IE49672B1 - Piperidine derivatives - Google Patents

Abstract

A compound of the formula wherein Q is -CO- or -CHOH-; either R1 is hydrogen or hydroxy and R2 is hydrogen or R1 and R2 together form a second bond between the carbon atoms bearing R1 and R2; n is an integer of from 1 to 5; R3 is CH3, CH2OH, COOH or COO(C1-6 alkyl); and one of A and B is hydrogen and the other is hydrogen or hydroxy, with the proviso that one of A and B is hydroxy when R3 is CH3; or a pharmaceutically acceptable acid addition salt thereof. They are used as anti-histamines, anti- allergy agents and bronchodilators.

Description

This invention relates to novel piperidine derivatives which can have pharmaceutical utility. Piperidine derivatives having antihistaminic properties are disclosed in US Patent Specification Nos. 3,806,526; 3,829,433; 3,862,173; 3,878,217; 3,931,197; 3,941,795; 3,946,022 and 3,965,257.

The novel compounds of this invention are of formula wherein Q is -CO- or -CHOH-; either is hydrogen or hydroxy and R2 is hydrogen or R^ and R2 together form a second bond between the carbon atoms bearing R^ and R2; n is an integer of from 1 to 5; R3 is CH^, CH2OH, COOH or COO(C^_6 alkyl); and one of A and B is hydrogen and the other is hydrogen or hydroxy, with the proviso that one of A and B is hydroxy when R3 is CH3; and include the pharma49672 - 3 ceutically acceptable acid addition salts thereof.

Illustrative examples of Cg_g alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.

Preferred compounds of the invention in which Q is -CO- are those in which R, is CHg or CHgOH. It is generally preferred that either Rg is hydroxy and Rg is hydrogen or Rg and R2 form a second bond. The combination of Rg as hydroxy and Rg as hydrogen is particularly preferred, n is preferably 3 or 4.

The most preferred classes of compounds of the invention are those in which Q is -CO-, either Rg is hydroxy and Rg is hydrogen or Rg and R2 form a second bond, n is 3 and B is hydrogen, with Rg as COOH being particularly preferred in this context; and those in which Q is -CHOH-, either Rg is hydroxy and Rg is hydrogen or Rg and Rg form a second bond, n is 3 and A and B are each hydrogen, Rg being COOH being particularly preferred in this context also.

As indicated above, this invention includes the pharmaceutically acceptable salts of the compounds of the invention, including those of the preferred groups identified above. Pharmaceutically acceptable acid addition salts of the compounds of this invention are those of any suitable inorganic or organic acid. Examples of suitable inorganic acids are hydrochloric, hydrobromic, sulfuric and phosphoric acids. Examples of suitable organic acids are carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids, and sulfonic acids such as methanesulfonic, ethanesulfonic and β-hydroxyethanesulfonic acids. Non-toxic - 4 salts of the compounds of the above-identified formulas formed with inorganic or organic bases are also included within the scope of this invention and include, for example those of alkali metals such as sodium, potassium and lith5 ium, alkaline earth metals such as calcium and magnesium, light metals of the group IIIA such as aluminium, amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. The salts are prepared by conventional means as, for example, by treating the free base of a compound of Formula I with an appropriate acid or, when Rj is COOH, with a base.

Illustrative examples of compounds of this invention in which Q is -CO- are: 4-/4-/4-(hydroxvdiphenylmethyl)-1-piperidiny17-115 oxobutyl7-a,a-dimethylbenzeneacetic acid, 4-/4-/4-(diphenylmethyl)-2-piperidinyl7-l-oxobutyl/α,α-dimethylbenzeneacetic acid, 4-/4-/4-(diphenylmethylene)-1-piperidiny17-1-OXO_ butyl7-a,?-dimethylbenzeneacetic acid, 4-/4-/4-(hydroxydiphenylmethyl)-2-piperidinyl7-loxobutyl7-“»ci-diinethyl- (3-hydroxybenzene) acetic acid, 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny1/-1oxobutyl7-a,a-dimethyl-(2-hydroxybenzene)acetic acid, 4- /4-/9-(diphenylmethylene)-1-piperidinyl/-l-oxo25 butyL7-a,a-dimethyl-(3-hydroxybenzene)acetic acid, - /4-/4-(diphenylmethylene)-l-piperidinyl7~l-oxopentyl/-a,α-dimethylbenzeneacetic acid, 3-/4-/4-(hydroxydiphenylmethyl)-l-piperidinyl7_loxopropylj'-a,α-dimethylbenzeneacetic acid, 2-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny 1/-1oxoethylf-a,α-dimethylbenzeneacetic acid, - 5 ethyl (hydroxydiphenylmethyl)-1-piperidinyl7 -l-oxobutyl7-a,a-dimethylbenzeneacetate, n-pentyl 4-/4-/4-(diphenylmethyl)-1-piperidiny17-1_ oxobutyl7-a,a-dimethylbenzeneacetate, ethyl 4-/4-/4-(diphenylmethylene)-1-piperidiny17_1“ oxobuty!7-a,α-dimethylbenzeneacetate, methyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny 17-l-oxobutyl7~a ,a-dimethylbenzeneacetate, ethyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny l7~l-oxobutyl7-a,a-dimethyl- (3-hydroxybenzene)acetate, n-propyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny l7-l-oxobutyl7-a,a-dimethyl- (2-hydroxybenzene)acetate, n-hexyl 4-/4-/4-(diphenylmethylene)-1-piperidiny1/l-oxobuty!7-a,a-dimethyl-(3-hydroxybenzene)acetate, ethyl 5-/4-/4-(diphenylmethylene,-1-piperidinyl/“ 1-oxopenty1/-α,a-dimethylbenzeneacetate, 4'-tert-butyl-21-hydroxy-4-/4-(hydroxydiphenylmethyl )-1-piperidiny1/butyrophenone, 41 -tert-butyl-3' hydroxy-4-,7’4- (hydroxydiphenylmethyl) -1-piperidinyl7butyrophenone, 4'-tert-butyl-21-hydroxy-4-,/4-(diphenylmethylene,1-piperidinyl7butyrophenone, 41-tert-butyl-31-hydroxy-4-/4-(diphenylmethyl)-1piperidiny!7butyrophenone, 41-tert-butyl-2'-hydroxy-3-/4-(hydroxydiphenylmethyl) -1-piperidinyl/propiophenone, 4'-tert-butyl-31-hydroxy-2-/4-(diphenylmethylene)1-piperidinyl/acetophenone, 4'-(hydroxy-tert-butyl)-2'-hydroxy-4-/4-(hydroxy49672 -6diphenylmethyl)-1-piperidiny17butyrophenone, 41 -(hydroxy-tert-butyl)-3'-hydroxy-4-/4-(hydroxydiphenylmethyl) -1-piperidinyl/butyrophenone, 4'-(hydroxy-tert-butyl)-2'-hydroxy-4-/4-(diphenyl5 methylene)-l-piperidinyl/butyrophenone, 4'-(hydroxy-tert-butyl)-3'-hydroxy-4-/4-(diphenylmethyl en e ) - 1 -piper idinyl7butyrophenone, 4'-)hydroxy-tert-buty1)-2'-hydroxy-3-/4-(hydroxydiphenylmethyl)-l-piperidinyl7propiophenone, 3'-hydroxy-4'-(hydroxy-tert-butyl)-2- £4-(diphenylmethylene) -1-piperidiny^acetophenone, 4'-(hydroxy-tert-butyl)-4-/4-(hydroxydiphenylmethyl) -1-piperidinyl7butyrophenone, 4'-(hydroxy-tert-butyl)-4-/4-(diphenylmethylene)-115 piperidinyl/butyrophenone, 4(hydroxy-tert-butyl)-3-/4-(diphenylmethyl)-1piperidinyl7propiophenone, and tert-butyl-2-/4-/4-(hydroxydiphenylmethyl)-1piperidinyl7-l-oxoethyl7-a,a- dimethylbenzeneacetate.

Illustrative examples of compounds of this invention in which Q is -CHOH- are: 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny1/ l-hydroxybutyl7-a,a-dimethylbenzeneacetic acid, 4-/4-/4-(diphenylmethyl)-1-piperidinyl7~l-hydroxy25 butyl/-a,a-dimethylbenzeneacetic acid, 4-/4-/4-(diphenylmethylene)-1-piperidiny1/-1hydroxybuty17~α,o-dimethylbenzeneacetic acid, 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny17~149672 -7hydroxybutyl/-a,α-dimethyl-(3-hydroxybenzene)acetic acid. 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny1/-1hydroxybutyl7~a,α-dimethyl-(2-hydroxybenzene)acetic acid, 4- /4-/4-(diphenylmethylene)-l-piperidinyl/-l-hydroxybutyl/-a,α-dimethyl-(3-hydroxybenzene)acetic acid, - /4-/4-(diphenylmethylene)-l-piperidinyl7-lhydroxypentyl/-»/α-dimethylbenzeneacetic acid, 3-/4-/4-(hydroxydiphenylmethyl)-1-piperidinyl7~lhydroxypropyl7~a,α-dimethylbenzeneacetic acid, 2-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny 17-Ihydroxyethyl/-a,a-dimethylbenzeneacetic acid, ethyl 4-/4-/4-(hydroxydiphenylmethyl)-l-piperidinyl7 -1-hydroxybutyl7~a,a- dimethylbenzeneacetate, n-pentyl 4-/4-/4-(diphenylmethyl)-1-piperidiny1/-1hydroxybuty17-a,a-dimethylbenzeneacetate. ethyl 4-/4-/4-(diphenylmethylene)-1-piperidiny1/-1hydroxybuty l/-a, a-dimethylbenzeneacetate, methyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny17 -1-hydroxybutyiy-α,a-dimethylbenzeneacetate, ethyl 4-/4-/4-(hydroxydiphenylmethyl)-l-piperidinyl7 -1-hydroxybutyl/-“/α-dimethyl-(3-hydroxybenzene)acetate, n-propyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidnyi/-l-hydroxybutyl/-a, α-dimethyl- (2-liydroxybenzaie) acetate, n-hexyl 4-/4-/4-(diphenylmethylene)-1-piperidiny17~ l-hydroxybutyl7-a,a-dimethyl-(3-hydroxybenzene)acetate, ethyl 5-/4-/4-(diphenylmethylene)-1-piperidiny1/-1hydroxypentyl7~a,a-dimethylbenzeneacetate, a,a-diphenyl-l-(4-(4-tert-butyl-2-hydroxy ) phenyl)4-hydroxybutyl-4-piperidinemethanol, 4967S - 8 α,α-diphenyl-l-(4-(4-tert-butyl-3-hydroxy)phenyl)-4hydroxybu ty1-4-piperidineme thanol, α,a-diphenyl-1-(3-(4-tert-butyl-2-hydroxy)phenyl)3-hydroxypropyl-4-piperldinemethanol, a,a-diphenyl-1-(4-(4-hydroxy-tert-buty1-2-hydroxy) phenyl)-4-hydroxybutyl-4-piperidinemethanol, a,a-diphenyl-1-(4-(4-hydroxy-tert-butyl-3-hydroxy)phenyl) -4-hydroxybuty1-4-piperidinemethanol, a,a-diphenyl-1-(3-(4-hydroxy-tert-buty1-2-hydroxy)10 phenyl)-3-hydroxypropyl-4-piperidinemethanol, a,a-diphenyl-1-(4-(4-hydroxy-tert-butyl)phenyl-4hydroxybutyl-4-piperidinemethanol, 1- (4-tert-butyl-2-hydroxyphenyl)-4-(4-(diphenylmethylene ) -1-piperidinyl) butanol, 1-(4-tert-butyl-3-hydroxyphenyl)-4-(4-(diphenylmethylene )-1-piperidinyl) butanol, 1-(4-tert-butyl-3-hydroxyphenyl)-2-(4-(diphenylmethylene)-1-piperidinyl)ethanol, 1-(4-hydroxy-tert-buty1-2-hydroxyphenyl)-4-(4-(diphenyl 20 methylene)-1-diperidinyl)butanol, 1-(4-hydroxy-tert-butyl-3-hydroxyphenyl)-4-(4-(diphenyl methylene)-1-piperidinyl) butanol, 1-(4-hydroxy-tert-butyl-3-hydroxyphenyl)-2-(4(diphenylmethylene)-1-piperidinyl)ethanol, 1-(4-hydroxy-tert-butylphenyl)-4-(4-(diphenylmethylene)-1-piperidinyl)butanol, 1-(4-hydroxy-tert-butylpheny1)-3-(4-diphenylmethyl)1-piperidinyl)propanol, and tert-butyl 2-/5-/4-(hydroxydiphenylmethyl)-1-piperi30 dinyl7-lhydroxyethyl7-a,a-dimethylbenzeneacetate. - 9 Compounds of formula I in which Q is -CO-, B is hydrogen and Rg is CHg or COO(Cj_g alkyl) may be prepared by alkylating a piperidine derivative of formula II wherein Rj and R2 are as defined above, with an ω-haloalkyl phenyl ketone of formula III wherein halo is a halogen atom such as chlorine, bromine or iodine, Z is hydrogen or β-methoxyethoxymethyl (memoxy), Rg is CH3 or COO(Cj_g alkyl) and n is as defined above.

When Z is memoxy, this group is cleaved in conventional manner, after the alkylation, to obtain the products in which A is hydroxy. The alkylation reaction is carried out in a suitable solvent, preferably in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide for 4 to 120 hours and at 70°C to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents such as methanol, ethanol, isopropyl alcohol or butanol, ketone solvents such as methyl isobutyl ketone, hydrocarbon sol4 9 672 - 10 vents such as benzene, toluene or xylene, and halogenated hydrocarbons such as chlorobenzene, methylene chloride or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases such as sodium bicarbonate potassium carbonate or potassium bicarbonate, and organic bases, e.g. a trialkylamine such as triethylamine, or pyridine. Alternatively, an excess of a compound of formula II may be used. Cleavage of any memoxy group is achieved using trifluoroacetic acid at room temperature or to 8 equivalents of powdered anhydrous zinc bromide in methylene chloride at 25-4O°C by the general procedure of E.J. Corey et al., Tetrahedron Letters 11, 809-812 (1976).

Compounds of formula lin which Q is -CO-, B is hydrogen and Rg is COOH may be prepared by base hydrolysis of a corresponding C^_g alkyl ester. Base hydrolysis may be achieved by treatment with an inorganic base such as sodium hydroxy or potassium hydroxide in an aqueous Cg_^ alcohol such as methanol, ethanol, isopropyl alcohol or nbutanol at reflux for % to 12 hours. When it is desired that A should be hydroxy, base hydrolysis of the correspond ing ester in which the A group is protected as memoxy may be effected before hydrolysis, but hydrolysis subsequent to cleavage is preferred.

Compounds of formula I in which Q is -CHOH, A is hydroxy, B is hydrogen and Rg is methyl may be prepared from the corresponding compounds in which Q is -CO- by reduction. Reduction may be achieved by using sodium borohydride or potassium borohydride in a C^_^ alcohol. Alternatively, lithium aluminium hydride or di30 borane may be used as the reducing agent, in which case suitable solvents are ethers such as ethyl ether, tetrahydrofuran or dioxane. These reduction reactions are carried out at from 0°C to the reflux temperature of the system. The reaction time may be from % to 8 hours.

Catalytic reduction may also be used. Suitable systems include Raney nickel, palladium, platinum or • 49672 - 11 rhodium catalysts in a Cj_4 alcohol or acetic acid, optionally in admixture with water, or by using aluminium isopropoxide in isopropyl alcohol. Catalytic reduction is less preferred in the specific embodiment discussed above.

Compounds of formula X in which Q is -CHOH- B is hydrogen and Rg is COO(Cj_6 alkyl) may be prepared from the corresponding compounds in which Q is -CO- by reduction, preferably using a borohydride or catalytic reduction.

Compounds of formula X in which Q is -CHOH-, B is hydrogen and Rg is COOH may be prepared from the corresponding compounds in which Q is -CO- by reduction, preferably using a borohydride or catalytic reduction. Alternatively, the same products may be prepared by base hydrolysis of the corresponding esters, using the conditions discussed above for base hydrolysis.

Compounds of formula I in which Q is -CHOH-, B is hydrogen and Rg is CH2OH may be prepared from compounds of formula I in which B is hydrogen and Rg is COOH or COO(Cj_g alkyl) by reduction. Lithium aluminium hydride is the preferred reducing agent when, in the starting material, Q is -CO- and Rg is COO(Cj_g alkyl). Diborane is the preferred reducing agent when Rg is COOH.

The starting materials for this sequence of reactions, i.e. the compounds of formulae II and III, are either known or can he prepared by procedures generally known in the art. For example, the compounds of formula II in which Rj is hydrogen or hydroxy and R2 is hydrogen are commercially available. The corresponding compound in which Rj and R2 form a second bond may be prepared by conventional dehydration of the compounds in which Rj is hydroxy and R2 is hydrogen.

The compounds of formula III in which Z is memoxy may be prepared by reacting a phenol of formula V - 12 HO CH. b- P CH. wherein R, is as defined above with an ω-haloalkanoic acid of the formula halo-(CHg)n-COOH wherein halo and n are as defined above in the presence of boron trifluoride by the procedure of Delschager and Mousa, Arch. Pharm. 306, 807 (1973). The phenol and acid are melted together at about 50°C and then cooled to about 10°C, after which boron trifluoride is added in an amount about 2.2 times the molar amount of phenol employed. The mixture is heated at about 70°C for about 2 hours, after which the reaction vessel is cooled, vented and treated with a 30% sodium acetate solution and extracted with ether. The organic layer is dried and the residue crystallised to give a hydroxy ketone corresponding to formula III but in which Z is hydroxy. The hydroxy ketone is then treated + — with a reagent of the formula CHgOCHgCHgOCHgNEtg Cl in acetonitrile according to the general procedure of E.J.

Cory et al., Tetrahedron Letters 11, 809-812 (1976).

The compounds of formula III wherein Z is hydrogen are prepared by reacting a C^_g alkyl ester of a,a-dimethylphenylacetic acid with a C^_g ω-haloalkanoyl halide under the general conditions of a Friedel-Crafts acylation. The reaction is carried out in a solvent such as carbon di25 sulfide (preferred), tetrachloroethane or nitrobenzene.

The reaction time varies from % to 8, preferably 3 to 5, hours, and the reaction temperature varies from 0 to 25°C. - 13 The esters and the acid halides are known or easily prepared by generally known methods.

The compound of formula V in which Rg is methyl is also commercially available. The compounds of formula V in which Rg is COO alkyl are prepared by treating a hot solution of 1 equivalent of a Cj_g alkyl ester of 3-trifluoroacetoxyphenylacetic acid in dimethoxyethane with a base such as sodium hydride under a nitrogen atmosphere, followed by the addition of 2.1 equivalents of methyl iodide in dimethoxyethane to the mixture over about 20 minutes.

The mixture is refluxed for about 3 hours and then concentrated to remove most of the solvent, after which ethyl ether and then water are added cautiously. The organic layer is separated, extracted with ethyl ether, dried over magnesium sulfate and distilled to give the appropriate ester of a,a-dimethyl-3-trifluoroacetoxyphenylacetic acid.

To a solution of the methylated ester in 50% alcohol/water is added 3x molar amount of potassium carbonate. The solution is stirred at about 25°C for about 8 hours and then concentrated to a semi-solid at reduced pressure at about 50°C. Upon cooling, water is added and the mixture is neutralised with dilute hydrochloric acid and then extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated to give the appropriate ester of 3-hydroxy-a,a-dimethylphenylacetic acid. The esters of 3-trifluoroacetoxyphenylacetic acid are known in the art or may be prepared by procedures generally known in the art, for example, from ethyl mhydroxyphenylacetate by treatment with trifiuoroacetic anhydride.

Compounds of formula X in which Q is -CHOH-, B is hydroxy and Rg is CH3 or COOH may be prepared by treating a compound of formula IV - 14 49673 wherein either Rg is hydrogen or trifluoroacetoxy and R^Q is hydrogen or Rg and R1Q together form a second bond, and n and Rg are as defined above, with a slight excess of thallium trifluoroacetate in trifluoroacetic acid at reflux temperature (about 72°C) for about 3 hours, after which 1 equivalent of lead tetraacetate in trifluoroacetic acid is added. The mixture is stirred for about % hour and then 1 equivalent of triphenylphosphine is added. Stirring is continued for about hour, followed by removal of excess solvent at reduced pressure and the addition of cold dilute (6 N) hydrochloride acid. The lead chloride and thallium chloride are filtered off, and the filtrate is made alkaline with 10% NaOH solution and any precipitate is dissolved in a minimum amount of ethanol. The solution is refluxed for about 4 hours, neutralised, concentrated, extracted with toluene, dried, filtered and concentrated.

Compounds of formula I in which Q is -CH0H-, B is hydroxy and Rg is COO(C^_g alkyl) may be obtained by esterifying the corresponding acid in which Rg is COOH, using 2 or 3 equivalents of boron trifluoride etherate and 20 or 30 equivalents of a C^_g alkanol. The mixture is refluxed for about 24 hours, according to the general procedure of Kadaba, J. Pharm. Sci. _6_3, 1333 (1947) . Upon cooling, the mixture is added to about 100 ml of water, concentrated at reduced pressure on a water bath, and the product purified by crystallisation from alcohols or mixtures thereof with toluene. 48672 - 15 Compounds of formula I in which Q is -CHOH-, B is hydroxy and Rj is CH2OH may be prepared from the corresponding compounds in which R is COOH or COO(Cj_g alkyl) by reduction, preferably using lithium aluminium hydride or diborane under the conditions described above.

Compounds of formula I in which Q is -CO-, B is hydrogen and Kj is CHj, COCH or COOfC^g alkyl) nay be prepared from the corresponding compound in which Q is -CHOH- by oxidation. Various oxidising agents may be used. For exam pie, chromium trioxide in pyridine or acetic acid at from 25 to 80°C for 1 to 8 hours may be employed. Alternatively, aluminium isqpropoxide or potassium tert-butoxide in acetone, cyclohexanone or benzophenone, usually with an aromatic solvent such as benzene or toluene, at 25°C to reflux for 8 to 24 hours may be employed. Another procedure is to use potassium dichromate in dilute sulfuric acid at 0 to 25°C, preferably 25°C, for about 1 to 8 hours. A further oxidation method uses MnO2 in CH2C12 at 0 to 40°C for about 2 to 10 hours.

Compounds of formula I in which Q is -CO- and R^ is CHjOH may be prepared from the corresponding compounds in which R3 is COOH or COO(Cj_g alkyl), by reduction. During the reduction, the Q group must be protected as a ketal.

The ketone may be converted to a ketal by treatment with a glycol such as ethylene glycol, propylene glycol or 2,2dimethylpropylene glycol in a hydrocarbon solvent such as benzene or toluene and in the presence of a catalytic amount of an acid such as g-toluenesulfonic acid or methanesulfonic acid. During the ketalisation step, water is removed continuously, e.g. in a Dean-Stark apparatus, and the reaction is carried out at reflux for 4 to 24 hours. Reduction of the ketalised derivative is achieved using, for example, lithium aluminium hydride or diborane in an ether solvent such as ethyl ether, tetrahydrofuran or dioxane at reflux for 15 minutes to 6 hours. When is COOH, the preferred reducing reagent is diborane. When R^ - 16 is COO(Cg g alkyl), the preferred reducing reagent is lithium aluminium hydride. Following the reduction, the carbonyl group is regenerated by treating the ketal with a dilute cold aqueous acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.

The starting materials of formula IV in which Rg is trifluoroacetoxy may be prepared by reacting a compound of formula I in which Q is -CO-, Rg is hydroxy, Rg is hydrogen and Rg is CHg or COO(Cg_g alkyl) with trifluoroacetic anhydride for 2 to 6 hours at 0 to 25°C with stirring, followed by catalytic reduction using, for example, platinum oxide in methanol and 1 atmosphere hydrogen in a Parr apparatus to take up an equivalent amount of hydrogen.

The following Examples 1 to 7 and 9 illustrate the preparation of compounds of formula I in which Q is -CO-. Examples 8 and 10 to 12 illustrate the preparation of compounds of formula I in which Q is -CHOH-.

EXAMPLE 1 Ethyl 4-/4-/4-(hydroxydiphenylmethyl)-l-piperidinyl7~l20 oxobutyl7-a,a-dimethylbenzeneacetate Hydrochloride (A) to 700 ml of carbon disulfide containing 36.5 g (0.254 mole) of 4-chlorobutyryl chloride are added 74.5 g (0.56 mole) of aluminium chloride with stirring in an ice bath (about -10°C). Stirring is continued for about 15 minutes at about 25°C then the mixture is recooled to 5°C and 48.4 g (0.294 mole) of ethyl a,a-dimethylphenylacetate in 100 ml of carbon disulfide are added. The reaction mixture is stirred on an ice bath for 3¾ hours then stirred for 15¾ hours at 25°C then poured into HCl-ice water and extracted with chloroform. The extract is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated giving as a solid ethyl-4(4-chloro-l-oxobutyl)a,α-dimethylphenylacetate. 48672 - 17 (Β) A mixture of 4.5 g (0.0163 mole) of 4-(α,αdiphenyl)piperidinemethanol, 6.1 g (0.0205 mole) of ethyl 4-(4-chloro-1-oxobutyl)-a,α-dimethylphenylacetate, 5 g (0.05 mole of potassium bicarbonate and 0.05 g of potassium iodide in 50 ml of toluene is stirred and refluxed for 72 hours then filtered. Ether, then ethereal hydrogen chloride,are added to the filtrate, and the resulting precipitate is collected and recrystallized several times from methanol/ butanone and butanone to give ethyl 4-/4-/4-(hydroxydi10 phenylmethyl)-1-piperidiny17-l-°x°buty17-α,a-dimethylbenzeneacetate hydrochloride. M.P. 205.5°-208°C.

EXAMPLE 2 4-/4-/4-(Hydroxydiphenylmethyl)-1-piperidinyl7-l-oxobutyl7_ α,α-dimethylbenzeneacetic Acid A mixture of 1 g of ethyl 4-/4-/4-(hydroxydiphenylmethyl) -1-piperidiny17“l“oxobutyl7~a,a-dimethylbenzeneacetate hydrochloride, 25 ml of methanol and 5 ml of 25% sodium hydroxide solution is stirred and refluxed for 2 hours then concentrated to a solid, neutralized with dilute hydro20 chloric acid and extracted with hot toluene. The toluene extract is filtered and concentrated to a residue which is recrystallized from chloroform/toluene to give 4-/4-/3(hydroxydiphenylmethyl)-1-piperidinyl/-l-oxobuty lj-α. ,adimethylbenzeneacetic acid.

EXAMPLE 3 4(hydroxy-tert-butyl)-4-/4-(hydroxydiphenylmethyl)-1piperidinyl7butyrophenone A mixture of 1.5 g of the free base of the compound of Example 1, that is, ethyl 4-/4-/4-(hydroxydiphenyl30 methyl)-1-piperidinyX7“l“oxobutyl/-a,a-dimethylbenzeneacetate, and 25 ml of ethylene glycol containing 0.1 g of - 18 g-toluenesulfonic acid is stirred at 100°C for four hours, then concentrated under vacuum to a residue. The residue is triturated with 5% sodium hydroxide solution, extracted with hot toluene, dried over sodium sulfate, filtered and concentrated to give the ketal as a solid. The ketal is added to a 3x excess of lithium aluminium hydride in tetrahydrofuran, stirred and refluxed for 18 hours. The excess lithium aluminium hydride is decomposed with water and the reaction mixture is concentrated to a solid residue. The residue is extracted with hot toluene, stirred over 10% aqueous HCI for 1 hour then made basic and extracted with chloroform, dried over magnesium sulfate, filtered and concentrated to give 41-(hydroxy-tert-butyl)-4-/4-(hydroxydiphenyImethy1) -1-piperidinyVbutyrophenone.

EXAMPLE 4 4'-tert-Butyl-2'-hydroxy-4-/4-(hydroxydiphenylmethyl)-1piperidinyl7butyrophenone (A) A solution of 0.10 mole of 3-tert-butylphenol in 0.20 mole of ω-chlorobutyric acid is heated in a press20 ure vessel at 50°C for about 1 hour, then cooled to 10°C after which 0.35 mole of boron trifluoride is added. The vessel is sealed and the mixture is heated to about 70°C for about 2 hours after which the mixture is cooled, the vessel vented and 200 ml of a 30% solution of sodium acetate is added followed by extraction with ether to give 41-tertbutyl-2'-hydroxy-4-chlorobutyrophenone. The phenone is treated with a 10% excess of β-methoxyethoxymethyl triethylammonium chloride (CH30CH2CH20CH2N(C2H5)^Cl) in 250 ml of dry acetonitrile with stirring for 18 hours at about 25°C. The precipitated triethylamine hydrochloride is filtered, and the filtrate concentrated to a semi-solid which is dissolved in dry ether. Residual amounts of triethylamine are removed by filtration. Concentration of the ether solution gives 41-tert-butyl-2'-memoxy-4-chlorobutyrophenone. - 19 (B) When in the procedure of Example 1(B) an appropriate amount of 4’-tert-butyl-4-chloro-21-memoxybutyrophenone is substituted for ethyl 4-(4-chloro-loxobutyl)-a-a,dimethylphenylacetate, 41-tert-butyl-2'5 memoxy-4-/4-(hydroxydiphenylmethyl)-1-piperidinyl)butyrophenone is obtained and treated with excess trifiuoroacetic acid at room temperature for 0.2-1.0 hours, followed by removal of the trifiuoroacetic acid at reduced pressure and then neutralized with dilute sodium bicarbonate solut10 ion. The organic layer is separated, dried (magnesium sulfate) and concentrated to give 41-tert-butyl-2'-hydroxy4-/4-(hydroxydiphenylmethyl)-l-piperidinyljfbutyrophenone.

EXAMPLE 5 When in the procedure of Example 1(B) an appropr15 iate amount of 4-(diphenylmethylene)piperidine or 4-(diphenylmethyl ) piperidine is substituted for 4-(α,α-diphenyl)piperidinemethanol the following respective products are obtained: ethyl 4-/4-/4-(diphenylmethylene)-1-piperidinyl7 -l-oxobutyl7_a»a-dimethylbenzeneacetate hydrochloride, and ethyl 4-/4-/4-(diphenylmethyl)-l-piperidinyI7-l-oxobuty1/a,α-dimethylbenzeneacetate hydrochloride.

EXAMPLE 6 When in the procedure of Example 2 an appropriate amount of ethyl 4-/4-/4-(diphenylmethylene)-1-piperidinyl/25 l-oxobutyl7-a,a-dimethylbenzeneacetate hydrochloride or ethyl 4-/4-/3(diphenylmethyl)-1-piperidinyl_7-l-oxobuty17α,α-dimethylbenzeneacetate hydrochloride is substituted for ethyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny1/-1oxobutyl7-a,a-dimethylbenzeneacetate hydrochloride, the following respective products are obtained: 4-/4-/4-(diphenylmethylene) -1-piperidinyl7-l-oxobutyl7-a,a-dimethylbenzeneacetic acid and 4-/4-/4-(diphenylmethyl)-1-piperidinyl7-l-oxobuty17-a,α-dimethylbenzeneacetic acid. - 20 It is readily apparent to one skilled in the art that upon substitution of an appropriate amount of the free base of the products of Example 5 for the starting material free base of Example 3, the following respective products are obtained: 4'-(hydroxy-tert-butyl)-4-/4-(diphenylmethylene)-1-piperidinyl7butyrophenone, and 4'(hydroxy-tert-butyl)-4-/4-(diphenylmethyl)-l-piperidinyl7~ butyrophenone.

EXAMPLE 7 Ethyl 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny17~1oxobutyl7-a,a-dimethyl-3-hydroxyphenylacetate (A) A hot solution of 1 equivalent of ethyl 3-trifluoroacetoxyphenylacetate in dimethoxyethane is treated with 2.1 equivalents in sodium hydride under a nitrogen atmosphere followed by the addition of 2.1 equivalents of methyl iodide in dimethoxyethane over about a 20 minute period. The mixture is refluxed for about 3 hours, then concentrated to remove most of the solvent after which diethyl ether then water are added cautiously. The organic layer is separated, extracted with ether, dried over magnesium sulfate, and distilled to give ethyl α,α-dimethyl 3-trifluoroacetoxyphenylacetate. To a solution of the methylated ester in 50% alcohol/water is added 3x molar amount of potassium carbonate. The solution is stirred at °C for 8 hours then concentrated to a semi-solid at reduced pressure at 50°C. Upon cooling water is added and the mixture is neutralized with dilute hydrochloric acid then extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated to give ethyl a,a-dimethyl-3-hydroxyphenylacetate.

When in the procedure of Example 4(A) an appropriate amount of ethyl a,a-dimethyl-3-hydroxyphenylacetate is substituted for 3-tert-butylphenyl, ethyl 4-(4-(chlorobutyryl) -3-memoxy-a,a-dimethylphenylacetate is obtained. - 21 (B) When in the procedure of Example 1(B) an appropriate amount of ethyl 4-(4-chlorobutyryl)-3-memoxya,α-dimethylphenylacetate is substituted for ethyl 4-(4chloro-l-oxobutyl)-a,a-dimethylphenylacetate, ethyl 4-/4(hydroxydiphenylmethyl,-l-piperidinylJ7-l-oxobutyX7-a,adimethyl-3-memoxyphenylacetate is obtained. One equivalent of the memoxy acetate is treated with excess trifluoroacetic acid at room temperature for 0.5 hour. The resulting solution is concentrated to a solid at room temperature and reduced pressure. The residue is triturated with ethyl acetate and shaken over dilute sodium bicarbonate solution, the organic layer is separated, dried and concentrated to give ethyl 4-/4-/4-(hydroxydiphenylmethyl)-1piperidinyl7-l-oxobutyl7-a,a-dimethyl-3-hydroxyphenylacetate.

The above obtained acetate derivative is converted to 4-/4-/4-(hydroxydiphenylmethyl)-l-piperidinyl7“l-oxobutyl/-a,a-dimethyl-3-hydroxyphenylacetic acid by refluxing with 25% aqueous sodium hydroxide in methanol according to the procedure of Example 2 above.

EXAMPLE 8 a,a-Diphenyl-l-/4-(4-tert-butyl-3-hydroxyphenyl)-4-hydroxybutyl7-4-piperidinemethanol A mixture of 0.1 mole of 41-tert-butyl-4-/4-(hydroxydiphenylmethyl)piperidinyl7butyrophenone in 30 ml of trifluoroacetic anhydride is stirred for 4 hours at 0°C, concentrated to a solid, then reduced catalytically in a Paar apparatus using platinum oxide in 200 ml of ethyl acetate until an equivalent amount of hydrogen is taken up to give a-(p-tert-butylphenyl)-4-(a-trlfluoroacetoxy-aphenylbenzyl)-1-piperidinebutanol which, after removal of catalyst and solvent, is treated with a slight excess of thallium trifluoroacetate in 50 ml of trifluoroacetic acid at 72°C for 3 hours, after which 1 equivalent of lead tetraacetate in 10 ml of trifluoroacetic acid is added. The mixture is stirred for 30 minutes, then 1 equivalent of tri49672 - 22 phenylphosphine is added. Stirring is continued for 30 minutes, then the excess solvent is removed at reduced pressure. Cold and dilute (6 N) hydrochloric acid (100 ml) is added and the mixture is filtered. The filtrate is made basic using 10% aqueous NaOH and any precipitate is dissolved in a minimum amount of ethanol. The solution is refluxed 4 hours, neutralized with dilute HCl, concentrated, extracted with toluene,dried, filtered and concentrated to give the title product.

EXAMPLE 9 4'-tert-Butyl-3'-hydroxy-4-/9-(hydroxydiphenylmethyl)-1piperidinyl/butyrophenone Hydrochloride To 0.25 mole of potassium tert-butoxide are added 500 ml of toluene, 0.1 mole of α,a-dipheny1-1-(4-(4-tert15 butyl-3-hydroxy)phenyl-4-hydroxy)butyl-4-piperidinemethanol and 0.5 mole of benzophenone. The mixture is flushed with dry nitrogen and refluxed for 10 hours. The reaction mixture is then cooled and neutralized using dilute hydrochloric acid. The organic phase is separated, dried over magnesium sulfate, filtered and treated with ethereal HCl. The resulting precipitate is collected and purified by recrystallization from methanol-butanone to give the title product.

EXAMPLE 10 a,α-Dipheny1-1-/9-/9-(hydroxy-tert-butyl)phenyl7-4-hydroxybutyl7~4-piperidinemethanol A suspension of 2.15 g (0.0038 mole) of ethyl 4-/9/9-(hydroxydiphenylmethyl)-1-piperidiny17-l-hydroxybutyl7~ a,a-dimethylbenzeneacetate in 50 ml of tetrahydrofuran was slowly added to a suspension of 0.7 g (0.0184 mole) of lithium aluminium hydride in 60 ml of tetrahydrofuran under a nitrogen atmosphere with stirring at such a rate to 49673 - 23 moderate the foaming. The mixture is stirred and heated at boiling for about 3 hours after which 30 ml of tetrahydrofuran are added. The mixture is refluxed for 4 hours and let stand overnight (about 16 hours). Stirring the mixture under a nitrogen atmosphere, 2 ml of water are added cautiously followed by 2 ml of 10% sodium hydroxide, 2 ml of water and 4 g of sodium sulfate. The mixture is warmed to 5O-55°C and stirred for 45 minutes, filtered and the solid material is washed with tetrahydrofuran. The combined filtrates are evaporated in vacuo, and the residue is recrystallized from ethanol to give α,α-diphenyl-l(4-(4-hydroxy-tert-butyl)phenyl)-4-hydroxybutyl-4-piperidinemethanol, M.P. 134-136°C.

EXAMPLE 11 Ethyl 4-/3-/4-(hydroxydiphenylmethyl)-1-piperidiny1/-1hydroxyhuty17-a,α-dimethylbenzeneacetate Hydrochloride A solution of 5.64 g (0.01 mole) of ethyl 4-/3-/4(hydroxydiphenyImethy1)-1-piperidinyl7-l_oxobutyl/-a,adimethylbenzeneacetate hydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and 0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 hour until the infrared showed no evidence of a ketone carbonyl function. The solution is filtered and the filtrate concentrated leaving a residue which is recrystallized from butanone and methanol-butanone to give ethyl 4-/3-/3-(hydroxydiphenylmethyl )-1-piperidiny17-1-hydroxybutyΐ/-α,α-dimethylbenzeneacetate HCI, M.P. 185-187°C.

EXAMPLE 12 4-/3-/3-(Hydroxydiphenylmethyl)-l-piperidinyl/-l-hydroxybutyl/-a,a-dimethylbenzeneacetic Acid To a solution of 0.6 g of ethyl 4-/3-/3-(hydroxydiphenylmethyl) -1-piperidinyl7-l-hydroxybutyl7-a,«-dimethyl49672 - 24 benzeneacetate in 20 ml of absolute ethanol are added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3-1/2 hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanol-butanone to give 4-/4-/4-(hydroxydiphenylmethyl)l-piperidinyl7-l-hydroxybutyl7-a,a-dimethylbenzeneacetic acid, M.P. 195-197°C.

When in the procedure of Example 8 an appropriate amount of ethyl 4-/3-/4-(hydroxydiphenylmethyl)-1-piperidinyl/-l-oxobutyl7-a,α-dimethylbenzeneacetate is substituted for 4'-tert-butyl-4-/4-(hydroxydiphenylmethyl)piperidinyl/15 butyrophenone, ethyl 4-/4-/4-(hydroxydiphenylmethyl)-lpiperidinyl7-l-hydroxybutyl7-a,a-dimethyl-(3-hydroxybenzene) acetate is obtained.

When in the procedure of Example 11 an appropriate amount of 4'-tert-butyl-2'-hydroxy-4-/4-(hydroxydiphenyl20 methyl)-1-piperidinyl7butyrophenone hydrochloride is substituted for 4-/4-/4-(hydroxydiphenylmethyl)-1-piperidiny17l-oxobutyl7-a,a-diinethylbenzene acetate, a,α-diphenyl-1-/4(4-tert-butyl-2-hydroxyphenyl)-4-hydroxybutyl7_4-piperidine· methanol hydrochloride is obtained.

When in the procedure of Example 11 an appropriate amount of ethyl 4-/3-(4-diphenylmethylene-l-piperidinyl)-1oxopropyl7~a,a-dimethylbenzeneacetate hydrochloride is substituted for ethyl 4-/4-/4-(hydroxydiphenylmethyl)-1piperidinyl/-l-oxobutyl7-a,α-dimethylbenzeneacetate hydro30 chloride, ethyl 4-/3-/4-(hydroxydiphenylmethyl)-1-piperidiny 17-1-hydroxypropyl7-ct,α-dimethylbenzeneacetate hydrochloride is obtained.

When in the procedure of Example 11 an appropriate amount of ethyl 4-/4-(4-hydroxydiphenylmethyl-l-piperidinyl) -l-oxobutyl7-rt,a-dimethyl-3-hydroxybenzeneacetate hydro48672 - 25 chloride is substituted for ethyl 4-/4-/4-(hydroxydiphenylmethyl) -1-piperidiny17“l-ox°butyl7-a,a-dimethylbenzeneacetate hydrochloride, ethyl 4-/4-(4-hydroxydiphenylmethyll-piperidinyl)-l-hydroxybutyl/-tt/a-dimethyl-3-hydroxybenzeneacetate is obtained, and when an appropriate amount of this last compound is substituted for 4-/4-(4-hydroxydiphenylmethy1-1-piperidinyl7-l-hydroxybuty_l7-aιa-dimethylbenzeneacetate in the procedure of Example 12, 4-/4-/4-(hydroxydipheny lmethyl) -1-piperidinyI7~l-hydroxybutyl/-a,a-dimethyl3-hydroxybenzeneacetic acid is obtained.

The compounds of this invention can have utility as anti-histamines, anti-allergy agents and bronchodilators.

For these purposes, they may be administered alone or in composition form.

A pharmaceutical composition according to the invention comprises a compound of the Invention in association with a physiologically acceptable excipient. Such compositions can be in solid or liquid form. Examples of such forms are tablets, capsules, powders, solutions, suspensions and eitiulsions.

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 bronchial tubes, for example, in an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form.

The quantity of novel compound administered will vary depending on the patient and the mode of administration and can be any effective amount. The quantity of novel compound administered may vary over a wide range to provide in a unit dosage an effective amount of from about 0.01 to 20 mg/kg of body weight of the patient per day to achieve the desired effect. For example, the desired antihistamine, antiallergy and bronchodilator effects can be obtained by 9672 - 26 consumption of a unit dosage form such as a tablet containing 1 to 50 mg of a novel compound of this invention taken 1 to 4 times daily.

The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricants and inert fillers such as lactose, sucrose or cornstarch. In another embodiment the novel compounds are tableted with conventional tablet bases such as lactose, sucrose or cornstarch in combination with binders such as acacia, cornstarch or gelatin, disintegrating agents such as cornstarch, potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

The compounds of this invention may also be administered in 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 oils are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil or mineral oil. 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.

For use as aerosols, the compounds of this invention in solution or suspension may be packaged in a pressurised aerosol container together with suitable propellants, for example, hydrocarbon propellants such as propane, butane or isobutane, or carbon dioxide or nitrogen or other environmentally acceptable propellants with the usual adjuvants as may be necessary or desirable. The compounds also may be administered in a non-pressurised form such as in a nebuliser or atomiser.

The compounds of the invention can be used to treat - 27 warm-blooded animals, birds and mammals. Examples of suitable subjects are humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

It is indicative of the utility of the compounds of this invention that ethyl 4-/4-(4-hydroxydiphenylmethyl1-piperidinyl)-l-oxobutyl7~a»α-dimethylbenzeneacetate hydrochloride and 4-/4-(hydroxydiphenylmethyl-1-piperidinyl)-1hydroxybutyl7~a,a-dimethylbenzeneacetic acid, each at a con_7 centration of 1 x 10 M, give a significant reduction in histamine-induced isolated guinea pig ileal muscle contraction.

The following Examples 13 to 17 illustrate compositions of the invention.

EXAMPLE 13 An illustrative composition for hard gelation capsules is as follows: (a) Ethyl 4-/4-/3-(hydroxydiphenylmethyl) -1-piperidiny Ij'-l-oxobutyl7-a,a- dimethylbenzeneacetate hydrochloride 10 mg (b) talc 5 mg (c) lactose 100 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 at a net fill of 115 mg per capsule.

EXAMPLE 14 An illustrative composition for tablets is as follows: (a) Ethyl 4-/3-/4-(hydroxydiphenyl)-1piperidinyl7-l-oxobutyl7-a,a-dimethyl49672 - 28 benzeneacetate hydrochloride 5 mg (b) 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 110 mg each.

EXAMPLE 15 An illustrative composition for an aerosol solution is the following Weight percent (a) 41 -(Hydroxy-tert-butyl)-4-/4(hydroxydiphenylmethyl)-1-piperidiny f/butyrophenone 5.0 (b) ethanol 35.0 (c) isobutane 6.00 The materials (a), and (c) are packaged in 15 ml 20 stainless steel containers equipped with a metering valve designed to meter 0.2 grams per dose, an equivalent of 10 mg of novel compound (a).

Example 16 An illustrative composition for an aerosol suspens25 ion is the following: - 29 Weight percent (a) 4-/3-/4-(Hydroxydiphenylmethyl)1-piperidinyx7-l-oxobutyl7-afa dimethylbenzeneacetic acid (Particle size <10 μ) 20.0 (b) sorbitan trioleate 0.5 (c) propane 79.5 The materials (a)-(c) are packaged in 15 ml stainsteel containers equipped with a metering valve designed to meter 50 mg per dose, an equivalent of 10 mg of novel compound (a,.

EXAMPLE 17 An illustrative composition for an injectable suspension is the following 1 ml ampoule for an intramuscular injection.

Weight percent (a) Ethyl 4-/3-/3-(hydroxydiphenylmethyl )-1-piperidiny17-l-oxobutyl7~ a,α-dimethylbenzeneacetate hydrochloride (particle size <10 μ) 1.0 (b) polyvinylpyrrolidone (M.W. 25000) 0.5 (c) lecithin 0.25 (d) water for injection to make 100.0 The materials (a)-(d) are mixed, homogenized, and filled into 1 ml ampoules which are sealed and autoclaved minutes at 121°C. Each ampoule contains 10 mg per ml of novel compound (a). - 30 Other active compounds of the invention can be substituted for those given in Examples 13 to 17. By way of further example, ct ,α-dipheny 1-1-/4-/4-(hydroxy-tertbutyl)phenyl7-4-hydroxybutyl7~4-piperidinemethanol may be 5 substituted for compound (a) in each of Examples 13, 15 and 17. Ethyl 4-/4-(4-hydroxydiphenylmethyl-l-piperidinyl-l-hydroxybutyl7-a,a-dimethylbenzeneacetate may be substituted for compound (a) in Example 14. 4-/4-(4hydroxydiphenylmethyl-l-piperidinyl-l-hydroxybutyl7-a,adimethylbenzeneacetic acid (particle size <10 μ) may be substituted for compound (a) in Example 16.

Claims (5)

1. CLAIMS;1. A compound of the formula wherein Q is -CO- or -CHOH-; either Rg is hydrogen or 5 hydroxy and Rg is hydrogen or Rg and R 2 together form a second bond between the carbon atoms bearing Rg and R 2 ; n is an integer of from 1 to 5; Rg is CHg, CHgOH, COOH or COO(C^_ 6 alkyl); and one of A and B is hydrogen and the other is hydrogen or hydroxy, with the proviso that one of 10 A and B is hydroxy when Rg is CHg; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1, wherein Q is -CO-.

3. A compound as claimed in claim 1, wherein Q is 15 -CHOH-.

4. A compound as claimed in claim 2, wherein Rg is CHg. 5. A compound as claimed in claim 2, wherein Rg is CHgOH. 6. A compound as claimed in any of claims 1 to 3, wherein Rg is COOH. 32 10 7. A compound as claimed in any of claims 1 to 3, wherein Rg is C00(Cj_ 6 alkyl). 8. A compound as claimed in any preceding claim, wherein either Rj is hydroxy and R 2 is hydrogen or Rj and R 2 form a second bond. 9. A compound as claimed in claim 8, wherein Rj is hydroxy and R 2 is hydrogen. 10. A compound as claimed in any preceding claim, wherein n is 3 or 4. 11. A compound as claimed in claim 2, wherein either Rj is hydroxy and R 2 is hydrogen or Rj and R 2 form a second bond, n is 3 and B is hydrogen. 12. A compound as claimed in claim 3, wherein either Rj is hydroxy and R 2 is hydrogen or Rj and R 2 form a second bond, n is 3 and A and B are each hydrogen. 13. A compound as claimed in claim 11 or claim 12, wherein R g is COOH. 14. 4-/4-(4-Hydroxydiphenylmethyl-l-piperidinyl)-1oxobutyl7 _ u,α-dimethylbenzeneacetic acid or a pharmaceutically acceptable salt thereof. 15. 4-/4-(4-DiphenyImethylene-l-piperidinyl)-1oxobutyl?-a,a-dimethylbenzeneacetic acid or a pharmaceutically acceptable salt thereof. 16. Ethyl 4-/4-(4-hydroxydiphenyImethy1-1-piperi25 dinyl)-l-oxobutyl7~a,a-dimethylbenzeneacetate or a pharmaceutically acceptable salt thereof. 17. Ethyl 4-/4-(4-diphenyImethylene-l-piperidinyl)l-oxobutyl7~a,α-dimethylbenzeneacetate or a pharmaceutically 48672 - 33 acceptable salt thereof. 18. 4’-tert-Butyl-2'-hydroxy-4-(4-hydroxydiphenylmethyl-l-piperidinyl)butyrophenone or a pharmaceutically acceptable salt thereof. 5 19. 4'-(i^draxy-t^t-butyl)-4-(4-hydrQxydiphenylnethyl-lpiperidinyl)butyrophenone or a pharmaceutically acceptable salt thereof. 20. 4 1 -(Hydroxy-tert-butyl)-4-(4-diphenylmethylene -1-piperidinyl)butyrophenone or a pharmaceutically accept10 able salt thereof. 21. Ethyl 4-/4-(4-hydroxydiphenylmethyl-l-piperidinyl)-l-oxobutyl7-a,a-dimethyl-3-hydroxyphenylacetate or a pharmaceutically acceptable salt thereof. 22. a,a-Diphenyl-l-/4-/4-(hydroxy-tert-butyl) 15 phenyl7-4-hydroxybutyl74-piperidinemethanol or a pharmaceutically acceptable salt thereof. 23. Ethyl 4-/4-(4-hydroxydiphenylmethyl-l-piperidinyl)-l-hydroxybutyl/-a,α-dimethylbenzeneacetate or a pharmaceutically acceptable salt thereof. 20 24. 4-/4-(4-Hydroxydiphenylmethyl-l-piperidinyl)1-hydroxybuty17-a,a-dimethylbenzeneacetic acid or a pharmaceutically acceptable salt thereof. 25. a,a-Dipheny1-1-/4-(4-tert-buty1-2-hydroxyphenyl)-4-hydroxybutyl7~4-piperidinemethanol or a pharmac25 eutically acceptable salt thereof. 26. 4-/4-(4-Hydroxydiphenylmethyl-l-piperidinyl)l-hydroxybuty!7 -a ra-dimethyl-3-hydroxybenzeneacetic acid or a pharmaceutically acceptable salt thereof. - 34 27. A compound as claimed in claim 1 substantially as described in any of Examples 1 to 7 and 9. 28. A compound as claimed in claim 1 substantially as described in any of Examples 8, 10, 11 and 12.

5. 29. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.