Alpha-aryl-4-substituted piperidinoalkanol derivatives
United States Patent 91 Carr et al.  
 [ 5] Apr. 15, 1975 ALPHA-ARYL-4-SUBSTITUTED PIPERIDINOALKANOL DERIVATIVES [22] Filed: July 12, 1973.  
  21 App]. No.: 378,561  
 Related U.S. Application Data [63] Continuation-in-part of Ser. No. 221,82l, Jan. 28,  
 1972, abandoned.  
 [52] U.S. Cl. 260/2 /2 260/268 PH; 260/293.68; 260/2937];  
 [51] Int. Cl C07d 29/28 [58] Field of Search 260/2475 G, 268 PH, 260/293.64,293.68,293.71,  
 [56] References Cited UNITED STATES PATENTS 3,687,956 8/1972 Zivkovic 260/293.83  
 Primary Examinerl-lenry N. Jiles Assistant Examiner-S. D. Winters Attorney, Agent, or FirmL. Ruth Hattan; Eugene O. Retter; George W. Rauchfuss, Jr.  
  57 ABSTRACT Novel compounds useful as antihistamine agents, antiallergy agents, and bronchodilators are represented by the following formula wherein R represents hydrogen or hydroxy; R represents hydrogen; or R and R taken together form a second bond between the carbon atoms bearing R and R; n is a positive whole integer of from 1 to 3; Z represents thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the phenyl ring and are selected from halogen, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, di( lower alkylamino, or a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino. Pharmaceutically. acceptable acid addition salts and individual optical isomers of compounds of the above formula are also included within this invention.  
 20 Claims, N0 Drawings ALPHA-ARYL- t-SUBSTITUTED PIPERIDINOALKANOL DERIVATIVES This is a continuation-in-part of copending application Ser. No. 221.821, filed .Ian. 28. 1972 and now abandoned. I  
 FIELD OF INVENTION This invention relates to novel substituted piperidine derivatives. More particularly this invention relates to a-aryl-4-substituted piperidinoalkanol derivatives which are useful as antihistamines. antiallergy agents and bronchodilators and to methods of making and using the same.  
 SUMMARY OF INVENTION The novel substituted piperidine derivatives of this invention useful as antihistamines, antiallergy agents, and bronchodilators are represented by the formula Formula I wherein R represents hydrogen or hydroxy; R represents hydrogen; or R and R&#39; taken together form a second bond between the carbon atoms bearing R and R; n is a positive whole integer of from I to 3; Z represents thienyl. phenyl or substituted phenyl wherein the substituents on the substituted phenyl are selected from a halogen atom, such as chlorine, fluorine. bromine. or iodine, a straight or branched lower alkyl chain of from l to 4 carbon atoms, a lower alkoxy group of from I to 4 carbon atoms. a di(|ower)alkylamino group, or a saturated monocyclic heterocyclic group .such as pyrrolidin&#39;o, piperidino. morpholino, or N- (lower)alkylpiperazino and may be attached at the ortho. meta, or para positions of the phenyl ring. Included in the scope of this invention are the pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds of Formuls l.  
 DETAILED DESCRIPTION OF INVENTION It can be seen from the above Formula I that compounds of this invention may be 4-diphenylmethylpiperidine derivatives as represented by the following Formula II. 4-(a-hydroxy-a-phenylbenzyl)piperidine derivatives as represented by the following Formula III, or 4-diphenylmethylenepiperidine derivatives as represented by the following Formula IV.  
  2 C H Formula I l C-OH Formula I l l N OH Formula IV In the above Formulas II, III and IV, a and Z have the same meanings as defined hereinbefore.  
  The term lower alkyl as used in describing the compounds of this invention is taken to mean a straight or branched alkyl chain of from 1 to 4 carbon atoms. As examples of lower alkyl groups that may be present in the compounds for Formulas l to IV as a straight or branched lower alkyl substituent, or in the di(lower)alkylamine substituent, or in the N-(lowei&#39;)alky lpiperazine substituent on Z when Z represents a substituted phenyl there may be mentioned, methyl, ethyl, npropyl. n-butyl. isopropyl, isobutyl and tert-butyl.  
  The preferred compounds of this invention are those of general Formulas Ill and IV wherein n and Z have the meanings defined hereinbefore, and may be represented by the following Formula V. These compounds have superior antihistamine and antiallergy properties and are bronchodilators. In addition these compounds lack central nervous system stimulant and depressant effects, thus making them particularly useful as antihistamine and antiallergy agents and as bronchodilators.  
 Formula V in the above Formula V, R represents hydroxy, and R represents hydrogen, or R and R taken together form a second bond between the carbon atoms bearing R and R; n is an integer of from i to 3, and Z represents thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta or para positions of the phenyl ring and are selected from a halogen atom, such as, chlorine. fluorine, or bromine, a straight or branched lower alkyl chain of from I to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino.  
  The more preferred compounds of this invention are those of general Formula V wherein n is equal to 3.  
  This invention also includes the pharmaceutically acceptable acid addition salts of the compounds of the hereinbefore set forth formulas, optical iosmers and salts thereof. Pharmaceutically acceptable acid addition salts of the compounds of this invention are those of any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulphuric, phosphoric acids and the like. Suitable organic acids include carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic,maleic, hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2- phenoxybenzoic, 2-acetoxybenzoic, mandelic acid and the like, sulfonic acids such as, for example, methanesulfonic cthanesulfonic, B-hydroxyethanesulfonic acid, and the like.  
  As examples of compounds illustrative of this invention there may be mentioned, for example, a-(pfluorophenyl)-4-(a-hydroxy a-phenylbeniyl)-lpiperidinebu&#39;tanol, 4-(diphenylmethyl&#39;) a (pfluoroph&#39;enyl l -pip&#39;eridinebutanol, (diphenylmethylj-bz-(p ethoxyphenyl)-lpiperidinepropanol, 4-(a-hydroxy-a-phenylbenzyl)-a- (p-morpholinophenyl)-l-piperidinebutanol, a-(p-tertbutylphenyl )-4-( a-hydroxy-a-phenyl benzyl lpiperidi nebutanol, 4-(diphenylmethylene)-a-(2- thienyl)&#39;-l-piperidin ebutanol, 4-(diphenylmethylene)- a-( p-fluorophenyl )-l -piperidinebutanol, 4- (diphenylmethylene)-z-(p-methoxyphenyl)-lpiperidinebutanol, 4-(diphenylmethylene)-a-(pdimethylaminophenyl)-l-piperidinepropanol, 4-(ahydroxy-a-phenylbenzyl)-a-pheriyl-l e piperidineethanol, 4-(diphenylmet&#39;hyl)-a-(p-isopropylphenyl)-l-piperidinebutanol.  
  The novel compounds of this invention are useful as antihistamines, antiallergy agents and bronchodilators and may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, for example, tablets, capsules, powders, solutions, suspensions, or emulsions.  
  The compounds of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or byapplication to mucous membranes such as that of the nose, throat, and bronchial tubes. for example in an aerosol spray containing small praticales of a compound of this invention in a spray or dry powder form.  
  The quantity&#34; of novel compound administered will vary. Depending on the-patient and the mode of administration, the quantity of novel compound administered may vary over a wide range to provide in a unit dosage of from about 0.01 to 20 milligrams per kilogram of body weight of the patient per dose to achieve the desired effect. For example the desired antihistamine, antiallergy and bronchodilator effects can be obtained by consumption of a unit dosage. form such as, for example, a tablet containing 1 to 50 milligrams of a novel compound of this invention taken one to four times daily.  
 &#39; The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be&#39; the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricant and inert fillers such as lactose, sucrose, corn starch, and the like. In another embodiment, the novel compounds are tabletted with conventional tablet bases such as lactose, sucrose, corn starch, and the like in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch, or alginic acid, and a lubricant such as stearic acid, or magnesium stearate.  
  The novel compounds may also be administered as injectable dosages by solution or .suspension of the compounds in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils there can be mentioned those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, and the like. In general, water, saline, aqueous dextrose, and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.  
 To illustrate the utility of the compounds of this invention the following tabulation indicates the amount of certain representative compounds of this invention required to reduce by 50 percent wheals induced by intradermal injections of l&#39;y of histamine into guinea pigs. Each compound was orally administered 1 hour prior to the histamine injection.  
 Ex. no. Compound ED mg/kg 1 a-( p-tert-Butylphenyl )-4-( ahydroxy-a-phenylbenzyll piperidinebutanol l .6 2 4-( Diphenylmethylene )-a-( pfluorophenyl l -piperidinehutarlol 3.8 3 4-( a-Hydroxy-a-phenylbenzyl l-a- (p-fluorophenyl l -piperidinebutanol 7.5 4 4-(a-Hydroxy-a-phcnylbenzyl)-a- (Z-thienyl l -piperidinebutanol 9.7  
 The minimal amounts of the compounds of Examples 1, 3 and 4 required to prevent aerosol antigen induced bronchial spasms and death in the guinea pig is respectively 1.0, 2.0 and 4.0 milligrams per kilogram of body weight orally.  
  The example numbers of the above compounds correspond to the example numbers of compounds used to specifically illustrate the invention.  
  The compounds of this invention may be prepared by reducing the corresponding aryl 4-substituted piperidinoalkyl ketone as illustrated below:  
 C-R C-R R1 ReductionE R1 N O N I ll l (CH C Z 1 Formula I In the above reaction R, R, n and Z have the meanings defined in Formula l.  
  Preferred reducing agents such as sodium borohydride may be employed in the above reaction using a lower alcohol solvent such as methanol, isopropyl alcohol. tert-butanol and the like. The reaction is carried out at temperatures ranging from about C to the reflux temperature of the solvent, and the reaction time varies from about 0.5 to about 8 hours. Other hydrides as reducing agents such as lithium aluminum hydride and diborane may also be used in an appropriate solvent such &#39;as diethyl ether.  
  This reaction may also be achieved by catalytic reduction using Raney nickel, palladium, platinum or rhodium catalysts in lower alcohol solvents, acetic acid, or their aqueous mixtures, or by aluminum isopropoxide in isopropanol.  
  The aryl substituted piperidinoalkyl ketones as represented by compound l may be prepared by an alkylation reaction of an appropriately substituted piperidine derivative with an w-haloalkyl aryl ketone derivative in an alcoholic or hydrocarbon solvent in the presence of a base as disclosed in copending application Ser. No. 221,823, now US. Pat. No. 3,806,526, incorporated herein by reference thereto.  
  The compounds of this invention may also be prepared by the alkylation of 4- diphenylmethylenepiperidine, 4-diphenylmethylpiperidine, or a,a-diphenyl-4-piperidinemethanol with an a-aryl-w-haloalkanol derivative in an alcoholic or a hydrocarbon solvent in the presence of a base for from about 24 to 72 hours at a temperature varying from about 70C to the reflux temperature of the solvent. The following examples are illustrative of the invention. The optical isomers of the compounds of this invention may be separated by using a or binaphthylphosphoric acid derivative or a salt of said derivative and an optically active base by the method described byR. Viterbo et al., in Tetrahedron Letters No. 48, pp. 4617-4620 1971) and in copending application Ser. No. 233,793. Specific Examples 26 and 27 disclosed herein illustrate this method.  
  The following specific examples are illustrative of the compounds of this invention.  
 ) added methanolic potassium hydroxide until the solution was basic. The solution was cooled in an ice bath with stirring and 5 g (0.13 mole) of sodium borohydride was added portionwise. The mixture was stirred an additional half hour, allowed to warm to room temperature then heated on a steam bath for half an hour. The solvent was removed at reduced pressure, and the remaining residue was washed with water and recrystallized from acetone to give the desired product, M.P. 146.5&#34; l48.5C.  
  The title compound may also be prepared by reducing at 2 atmospheres of hydrogen pressure in the presence of rhodium on charcoal catalyst for about 3 hours the corresponding butyrophenone derivative dissolved in methanol. Following the reduction reaction the catalyst is removed by filtration, and the remaining material is concentrated to a solid which is purified by recrystallization to give the desired product.  
 EXAMPLE 2 4-( Diphenylmethylene )-a-( p-fluorophenyl lpiperidinebutanol hydrochloride To 12 g (0.029 mole) of 4-fluoro-4-(4-diphenylmethylenepiperidino)butyrophenone dissolved in 1000 ml of isopropyl alcohol was added I g (0.027 mole) of sodium borohydride. The mixture was allowed to stand for 45 minutes after which it was heated to boiling. The solvent was removed, and the remaining residue was triturated with water then petroleum-ether and filtered. The residue was recrystallized from ether-petroleumether to give 4-(diphenylmethylene)-a-(pfluorophenyl)-l-piperidinebutanol which was subsequently converted to the hydrochloride salt, M.P. l93194C.  
 EXAMPLE 3 4-( a-Hydroxy-wphenylbenzyl )-a-( p-fluorophenyl l piperidinebutanol To 43.15 g (0.l mole) of 4&#39;-fluoro-4-[4-(a-hydroxya-phenylb&#39;enzyl)piperidino]butyrophenone in 3 liters of methanol was added portionwise at room temperature 3.78 g (0.] mole) of sodium borohydride. The mixture was allowed to stand at room temperature for 1 hour after which the solvent was removed at reduced EXAMPLE 4 4-(a-Hydroxy-a-phenylbenzyl )-a-( Z-thienyl l piperidinebutanol To 15.1 g (0.03 mole) of 4-[4-(a-hydroxy-aphenylbenzyl)piperidinol-l-(2-thienyl)butan-l-one hydrochloride, dissolved in 600 ml of methanol was added alcoholic potassium hydroxide until the solution was basic. To this solution 4 g (0.11 mole) of sodium borohydride was added portionwise, and the mixture was allowed to stand overnight. The solvent was removed on a steam bath. and 150 ml of water was added to the remaining residue which then solidified. The solid was filtered and washed with water and recrystallized from acetone and hexane to give the desired product, M.P. l34l36C.  
 EXAMPLE 5 a-( p-Bromophenyl )-4-( a-hydroxy-a-phenylbenzyl l piperidinebutanol To a solution of 23 g (0.044 mole) of4&#39;-bromo-4-[4- (a-hydroxy-a-phenylbenzyl)piperidinoIbutyrophenone hydrochloride in 900 ml of methanol, which was previously treated with excess alcoholic potassium hydroxide cooled to 0C, was added 4 g (0.1 1 mole) of sodium borohydride. The mixture was stirred for minutes maintaining the reaction temperature at 0C then slowly warmed to room temperature. The solvent was removed and water was added. An oil formed which was extracted into toluene, dried over magnesium sulfate and filtered. The filtrate was concentrated to a 100 ml volume then 250 ml of 7590 petroleumether was added, and the material was cooled. The resulting precipitate was recrystallized from ether, 75-90 petroleum-ether and acetone to give the desired product, M.P. l34l37C.  
 EXAMPLE 6 a-( p-Bromophenyl )-4-( diphenylmethylene piperidinebutanol hydrochloride To 7.3 g (0.019 mole) of 4&#39;-bromo-4-(4-diphenylmethylenepiperidino)butyrophenone hydrochloride dissolved in 1500 ml of methanol was added methanolic potassium hydroxide until the solution was basic after which 2 g (0.053 mole) of sodium borohydride was added. The mixture was allowed to stand for 3 hours, then the methanol was removed by heating at reduced pressure. Water was added to the residue and the resulting solid was collected by filtration and dissolved in eith. The ether solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was treated with ethereal HCl, and the resulting precipitate was recrystallized from methanol-ethyl acetate to give the desired product, M.P. 2l5-2 l7C.  
 EXAMPLE 7 4-( Diphenylmethyl )-a-phenyll -piperidinebutanol A mixture of 39.76 g (0.1 mole) of 4-(4-diphenylmethylpiperidino)butyrophenone. 3 liters of isopropyl alcohol, 500 ml of methanol and 8 g (0.21 mole) of sodium borohydride was allowed to stand at room temperature for 63 hours. The solvent was removed at reduced pressure after which 1 liter of water was added. The resulting solid was filtered off and recrystallized from petroleumether to give the desired product. M.P. 122.5-124C.  
 EXAMPLE 8 4-( Diphenylmethyl )-a-(p-fluorophenyl l piperidinebutanol To a mixture of 45.2 g (0.1 mole) of 4-fluoro-4-(4- diphenylmethylpiperidino)butyrophenone hydrochloride, 2500 ml of warm isopropyl alcohol and 5.6 g of potassium hydroxide was added 4 g (0.105 mole) of sodium borohydride. The mixture was allowed to stand one/half hour after which another 4 g (0.105 mole) of sodium borohydride was added. The mixture was allowed to stand for 1 hour, then it was heated to boiling. The solvent was removed under vacuum, and water was added to the solid residue. The solid was collected on a filter. washed with water and recrystallized from -90 petroleum ether to give the desired product, M.P. l29l3lC.  
  Similarly, by the procedure of Example 1. only substituting for 4-tert-butyl-4-[4-(a-hydroxy-aphenylbenzyl)piperidino]butyrophenone hydrochloride, an appropriate molar equivalent amount of one of the starting materials listed in the following Table l, the respective products listed in Table l are obtained.  
 Table 1 Example No. Starting Material Product 9 4-[ 4-( a-Hydroxy-a-phenyl- 4-( a-Hydroxy-abenzyl )piperidino1butyrophenone hydrochloride. M.P. 193.5-C.  
 4-{ 4-( a-Hydroxy-a-phcnylhenzyl )piperidino 1 4&#39;- methylbutyrophenone hydrochloride. M.P. 236- ITC phenylhenzyl l-aphenyl-l-piperidinebutanol 4-( a-Hydroxy-aphenylhenzyl )-a- (p-methylphcnyl l-piperidinebutanol 4 &#39;-Fluoro-4-[ 4-( a-hydroxya-phenylhenzyl )piperidinoI- hutyrophcnonc hydrochloride. M.P. l7ll74C.  
 a-( pFluorophenyl 4-( a-hydroxy-aphenylbenzyl l piperidinebutanol Table II appropriate Starting Material Product 12 4&#39;-Fluoro-3-[4-(a-hydroxya-phenylbenzyl )piperidinopropiophenone, M.P. 250C a-l p-Fluorophenyl 4-( a-hydroxy-aphenylbenzyl l piperidinepropanol 4-( a-Hydroxy-aphenylbenzyl )-a- (p-piperidinophcnyl )-1-piperidinebutanol. M.P. 74-7 8C 4-[ 4-( a-Hydroxy-a-phenylbenzyl )piperidino ]-4&#39;- piperidinobutyrophenone. M.P. 137.5-1 39C.  
 EXAMPLE l4 An illustrative composition for hard gelatin capsules is as follows:  
  phenylhcnzyl l -piperidinehutanol l mg (b) tale mg (c) lactose I00 mg The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard gelatin capsules&#39;at a net fill of 1 15 mg per capsule.  
 EXAMPLE 15 An illustrative composition for tablets is as follows:  
 (a) a-( p-tcrt-hl.ltylphenyl l--l-( tx-hydroxy-aphenylhcnzyl l -piperidinebutanol 5. mg (h) starch 43 mg (c) lactose 60 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried. screened. and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 1 mg each.  
 EXAMPLE 16 An illustrative composition for an aerosol solution is the following:  
 Weight per cent (a) -l-( a-hydroxya-phcnylhenzyl l-a- (p-fluorophenyl l -piperidinebutanol 5.0 (h) ethanol 35.0 (c) dichlorodilluoromcthanc (10.0  
 The materials (a). (b) and (c) are packaged in ml stainless steel containers equipped with a metering valve designed to meter 0.2 grams per does. an equivalent of 10 mg of novel compound (a).  
 EXAMPLE l7 An illustrative composition for an aerosol suspension isthe following:  
 (a) 4-( u-hydroxy-a-phcnylhcnzyl J-a- (Z-thienyl l -piperidinehutaiml (Particle size lUL) 20.0 (h) sorhitan trioleate 0.5 (c) dichlorodit&#39;luoromcthane 39.75 ((1) dichlorodifluoroethanc 39.75  
 The materials (a)(d) are packaged in 15 ml stainless steel containers equipped with a metering valve designed to meter 50 mg per dose. an equivalent of 10 mg of novel compound(a).  
 EXAMPLE 18 An illustrative composition for an injectable suspension is the following 1 ml ampul for an intramuscular injection.  
 Weight per cent Weight per cent (a) u-( p-tcrt-butylphenyl )-4- (a-hydroxy-a-phcnylhcnzyl l-piperidinchutanol (particle size l0u) (h) polyvinylpyrrolidone (MAN. 25000) 0.5 (c) lccithin 0.25 (dt water for injection to make I000 The materials (a)-(d) are mixed. homogenized. and filled into 1 ml ampuls which are sealed and autoclaved 20 minutes at l2lC. Each ampul contains 10 mg per ml of novel compound (a).  
 EXAMPLE 19 a-( p-Dimethylaminophenyl )-4-( a-hydroxy-a-phenylbenzyl l -piperidinebutanol EXAMPLE 20 4-(a-Hydroxy-a-phenylbenzyl )-ct-( p-methoxyphenyl l-piperidinebutanol By the procedure of Example 1. only substituting for 4&#39;-tert-butyl-4-[4-(a-hydroxy-a-phenylbenzyl)- piperidino]-butyrophenone hydrochloride an appropriate amount of 4-[4-( a-hydroxy-aphenylbenzyl)piperidino1-4&#39;-methoxybutyrophenone hydrochloride. and using potassium borohydride instead of sodium borohydride the title compound was obtained, M.P. l30l33C.  
 EXAMPLE 2! a-( p-Fluorophenyl )-4-( a-hydroxy-a-phenylbenzyl l piperidineethanol By the procedure of Example 1. only substituting for 4&#39;-tert-butyl-4-[ 4-( a-hydroxy-a-phenylbenzyl piperidino]-butyrophenone an appropriate amount of 4&#39;-fluoro-2-[4-(a-hydroxy-a-phenylbenzyl)- piperidinolacetophenone and using potassium borohydride instead of sodium borohydride the title compound was obtained. M.P. l68-l70C.  
 EXAMPLE 22 a-( p-tert-Butylphenyl )-4-( diphenylmethylene l piperidinebutanol To 9.76 g (0.02 mole) of 4&#39;-tert-butyl-4-I4- (diphenylmethylene)piperidino]butyrophenone hydrochloride in 50 ml of methanol was added 1.] g (0.02 mole) of sodium methoxide and then 2.7 g (0.05 mole) of potassium borohydride. and the mixture was stirred at room temperature for 2 hours. The methanol was removed at reduced pressure on a steam bath after which 50 ml of 10 percent sodium hydroxide solution was added. The mixture was stirred for l5 minutes, and  
 ml of chloroform was added. Stirring was continued for one/half hour. The chloroform layer was separated and combined with two 25 ml chloroform extracts of the aqueous phase. The combined chloroform extracts were washed with water then with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to a solid. The solid material was recrystallized from ethanol-water to give a-(p-tertbutylphenyl)-4-(diphenylmethylene)-lpiperidinebutanol, M.P. 122124C.  
 EXAMPLE 23 4-( oz-Hydroxy-a-phenylbenzyl )-a-[ p-( N-methylpiperazino )-phenyl]- l -piperidinebutanol When in the procedure of Example 19. 7 g (0.013 mole) of 4-[4-(a-hydroxy-a-phenylbenzyl)piperidino]- 4&#39;-(N-methylpiperazino)butyrophenone was substituted for 4&#39;-dimethylamino-4-[4-(a-hydroxy-aphenylbenzyl)piperidino]-butyrophenone, and 1.4 g (0.026 mole) of potassium borohydride was used, 4-ahydroxy-a-phenylbenzyl)-a-[4-(N-methylpiperazino)- phenyl]-l-piperidinobutanol recrystallized from acetone-hexane was obtained, M.P. 158-160C. (polymorph, M.P. 83-86C.).  
 EXAMPLE 24 4-( a-Hydroxy-a-phenylbenzyl )-a-( p-morpholinophenyl l -piperidinebutanol When in the procedure of Example 19, 2 g(0.004 mole) of 4-[4-(a-hydroxy-a-phenylbenzyl)piperidino1- 4&#39;-morpholinobutyrophenone was substituted for 4- dimethylamino-4-[4-( rx-hydroxy-a-phenylbenzyl piperidino]butyrophenone, and 0.43 g (0.008 mole) of potassium borohydride was used, 4-(a-hydroxy-aphenylbenzyl )-a-( p-morpholinophenyl lpiperidinobutanol was obtained. M.P. 8386C.  
 EXAMPLE 25 4-( Diphenylmethylene )-a-(p-pyrrolidinophenyl l piperidinebutanol When in the procedure of Example 19, 5 g (0.01 mole) of 4-[4-(diphenylmethylene)piperidino-4&#39;- pyrrolidinobutyrophenone was substituted for 4- dimethylamino-4-[4-(a-hydroxy-a-phenylbenzyl)- piperidino]butyrophenone. and 1.6 g (0.03 mole) of potassium borohydride was used, 4- diphenylmethylene-a-(p-pyrrolidinophenyl)-lpiperidinebutanol was obtained, M.P. l25l27C.  
 EXAMPLE,26  
  ()-a-( p-tert-Butylphenyl )-4-( a-hydroxy-a-phenylbenzyl)-l-piperidinebutanol A mixture of 9.5 g (0.02 mole) of a-(4-tertbutylphenyl )-4-( 01-hydroxy-a-phenylbenzyl)-lpiperidinebutanol, 7.0 g (0.02 mole) of(+) binaphthylphosphoric acid and 70 ml of methanol was heated at 55C to form a solution. The solution was allowed to stand at 25C for hours to slowly crystallize. The solid was filtered and the residue (7.6 g) was recrystallized seven times from methanol by dissolving in 4-7 ml/g after which it was allowed to stand 20 hours at C to give 1.4 g of the binaphthylphosphoric acid salt of a-(4-tert-butylphenyl)-4-(a-hydroxy-aphenylbenzyl)-l-piperidinebutanol. This salt was mixed with 11 ml of acetone and 1.0 ml of 10 percent sodium hydroxide solution, and the mixture was warmed to form a solution. The solution was concentrated to a volume of 3 ml, diluted with water until cloudy, cooled and filtered. The solid was recrystallized from acetone-water to give 0.62 g of ()-a-(4-tertbutylphenyl)-4-(01-hydroxy-a-phenylbenzyl)-1- piperidinebutanol, M.P. l44l45C., [01],, =46.l2 (CHCl C 4.3303).  
 EXAMPLE 27 (+)-a-( p-tert-Butylphenyl )-4-( a-hydroxy-a-phenylbenzyl)-1-piperidinebutanol A mixture of 5.6 g (0.0119 mole) of a-(4-tertbutylphenyl )-4-( a-hydroxy-a-phenylbenzyl l piperidinebutanol. 4.1 g (0.01 19 mole) of binaphthylphosphoric acid and 50 ml of methanol was heated at 55C to form a solution. The solution was concentrated to 25 ml and allowed to stand at 25C for 4 hours to crystallize. The mixture was cooled to 5C for 48 hours and filtered. The residue (5.5 g) was recrystallized seven times from methanol by dissolving in 3-6 ml/g after which it was allowed to stand 20 hours at 25C to give 1.12 g of the binaphthylphosphoric acid slat of (+)-a-(4-tert-butylpheny)-4-(a-hydroxy-aphenylbenzyl)-l-piperidinebutanol. This salt was dissolved in 12 ml of acetone, treated with 2-3 ml of 10 percent sodium hydroxide solution, concentrated to 8 ml,&#39;cooled in an ice bath and filtered. The solid was recrystallized two times from acetone-water to give 0.46 g of (+)-a-(4-tert-butylphenyl)-4-(a-hydroxy-aphenylbenzyl)-1-pipcridinebutanol, M.P. l44l45C; [02],, +44.61(CHC1,,, C 4.139).  
 We claim:  
 1. A compound selected from a base of the formula wherein R is selected from the group consisting of hydrogen or hydroxy; R is hydrogen; or R and R takentogether form a second bond between the carbon atoms bearing R and R; n is a positive whole integer of from 1 to 3; and Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted pheny may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower- )alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N- (lower)alkylpiperazino. or pharmaceutically acceptable acid addition salts thereof.  
 2. A compound of claim 1 where R is hydrogen.  
 3. A compound of claim 2 wherein n is 3.  
  4. A compound of claim 3 which is 4- (diphenylmethyl)-a-phenyl-l-piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  5. A compound of claim 3 which is 4- (diphenylmethyl)-a-(p-fluorophenyl )-1- piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
 6. A compound of claim 1 wherein R is hydroxy.  
 7. A compound of claim 6 wherein n is 3.  
  8. A compound of claim 7 which is a-(pfluorophenyl)-4-(a-hydroxy-a-phenylbenzyl)-lpiperidinebutanol or a pharmaceuticalLv acceptable acid addition salt thereof.  
  9. A compound of claim 7 which is a-(p-tertbutylphenyl )-4-( a-hydroxy-a-phenylbenzyl l piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  10. A compound of claim 7 which is 4-(a-hydroxy-aphenylbenzyl)-a-(2-thienyl)-l-piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  11. A compound of claim 7 which is 4(a-hydroxy-aphenylbenzyl)-a-(p-piperidinophenyl)-lpiperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  12. A compound of claim 7 which is 4-(a-hydroxy-aphenylbenzyl)-a-(p-dimethylaminophenyl)-lpiperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
 13. A compound of claim 6 wherein n is l.  
  14. A compound of claim 13 which is a-(pfluorophenyl )-4-( a-hydroxy-a-phenylbenzyl lpiperidineethanol or a pharmaceutically acceptable acid addition salt thereof.  
  15. A compound of claim 1 wherein R and R taken together form a second bond between the carbon atoms bearing R and R.  
 16. A compound of claim 15 wherein n is 3.  
  17. A compound of claim 16 which is a-(pbromophenyl)-4-(diphenylmethylene)-lpiperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  18. A compound of claim 16 which is a-.(pfluorophenyl J-4-(diphenylmethylene l piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  19. The compound (+)-a-(p-tert-butylphenyl)-4-(ahydroxya-phenylbenzyl)-l-piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
  20. The compound (-)-a-(p-tert-butylphenyl)-4-(ahydroxy-a-phenylbenzyl)-1-piperidinebutanol or a pharmaceutically acceptable acid addition salt thereof.  
 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 5,878,217 DATED 1 April 15, 1975 INVENTOR(S) A lbert A Carr and C Richard Kinsolvi ng It is certified that error appears in the ElbOVE-ldfifltlflGd patent and that said Letters Patent are hereby corrected as shown below: In the abstract, 1 ine 11 after the structure, &#34;atoms, di( loweralkylamino... should read atoms, di( lower)all lamino&#34;. Column 3, l ine 66, pratlcales should read particles Column 6, line 5 &#34;1 -l6.51 l8.5C&#34; should read &#34;1 l6.5&#39;1 l8.5C&#34;. Column 7 line 59, &#34;eith.&#34; should read &#34;ether&#34;. Column 11, line 10, &#34;M.P. 122-124? should read &#34;122.5-12 -lC&#34;; line 21, l-o.- hydroxy-c.&#34; should read &#34;4-(or-hydroxy-a&#34;.  
 Signed and Scaled this seventeenth D ay Of February 1 9 76 [SEAL] A ttesr:  
 RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner ujParenrs and Trademarks UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE EXTENDING PATENT TERM UNDER 35 U. S. C. 156  
 Patent No. 3,878,217  
 Dated Apr. 15, 1975 lnventor(s Carr et al.  
 Patent Owner Merrell Dow Pharmaceuticals Inc.  
 This is to cert i fy that there has been presented to the COMMISSIONER G? PATENTS AND TRADEMARKS an application under 35 U. S. C. 156 for an extension of the patent term. Since it appears that the requirements of law have been met, this certificate extends the term of the patent for the period of 2 YEARS with all rights pertaining thereto as provided by 35 USC 156(k)).  
 I have caused the sea of the Patent- Donald J. Quigg Assistant Secretary and Commissioner of Patents and Trademarks