MXPA97008612A - Derivatives of alpha- (alkylphenyl replaced) -4- (hydroxydyphenyl methyl) -1-piperidinbutanol, its preparation and its use as antihistamines, antialergic agents, and broncodilated - Google Patents

Abstract

This invention relates to novel substituted piperidine derivatives. More particularly, this invention relates to 4-substituted phenyl-substituted piperidinoalkanol derivatives of the formula (I), wherein R 1 is -CH 3, -CH 2 OH, -COOH, or -COO-alkyl (from 1 to 6) carbon), and A is hydrogen or hydroxy, to the stereoisomers, enantiomers, racemic mixtures thereof, or pharmaceutically acceptable salts thereof, which are useful as antihistamines, antiallergic agents, and bronchodilator

Description

ALPHA- DERIVATIVES (SUBSTITUTED ALKYLPHENYL) -4- (HYDROXIDIPHENYL ETHYL) -1-PIPERIDI BÜTANOL. YOUR PREPARATION AND YOUR US CQMQ AWTglSTAMiyAg, AgEWT g AffTIALERg CQS, AND BRONCODILATADORES BACKGROUND OF THE INVENTION This invention relates to novel piperidine diphenylmetyl derivatives. More particularly, this invention relates to 4-diphenylmethylpiperi-dinbutanol derivatives useful as antihistamines, antiallergic agents, and bronchodilators.

COMPENDIUM OF THE INVENTION More specifically, this invention relates to compounds of the formula (I): Formula (I) wherein Ri is -CH3, -CH2OH, -COOH or -COO-alkyl (of the ß carbon atoms), - A is hydrogen or hydroxy, the stereoisomers, enantiomers, racemic mixtures thereof, or the pharmaceutically acceptable salts of the same. The present invention further provides a method for the treatment of allergic reactions in a patient in need, which comprises administering to this patient an effective antiallergic or antihistaminic amount of the compound of the formula (I). As used herein, in this application: (a) the term "alkyl" means a univalent radical (-R). It includes straight and branched chain saturated aliphatic hydrocarbon fractions, which have the indicated number of carbon atoms. For example, the term "C 1-6 -alkyl" refers to a saturated straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms, preferably having 1 to 4 carbon atoms ("alkyl of 1 to 4 carbon atoms"), and more preferably having 1 to 3 carbon atoms ("alkyl of 1 to 3 carbon atoms"). Within the scope of this term, include methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, and the like; (b) the designation -C (0) or -CO- refers to a carbonyl group of the formula: The term -COOR includes those alkoxycarbonyl moieties wherein R is H or an alkyl moiety of 6 carbon atoms, or preferably an alkyl moiety of 1 to 3 carbon atoms, encompassing, for example, methoxycarbonyl, ethoxycarbonyl , tertiary butyloxycarbonyl, and the like. It is also understood that an alkoxycarbonyl wherein R is different from H, is also referred to as an ester; (c) piperidino refers to a compound of the formula: (d) the term "halo" refers to a halogen, such as a fluorine atom, a chlorine atom, or a bromine atom, or an iodine atom. The term "pharmaceutically acceptable salts" includes those acid addition salts derived by reaction with acids, for example, hydrochloric, hydrobromic, sulfuric, nitric, or phosphoric acids, and organic carboxylic acids such as acetic, propionic, glycolic, maleic acids , tartaric, citric, salicylic, 2-acetyloxybenzoic, or organic sulfonic acids such as methanesulfonic, 4-toluenesulfonic, and naphthalenesulfonic acids. Of course, other acids well known in the pharmaceutical art can also be used. The term "pharmaceutically acceptable salts" may also include hydrates. The stereoisomers of the compounds of the formula (I) are a general term for all isomers of these compounds that differ only in the orientation of their atoms in space. They include geometric isomers. { cis / trans), and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers or diastereoisomers). The term "enantiomer" refers to two stereoisomers that are mirror images of one another, and are not identical, and can not be superimposed. The term "chiral center" refers to a carbon atom to which four different groups are attached. The R / S nomenclature is used in IUPAC-IUB Joint Commission on Biochemical Nomenclature, Eur. J. Biochem. 138: 9-37 (1984). A chiral material can contain an equal amount of the R and S isomers, in which case it is called "radicle mixture", or it may not contain equal amounts of R and S isomers, in which case it is called "optically active" or "non-racemic mixture". A mixture can be resolved or isolated according to standard procedures and standards well known in the art, for example, chromatographic separation on chiral stationary phase, use of optically active esters, and fractional crystallization of addition salts formed by reagents used for that purpose. purpose, as described in "Enantiomers, Racemates, and resolutions", J. Jacques, A. Collet, and SH ilen, Wiley (1981), enzymatic resolution, and the like. The resolution of stereoisomers is carried out on the intermediates, or the final products of the formula (I). The term "resolution" means the separation of racemic mixture into its optically active components. In addition, the enantiomers can be prepared by the use of enantioselective or asymmetric synthesis, which is well known to a person of ordinary experience in this field. The term "enantioselective" or "asymmetric" means the ability to produce a product in an optically active form. It is understood that the compounds of the formula (I) can exist in a variety of stereoisomeric configurations. It is further understood that the compounds of the present invention encompass those compounds of the formula (I) in each of its different structural and stereoisomeric configurations as individual isomers or as mixtures of isomers.

The compounds of this invention are prepared by different means, and certain compounds of the invention are used to prepare other compounds of the invention. The compounds of formula (I) can be synthesized by one of ordinary skill in the art, employing the procedures as described more fully in the following US Pat. No. 4,254,129 issued March 3, 1981, and US Pat. United States of America Number 4,254,130 issued March 3, 1981, which are incorporated herein by reference. Carr and Kinsolving disclose different piperidinoalkanol alpha-aryl-4-substituted derivatives in Offenlegungsschrift 2,303,306, which are useful as antihistaminic agents, anti-allergic agents, and bronchodilators. RC Krauss et al. Disclose novel intermediates for the preparation of anti-histamine 4-diphenylmetidiphenylmethoxypiperidine derivative in international publication number WO 95/00480 published on January 5, 1995. In addition, E. Molinari discloses a process for the preparation of alpha- (alkylphenyl) -4- (hydroxydiphenylmethyl) -1-piperidinebutanol in European Patent Specification No. 0,292,735 Bl, published August 19, 1992.

SCHEME 1 Step A: Friedel Crafts Acylation; Step B: Alkylation; Step C: Reduction SCHEME X In general, the compounds of the formula I, wherein Rt is -CH 3, -COOH, or -COO- (alkyl of 1 to 6 carbon atoms), can be synthesized following the general scheme l.

Step A The α -halophenylbutanone derivative of structure (3), wherein Z is hydrogen, hydroxy, or a protected hydroxy, can be prepared by the reaction of an appropriate phenyl derivative of the formula (2), wherein Z is hydrogen, hydroxy, or a protected hydroxy, with an appropriate α-halogen compound of the structure (6) halo- (CH 2) 3-C (= 0) -B, wherein B is halogen or hydroxy, halogen is Cl , Br, or I, which is known in the art or prepared by methods well known in the art, under the general conditions of a Friedel Crafts acylation as disclosed in Methoden der Organischen Chemie (Houden-Weyl, VII / 2a Teil I, 1973); or in Friedel-Crafts and related reactions (Interscience, New York, 1963-1964), which are incorporated herein by reference. The reaction is most commonly performed in a solvent such as methylene chloride, dichloroethane, tetrachloroethane, chlorobenzene, nitromethane, 1-nitropropane, diethyl ether, acetonitrile, normal hexane or carbon disulfide, or without a solvent, in the presence of an acid of Lewis, such as ferric chloride, iodine, zinc chloride, aluminum chloride, and iron. More preferably, the reaction is carried out using methylene chloride as the solvent, and aluminum chloride or ferric chloride as the catalyst. The reaction time varies from half an hour to 25 hours, preferably from 4 to 10 hours, and the reaction temperature varies from -15 ° C to 100 ° C, preferably from -10 ° C to 20 ° C. The corresponding β -halophenylbutanone derivative of structure (3) is recovered from the reaction zone by an aqueous quench followed by extraction as known in this field. The β -halophenylbutanone derivative of structure (3) can be purified by procedures well known in the art, such as crystallization and / or distillation.

Step B The diphenylmethylpiperidinoxobutyl derivative of the formula (5) is obtained by the alkylation of 4- (o-, or? -dipheniDpiperidinemethanol) of the formula (4) with a? -haloalkylphenylbutanone derivative of the formula (3), where halogen is Cl, Br, or I, and Z is hydrogen or hydroxy, or protected hydroxy as described in U.S. Patent No. 4,254,130. The alkylation reaction is carried out in a suitable solvent, preferably in the presence of a suitable non-nucleophilic base, and optionally in the presence of a catalytic amount of an iodine source, such as potassium or sodium iodide. The reaction time varies from about 4 to 120 hours, and the reaction temperature ranges from about 40 ° C to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents, such as methanol, ethanol, isopropyl alcohol, or normal butanol; ketone solvents, such as cyclohexanone, methyl isobutyl ketone, hydrocarbon solvents, such as benzene, toluene, or xylenes; halogenated hydrocarbons, such as chlorobenzene or methylene chloride or dimethyl formamide. More preferably a mixture of water and hydrocarbon solvents, such as xylenes, is used. Non-nucleophilic bases suitable for the alkylation reaction include inorganic bases, for example sodium bicarbonate, potassium carbonate, or potassium bicarbonate, or organic bases such as a trialkylene amine, for example triethyl amine or pyridine, or a excess of 4- (a, a-difeniDpiperidinmethanol of the formula (4).) The desired compound of the formula (I) can be prepared in one step by reducing the ketone (5) thus produced, or in two steps, by reduction of the ketone (5), followed by hydrolysis with base, or in two steps by hydrolysis with base followed by reduction of the ketone (5), depending on the desired compound and the reducing agent employed, as disclosed in the Patent of the States United States of America Number 4,285,957. For example, the reduction of the appropriate diphenylmethylpiperidinoxobutyl derivative of structure (5), wherein Rj is -CH3 or -COO- (alkyl of 1 to 6 carbon atoms), using, for example, a suitable reducing agent, such As sodium borohydride, potassium borohydride, sodium cyanoborohydride, or tetramethyl ammonium borohydride, it is carried out in lower alcohol solvents, such as methanol, ethanol, isopropyl alcohol, or normal butanol, or in aqueous solutions of lower alcohol, at temperatures from about 0 ° C to the reflux temperature of the solvent, and the reaction time varies from about one-half hour to eight hours. Preferably, the reaction is carried out using sodium borohydride or potassium borohydride as reducing agent, in the presence of sodium hydroxide in an aqueous solution of alcohol, such as methanol or ethanol. Other suitable reducing agents are, for example, tertiary tributyl aluminum hydride and lithium, and diisobutyl aluminum hydride. These reduction reactions are carried out in suitable solvents such as diethyl ether, tetrahydrofuran, or dioxane, at temperatures of about 0 ° C to the reflux temperature of the solvent, and the reaction time varies from about one-half hour to eight hours.

Catalytic reduction can also be used in the preparation of the appropriate diphenylmethylpiperidine derivative of structure (I), where Ri is -CH 3 or -COO- (C 1-6 alkyl), from an appropriate diphenylmethylmethylpiperidinoxobutyl derivative of structure (5), wherein Rj is -CH 3 or -COO- (C 1-6 alkyl), using hydrogen gas in the presence of a suitable catalyst such as Raney nickel, palladium catalysts, platinum, or rhodium, in lower alcohol solvents, such as methanol, ethanol, isopropyl alcohol, or normal butanol, or acetic acid, or their aqueous mixtures, or by the use of aluminum isopropoxide in isopropyl alcohol. Reduction is preferred using sodium borohydride or potassium borohydride over the catalytic reduction for the diphenylmethylpiperidine derivatives of the structure (I) wherein Rj is -CH3 or -COO- (alkyl of 1 to 6 carbon atoms). In addition, a chiral reduction of the appropriate diphenylmethylpiperidinoxobutyl derivative of structure (5), wherein Ri is -CH 3 or -COO- (alkyl of 1 to 6 carbon atoms). Using, for example, (+) or (-) - B-chlorodiisopinocanphenylborane gives the corresponding (R) or (S) -diphenylmethylpiperidine derivative of structure (I), where Rt is -CH 3 or -COO- ( 1 to 6 carbon atoms). Other suitable chiral reduction agents are, (R) - and (S) -oxazaborolidine / BH3, 9-0- (1, 2: 5, 6-di-0-isopropylidene-aD-glucofuranosyl) -9-boratabicyclo [3.3 .1] - potassium nonane, (R) and (S) -B-3-pinanyl-9-borabicyclo [3.3.l] nonane, NB-enantride, aluminum hydride (R) - (+) - and (S ) - (-) -2,2 '-dihydroxy-1,1' -bubylathylalcoxylic acid, complex of (R) - (+) - and (S) - (-) -2, 2'-dihydroxy-6, 6'-dimethylbiphenylborane-amine, aluminum tris [[(1S, 2S, 5R) -2-isopropyl-5-methyl-cyclohex-1-yl] methyl], chloride [[(IR, 3R) -2, 2- dimethylbicyclo [2.2.1] -hep-3-yl] methyl] beryllium, complex of (R) -BINAP-ruthenium / H2, and 6,6 '-bis (diphenylphosphino) -3,3'-dimethoxy-2, 2 ', 4,4'-tetramethyl-1, 1' -biphenyl. The compounds wherein Rj is -COO- (alkyl of 1 to 6 carbon atoms) can be hydrolyzed by treatment with an inorganic base, to give the corresponding diphenylmethylpiperidine derivative of the formula (I), wherein Rj is -COOH . For example, hydrolysis can be achieved by using a suitable non-nucleophilic base such as sodium methoxide in methanol, as is known in this field. Other methods known in the art for ester dissociation include potassium carbonate in methanol, methanolic ammonia, potassium carbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium hydroxide / pyridine in methanol, potassium cyanide in methanol, and sodium hydroxide in aqueous alcohols, with preference being given to potassium hydroxide. The reaction is typically carried out in an aqueous lower alcohol solvent, such as methanol, ethanol, isopropyl alcohol, normal butanol, 2-ethoxyethanol, or ethylene glycol or pyridine, at temperatures from room temperature to the reflux temperature of the solvent, and the reaction time varies from about half an hour to 100 hours. The diphenylmethylpiperidine derivative of the formula (I), wherein Rj is -CH2OH, can be prepared by reducing the corresponding derivative wherein Rj is -COOH or -COO- (alkyl of 1 to 6 carbon atoms). For example, the reduction of the appropriate diphenylmethylpiperidinoxobutyl derivative of structure (5), wherein R i is -CH 2 OH, using, for example, a suitable reducing agent, such as lithium aluminum hydride or diborane, is carried out in solvents of ether such as, for example, diethyl ether, tetrahydrofuran, or dioxane, at temperatures from about 0 ° C to the reflux temperature of the solvent, and the reaction time varies from about one-half hour to eight hours. In addition, the individual (R) and (S) isomers of the diphenylmethylpiperidine derivative of the formula (I) can be prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art.

For example, the mixture of (R) and (S) isomers of the diphenylmethylpiperidine derivative of the formula (I) can be subjected to chiral chromatography to give the corresponding individual (R) -diphenylmethylpiperidine derivative of the formula (I), and the (S) -diphenylmethylpiperidine derivative of the formula (I). In addition, the individual (R) and (S) isomers of the diphenylmethylpiperidinoxobutyl derivative of the formula (5), and the diphenylmethylpiperidine derivative of the formula (I), can be prepared by techniques and procedures well known and appreciated by an expert ordinary in this field, and described in "Enantiomers, Racemates, and Resolutions", Jacques, Collet and Wilen, Wiley (1981). One of these methods involves reacting the mixture of isomers (R) and (S) of the diphenylmethylpiperidine derivative of the formula (I), with appropriate chiral acids, to give the corresponding mixture of diastereomeric acid addition salts. The individual (R) -acid addition salts of the diphenylmethylpiperidine compound of structure (I), and the (S) -cyclic acid addition salts of the diphenylmethylpiperidine compound of structure (I), are obtained by recrystallization , and the individual chiral (R) -diphenylmethylpiperidine compound of structure (I), and the chiral diphenylmethylpiperidine compound of structure (I), are obtained by subjecting the individual acid addition salts (R) -quirals of the compound of diphenylmethylpiperidine of structure (I), and of the (S) -cyclic acid addition salts of the diphenylmethylpiperidine compound of structure (I), to a base, for the purpose of liberating the nitrogen of the piperidine from the addition of acid. Examples of suitable chiral acids are tartaric acid (+), (-), 0.0'-dibenzoyltartaric acid (+), (-), acid 0,0 '-di-p-toluyltartaric acid (+), (-) , 2-nitrotartranilic acid (+), (-), mandelic acid (+), (-), malic acid (+), (-), 2-phenoxypropionic acid (+), hydratropic acid (+), (-) , N-acetylic (-), (+), succinamide N- (α-methylbenzyl) (+), (-), N- (QÍ-methylbenzyl) -phthalamic acid (+), (-), camphoric acid 10-sulphonic (+), 3-bromo-camphor-9-sulfonic acid (+), (-), camphor-3-sulfonic acid (+), quinic acid (+), (-), di-0- acid isopropylidene-2-oxo-L-gulonic (-), lasaloside (-), 1,1'-biphenyl-2, 2'-phosphonic acid (+), (-), cloestenonsulfonic acid. In addition, the individual (R) and (S) isomers of the diphenylmethylpiperidine derivative of the formula (I), can be prepared by reaction of the mixture of the (R) and (S) isomers of the diphenylmethylpiperidine derivative of the formula (I), with appropriate organic chiral acids, to give the corresponding mixture of diastereomeric acid esters. The individual chiral ester of the (R) -diphenylmethylpiperidine compound of structure (I), and the chiral ester of the (S) -diphenylmethylpiperidine compound of structure (I), are obtained by recrystallization or chromatography, and the compound of R) - chiral diphenylmethylpiperidine of the structure (I) and the chiral (S) -diphenylmethylpiperidine compound of the individual structure (I) are obtained by subjecting the chiral ester of the compound of (R) -diphenylmethylpiperidine of the structure (I), and the chiral ester of chiral (S) -diphenylmethylpiperidine compound of structure (I), under hydrolysis conditions. It is understood that each hydroxy group in the compounds described in this invention is optionally protected or unprotected. The selection and use of suitable protecting groups is well known to one of ordinary skill in the art, and is described in "Protective Groups In Organic Chemistry," Theodora W. Greene, Wiley (1981), which is incorporated herein by reference . For example, suitable protecting groups for the hydroxy functionalities present include ethers, such as methyl ether, cyclohexyl ether, isopropyl ether, tertiary butyl ether, or methoxymethyl ether, tetrahydropyran, tetrahydrothiofuranyl, 2-phenylethylethyl ester, o-nitrobenzyl ether, ether trimethylsilyl, tertiary butyl diphenylsilyl ether, tribencylsilyl ether, isopropyldimethylsilyl ether, tertiary butyl dimethyl silyl ether, tertiary butyl diphenylsilyl ether, tribenzylsilyl ether, triisopropylsilyl ether; and ester, such as acetate ester, levulinate ester (CH3COCH2CH2C02-), pivaloate ester ((CH3) 3CC02-), benzoate ester, 2, 4, 6-trimethylbenzoate ester (mesitoate), methyl carbonate, carbonate of p-nitrophenyl, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, and N-phenyl carbamate, phosphinates such dimethylphosphonic ester ((CH 3) 2 P (0) 0-), sulfonates such as methyl or mesyl sulfonate (- OS02CH3), or toluene or tosyl sulfonate (-0S02C6H-p-CH3). The 4- (a, c, -diphenyl) piperidinemethanol of structure (4) is readily available to one of ordinary skill in the art, and is described in U.S. Patent No. 4,254,129, March 3, 1981 , in the Patent of the United States of America Number 4,254,130, of March 3, 1981, in the Patent of the United States of America Number 4,285,958, of April 25, 1981, and in the Patent of the United States of North America Number 4,550,116, October 29, 1985. The derivatives of the formula (2) are commercially available, or are prepared by one of ordinary skill in the art. Alternatively, one of ordinary skill in the art can synthesize the compounds of the formula (I), by using the methods disclosed in the TCP application number W093 / 21156 published on October 28, 1993, or in the application of the TCP number WO95 / 00480 published on January 5, 1995, which are incorporated herein by reference. The following examples present typical syntheses as described in Scheme 1. It is understood that these examples are illustrative only, and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "ml" refers to milliliters; "pe" refers to boiling point, - "pf" refers to melting point; "° C" refers to degrees Celsius; "pa" refers to paséales; "μL" refers to microliters; "μg" refers to micrograms; and "μM" refers to micromolar; "TLC" refers to thin layer chromatography; "M" refers to molarity; "N" refers to normal; "[a] D20" refers to the specific rotation of the sodium D line at 20 ° C obtained in a 1 decimeter cell; "GC" refers to gas chromatography; "Rf" refers to retention factor, and "RPM" refers to revolutions per minute.

EXAMPLE 1 ACETATE OF 4- [4- C4- (HYDROXIDIPENOMETHYL METHYL) -1-PIPERIDINYL1 - 1-HYDROXY-BUTILl-TW-METHYLENE Step 1; ESTER OF ACID 2-PHENYLPROPIONIC ETHYL In a round bottom flask equipped with a condenser and a magnesium sulfate drying tube on top, 2-phenylpropionic acid (1.51 moles, 226 grams), concentrated sulfuric acid (3.32 grams, 0.033 moles), and absolute ethanol ( 1 liter) . The resulting solution is heated to reflux for 22.5 hours. The solution is concentrated under vacuum to obtain an oil (277 grams). One liter of fresh ethanol is added to the oil, and the resulting solution is heated to reflux for a further 19.6 hours. Sodium ethoxide (21 weight percent in ethanol, 30 milliliters) is added to the reaction at room temperature. Then glacial acetic acid (2 grams) is added in order to establish a slightly acidic pH. The solids are removed from the paste by filtration with suction. The filtrate is concentrated under vacuum on a rotary evaporator. Heptane (400 milliliters) is added to the residue, and this solution is concentrated in vacuo in order to separate the remaining traces of ethanol, to give ethyl 2-phenylpropionic acid ester as an oil (276.7 grams).

Step 2: 4- (4-CHLORO-l-OXOBUTIL) -TH-METHYLPHENYL ACETATE In a round bottom flask equipped with a condenser having a magnesium sulfate drying tube on top, aluminum chloride (458 grams, 3.44 moles) and methylene chloride (200 milliliters) are charged. The resulting paste is stirred at 250 RPM, and cooled to 2 ° C by means of an ice / water balloon. 4-Chlorobutyryl chloride (210 milliliters, 1.87 moles), and methylene chloride (20 milliliters) are added to the cold paste over a period of 40 minutes, to keep the temperature of the pulp below 15 ° C. The paste is again cooled to 2 ° C, and ethyl 2-phenylpropionic acid ester (276.7 grams, 1.55 moles) is added via an addition funnel over a period of 70 minutes, to keep the temperature of the solution below 15 ° C. ° C. Methylene chloride (100 milliliters) is added to rinse. The solution is allowed to warm to room temperature over a period of 80 minutes. The solution is heated from 22 ° C to 42 ° C for a period of 3.3 hours. Ice (1.5 kilograms) is placed in a 4 liter beaker. It is poured into this ice, with stirring, at about half the methylene reaction (500 milliliters). Stir for 10 minutes, and add a second volume of methylene chloride (100 milliliters). The aqueous organic solution is filtered by suction through a filter aid cushion onto a coarse sintered glass funnel. The organic and aqueous phases are separated, and the aqueous phase is extracted with methylene chloride (200 milliliters). Methylene chloride is added to the organic layer. The other half of the un-quenched methylene chloride solution is worked in a similar manner. Concentrate the combined organic layers under vacuum, up to 90 ° C to 25 mm Hg (3.33 kPa), to give a brown and solid oil (465.4 grams). Ethanol (300 milliliters) is added to the mixture. The resulting solution is placed in a round bottom flask, adapted with an overhead stirrer, a reflux condenser (with a drying tube on top), and a gas dispersion tube. Anhydrous hydrogen chloride (22.25 grams, 0.61 moles) is dispersed in the stirred solution. The solution is heated at 56 ° C, for a period of 3.75 hours with agitation. Sodium ethoxide (21 weight percent in absolute ethanol, 835 grams, 2.58 moles of sodium ethoxide) is added to the solution over a period of 100 minutes at 56 ° C. The resulting liquid / solid paste is heated for a period of 15 minutes at 52 ° C. The solution is cooled to less than 20 ° C by an ice / water bath. Glacial acetic acid (25.5 milliliters, 445 moles) is added to the paste (the pH of a diluted aliquot with an equal volume of water is 5.0 to 5.2). Heptane (250 milliliters) is added, and the paste is allowed to stand at room temperature overnight. It is filtered by suction through a filter auxiliary cushion on a thick sintered glass funnel. The filter cake is washed with absolute heptane / ethanol (400 milliliters, 2/1 (volume / volume)). The combined filtrate is concentrated and washed on a rotary evaporator up to 95 ° C at 110 mm Hg (14.3 kPa), to obtain a brown liquid and solid residues (433 grams). The residue is distilled by evaporation through a pump guard and a Claisen head without rectification at a vacuum of 1 mm Hg. The distillate is collected at temperatures above 40 to 175 ° C to obtain a light yellow oil (346.7 grams). The distillation vessel is discarded. The oil thus produced is purified as a mixture of 3- and 4- (cyclopropylcarbonyl) -o-methylphenyl ethyl acetate by distillation by vacuum evaporation through a 0.0254 meter (1 inch) internal diameter column, and a length of 1,346 meters (53 inches), packed with 316 High Goodloe stainless steel 773. The desired derivative of 4- (cyclopropylcarbonyl) -a-methylphenyl ethyl acetate (95.9 grams) is collected at temperatures above 146-147 ° C. Place 4- (cyclopropylcarbonyl) -a-methylphenyl ethyl acetate (73.89 grams, 0.300 moles), mixed xylenes (400 milliliters), and absolute ethanol (90 milliliters) in a round bottom flask fitted with an overhead paddle stirrer, a gas dispersion tube with the frit end, and a reflux condenser with a magnesium sulfate drying tube. Hydrogen chloride gas is dispersed from a reading bottle (36.68 grams, 1061 moles, 99 percent anhydrous) in the stirred solution over a period of 15 minutes. The gas dispersion tube is replaced with a glass stopper. The solution is heated with stirring, raising the temperature from 40 ° C to 79 ° C in 45 minutes. The temperature is maintained at 79 ° C for another 15 minutes. The reflux condenser is replaced with an adapted single still head with a condenser and a thermometer. It is distilled and collected at the higher temperature (80-138 ° C). The yellow solution is allowed to cool to room temperature, and the xylene solvents are removed by rotary evaporation to 75 ° C to 12 mm Hg (1.6 kPa), to leave the 4- (4-choromethyl) acetate. oxobutyl) -a-methylphenyl (87.4 grams) as a yellow solid.

Step 3: ACETATE OF 4- T4-T4- (HYDROXIDIPENOMMETIL) -1- PIPERIDINIL1 -1-OXOBÜTIL1-CL-METHYLPHENYL ETYLIC 4- (4-Chloro-1-oxobutyl) -a-methylphenyl ethyl acetate (7.6 grams, 26.9 mmol) is added to a solution of 4- (a, a-diphenyl) piperidinemethanol (15.8 grams, 59.0 mmol) in xylenes (27 milliliters), in a single-neck round-bottomed flask equipped with a water-cooled reflux condenser, and at the outlet, a drying tube filled with calcium sulfate. The reaction is stirred and heated at 140 ° C for 5.5 hours. The reaction is cooled in paste to room temperature, and xylenes (15 milliliters) are added. The reaction is heated in a paste diluted to 50 ° C, and glacial acetic acid (1.52 grams, 25.3 mmol) is added. The reaction is cooled to room temperature, and filtered by suction. The filter cake is washed with xylenes (25 milliliters), and the filter wash is added to the original filtrate. The filtrate is stirred at room temperature, and 37 percent aqueous hydrochloric acid (3.02 grams, 30.6 millimoles) is added over a period of 70 minutes, to provide a thick solid / liquid paste. Absolute 2B ethanol (3 milliliters) is added to the pulp, and the resulting paste is stirred for 10 minutes. The solids are collected by suction filtration, and the filter cake is washed with fresh xylenes (20 milliliters) and heptane (10 milliliters).

The filter cake is dried overnight in a vacuum oven at 47 ° C to obtain 11.05 grams of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -a-methylphenyl acetate. Ethyl crude as a light tan solid. The 4- (4-chloro-l-oxobutyl) -a-methylphenyl acetate thus produced is reduced following the procedure described in Example 4, step 3, to give 4- (4-chloro-l-hydroxybutyl) acetate. corresponding ethyl a-methylphenyl.

EXAMPLE 2 ACID 4 - T4 - T4 - (HYDROXYDYPHENYLMEETHYL) - 1-PIPERIDINYL1 - 1-HYDROXY-BUTYL-1-t-METHYLPHENYLACE 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -a-methylphenyl ethyl ester (6.00 grams, 10.5 mmol) is added to a solution of methanol (30 milliliters), aqueous sodium hydroxide. to 50 percent (4.30 grams, 53.8 millimoles), and water (3.5 grams). It is heated under reflux for 1.75 hours. Dissolve the solids that are formed by the addition of water (6 milliliters). The reaction is cooled to 41 ° C, and sodium borohydride (0.22 grams, 5.82 millirales) is added. The reaction is stirred at 40 ° C for 1.82 hours. Acetone (1.65 milliliters, 22.5 millimoles) is added to the solution, and stirred at 40 ° C for 0.5 hours, and overnight at room temperature. The solution is heated to 32 ° C, and 37 percent aqueous hydrochloric acid (6.66 grams, 67.6 millimoles) and 5 percent aqueous hydrochloric acid (7.10 grams, 9.7 millimoles) are added in order to reduce the pH of the solution. solution up to 2.0. Water (24 grams) is added, and the resulting solution is heated to 37 ° C. The solution is cooled slowly to -20 ° C, and the solids are collected by suction filtration. The filter cake is washed with cold water (10 milliliters), and dried at 52 ° C for 70 minutes under vacuum, to obtain 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1 acid hydrate. -oxobutyl] -a-methylphenylacetic acid as a white solid (5.85 grams). The hydrate thus produced is added (5.00 grams) to a solution of acetone (15 milliliters) and water (0.56 grams). The mixture is stirred at room temperature until almost all the solids dissolve. The solution is filtered through a filter aid by suction to obtain a clear solution, and rinsed with acetone (2 milliliters). Transfer the filtrate to a single neck round bottom flask using acetone (13 milliliters). It is stirred and heated under reflux. Ethyl acetate (30 milliliters) is added slowly to the solution which is refluxing, a second liquid phase appears after 12 milliliters of ethyl acetate have been added. The liquid / liquid mixture is stirred at room temperature overnight. The mixture is reheated for 1 hour at reflux, and cooled to 40 ° C. The supernatant solvent phase is removed with a pipette. Fresh acetone (30 milliliters) is added and the solution is heated under reflux. Ethyl acetate (30 milliliters) is added to the solution which is refluxing, for a period of 45 minutes. The solids are decomposed by means of a spatula. The resulting paste is heated under reflux for another hour, and then cooled to room temperature. The solid is collected by suction filtration, and the filter cake is washed with ethyl acetate (10 milliliters). Dry the filter cake in a vacuum oven at 55 ° C, and air-dry overnight to obtain 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a acid. anhydrous methylphenylacetic acid as a white solid (3.09 grams, 63 percent).

EXAMPLE 3 ALCOHOL 4- [4- [4- (HYDROXYDYPHENYLMEAMETHYL) -1-PIPERIDINYL1 - 1-HYDROXY-BUTIL1 -2-MET LFENETIL CO A suspension of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-methylphenylmethyl ester (4 mmol) in tetrahydrofuran (50 milliliters) is added slowly to a suspension of hydride. aluminum and lithium (18 mmol) in tetrahydrofuran (60 milliliters) under a nitrogen atmosphere with stirring. The mixture is stirred and heated under reflux for about 3 hours, and tetrahydrofuran (30 milliliters) is added. It is heated under reflux for 4 hours, and allowed to stand overnight (approximately 16 hours). The mixture is stirred under a nitrogen atmosphere, and water (2 milliliters) is added with caution, followed by an aqueous solution of sodium hydroxide (10 percent, 2 milliliters), water (2 milliliters), and sodium sulfate ( 4 grams). The mixture is heated to 50-55 ° C, and stirred for 45 minutes, filtered, and the solids and material are washed with tetrahydrofuran. The filtrates are combined and evaporated under vacuum. The residue is recrystallized from ethanol to give 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -2-methylphenethyl alcohol.

EJEJffl.QS i, 5, Y 5 ACETATE OF 4- t4- .4- (HYDROXIDIPHENYLMETHYL) -1-PIPERIDINYL-1-l-HYDROXY-BUTILl-tt-METHYL-3-HYDROXYPENYL, ACID 4- [4- T4- (HYDROXYDYPHENYLENE ) -1-PIPERID NILl -1- HIDRQX -BUTIL] - «- METIh-3-BIPRQXIFEKILACETICQr AND ALCOHOL 4- [4- t4- (HYDROXYDYPHENYLMETHYL) -1-PIPERIDINYL-1-HYDROXY-BUTIL] -2-METHYL-2- (3-HYDROXYPENYL) -ETHYLLIC Can be prepared by an ordinary expert in this field, following examples 1, 2, and 3 described above, but using 2- (3-hydroxyphenyl) propionic acid as the starting material, instead of 2-phenylpropionic acid. The hydroxy group can be protected, more preferably a methoxymethyl ether group is used. 2- (3-HYDROXYPENYL) PROPIONIC ACIDE One of ordinary skill in the art can prepare ethyl 2- (3-methoxyphenyl) propionic acetate, following the procedure described by Sedgeworth et al., In J. Chem. Soc. Per T 1 (12 ), 2677-2687 (1985), which is incorporated herein by reference. The ethyl 2- (3-methoxyphenyl) propionic ethyl ester is further deprotected, and hydrolyzed according to procedures well known in the art, disclosed in "Protective Groups In Organic Chemistry," which is incorporated herein by reference. reference.

EXAMPLE 7 4- C4- C4- (HYDROXYDYPHENYLMETHYL) -1-PIPERIDINYL1 -1- (4 ISOPROPYLPHENYL) BUTANOL Step 1: l-CHLORINE-4- (4-ISOPROPYLPHENIL) BUTANONE Aluminum chloride (501.52 grams, 3.76 moles) and methylene chloride (1.4 liters) are stirred in a round bottom flask equipped with a nitrogen sparger. The resulting paste is cooled to -10 ° C by means of an ice / ethanol bath. 4-Chlorobutyryl chloride (546.05 grams, 3.87 moles) is added over a period of 45 minutes, to maintain the temperature of the paste solution below -3 ° C. The resulting solution is cooled to -10 ° C, and eumeno (477 milliliters, 3.43 moles) is added over a period of 80 minutes, maintaining the temperature of the solution around -10 ° C. In a 4 liter beaker with ice (1 kilogram) and with stirring, about half of the above methylene solution is poured. The mixture is stirred for 30 minutes. The organic and aqueous phases are separated. The organic phase is washed with water (500 milliliters) and then with an aqueous solution of 1 percent sodium bicarbonate. (500 milliliters). The other half of the un-quenched methylene chloride solution is worked in a similar manner. The organic phases are combined and concentrated in vacuo.

After collecting 1.3 liters of methylene chloride solution, heptane (400 milliliters) is added to the residue, in order to finish the drying of the isopropyl ketone. The heptane is removed in vacuo to give a yellow oil. Methanol (700 milliliters) is added to this oil, and the solution is stored at -20 ° C for 16 hours. The solids formed from the supernatant are separated by decantation. Hexane (100 milliliters) is added, and the solids are ground in the hexane paste. The paste is collected by suction filtration, and the filter cake is washed with hexane (300 milliliters). Dry the solid from the filter cake under vacuum (1 mm Hg, 0.13 kPa) at room temperature, to give 1-chloro-4- (4-isopropylphenyl) butanone (561.43 grams, 73 percent).

Step 2: 4- T4- f4- (HYDROXYDYPHENYLMETHYL) -1-PIPERIDINYL1 - l- (4-TSQP QPl FEytt,) pu QNA 4- (a, Diphenyl) piperidinemethanol hydrochloride (131.0 grams, 0.43 mole), potassium carbonate (71.3 grams, 0.52 mole), and water (200.0 grams) are stirred in a round-bottomed flask equipped with a sparger. nitrogen. Add a solution of l-chloro-4- (4-isopropylpheniDbutanone (129.3 grams, 0.58 moles), in warm xylenes (70 milliliters) to the mixture, add xylenes (70 milliliters) to rinse, heat the mixture to 80 ° C for 30 minutes at 300 RPM, and then at 100 ° C at 300 RPM for 1 hour, and then heated for 18 hours to 200 RPM Xylenes (150 milliliters) are added, and the resulting mixture is stirred for 2 hours at 92 ° C. Allow the mixture to settle, and remove the aqueous phase from the bottom. The organic phase is washed three times with 140 milliliters of water each time, heating each time above 90 ° C during the operations of agitation, settlement, and decanting. Some of the xylene solvents are removed by distillation at atmospheric pressure, leaving approximately 180 milliliters of xylenes remaining in the distillation vessel. The solution is cooled to 40 ° C, and heptane (400 milliliters) is added. The solution is stored at -20 ° C for 18 hours, to provide a liquid / solid paste. The solids are collected by suction filtration, and washed with heptane (400 milliliters). Dry the solids in vacuo (1 mm Hg, 0.13 kPa) at room temperature to give 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- (4-isopropylpheniDbutanone as a white powder (179.16) grams, 0.39 moles, 91 percent).

Step 3: 4-, 4-, 4- (HYDROXYDYPHENYLMETHYL) -1-PIPERIDINYLl -1- (4-ISOPROPYLPHENYL) BUTANOL 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl] -1- (4-isopropylphenyl) butanone (22.78 grams, 50 mmol) is added to an ethanol / water solution (126 milliliters, 90/10). The solution is stirred and heated under reflux. An aqueous solution of sodium borohydride (12 percent, 24.4 millimoles) and sodium hydroxide (40 percent) is added. Rinse with additional water (10 milliliters). It is heated under reflux for an additional 25 minutes after the addition is completed. Water (84 grams) is added to the solution under reflux. The mixture is allowed to cool slowly to room temperature. The white solid is collected by suction filtration, and the filter cake is washed with water at room temperature (60 milliliters), and water at 92 ° C (115 milliliters). The solids are dried in the air for 3 days to obtain 21.76 grams. The resulting compound (21.00 grams) is placed in an Erlenmeyer flask with a solution of ethanol and water (150 milliliters, 90/10). The solution is heated to reflux, and then the hot polished filter is placed through fluted filter paper. The filter is washed with hot ethanol / water (25 milliliters, 90/10). The filtrate is combined and transferred to a 500 milliliter single neck round bottom flask. It is heated under reflux. Water (36 milliliters) is added to obtain some solids. Absolute ethanol (30 milliliters) is added to the refluxed mixture to obtain the dissolution of most of all solids. The mixture is allowed to cool to room temperature, and then to the temperature of the ice / water bath. The resulting white solid is collected by suction filtration, the filter cake is washed with ethanol / water (20 milliliters, 50/50), and then with cold ethanol / water (24 milliliters, 50/50). The solids are dried overnight in air to give 17.50 grams (77 percent) of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- (4-isopropylphenyl) butanol.

EXAMPLE 8 4- ÍA- ÍA- (HYDROXIDIPENOMETHYLMETHYL) -1-PIPERIDINYL1 -1- (4-ISO-PROPYL-3-HYDROXYPENYL) BUTANOL It can be prepared by an ordinary expert in this field, following example 7 described above, but using 3-isopropylphenol as the starting material, instead of eumeno. The hydroxy group can be protected, and more preferably a -o-methoxymethyl group is used. 3-Isopropylphenol is commercially available. The compounds of the present invention are useful as antihistamines, antiallergic agents, and bronchodilators, as described more fully in the Patents of the United States of North America Numbers 4,254,129 issued March 3, 1981, and 4,254,130 issued March 3, 1981. The compounds can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the selected compound, the selected route of administration, and conventional pharmaceutical practice. The compounds of the invention, while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, greater solubility, and the like. The compounds of this invention can be administered orally, parenterally, for example subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, or by application to mucous membranes, such as those of the nose, throat, and tubes. bronchial, for example in an aerosol spray containing small particles of a compound of this invention in a pulverized or dry powder form. One of skill in the art of preparing formulations can easily select the appropriate form and mode of administration, depending on the particular characteristics of the selected compound, the disorder to be treated, the disorder stage, and other relevant circumstances. .

The compounds of the present invention can be enclosed in gelatin capsules, or can be compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients, and may be used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These preparations should contain at least 4 percent of the compound of the invention, the active ingredient, but may vary depending on the particular form, and may conveniently be between 4 percent and about 70 percent of the unit's weight. The amount of the compound present in the compositions is such that a suitable dosage is obtained. Preferred compositions and preparations according to the present invention are prepared in such a way that a unit dosage form oral contains between 5.0 and 300 milligrams of a compound of the invention. Tablets, pills, capsules, troches, and the like, may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, primogel, corn starch, and the like, lubricants such as magnesium stearate or Sterotex; brighteners such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin, which may be added, or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as polyethylene glycol or a fatty acid. Other unit dosage forms may contain other different materials that modify the physical form of the unit dosage, for example, as coatings. Accordingly, tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent, and certain preservatives, dyes, and colorants, and flavorings. The materials used in the preparation of these different compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, including local administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1 percent of a compound of the invention, it can be varied between 0.1 and about 50 percent of the weight thereof. The amount of the compound of the invention present in these compositions is such that a suitable dosage is obtained. Preferred compositions and preparations according to the present invention are prepared in such a way that a parenteral dosage unit contains between 5.0 and 100 milligrams of the compound of the invention. The solutions or suspensions may also include one or more of the following auxiliaries: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben antioxidants such as ascorbic acid or sodium bisulfite chelating agents such as ethylenediaminetetraacetic acid pH regulators such as acetates, citrates, or phosphates, and agents for tonicity adjustment, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. The amount of the novel compound of the formula (I) administered will vary depending on the patient and the mode of administration, and can be any effective amount. The amount of the novel compound can vary over a wide range to provide, in a unit dosage, an effective amount of about 0.01 to 60 milligrams / -kilogram of the patient's body weight per day to achieve the desired effect. For example, the desired antihistamine, antiallergic, and bronchodilator effects can be obtained by consuming a unit dosage form such as a tablet containing 1 to 200 milligrams of a novel compound of this invention, taken 1 to 4 times up to date. For use as aerosols, the compounds of this invention in solution or in suspension, can be packaged in a pressurized aerosol container together with suitable propellants, for example hydrocarbon propellants, such as propane, butane, or isobutane, with customary auxiliaries that can be necessary or desirable. The compounds can also be administered in a non-pressurized form, such as in a nebulizer or atomizer. The term "patient", as used herein, means warm-blooded animals, birds, and mammals, for example humans, cats, horses, dogs, sheep, bovine cows, pigs, sheep, rats, mice, and guinea pigs. . In another embodiment, the present invention provides compositions comprising a compound of the formula (I) mixed or otherwise in association with one or more inert carriers. These compositions are useful, for example, as test standards, as convenient elements for making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of the formula (I) is an amount that can be easily measured by conventional test methods and techniques, as is well known and appreciated by those skilled in the art. The assayable amounts of a compound of the formula (I) will generally vary from about 0.001 percent to about 75 percent of the composition by weight. Inert carriers can be any material that does not degrade or otherwise react covalently with a compound of formula (I). Examples of suitable inert carriers are water; aqueous regulators, such as those that are generally useful in the analysis of High Performance Liquid Chromatography (HPLC); organic solvents such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients. More particularly, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of formula (I), mixed or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. An effective amount of a compound of the formula (I), refers to an amount that is effective, on the administration of a single dose or of multiple doses to the patient, to provide the desired antihistaminic, antiallergic, or bronchodilator effects, beyond than expected in the absence of this treatment. An effective amount of a compound of the formula (I), such as an effective antiallergic amount, or an effective antihistaminic amount, can be readily determined by the person diagnosing and attending, as one skilled in the art, by the use of techniques known, and by observing the results obtained under analogous circumstances. In determining the effective amount or dose, the person diagnosing the assistant considers a number of factors, including, but not limited to: the species of the mammal, its size, age, and general health; the response of the individual patient; the particular compound administered; the mode of administration, - the bioavailability characteristics of the preparation administered, - the selected dosage regimen, - the use of concomitant medications; and other relevant circumstances. Treating a patient means preventing or alleviating the patient's illness or condition. As is true for most compounds suitable for use as therapeutic agents, certain subclasses and certain specific compounds are more preferred than others. In this case, it is preferred that A is H, and more preferably A is H and] is -CH 3 or -COOH.

Claims (20)

1. A compound of the formula: wherein Ri is -CH20H, -COOH or -COO-alkyl (of 1 to 6 carbon atoms); and A is hydrogen or hydroxy; stereoisomers, enantiomers, racemic mixtures thereof, or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein A is H.

3. A compound according to claim 1, wherein A is OH.

4. A compound according to claim 1, wherein R1 is -CH2OH.

5. A compound according to claim 1, wherein Ri is -COOH.

6. A compound according to claim 1, wherein Ri is -COO-alkyl (from 1 to ß carbon atoms).

7. A compound according to claim 1, wherein R ^ is -COO-alkyl (of 1 to 3 carbon atoms).

8. A compound according to claim 1, wherein the compound is 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -a-methylphenylacetic acid.

9. A compound according to the claim 1, wherein the compound is ethyl-4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a-methylphenyl acetate.

10. A compound according to claim 1, wherein the compound is 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -2-methylphenethyl alcohol.

11. A composition comprising a test amount of a compound of claim 1, mixed or otherwise in association with one or more inert carriers.

12. A pharmaceutical composition comprising an effective antiallergic amount of the compound of claim 1, mixed or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

13. A pharmaceutical composition comprising an effective antihistaminic amount of the compound of claim 1, mixed or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

14. A method for the treatment of allergic reactions in a patient in need thereof, which comprises administering to this patient an effective antiallergic amount of the compound of claim 1.

15. A method for the treatment of allergic reactions in a patient who need, which comprises administering to this patient, an effective antihistaminic amount of the compound of claim 1.

16. A compound of claims 1 to 10, for use as a medicament.

17. A compound of claims 1 to 10, for use as an effective antiallergic compound.

18. A compound of claims 1 to 10, for use as an effective antihistamine compound.

19. The use of a compound according to claims 1 to 10, for preparing a medicament for use in the treatment of allergic reactions.

20. A process for the preparation of a compound of the formula: where R? is -CH2OH, -COOH or -COO-alkyl (of 1 to 6 carbon atoms), and -A is hydrogen or hydroxy; including stereoisomers, enantiomers, racemic mixtures thereof, or pharmaceutically acceptable salts thereof, which comprises the step of reducing the compound of the formula: