical isomers and mixtures thereof, the pharma ceutically acceptable salts thereof, wherein n is 2, 3 or 4 and each of R1, R2, R3 and R4 independently rçresents hydrogen, C1 6 alkyl, halogen, trifluoromethyl, hydroxy, C16 alkoxy, or amino. Representative of the R1 to R4 substituents for C16 alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, t hut5, pentyl, hexyl, cyclopropyl, cyclopentyl with methyl and ethyl being preferred. All halogens are embraced with fluoro and chloro being preferred. Representative C1-6 alkoxy substituents are methoxy, ethoxy, isopropoxy and such of the aforementioned alkyl groups attached thru an oxygen. In those instances wherein R1 to R4 are other than hydrogen, the substituents may be located at any position, (ortho, meta or para) but para is preferred for monosubstituted phenyl moieties. The 2,3-, 2,4-, 2,5-, 3,4-, or 3,5- disubstituted phenyl moieties are embraced herein. The compounds of Formula I contain an asymmetric carbon atom and thus exist in optically isomeric forms. Embraced within this invention are the individual optical isomers and the mixtures thereof. Such mixtures may readily be separated by standard techniques well known in the art. Preferred are the following compounds of the general formula (I): The compounds wherein n is 2; the compounds wherein n is 3; the compounds wherein R3 and R4 are hydrogen; the compounds wherein R1 to R4 are hydrogen; the compounds wherein R1 and R2 are methoxy and R3 and R4 are hydrogen; the compounds wherein R1 is methoxy and each of R2, R3 and R4 is hydrogen; the compounds wherein R1 and R2 are halogen 3 4 and R and R4 are hydrogen; and the compounds wherein R1 is methyl and R2, R3 and R4 are hydrogen. The preparation of the compounds of this invention ay be achieved by standard chemical reactions analogously known in the art. The compounds of the general formula I may be prepared by one of the following processes: A) the chemical reduction of a compound of the formula EMI3.1 B) the alkylation of a compound of the formula EMI3.2 with a reactive derivative having the formula EMI4.1 wherein X is a reactive moiety, preferably a halide, tosylate, mesylate or a functional equivalent thereof, or CC) the exaction of a Grignard reagent V with an aldehyde of the formula VI EMI4.2 -and hydrolyzing the reaction product, wherein R1 to R4 and n is defined as above. Especially preferred is the compound of formula VII EMI5.1 This compound can be obtained according to one of the following methods: A) the chemical reduction of a compound of the formula EMI5.2 B) the alkylation of the compound of formula IX EMI5.3 with an alkylating agent of the formula X EMI6.1 wherein the X-substituent is a halide, tosylate, mesylate or a functional equivalent thereof, or (C) the reaction of a Grignard reagent XI with an aldehyde of the formulae XII EMI6.2 and hydrolyzing the reaction product. To obtain the compounds of formula IIa it is preferred to Nalkylate an appropriately R1,R2-substituted phenyl 4piperidinemethanone (XIII) to produce a R11R2 phenyl-Jl-R31R4- phenylalkyl-4-piperidinyl7 methanone intermediate (via), which intermediate is then chemically reduced to the desired product (I). Alternately the 4-piperidinones (XIII)may be chemically reduced to their alcohols (TRI) and these intermediates may be N-alkylated to the desired products (I). The chemical reduction of the ketones to their correspond ing alcohols may be effected by standard reduction procedures such as by catalytic hydrogenation or metal hydride reduction preferably with sodium or potassium borohydride. In either case in those instances wherein any R1 to R4 substituent represents a reactive hydroxy group then such group should first be protected (using such standard protecting groups as acetate, trifluoroacetate, benzyloxy, benzyloxycarbonyl and the like) and then, following the foregoing N-alkylationreduction reactions, the protecting group is removed. Standard techniques for protecting and de-protecting hydroxy functions are well known in the art. Analogously in those instances wherein any R1 to R4 gxp req?reserrts an amino moiety, it is preferred to prepare the appropriate nitro analog and, as a last step, reduce the nitro group to the desired amino moiety. The foregoing reactions may conveniently be depicted by the following reaction scheme. Reaction Scheme A EMI8.1 wherein X is a suitable leaving group (e.g., halide, tosylate or other functional equivalent thereof) and n, R1, R2 ,R3 and R4 are as defined for compounds of Formula I. The N-alkylation procedures are effected by reacting about equimolar quantities of the N-alkylating reactants (IV) with an appropriately substituted 4-piperidine methanol (III) or 4-piperidinylmethanone xxIII)in a suitable solvent, in the presence of an acid acceptor (e.g., the carbonates or bicarbonates of potassium or sodium, or ., excess of the piperidine reactant), optionally with a small amount of potassium iodide being present. Suitable solvents are toluene, xylene, chlorobenzene, N, Ndimethylformamide, N, N-dimethylacetamide, ketones (acetone, butanone, MIBK, cyclohexanone, cyclopentanone, etc.) and alcohols (ethanol, propanol, butanol, etc.) The reaction mixture is heated over a wide range of temperatures (50"C-1800C) although it is preferred to heat at reflux temperatures of the reaction mixture. The reaction is continued until completed, generally a period of several hours to several days. After completion of the reaction, the reaction mixture is filtered, the product optionally converted to its mineral or organic acid salt and the desired product is recrystallized by techniques well-known in the art. Suitable solvents for recrystallization are methanol, ethanol, isopropanol, butanone, acetone, ethyl acetate, diethylether and the like. The intermediate R1,R2-substituted phenyl 4-piperidyl ketones (XIII).used in the preparation of the compounds of Reaction Scheme A may be prepared by a Friedel-Craft reaction of benzene or a R1R 2substituted benzene with isonipecotic acid chloride HC1 or N-(trifluoroacetyl) isonipecotic trifluoroacetic anhydride followed by aqueous potassium carbonate hydrolysis in the latter case. Reaction of a substituted phenyl Grignard reagent with 4cyanopiperidine (prepared by hydrolyzing N-trifluoroacetl4-cyanopiperidine) will also yield the intermediate ketones. Alternative methods of synthesis of the compounds of this invention include the reactions of either a R RZ- phenylmagnesium halide for a RÚ, R2-substituted phenyl lithium reactant with 1- (-R3,R4-phenyl alkyl)-4-piperidine carboxaldehyde (VI) .Anotheralternative procedure includes the catalytic hydrogenation of an alpha-(RÚ,Rê,phenyl- methanol)-1-(R3,R4-phenylalkyl)pyridinium halide, or its ketone analog. (IIc), to L Besired product. Still another method is the chemical reduction of a RÚ,Rê-phenyl[-1-([2- i, R4- phenacyl]-4-piperidinyl]-methanone (IId) to the desired products of this invention. For these foregoing reactions standard procedures well known in the art may be used in the preparation of the necessary intermediates as well as for the final step producing the desired products. Having taught the general methods for the preparation of the compounds of this invention the following examples typify the preferred routes of preparation. EXAMPLE 1 ALPHA-PHENYL-1-(2-PHENYLETEYL)-4-PIPERIDINEMETHANOL SC1 Step A: Phenyl[1-(2-phenylethyl)-4-piperidinyl]- methanone HCl. A reaction mixture containing phenyl(4piperidinyl)methanone (20.5 g, 0.108 mol), K2C03 (33.17 g, 0.18 mol), potassium iodide (0.2 g) and 2-bromoethyl benzene (22.2 g, 0.12 mol, 16.4 ml) in toluene (250 ml) was stirred at reflux temperature for 66 h. The reaction mixture was filtered and the filtrate concentrated te a residue which was dissolved in dry Et2O (500 ml) and treated dropwise with a solution of BC1 (0.11 mol) in EtOAc. The resultant precipitate was recrystallized from. EtOB:CH30E, 4:1 (500 ml) to give phenyltl-(2-phenylethyl)- 4-piperidinyl3-methanone hydrochloride, mp 258-2600C. SteP B: A solution of phenyltl-(2-phenylethyl)-4 piperidinyl-methanone (11.0 g, 0.037 mol) in absolute EtOH (150 ml) was stirred at room temperature and treated portionwise with NABH4 (2.84 g, 0.075 mol) and was stirred overnight (16 h). The reaction mixture was concentrated at reduced pressure to give a residue which was partitioned between CH2C12 (250 ml) and 10% NaOH solution (100 ml). The aqueous layer was further extracted with CH2C12 (2 X 50 ml) and the combined extracts washed with saturated NaCl solution (100 ml) and dried over MgSO4. The mixture was filtered and concentrated to give a solid (10 g) which was dissolved in dry Et20fEtOAc (1:1, 350 ml) and treated with HC1 (0,034 mol) dissolved in EtOAc/CH3oH (3:1, 20 ml). The resultant precipitate was recrystallized twice from methanol/butanone to give phenyl-l- (2-phenyl-ethyl) -4-piperidinemethanol hydrochloride, mp 141-143.5 C. EXAMPLE 2 ALPHA-PHENYL-1-(2-PHENYLETHYL)-4-PIPERIDINEMETHANOL A mixture of alpha-phenyl-4-piperidinemethanol (1.5 g, 7.8 mmol), 2-bromoethyl benzene (1.1 ml, 8.0 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in dry DMF (20 ml) was heated at 800C over the weekend (60 h). The excess DME was distilled off at reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was washed with H20 (3 X 100 ml), saturated aqueous NaCl (1 X 100 ml), dried (NgSO4), filtered and evaporated to give a pale yellow oil which eventually crystallized. After recrystallization from ethyl acetate-hexane, a white crystalline solid was obtained, mp 125-128 C. EXAMPLE 3 ALPHA-PRENYL-1-(3-PHENYLPRQPYL)-4-PIPERIDINEMETHANOL Step A: Phenyl ±l-(3-phenylpropyl)-4-piperidinyl3- methanone hydrochloride. A solution of phenyl (4-piperidinyl)methanone (18.1 g, 0.096 mol) was dissolved in toluene {2w0 ml) containing l-bromo-3-phenylpropane (21.9 g, 0.11 mol, 16.7 ml), K2C03 (30.4 g, 0.22 mol) and KI (0.2 g ) and was refluxed for 64 h. The reaction mixture was filtered and concentrated to give a light yellow oil. This material was dissolved in toluene/EtOAc (1:1) and treated with HC1 (0.096 mol) dissolved in CH30H/EtOAc (2:5, 35 ml) to give a precipitate which was filtered off and recrystallized twice from EtOH/Et2O (150 ml) to give phenyltl-(3-phenylpropyl)-4-piperidinyl3-methanone hydrochloride, mp 199-2000C. Step B: To a stirred solution of phenylEl-(3-phenyl- propyl)-4-piperidinyl3-methanone hydrochloride (6.8 g, 0.02 mol) in absolute ethanol (120 ml) was added sodium methoxide (1.08 g, 0.04 mol) followed by sodium borohydride (1.51 g, 0.04 mol). The reaction mixture was stirred for 72 h and then concentrated at reduced pressure to a solid residue. This material was stirred with aqueous 10% NaOE for 1 h and then extracted with toluene (2 X 50 ml). The extracts were washed with water and then saturated NaCl solution. The toluene solution was dried over MgSO4, filtered and concentrated to a colorless oil. This material was dissolved in dry Et2O (50 ml) and treated with a solution of EC1 (0.C2 mol) in CE3OHJEtOAc (1:4, 12.5 ml). The resultant precipitate was dissolved in water, basified using 10% aqueous NaO! and extracted into toluene. The toluene solution was washed with saturated aqueous NaCI dried over MgSO4, filtered and concentrated to a solid. This material was flash chromatographed on a 2.5 X 6.0 inch silica gel column, and eluted with CH3OB/CB2Cl2 (1:9). The resultant fractions (7-9) eventually solidified and were recrystallized from acetone to give alpha-phenyl-l-(3-phenylpropyl)-4- piperidinemethanol, mp 87-884C. EXAMPLE 4 ALPHA-(4-METHYLPHENYL)-1-(2-PHENYLETHYL) -4-PIPERID INEMETHANOL BC1 Step A: (4-Methyiphenyl) El-(2-phenylethyl) -4-piper- idinyll-methanone HCl. A mixture containing 4-(methylphenyl)(4-piperidinyl)methanone (10.5 g, 0.052 mol), 2bromoethyl benzene (11.1 g, 0.06 mol, 8.2 ml) in dry DMF (125 ml) was stirred at 1000C for 23 h. The cooled reaction mixture was poured into B20 (600 ml) and extracted with toluene (4 X 200 ml). The extracts were washed with H20 (2 X 100 ml) saturated aqueous NaCl (100 ml) and dried over MgSO4. The mixture was filtered and the filtrate concentrated to a solid residue which was dissolved in dry Et20 and filtered. The filtrate was treated with a solution of HC1 (0.052 mol) in CH30H/EtOAc (9:20, 29 ml). The mixture was cooled and filtered to give a light tan powder. The solid was recrystallized twice from EtOH/Et20 to give (4-methylphenyl)ll-(2- phenylethyl)-4-piperidinyl]-methanone hydrochloride, which contains 0.4 mol of water of hydration and melts at 26l-2630C. Step B: A solution of (4-methyiphenyl) ±l-(2-phenyl- ethyl) -4-piperidinyl1 -methanone hydrochloride (9.5 g, 0.028 mol) in absolute ethanol (350 ml) was treated first by the addition of NaOCB3 (1.62 g, 0.03 mol) and then, portionwise, with sodium borohydride (2.27 g, 0.06 mol) and stirred at room temperature for 18 h. The reaction mixture was concentrated to a solid and stirred with 10% aqueous NaOH. The mixture was extracted with CH2C12 (3 X 50 ml). The CH2C12 solution was washed with water and then saturated NaCI solution, and dried over Na2S04. After filtering off the Na2SO4, the filtrate was concentrated to a solid. This material was dissolved in EtOAc/Et2O (1:1, 200 ml) and treated with a solution of HC1 (0.023 mol) in CH30E/EtOAc (3:10, 13 ml). The resulting precipitate was twice recrystallized from butanone containing a small amount of CH3OH to give alpha (4-methylphenyl)-1-(2-phenylethyl)-4-piperidinemethanol hydrochloride, mp 181-1830C. EXAMPLE 5 ALPHA-(4-METHOXYPHENYL)-1-(2-PHENYLETHYL) -I-PIPERDINEMETHANOL HC1 SteP A: (4-Methoxyphenyl)[1-(2-phenylethyl)-4- piperidinyll-methanone HCl. A reaction mixture containing 4-(methoxyphenyl) (4-piperidinyl)methanone (10.3 g, 0.047 mol), 2-bromoethylbenzene (9.57 g, 0.052 mol, 7.1 ml) and K2C03 (15.2 g, 0.11 mol) in dry DMF (100 ml) was stirred at 900 for 65 h. The cooled reaction mixture was poured into H20 (500 ml) and extracted with toluene (3 X 100 ml). The extracts were washed with E2O, saturated aqueous NaCl solution and dried over MgSO4. The mixture was filtered and the filtrate concentrated to a residue which was triturated with hexane and filtered. The resulting precipitate (0.022 mol) was dissolved in dry Et20 and treated with a solution of HCl (0.022 mol) in CH3OH/EtOAc (2:5, 14 ml) to give a precipitate which was twice recrystallized from EtOR/Et20, to give (4methoxyphenyl)ll-(2-phenylethyl)-4-piperidinyli-methanone hydrochloride, mp 238.5-239.5 C. Step by A solution of (4-methoxyphenyl) [l-(2-phenyl- ethyl)-4-piperidinyll-methanone hydrochloride (3.5 g, 9.7 mmol) in absolute EtOH (75 ml) was treated with sodium methoxide (0.53 g, 9.7 mmol) followed by sodium borohydride (1.08 g, 20 mmol) and the mixture stirred for 42 h at room temperature. The reaction mixture was filtered and the filtrate concentrated to a solid residue which was dissolved in absolute Et20 and treated with HCl (9.7 mmol) dissolved in CH3OH/EtOAc (1:3, 8 ml). The resulting precipitate was filtered and recrystallized from CH3OH/Et20 to give alpha-(4-methoxyphenyl)-1-(2-phenyl- ethyl)-4-piperidinemethanol hydrochloride, mp 162.5-164 C. EXAMPLE6 ALPHA- [4- (1-METHYLETIlYL) PH;NYLJ 1- (2-PHENYLETHYL) PIPRIDINYL) -METaNOL HCl Sten A: [4-[1-methylethyl)phenyl][1-(2-phenylethyl)- piperidinyl3-methanone SC1. A solution of [4-(l-methyl- ethyl)phenyll(4-piperidinyl)-methanone (43 g, 0.19 mol) in toluene (500 ml) was treated with 2-bromoethylbenzene t37 g, 0.2 mol), K2C03 (25 g, 0.18 mol), KHC03 t25 g, 0.25 mol) and potassium iodide (0.1 g) and the mixture heated on a steam bath for 68 h. The reaction mixture was filtered and the filtrate treated with ethereal hydrogen chloride until acid to congo red indicator paper. The resultant precipitate was filtered off and recrystallized twice from CHOB/butanone to give [4-(l-methylethyl)- phenyl) [1- ( 2-phenylethyl) piperidinyl-methanone hydrochloride, mp 251-2530C, By following the sodium borohydride reduction procedure of the foregoing example there is obtained the desired product of this example. EXAMPLE 7 ALPEA-(3,5-DIMETHYLPHENYL)-1-(2-PHENYLETEYL) ALPHA-4-PIERIDINEMETHANOL SteP A: (3 ,5-Dimethylphenyl) [l-(2-phenylethyl) -4- piperidinyl3-methanone HC1, A solution of 5-bromo-mxylene (22.3 g, 0.12 mol) in dry THF (50 ml) was added under N2 to an oven dried 1 L round bottom flask containing Mg turnings (3.0 g, 0.12 mol) and a crystal of I2 covered with dry THF (50 ml) at a rate such that the TEF gently refluxed once the reaction had commenced. After the addition was complete, the mixture was stirred for 1 h at room temperature. At this time the Grignard solution was diluted to 500 ml with dry THF and 4-cyano-1-(2phenylethyl)piperidine (15.0 g, 0.12 mol) in dry TBF (50 ml) was added over a period of 15 min. Dry toluene (250 ml) was added and the mixture refluxed while THF was distilled off until a reaction temperature of 850C was reached. The mixture was refluxed at this temperature overnight (16 h). It was then cooled in an ice bath and 1N H2SO4 (200 ml) was added dropwise with vigorous stirring. When the addition was complete, the mixture was warmed to room temperature and stirred an additional 3 h. The aqueous phase was separated and washed twice more with toluene (200 ml) before it was basified with aqueous 2N NaOH and extracted with Et20 (3 X 200 ml). The extract was washed with saturated aqueous NaCl (1 X 250 ml), dried (MgSO4), filtered and evaporated to give a yellow oil. This oil was distilled (Sugelrohr) to give a yellow glass which crystallized upon standing. This material was recrystallized from ether to give a white crystalline powder, mp 76-780C. The hydrochloride salt was prepared by adding the free base to a cold methanol solution containing one equivalent of HC1. This solution was evaporated to dryness and the residue recrystallized from methanol-butanone to give fluffy white crystals, mp 211-2140C. SteD B: To a solution of (3,5-dimethylphenyl)11-(2- phenylethyl)-4-piperidinyll-methanone (21.5 g, 66.9 mmol) in methanol (300 ml) cooled in an ice bath was added portionwise with stirring sodium borohydride (2.53 g, 66.9 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). This mixture was evaporated and the residue stirred in Et20, washed with H20 (3 X 100 ml), saturated aqueous NaCI (1 X 100 ml), dried (MgSO4), filtered and evaporated to give a light yellow solid. This solid was recrystallized from butanone to give a white crystalline solid, mp 150-154QC. EXAMPLE 8 1- (2-PHENYLETHYL) -ALPHA- [3- (TRIFLUOROMETHYL) PBENYLI-4-PIPERI¯DINEMETHANOL Step A: [1-(2-Phenylethyl)-4-piperidinyl][3-(tri- fluoromethyl)-phenyl-methanone HC1. A solution of 3bromobenzotrifluoride (17 mlt 0.12 mol) in dry THF (50 ml) was added under N2 to an oven dried 1 L round bottom flask containing Mg turnings (3.0 g, 0.12 mol) and a crystal of I2 covered with dry THF (50 ml) at a rate such that the THF gently refluxed once the reaction had commenced. After the addition was complete, the mixture was stirred for 1 h at room temperature. At this time the Grignard solution was diluted to 500 ml with dry THF and 4-cyano-l (2-phenylethyl)piperidine (15.0 9r 0.12 mol) in dry TEF (50 ml) was added over a period of 15 min. Dry toluene (250 ml) was added and the mixture refluxed while TEF was distilled off until a reaction temperature of 850C was reached. The mixture was refluxed at this temperature overnight (16 h). It was then cooled in an ice bath and 1N H2SO4 (200 ml) was added dropwise with vigorous stirring. When the addition was complete, the mixture was warmed to room temperature and stirred an additional 1 h. The aqueous phase was separated and washed twice more with toluene (200 ml) before it was basified with aqueous 2N NaOH and extracted with Et20 (3 X 200 ml). The extract was washed with aqueous saturated NaCl (1 X 250 ml), dried (MgSO4), filtered and evaporated to an orange oil. This oil was distilled (Kugelroh-r) to give a yellow glass (bp 120-1300C, 1 mm Hg) which crystallized upon standing. This material was recrystallized from Et20 to give white needles, mp 70-730C. The hydrochloride salt was prepared by adding a solution of free base in methanol to a cold methanol solution containing one equivalent of HCl. This solution was evaporated to dryness and the residue recrystallized from methanol-butanone to give a white crystalline solid, mp 248-2510C. Step B: To a solution of fl-(2-phenylethyl)-4- piperidinyllE3-(trifluoromethyl)-phenyll-methanone (2.8 g, 7.75 mmol) in methanol (50 ml) cooled in an ice bath was added portionwise sodium borohydride (0.3 g, 7.75 mmol). The reaction was allowed to warm to room temperature and stirred an additional 4 h. The mixture was evaporated and the residue extracted with Et20, washed with H20 (3 X 100 ml), saturated aqueous NaCI (1 X 100 ml), dried (Mg SO4), filtered and evaporated to give a white solid. This solid was recrystallized from ether-hexane to give white needles, mp 143-147tC. EXAMPLE 9 ALPHA-(2,3-DIMETBOXYPRENYL) 2-PEENYLETEYL) -4-PIPERIDINEMETRANOL HC; SteP A: 2-Phenylethyl)piperidine-4-carbox- aldehyde. To a solution of 4-cyano-1-(2-phenylethyl)piperidine (6.5 g, 30.3 mmol) in dry toluene (100 ml) cooled in an ice bath was added dropwise 43 ml (43 mmol) of lM diisobutylaluminum hydride in hexane. After the addition was complete, the mixture was warmed to room temperature and stirred overnight (16 h). Methanol was added to decompose any unreacted reagent and H20 was adder with vigorous stirring. The gelatinous aluminum salts were removed by filtration through Celite and the filtrate extracted with toluene (2 X 100 ml). The extracts were combined, washed with saturated aqueous NaCl, dried (MgSO4) filtered and evaporated to give a clear oil. This oil was flash chromatographed on silica gel using acetone as eluent to give product as a clear oil, which was used without further purification. Step B: To a solution of veratrole (2.5 ml, 19.6 mmol) in dry TEF (150 ml) cooled to OOC was added 13 ml (20.7 mmol) of 1.6 M n-butyllithium dropwise. This mixture was kept at OOC for another 5 h before it was cooled to -45 0C and 1- ( 2-phenylethyl) piperidine-4-carboxaldehyde (3.6 g, 16.6 mmol) in dry THF (10 ml) was added dropwise. The mixture was kept at -450C for 1 h before it was allowed to warm to room temperature and stirred overnight (16 h). The reaction mixture was poured into 5% aqueous NH4C1, extracted with Et20 (3 X 100 ml), dried (MgSO4), filter and evaporated to an orange oil. The hydrochloride salt was prepared by adding a solution of the free base in methanol to a cold methanol solution containing one equivalent of HC1. This solution was evaporated to give a foam which crystallized from a vigorously stirred acetone-hexane solution. Two recrystallizations from methanol-butanone gave pale orange crystals, mp 182-1850C. EXAMPLE 10 ALPHA- (3 ,4-DICHLOROPHENYL) -1- (2-PHENYLETHYL) -4- PIPERIDINEMETHANOL HYDROCHLORIDE Step A: (3,4-Dichlorophenyl) ±l-(2-phenylethyl)-4- piperidinyl3-methanone HCl. A solution of l-bromo-3,4dichlorobenzene (10.0 g, 44.2 mmol) in dry THF (50 ml) was added under N2 to an oven dried 1 L round bottom flask containing Mg turnings (1.2 g, 49.4 mmol) and a crystal of I2 covered with dry THF (50 ml) at a rate such that the THF gently refluxed once the reaction had commenced. After the addition was completed the mixture was stirred for 1 h at room temperature. At this time the Grignard solution was diluted to 500 ml with dry THF and 4-cyano-l (2-phenylethyl)piperidine (9.5 g, 44.2 mmol) in dry THF (50 ml) was added over a period of 15 min. Dry toluene (250 ml) was added and the mixture refluxed while THF was distilled off until a reaction temperature of 80aS was reached. The mixture was refluxed at this temperature overnight (16 h). It was then cooled in an ice bath and 1N H2S04 (200 ml) was added dropwise with vigorous stirring. When this addition was completed, the mixture was warmed to room temperature and stirred an additional 3 h. The aqueous phase was separated and washed twice more with toluene (200 ml), basified with aqueous 2N NaOH and extracted with Et20 (3 X 200 ml). The extract was washed with saturated aqueous NaCl (1 X 250 ml), dried (MgSO4), filtered and evaporated to give an orange solid. This solid was flashed chromatographed on silica gel using 20% acetonedichloromethane as eluent and the resultant product triturated with Et20 to give a light orange solid. The hydrochloride salt was prepared by adding the free base to a cold methanol solution containing one equivalent of HCl. This solution was evaporated to dryness and the residue recrystallized from methanol-butanone to give a white solid, mp 238-2420C with decomposition. Step B: To a solution of (3,4-dichlorophenyl)tl-(2 phenylethyl)-4-piperdinyl)-methanone (1.9 g, 5.2 mmol) in methanol (50 ml) cooled in an ice bath was added portionwise sodium borohydride (0.6 g, 15.9 mmol), The reaction was allowed to warm to room temperature and stirred an additional 4 h. The mixture was evaporated and the residue stirred in Et20, washed with H20 (3 X 100 ml), saturated aqueous NaCl (1 X 100 ml), dried (MgSO4), filtered and evaporated to give a white solid. The hydrochloride salt was prepared by adding the free base to a cold methanol solution containing one equivalent of HC1. This solution was evaporated to give a pale yellow foam which crystallized from a vigorously stirred acetone-hexane solution. Recrystallization from methanol-butanone gave a white solid, mp 161-1640C. In a similar manner, by substantially following the teachings of the foregoing examples substituting the appropriate reactants there may be produced the following compounds. (4-fluorophenyl) [1-(2-phenethyl)-4-piperidinyl]methanol. Alpha-phenyl-[-1(4-Phenylbutyl)-4 piperidinyl3metbanol, Alpha-(3,4-dimethoxyphenyl)tl-(2-Phenylethyl)-4- piperidinyl]methanol, Alpha-phenyl[l-(4-aminophenylethyl)-4-piperidinyl methanol, Alpha-phenyl[l-(4-methoxyphenylethyl)]-4-piperidinyl methanol, Alpha-(4-methoxyphenyl) - !l- (4-methoxyphenylethyl) 3-4- piperidinyl methanol, Alpha-(2,3-dimethoxyphenyl)-[1-(4- methoxyphenylethyl)]-4-piperidinyl methanol, Alpha-phenylEl- (4-methylphenylethyl3-4-piperidinyl methanol, Alpha-phenyl[1-(4-fluorophenylethyl)]-4-piperidinyl methanol, Alpha-(4-hydroxyphenyl)-[1-(2-phenylethyl)-4- piperidinyl methanol, Alpha-(3,4 -dihydroxyphenyl)-11-(2-phenylethyll-4- piperidinyl methanol, The compounds of this invention have very interesting biochemical and pharmacological activities. The compounos (I) are potent and selective serotonin antagonists in that, at relatively low doses, they inhibit the binding v;f serotonin at the 5HT2 receptor sites with little, if any, inhibition of the binding of serotonin at the 5HT1 receptor sites. Further, since it has been reported that the receptor subserving the serotonin vasoconstriction is of the 5ST2 subtype, the serotonin antagonism at the SBTp receptor sites of the compounds of this invention will also be useful in the treatment of such serotonin-mediatx disease states as anorexia nervosa, variant angina, Raynaud's phenomena and coronary vasospasms and in the prophylactic treatment of migraine. Using standard laboratory in vitro and in vivo methodology, either alone or in comparison studies with known serotonin antagonists, it is readily seen that the compounds of this invention are potent serotonin antag- onists at the 5HT2 receptor sites with virtually no act) ivity at the 5HT1, adrenergic alpha-l, dopamine D-2 or muscarinic cholinergic receptors. By contrast with sucb: well-known agents as ketanserin, methysergide and cyproheptadine such selectivity is, indeed, unique. For example, utilizing anesthetized ganglion-block dog to assess alpha-adrenergic and sertoninergic blockad, it is to be found that the compounds of this invention antagonize the effects of a serotonin challenge in vivc (i.e., eliminated the pressor response to serotonin) afc had no effect on the phenylephrine in vivo challenge t)L demonstrating in vivo antagonism of the vascular effect of serotonin which is accompanied with little, if any alpha-adrenergic receptor blocking activity. Ketanse on the other hand will block both. As with both ketanserin and cyproheptadine, the compounds of this invention were effective in blocking the effects of serotonin as measured in the standard 5hydroxytryptophan-induced ahead twitchs in vivo (mice) laboratory model. Further, contrary to findings with ketanserin, it is to be found that compounds of'this invention have no significant antihypetensive activity in conscious spontaneously hypertensive rats (SER). However, in anesthetized spontaneously hypertensive rats, compounds of this invention produce a marked decrease in systolic blood pressure. In summary, based on comparative studies it is expected that in view of their selectivity in exerting potent anti-serotonin effects, the compounds of this invention will exhibit an improved pharmacologically active profile over that exhibited by ketanserin (a compound being clinically evaluated for use in the treatment of cardiovascular diseases, e.g. hypertension, peripheral vascular disease, thrombotic episodes and cardiopulmonary emergencies) for, although a potent SHT2 antagonist, it is non-selective in that it blocks H-l and alpha-l adrenergic receptors. Similarly, because of their numerous side effects the marketed serotonin antagonists methysergide and cyproheptadine have a less desirable pharnacological profile than that possessed by the compounds of this invention. In addition, the compounds of this invention exhibit topical anesthetic activity similar in effect to that of procaine, and they also exhibit an analgesic effect in the standard acetic-acid-induced writhing test. The compounds (I) exert their serotonin antagonistinduced pharmacological activities at 1-10 mg/kg when parenterally administered and at 0.1-3 mp/kg when intravenously administered. On comparative bases it is expected that the compounds of this will exert their end-use therapeutic effects at 30-600 mg per day (on 70 kg body weight), this amount being administered in divided doses. In each specific instance, depending on the severity and type of disease state, the attending diagnostician will readily be able to determine the dosage and its frequency of administration. Further, the compounds of this invention also exhibit significant anti-fibrillatory effects when tested according to standard laboratory techniques, said techniques being useful in the determination of antiarrythmic properties. Thus, the compounds particularly, alpha-phenyl-l- (2-phenethyl) -4-piperidinemethanol (and its salts), are useful in the prevention and/or treatment of ventricular fibrillatory aberrations due to acute myocardial ischemia. Other arrhythmic conditions comtemplated include ventricular tachycardia, atrioventricular nodal beats, auricular flutter, auricular fibrillation and premature ventricular contractions. The compounds of this invention exert their antiarrythmic pharmacological activities at 1-100 mg/kg when enterally administered and at 0.1-10 mg/kg when administered intravenously. The compounds of this invention, as defined by Formula I, can be administered as such, or can be administered in the 9orm of a composition. comprising the active ingredient and any of the commonly used pharmaceutical carriers. These carrier-s must be compatible with the active ingredient, and can be either solid or liquid, therapeutically active or insert. By using such carriers, one can make these compositions in the form of tablets, capsules, powders, suppositories, oral suspensions, or syrups. The compositions can also be made in the form of sterile solutions which are suitable for injection. The compositions will contain from 1% to 95% by weight of active compound, and from 5% to 99% by weight of a suitable pharmaceutical carrier. These ranges, however-, are not critical and can be varied as desired according to the circumstances. A sterile solution suitable for injection is prepare -by admixing from 0.5 to 5 parts by weight of theaactive ingredient, preferably in the form of its salt, and from 95 to 99.5 parts by weight of water or isotonic saline solution at a temperature and for time sufficient to dissolve the active ingredient. This solution is then sterilized by filtration or by the appLication of heat. These injectable solutions can be prepared with a high concentration of active ingredient. The solution is then diluted to a desired concentration before it is used. The compounds of Formula I can also be administered in the form of hard or soft gelatin capsules. These capsules are filled with the proper amount of active ingredient and solid filler, such as starch, gelatin, lactose, talc, stearic acid, or magnesium stearate. Such a capsule can contain from 5 to 50 milligrams of active material, thus providing a minimum dose of active ingredient in a form convenient for oral administration. The compounds of Formula I, when mixed with a suitable carrier, can also be formulated as tablets. Such carriers must be compatible with the active ingredient and can be the carriers mentioned for use with capsules, or can be such binders or fillers as cornstarch, acacia, gelatin, or cellulosic materials. Generally, any of the tableting materials conventionally used in pharmaceutical practice can be employed if there is no incompatibility with the active ingredient. The tablets are made by admixing the active ingredient, a suitable filler, a lubricant or mold-release agent, and a binder, and compressing the mixture in a conventional tableting machine into tablets of a preselected size. Preferably, each tablet will contain from 5 to 50 milligrams of active ingredient. The tablet can be scored so that they are easily broken. Optionally, the tablets can be coated with tablet-coating materials in order to make them more attractive and palatable. They can also have enteric coatings so that they will release their ingredients slowly and over a longer period. The pharmaceutical carrier in such suspensions or syrups can be an aqueous vehicle such as an aromatic water, a syrup, or a pharmaceutical mucilage. Suitable aromatic waters include the following: Anise Water, N.F. (IX); Bitter Almond Water, N.F. (VIII); Camphor Water, N.F.; Cinnamon Water, U.S.P.; Fennel Water, N.F.; Pepper mint Water, U.S.P.. Spearmint Water, N.F. (IK); Wintergreen Water, N.F. (IX). Suitable syrups include the following: Syrup (Simple Syrup), U.S.P.; Acacia Syrup, U.S.P.; Aromatic Eriodictyon Syrup, N.F.; Aromatic Rhubarb Syrup, N.F. (IX); Cacao Syrup, U.S.P.; Cherry Syrup, U.S.P.; Cinnamon Syrup, N.F. liy); Citric Acid Syrup, U.S.P.; Compound Sarsparilla Syrup, N.F.; Compound White Pine Syrup, N.F.; Ginger Syrup, N.F. (IX); Glycyrrhiza (Licorice) Syrup, U.S.P.; Orange Syrup, U.S.P.; Orange Flower Syrup, N.F.; Raspberry Syrup, U.S.P.; Rhubarb Syrup, N.F. (IX); Tolu Balsam Syrup, tJ.s.p.; Wild Cherry Syrup, U.S.P. Suitable pharmaceutical mucilages include the following: Acacia (Gum Arabic), U.S.P.; Acacia Mucilage, U.S.P.; Tragacanth, U.S.P.; Tragacanth Mucilage, N.F. The pharmaceutical carrier in the suspensions or syrups can also be a hydroalcoholic vehicle, such as an elixir. Suitable elixirs include the following: Aromatic Elixir, U.S.P.; Red Aromatic Elixir, N.F.; Glycyrrhiza Elixir, N.F.; Iso-Alcoholic Elixir (Iso-Elixir), N.F. Coloring agents, tinctures, spirits and other adjuvants can be admixed with the composition if desired. Typical formulations incorporating the compounds of Formula I are described below. These formulations are intended to be illustrative merely and no limitation is implied or intended. TABLET FORMULATION Formula Grams per 1000 tablets Active Ingredient* 20.0 Lactose 270.0 Dicalcium phosphate, hydrous 122.5 Polyvinylpyrrolidone 25.0 Polyvinylglycol 1500 7.5 Corn starch 50.0 Magnesium stearate 5.0 500.0 *Title compound of example 1 Mix the active ingredient , the lactose and the dicalcium phosphate. Dissolve the polyethylene glycol 1500 and the polyvinylpyrrolidone in approximattely 20 ml of water. Granulate the powder blend with the water solution, adding additional water if necessary, to produce a damp mass. Pass the wet granulation through a 12 mesh screen; spread on trays and air dry at 350C. Blend the dry granules with the starch and the magnesium stearate. Compress into 500 mg tablets. CAPSULE FORMULATION Formula Grams per 1000 capsules Active Ingredient* 20.0 Lactose 378.0 Magnesium stearate 2.0 400.0 *Title compound of example 1 Blend the ingredients and fill into hard gelatin capsules. ELIXIR FORMULATION Formula Grams per 1000 liters Active Ingredient* 40.0 Sugar do 500.0 Glycerin do 200.0 Compound orange spirit ml 10.0 Alcohol ml 100.0 Amaranth ml 0.1 Water, q.s. 1000.0 ml. *Title compound of example 1 Dissolve the active ingredient, the sugar, the glycerin and the ammranth successively in approximately 400 ml of water with the aid of heat. Cool the solution to room temperature. Dissolve the compound orange spirit in the alcohol and add the alcoholic solution to the elixir base. Add sufficient water to make the product measure 1000 ml and agitated until homogeneous. Clarify the elixir by passing it through an asbestos pad, using a filter aid if necessary. INJECTION FORMULATION Formula Grams per 1000 ampuls Active Ingredient* 110.0 Water for injection, q.s. 1100.0 ml. *Title compound of example 1 Dissolve the active ingredient in the water for injection. Pass the solution through a sterile 0.45 micron membrance filter. Fill asceptically into ampuls (1.1 ml per ampul). Autoclave the sealed ampuls for 30 minutes under 20 p.s.i.g. stream pressure. In order to achieve a satisfactory response, usually no more than 1 to 3 tablets or capsules as described above need be administered daily. The elixir described is usually administered in the amount of 1 to 3 teaspoons (5 cc.) per day while the usual injection dosage is 1 to 3 cc. per day. In severe or aggravated conditions, additional medicine may be administered. As is true for most classes of compounds useful as therapeutic agents not all members have the same biological profile. In the present instance, on the basis of in vitro and in vivo studies, particularly when compared with prior art compounds, it is to be that when those compounds of Formula I wherein n is 2 such compounds are most preferred. When the R and R1 groups of the phenalkyl moiety attached directly to the nitrogen atom of the piperidinal moiety are hydrogen and such compounds are preferred. Preferred substituents on the over phenyl moiety are 4-methoxy, 4-methyl, 3-trifluomethyl, 3,4dichloro, 3,4-dimethoxy, 3,5-dimethyl and most preferred is when all R groups are hydrogen. Preferred specific compounds are: alpha-phenyl-l-(2-phenethyl)-4-piperidine methanol, alpha-phenyl-l- (3-phenpropyl) -4-piperidine methanol, alpha- (4-methylphenyl) -1- (2-phenethyl) -4-piperidine methanol, alpha-(4-methoxyphenyl)-1-(2-phenethyl)-4-piperidine methanol, alpha-(3,5 dimethylphenyl)-1-(2-phenethyl)-4-piperidine methanol, alpha- (3- (trifluoromethyl)phenyl) -1- (2-phenethyl) -4- piperidine methanol, alpha- (2, 3-dimethoxyphenyl) -1- (2-phenethyl) -4-piperidine methanol, the first and last named compounds being most preferred.

Claims: C 1 a i m s 1. A compound of the general formula (I), EMI34.1 the optical isomers thereof and the pharmaceutically acceptable salts thereof wherein n is 2, 3 or 4, each of R1,R2,R3,R4 independently is hydrogen, halogen, trifluormethyl, C16 alkyl, C16 alkoxy, hydroxy or amino. 2. A compound of claim I wherein n is 2. 3. A compound of claim 1 wherein n is 3. 4. A compound of claim 1 wherein R3 and R4 are hydrogen. 5. A compound of claim 4 wherein R1 and R2 are hydrogen. 6. A compound of claim 1 wherein R1 and R2 are methoxy and R3 and R4 are hydrogen. 7. A compound of claim 1 wherein R1 is methoxy and each of R2, R3 and R4 is hydrogen. 8. A compound of claim 1 wherein R1 and R2 are halogen and R3 and R4 is hydrogen. 9. A compound of claim 1 wherein R is methyl and R2, R3, R4 are hydrogen. 10. The process for preparing a compound of the general formula (I) according to claim 1 which comprises A) the chemical reduction of a compound of the formula EMI35.1 B) the alkylation of a compound of the formula EMI35.2 with a reactive derivative having the formula EMI36.1 therein X is a reactive moiety, preferably a halide, tosylate, mesylate or a functional equivalent thereof, or (C) the reaction of a.Grinard reagent V with an aldehyde of the formula VI EMI36.2 -and hydrolyzing the reaction product, wherein R1 to R4 and n are defined as in claim 1. 11. The process for preparing a compound of formula EMI37.1 which comprises A) tne chemical reduction of a compound o± the EMI37.2 B) the alkylation of the compound of formula IX EMI37.3 with an alkylating agent of the formula X EMI38.1 wherein the X-substituent is G halide, tosylate, mesyate or a functional ecuivalent thereof, and (C) the reaction of a Grignard reagent XI with an aldehyde of the formulae XII EMI38.2 and hydrolyzing the reaction product. 12. A compound of the general formula I according to any of claims 1 to 9 for use as a therapeutical agent. 13. A compound of the general formula I according to any of claims 1 to 9 for use in prophylactically treating migraine. 14. A compound of the general formula I according to any of claims 1 to 9 for use in treating Raymand's phenomenon. 15. A compound of the general formula I according to any of claims 1 to 9 for use in treating variant angina. 16. A compound of the general formula I according to any of claims 1 to 9 for use in treating cardiac arrhythmias. 17. Pharmaceutical composition comprising a compound of the general formula I according to any of claims 1 to 9 and usual carriers and/or additives.

Inventors: CARR, ALBERT A., WIECH, NORBERT L.
Applicants: MERRELL DOW PHARMACEUTICALS INC.
Application year: 1986
Main classification: C07D211
IPC codes: A61P3, A61P43, C07D211, A61P9, A61K31, A61P25